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ACS Omega
ACS Omega
ao
acsodf
ACS Omega
2470-1343
American Chemical Society

10.1021/acsomega.4c03842
Article
Cascade Cyclization of o-(2-Acyl-1-ethynyl)benzaldehydes with Amino Acid Derivatives: Synthesis of Indeno[2,1-c]pyran-3-ones and 1-Oxazolonylisobenzofurans via the Erlenmeyer–Plöchl Azlactone Reaction
Worayuthakarn Rattana †
Suddee Nattanit ‡
Theppitak Chatphorn §
Chainok Kittipong §
Ruchirawat Somsak †‡∥
https://orcid.org/0000-0002-0572-4871
Thasana Nopporn *†‡∥
† Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, Laksi, Bangkok 10210, Thailand
‡ Chemical Sciences Program, Chulabhorn Graduate Institute, Laksi, Bangkok 10210, Thailand
§ Thammasat University Research Unit in Multifunctional Crystalline Materials and Applications (TU-MCMA), Faculty of Science and Technology, Thammasat University, Pathum Thani 12121, Thailand
∥ Center of Excellence on Environmental Health and Toxicology (EHT), OPS, Ministry of Education, Science, Research and Innovation, Bangkok 10400, Thailand
* Email: nopporn@cri.or.th.
28 08 2024
10 09 2024
9 36 3781437842
22 04 2024
16 08 2024
05 08 2024
© 2024 The Authors. Published by American Chemical Society
2024
The Authors
https://creativecommons.org/licenses/by-nc-nd/4.0/ Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/).

A highly regioselective divergent approach is reported for the synthesis of both indeno[2,1-c]pyran-3-one and 1-oxazolonylisobenzofuran derivatives using the Erlenmeyer–Plöchl azlactone (EPA) reaction. This approach involves the synthesis of o-(2-acyl-1-ethynyl)benzaldehydes, which reacted with various amino acids. Reaction with N-acylglycines resulted in the formation of indeno[2,1-c]pyran-3-ones, involving the sequential formation of two C–C bonds and two C–O bonds. Conversely, when the same conditions were applied to free amino acids, 1-oxazolonylisobenzofurans were obtained. This reaction involved the formation of a C–C bond between oxazolone and o-(2-acyl-1-ethynyl)benzaldehyde, followed by the formation of a C–O bond through a selective 5-exo-dig cyclization.

Ministry of Higher Education, Science, Research and Innovation, Thailand 10.13039/501100016204 48296 / 4691996 Ministry of Higher Education, Science, Research and Innovation, Thailand 10.13039/501100016204 FRB660044/0240 / 180874 document-id-old-9ao4c03842
document-id-new-14ao4c03842
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pmcIntroduction

In recent years, o-(2-acyl-1-ethynyl)benzaldehydes have been elaborated as a useful and versatile building block for constructing various structurally diverse organic frameworks including polycyclic products,1 isoindolinone,2 indenamine,2a,3 isobenzofuran,4 and indanone derivatives5 frequently found as cores in many synthetically derived pharmaceuticals as well as natural products.6 Indenopyrans, the 6/5/6-tricyclic-core-containing indenone derivatives fused with a pyran unit, are common in naturally occurring compounds with significant bioactivities as alcoholic fermentation activators and potential estrogen receptor binders while also displaying photoluminescence properties.7 Nodulisporic acid (Figure 1A), isolated from an endophytic fungus, was used as an insecticidal agent since it exhibited both in vitro and in vivo antifeedant activity against fleas without toxicity to mammals.8,9 Janthitrems E (Figure 1B) was isolated from cultures of Penicillium janthinellum.10 Shearinine A (Figure 1C), an anti-insect, was isolated from the marine-derived fungus Eupenicillium shearii (NRRL 3324)11 and Penicillium janthinellum Biourge12 which was shown to induce apoptosis in human leukemia HL-60 cells. Isobenzofurans or phthalans are generally known as heterocyclic building blocks in a number of natural products with unique biological activities such as acremonide (Figure 1D), which was isolated from Rhizophora apiculate and showed antifungal activity against C. albicans and C. neoformans.6a,13 In addition, (Z)-3-butylidenephthalide (Figure 1E), isolated from Angelica glauca, Levisticum officinale, and Ligusticum porteri, exhibits hypoglycemic activity,14−17 while sinaspirolide (Figure 1F) is a dimeric phthalide natural product found in Angelica sinensis and contributes to the serotonergic activity.18

Figure 1 Selected bioactive compounds containing indenopyran and isobenzofuran skeletons.

Various synthetic methodologies have been developed to construct indenopyrans and isobenzofurans from o-(2-acyl-1-ethynyl)benzaldehyde as a valuable synthon. Previously, Han reported an unexpected addition of acetic acid to o-(2-acyl-1-ethynyl)benzaldehydes catalyzed by palladium(II) acetate to provide dihydroisobenzofurans.19a Cao and You developed a KOtBu-mediated domino reaction of enynals with indoles to afford the corresponding indolyl-substituted isobenzofuran (Scheme 1a, Nu = indole).19b Other methods for the synthesis of isobenzofurans including iodocyclizations19c or intramolecular oxa-Michael reaction,19d oxo-cyclization/coupling,19e or intermolecular Heck coupling followed by intramolecular oxo-cyclization were previously reported through 5-exo-dig cyclization.19f However, another possibility for the reaction via 6-endo-dig cyclization was also reported. For instance, Li reported palladium-catalyzed domino reactions of o-(2-acyl-1-ethynyl)benzaldehydes with indoles to prepare 3-(1H-isochromen-1-yl)-1H-indole (Scheme 1b, Nu = indole).20 Belmont and Michelet also reported hydroarylation/cycloisomerization reactions of o-(2-acyl-1-ethynyl)benzaldehydes by silver catalysis to furnish the corresponding isochromene derivatives (Scheme 1b).21 On the contrary, Cao and You reported the synthesis of tetracyclic indeno[2,1-c]chromen-7-one by acid-catalyzed domino reaction of o-(2-acyl-1-ethynyl)benzaldehydes with phenols (Scheme 1c).22

Scheme 1 General Strategies for the Synthesis of (a) Isobenzofuran, (b) Isochroman, and (c) Indenopyran Using o-(2-Acyl-1-ethynyl)benzaldehydes and Our Strategy (d and e)

Despite the previous advances on the cyclization of o-(2-acyl-1-ethynyl)benzaldehydes, there is scope to develop novel cyclization pathways. To the best of our knowledge, there has been no report on the synthesis of indeno[2,1-c]pyran-3-ones and 1-oxazolonylisobenzofurans via the Erlenmeyer–Plöchl azlactone (EPA) reaction. In continuation of our efforts which have focused on the synthetic applications of azlactones,23 herein, we describe the first examples of a divergent strategy utilizing o-(2-acyl-1-ethynyl)benzaldehydes 1 under the EPA reactions with different types of amino acids 4 including N-acylglycines (Scheme 1d) and free amino acids (Scheme 1e) to furnish the indeno[2,1-c]pyran-3-ones 2 and 1-oxazolonylisobenzofurans 3.

We envisaged that, under the EPA reaction, o-(2-acyl-1-ethynyl)benzaldehyde 1 could react with hippuric acid 4a to afford the oxazolone, which further reacts with the aldehyde to form a reactive intermediate 5. This intermediate could undergo a series of cascade cyclizations induced by the acetate anion, resulting in the formation of two C–C and two C–O bonds, ultimately constructing indeno[2,1-c]pyran-3-ones 2. Additionally, using free amino acids instead of hippuric acid could lead to the formation of 1-oxazolonylisobenzofurans 3. This process involves the initial formation of oxazolone, followed by a 1,2-addition at the aldehyde, and culminates in the formation of isobenzofuran via a 5-exo-dig cyclization.

Results and Discussion

Initially, our investigation was carried out by using o-(2-acyl-1-ethynyl)benzaldehyde 1a, hippuric acid 4a, and NaOAc as a base in a 1:1.5:0.5 mol ratio at 50 °C with Ac2O (5 equiv) as the solvent (Table 1). The reaction was performed for 1.5 h, and oxazolone 5a was obtained in 29% yield via the Dakin–West-like reaction (entry 1).24 Increasing the reaction temperature to 60 °C gave a higher yield (56%) of 5a (entry 2). At 80 °C, the desired cascade cyclization product 2a could be obtained in 32% yield (entry 3). Using other bases such as sodium trifluoroacetate under EPA reaction resulted in lower yield of the product 2a (6% yield), and compound 5a (19% yield) revealed the importance of NaOAc as a base in this reaction (entry 4).

Table 1 Attempted Optimization of Reaction Conditions for the Synthesis of Indeno[2,1-c]pyran-3-one 2a

entry	NaOAc (equiv)	additive (equiv)	T (°C)	time (h)	yield 5aa (%)	yield 2aa (%)	yield 6aa (%)	
1	0.5	Ac2O (5)	50	1.5	29	-	-	
2	0.5	Ac2O (5)	60	1	56	-	-	
3	0.5	Ac2O (5)	80	1.5	-	32	-	
4b	0.5	Ac2O (5)	80	1.5	19	6	-	
5	1.1	Ac2O (5)	100	1	-	35	-	
6c	1.1	Ac2O (2.2)	100	1	-	56	-	
7c,d	1.1	Ac2O (2.2)	100	1	-	54	-	
8c,e	1.1	-	100	1	-	-	9	
9c,f	1.1	HOAc (2.2)	100	1	-	-	27	
a Isolated yields.

b Using sodium trifluoroacetate as a base instead of NaOAc.

c Using CH3CN (2 M) as a cosolvent.

d Using sodium bicarbonate as a base instead of NaOAc.

e RSM 58% yield.

f RSM 40% yield.

The yield of product 2a was improved by increasing the amount of base from 0.5 equiv to 1.1 equiv and the reaction temperature from 80 to 100 °C for 1 h (entry 5). In addition, using CH3CN (2 M) as a cosolvent under standard conditions and decreasing the amount of Ac2O from 5 equiv to 2.2 equiv at 100 °C for 1 h could furnish the desired product 2a in 56% yield (entry 6). The reaction was performed with sodium bicarbonate and resulted in the product 2a in 54% yield (entry 7). This result demonstrated the important role of acetic anhydride. When the reaction was performed without Ac2O or using HOAc instead, compound 6a was obtained in 9% and 27% yields, respectively (entries 8–9). This result suggested that Ac2O played an important role in the reaction to promote the Dakin–West-like reaction24 in the first step. Without Ac2O, the intermediate 5a could not be generated, while HOAc may attack the aldehyde followed by cyclization to form isobenzofuran 6a via the 5-exo-dig cyclization. Based on our attempted optimization for the synthesis of indeno[2,1-c]pyran-3-one, 2a was found to be NaOAc as a base (1.1 equiv) in CH3CN as a cosolvent and Ac2O (2.2 equiv) at 100 °C for 1 h.

With workable conditions in hand, we then explored the scope and generality of this EPA cascade cyclization for accessing a set of functionalized indeno[2,1-c]pyran-3-ones 2 as indicated in Scheme 2. The electronic effect of the substituent R1 on the o-(2-acyl-1-ethynyl)benzaldehydes 1 was investigated; no influence on the yields of products 2 arising from the electronic effect was found. Methyl ketone delivered the product 2 in higher yields than a phenyl group. In addition, the certain acyl substituents R3 of glycine derivatives 4a (R3 = phenyl) and 4c (R3 = furan) gave the desired products 2 in higher yields than the others, 4b (R3 = Me), 4d (R3 = thiophenyl), and 4e (R3 = nicotinyl).

Scheme 2 Substrate Scope for the Synthesis of Indeno[2,1-c]pyran-3-ones 2

All reactions used NaOAc (1.1 equiv) and Ac2O (2.2 equiv) in CH3CN (2 M) and were heated at 80–100 °C.

Without CH3CN.

Used Ac2O (5 equiv).

Used CH3CN (0.25 M) instead.

We then extended the scope for this cascade cyclization reaction by using N-acetyl-dl-alanine 4f instead of N-acetyl-glycine 4b. Initially, o-(2-acyl-1-ethynyl)benzaldehyde 1c and N-acetyl-dl-alanine 4f were chosen as a model substrate as shown in Scheme 3. Surprisingly, using EPA reaction of compound 1c with 4f at 80 °C for 3 h, the reaction provided compound 3cj in 51% yield (>99:1 Z/E). The configurations of product 3cj could be established by the formation of an oxazolone intermediate from racemic 4f. Subsequently, the 1,2-addition of the oxazolone ring to the aldehyde followed by oxynucleophilic cyclization via the 5-exo-dig cyclization yielded product 3cj. The geometry of the exo-cyclic double olefin of 3cj is the Z-configuration, as confirmed by comparisons of the NMR spectra of Z and E-3ag and X-ray crystallography analysis of Z-3ag and E-3cg (Figure 2).

Scheme 3 Reaction of 1c with N-Acetyl-dl-alanine 4f

Figure 2 (a,b) NOE correlations of Z-3ag and E-3ag,25 (c) structure of E-3cg,26 and (d,e) X-ray structures of Z-3ag and E-3cg.

To extend the utility of this divergent synthesis using compound 1a as a precursor to react with dl-phenylalanine 4g under EPA reaction, we then optimized the reaction conditions for the synthesis of 1-oxazolonylisobenzofurans 3 as shown in Table 2. Initially, the reaction was performed for 4 h, and the desired product 3ag was obtained in 53% yield (>99:1 Z/E) (entry 1). Decreasing the reaction time to 1.5 h while lowering or increasing the reaction temperature to 50 and 100 °C, the yields of 3ag were dramatically decreased to 22%, 30% and 43% yields, respectively (entries 2–4).

Table 2 Attempted Optimization of Reaction Conditions for the Synthesis of 1-Oxazolonylisobenzofurans 3ag

entry	conditions	yield (3ag)a (% Z/E)	
1	none	53 (>99:1)	
2	1.5 h instead of 4 h	22 (>99:1)	
3	T = 50 °C instead of 80 °C	30 (60:40)	
4	T = 100 °C instead of 80 °C	43 (>99:1)	
5	sodium trifluoroacetate as base	12 (>99:1)b	
6	Et3N as base	53 (>99:1)	
7	THF as solvent	47 (>99:1)	
8	toluene as solvent	48 (>99:1)	
9	CH3CN as solvent	54 (>99:1)	
10	Et3N as base and CH3CN as solvent	66 (53:47)	
11	TFAA as an anhydride at 40 °C	NR	
12	Tf2O as an anhydride	NR	
13	without amino acid 4g	NR	
14	l-Phenylalanine methyl ester hydrochloride instead of dl-phenylalanine	NR	
a Isolated yields.

b 1a = 0.25 mmol. NR = no reaction.

Other bases were screened such as sodium trifluoroacetate and Et3N, but the yields of 3ag did not improve as compared to that obtained when using NaOAc (entries 5–6). Using other solvents including THF, toluene, and CH3CN led to the desired product 3ag in 47%, 48%, and 54% yields, respectively (entries 7–9). To improve the product yield, using NEt3 as a base and CH3CN as a cosolvent resulted in 66% yield of a mixture of Z/E-3ag with the geometric ratio of 53:47 (entry 10). Further investigation with other anhydrides including TFAA and Tf2O gave no 1-oxazolonylisobenzofuran formation (entries 11–12). The reactions performed without amino acid or using methyl ester also gave no formation of isobenzofuran (entries 13–14). The workable condition for the synthesis of 1-oxazolonylisobenzofuran was found to be NaOAc as a base (1.1 equiv) in neat Ac2O (5 equiv) at 80 °C for 4 h.

A single-crystal X-ray crystallography analysis was performed on the major isomer of Z-3ag (Figure 2a, 2d). The result confirmed the C–C bond formation of the 1-oxazolonylisobenzofuran framework and the C–O bond formation via the 5-exo-dig cyclization. The configuration of the exo-cyclic double bond was also determined to be Z with NOE correlation between the olefinic proton at δH 5.74 (s, 1H) and an aromatic proton of the benzofuran ring at δH 7.65–7.45 (m, Ha), thus confirming that the major product was Z-1-(isobenzofuran-1(3H)-ylidene)propan-2-one (Z-3ag). The minor product 3ag was assigned to be E-1-(isobenzofuran-1(3H)-ylidene)propan-2-one.25 In addition, the Hb aromatic proton appeared at a downfield chemical shift (δH 9.48–9.40 ppm) as a result of a through-space deshielding from the carbonyl of the acyl group, implying the E-isomer configuration (Figure 2b). The relative configurations of the two stereogenic centers at benzylic (C1) and α(C12)-carbons of a single diastereomer were also determined as (1R*,12R*)-Z-3ag and (1S*,12S*)-E-3ag, respectively. In the case of using NEt3 as a base (entry 10), the reaction gave a 1:1 mixture of Z/E-3ag which was separated by column chromatography on silica gel.

Next, we sought to explore the scope of free amino acids 4 with a series of o-(2-acyl-1-ethynyl)benzaldehydes 1 to synthesize a set of 1-oxazolonylisobenzofurans 3 by decorating substituents R1, R2, and R4 on the starting materials (Scheme 4). The o-(2-acyl-1-ethynyl)benzaldehydes 1 bear both EDG (R1 = OMe) and EWG (R1 = Cl, F) with free amino acids 4g–j under the standard conditions. The reactions proceeded smoothly and gave moderate to good yields of the desired products.

Scheme 4 Substrate Scope of 1-Oxazolonylisobenzofurans Derived from o-(2-Acyl-1-ethynyl)benzaldehydes,

Reaction conditions: 1 (0.5 mmol), 4 (0.75 mmol), NaOAc (0.55 mmol), and Ac2O (2.5 mmol) and heated at 80 °C for 4 h.

Isolated yields and the geometric ratio (Z/E) values were determined by 1H NMR.

Scale up to 7.31 mmol (3cg; 48% (96:4 Z/E)).

Bz2O (1.05 mmol) was used as an anhydride instead of Ac2O in CH3CN (0.14 mL).

The reactions were highly stereoselective when arylbutynone derivatives (1, R2 = Me) were used as starting materials. Using the diarylpropynone derivatives (1, R2 = Ph), the reactions provided a mixture of Z- and E-isomers. The geometric ratio (Z/E) values were determined by 1H NMR spectroscopy. Free racemic amino acids substituted with R4 including phenylalanine (Phe, 4g), tyrosine (Tyr, 4h), valine (Val, 4i), and alanine (Ala, 4j) were screened. The results indicated that amino acids 4g–i provided the corresponding products 3 in moderate to good yields, whereas 4j gave the lower yields. Other amino acids including proline, serine, and cysteine were also screened, but the reactions did not proceed to furnish any desired products. In the case when benzoic anhydride was used instead of acetic anhydride in the presence of 1.1 equiv NaOAc and CH3CN, the reaction provided compound 3′ag in 46% yield (71:29 Z/E) (Scheme 4). The structures of these 1-oxazolonylisobensofuran derivatives 3 were characterized by their NMR spectroscopy and HRMS. In the case of E-3cg, its structure was unequivocally confirmed by carrying out single-crystal X-ray diffraction (Figure 2c and e).

In order to gain insight into both reaction mechanisms, some mechanistic studies were explored as shown in Scheme 5. Using a proposed intermediate 5a under the workable reaction conditions resulted in the formation of the corresponding product 2a in 56% yield (Scheme 5a). In the case of no amino acid addition, compound 1a could undergo the formation of compound 6a in 46% yield under the EPA reaction (Scheme 5b).19a The result supported that the oxazolone was formed first from the alpha-amino acid via the Dakin–West-like reaction. This was further demonstrated when the oxazolone 8(27) was reacted with compound 1c which furnished 3cg in 48% yield (23:77 Z/E) (Scheme 5c). Changing the conjugated ynone substrate to the alkynol 1i,28 the reaction proceeded to give the β-lactone 9 in 32% yield instead (Scheme 5d). Proline (4k) was also used as a representative of a secondary amine. The reaction proceeded to give the isobenzofuran 6c in 31% yield without the incorporation of the proline moiety (Scheme 5e). These experiments revealed that the reaction required the internal alkyne containing the conjugated EWG for substrate 1. This reaction condition was shown to be amenable to a relatively broad substrate scope of the amino acids containing the primary amino group and the free carboxylic acid.

Scheme 5 Mechanistic Study

Based on the results, a tentative cascade cyclization mechanism was proposed as shown in Scheme 6. Under EPA reaction between compound 1 and hippuric acid 4a, the intermediate 5 was formed in situ through the Dakin–West-like reaction;24 this intermediate was isolated from this reaction performed at 50–60 °C for 1.5 h (Table 1, entries 1–2). After dehydration, the intermediate 5 was converted to the corresponding ene-yne-one oxazolone 7. Acetate undergoes 1,4-addition to compound 7, generating the allene-enolate anion intermediate I.2a Intramolecular 1,4-addition of the intermediate I resulted in the C–C bond formation of the indene ring system with the concurrent ring opening of the oxazolone moiety to form the ketene intermediate II. Intramolecular cyclization and lactonization could lead to the intermediate III. Subsequent aromatization via intermediate IV would lead to the formation of compound 2. Overall, the 6/5/6 skeleton of 2 was accomplished by the cascade cyclization to construct two C–C and two C–O bond formations in a single step.

Scheme 6 Proposed Mechanism for the Formation of Indeno[2,1-c]pyran-3-one 2 and 1-Oxazolonylisobenzofuran 3

According to our plausible mechanism of 3, we hypothesized that under the EPA reaction amino acids V could result in the generation of the oxazolone intermediate VIin situ through the Dakin–West-like reaction.24 The deprotonated oxazolone VII, with carbanionic character at the α-position, could react with the carbonyl carbon of the aldehyde to furnish the alcohol VIII. Subsequently oxa-Michael addition and then protonation of the intermediate VIII via 5-exo-dig cyclization would ultimately yield the corresponding 1-oxazolonylisobenzofuran 3.

Indeno[2,1-c]pyran-3-ones 2 and 1-oxazolonylisobenzofurans 3 were further evaluated for their cytotoxicity against a panel of four human tumor cell lines: cholangiocarcinoma HuCCA-1, lung carcinoma A549, hepatoblastoma HepG2, and T-lymphoblast (acute lympho-blastic leukemia) MOLT-3. The results of the cytotoxicity assays indicated that compounds 2 and 3 had no cytotoxicity against these tumor cell lines.

Indeno[2,1-c]pyran-3-one 2a and 1-oxazolonylisobenzofuran Z-3cg could undergo further transformations (Scheme 7). Saponification using 5% KOH in EtOH followed by PCC oxidation of 2a led to the desired indeno[2,1-c]pyran 10 in 43% yield over two steps. Reduction of 2a with NaBH4 in EtOH furnished the corresponding indene 11 in 41% yield. The lactone underwent ring opening induced by the acetate leaving group, which performed ethanolysis followed by an E1cb-like reaction and reduction of ketone to yield indene 11. The 1H NMR spectrum showed very clearly the olefinic signal of indene as well as the substituted signals corresponding with the 13C NMR spectrum (see the Supporting Information). Hydrogenation of Z-3cg was carried out using Pd/C as a catalyst which effectively reduced the exo-cyclic olefin to give compound 12 in 53% yield. Ethanolysis of Z-3cg by using 5% KOH in EtOH which also accompanied the ring opening of the oxazolone provided the compound Z-13 in excellent yield (99%). The Van Leusen oxazole synthesis29a of Z-3cg involved the [3 + 2] cycloaddition of the carbonyl lactone to the oxazolone ring using toluenesulfonylmethyl isocyanide (TosMIC)29 as a reagent, resulting in the formation of oxazole Z-14 in 48% yield. Compound Z-13 was further transformed to compound 15:15′ in 51% yield (65:35 dr) by reacting with benzyne30 generated in situ via the 1,2-addition of the exo-cyclic double bond.

Scheme 7 Transformation of Compounds 2a and Z-3cg

In conclusion, we have successfully developed a highly regioselective and divergent approach for synthesizing indeno[2,1-c]pyran-3-ones 2 and 1-oxazolonylisobenzofurans 3 from the common o-(2-acyl-1-ethynyl)benzaldehyde 1. Using the Erlenmeyer–Plöchl azlactone (EPA) reaction, we have synthesized these compounds by employing various N-acylglycines and free amino acids. Our developed method is operationally straightforward, conducted under mild conditions, and free from metal and catalyst requirements and demonstrates an atom-economic process with a relatively broad substrate scope. As a result, two distinct scaffolds could be selectively prepared.

Experimental Section

General Information

All reagents and solvents were purchased from commercial sources and used without further purification. All reactions were heated by an oil bath. 1H NMR (300 and 400 MHz), 13C{1H} NMR (75 and 100 MHz), and 19F{1H} NMR spectra (376 MHz) were recorded on a Bruker Ultra shield model AV300 spectrometer and Bruker AVANCE 400 spectrometer, respectively. Chemical shifts were reported in parts per million on the scale relative to the internal standard (tetramethylsilane, TMS (0 ppm)) in CDCl3 and solvent signals (2.50 ppm) in DMSO-d6. The 13C NMR chemical shifts were determined relative to the internal solvent signals (77.0 ppm) in CDCl3 and (39.5 ppm) in DMSO-d6. 19F NMR chemical shifts were determined relative to C6F6 (δ – 164.9 ppm) as the internal standard. Coupling constants (J) were given in hertz (Hz). Infrared spectra were measured using a PerkinElmer FT-IR spectrometer, in cm–1. High resolution mass spectra (HRMS) were obtained using time-of-flight (TOF) via the electrospray ionization (ESI). Single-crystal was determined with an X-ray single-crystal diffractometer. All crystals were grown in CH2Cl2 and hexane (1:1; v/v) for 1 week at 25 °C. Melting points were measured on a Thermo Scientific digital melting point apparatus in open capillaries. The products were purified by column chromatography (silica gel 60, size 0.06–0.20 mm; 70–230 mesh ASTM). TLC-Aluminum sheets on silica gel 60 GF254 (thin layer chromatography on an aluminum sheet) were used for monitoring the reaction. Rotary evaporations were applied to remove organic solvent.

General Procedure for Preparation of o-(2-Acyl-1-ethynyl)benzaldehyde 1(2a)

The Schlenk flask charged with a stirring bar, a derivative of 2-bromobenzaldehyde (1.0 equiv), PdCl2(PPh3)2 (3 mol %), and CuI (5 mol %) was evacuated and filled with Ar (g) three times, and then dry THF (0.27 M) was added under an argon atmosphere. To the above suspension was added alkynol (1.2 equiv) and Et3N (0.25–0.53 M) sequentially. The resulting mixture was stirred at 60 °C overnight (18 h). The resulting mixture was cooled, and then the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate in hexane) to give product S1.

Compound S1 was dissolved with CH2Cl2 (0.2 M) at room temperature, and celite (0.25 g/mmol) and PCC (2.0 equiv) were added. The resulting mixture was stirred at room temperature (26 °C) for 2–3 h. After completion, the mixture was filtered through a short silica gel column using CH2Cl2 as the eluent, and then the solvent was removed to furnish compounds 1.

5-Chloro-2-(3-hydroxy-3-phenylprop-1-yn-1-yl)benzaldehyde (S1f)

Following the general procedure, 2-bromo-5-chlorobenzaldehyde (1.76 g, 8.00 mmol, 1 equiv), 1-phenylprop-2-yn-1-ol (1.20 mL, 9.60 mmol, 1.2 equiv), PdCl2(PPh3)2 (168.4 mg, 0.24 mmol, 3 mol %), CuI (75.0 mg, 0.39 mmol, 5 mol %), NEt3 (15 mL, 0.53 M), and THF (30 mL, 0.27 M) were stirred at room temperature (26 °C) overnight. The crude product was purified by column chromatography using 15% EtOAc in hexane as eluent to furnish S1f (1.66 g, 77% yield) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 10.42 (s, 1H, CH=O), 7.87 (dd, J = 1.4, 1.4 Hz, 1H, Ar–H), 7.62–7.56 (m, 2H, Ar–H), 7.54–7.51 (m, 2H, Ar–H), 7.47–7.34 (m, 3H, Ar–H), 5.75 (d, J = 5.7 Hz, 1H, ArCHOH), 2.52 (d, J = 5.7 Hz, 1H, ArCHOH). 13C{1H} NMR (75 MHz, CDCl3) δ 190.0 (CO), 139.9, 137.2, 135.6, 134.7, 133.8, 128.9 (2C), 128.8, 127.4, 126.5 (2C), 124.0, 96.8 (C ≡ C), 81.2 (C ≡ C), 65.2 (ArCHOH). IR (UATR) νmax 3374 (OH), 3064, 3032, 2849, 2200 (C≡C), 1694 (CO), 1588, 1474 cm–1. HRMS (ESI) calcd. for C16H11ClNaO2 [M + Na]+: 293.0340, found 293.0339.

5-Chloro-2-(3-oxo-3-phenylprop-1-yn-1-yl)benzaldehyde (1f)

Following the general procedure, compound S1f (1.66 g, 6.15 mmol, 1 equiv), Celite (1.54 g, 0.25 g/mmol) and PCC (2.65 g, 12.3 mmol, 2 equiv) in CH2Cl2 (31 mL, 0.2 M) were stirred at room temperature (26 °C) for 2 h. The mixture was filtered through a short silica gel column to furnish compound 1f (1.47 g, 89% yield) as a light-yellow solid. Mp 111.1–113.2 °C. 1H NMR (300 MHz, CDCl3) δ 10.54 (s, 1H, CH=O), 8.26–8.20 (m, 2H, Ar–H), 7.99 (d, J = 2.1 Hz, 1H, Ar–H), 7.78 (d, J = 8.1 Hz, 1H, Ar–H), 7.73–7.63 (m, 2H, Ar–H), 7.60–7.52 (m, 2H, Ar–H). 13C{1H} NMR (75 MHz, CDCl3) δ 188.9 (CH=O), 177.2 (CO), 138.2, 137.9, 136.5, 135.9, 134.6, 134.0, 129.6 (2C), 128.9 (2C), 128.5, 121.0, 92.9 (C ≡ C), 86.4 (C ≡ C). IR (UATR) νmax 3065, 2871, 2194 (C≡C), 1793 (CO), 1696 (CO), 1642, 1596, 1579 cm–1. HRMS (ESI) calcd. for C16H9ClNaO2 [M + Na]+: 291.0183, found 291.0181.

5-Fluoro-2-(3-hydroxy-3-phenylprop-1-yn-1-yl)benzaldehyde (S1g)

Following the general procedure, 2-bromo-5-fluorobenzaldehyde (1.63 g, 8.00 mmol, 1 equiv), 1-phenylprop-2-yn-1-ol (1.20 mL, 9.60 mmol, 1.2 equiv), PdCl2(PPh3)2 (167.6 mg, 0.24 mmol, 3 mol %), CuI (75.2 mg, 0.40 mmol, 5 mol %), NEt3 (15 mL, 0.53 M), and THF (30 mL, 0.27 M) were stirred at 60 °C overnight. The crude product was purified by column chromatography using 20% EtOAc in hexane as eluent to furnish compound S1g (1.69 g, 83% yield) as a brown oil. 1H NMR (300 MHz, CDCl3) δ 10.40 (d, J = 3.0 Hz, 1H, CH=O), 7.60–7.50 (m, 4H, Ar–H), 7.44–7.30 (m, 3H, Ar–H), 7.28–7.18 (m, 1H, Ar–H), 5.71 (br s, 1H, ArCHOH), 3.18 (br d, J = 3.3 Hz, 1H, ArCHOH). 13C{1H} NMR (75 MHz, CDCl3) δ 190.3 (d, 4JC–F = 1.1 Hz, CH=O), 162.5 (d, 1JC–F = 251.6 Hz, CF), 140.0, 138.1 (d, 3JC–F = 6.8 Hz), 135.5 (d, 3JC–F = 7.7 Hz), 128.8 (2C), 128.7, 126.5 (2C), 121.9 (d, 4JC–F = 3.3 Hz), 121.3 (d, 2JC–F = 22.7 Hz), 113.8 (d, 2JC–F = 23.0 Hz), 95.7 (C ≡ C), 81.0 (C ≡ C), 65.0 (ArCHOH). IR (UATR) νmax 3376 (OH), 3067, 2852, 1694 (CO), 1603, 1487 cm–1. HRMS (ESI) calcd. for C16H11FNaO2 [M + Na]+: 277.0635, found 277.0635.

5-Fluoro-2-(3-oxo-3-phenylprop-1-yn-1-yl)benzaldehyde (1g)

Following the general procedure, compound S1g (1.69 g, 6.65 mmol, 1 equiv) and Celite (1.66 g, 0.25 g/mmol) and PCC (2.87 g, 13.3 mmol, 2 equiv) in CH2Cl2 (34 mL, 0.2 M) were stirred at room temperature (26 °C) for 2 h. The mixture was filtered through a short silica gel column to furnish compound 1f (1.22 g, 73% yield) as a white solid. Mp 96.3–98.2 °C. 1H NMR (300 MHz, CDCl3) δ 10.54 (d, J = 3.0 Hz, 1H, CH=O), 8.24–8.16 (m, 2H, Ar–H), 7.84 (dd, JH–H = 7.9 Hz and JH–F = 5.0 Hz, 1H, Ar–H), 7.71–7.63 (m, 2H, Ar–H), 7.54–7.50 (m, 2H, Ar–H), 7.39 (ddd, J = 10.4, 7.9, 2.7 Hz, 1H, Ar–H). 13C{1H} NMR (75 MHz, CDCl3) δ 188.8 (d, 4JC–F = 1.6 Hz, CH=O), 177.2 (CO), 163.7 (d, 1JC–F = 255.0 Hz, CF), 139.4 (d, 3JC–F = 7.1 Hz), 137.0 (d, 3JC–F = 8.1 Hz), 136.4, 134.5, 129.5 (2C), 128.8 (2C), 121.5 (d, 2JC–F = 22.7 Hz), 118.9 (d, 4JC–F = 3.6 Hz), 115.0 (d, 2JC–F = 23.1 Hz), 92.0 (d, 5JC–F = 1.7 Hz, C ≡ C), 86.5 (C ≡ C). IR (UATR) νmax 3092, 2877, 2197 (C≡C), 1695 (CO), 1642, 1596, 1578 cm–1. HRMS (ESI) calcd. for C16H9FNaO2 [M + Na]+: 275.0479, found 275.0475.

2-(3-Hydroxy-3-phenylprop-1-yn-1-yl)-5-methoxybenzaldehyde (S1h)

Following the general procedure, using the 2-bromo-5-methoxybenzaldehyde (1.72 g, 8.00 mmol, 1 equiv), 1-phenylprop-2-yn-1-ol (1.20 mL, 9.60 mmol, 1.2 equiv), PdCl2(PPh3)2 (169.0 mg, 0.24 mmol, 3 mol %), CuI (76.7 mg, 0.40 mmol, 5 mol %), NEt3 (15 mL, 0.53 M), and THF (30 mL, 0.27 M) were stirred at 60 °C overnight. The crude product was purified by column chromatography using 20% EtOAc in hexane as eluent to furnish S1h (2.09 g, 99% yield) as a brown oil. 1H NMR (300 MHz, CDCl3) δ 10.45 (s, 1H, CH=O), 7.63–7.57 (m, 2H, Ar–H), 7.50 (d, J = 8.7 Hz, 1H, Ar–H), 7.46–7.32 (m, 4H, Ar–H), 7.10 (dd, J = 8.7, 2.7 Hz, 1H, Ar–H), 5.74 (br d, J = 4.5 Hz, 1H, ArCHOH), 3.86 (s, 3H, Ar−OCH3), 2.52 (br d, J = 5.7 Hz, 1H, ArCHOH). 13C{1H} NMR (75 MHz, CDCl3) δ 191.3 (CH=O), 160.0 (CO), 140.3, 137.6, 134.8, 128.8 (2C), 128.6, 126.6 (2C), 121.5, 118.5, 110.1, 94.3 (C ≡ C), 82.1 (C ≡ C), 65.2 (ArCHOH), 55.6 (Ar–OCH3). IR (UATR) νmax 3396, 3032, 2843, 1688 (CO), 1601, 1561, 1492 cm–1. HRMS (ESI) calcd. for C17H14NaO3 [M + Na]+: 289.0835, found 289.0831.

2-(3-Hydroxy-3-phenylprop-1-yn-1-yl)-5-methoxybenzaldehyde (1h)

Following the general procedure, compound S1h (2.09 g, 7.92 mmol, 1 equiv) and Celite (1.98 g, 0.25 g/mmol), PCC (3.41 g, 15.8 mmol, 2 equiv), and CH2Cl2 (40 mL, 0.2 M) were stirred at room temperature (26 °C) for 2 h. The mixture was filtered through a short silica gel column to furnish compound 1h (1.56 g, 75% yield) as a white solid. Mp 96.3–98.2 °C. 1H NMR (300 MHz, CDCl3) δ 10.57 (s, 1H, CH=O), 8.25–8.18 (m, 2H, Ar–H), 7.75 (d, J = 8.4 Hz, 1H, Ar–H), 7.69–7.61 (m, 1H, Ar–H), 7.57–7.50 (m, 2H, Ar–H), 7.48 (d, J = 2.8 Hz, 1H, Ar–H), 7.20 (dd, J = 8.4, 2.8 Hz, 1H, Ar–H), 3.92 (s, 3H, Ar−OCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 190.1 (CH=O), 177.5 (CO), 161.7, 138.9, 136.7, 136.5, 134.3, 129.5 (2C), 128.7 (2C), 121.2, 115.0, 111.6, 91.8 (C ≡ C), 88.5 (C ≡ C), 55.8 (Ar–OCH3). IR (UATR) νmax 3082, 3064, 2851, 2184, 1699, 1638, 1596, 1579 cm–1. HRMS (ESI) calcd. for C17H12NaO3 [M + Na]+: 287.0679, found 287.0676.

General Procedure for the Synthesis of Indeno[2,1-c]pyran-3-ones 2

To a suspension of o-(2-acyl-1-ethynyl)benzaldehyde derivatives 1 (1 equiv), amino acid derivatives 4a–e (1.5 equiv), NaOAc (1.1 equiv), and Ac2O (2.2–5 equiv) in CH3CN (0.25–2 M) or without CH3CN in a sealed tube were added and stirred at 80–100 °C for 1–6.5 h. The reaction mixture was allowed to cool to room temperature and then quenched with sat. Na2CO3 (10 mL) and extracted with CH2Cl2 (3 × 10 mL). Combined organic layers were washed with sat. Na2CO3 until pH = 7, followed by water and brine, dried over anh. Na2SO4, and concentrated to give a brown oil. The crude product was purified by column chromatography on silica gel using 30–60% EtOAc in hexane or 10–70% EtOAc in CH2Cl2 to afford indeno[2,1-c]pyran-3-ones 2.

4-Benzamido-1-methyl-3-oxo-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2a)

Following the general procedure, compound 1a (172 mg, 1.00 mmol, 1 equiv), hippuric acid 4a (269 mg, 1.50 mmol, 1.5 equiv), NaOAc (90.0 mg, 1.10 mmol, 1.1 equiv) and Ac2O (0.21 mL, 2.20 mmol, 2.2 equiv) in CH3CN (0.48 mL, 2 M) in a sealed tube were stirred at 100 °C for 1 h. The crude product was purified by column chromatography on silica gel using 40–50% EtOAc in hexane to furnish compound 2a (209 mg, 56%) as a yellow-brown solid. Mp 214.8–215.9 °C. 1H NMR (300 MHz, CDCl3) δ 8.20 (br s, 1H, – NH), 7.98 (d, J = 7.5 Hz, 2H, Ar–H), 7.63–7.57 (m, 2H, Ar–H), 7.56–7.37 (m, 5H, Ar–H), 7.01 (s, 1H, – CH), 2.32 (s, 3H, CH3), 2.17 (s, 3H, OCOCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 171.0 (OCOCH3), 166.0 (CONH), 162.6 (COO), 154.8, 146.1, 144.8, 135.8, 133.2, 132.5, 130.2, 128.9 (3C), 127.7 (2C), 127.6, 126.1, 117.4, 112.8, 71.6 (CH), 20.9 (OCOCH3), 17.1 (CH3). IR (UATR) νmax 3292 (NH), 1739 (CO), 1699 (CO), 1668 (CO), 1613, 1601, 1512 cm–1. HRMS (ESI) calcd. for C22H17NNaO5 [M + Na}+: 398.0999, found 398.0994.

The structure of product 2a was elucidated based on the comprehensive NMR spectroscopic techniques. The 1H NMR spectrum showed key signals of indeno[2,1-c]pyran-3-one core structure at δH 8.20 (br s, 1H) for the secondary amide proton, at δH 7.01 (s, 1H) for the sp3 oxymethine proton, at δH 2.32 (s, 3H) for the methyl group on the α-pyrone ring, and at δH 2.17 (s, 3H, OAc) for the indanyl acetate group. The 13C NMR spectrum displayed five carbon characteristic peaks of the α-pyrone ring at δC 162.6, 154.8, 146.1, 117.4, and 112.8, with a methyl adjacent to the α-pyrone ring at δC 17.1, the carbonyl peak of N-acetyl amide at δC 166.0, the oxymethine carbon at δC 71.6, and the indanyl acetate at δC 171.0 and 20.9. The HMBC spectrum confirmed the correlations of the secondary amide proton (δH 8.20) to the sp2 hybridized carbon (δC 146.1) at the α-position of the carbonyl of the α-pyrone ring; the oxymethine proton (δH 7.01) and the adjacent methyl protons (δH 2.32) to the sp2 hybridized carbons (δC 154.8, 117.4); and the oxymethine proton (δH 7.01) and the acetyl protons (δH 2.17) to the carbonyl ester carbon (δC 171.0). Taken together, all spectroscopic data were consistent with and confirmed the framework of N-(6-methyl-2-oxo-2H-pyran-3-yl)benzamide fused with 1H-inden-1-yl acetate as also supported by the IR absorptions at υmax 1739, 1699, and 1668 cm–1 (see the Supporting Information (SI), pages S23–24).

4-Benzamido-6-chloro-1-methyl-3-oxo-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2b)

Following the general procedure, compound 1b (103 mg, 0.50 mmol, 1 equiv), hippuric acid 4a (134 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.11 mL, 1.10 mmol, 2.2 equiv) in CH3CN (0.24 mL, 2 M) in sealed tubes were stirred at 100 °C for 1 h. The crude product was purified by column chromatography on silica gel using 40% EtOAc in hexane to furnish compound 2b (82.5 mg, 40%) as a yellow-brown solid. Mp 223.6–224.3 °C. 1H NMR (300 MHz, CDCl3) δ 8.16 (br s, 1H, – NH), 8.00–7.94 (m, 2H, Ar–H), 7.66–7.49 (m, 4H, Ar–H), 7.39 (dd, J = 8.6, 1.8 Hz, 1H, Ar–H), 7.30 (d, J = 8.6 Hz, 1H, Ar–H), 6.95 (s, 1H, – CH), 2.32 (s, 3H, CH3), 2.19 (s, 3H, OCOCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 170.9 (OCOCH3), 165.8 (CONH), 162.3 (COO), 154.7, 146.2, 138.2, 134.5, 133.1, 132.8, 130.6, 129.0 (3C), 128.7, 127.7 (2C), 126.5, 117.2, 112.9, 71.2 (CH), 20.9 (OCOCH3), 17.2 (CH3). IR (UATR) νmax 3328, 3070 (NH), 1740 (CO), 1701 (CO), 1674 (CO), 1600, 1504, 1477 cm–1. HRMS (ESI) calcd. for C22H16ClNNaO5 [M + Na]+: 432.0609, found 432.0604.

4-Benzamido-6-fluoro-1-methyl-3-oxo-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2c)

Following the general procedure, compound 1c (95.0 mg, 0.50 mmol, 1 equiv), hippuric acid 4a (134 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.11 mL, 1.10 mmol, 2.2 equiv) in CH3CN (0.24 mL, 2 M) in a sealed tube were stirred at 100 °C for 1 h. The crude product was purified by column chromatography on silica gel using 50% EtOAc in hexane to furnish compound 2c (85.7 mg, 44%) as a brown solid. Mp 238.3–240.0 °C. 1H NMR (400 MHz, CDCl3) δ 8.18 (br s, 1H, – NH), 7.98 (d, J = 7.2 Hz, 2H, Ar–H), 7.65–7.59 (m, 1H, Ar–H), 7.56–7.50 (m, 2H, Ar–H), 7.39 (dd, JH–H = 8.7 Hz and JH–F = 5.0 Hz, 1H, Ar–H), 7.31 (dd, JH–F = 8.6 Hz and JH–H = 2.4 Hz, 1H, Ar–H), 7.12 (ddd, JH–H = 8.7 Hz, JH–F = 8.6 Hz and JH–H = 2.4 Hz, 1H, Ar–H), 6.95 (s, 1H, – CH), 2.32 (s, 3H, CH3), 2.19 (s, 3H, OCOCH3). 13C{1H} NMR (100 MHz, CDCl3) δ 170.9 (OCOCH3), 166.0 (CONH), 164.9 (d, 1JC–F = 253.3 Hz, CF), 162.4 (COO), 154.6, 147.3 (d, 3JC–F = 9.1 Hz), 144.6, 133.1, 132.7, 132.1 (d, 4JC–F = 2.3 Hz), 129.6 (d, 3JC–F = 9.4 Hz), 128.9 (2C), 127.7 (2C), 117.9 (d, 2JC–F = 23.2 Hz), 117.4, 113.6 (d, 2JC–F = 23.4 Hz), 112.4, 71.3 (d, 5JC–F = 1.9 Hz, CH), 20.8 (OCOCH3), 17.2 (CH3). 19F{1H} NMR (376 MHz, CDCl3) δ – 108.63. IR (UATR) νmax 3328 (NH), 3077, 2925, 1740 (CO), 1674 (CO), 1662 (CO), 1607, 1505, 1478 cm–1. HRMS (ESI) calcd. for C22H17FNO5 [M + H]+: 394.1085, found 394.1086.

4-Benzamido-6-methoxy-1-methyl-3-oxo-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2d)

Following the general procedure, compound 1d (102 mg, 0.50 mmol, 1 equiv), hippuric acid 4a (134 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.11 mL, 1.10 mmol, 2.2 equiv) in CH3CN (0.24 mL, 2 M) in a sealed tube were stirred at 100 °C for 1 h. The crude product was purified by column chromatography on silica gel using 40% EtOAc in hexane to furnish compound 2d (75.8 mg, 37%) as a yellow solid. Mp 212.1–213.7 °C. 1H NMR (300 MHz, CDCl3) δ 8.12 (br s, 1H, – NH), 8.00–7.94 (m, 2H, Ar–H), 7.62–7.55 (m, 1H, Ar–H), 7.55–7.45 (m, 2H, Ar–H), 7.36 (d, J = 8.7 Hz, 1H, Ar–H), 7.09 (d, J = 2.5 Hz, 1H, Ar–H), 6.94 (dd, J = 8.7, 2.5 Hz, 1H, Ar–H), 6.93 (s, 1H, – CH), 3.83 (s, 3H, Ar−OCH3), 2.20 (s, 3H, CH3), 2.17 (s, 3H, OCOCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 171.1 (OCOCH3), 166.0 (CONH), 163.1, 162.7 (COO), 154.3, 147.2, 146.2, 133.4, 132.5, 129.0, 128.8 (2C), 128.5, 127.7 (2C), 117.7, 116.9, 111.0, 110.9, 71.5 (CH), 55.7 (Ar–OCH3), 20.9 (OCOCH3), 17.1 (CH3). IR (UATR) νmax 3325 (NH), 2942, 1739 (CO), 1700 (CO), 1674 (CO), 1605 cm–1. HRMS (ESI) calcd. for C23H19NNaO6 [M + Na]+: 428.1105, found 428.1103.

4-Acetamido-1-methyl-3-oxo-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2e)

Following the general procedure, compound 1a (86.0 mg, 0.50 mmol, 1 equiv), N-acetylglycine 4b (88.0 mg, 0.75 mmol, 1.5 equiv), and NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv) in Ac2O (0.10 mL, 1.10 mmol, 2.2 equiv) were stirred at 80 °C for 2.5 h. The crude product was purified by column chromatography on silica gel using 10–30% EtOAc in CH2Cl2 to furnish compound 2e (44.6 mg, 28%) as a yellow solid. Mp 199.6–202.0 °C. 1H NMR (400 MHz, CDCl3) δ 7.65–7.56 (m, 2H, – NH and Ar–H), 7.53–7.44 (m, 3H, Ar–H), 6.96 (s, 1H, – CH), 2.31 (s, 3H, CH3), 2.29 (s, 3H, CH3), 2.16 (s, 3H, OCOCH3). 13C{1H} NMR (100 MHz, CDCl3) δ 171.0 (OCOCH3), 169.1 (CONH), 162.6 (COO), 155.1, 146.8, 144.8, 135.7, 132.1, 130.2, 127.4, 126.1, 117.3, 112.4, 71.5 (CH), 23.7 (CH3), 20.9 (OCOCH3), 17.2 (CH3). IR (UATR) νmax 3331 (NH), 2996, 1718 (CO), 1694 (CO), 1677 (CO), 1614, 1508 cm–1. HRMS (ESI) calcd. for C17H15NNaO5 [M + Na]+: 336.0842, found 336.0852.

4-Acetamido-6-chloro-1-methyl-3-oxo-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2f)

Following the general procedure, compound 1b (103 mg, 0.50 mmol, 1 equiv), N-acetylglycine 4b (88.0 mg, 0.75 mmol, 1.5 equiv), and NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv) in Ac2O (0.10 mL, 1.10 mmol, 2.2 equiv) were stirred at 80 °C for 3.5 h. The crude product was purified by column chromatography on silica gel using 10–50% EtOAc in CH2Cl2 to furnish compound 2f (34.9 mg, 20%) as a pale brown solid. Mp 238.6–239.6 °C. 1H NMR (400 MHz, CDCl3) δ 7.59 (br s, 1H, – NH), 7.48–7.42 (m, 2H, Ar–H), 7.33 (d, J = 8.4 Hz, 1H, Ar–H), 6.91 (s, 1H, – CH), 2.31 (s, 3H, CH3), 2.29 (s, 3H, CH3), 2.18 (s, 3H, OCOCH3). 13C{1H} NMR (100 MHz, CDCl3) δ 170.9 (OCOCH3), 168.9 (CONH), 162.3 (COO), 155.0, 146.2, 144.9, 138.3, 134.3, 130.6, 128.5, 126.5, 117.0, 112.6, 71.1 (CH), 23.9 (CH3), 20.8 (OCOCH3), 17.2 (CH3). IR (UATR) νmax 3333 (NH), 2923, 2853, 1721 (CO), 1694 (CO), 1616, 1600, 1513 cm–1. HRMS (ESI) calcd. for C17H14ClNNaO5 [M + Na]+: 370.0453, found 370.0457.

4-Acetamido-6-fluoro-1-methyl-3-oxo-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2g)

Following the general procedure, compound 1c (95.0 mg, 0.50 mmol, 1 equiv), N-acetylglycine 4b (88.0 mg, 0.75 mmol, 1.5 equiv), and NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv) in Ac2O (0.10 mL, 1.10 mmol, 2.2 equiv) were stirred at 80 °C for 3 h. The crude product was purified by column chromatography on silica gel using 10–50% EtOAc in CH2Cl2 to furnish compound 2g (46.5 mg, 28%) as a yellow-brown solid. Mp 246.4–247.4 °C. 1H NMR (400 MHz, CDCl3) δ 7.47 (br s, 1H, – NH), 7.41 (dd, JH–H = 8.4 Hz and JH–F = 5.2 Hz, 1H, Ar–H), 7.30 (dd, JH–F = 8.4 Hz and JH–H = 2.0 Hz, 1H, Ar–H), 7.18 (ddd, JH–H = 8.4 Hz, JH–F = 8.4 Hz and JH–H = 2.0 Hz, 1H, Ar–H), 6.91 (s, 1H, – CH), 2.31 (s, 3H, CH3), 2.29 (s, 3H, CH3), 2.18 (s, 3H, OCOCH3). 13C{1H} NMR (100 MHz, CDCl3) δ 170.9 (OCOCH3), 169.0 (CONH), 164.9 (d, 1JC–F = 253.2 Hz, CF), 162.4 (COO), 154.9, 147.3 (d, 3JC–F = 9.2 Hz), 145.3, 131.9 (d, 4JC–F = 1.7 Hz), 129.4 (d, 3JC–F = 9.4 Hz), 117.8 (d, 2JC–F = 23.0 Hz), 117.3, 113.6 (d, 2JC–F = 23.6 Hz), 112.0, 71.1 (CH), 23.8 (CH3), 20.8 (OCOCH3), 17.2 (CH3). 19F{1H} NMR (376 MHz, CDCl3) δ – 108.54. IR (UATR) νmax 3337 (NH), 1721 (CO), 1694 (CO), 1682 (CO), 1608, 1511 cm–1. HRMS (ESI) calcd. for C17H14FNNaO5 [M + Na]+: 354.0748, found 354.0744.

4-Acetamido-6-methoxy-1-methyl-3-oxo-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2h)

Following the general procedure, compound 1d (101 mg, 0.50 mmol, 1 equiv), N-acetylglycine 4b (88.0 mg, 0.75 mmol, 1.5 equiv), and NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv) in Ac2O (0.10 mL, 1.10 mmol, 2.2 equiv) were stirred at 80 °C for 6.5 h. The crude product was purified by column chromatography on silica gel using 10–50% EtOAc in CH2Cl2 to furnish compound 2h (60.6 mg, 35%) as a brown solid. Mp 216.4–217.5 °C. 1H NMR (400 MHz, CDCl3) δ 7.53 (br s, 1H, – NH), 7.39 (d, J = 8.8 Hz, 1H, Ar–H), 7.07 (d, J = 2.1 Hz, 1H, Ar–H), 7.00 (dd, J = 8.8, 2.1 Hz, 1H, Ar–H), 6.89 (s, 1H, – CH), 3.86 (s, 3H, Ar−OCH3), 2.29 (s, 3H, CH3), 2.26 (s, 3H, CH3), 2.16 (s, 3H, OCOCH3). 13C{1H} NMR (100 MHz, CDCl3) δ 171.0 (OCOCH3), 169.2 (CONH), 163.1, 162.7 (COO), 154.6, 147.2, 147.0, 128.8, 128.3, 117.5, 116.9, 110.8, 110.7, 71.4 (CH), 55.7 (Ar–OCH3), 23.7 (CH3), 20.9 (OCOCH3), 17.1 (CH3). IR (UATR) νmax 3258 (NH), 2942, 2845, 1715 (CO), 1681 (CO), 1602, 1487 cm–1. HRMS (ESI) calcd. for C18H17NNaO6 [M + Na]+: 366.0948, found 366.0948.

4-(Furan-3-carboxamido)-1-methyl-3-oxo-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2i)

Following the general procedure, compound 1a (86.5 mg, 0.50 mmol, 1 equiv), (furan-3-carbonyl)glycine 4c (127 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.10 mL, 1.10 mmol, 2.2 equiv) in CH3CN (0.24 mL, 2 M) in a sealed tube were stirred at 80 °C for 4 h. The crude product was purified by column chromatography on silica gel using 45–50% EtOAc in hexane to furnish compound 2i (92.8 mg, 51%) as a yellow solid. Mp 212.8–213.5 °C. 1H NMR (300 MHz, CDCl3) δ 8.23 (br s, 1H, – NH), 8.11 (br s, 1H, Ar–H), 7.62–7.55 (m, 1H, Ar–H), 7.53–7.38 (m, 4H, Ar–H), 6.98 (s, 1H, – CH), 6.82 (br d, J = 1.2 Hz, 1H, Ar–H), 2.30 (s, 3H, CH3), 2.16 (s, 3H, OCOCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 171.0 (OCOCH3), 162.9 (CONH), 161.2 (COO), 155.1, 147.3, 146.1, 144.8, 144.1, 135.7, 132.2, 130.3, 127.5, 126.1, 121.8, 117.5, 112.2, 108.7, 71.5 (CH), 20.9 (OCOCH3), 17.2 (CH3). IR (UATR) νmax 3320 (NH), 3151, 1735 (CO), 1701 (CO), 1681 (CO), 1615, 1515, 1490 cm–1. HRMS (ESI) calcd. for C20H15NNaO6 [M + Na]+: 388.0792, found 388.0793.

6-Chloro-4-(furan-3-carboxamido)-1-methyl-3-oxo-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2j)

Following the general procedure, compound 1b (103 mg, 0.50 mmol, 1 equiv), (furan-3-carbonyl)glycine 4c (127 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.10 mL, 1.10 mmol, 2.2 equiv) in CH3CN (0.24 mL, 2 M) in a sealed tube were stirred at 80 °C for 3 h. The crude product was purified by column chromatography on silica gel using 40–50% EtOAc in hexane to furnish compound 2j (74.7 mg, 37%) as a brown solid. Mp 241.7–243.0 °C. 1H NMR (300 MHz, CDCl3) δ 8.45 (br, 1H, – NH), 8.14 (dd, J = 1.5, 0.9 Hz, 1H, Ar–H), 7.56–7.37 (m, 4H, Ar–H), 6.91 (s, 1H, – CH), 6.83 (dd, J = 2.1, 0.9 Hz, 1H, Ar–H), 2.30 (s, 3H, CH3), 2.16 (s, 3H, OCOCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 170.9 (OCOCH3), 162.6 (CONH), 161.3 (COO), 155.4, 146.2, 146.1, 144.1, 142.9, 137.3, 136.3, 132.2, 127.5, 127.1, 121.5, 117.4, 112.9, 108.6, 71.0 (CH), 20.8 (OCOCH3), 17.1 (CH3). IR (UATR) νmax 3315 (NH), 3147, 1740 (CO), 1701 (CO), 1678 (CO), 1612, 1600, 1515, 1489 cm–1. HRMS (ESI) calcd. for C20H14ClNNaO6 [M + Na]+: 422.0402, found 422.0394.

6-Fluoro-4-(furan-3-carboxamido)-1-methyl-3-oxo-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2k)

Following the general procedure, compound 1c (95.0 mg, 0.50 mmol, 1 equiv), (furan-3-carbonyl)glycine 4c (127 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.10 mL, 1.10 mmol, 2.2 equiv) in CH3CN (0.24 mL, 2 M) in a sealed tube were stirred at 80 °C for 2 h. The crude product was purified by column chromatography on silica gel using 50% EtOAc in hexane to furnish compound 2k (53.9 mg, 28%) as a brown solid. Mp 245.8–247.5 °C. 1H NMR (300 MHz, DMSO-d6) δ 9.93 (br s, 1H, – NH), 8.44 (br s, 1H, Ar–H), 7.84 (dd, J = 1.6, 1.2 Hz, 1H, Ar–H), 7.71 (dd, JH–H = 8.1 Hz and JH–F = 5.0 Hz, 1H, Ar–H), 7.50–7.38 (m, 2H, Ar–H), 7.02 (d, J = 0.9 Hz, 1H, Ar–H), 6.99 (s, 1H, – CH), 2.30 (s, 3H, CH3), 2.16 (s, 3H, OCOCH3). 13C{1H} NMR (75 MHz, DMSO-d6) δ 170.5 (OCOCH3), 164.3 (d, 1JC–F = 250.1 Hz, CF), 161.1 (CONH), 160.8 (COO), 156.9, 148.0, 147.7 (d, 3JC–F = 9.4 Hz), 146.4, 144.4, 131.4 (d, 4JC–F = 2.0 Hz), 128.3 (d, 3JC–F = 9.7 Hz), 121.8, 118.0 (d, 2JC–F = 23.2 Hz), 116.1, 113.6 (d, 2JC–F = 23.5 Hz), 112.3, 109.2, 70.7 (d, 5JC–F = 1.4 Hz, CH), 20.6 (OCOCH3), 17.0 (CH3). 19F{1H} NMR (376 MHz, DMSO-d6) – 108.13. IR (UATR) νmax 3316 (NH), 3151, 1741 (CO), 1702 (CO), 1678 (CO), 1608 cm–1. HRMS (ESI) calcd. for C20H14FNNaO6 [M + Na]+: 406.0697, found 406.0700.

4-(Furan-3-carboxamido)-6-methoxy-1-methyl-3-oxo-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2l)

Following the general procedure, compound 1d (101 mg, 0.50 mmol, 1 equiv), (furan-3-carbonyl)glycine 4c (127 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.10 mL, 1.10 mmol, 2.2 equiv) in CH3CN (0.24 mL, 2 M) in a sealed tube were stirred at 80 °C for 3 h. The crude product was purified by column chromatography on silica gel using 50% EtOAc in hexane to furnish compound 2l (69.0 mg, 35%) as a yellow solid. Mp 217.7–218.5 °C. 1H NMR (300 MHz, CDCl3) δ 8.26 (br s, 1H, – NH), 8.09 (s, 1H, Ar–H), 7.46 (dd, J = 1.8, 1.4 Hz, 1H, Ar–H), 7.41 (d, J = 8.7 Hz, 1H, Ar–H), 7.07 (d, J = 2.4 Hz, 1H, Ar–H), 6.96 (dd, J = 8.7, 2.4 Hz, 1H, Ar–H), 6.91 (s, 1H, – CH), 6.81 (d, J = 1.4 Hz, 1H, Ar–H), 3.84 (s, 3H, Ar−OCH3), 2.27 (s, 3H, CH3), 2.17 (s, 3H, OCOCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 171.0 (OCOCH3), 163.2 (CONH), 163.1, 161.3 (COO), 154.7, 147.6, 147.3, 146.0, 144.0, 128.8, 128.3, 121.9, 117.8, 116.9, 110.9, 110.5, 108.7, 71.4 (CH), 55.7 (Ar–OCH3), 20.9 (OCOCH3), 17.1 (CH3). IR (UATR) νmax 3315 (NH), 3146, 2945, 1740 (CO), 1698 (CO), 1674 (CO), 1604, 1489 cm–1. HRMS (ESI) calcd. for C21H17NNaO7 [M + Na]+: 418.0897, found 418.0884.

1-Methyl-3-oxo-4-(thiophene-2-carboxamido)-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2m)

Following the general procedure, compound 1a (86.5 mg, 0.50 mmol, 1 equiv), (thiophene-2-carbonyl)glycine 4e (139 mg, 0.75 mmol, 1.5 equiv), and NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv) in Ac2O (0.24 mL, 2.50 mmol, 5 equiv) were stirred at 80 °C for 4 h. The crude product was purified by column chromatography on silica gel using 30–50% EtOAc in hexane to furnish compound 2m (59.3 mg, 31%) as a brown solid. Mp 230.0–230.9 °C. 1H NMR (300 MHz, DMSO-d6) δ 10.22 (br s, 1H, – NH), 8.09 (d, J = 3.3 Hz, 1H, Ar–H), 7.91 (dd, J = 4.8, 0.8 Hz, 1H, Ar–H), 7.74 (d, J = 7.2 Hz, 1H, Ar–H), 7.68–7.51 (m, 3H, Ar–H), 7.28 (dd, J = 4.8, 3.9 Hz, 1H, Ar–H), 7.02 (s, 1H, – CH), 2.32 (s, 3H, CH3), 2.15 (s, 3H, OCOCH3). 13C{1H} NMR (75 MHz, DMSO-d6) δ 170.5 (OCOCH3), 160.8 (CONH), 160.6 (COO), 157.0, 149.4, 144.9, 138.5, 134.9, 132.7, 132.3, 130.4, 129.8, 128.3, 126.4, 126.0, 116.0, 112.7, 71.1 (CH), 20.6 (OCOCH3), 17.0 (CH3). IR (UATR) νmax 3318 (NH), 3106, 1734 (CO), 1698 (CO), 1671 (CO), 1612, 1489 cm–1. HRMS (ESI) calcd. for C20H15NNaO5S [M + Na]+: 404.0563, found 404.0555.

6-Chloro-1-methyl-3-oxo-4-(thiophene-2-carboxamido)-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2n)

Following the general procedure, compound 1b (103 mg, 0.50 mmol, 1 equiv), (thiophene-2-carbonyl)glycine 4e (136 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.10 mL, 1.10 mmol, 2.2 equiv) in CH3CN (0.24 mL, 2 M) in a sealed tube were stirred at 80 °C for 3 h. The crude product was purified by precipitation with EtOAc and filtered off solid to furnish compound 2n (110 mg, 27%) as a brown solid. Mp 243.0–243.5 °C. 1H NMR (300 MHz, DMSO-d6) δ 10.26 (br s, 1H, – NH), 8.10 (d, J = 3.1 Hz, 1H, Ar–H), 7.92 (dd, J = 5.0, 0.9 Hz, 1H, Ar–H), 7.74–7.63 (m, 3H, Ar–H), 7.28 (dd, J = 4.9, 3.8 Hz, 1H, Ar–H), 7.00 (s, 1H, – CH), 2.32 (s, 3H, CH3), 2.16 (s, 3H, OCOCH3). 13C{1H} NMR (75 MHz, DMSO-d6) δ 170.6 (OCOCH3), 160.7 (CONH), 160.6 (COO), 157.3, 148.1, 146.8, 138.4, 137.2, 133.7, 132.5, 130.7, 130.0, 128.4, 127.5, 126.6, 115.8, 113.0, 70.8 (CH), 20.7 (OCOCH3), 17.1 (CH3). IR (UATR) νmax 3315 (NH), 3101, 1739 (CO), 1698 (CO), 1670 (CO), 1611, 1602, 1487 cm–1. HRMS (ESI) calcd. for C20H14ClNNaO5S [M + Na]+: 438.0173, found 438.0171.

6-Fluoro-1-methyl-3-oxo-4-(thiophene-2-carboxamido)-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2o)

Following the general procedure, compound 1c (95.0 mg, 0.50 mmol, 1 equiv), (thiophene-2-carbonyl)glycine 4e (139 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.10 mL, 1.10 mmol, 2.2 equiv) in CH3CN (0.24 mL, 2 M) in a sealed tube were stirred at 80 °C for 3 h. The crude product was purified by column chromatography on silica gel using 30–40% EtOAc in hexane to furnish compound 2o (55.5 mg, 28%) as a brown solid. Mp 244–246 °C. 1H NMR (300 MHz, DMSO-d6) δ 10.22 (br s, 1H, – NH), 8.09 (d, J = 3.0 Hz, 1H, Ar–H), 7.91 (dd, J = 4.8, 0.9 Hz, 1H, Ar–H), 7.75 (dd, JH–H = 8.1 Hz and JH–F = 5.1 Hz, 1H, Ar–H), 7.51–7.40 (m, 2H, Ar–H), 7.28 (dd, J = 5.1, 3.8 Hz, 1H, Ar–H), 6.99 (s, 1H, – CH), 2.31 (s, 3H, CH3), 2.16 (s, 3H, OCOCH3). 13C{1H} NMR (75 MHz, DMSO-d6) δ 170.5 (OCOCH3), 164.4 (d, 1JC–F = 250.1 Hz, CF), 160.7 (CONH), 160.68 (COO), 157.0, 148.3, 147.7 (d, 3JC–F = 9.4 Hz), 138.4, 132.4, 131.3 (d, 4JC–F = 2.2 Hz), 129.9, 128.3, 128.2 (d, 3JC–F = 11.7 Hz), 118.1 (d, 2JC–F = 23.3 Hz), 116.1, 113.7 (d, 2JC–F = 23.6 Hz), 112.3 (d, 4JC–F = 1.5 Hz), 70.7 (d, 5JC–F = 1.6 Hz, CH), 20.6 (OCOCH3), 17.0 (CH3). 19F{1H} NMR (376 MHz, DMSO-d6) – 107.99. IR (UATR) νmax 3315 (NH), 3108, 3078, 1740 (CO), 1696 (CO), 1670 (CO), 1653, 1608, 1488 cm–1. HRMS (ESI) calcd. for C20H14FNNaO5S [M + Na]+: 422.0469, found 422.0467.

6-Methoxy-1-methyl-3-oxo-4-(thiophene-2-carboxamido)-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2p)

Following the general procedure, compound 1d (101 mg, 0.50 mmol, 1 equiv), (thiophene-2-carbonyl)glycine 4e (139 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.10 mL, 1.10 mmol, 2.2 equiv) in CH3CN (0.24 mL, 2 M) in a sealed tube were stirred at 80 °C for 4 h. The crude product was purified by column chromatography on silica gel using 25–40% EtOAc in hexane to furnish compound 2p (36.5 mg, 18%) as a yellow-orange solid. Mp 233.0–233.5 °C. 1H NMR (300 MHz, DMSO-d6) δ 10.13 (br s, 1H, – NH), 8.08 (d, J = 3.3 Hz, 1H, Ar–H), 7.90 (dd, J = 5.1, 0.9 Hz, 1H, Ar–H), 7.65–7.58 (m, 1H, Ar–H), 7.27 (dd, J = 5.1, 3.8 Hz, 1H, Ar–H), 7.18–7.10 (m, 2H, Ar–H), 6.95 (s, 1H, – CH), 3.82 (s, 3H, Ar−OCH3), 2.28 (s, 3H, CH3), 2.16 (s, 3H, OCOCH3). 13C{1H} NMR (75 MHz, DMSO-d6) δ 170.6 (OCOCH3), 162.9 (CONH), 160.9, 160.6 (COO), 156.4, 149.4, 147.4, 138.7, 132.2, 129.7, 128.2, 127.4, 127.3, 117.0, 116.3, 111.1, 110.7, 70.9 (CH), 55.8 (Ar–OCH3), 20.6 (OCOCH3), 16.9 (CH3). IR (UATR) νmax 3309 (NH), 1736 (CO), 1697 (CO), 1671 (CO), 1648, 1606, 1488 cm–1. HRMS (ESI) calcd. for C21H17NNaO6S [M + Na]+: 434.0669, found 434.0670.

1-Methyl-4-(nicotinamido)-3-oxo-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2q)

Following the general procedure, compound 1a (86.0 mg, 0.50 mmol, 1 equiv), nicotinoylglycine 4f (135 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.10 mL, 1.10 mmol, 2.2 equiv) in CH3CN (2 mL, 0.25 M) in a sealed tube were stirred at 100 °C for 2 h. The crude product was purified by column chromatography on silica gel using 10–50% EtOAc in CH2Cl2 to furnish compound 2q (38.2 mg, 20%) as a pale-yellow solid. Mp 213.4–214.9 °C. 1H NMR (300 MHz, DMSO-d6) δ 10.43 (s, 1H, – NH), 9.21 (br s, 1H, Ar–H), 8.82 (dd, J = 4.8, 0.9 Hz, 1H, Ar–H), 8.39 (d, J = 7.8 Hz, 1H, Ar–H), 7.76 (d, J = 7.8 Hz, 1H, Ar–H), 7.67–7.49 (m, 4H, Ar–H), 7.02 (s, 1H, – CH), 2.32 (s, 3H, CH3), 2.16 (s, 3H, OCOCH3). 13C{1H} NMR (75 MHz, DMSO-d6) δ 170.5 (OCOCH3), 164.6 (CONH), 160.7 (COO), 157.0, 152.6, 149.3, 148.8, 144.9, 135.5, 134.8, 132.7, 130.5, 128.9, 126.4, 126.2, 123.7, 116.0, 112.8, 71.1 (CH), 20.6 (OCOCH3), 17.0 (CH3). IR (UATR) νmax 3322 (NH), 3069, 2926, 1735 (CO), 1697 (CO), 1676 (CO), 1611, 1505 cm–1. HRMS (ESI) calcd. for C21H16N2NaO5 [M + Na]+: 399.0951, found 399.0955.

6-Chloro-1-methyl-4-(nicotinamido)-3-oxo-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2r)

Following the general procedure, compound 1b (103 mg, 0.50 mmol, 1 equiv), nicotinoylglycine 4f (135 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.10 mL, 1.10 mmol, 2.2 equiv) in CH3CN (2 mL, 0.25 M) in a sealed tube were stirred at 100 °C for 3 h. The crude product was purified by column chromatography on silica gel using 10–50% EtOAc in CH2Cl2 to furnish compound 2r (30.9 mg, 15%) as a brown solid. Mp 228.0–228.5 °C. 1H NMR (300 MHz, CDCl3) δ 9.22 (d, J = 1.5 Hz, 1H, Ar–H), 8.81 (dd, J = 4.8, 1.5 Hz, 1H, Ar–H), 8.69 (s, 1H, – NH), 8.28 (dt, J = 8.1, 1.8 Hz, Ar–H), 7.55 (d, J = 8.1 Hz, 1H, Ar–H), 7.49–7.40 (m, 2H, Ar–H), 7.37 (d, J = 1.5 Hz, 1H, Ar–H), 6.92 (s, 1H, – CH), 2.32 (s, 3H, CH3), 2.17 (s, 3H, OCOCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 170.9 (OCOCH3), 164.5 (CONH), 162.2 (COO), 155.7, 153.2, 148.7, 145.9, 143.1, 137.2, 136.3, 135.5, 132.3, 128.8, 127.34, 127.28, 123.7, 117.3, 112.9, 71.0 (CH), 20.8 (OCOCH3), 17.2 (CH3). IR (UATR) νmax 3262 (NH), 3062, 2929, 1714 (CO), 1678 (CO), 1615, 1591, 1505, 1221, 1020 cm–1. HRMS (ESI) calcd. for C21H15ClN2NaO5 [M + Na]+: 433.0562, found 433.0559.

6-Fluoro-1-methyl-4-(nicotinamido)-3-oxo-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2s)

Following the general procedure, compound 1c (95.0 mg, 0.50 mmol, 1 equiv), nicotinoylglycine 4f (135 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.10 mL, 1.10 mmol, 2.2 equiv) in CH3CN (2 mL, 0.25 M) in a sealed tube were stirred at 100 °C for 4 h. The crude product was purified by column chromatography on silica gel using 20–70% EtOAc in CH2Cl2 to furnish compound 2s (58.1 mg, 29%) as a pale-yellow solid. Mp 234.8–236.3 °C. 1H NMR (300 MHz, DMSO-d6) δ 10.42 (s, 1H, – NH), 9.20 (br s, 1H, Ar–H), 8.82 (dd, J = 4.8, 1.5 Hz, 1H, Ar–H), 8.38 (d, J = 7.8 Hz, 1H, Ar–H), 7.78 (dd, JH–H = 8.4 Hz and JH–F = 5.1 Hz, 1H, Ar–H), 7.62 (dd, J = 7.8, 4.8 Hz, 1H, Ar–H), 7.50–7.34 (m, 2H, Ar–H), 7.00 (s, 1H, – CH), 2.32 (s, 3H, CH3), 2.16 (s, 3H, OCOCH3). 13C{1H} NMR (75 MHz, DMSO-d6) δ 170.5 (OCOCH3), 164.7 (CONH), 164.4 (d, 1JC–F = 250.4 Hz, CF), 160.6 (COO), 157.1, 152.7, 148.8, 148.2, 147.8 (d, 3JC–F = 9.3 Hz), 135.6, 131.3, 128.9, 128.5 (d, 3JC–F = 9.9 Hz), 123.7, 118.1 (d, 2JC–F = 23.3 Hz), 116.2, 113.7 (d, 2JC–F = 23.6 Hz), 112.5, 70.7 (CH), 20.6 (OCOCH3), 17.0 (CH3). 19F{1H} NMR (376 MHz, DMSO-d6) δ – 107.99. IR (UATR) νmax 3319 (NH), 3082, 2940, 1742 (CO), 1699 (CO), 1678 (CO), 1669, 1606, 1589, 1505, 1224 cm–1. HRMS (ESI) calcd. for C21H15FN2NaO5 [M + Na]+: 417.0857, found 417.0860.

6-Methoxy-1-methyl-4-(nicotinamido)-3-oxo-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2t)

Following the general procedure, compound 1d (101 mg, 0.50 mmol, 1 equiv), nicotinoylglycine 4f (135 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv) in CH3CN (2 mL, 0.25 M) in a sealed tube were stirred at 100 °C for 3.5 h. The crude product was purified by column chromatography on silica gel using 20–70% EtOAc in CH2Cl2 to furnish compound 2t (49.4 mg, 24%) as a yellow solid. Mp 222.0–223.5 °C. 1H NMR (400 MHz, DMSO-d6) δ 10.34 (br s, 1H, – NH), 9.21 (br s, 1H, Ar–H), 8.82 (d, J = 4.0 Hz, 1H, Ar–H), 8.38 (d, J = 8.0 Hz, 1H, Ar–H), 7.66 (d, J = 8.4 Hz, 1H, Ar–H), 7.62 (dd, J = 8.0, 5.0 Hz, 1H, Ar–H), 7.15 (s, 1H, Ar–H), 7.13 (overlapped, 1H, Ar–H), 6.96 (s, 1H, – CH), 3.82 (s, 3H, Ar−OCH3), 2.29 (s, 3H, CH3), 2.16 (s, 3H, OCOCH3). 13C{1H} NMR (100 MHz, DMSO-d6) δ 170.6 (OCOCH3), 164.6 (CONH), 163.0, 160.8 (COO), 156.5, 152.6, 149.3, 148.8, 147.5, 135.6, 129.0, 127.6, 127.2, 123.7, 117.1, 116.4, 111.1, 110.8, 70.9 (CH), 55.8 (Ar–OCH3), 20.7 (OCOCH3), 17.0 (CH3). IR (UATR) νmax 3316 (NH), 1739 (CO), 1694 (CO), 1667 (CO), 1603, 1258, 1221 cm–1. HRMS (ESI) calcd. for C22H18N2NaO6 [M + Na]+: 429.1057, found 429.1053.

4-Acetamido-3-oxo-1-phenyl-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2u)

Following the general procedure, compound 1e (117 mg, 0.50 mmol, 1 equiv), N-acetylglycine 4b (88.0 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.10 mL, 1.10 mmol, 2.2 equiv) in CH3CN (0.24 mL, 2 M) in a sealed tube were stirred at 100 °C for 3 h. The crude product was purified by column chromatography on silica gel using 10% EtOAc in CH2Cl2 to furnish compound 2u (36.4 mg, 19%) as a pale-brown solid. Mp 199.8–200.5 °C. 1H NMR (300 MHz, CDCl3) δ 7.93 (br s, 1H, – NH), 7.75–7.65 (m, 2H, Ar–H), 7.64–7.55 (m, 1H, Ar–H), 7.55–7.42 (m, 6H, Ar–H), 7.30 (s, 1H, – CH), 2.34 (s, 3H, COCH3), 1.79 (s, 3H, OCOCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 170.9 (NCOCH3), 169.2 (OCOCH3), 162.0 (COO), 153.4, 147.4, 145.0, 135.4, 132.1, 130.9, 130.6, 130.1, 128.7 (2C), 127.4 (2C), 127.3, 125.9, 117.5, 113.4, 72.0 (CH), 23.8 (COCH3), 20.4 (OCOCH3). IR (UATR) νmax 3264 (NH), 3060, 1699 (CO), 1599, 1496 cm–1. HRMS (ESI) calcd. for C22H17NNaO5 [M + Na]+: 398.0999, found 398.0990.

4-Acetamido-6-chloro-3-oxo-1-phenyl-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2v)

Following the general procedure, compound 1f (134 mg, 0.50 mmol, 1 equiv), N-acetylglycine 4b (88.0 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.10 mL, 1.10 mmol, 2.2 equiv) in CH3CN (0.24 mL, 2 M) in a sealed tube were stirred at 100 °C for 3 h. The crude product was purified by column chromatography on silica gel using 5–20% EtOAc in CH2Cl2 to furnish compound 2v (64.2 mg, 31%) as a pale-brown solid. Mp 227–229 °C. 1H NMR (300 MHz, CDCl3) δ 7.74 (br s, 1H, – NH), 7.72–7.65 (m, 2H, Ar–H), 7.59 (br s, 1H, Ar–H), 7.52–7.43 (m, 4H, Ar–H), 7.37 (d, J = 8.1 Hz, 1H, Ar–H), 7.26 (s, 1H, – CH), 2.35 (s, 3H, COCH3), 1.81 (s, 3H, OCOCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 170.9 (NCOCH3), 169.0 (OCOCH3), 161.8 160.6 (COO), 153.5, 146.5, 145.5, 138.3, 134.0, 130.8 (2C), 130.6, 128.8 (2C), 128.4, 127.4 (2C), 126.2, 117.2, 113.4, 71.6 (CH), 23.9 (COCH3), 20.4 (OCOCH3). IR (UATR) νmax 3315 (NH), 2932, 1737 (CO), 1708 (CO), 1687 (CO), 1594, 1516, 1228 cm–1. HRMS (ESI) calcd. for C22H16ClNNaO5 [M + Na]+: 432.0609, found 432.0598.

4-Acetamido-6-fluoro-3-oxo-1-phenyl-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2w)

Following the general procedure, compound 1g (126 mg, 0.50 mmol, 1 equiv), N-acetylglycine 4b (88.0 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.10 mL, 1.10 mmol, 2.2 equiv) in CH3CN (0.24 mL, 2 M) in a sealed tube were stirred at 100 °C for 4 h. The crude product was purified by column chromatography on silica gel using 10–20% EtOAc in CH2Cl2 to furnish compound 2w (48.5 mg, 25%) as a pale-brown solid. Mp 221.0–222.8 °C. 1H NMR (300 MHz, CDCl3) δ 7.89 (br s, 1H, – NH), 7.73–7.64 (m, 2H, Ar–H), 7.52–7.42 (m, 4H, Ar–H), 7.29 (dd, J = 8.3, 2.0 Hz, 1H, Ar–H), 7.25 (s, 1H, – CH), 7.19 (ddd, J = 8.7, 8.3, 2.0 Hz, 1H, Ar–H), 2.35 (s, 3H, COCH3), 1.81 (s, 3H, OCOCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 170.8 (NCOCH3), 169.2 (OCOCH3), 164.9 (d, 1JC–F = 252.8 Hz, CF), 161.9 (COO), 153.4, 147.5 (d, 3JC–F = 9.1 Hz), 146.0, 131.6, 130.8, 130.7, 129.3 (d, 3JC–F = 9.2 Hz), 128.8 (2C), 127.4 (2C), 117.8 (d, 2JC–F = 23.0 Hz), 117.4, 113.3 (d, 2JC–F = 23.5 Hz), 113.0, 71.7 (d, 5JC–F = 2.0 Hz, CH), 23.8 (COCH3), 20.3 (OCOCH3). 19F{1H} NMR (376 MHz, CDCl3) δ – 108.44. IR (UATR) νmax 3275 (NH), 2926, 1706 (CO), 1607, 1589, 1368, 1219 cm–1. HRMS (ESI) calcd. for C22H16FNNaO5 [M + Na]+: 416.0905, found 416.0905.

4-Acetamido-6-methoxy-3-oxo-1-phenyl-3,9-dihydroindeno[2,1-c]pyran-9-yl Acetate (2x)

Following the general procedure, compound 1h (52.8 mg, 0.20 mmol, 1 equiv), N-acetylglycine 4b (35.0 mg, 0.30 mmol, 1.5 equiv), NaOAc (18.0 mg, 0.22 mmol, 1.1 equiv), and Ac2O (40 μL, 0.44 mmol, 2.2 equiv) in CH3CN (0.24 mL, 2 M) in a sealed tube were stirred at 100 °C for 3 h. The crude product was purified by column chromatography on silica gel using 10% EtOAc in CH2Cl2 to furnish compound 2x (25.9 mg, 32%) as a pale-yellow solid. Mp 199–200 °C. 1H NMR (400 MHz, CDCl3) δ 7.99 (br s, 1H, – NH), 7.72–7.63 (m, 2H, Ar–H), 7.50–7.40 (m, 4H, Ar–H), 7.22 (s, 1H, – CH), 7.06 (br s, 1H, Ar–H), 7.00 (dd, J = 8.7, 2.0 Hz, 1H, Ar–H), 3.84 (s, 3H, Ar−OCH3), 2.33 (s, 3H, COCH3), 1.79 (s, 3H, OCOCH3). 13C{1H} NMR (100 MHz, CDCl3) δ 171.0 (NCOCH3), 169.4 (OCOCH3), 163.1, 162.2 (COO), 153.1, 147.8, 147.4, 130.9, 130.5, 128.63 (2C), 128.59, 127.9, 127.4 (2C), 117.7, 117.0, 111.5, 110.4, 71.9 (CH), 55.7 (Ar–OCH3), 23.7 (COCH3), 20.4 (OCOCH3). IR (UATR) νmax 3264 (NH), 2941, 1698 (CO), 1598, 1488, 1368, 1257, 1223 cm–1. HRMS (ESI) calcd. for C23H19NNaO6 [M + Na]+: 428.1105, found 428.1109.

General Procedure for the Synthesis of 1-Oxazolonylisobenzofurans Z/E-3

In a round-bottom flask with a magnetic bar, compounds 1 (1 equiv), amino acid derivatives 4g–j (1.5 equiv), NaOAc (1.1 equiv), and Ac2O (5 equiv) were stirred at 80 °C for 4 h. The reaction mixture was allowed to cool to room temperature (26 °C) and then quenched with sat. Na2CO3 (10 mL) and extracted with CH2Cl2 (3 × 10 mL). Combined organic layers were washed with sat. Na2CO3 until pH = 7, followed by water and brine, and dried over anh. Na2SO4 and concentrated to give a dark brown sticky gum. The crude product was purified by column chromatography on silica gel using 30–60% EtOAc in hexane or 0–50% EtOAc in CH2Cl2 to afford 1-oxazolonylisobenzofurans Z/E-3

(Z)-4-Benzyl-2-methyl-4-(3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)oxazol-5(4H)-one (Z-3ag) and (E)-4-Benzyl-2-methyl-4-(3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)oxazol-5(4H)-one (E-3ag)

Following the general procedure, using compound 1a (86.7 mg, 0.51 mmol, 1 equiv), dl-phenylalanine 4g (124 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.5 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by column chromatography on silica gel using 40% EtOAc in hexane to furnish compound Z/E-3ag (95.2 mg, 53% (>99:1 Z/E)).

Z-3ag

(95.2 mg, 53% (75:25 dr) mixture of isomer) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.65–7.45 (m, 4H, Ar–H, major), 7.38–7.11 (m, 5H, Ar–H, major), 5.95 (s, 1H, ArCHO, major), 5.94 (s, 1H, ArCHO, minor), 5.82 (s, 1H, =CHCOCH3, minor), 5.75 (s, 1H, =CHCOCH3, major), 3.46 (AB q, J = 13.8 Hz, 2H, CH2Ph, major), 3.42 (AB q, J = 13.5 Hz, 2H, CH2Ph, minor), 2.58 (s, 3H, =CHCOCH3, minor), 2.50 (s, 3H, =CHCOCH3, major), 1.96 (s, 3H, N=CCH3, major), 1.78 (s, 3H, N=CCH3, minor). 13C{1H} NMR (75 MHz, CDCl3) δ 197.12 (COCH3, major), 197.07 (COCH3, minor), 175.9 (COO, major), 164.72 (N=CCH3, major), 164.67 (N=CCH3, minor), 164.0 (=CO, major), 138.6 (major), 134.2 (major), 133.9 (minor), 132.9 (minor), 132.7 (major), 131.7 (minor), 131.6 (major), 130.3 (2C, major), 130.2 (2C, minor), 130.1 (major), 129.9 (minor), 128.4 (2C, major), 128.3 (2C, minor), 127.7 (major), 127.6 (minor), 122.4 (major), 122.3 (major), 122.1 (minor), 121.7 (minor), 99.3 (=CHCOCH3, minor), 98.9 (=CHCOCH3, major), 87.8 (ArCHO, minor), 87.1 (ArCHO, major), 76.72 (C, minor), 76.68 (C, major), 39.4 (CH2Ph, minor), 39.0 (CH2Ph, major), 31.1 (=CHCOCH3, minor), 31.0 (=CHCOCH3, major), 14.7 (N=CCH3, major), 14.3 (N=CCH3, minor). IR (UATR) νmax 3034, 2925, 1823 (CO), 1684 (C=N), 1633, 1493, 1467, 1431, 1383, 1365 cm–1. HRMS (ESI) calcd. for C22H19NNaO4 [M + Na]+: 384.1206, found 384.1210.

(Z)-4-Benzyl-4-(6-chloro-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyloxazol-5(4H)-one (Z-3bg) and (E)-4-Benzyl-4-(6-chloro-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyloxazol-5(4H)-one (E-3bg)

Following the general procedure, using compound 1b (105 mg, 0.51 mmol, 1 equiv), dl-phenylalanine 4g (124 mg, 0.75 mmol, 1.5 equiv), NaOAc (46.3 mg, 0.56 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by column chromatography on silica gel using 35% EtOAc in hexane to furnish compound Z/E-3bg (104 mg, 53% (>99:1 Z/E)).

Z-3bg

(104 mg, 53% (65:35 dr) mixture of isomer) as a pale-brown solid. 1H NMR (300 MHz, CDCl3) δ 7.55–7.10 (m, 8H, Ar–H, major), 5.91 (s, 1H, ArCHO, major), 5.87 (s, 1H, ArCHO, minor), 5.77 (s, 1H, =CHCOCH3, minor), 5.70 (s, 1H, =CHCOCH3, major), 3.43 (AB q, J = 13.4 Hz, 2H, CH2Ph, major), 3.34 (s, 2H, CH2Ph, minor), 2.56 (s, 3H, =CHCOCH3, minor), 2.48 (s, 3H, =CHCOCH3, major), 1.98 (s, 3H, N=CCH3, major), 1.85 (s, 3H, N=CCH3, minor). 13C{1H} NMR (75 MHz, CDCl3) δ 196.8 (COCH3, major), 176.0 (COO, minor), 175.6 (COO, major), 164.3 (N=CCH3, major), 136.5 (major), 163.4 (minor), 163.1 (minor), 140.3 (minor),140.2 (major), 137.9 (minor), 137.8 (major), 132.7 (minor), 132.6 (major), 132.50 (minor), 132.46 (major), 130.6 (major), 130.5 (minor), 130.3 (2C, major), 130.2 (2C, minor), 128.4 (2C, major), 128.3 (2C, minor), 127.8 (major), 127.7 (minor), 123.2 (major), 123.1 (minor), 122.9 (major), 122.4 (minor), 99.6 (=CHCOCH3, minor), 99.3 (=CHCOCH3, major), 87.1 (ArCHO, minor), 86.5 (ArCHO, major), 76.5 (C, major), 76.4 (C, minor), 39.0 (CH2Ph, minor), 38.9 (CH2Ph, major), 31.1 (=CHCOCH3, minor), 31.0 (=CHCOCH3, major), 14.7 (N=CCH3, major), 14.4 (N=CCH3, minor). IR (UATR) νmax 3276, 3031, 2959, 2927, 2853, 1825 (CO), 1805 (CO), 1679 (C=N), 1626, 1605 cm–1. HRMS (ESI) calcd. for C22H18ClNNaO4 [M + Na]+: 418.0817, found 418.0819.

(Z)-4-Benzyl-4-(6-fluoro-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyloxazol-5(4H)-one (Z-3cg) and (E)-4-Benzyl-4-(6-fluoro-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyloxazol-5(4H)-one (E-3cg)26

Following the general procedure, using compound 1c (95.2 mg, 0.50 mmol, 1 equiv), dl-phenylalanine 4g (124 mg, 0.75 mmol, 1.5 equiv), NaOAc (48.8 mg, 0.59 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by column chromatography on silica gel using 40% EtOAc in hexane to furnish compound Z/E-3cg (73.0 mg, 38% (>99:1 Z/E)).

Gram Scale Synthesis of (Z)-4-Benzyl-4-(6-fluoro-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyloxazol-5(4H)-one (Z-3cg) and (E)-4-Benzyl-4-(6-fluoro-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyloxazol-5(4H)-one (E-3cg)

According to the general procedure, using compound 1c (1.39 g, 7.31 mmol, 1 equiv), dl-phenylalanine 4g (1.81 g, 11.0 mmol, 1.5 equiv), NaOAc (0.66 g, 8.05 mmol, 1.1 equiv), and Ac2O (3.45 mL, 36.7 mmol, 5 equiv), the product Z/E-3cg was obtained (1.33 g, 48% (96:4 Z/E)).

Z-3cg

(73.0 mg, 38% (58:42 dr) mixture of isomer) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.58 (dd, JH–H = 8.7 Hz and JH–F = 4.8 Hz, 1H, Ar–H, major), 7.35–7.10 (m, 7H, Ar–H, major), 5.92 (s, 1H, ArCHO, minor), 5.88 (s, 1H, ArCHO, major), 5.75 (s, 1H, =CHCOCH3, major), 5.69 (s, 1H, =CHCOCH3, minor), 3.43 (AB q, J = 13.1 Hz, 2H, CH2Ph, minor), 3.35 (s, 2H, CH2Ph, major), 2.57 (s, 3H, =CHCOCH3, major), 2.49 (s, 3H, =CHCOCH3, minor), 1.98 (s, 3H, N=CCH3, minor), 1.84 (s, 3H, N=CCH3, major). 13C{1H} NMR (75 MHz, CDCl3) δ 196.9 (COCH3, major), 176.0 (COO, major), 175.6 (COO, minor), 164.8 (d, 1JC–F = 246.8 Hz, CF, major), 164.7 (d, 1JC–F = 244.6 Hz, CF, minor), 164.3 (=CO, minor), 163.7 (=CO, major), 163.0 (N=CCH3, major), 141.0 (d, 3JC–F = 9.5 Hz, major), 140.9 (d, 3JC–F = 10.7 Hz, minor), 132.6 (major), 132.5 (minor), 130.3 (2C, minor), 130.2 (2C, major), 129.9 (d, 4JC–F = 2.6 Hz, major), 128.4 (2C, minor), 128.3 (2C, major), 127.8 (minor), 127.7 (major), 124.1 (d, 3JC–F = 9.8 Hz, minor), 124.0 (d, 3JC–F = 9.6 Hz, major), 118.1 (d, 2JC–F = 23.7 Hz, minor), 117.9 (d, 2JC–F = 23.8 Hz, major), 110.0 (d, 2JC–F = 25.1 Hz, minor), 109.6 (d, 2JC–F = 25.0 Hz, major), 99.2 (d, 6JC–F = 1.5 Hz, =CHCOCH3, major), 98.8 (d, 6JC–F = 1.5 Hz, =CHCOCH3, minor), 87.1 (d, 4JC–F = 2.9 Hz, ArCHO major), 86.4 (d, 4JC–F = 2.9 Hz, ArCHO, minor), 76.5 (C, minor), 76.4 (C, major), 39.1 (CH2Ph, major), 39.0 (CH2Ph, minor), 31.1 (=CHCOCH3, major), 31.0 (=CHCOCH3, minor), 14.7 (N=CCH3, minor), 14.4 (N=CCH3, major). 19F{1H} NMR (376 MHz, CDCl3) δ – 109.17 (minor), – 109.46 (major). IR (UATR) νmax 3090, 3034, 2928, 1822 (CO), 1715 (CO), 1682 (C=N), 1635, 1619, 1599, 1526, 1482, 1456, 1432 cm–1. HRMS (ESI) calcd. for C22H18FNNaO4 [M + Na]+: 402.1112, found 402.1108.

(Z)-4-Benzyl-4-(6-methoxy-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyloxazol-5(4H)-one (Z-3dg) and (E)-4-Benzyl-4-(6-methoxy-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyloxazol-5(4H)-one (E-3dg)

Following the general procedure, using compound 1d (104 mg, 0.51 mmol, 1 equiv), dl-phenylalanine 4g (125 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.3 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by column chromatography on silica gel using 40% EtOAc in hexane to furnish compound Z/E-3dg (46.9 mg, 24% (>99:1 Z/E)).

Z-3dg

(46.9 mg, 24% (84:16 dr) mixture of isomer) as a brown sticky-gum. 1H NMR (300 MHz, CDCl3) δ 7.51 (d, J = 8.7 Hz, 1H, Ar–H, major), 7.31–7.12 (m, 5H, Ar–H, major), 7.03 (dd, J = 8.7, 2.1 Hz, 1H, Ar–H, major), 6.95 (d, J = 2.1 Hz, 1H, Ar–H, major), 6.83 (d, J = 2.1 Hz, Ar–H, minor), 5.88 (s, 1H, ArCHO, major), 5.85 (s, 1H, ArCHO, minor), 5.70 (s, 1H, =CHCOCH3, minor), 5.64 (s, 1H, =CHCOCH3, major), 3.87 (s, 3H, Ar−OCH3, major), 3.85 (s, 3H, Ar−OCH3, minor), 3.45 (AB q, J = 12.3 Hz, 2H, CH2Ph, major), 3.39 (AB q, J = 13.2 Hz, 2H, CH2Ph, minor), 2.55 (s, 3H, =CHCOCH3, minor), 2.48 (s, 3H, =CHCOCH3, major), 1.98 (s, 3H, N=CCH3, major), 1.82 (s, 3H, N=CCH3, minor). 13C{1H} NMR (75 MHz, CDCl3) δ 196.91 (COCH3, major), 196.88 (COCH3, minor), 176.3 (COO, minor), 175.8 (COO, major), 164.93 (=CO, major), 164.91 (=CO, minor), 164.1 (N=CCH3, major), 162.82 (N=CCH3, minor), 162.76 (minor), 162.66 (major), 140.9 (minor), 140.8 (major), 132.9 (minor), 132.7 (major), 130.3 (2C, major), 130.2 (2C, minor), 128.4 (2C, major), 128.3 (2C, minor), 127.7 (major), 127.6 (minor), 126.4 (major), 126.1 (minor), 123.6 (major), 123.4 (minor), 116.7 (minor), 116.5 (major), 107.5 (major), 106.4 (minor), 98.0 (=CHCOCH3, minor), 97.7 (=CHCOCH3, major), 87.3 (ArCHO, minor), 86.5 (ArCHO, major), 76.60 (C, minor), 76.56 (C, major), 55.81 (Ar–OCH3, minor), 55.76 (Ar–OCH3, major), 39.3 (CH2Ph, minor), 39.0 (CH2Ph, major), 30.9 (=CHCOCH3, minor), 30.8 (=CHCOCH3, major), 14.7 (N=CCH3, major), 14.4 (N=CCH3, minor). IR (UATR) νmax 3100, 3020, 2929, 2840, 1822 (CO), 1680 (C=N), 1633, 1605, 1489, 1456, 1436, 1364 cm–1. HRMS (ESI) calcd. for C23H21NNaO5 [M + Na]+: 414.1312, found 414.1314.

(Z)-4-Benzyl-2-methyl-4-(3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)oxazol-5(4H)-one (Z-3eg) and (E)-4-Benzyl-2-methyl-4-(3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)oxazol-5(4H)-one (E-3eg)

Following the general procedure, using compound 1e (117 mg, 0.50 mmol, 1 equiv), dl-phenylalanine 4g (124 mg, 0.75 mmol, 1.5 equiv), NaOAc (48.8 mg, 0.59 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by column chromatography on silica gel using 0–4% EtOAc in CH2Cl2 to furnish compound Z/E-3eg (139.6 mg, 66% (77:23 Z/E)).

Z-3eg

(107.9 mg, 51%) as a pale-yellow sticky-gum. 1H NMR (300 MHz, CDCl3) δ 8.06–7.99 (m, 2H, Ar–H), 7.79–7.71 (m, 1H, Ar–H), 7.57–7.39 (m, 6H, Ar–H), 7.30–7.15 (m, 5H, Ar–H), 6.54 (s, 1H, =CHCOPh), 5.90 (s, 1H, ArCHO), 3.40 (AB q, J = 13.4 Hz, 2H, CH2Ph), 1.97 (s, 3H, N=CCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 189.1 (COPh), 175.6 (COO), 165.8 (N=CCH3), 164.3 (=CO), 139.9, 139.3, 134.6, 133.1, 131.8, 131.6, 130.5 (2C), 129.9, 128.29 (2C), 128.26 (2C), 128.0 (2C), 127.4, 122.3, 122.0, 93.0 (=CHCOPh), 86.6 (ArCHO), 76.3 (C), 39.3 (CH2Ph), 14.7 (N=CCH3). IR (UATR) νmax 3059, 3032, 1822 (CO), 1716 (CO), 1660 (C=N), 1599, 1589, 1573, 1496, 1467 cm–1. HRMS (ESI) calcd. for C27H21NNaO4 [M + Na]+: 446.1363, found 446.1366.

E-3eg

(31.7 mg, 15%) as a pale-yellow sticky-gum. 1H NMR (300 MHz, CDCl3) δ 9.49–9.41 (m, 1H, Ar–H), 8.06–7.98 (m, 2H, Ar–H), 7.62–7.42 (m, 6H, Ar–H), 7.33–7.14 (m, 5H, Ar–H), 6.88 (s, 1H, =CHCOPh), 5.82 (s, 1H, ArCHO), 3.44 (s, 2H, CH2Ph), 1.95 (s, 3H, N=CCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 189.3 (COPh), 176.1 (COO), 170.2 (N=CCH3), 163.8 (=CO), 141.5, 139.9, 132.9, 132.3, 132.1, 132.0, 130.3 (2C), 129.9, 128.6, 128.4 (2C), 128.3 (2C), 127.9 (2C), 127.6, 121.7, 98.3 (=CHCOPh), 84.6 (ArCHO), 76.7 (C), 38.9 (CH2Ph), 14.7 (N=CCH3). IR (UATR) νmax 3062, 3032, 2926, 2855, 1822 (CO), 1730 (CO), 1681 (C=N), 1650, 1588, 1567, 1496, 1466, 1383 cm–1. HRMS (ESI) calcd. for C27H21NNaO4 [M + Na]+: 446.1363, found 446.1357.

(Z)-4-Benzyl-4-(6-chloro-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyloxazol-5(4H)-one (Z-3fg) and (E)-4-Benzyl-4-(6-chloro-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyloxazol-5(4H)-one (E-3fg)

Following the general procedure, using compound 1f (136 mg, 0.50 mmol, 1 equiv), dl-phenylalanine 4g (125 mg, 0.76 mmol, 1.5 equiv), NaOAc (46.7 mg, 0.57 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by column chromatography on silica gel using 0–2% EtOAc in CH2Cl2 to furnish compound Z/E-3fg (176.3 mg, 77% (75:25 Z/E)).

Z-3fg

(132.8 mg, 58%) as a pale-yellow solid. Mp 189.2–190.0 °C. 1H NMR (400 MHz, CDCl3) δ 8.04–7.98 (m, 2H, Ar–H), 7.67 (d, J = 8.4 Hz, 1H, Ar–H), 7.56–7.46 (m, 4H, Ar–H), 7.40 (br s, 1H, Ar–H), 7.31–7.23 (m, 3H, Ar–H), 7.23–7.16 (m, 2H, Ar–H), 6.49 (s, 1H, =CHCOPh), 5.85 (s, 1H, ArCHO), 3.42 (AB q, J = 13.2 Hz, 2H (CH2Ph), 2.00 (s, 3H, N=CCH3). 13C{1H} NMR (100 MHz, CDCl3) δ 189.0 (COPh), 175.4 (COO), 164.54 (=CO), 164.52 (N=CCH3), 140.9, 139.7, 137.8, 133.3, 132.9, 132.0, 130.5 (3C), 128.4 (2C), 128.3 (2C), 128.0 (2C), 127.6, 123.0, 122.8, 93.4 (=CHCOPh), 86.1 (ArCHO), 76.2 (C), 39.2 (CH2Ph), 14.7 (N=CCH3). IR (UATR) νmax 3062, 3034, 2927, 1801 (CO), 1728 (CO), 1682 (C=N), 1665, 1606, 1576, 1495, 1469, 1455, 1432, 1383 cm–1. HRMS (ESI) calcd. for C27H20ClNNaO4 [M + Na]+: 480.0973, found 480.0966.

E-3fg

(43.5 mg, 19% (78:22 dr) mixture of isomer) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 9.43 (d, J = 8.7 Hz, 1H, Ar–H, minor), 9.42 (d, J = 8.7 Hz, 1H, Ar–H, major), 8.06–7.97 (m, 2H, Ar–H, major), 7.58–7.43 (m, 4H, Ar–H, major), 7.37–7.33 (m, 1H, Ar–H, minor), 7.31–7.23 (m, 4H, Ar–H, major), 7.23–7.12 (m, 2H, Ar–H, major), 6.99 (s, 1H, =CHCOPh, minor), 6.88 (s, 1H, =CHCOPh, major), 5.77 (s, 1H, ArCHO, major), 5.75 (s, 1H, ArCHO, minor), 3.41 (s, 2H, CH2Ph, major), 3.35 (AB q, J = 13.2 Hz, 2H, CH2Ph, minor), 1.98 (s, 3H, N=CCH3, major), 1.82 (s, 3H, N=CCH3, minor). 13C{1H} NMR (75 MHz, CDCl3) δ189.4 (COPh, minor), 189.3 (COPh, major), 176.4 (COO, minor), 175.9 (COO, major), 169.2 (=CO, minor), 169.1 (=CO, major), 164.1 (N=CCH3, major), 163.1 (N=CCH3, minor), 143.5 (minor), 143.2 (major), 139.8 (minor), 139.7 (major), 138.5 (minor), 138.3 (major), 132.9 (minor), 132.7 (major), 132.2 (major), 130.9 (major), 130.7 (minor), 130.4 (2C, major), 130.3 (major), 130.2 (minor), 129.8 (major), 129.7 (minor), 128.5 (2C, major), 128.4 (2C, major), 128.3 (2C, minor), 128.0 (2C, major), 127.7 (major), 127.6 (minor), 122.1 (major), 121.4 (minor), 99.2 (=CHCOPh, minor), 98.6 (=CHCOPh, major), 84.8 (ArCHO, minor), 84.2 (ArCHO, major), 77.2 (C, minor), 76.5 (C, major), 39.2 (CH2Ph, minor), 38.9 (CH2Ph, major), 14.7 (N=CCH3, major), 14.5 (N=CCH3, minor). IR (UATR) νmax 3063, 3033, 2928, 1823 (CO), 1682 (C=N), 1650, 1602, 1584, 1568, 1495, 1456, 1428, 1383 cm–1 HRMS (ESI) calcd. for C27H21ClNO4 [M + H]+: 458.1154, found 458.1156.

(Z)-4-Benzyl-4-(6-fluoro-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyloxazol-5(4H)-one (Z-3gg) and (E)-4-Benzyl-4-(6-fluoro-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyloxazol-5(4H)-one (E-3gg)

Following the general procedure, using compound 1g (126 mg, 0.50 mmol, 1 equiv), dl-phenylalanine 4g (125 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.4 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by column chromatography on silica gel using 0–50% EtOAc in CH2Cl2 to furnish compound Z/E-3gg (63.9 mg, 29% (72:28 Z/E)).

Z-3gg

(46.3 mg, 21%) as a pale-yellow sticky-gum. 1H NMR (300 MHz, CDCl3) δ 8.04–7.98 (m, 2H, Ar–H), 7.72 (dd, JH–H = 8.7 Hz and JH–F = 4.8 Hz, 1H, Ar–H), 7.56–7.43 (m, 3H, Ar–H), 7.30–7.16 (m, 6H, Ar–H), 7.10 (dd, J = 7.8, 2.1 Hz, 1H, Ar–H), 6.48 (s, 1H, =CHCOPh), 5.86 (s, 1H, ArCHO), 3.42 (AB q, J = 13.5 Hz, 2H, CH2Ph), 2.00 (s, 3H, N=CCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 189.0 (COPh), 175.4 (COO), 164.7 (=CO), 164.6 (d, 1JC–F = 252.0 Hz, CF), 164.5 (N=CCH3), 141.6 (d, 3JC–F = 9.4 Hz), 139.8, 132.9, 131.9, 130.7 (d, 4JC–F = 2.3 Hz), 130.5 (2C), 128.3 (4C), 128.0 (2C), 127.6. 123.9 (d, 3JC–F = 9.8 Hz), 117.9 (d, 2JC–F = 23.9 Hz), 109.9 (d, 2JC–F = 24.9 Hz), 92.9 (d, 6JC–F = 1.4 Hz, =CHCOPh), 86.0 (d, 4JC–F = 2.8 Hz, ArCHO), 76.1 (C), 39.3 (CH2Ph), 14.8 (N=CCH3). 19F{1H} NMR (376 MHz, CDCl3) δ – 109.41. IR (UATR) νmax 3063, 3034, 2929, 1824 (CO), 1720 (CO), 1678 (C=N), 1661, 1592, 1573, 1480, 1456, 1447 cm–1. HRMS (ESI) calcd. for C27H21FNO4 [M + H]+: 442.1449, found 442.1437.

E-3gg

(17.6 mg, 8% (65:35 dr) mixture of isomer) as a pale-yellow sticky-gum. 1H NMR (300 MHz, CDCl3) δ 9.53 (dd, JH–H = 9.0 Hz and JH–F = 5.4 Hz, 1H, Ar–H, major), 8.06–7.97 (m, 2H, Ar–H, major), 7.58–7.43 (m, 3H, Ar–H, major), 7.31–7.12 (m, 7H, Ar–H, major), 7.05 (dd, J = 7.8, 2.4 Hz, 1H, Ar–H, minor), 6.97 (s, 1H, =CHCOPh, minor), 6.86 (s, 1H, =CHCOPh, major), 5.78 (s, 1H, ArCHO, major), 5.76 (s, 1H, ArCHO, minor), 3.41 (s, 2H, CH2Ph, major), 3.36 (AB q, J = 13.5 Hz, 2H, CH2Ph, minor), 1.97 (s, 3H, N=CCH3, major), 1.87 (s, 3H, N=CCH3, minor). 13C{1H} NMR (75 MHz, CDCl3) δ 189.3 (COPh, minor), 189.2 (COPh, major), 176.5 (COO, minor), 175.8 (COO, major), 169.4 (=CO, minor), 169.3 (=CO, major), 164.7 (d, 1JC–F = 253.6 Hz, CF, major), 164.1 (N=CCH3, major), 144.5 (d, 3JC–F = 9.4 Hz, minor), 144.2 (d, 3JC–F = 9.3 Hz, major), 139.9 (minor), 139.8 (major), 132.9 (minor), 132.7 (major), 132.1 (d, 4JC–F = 2.6 Hz, major), 131.03 (d, 3JC–F = 9.5 Hz, major), 130.96 (d, 3JC–F = 9.3 Hz, minor), 130.34 (2C, major), 130.28 (2C, minor), 128.6 (d, 4JC–F = 2.5 Hz, major), 128.44 (2C, major), 128.37 (2C, major), 128.30 (2C, minor), 128.0 (2C, minor), 127.9 (2C, major), 127.7 (major), 127.6 (minor), 117.4 (d, 2JC–F = 22.2 Hz, major), 117.3 (d, 2JC–F = 22.3 Hz, minor), 109.2 (d, 2JC–F = 25.0 Hz, major), 108.6 (d, 2JC–F = 24.7 Hz, minor), 98.4 (=CHCOPh, minor), 97.9 (=CHCOPh, major), 84.9 (d, 4JC–F = 3.0 Hz, ArCHO, minor), 84.2 (d, 4JC–F = 2.8 Hz, ArCHO, major), 77.2 (C, minor), 76.5 (C, major), 39.2 (CH2Ph, minor), 38.9 (CH2Ph, major), 14.7 (N=CCH3, major), 14.4 (N=CCH3, minor). 19F{1H} NMR (376 MHz, CDCl3) δ – 107.94 (minor), – 108.27 (major). IR (UATR) νmax 3063, 3034, 2929, 1824 (CO), 1720 (CO), 1678 (C=N), 1661, 1592, 1573, 1480 cm–1. HRMS (ESI) calcd. for C27H21FNO4 [M + H]+: 442.1449, found 422.1437.

(Z)-4-Benzyl-4-(6-methoxy-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyloxazol-5(4H)-one (Z-3hg) and (E)-4-Benzyl-4-(6-methoxy-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyloxazol-5(4H)-one (E-3hg)

Following the general procedure, using compound 1h (133 mg, 0.50 mmol, 1 equiv), dl-phenylalanine 4g (125 mg, 0.75 mmol, 1.5 equiv), NaOAc (47.4 mg, 0.57 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by column chromatography on silica gel using 2–20% EtOAc in CH2Cl2 to furnish compound Z/E-3hg (97.5 mg, 43% (75:25 Z/E)).

Z-3hg

(72.6 mg, 32%) as a pale brown solid. Mp 183.5–184.5 °C. 1H NMR (300 MHz, CDCl3) δ 8.01 (dd, J = 8.0, 1.7, 2H, Ar–H), 7.65 (d, J = 8.7 Hz, 1H, Ar–H), 7.55–7.42 (m, 3H, Ar–H), 7.31–7.17 (m, 5H, Ar–H), 7.03 (dd, J = 8.6, 2.3 Hz, 1H, Ar–H), 6.88 (d. J = 2.1 Hz, 1H, Ar–H), 6.42 (s, 1H, =CHCOPh), 5.82 (s, 1H, ArCHO), 3.85 (s, 3H, Ar−OCH3), 3.45 (AB q, J = 13.5 Hz, 2H, CH2Ph), 2.00 (s, 3H, N=CCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 189.0 (COPh), 175.5 (COO), 166.1, 164.2 (=CO), 162.7 (N=CCH3), 141.6, 140.2, 133.1, 131.6, 130.5 (2C), 128.3 (2C), 128.2 (2C), 127.9 (2C), 127.5, 127.0, 123.4, 116.6, 107.2, 91.7 (=CHCOPh), 86.1 (ArCHO), 76.2 (C), 55.8 (Ar–OCH3), 39.4 (CH2Ph), 14.8 (N=CCH3). IR (UATR) νmax 3062, 3031, 2927, 2841, 1823 (CO), 1768 (CO), 1680 (C=N), 1656, 1599, 1586, 1571, 1488, 1455, 1382 cm–1. HRMS (ESI) calcd. for C28H23NNaO5 [M + Na]+: 476.1468, found 476.1468.

E-3hg

(24.9 mg, 11% (50:50 dr) mixture of isomer) as a brown sticky-gum. 1H NMR (300 MHz, CDCl3) δ 9.47 (d, J = 9.0 Hz, 1H), 9.46 (d, J = 8.7 Hz, 1H, Ar–H), 8.02 (d, J = 8.4 Hz, 2H, Ar–H), 8.00 (d, J = 8.4 Hz, 2H, Ar–H), 7.56–7.41 (m, 6H, Ar–H), 7.31–7.12 (m, 10H, Ar–H), 7.06 (dd, J = 8.4, 2.3 Hz, 1H, Ar–H), 7.04 (dd, J = 8.4, 2.3 Hz, 1H, Ar–H), 6.96 (d, J = 1.8 Hz, 1H, Ar–H), 6.88 (s, 1H, =CHCOPh), 6.79 (d, J = 2.1 Hz, 1H, Ar–H), 6.77 (s, 1H, =CHCOPh), 5.74 (s, 2H, ArCHO), 3.88 (s, 3H, Ar−OCH3), 3.86 (s, 3H, Ar−OCH3), 3.43 (AB q, J = 13.8 Hz, 2H, CH2Ph), 3.40 (AB q, J = 13.2 Hz, 2H, CH2Ph), 1.97 (s, 3H, N=CCH3), 1.78 (s, 3H, N=CCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 189.3 (COPh), 189.2 (COPh), 176.7 (COO), 176.0 (COO), 170.6 (=CO), 170.5 (=CO), 163.9 (N=CCH3), 163.0 (N=CCH3), 162.8, 162.7, 144.5, 144.2, 140.3, 140.2, 133.0, 132.9, 131.8, 131.7, 134.0, 130.34 (3C), 130.29 (2C), 128.3 (6C), 128.2 (2C), 127.9 (2C), 127.7 (2C), 127.6, 127.5, 125.0, 124.7, 115.6, 115.3, 107.3, 105.9, 97.1 (=CHCOPh), 96.5 (=CHCOPh), 85.0 (ArCHO), 84.2 (ArCHO), 76.9 (C), 76.5 (C), 55.74 (Ar–OCH3), 55.70 (Ar–OCH3), 39.4 (CH2Ph), 38.9 (CH2Ph), 14.7 (N=CCH3), 14.4 (N=CCH3). IR (UATR) νmax 3061, 3033, 2932, 2839, 1821 (CO), 1725 (CO), 1680 (C=N), 1649, 1598, 1582, 1557, 1484, 1437 cm–1. HRMS (ESI) calcd. for C28H24NO5 [M + H]+: 454.1649, found 454.1646.

(Z)-4-((2-Methyl-5-oxo-4-(3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-4,5-dihydrooxazol-4-yl)methyl)phenyl Acetate (Z-3ah) and (E)-4-((2-Methyl-5-oxo-4-(3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-4,5-dihydrooxazol-4-yl)methyl)phenyl Acetate (E-3ah)

Following the general procedure, using compound 1a (86.7 mg, 0.50 mmol), l-tyrosine 4h (137 mg, 0.76 mmol), NaOAc (46.8 mg, 0.59 mmol), and Ac2O (0.24 mL, 2.50 mmol), the crude product was purified by column chromatography on silica gel using 50% EtOAc in hexane to furnish compound Z/E-3ah (101 mg, 48% (>99:1 Z/E)).

Z-3ah

(101 mg, 48% (79:21 dr) mixture of isomer) as a brown sticky-gum. 1H NMR (300 MHz, CDCl3) δ 7.65–7.44 (m, 4H, Ar–H, major), 7.38–7.33 (m, 1H, Ar–H, minor), 7.21 (d, J = 8.4 Hz, 2H, Ar–H, major), 7.16 (d, J = 8.4 Hz, 2H, Ar–H, minor), 7.02 (d, J = 8.7 Hz, 2H, Ar–H, major), 7.00 (d, J = 8.1 Hz, 2H, Ar–H, minor), 5.933 (s, 1H, ArCHO, major), 5.925 (s, 1H, ArCHO, minor), 5.81 (s, 1H, =CHCOCH3, minor), 5.75 (s, 1H, =CHCOCH3, major), 3.45 (s, 2H, CH2Ph, major), 3.40 (AB q, J = 13.2 Hz, 2H, CH2Ph, minor), 2.57 (s, 3H, =CHCOCH3, minor), 2.50 (s, 3H, =CHCOCH3, major), 2.28 (s, 3H, OCOCH3, major), 2.27 (s, 3H, OCOCH3, minor), 1.98 (s, 3H, N=CCH3, major), 1.80 (s, 3H, N=CCH3, minor). 13C {1H} NMR (75 MHz, CDCl3) δ 197.0 (COCH3, major), 196.9 (COCH3, minor), 176.2 (OCOCH3, minor), 175.9 (OCOCH3, major), 169.2 (COO, major), 164.57 (COO, minor), 164.6 (=CO, major), 164.2 (N=CCH3, major), 162.9 (N=CCH3, minor), 150.20 (major), 150.16 (minor), 138.5 (major), 134.1 (major), 133.8 (minor), 131.7 (minor), 131.6 (major), 131.3 (2C, major), 131.2 (2C, minor), 130.5 (minor), 130.3 (major), 130.1 (major), 129.9 (minor), 122.4 (major), 122.3 (major), 122.1 (minor), 121.7 (minor), 121.5 (2C, major), 121.4 (2C, minor), 99.3 (=CHCOCH3, minor), 98.9 (=CHCOCH3, major), 87.7 (ArCHO, minor), 86.9 (ArCHO, major), 76.5 (C, major), 38.7 (CH2Ph, minor), 38.4 (CH2Ph, major), 31.1 (=CHCOCH3, minor), 31.0 (=CHCOCH3, major), 21.0 (OCOCH3, major), 14.7 (N=CCH3, major), 14.3 (N=CCH3, minor). IR (UATR) νmax 3055, 2927, 1820 (CO), 1757 (CO), 1681 (C=N), 1633, 1605, 1507 cm–1. HRMS (ESI) calcd. for C24H22NO6 (M + H)+: 420.1442, found 420.1445.

(Z)-4-((4-(6-Chloro-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyl-5-oxo-4,5-dihydrooxazol-4-yl)methyl)phenyl Acetate (Z-3bh) and (E)-4-((4-(6-Chloro-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyl-5-oxo-4,5-dihydrooxazol-4-yl)methyl)phenyl Acetate (E-3bh)

Following the general procedure, using compound 1b (104 mg, 0.50 mmol, 1 equiv), l-tyrosine 4h (135 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.8 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by column chromatography on silica gel using 50% EtOAc in hexane to furnish compound Z/E-3bh (131 mg, 58% (>99:1 Z/E)).

Z-3bh

(131 mg, 58% (94:6 dr) mixture of isomer) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 7.55–7.37 (m, 3H, Ar–H, major), 7.21 (d, J = 8.4 Hz, 2H, Ar–H, major), 7.03 (d, J = 8.7 Hz, 2H, Ar–H, major), 5.89 (s, 1H, ArCHO, major), 5.86 (s, 1H, ArCHO, minor), 5.77 (s, 1H, =CHCOCH3, minor), 5.70 (s, 1H, =CHCOCH3, major), 3.42 (AB q, J = 13.5 Hz, 2H, CH2Ph, major), 3.33 (s, 2H, CH2Ph, minor), 2.55 (s, 3H, =CHCOCH3, minor), 2.48 (s, 3H, =CHCOCH3, major), 2.28 (s, 3H, OCOCH3, major), 2.17 (s, 3H, OCOCH3, minor), 2.00 (s, 3H, N=CCH3, major), 1.87 (s, 3H, N=CCH3, minor). 13C{1H} NMR (75 MHz, CDCl3) δ 196.7 (COCH3, major), 175.5 (OCOCH3, major), 169.1 (COO, major), 164.5 (=CO, major), 163.4 (N=CCH3, major), 150.3 (major), 140.1 (major), 137.8 (major), 132.7 (major), 131.3 (2C, major), 131.2 (2C, minor), 130.6 (major), 130.5 (minor), 130.0 (major), 123.2 (major), 123.1 (minor), 122.8 (major), 122.4 (minor), 121.6 (2C, major), 121.5 (2C, minor), 99.6 (=CHCOCH3, minor), 99.2 (=CHCOCH3, major), 87.0 (ArCHO, minor), 86.3 (ArCHO, major), 76.4 (C, major), 38.3 (CH2Ph, major), 31.1 (=CHCOCH3, minor), 31.0 (=CHCOCH3, major), 21.0 (OCOCH3, major), 14.7 (N=CCH3, major), 14.4 (N=CCH3, minor). IR (UATR) νmax 3072, 3049, 2932, 1823 (CO), 1759 (CO), 1684 (C=N), 1622, 1507, 1469, 1427, 1364 cm–1. HRMS (ESI) calcd. for C24H21ClNO6 [M + H]+: 454.1052, found 454.1048.

(Z)-4-((4-(6-Fluoro-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyl-5-oxo-4,5-dihydrooxazol-4-yl)methyl)phenyl Acetate (Z-3ch) and (E)-4-((4-(6-Fluoro-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyl-5-oxo-4,5-dihydrooxazol-4-yl)methyl)phenyl Acetate (E-3ch)

Following the general procedure, using compound 1c (95.7 mg, 0.50 mmol, 1 equiv), l-tyrosine 4h (137 mg, 0.75 mmol, 1.5 equiv), NaOAc (46.9 mg, 0.57 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by column chromatography on silica gel using 50% EtOAc in hexane to furnish compound Z/E-3ch (74.1 mg, 34% (>99:1 Z/E)).

Z-3ch

(74.1 mg, 34% (88:12 dr) mixture of isomer) as a brown sticky-gum. 1H NMR (300 MHz, CDCl3) δ 7.58 (dd, JH–H = 8.7 Hz and JH–F = 4.7 Hz, 1H, Ar–H, major), 7.30–7.06 (m, 4H, Ar–H, major), 7.02 (d, J = 8.4 Hz, 2H, Ar–H, major), 5.90 (s, 1H, ArCHO, major), 5.87 (s, 1H, ArCHO, minor), 5.75 (s, 1H, =CHCOCH3, minor), 5.69 (s, 1H, =CHCOCH3, major), 3.42 (AB q, J = 13.5 Hz, 2H, CH2Ph, major), 3.33 (s, 2H, CH2Ph, minor), 2.55 (s, 3H, =CHCOCH3, minor), 2.48 (s, 3H, =CHCOCH3, major), 2.28 (s, 3H, OCOCH3, major), 2.00 (s, 3H, N=CCH3, major), 1.86 (s, 3H, N=CCH3, minor). 13C{1H} NMR (75 MHz, CDCl3) δ 196.7 (COCH3, major), 175.9 (OCOCH3, minor), 175.5 (OCOCH3, major), 169.1 (COO, major), 164.7 (d, 1JC–F = 252.9 Hz, CF, minor), 164.6 (d, 1JC–F = 252.0 Hz, CF, major), 164.4 (=CO, major), 163.6 (N=CCH3, major), 163.3 (N=CCH3, minor), 150.21 (major), 150.16 (minor), 140.7 (d, 3JC–F = 9.2 Hz, major), 131.3 (2C, major), 131.2 (2C, minor), 130.1 (minor), 130.02 (2C, minor), 130.0 (2C, major), 124.1 (d, 3JC–F = 9.8 Hz, major), 123.9 (d, 3JC–F = 10.7 Hz, minor), 121.5 (2C, major), 121.4 (2C, minor), 118.0 (d, 2JC–F = 23.7 Hz, major), 117.9 (d, 2JC–F = 23.8 Hz, minor), 109.9 (d, 2JC–F = 25.1 Hz, major), 109.5 (d, 2JC–F = 24.9 Hz, minor), 99.0 (d, 6JC–F = 1.1 Hz, =CHCOCH3, minor), 98.7 (d, 6JC–F = 1.4 Hz, =CHCOCH3, major), 86.9 (d, 4JC–F = 2.9 Hz, ArCHO, minor), 86.2 (d, 4JC–F = 2.9 Hz, ArCHO, major), 76.3 (C, major), 76.2 (C, minor), 38.3 (CH2Ph, major), 31.0 (CH2Ph, minor), 30.9 (=CHCOCH3, major), 21.0 (OCOCH3, major), 14.6 (N=CCH3, major), 14.4 (N=CCH3, minor). 19F{1H} NMR (376 MHz, CDCl3) δ – 109.03 (minor), – 109.33 (major). IR (UATR) νmax 3059, 2931, 1822 (CO), 1758 (CO), 1680 (C=N), 1637, 1616, 1597, 1506, 1481, 1432, 1366 cm–1. HRMS (ESI) calcd. for C24H21FNO6 [M + H]+: 438.1347, found 438.1342.

(Z)-4-((4-(6-Methoxy-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyl-5-oxo-4,5-dihydrooxazol-4-yl)methyl)phenyl Acetate (Z-3dh) and (E)-4-((4-(6-Methoxy-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyl-5-oxo-4,5-dihydrooxazol-4-yl)methyl)phenyl Acetate (E-3dh)

Following the general procedure, using compound 1d (101 mg, 0.50 mmol, 1 equiv), l-tyrosine 4h (134 mg, 0.74 mmol, 1.5 equiv), NaOAc (49.9 mg, 0.61 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by column chromatography on silica gel using 50% EtOAc in hexane to furnish compound Z/E-3dh (60.5 mg, 27% (>99:1 Z/E)).

Z-3dh

(60.5 mg, 27%) as a brown sticky-gum. 1H NMR (300 MHz, CDCl3) δ 7.51 (d, J = 8.4 Hz, 1H, Ar–H), 7.21 (d, J = 8.7 Hz, 2H, Ar–H), 7.06–6.97 (m, 3H, Ar–H), 6.93 (d, J = 2.1 Hz, 1H, Ar–H), 5.85 (s, 1H, ArCHO), 5.64 (s, 1H, =CHCOCH3), 3.87 (s, 3H, Ar−OCH3), 3.45 (s, 2H, CH2Ph), 2.47 (s, 3H, =CHCOCH3), 2.28 (s, 3H, OCOCH3), 2.00 (s, 3H, N=CCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 196.9 (COCH3), 175.7 (OCOCH3), 169.2 (COO), 164.9 (=CO), 164.2 (N=CCH3), 162.7, 150.2, 140.7, 131.3 (2C), 130.3, 126.4, 123.6, 121.5 (2C), 116.5, 107.5, 97.6 (=CHCOCH3), 86.4 (ArCHO), 76.4 (C), 55.8 (Ar–OCH3), 38.4 (CH2Ph), 30.8 (=CHCOCH3), 21.0 (OCOCH3), 14.7 (N=CCH3). IR (UATR) νmax 3058, 2939, 2837, 1821 (CO), 1757 (CO), 1679 (C=N), 1632, 1605, 1506, 1488, 1434, 1365 cm–1. HRMS (ESI) calcd. for C25H24NO7 [M + H]+: 450.1547, found 450.1548.

(Z)-4-((2-Methyl-5-oxo-4-(3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-4,5-dihydrooxazol-4-yl)methyl)phenyl Acetate (Z-3eh) and (E)-4-((2-Methyl-5-oxo-4-(3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-4,5-dihydrooxazol-4-yl)methyl)phenyl Acetate (E-3eh)

Following the general procedure, using compound 1e (119 mg, 0.51 mmol, 1 equiv), l-tyrosine 4h (136 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.4 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by column chromatography on silica gel using 0–10% EtOAc in CH2Cl2 to furnish compound Z/E-3eh (127 mg, 53% (81:19 Z/E)).

Z-3eh

(103 mg, 43%) as a yellow sticky-gum. 1H NMR (300 MHz, CDCl3) δ 8.07–7.99 (m, 2H, Ar–H), 7.79–7.71 (m, 1H, Ar–H), 7.60–7.36 (m, 6H, Ar–H), 7.22 (d, J = 8.7 Hz, 2H, Ar–H), 6.99 (d, J = 8.7 Hz, 2H, Ar–H), 6.53 (s, 1H, =CHCOPh), 5.86 (s, 1H, ArCHO), 3.44 (s, 2H, CH2Ph), 2.27 (s, 3H, OCOCH3), 2.00 (s, 3H, N=CCH3). 13C {1H} NMR (75 MHz, CDCl3) δ 189.2 (COPh), 175.6 (OCOCH3), 169.2 (COO), 165.7 (=CO), 164.3 (N=CCH3), 150.1, 140.0, 139.2, 134.6, 131.8, 131.6 (2C), 131.4, 130.1, 130.0, 128.3 (2C), 128.0 (2C), 122.3, 122.1, 121.4 (2C), 93.1 (=CHCOPh), 86.4 (ArCHO), 76.1 (C), 38.8 (CH2Ph), 21.1 (OCOCH3), 14.8 (N=CCH3). IR (UATR) νmax 3058, 2930, 1821 (CO), 1757 (CO), 1682 (C=N), 1662, 1600, 1589, 1573, 1508, 1467, 1433, 1370 cm–1. HRMS (ESI) calcd. for C29H23NNaO6 [M + Na]+: 504.1418, found 504.1414.

E-3eh

(24.0 mg, 10% (83:17 dr) mixture of isomer) as a brown sticky-gum. 1H NMR (400 MHz, CDCl3) δ 9.48–9.41 (m, 1H, Ar–H, major), 8.06–7.97 (m, 2H, Ar–H, major), 7.60–7.42 (m, 6H, Ar–H, major), 7.20 (d, J = 8.4 Hz, 2H, Ar–H, major), 7.17 (d, J = 8.4 Hz, 2H, Ar–H, major), 7.03–6.96 (m, 2H, Ar–H, major), 6.88 (s, 1H, =CHCOPh, major), 5.79 (s, 1H, ArCHO, minor), 5.78 (s, 1H, ArCHO, major), 3.42 (s, 2H, CH2Ph, major), 3.41 (AB q, J = 13.4 Hz, 2H, CH2Ph, minor), 2.25 (s, 3H, OCOCH3, major), 1.96 (s, 3H, N=CCH3, major), 1.74 (s, 3H, N=CCH3, minor). 13C {1H} NMR (100 MHz, CDCl3) δ 189.2 (COPh, minor), 189.1 (COPh, major), 176.5 (OCOCH3, minor), 176.0 (OCOCH3, major), 170.2 (COO, minor), 170.1 (COO, major), 169.1 (=CO, major), 163.9 (N=CCH3, major), 162.8 (N=CCH3, minor), 150.06 (major), 150.03 (minor), 141.4 (minor), 141.3 (major), 139.9 (minor), 139.8 (major), 132.19 (major), 132.15 (minor), 132.0 (major), 131.9 (major), 131.8 (minor), 131.3 (2C, major), 131.2 (2C, minor), 130.7 (minor), 130.5 (major), 129.8 (major), 129.6 (minor), 128.4 (major), 128.3 (2C, major), 127.8 (2C, major), 121.6 (major), 121.4 (2C, major), 121.3 (2C, minor), 120.7 (minor), 98.8 (=CHCOPh, minor), 98.2 (=CHCOPh, major), 85.2 (ArCHO, minor), 84.4 (ArCHO, major), 76.7 (C, minor), 76.4 (C, major), 38.7 (CH2Ph, minor), 38.2 (CH2Ph, major), 21.0 (OCOCH3, major), 14.6 (N=CCH3, major), 14.2 (N=CCH3, minor). IR (UATR) νmax 3060, 2930, 1820 (CO), 1759 (CO), 1682 (C=N), 1652, 1589, 1567, 1508, 1466, 1447, 1432, 1383, 1370 cm–1. HRMS (ESI) calcd. for C29H23NNaO6 [M + Na]+: 504.1418, found 504.1412.

(Z)-4-((4-(6-Chloro-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyl-5-oxo-4,5-dihydrooxazol-4-yl)methyl)phenyl Acetate (Z-3fh) and (E)-4-((4-(6-Chloro-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyl-5-oxo-4,5-dihydrooxazol-4-yl)methyl)phenyl Acetate (E-3fh)

Following the general procedure, using compound 1f (135 mg, 0.50 mmol, 1 equiv), l-tyrosine 4h (136 mg, 0.75 mmol, 1.5 equiv), NaOAc (44.3 mg, 0.54 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by column chromatography on silica gel using 0–20% EtOAc in CH2Cl2 to furnish compound Z/E-3fh (171 mg, 66% (77:23 Z/E)).

Z-3fh

(132 mg, 51%) as a brown sticky-gum. 1H NMR (300 MHz, CDCl3) δ 8.04 (m, 2H, Ar–H), 7.66 (d, J = 8.1 Hz, 1H, Ar–H), 7.57–7.42 (m, 4H, Ar–H), 7.37 (br s, 1H, Ar–H), 7.21 (d, J = 8.7 Hz, 2H, Ar–H), 7.00 (d, J = 8.4 Hz, 2H, Ar–H), 6.49 (s, 1H, =CHCOPh), 5.81 (s, 1H, ArCHO), 3.40 (s, 2H, CH2Ph), 2.26 (s, 3H, OCOCH3), 2.02 (s, 3H, N=CCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 188.9 (COPh), 175.3 (OCOCH3), 169.2 (COO), 164.6 (=CO), 164.4 (N=CCH3), 150.1, 140.7, 139.6, 137.7, 133.1, 131.9, 131.5 (2C), 130.4 (2C), 128.3 (2C), 127.9 (2C), 123.0, 122.7, 121.4 (2C), 93.4 (=CHCOPh), 85.8 (ArCHO), 75.9 (C), 38.6 (CH2Ph), 21.0 (OCOCH3), 14.7 (N=CCH3). IR (UATR) νmax 3060, 2936, 1808 (CO), 1754 (CO), 1660 (C=N), 1600, 1587, 1574, 1507, 1464, 1447, 1424, 1370 cm–1. HRMS (ESI) calcd. for C29H22ClNNaO6 [M + Na]+: 538.1028, found 538.1021.

E-3fh

(38.6 mg, 15% (81:19 dr) mixture of isomer) as a pale-yellow sticky-gum. 1H NMR (300 MHz, CDCl3) δ 9.43 (d, J = 8.7 Hz, 1H, Ar–H, minor), 9.42 (d, J = 8.7 Hz, 1H, Ar–H, major), 8.06–7.96 (m, 2H, Ar–H, major), 7.70–7.63 (m, 1H, Ar–H, minor), 7.59–7.42 (m, 5H, Ar–H, major), 7.36–7.32 (m, 1H, Ar–H, minor), 7.21 (d, J = 8.4 Hz, 2H, Ar–H, major), 7.16 (d, J = 8.7 Hz, 2H, Ar–H, minor), 7.05–6.98 (m, 2H, Ar–H, major), 6.88 (s, 1H, =CHCOPh, major), 6.64 (s, 1H, =CHCOPh, minor), 5.75 (s, 1H, ArCHO, major), 5.74 (s, 1H, ArCHO, minor), 3.41 (s, 2H, CH2Ph, major), 3.37 (AB q, J = 13.5 Hz, 2H, CH2Ph, minor), 2.28 (s, 3H, OCOCH3, major), 2.00 (s, 3H, N=CCH3, major), 1.83 (s, 3H, N=CCH3, minor). 13C{1H} NMR (75 MHz, CDCl3) δ 189.33 (COPh, minor), 189.25 (COPh, major), 176.4 (OCOCH3, minor), 175.8 (OCOCH3, major), 169.2 (COO, major), 169.1 (COO, minor), 169.0 (=CO), major), 164.3 (N=CCH3, major), 163.2 (N=CCH3, minor), 150.24 (major), 150.19 (minor), 143.4 (minor), 143.1 (major), 139.8 (major), 139.7 (minor), 138.5 (minor), 138.3 (major), 132.2 (major), 131.4 (2C, major), 131.3 (2C, minor), 130.9 (major), 130.6 (minor), 130.5 (minor), 130.3 (2C, major), 130.2 (minor), 129.8 (major), 129.7 (minor), 128.5 (2C, major), 128.0 (2C, major), 122.0 (major), 121.5 (2C, major), 121.44 (2C, minor), 121.37 (2C, minor), 99.2 (=CHCOPh, minor), 98.6 (=CHCOPh, major), 84.7 (ArCHO, minor), 84.0 (ArCHO, major), 76.4 (C, major), 38.6 (CH2Ph, minor), 38.3 (CH2Ph, major), 21.1 (OCOCH3, major), 20.9 (OCOCH3, minor), 14.7 (N=CCH3, major), 14.5 (N=CCH3, minor). IR (UATR) νmax 3061, 2927, 2853, 1753 (CO), 1656 (C=N), 1600, 1587, 1507, 1464, 1447, 1424, 1370 cm–1. HRMS (ESI) calcd. for C29H22ClNNaO6 [M + Na]+: 538.1028, found 538.1023.

(Z)-4-((4-(6-Fluoro-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyl-5-oxo-4,5-dihydrooxazol-4-yl)methyl)phenyl Acetate (Z-3gh) and (E)-4-((4-(6-Fluoro-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyl-5-oxo-4,5-dihydrooxazol-4-yl)methyl)phenyl Acetate (E-3gh)

Following the general procedure, using compound 1g (127 mg, 0.50 mmol, 1 equiv), l-tyrosine 4h (137 mg, 0.75 mmol, 1.5 equiv), NaOAc (49.1 mg, 0.60 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by column chromatography on silica gel using 2–50% EtOAc in CH2Cl2 to furnish compound Z/E-3gh (171 mg, 68% (59:41 Z/E)).

Z-3gh

(101 mg, 40%) as a yellow sticky-gum. 1H NMR (300 MHz, CDCl3) δ 8.01 (d, J = 8.1 Hz, 2H, Ar–H), 7.72 (dd, JH–H = 8.6 Hz and JH–F = 4.7 Hz, 1H, Ar–H), 7.58–7.43 (m, 3H, Ar–H), 7.30–7.24 (m, 1H, Ar–H), 7.22 (d, J = 8.4 Hz, 2H, Ar–H), 7.08 (dd, J = 7.8, 1.8 Hz, 1H, Ar–H), 7.00 (d, J = 8.4 Hz, 2H, Ar–H), 6.48 (s, 1H, =CHCOPh), 5.82 (s, 1H, ArCHO), 3.41 (AB q, J = 13.7 Hz, 2H, CH2Ph), 2.28 (s, 3H, OCOCH3), 2.03 (s, 3H, N=CCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 189.1 (COPh), 175.3 (OCOCH3), 169.3 (COO), 164.7 (=CO), 164.6 (N=CCH3), 164.2 (d, 1JC–F = 252.2 Hz, CF), 150.1, 141.5 (d, 3JC–F = 9.3 Hz), 139.8, 131.9, 131.6 (2C), 130.6 (d, 4JC–F = 2.3 Hz), 130.5, 128.3 (2C), 128.0 (2C), 123.9 (d, 3JC–F = 9.7 Hz), 121.5 (2C), 118.0 (d, 2JC–F = 23.8 Hz), 109.8 (d, 2JC–F = 25.0 Hz), 93.0 (d, 6JC–F = 1.8 Hz, =CHCOPh), 85.8 (d, 4JC–F = 2.7 Hz, ArCHO), 75.9 (C), 38.8 (CH2Ph), 21.1 (OCOCH3), 14.8 (N=CCH3). 19F{1H} NMR (376 MHz, CDCl3) δ – 109.31. IR (UATR) νmax 3063, 2930, 1822 (CO), 1758 (CO), 1678 (C=N), 1662, 1592, 1575, 1507, 1481, 1436, 1370 cm–1. HRMS (ESI) calcd. C29H22FNNaO6 for [M + Na]+: 522.1323, found 522.1308.

E-3gh

(70.3 mg, 28%) as a pale-yellow sticky-gum. 1H NMR (300 MHz, CDCl3) δ 9.52 (dd, JH–H = 8.9 Hz and JH–F = 5.3 Hz, 1H, Ar–H), 8.04–7.97 (m, 2H, Ar–H), 7.58–7.44 (m, 3H, Ar–H), 7.31–7.25 (m, 1H, Ar–H), 7.21 (d, J = 8.7 Hz, 2H, Ar–H), 7.15 (dd, J = 8.0, 2.0 Hz, 1H, Ar–H), 7.02 (d, J = 8.4 Hz, 2H, Ar–H), 6.87 (s, 1H, =CHCOPh), 5.77 (s, 1H, ArCHO), 3.41 (AB q, J = 13.8 Hz, 2H, CH2Ph), 2.28 (s, 3H, OCOCH3), 2.00 (s, 3H, N=CCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 189.3 (COPh), 175.7 (OCOCH3), 169.3 (COO), 169.2 (=CO), 164.7 (d, 1JC–F = 253.4 Hz, CF), 164.3 (N=CCH3), 150.2, 144.1 (d, 3JC–F = 9.5 Hz), 139.8, 132.1, 131.4 (2C), 131.1 (d, 3JC–F = 9.5 Hz), 130.3, 128.52 (d, 4JC–F = 2.2 Hz), 128.47 (2C), 127.9 (2C), 121.6 (2C), 117.4 (d, 2JC–F = 22.1 Hz), 109.2 (d, 2JC–F = 24.7 Hz), 98.0 (=CHCOPh), 84.1 (d, 4JC–F = 2.7 Hz, ArCHO), 76.3 (C), 38.4 (CH2Ph), 21.1 (OCOCH3), 14.8 (N=CCH3). 19F{1H} NMR (376 MHz, CDCl3) δ – 108.19. IR (UATR) νmax 3063, 2927, 2851, 1822 (CO), 1760 (CO), 1682 (C=N), 1652, 1597, 1584, 1569, 1508, 1477, 1447, 1433, 1370 cm–1. HRMS (ESI) calcd. C29H22FNNaO6 for [M + Na]+: 522.1323, found 522.1330.

(Z)-4-((4-(6-Methoxy-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyl-5-oxo-4,5-dihydrooxazol-4-yl)methyl)phenyl Acetate (Z-3hh) and (E)-4-((4-(6-methoxy-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyl-5-oxo-4,5-dihydrooxazol-4-yl)methyl)phenyl Acetate (E-3hh)

Following the general procedure, using compound 1h (133 mg, 0.50 mmol, 1 equiv), l-tyrosine 4h (136 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.3 mg, 0.59 mmol, 1.1 equiv) and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by column chromatography on silica gel using 2–30% EtOAc in CH2Cl2 to furnish compound Z/E-3hh (99.6 mg, 39% (>99:1 Z/E)).

Z-3hh

(99.6 mg, 39%) as an orange brown sticky-gum. 1H NMR (300 MHz, CDCl3) δ 7.97–8.04 (m, 2H, Ar–H), 7.65 (d, J = 8.4 Hz, 1H, Ar–H), 7.55–7.42 (m, 3H, Ar–H), 7.25–7.20 (m, 2H, Ar–H), 7.07–6.85 (m, 4H, Ar–H), 6.42 (s, 1H, =CHCOPh), 5.79 (s, 1H, ArCHO), 3.85 (s, 3H, Ar−OCH3), 3.44 (s, 2H, CH2Ph), 2.27 (s, 3H, OCOCH3), 2.03 (s, 3H, N=CCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 189.1 (COPh), 175.4 (OCOCH3), 169.2 (COO), 166.1 (=CO), 164.4 (N=CCH3), 162.7, 150.1, 141.5, 140.2, 131.6 (3C), 130.7, 128.3 (2C), 128.0 (2C), 126.9, 123.5, 121.4 (2C), 116.6, 107.2, 91.9 (=CHCOPh), 85.9 (ArCHO), 76.0 (C), 55.8 (Ar–OCH3), 38.8 (CH2Ph), 21.1 (OCOCH3), 14.8 (N=CCH3). IR (UATR) νmax 3059, 2930, 2843, 1822 (CO), 1757 (CO), 1657 (C=N), 1599, 1585, 1569, 1506, 1487, 1436, 1369, 1290, 1216, 1194, 1167, 1113, 1011 cm–1. HRMS (ESI) calcd. for C30H25NNaO7 [M + Na]+: 534.1523, found 534.1520.

(Z)-4-Isopropyl-2-methyl-4-(3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)oxazol-5(4H)-one (Z-3ai) and (E)-4-Isopropyl-2-methyl-4-(3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)oxazol-5(4H)-one (E-3ai)

Following the general procedure, using compound 1a (85.9 mg, 0.50 mmol, 1 equiv), l-valine 4i (88.4 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.8 mg, 0.56 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by recrystallization with CH2Cl2 in hexane to furnish compound Z/E-3ai (56.4 mg, 36% (>99:1 Z/E)).

Z-3ai

(56.4 mg, 36% (77:23 dr) mixture of isomer) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 7.63–7.30 (m, 4H, Ar–H, major), 6.05 (s, 1H, ArCHO, major), 6.04 (s, 1H, ArCHO, minor), 5.76 (s, 1H, =CHCOCH3, minor), 5.73 (s, 1H, =CHCOCH3, major), 2.62 (sept, J = 6.9 Hz, 1H, CH(CH3)2, major), 2.48 (s, 3H, =CHCOCH3, major), 2.46 (s, 3H, =CHCOCH3, minor), 2.20 (s, 3H, N=CCH3, major), 2.09 (s, 3H, N=CCH3, minor), 1.18 (d, J = 6.9 Hz, 3H, CH(CH3)(CH3), major), 1.13 (d, J = 6.9 Hz, 3H, CH(CH3)(CH3), major). 13C{1H} NMR (75 MHz, CDCl3) δ 197.3 (COCH3, major), 196.9 (COCH3, minor), 176.3 (COO, major), 165.0 (=CO, major), 164.6 (=CO, minor), 164.2 (N=CCH3, major), 138.8 (major), 138.4 (minor), 134.1 (major), 131.6 (major), 129.9 (major), 129.8 (minor), 122.3 (major), 122.2 (minor), 121.9 (major), 121.6 (minor), 99.2 (=CHCOCH3, minor), 98.9 (=CHCOCH3, major), 86.8 (ArCHO, minor), 85.4 (ArCHO, major), 78.3 (C, major), 31.7 (CH(CH3)2, minor), 31.4 (CH(CH3)2, major), 30.9 (=CHCOCH3, major), 30.8 (=CHCOCH3, minor), 17.1 (CH(CH3)(CH3), minor), 16.8 (CH(CH3)(CH3), major), 16.6 (CH(CH3)(CH3), major), 16.4 (CH(CH3)(CH3), minor), 15.0 (N=CCH3, major), 14.7 (N=CCH3, minor). IR (UATR) νmax 3106, 3026, 2977, 2942, 2885, 1821 (CO), 1794 (CO), 1674 (C=N), 1633, 1605, 1464, 1434, 1416 cm–1. HRMS (ESI) calcd. for C18H20NO4 [M + H]+: 314.1387, found 314.1388.

(Z)-4-(6-Chloro-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-4-isopropyl-2-methyloxazol-5(4H)-one (Z-3bi) and (E)-4-(6-Chloro-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-4-isopropyl-2-methyloxazol-5(4H)-one (E-3bi)

Following the general procedure, using compound 1b (103 mg, 0.50 mmol, 1 equiv), l-valine 4i (89.3 mg, 0.76 mmol, 1.5 equiv), NaOAc (47.4 mg, 0.57 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by recrystallization with CH2Cl2 in hexane to furnish compound Z/E-3bi (53.9 mg, 31% (>99:1 Z/E)).

Z-3bi

(53.9 mg, 31%) as a brown solid. Mp 187.0–189.0 °C. 1H NMR (300 MHz, CDCl3) δ 7.50 (d, J = 8.4 Hz, 1H, Ar–H), 7.46 (dd, J = 8.4, 1.5 Hz, 1H, Ar–H), 7.34 (br s, 1H, Ar–H), 6.01 (s, 1H, ArCHO), 5.68 (s, 1H, =CHCOCH3), 2.58 (sept, J = 6.9 Hz, 1H, CH(CH3)2), 2.46 (s, 3H, =CHCOCH3), 2.21 (s, 3H, N=CCH3), 1.18 (d, J = 6.9 Hz, 3H, CH(CH3)(CH3)), 1.12 (d, J = 6.9 Hz, 3H, CH(CH3)(CH3)). 13C{1H} NMR (75 MHz, CDCl3) δ 196.9 (COCH3), 176.0 (COO), 164.5 (=CO), 163.7 (N=CCH3), 140.4, 137.9, 132.8, 130.5, 123.3, 122.5, 99.3 (=CHCOCH3), 85.0 (ArCHO), 78.2 (C), 31.3 (CH(CH3)2), 30.9 (=CHCOCH3), 16.8 (CH(CH3)(CH3)), 16.5 (CH(CH3)(CH3)), 14.9 (N=CCH3). IR (UATR) νmax 3365, 3293, 2974, 2880, 2359, 2341, 1818 (CO), 1707 (CO), 1680 (C=N), 1634, 1606, 1559, 1507, 1465, 1421 cm–1. HRMS (ESI) calcd. for C18H19ClNO4 [M + H]+: 348.0997, found 348.998.

(Z)-4-(6-Fluoro-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-4-isopropyl-2-methyloxazol-5(4H)-one (Z-3ci) and (E)-4-(6-Fluoro-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-4-isopropyl-2-methyloxazol-5(4H)-one (E-3ci)

Following the general procedure, using compound 1c (95.3 mg, 0.50 mmol, 1 equiv), l-valine 4i (88.3 mg, 0.75 mmol, 1.5 equiv), NaOAc (46.5 mg, 0.57 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by recrystallization with CH2Cl2 in hexane to furnish compound Z/E-3ci (33.1 mg, 20% (>99:1 Z/E)).

Z-3ci

(33.1 mg, 20%) as a pale brown solid. Mp 183.6–185.6 °C. 1H NMR (300 MHz, CDCl3) δ 7.56 (dd, JH–H = 8.7 Hz and JH–F = 4.8 Hz, 1H, Ar–H), 7.20 (td, J = 8.6, 2.1 Hz, 1H, Ar–H), 7.06 (dd, J = 8.0, 2.1 Hz, 1H, Ar–H), 6.02 (s, 1H, ArCHO), 5.66 (s, 1H, =CHCOCH3), 2.59 (sept, J = 6.8 Hz, 1H, CH(CH3)2), 2.46 (s, 3H, =CHCOCH3), 2.22 (s, 3H, N=CCH3), 1.17 (d, J = 6.8 Hz, 3H, CH(CH3)(CH3)), 1.13 (d, J = 6.8 Hz, 3H, CH(CH3)(CH3)). 13C{1H} NMR (75 MHz, CDCl3) δ 197.0 (COCH3), 176.0 (COO), 164.7 (d, 1JC–F = 251.9 Hz, CF), 164.5 (=CO), 163.9 (N=CCH3), 141.0 (d, 3JC–F = 9.2), 130.1 (d, 4JC–F = 2.5 Hz), 124.1 (d, 3JC–F = 9.8 Hz), 117.9 (d, 2JC–F = 23.8 Hz), 109.6 (d, 2JC–F = 25.0), 98.7 (d, 6JC–F = 1.5 Hz, =CHCOCH3), 84.8 (d, 4J = 2.9 Hz, ArCHO), 78.1 (C), 31.3 (CH(CH3)2), 30.8 (=CHCOCH3), 16.7 (CH(CH3)(CH3)), 16.5 (CH(CH3)(CH3)), 14.9 (N=CCH3). 19F{1H} NMR (376 MHz, CDCl3) δ – 109.64. IR (UATR) νmax 3076, 3049, 2974, 2942, 2880, 1820 (CO), 1798 (CO), 1680 (C=N), 1630, 1613, 1597, 1483, 1469, 1431, 1387 cm–1. HRMS (ESI) calcd. for C18H19FNO4 [M + H]+: 332.1293, found 332.1294.

(Z)-4-Isopropyl-4-(6-methoxy-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyloxazol-5(4H)-one (Z-3di) and (E)-4-Isopropyl-4-(6-methoxy-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyloxazol-5(4H)-one (E-3di)

Following the general procedure, using compound 1d (103 mg, 0.51 mmol, 1 equiv) l-valine 4i (88.7 mg, 0.75 mmol, 1.5 equiv), NaOAc (46.6 mg, 0.57 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by recrystallization with CH2Cl2 in hexane to furnish compound Z/E-3di (35.0 mg, 20% (>99:1 Z/E)).

Z-3di

(35.0 mg, 20% (95:5 dr)) as a dark brown solid. 1H NMR (300 MHz, CDCl3) δ 7.49 (d, J = 8.7 Hz, 1H, Ar–H, major), 7.01 (dd, J = 8.7, 2.1 Hz, 1H, Ar–H, major), 6.84 (d, J = 2.1 Hz, 1H, Ar–H, major), 6.78 (d, J = 1.5 Hz, 1H, Ar–H, minor), 5.97 (s, 1H, ArCHO, major), 5.63 (s, 1H, =CHCOCH3, minor), 5.61 (s, 1H, =CHCOCH3, major), 3.86 (s, 3H, Ar−OCH3, major), 2.62 (sept, J = 6.8 Hz, 1H, CH(CH3)2, major), 2.46 (s, 3H, =CHCOCH3, major), 2.43 (s, 3H, =CHCOCH3, minor), 2.22 (s, 3H, N=CCH3, major), 2.12 (s, 3H, N=CCH3, minor), 1.16 (d, J = 7.2 Hz, 3H, CH(CH3)(CH3), major), 1.14 (d, J = 7.2 Hz, 3H, CH(CH3)(CH3), major). 13C{1H} NMR (75 MHz, CDCl3) δ 197.0 (COCH3, major), 176.1 (COO, major), 165.1 (=CO, major), 164.2 (N=CCH3, major), 162.7 (major), 140.9 (major), 126.3 (major), 123.6 (major), 123.5 (minor), 116.3 (minor), 116.2 (major), 107.2 (major), 106.5 (minor), 97.8 (=CHCOCH3, minor), 97.6 (=CHCOCH3, major), 86.2 (ArCHO, minor), 84.8 (ArCHO, major), 78.2 (C, major), 55.8 (Ar–OCH3, minor), 55.7 (Ar–OCH3, major), 31.6 (CH(CH3)2, minor), 31.3 (CH(CH3)2, major), 30.7 (=CHCOCH3, major), 17.1 (CH(CH3)(CH3), minor), 16.7 (CH(CH3)(CH3), major), 16.5 (CH(CH3)(CH3), major), 16.4 (CH(CH3)(CH3), minor), 14.9 (N=CCH3, major), 14.7 (N=CCH3, minor). IR (UATR) νmax 3049, 3011, 2969, 2938, 2883, 2848, 1811 (CO), 1787 (CO), 1680 (C=N), 1626, 1607, 1488, 1468, 1432, 1414, 1386 cm–1. HRMS (ESI) calcd. for C19H22NO5 [M + H]+: 344.1492, found 344.1489.

(Z)-4-Isopropyl-2-methyl-4-(3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)oxazol-5(4H)-one (Z-3ei) and (E)-4-Isopropyl-2-methyl-4-(3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)oxazol-5(4H)-one (E-3ei)

Following the general procedure, using compound 1e (117 mg, 0.50 mmol, 1 equiv), l-valine 4i (88.3 mg, 0.75 mmol, 1.5 equiv), NaOAc (46.2 mg, 0.56 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by column chromatography on silica gel using 2–20% EtOAc in CH2Cl2 to furnish compound Z/E-3ei (130.7 mg, 70% (79:21 Z/E)).

Z-3ei

(103.1 mg, 55% (83:17 dr) mixture of isomer) as a brown sticky-gum. 1H NMR (300 MHz, CDCl3) δ 8.03–7.94 (m, 2H, Ar–H, major), 7.76–7.70 (m, 1H, Ar–H, major), 7.56–7.40 (m, 5H, Ar–H, major), 7.40–7.31 (m, 1H, Ar–H, major), 6.58 (s, 1H, =CHCOPh, minor), 6.54 (s, 1H, =CHCOPh, major), 6.08 (s, 1H, ArCHO, minor), 6.03 (s, 1H, ArCHO, major), 2.67 (sept, J = 6.9 Hz, 1H, CH(CH3)2, major), 2.19 (s, 3H, N=CCH3, major), 2.08 (s, 3H, N=CCH3, minor), 1.14 (d, J = 6.6 Hz, 3H, CH(CH3)(CH3), major), 1.11 (d, J = 6.9 Hz, 3H, CH(CH3)(CH3), minor), 1.06 (d, J = 6.9 Hz, 3H, CH(CH3)(CH3), major). 13C {1H} NMR (75 MHz, CDCl3) δ 189.0 (COPh, major), 188.6 (COPh, minor), 176.6 (COO, minor), 176.1 (COO, major), 166.2 (=CO, major), 166.0 (=CO, minor), 164.4 (N=CCH3, major), 163.0 (N=CCH3, minor), 140.0 (minor), 139.9 (major), 139.6 (major), 139.2 (minor), 134.7 (major), 134.5 (minor), 131.7 (major), 131.6 (major), 129.8 (major), 129.6 (minor), 128.2 (2C, major), 127.9 (2C, major), 127.8 (2C, minor), 122.0 (major), 121.9 (major), 121.8 (minor), 121.6 (minor), 92.8 (=CHCOPh, minor), 92.6 (=CHCOPh, major), 86.9 (ArCHO, minor), 85.1 (ArCHO, major), 79.0 (C, minor), 78.2 (C, major), 31.6 (CH(CH3)2, minor), 31.3 (CH(CH3)2, major), 17.1 (CH(CH3)(CH3), minor), 16.8 (CH(CH3)(CH3), major), 16.7 (CH(CH3)(CH3), major), 16.6 (CH(CH3)(CH3), minor), 15.0 (N=CCH3, major), 14.6 (N=CCH3, minor). IR (UATR) νmax 3294, 3061, 2969, 2878, 1770 (CO), 1720 (CO), 1661 (C=N), 1619, 1560, 1590, 1573, 1528, 1467, 1448, 1374 cm–1. HRMS (ESI) calcd. for C23H21NNaO4 [M + Na]+: 398.1363, found 398.1368.

E-3ei

(27.6 mg, 15%) as a pale-yellow sticky-gum. 1H NMR (300 MHz, CDCl3) δ 9.48–9.40 (m, 1H, Ar–H), 8.05–7.97 (m, 2H, Ar–H), 7.60–7.41 (m, 5H, Ar–H), 7.41–7.32 (m, 1H, Ar–H), 6.85 (s, 1H, =CHCOPh), 5.91 (s, 1H, ArCHO), 2.65 (sept, J = 6.9 Hz, 1H, CH(CH3)2), 2.21 (s, 3H, N=CCH3), 1.15 (d, J = 6.6 Hz, 3H, CH(CH3)(CH3)), 1.13 (d, J = 6.9 Hz, 3H, CH(CH3)(CH3)). 13C{1H} NMR (75 MHz, CDCl3) δ 189.3 (COPh), 176.5 (COO), 170.5 (=CO), 164.1 (N=CCH3), 141.7, 140.0, 132.3, 132.1, 132.0, 129.8, 128.6, 128.4 (2C), 128.0 (2C), 121.1, 98.1 (=CHCOPh), 82.7 (ArCHO), 78.3 (C), 31.2 (CH(CH3)2), 16.9 (CH(CH3)(CH3)), 16.7 (CH(CH3)(CH3)), 15.0 (N=CCH3). IR (UATR) νmax 3060, 2970, 2936, 2879, 1821 (CO), 1776 (CO), 1681 (C=N), 1661, 1600, 1590, 1568, 1467, 1384 cm–1. HRMS (ESI) calcd. for C23H21NNaO4 [M + Na]+: 398.1363, found 398.1364.

(Z)-4-(6-Chloro-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-4-isopropyl-2-methyloxazol-5(4H)-one (Z-3fi) and (E)-4-(6-Chloro-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-4-isopropyl-2-methyloxazol-5(4H)-one (E-3fi)

Following the general procedure, using compound 1f (134 mg, 0.50 mmol, 1 equiv), l-valine 4i (89.4 mg, 0.76 mmol, 1.5 equiv), NaOAc (46.2 mg, 0.56 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by column chromatography on silica gel using 0–10% EtOAc in CH2Cl2 to furnish compound Z/E-3fi (138 mg, 67% (71:29 Z/E)).

Z-3fi

(97.0 mg, 47%) as a yellow solid. Mp 177.5–178.4 °C. 1H NMR (300 MHz, CDCl3) δ 8.01–7.94 (m, 2H, Ar–H), 7.65 (d, J = 8.4 Hz, 1H, Ar–H), 7.56–7.41 (m, 4H, Ar–H), 7.35–7.31 (m, 1H, Ar–H), 6.50 (s, 1H, =CHCOPh), 5.99 (s, 1H, ArCHO), 2.62 (sept, J = 6.8 Hz, 1H, CH(CH3)2), 2.20 (s, 3H, N=CCH3), 1.13 (d, J = 6.9 Hz, 3H, CH(CH3)(CH3)), 1.08 (d, J = 7.2 Hz, 3H, CH(CH3)(CH3)). 13C{1H} NMR (75 MHz, CDCl3) δ 188.7 (COPh), 175.9 (COO), 164.9 (=CO), 164.7 (N=CCH3), 141.2, 139.6, 137.8, 133.3, 131.9, 130.3, 128.3 (2C), 127.9 (2C), 123.0, 122.5, 93.0 (=CHCOPh), 84.7 (ArCHO), 78.2 (C), 31.2 (CH(CH3)2), 16.7 (CH(CH3)(CH3)), 16.6 (CH(CH3)(CH3)), 14.9 (N=CCH3). IR (UATR) νmax 3093, 2972, 2932, 1803 (CO), 1682 (C=N), 1663, 1602, 1576, 1466 cm–1. HRMS (ESI) calcd. for C23H20ClNNaO4 [M + Na]+: 432.0973, found 432.0983.

E-3fi

(41.0 mg, 20% (77:23 dr) mixture of isomer) as a brown sticky-gum. 1H NMR (400 MHz, CDCl3) δ 9.41 (d, J = 8.0 Hz, 1H, Ar–H, minor), 9.40 (d, J = 8.0 Hz, 1H, Ar–H, major), 8.20–7.95 (m, 2H, Ar–H, major), 7.56–7.42 (m, 4H, Ar–H, major), 7.31 (br s, 1H, Ar–H, major), 7.23 (br s, 1H, Ar–H, minor), 6.85 (s, 1H, =CHCOPh, minor), 6.83 (s, 1H, =CHCOPh, major), 5.87 (s, 1H, ArCHO, major), 2.60 (sept, J = 8.0 Hz, 1H, CH(CH3)2, major), 2.21 (s, 3H, N=CCH3, major), 2.07 (s, 3H, N=CCH3, minor), 1.21 (d, J = 8.0 Hz, 3H, CH(CH3)(CH3), minor), 1.14 (d, J = 8.0 Hz, 3H, CH(CH3)(CH3), major), 1.12 (d, J = 8.0 Hz, 3H, CH(CH3)(CH3), major), 1.04 (d, J = 8.0 Hz, 3H, CH(CH3)(CH3), minor). 13C{1H} NMR (100 MHz, CDCl3) δ 189.2 (COPh, major), 176.13 (COO, major), 176.10 (COO, minor), 169.3 (=CO, major), 169.1 (=CO, minor), 164.4 (N=CCH3, major), 163.1 (minor), 143.41 (major), 143.35 (minor), 139.8 (minor), 139.7 (major), 138.3 (minor), 138.2 (major), 132.1 (major), 132.0 (minor), 130.8 (major), 130.7 (minor), 130.0 (major), 129.9 (minor), 129.7 (major), 129.6 (minor), 128.40 (2C, major), 128.37 (2C, major), 121.6 (major), 120.8 (minor), 98.8 (=CHCOPh, minor), 98.3 (=CHCOPh, major), 83.5 (ArCHO, minor), 82.3 (ArCHO, major), 78.6 (C, minor), 78.2 (C, major), 31.8 (CH(CH3)2, minor), 31.1 (CH(CH3)2, major), 17.0 (CH(CH3)(CH3), minor), 16.8 (CH(CH3)(CH3), major), 16.5 (CH(CH3)(CH3), major), 16.3 (CH(CH3)(CH3), minor), 14.9 (N=CCH3, major), 14.6 (N=CCH3, minor). IR (UATR) νmax 3060, 2973, 2938, 2880, 1822 (CO), 1751 (CO), 1682 (C=N), 1652, 1600, 1584, 1568, 1459, 1431, 1385 cm–1. HRMS (ESI) calcd. for C23H20ClNNaO4 [M + Na]+: 432.0973, found 432.0977.

(Z)-4-(6-Fluoro-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-4-isopropyl-2-methyloxazol-5(4H)-one (Z-3gi) and (E)-4-(6-Fluoro-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-4-isopropyl-2-methyloxazol-5(4H)-one (E-3gi)

Following the general procedure, using compound 1g (131 mg, 0.52 mmol, 1 equiv), l-valine 4i (90.3 mg, 0.77 mmol, 1.5 equiv), NaOAc (47.3 mg, 0.58 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by column chromatography on silica gel using 2–10% EtOAc in CH2Cl2 to furnish compound Z/E-3gi (142 mg, 72% (65:35 Z/E)).

Z-3gi

(92.9 mg, 47% (83:17 dr) mixture of isomer) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.03–7.91 (m, 2H, Ar–H, major), 7.71 (dd, JH–H = 8.7 Hz and JH–F = 4.8 Hz, 1H, Ar–H, major), 7.57–7.40 (m, 3H, Ar–H, major), 7.21 (td, J = 8.6, 2.1 Hz, 1H, Ar–H, major), 7.04 (dd, J = 8.0, 2.0 Hz, 1H, Ar–H, major), 6.51 (s, 1H, =CHCOPh, minor), 6.48 (s, 1H, =CHCOPh, major), 6.04 (s, 1H, ArCHO, minor), 5.99 (s, 1H, ArCHO, major), 2.64 (sept, J = 6.6 Hz, 1H, CH(CH3)2, major), 2.21 (s, 3H, N=CCH3, major), 2.15 (s, 3H, N=CCH3, minor), 1.12 (d, J = 6.9 Hz, 3H, CH(CH3)(CH3), minor), 1.14 (d, J = 6.6 Hz, 3H, CH(CH3)(CH3), major), 1.06 (d, J = 6.9 Hz, 3H, CH(CH3)(CH3), major). 13C{1H} NMR (75 MHz, CDCl3) δ 188.8 (COPh, major), 188.4 (COPh, minor), 176.4 (COO, minor), 175.9 (COO, major), 165.1 (=CO, major), 164.9 (=CO, minor), 164.73 (d, 1JC–F = 252.2 Hz, CF, minor), 164.66 (d, 1JC–F = 251.9 Hz, CF, major), 164.65 (N=CCH3, major), 163.3 (N=CCH3, minor), 141.9 (d, 3JC–F = 9.3 Hz, major), 141.5 (d, 3JC–F = 9.5 Hz, minor), 139.9 (minor), 139.7 (major), 131.8 (major), 130.7 (d, 4JC–F = 2.2 Hz, major), 128.3 (2C, major), 127.9 (2C, major), 127.8 (2C, minor), 123.8 (d, 3JC–F = 9.6 Hz, major), 123.7 (d, 3JC–F = 9.5 Hz, minor), 117.7 (d, 2JC–F = 23.7 Hz, major), 117.6 (d, 2JC–F = 23.7 Hz, minor), 109.5 (d, 2JC–F = 24.9 Hz, major), 109.3 (d, 2JC–F = 24.8 Hz, minor), 92.7 (d, 6JC–F = 1.5 Hz, =CHCOPh, minor), 92.5 (d, 6JC–F = 1.4 Hz, =CHCOPh, major), 86.3 (d, 4JC–F = 2.9 Hz, ArCHO, minor), 84.6 (d, 4JC–F = 2.9 Hz, ArCHO, major), 78.9 (C, minor), 78.1 (C, major), 31.5 (CH(CH3)2, minor), 31.3 (CH(CH3)2, major), 17.0 (CH(CH3)(CH3), minor), 16.7 (CH(CH3)(CH3), major), 16.63 (CH(CH3)(CH3), major), 16.58 (CH(CH3)(CH3), minor), 14.9 (N=CCH3, major), 14.7 (N=CCH3, minor). 19F{1H} NMR (376 MHz, CDCl3) δ – 109.32 (minor), – 109.60 (major). IR (UATR) νmax 3063, 2971, 2880, 1822 (CO), 1804 (CO), 1681 (C), 1661, 1592, 1575, 1481, 1447, 1383 cm–1. HRMS (ESI) calcd. for C23H20FNNaO4 [M + Na]+: 416.1269, found 416.1268.

E-3gi

(49.5 mg, 25% (82:18 dr) mixture of isomer) as a dark brown sticky-gum. 1H NMR (300 MHz, CDCl3) δ 9.51 (dd, JH–H = 9.0 Hz and JH–F = 5.4 Hz, 1H, Ar–H, major), 8.04–7.96 (m, 2H, Ar–H, major), 7.58–7.43 (m, 3H, Ar–H, major), 7.23 (td, J = 8.8, 2.3 Hz, 1H, Ar–H, major), 7.03 (dd, J = 8.1, 2.1 Hz, 1H, Ar–H, major), 6.95 (dd, J = 8.1, 1.8 Hz, 1H, Ar–H, minor), 6.84 (s, 1H, =CHCOPh, minor), 6.82 (s, 1H, =CHCOPh, major), 5.88 (s, 1H, ArCHO, major), 2.62 (sept, J = 6.9 Hz, 1H, CH(CH3)2, major), 2.22 (s, 3H, N=CCH3, major), 2.06 (s, 3H, N=CCH3, minor), 1.23 (d, J = 6.9 Hz, 3H, CH(CH3)(CH3), minor), 1.132 (d, J = 7.2 Hz, 3H, CH(CH3)(CH3), major), 1.128 (d, J = 6.6 Hz, 3H, CH(CH3)(CH3), major), 1.03 (d, J = 6.9 Hz, 3H, CH(CH3)(CH3), minor). 13C{1H} NMR (75 MHz, CDCl3) δ 189.2 (COPh, major), 176.2 (COO, major), 169.5 (=CO, major), 169.3 (=CO, minor), 164.8 (d, 1JC–F = 253.1 Hz, CF, major), 164.4 (N=CCH3, major), 144.44 (d, 3JC–F = 9.4 Hz, major), 144.40 (d, 3JC–F = 9.4 Hz, minor), 139.9 (minor), 139.8 (major), 132.0 (major), 131.02 (d, 3JC–F = 9.5 Hz, major), 130.97 (d, 3JC–F = 9.8 Hz, minor), 128.5 (d, 4JC–F = 2.3 Hz, major), 128.4 (2C, major), 127.9 (2C, major), 117.2 (d, 2JC–F = 22.2 Hz, major), 117.1 (d, 2JC–F = 22.4 Hz, minor), 108.7 (d, 2JC–F = 24.8 Hz, major), 108.0 (d, 2JC–F = 25.6 Hz, minor), 98.2 (d, 6JC–F = 1.9 Hz, =CHCOPh, minor), 97.7 (d, 6JC–F = 1.4 Hz, =CHCOPh, major), 83.6 (d, 4JC–F = 3.5 Hz, ArCHO, minor), 82.3 (d, 4JC–F = 2.8 Hz, ArCHO, major), 78.6 (C, minor), 78.2 (C, major), 31.8 (CH(CH3)2, minor), 31.2 (CH(CH3)2, major), 17.0 (CH(CH3)(CH3), minor), 16.8 (CH(CH3)(CH3), major), 16.6 (CH(CH3)(CH3), major), 16.3 (CH(CH3)(CH3), minor), 15.0 (N=CCH3, major), 14.6 (N=CCH3, minor). 19F{1H} NMR (376 MHz, CDCl3) δ – 108.23 (minor), – 108.52 (major). IR (UATR) νmax 2969, 2936, 2878, 1823 (CO), 1804 (CO), 1725 (CO), 1682 (C=N), 1661, 1600, 1593, 1575, 1530, 1480, 1384 cm–1. HRMS (ESI) calcd. for C23H20FNNaO4 [M + Na]+: 416.1269, found 416.1266.

(Z)-4-Isopropyl-4-(6-methoxy-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyloxazol-5(4H)-one (Z-3hi) and (E)-4-Isopropyl-4-(6-methoxy-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyloxazol-5(4H)-one (E-3hi)

Following the general procedure, using compound 1h (132. mg, 0.50 mmol, 1 equiv), l-valine 4i (87.0 mg, 0.75 mmol, 1.5 equiv), NaOAc (46.1 mg, 0.56 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by column chromatography on silica gel using 2–20% EtOAc in CH2Cl2 to furnish compound Z/E-3hi (119 mg, 59% (66:34 Z/E)).

Z-3hi

(78.9 mg, 39%) as a brown solid. Mp 120.0–122.0 °C. 1H NMR (300 MHz, CDCl3) δ 8.03–7.94 (m, 2H, Ar–H), 7.64 (d, J = 8.7 Hz, 1H, Ar–H), 7.55–7.40 (m, 3H, Ar–H), 7.02 (dd, J = 8.6, 2.3 Hz, 1H, Ar–H), 6.83 (d, J = 1.8 Hz, 1H, Ar–H), 6.42 (s, 1H, =CHCOPh), 5.96 (s, 1H, ArCHO), 3.86 (s, 3H, Ar−OCH3), 2.69 (sept, J = 6.8 Hz, 1H, CH(CH3)2), 2.21 (s, 3H, N=CCH3), 1.16 (d, J = 6.6 Hz, 3H, CH(CH3)(CH3)), 1.04 (d, J = 6.9 Hz, 3H, CH(CH3)(CH3)). 13C{1H} NMR (75 MHz, CDCl3) δ 188.8 (COPh), 176.0 (COO), 166.5 (=CO), 164.4 (N=CCH3), 162.7, 142.0, 140.2, 131.5, 128.2 (2C), 127.9 (2C), 127.0, 123.4, 116.3, 107.0, 91.5 (=CHCOPh), 84.6 (ArCHO), 78.2 (C), 55.8 (Ar–OCH3), 31.3 (CH(CH3)2), 16.8 (2C, CH(CH3)2), 15.0 (N=CCH3). IR (UATR) νmax 3365, 2969, 2939, 2604, 1821 (CO), 1716 (CO), 1656 (C=N), 1618, 1599, 1586, 1569, 1517, 1486, 1436, 1375 cm–1. HRMS (ESI) calcd. for C24H23NNaO5 [M + Na]+: 428.1468, found 428.1467.

E-3hi

(40.2 mg, 20% (67:23 dr) mixture of isomer) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 9.45 (d, J = 9.0 Hz, 1H, Ar–H, major), 9.44 (d, J = 9.0 Hz, 1H, Ar–H, minor), 8.03–7.95 (m, 2H, Ar–H, major), 7.55–7.38 (m, 3H, Ar–H, major), 7.07–6.99 (m, 1H, Ar–H, major), 6.83 (d, J = 2.1 Hz, 1H, Ar–H, major), 6.76 (s, 1H, =CHCOPh, minor), 6.74 (s, 1H, =CHCOPh, major), 6.72 (d, J = 2.4 Hz, 1H, Ar–H, minor), 5.85 (s, 1H, ArCHO, minor), 5.84 (s, 1H, ArCHO, major), 3.873 (s, 3H, Ar−OCH3, major), 3.868 (s, 3H, Ar−OCH3, minor), 2.66 (sept, J = 6.9 Hz, 1H, CH(CH3)2, major), 2.65 (sept, J = 6.9 Hz, 1H, CH(CH3)2, minor), 2.60 (s, 3H, N=CCH3, major), 2.03 (s, 3H, N=CCH3, minor), 1.24 (d, J = 6.9 Hz, 3H, CH(CH3)(CH3), minor), 1.13 (d, J = 6.8 Hz, 3H, CH(CH3)(CH3), major), 1.12 (d, J = 6.8 Hz, 3H, CH(CH3)(CH3), major), 1.02 (d, J = 6.9 Hz, 3H, CH(CH3)(CH3), minor). 13C{1H} NMR (75 MHz, CDCl3) δ 189.2 (COPh, major), 176.5 (COO, minor), 176.3 (COO, major), 170.8 (=CO, major), 170.7 (=CO, minor), 164.1 (N=CCH3, major), 163.0 (N=CCH3, minor), 162.8 (major), 162.7 (minor), 144.5 (minor), 144.4 (major), 140.3 (major), 131.70 (major), 131.66 (minor), 130.5 (major), 130.4 (minor), 128.3 (2C, major), 127.8 (2C, major), 125.0 (major), 115.3 (minor), 115.0 (major), 106.9 (major), 105.6 (minor), 96.8 (=CHCOPh, minor), 96.3 (=CHCOPh, major), 83.6 (ArCHO, minor), 82.3 (ArCHO, major), 78.8 (C, minor), 78.3 (C, major), 55.73 (Ar–OCH3, minor), 55.66 (Ar–OCH3, major), 31.9 (CH(CH3)2, minor), 31.1 (CH(CH3)2, major), 17.1 (CH(CH3)(CH3), minor), 16.8 (CH(CH3)(CH3), major), 16.6 (CH(CH3)(CH3), major), 16.3 (CH(CH3)(CH3), minor), 15.0 (N=CCH3, major), 14.6 (N=CCH3, minor). IR (UATR) νmax 3059, 2969, 2939, 1822 (CO), 1681 (C=N), 1647, 1582, 1557, 1485, 1448, 1387 cm–1. HRMS (ESI) calcd. for C24H24NO5 [M + H]+: 406.1649, found 406.1644.

(Z)-2,4-Dimethyl-4-(3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)oxazol-5(4H)-one (Z-3aj) and (E)-2,4-Dimethyl-4-(3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)oxazol-5(4H)-one (E-3aj)

Following the general procedure, using compound 1a (87.3 mg, 0.51 mmol, 1 equiv), l-alanine 4j (66.8 mg, 0.75 mmol, 1.5 equiv), NaOAc (46.3 mg, 0.56 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by recrystallization with CH2Cl2 in hexane to furnish compound Z/E-3aj (33.8 mg, 24% (>99:1 Z/E)).

Z-3aj

(33.8 mg, 24%) as a brown solid. Mp 163.0–164.2 °C. 1H NMR (300 MHz, CDCl3) δ 7.63–7.45 (m, 4H, Ar–H), 5.83 (s, 1H, ArCHO), 5.71 (s, 1H, =CHCOCH3), 2.45 (s, 3H, =CHCOCH3), 2.15 (s, 3H, N=CCH3), 1.73 (s, 3H, CH3). 13C{1H} NMR (75 MHz, CDCl3) δ 197.1 (COCH3), 177.5 (COO), 164.7 (=CO), 163.9 (N=CCH3), 138.6, 134.1, 131.6, 130.0, 122.3, 122.2, 98.8 (=CHCOCH3), 88.0 (ArCHO), 71.7 (C), 30.9 (=CHCOCH3), 19.0 (CH3), 15.1 (N=CCH3). IR (UATR) νmax 3059, 2936, 1819 (CO), 1683 (C=N), 1630, 1467, 1430, 1363 cm–1. HRMS (ESI) calcd. for C16H15NNaO4 [M + Na]+: 308.0893, found 308.0898.

(Z)-4-(6-Chloro-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2,4-dimethyloxazol-5(4H)-one (Z-3bj) and (E)-4-(6-Chloro-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2,4-dimethyloxazol-5(4H)-one (E-3bj)

Following the general procedure, using compound 1b (103 mg, 0.50 mmol, 1 equiv), l-alanine 4j (66.6 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.2 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by recrystallization with CH2Cl2 in hexane to furnish compound Z/E-3bj (48.0 mg, 30% (>99:1 Z/E)).

Z-3bj

(48.0 mg, 32% (97:3 dr) mixture of isomer) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 7.55–7.40 (m, 3H, Ar–H, major), 5.80 (s, 1H, ArCHO, major), 5.72 (s, 1H, ArCHO, minor), 5.69 (s, 1H, =CHCOCH3, minor), 5.66 (s, 1H, =CHCOCH3, major), 2.50 (s, 3H, =CHCOCH3, minor), 2.43 (s, 3H, =CHCOCH3, major), 2.16 (s, 3H, N=CCH3, major), 2.05 (s, 3H, N=CCH3, minor), 1.72 (s, 3H, CH3, major), 1.59 (s, 3H, CH3, minor). 13C{1H} NMR (75 MHz, CDCl3) δ 196.9 (COCH3, major), 177.2 (COO, major), 164.3 (=CO, major), 163.5 (N=CCH3, major), 140.1 (major), 137.9 (major), 132.7 (major), 131.8 (minor), 130.5 (major), 123.5 (minor), 123.2 (major), 122.8 (major), 122.2 (minor), 99.5 (=CHCOCH3, minor), 99.2 (=CHCOCH3, major), 87.7 (ArCHO, minor), 87.4 (ArCHO, major), 71.6 (C, major), 31.0 (=CHCOCH3, minor), 30.9 (=CHCOCH3, major), 19.0 (CH3, major), 15.1 (N=CCH3, major). IR (UATR) νmax 3083, 3054, 2977, 2925, 1823 (CO), 1799 (CO), 1681 (C=N), 1625, 1608, 1469, 1445, 1425, 1383 cm–1. HRMS (ESI) calcd. for C16H15ClNO4 [M + H]+: 320.0684, found 320.0683.

(Z)-4-(6-Fluoro-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2,4-dimethyloxazol-5(4H)-one (Z-3cj) and (E)-4-(6-Fluoro-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2,4-dimethyloxazol-5(4H)-one (E-3cj)

Following the general procedure, compound 1c (94.8 mg, 0.50 mmol, 1 equiv), l-alanine 4j (66.3 mg, 0.74 mmol, 1.5 equiv), NaOAc (47.4 mg, 0.58 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by recrystallization with CH2Cl2 in hexane to furnish compound Z/E-3cj (45.5 mg, 30% (>99:1 Z/E)).

Z-3cj

(45.5 mg, 30%) as a pale-yellow solid. Mp. 178.9–179.9 °C. 1H NMR (300 MHz, CDCl3) δ 7.57 (dd, JH–H = 8.4 Hz and JH–F = 4.8 Hz, 1H, Ar–H), 7.28–7.15 (m, 2H, Ar–H), 5.80 (s, 1H, ArCHO), 5.65 (s, 1H, =CHCOCH3), 2.43 (s, 3H, =CHCOCH3), 2.16 (s, 3H, N=CCH3), 1.72 (s, 3H, CH3). 13C{1H} NMR (75 MHz, CDCl3) δ 196.9 (COCH3), 177.2 (COO), 164.7 (d, 1JC–F = 252.1 Hz, CF), 164.2 (=CO), 163.7 (N=CCH3), 140.8 (d, 3JC–F = 9.3 Hz), 130.1 (d, 4JC–F = 2.4 Hz), 124.1 (d, 3JC–F = 9.6 Hz), 118.0 (d, 2JC–F = 23.7 Hz), 110.0 (d, 2JC–F = 24.9 Hz), 98.7 (d, 6JC–F = 1.6 Hz, =CHCOCH3), 87.4 (d, 4JC–F = 2.9 Hz, ArCHO), 71.6 (CO), 30.8 (=CHCOCH3), 19.0 (CH3), 15.1 (N=CCH3). 19F{1H} NMR (376 MHz, CDCl3) δ – 109.49. IR (UATR) νmax 3045, 2999, 2935, 1827 (CO), 1734 (CO), 1682 (C=N), 1617, 1598 cm–1. HRMS (ESI) calcd. for C16H15FNO4 [M + H]+: 304.0980, found 304.0981.

(Z)-4-(6-Methoxy-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2,4-dimethyloxazol-5(4H)-one (Z-3dj) and (E)-4-(6-Methoxy-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2,4-dimethyloxazol-5(4H)-one (E-3dj)

Following the general procedure, using compound 1d (102 mg, 0.50 mmol, 1 equiv), l-alanine 4j (67.3 mg, 0.76 mmol, 1.5 equiv), NaOAc (46.4 mg, 0.57 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by recrystallization with CH2Cl2 in hexane to furnish compound Z/E-3dj (19.4 mg, 12% (>99:1 Z/E)).

Z-3dj

(19.4 mg, 12% (91:9 dr) mixture of isomer) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.50 (d, J = 8.7 Hz, 1H, Ar–H, major), 7.03 (dd, J = 8.4, 2.1 Hz, 1H, Ar–H, major), 6.95 (d, J = 2.1 Hz, 1H, Ar–H, major), 6.86 (d, J = 1.8 Hz, 1H, Ar–H, minor), 5.76 (s, 1H, ArCHO, major), 5.67 (s, 1H, ArCHO, minor), 5.65 (s, 1H, =CHCOCH3, minor), 5.60 (s, 1H, =CHCOCH3, major), 3.88 (s, 3H, Ar−OCH3, major), 3.87 (s, 3H, Ar−OCH3, minor), 2.49 (s, 3H, =CHCOCH3minor), 2.42 (s, 3H, =CHCOCH3major), 2.16 (s, 3H, N=CCH3, major), 2.13 (s, 3H, N=CCH3, minor), 1.73 (s, 3H, CH3, major), 1.62 (s, 3H, CH3, minor). 13C{1H} NMR (75 MHz, CDCl3) δ 197.1 (COCH3, major), 177.5 (COO, major), 165.0 (=CO, major), 164.0 (N=CCH3, major), 162.7 (major), 140.8 (major), 126.4 (major), 123.6 (major), 116.8 (minor), 116.4 (major), 107.5 (major), 106.7 (minor), 98.0 (=CHCOCH3, minor), 97.7 (=CHCOCH3, major), 87.6 (ArCHO, minor), 87.5 (ArCHO, major), 77.2 (C, minor), 71.7 (C, major), 55.8 (Ar–OCH3, major), 30.9 (=CHCOCH3, minor), 30.8 (=CHCOCH3, major), 19.4 (CH3, minor), 19.0 (CH3, major), 15.15 (N=CCH3, major), 15.05 (N=CCH3, minor). IR (UATR) νmax 3356, 2935, 2841, 1805 (CO), 1668 (C=N), 1604, 1488, 1443, 1369 cm–1. HRMS (ESI) calcd. for C17H18NO5 [M + H]+: 316.1180, found 316.1177.

(Z)-2,4-Dimethyl-4-(3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)oxazol-5(4H)-one (Z-3ej) and (E)-2,4-Dimethyl-4-(3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)oxazol-5(4H)-one (E-3ej)

Following the general procedure, using compound 1e (118 mg, 0.50 mmol, 1 equiv), l-alanine 4j (67.1 mg, 0.75 mmol, 1.5 equiv), NaOAc (46.7 mg, 0.57 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by column chromatography on silica gel using 0–50% EtOAc in CH2Cl2 to furnish compound Z/E-3ej (52.1 mg, 30% (>99:1 Z/E)).

Z-3ej

(52.1 mg, 30% (90:10 dr) mixture of isomer) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 8.02–7.92 (m, 2H, Ar–H, major), 7.76–7.66 (m, 1H, Ar–H, major), 7.56–7.34 (m, 6H, Ar–H, major), 6.59 (s, 1H, =CHCOPh, minor), 6.54 (s, 1H, =CHCOPh, major), 5.85 (s, 1H, ArCHO, minor), 5.83 (s, 1H, ArCHO, major), 2.12 (s, 3H, N=CCH3, major), 2.05 (s, 3H, N=CCH3, minor), 1.75 (s, 3H, CH3, minor), 1.71 (s, 3H, CH3, major). 13C{1H} NMR (75 MHz, CDCl3) δ 188.6 (COPh, major), 177.2 (COO, major), 165.9 (=CO, major), 164.4 (N=CCH3, major), 139.8 (major), 139.3 (major), 134.7 (major), 131.8 (major), 131.7 (minor), 131.6 (minor), 131.5 (major), 129.8 (major), 129.7 (minor), 128.4 (2C, minor), 128.3 (2C, major), 127.8 (2C, major), 122.4 (major), 121.9 (major), 121.8 (minor), 121.6 (minor), 92.9 (=CHCOPh, minor), 92.5 (=CHCOPh, major), 88.5 (ArCHO, minor), 87.8 (ArCHO, major), 71.5 (C, major), 20.0 (CH3, minor), 19.2 (CH3, major), 15.1 (N=CCH3, major), 14.8 (N=CCH3, minor). IR (UATR) νmax 3277, 3061, 2941, 2613, 1733 (CO), 1655 (C=N), 1587, 1566, 1467, 1375 cm–1. HRMS (ESI) calcd. for C21H18NO4 [M + H]+: 348.1230, found 348.1231.

(Z)-4-(6-Chloro-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-2,4-dimethyloxazol-5(4H)-one (Z-3fj) and (E)-4-(6-Chloro-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-2,4-dimethyloxazol-5(4H)-one (E-3fj)

Following the general procedure, using compound 1f (134 mg, 0.50 mmol, 1 equiv), l-alanine 4j (66.2 mg, 0.74 mmol, 1.5 equiv), NaOAc (46.5 mg, 0.57 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by short-pad silica gel eluted with 5–15% EtOAc in CH2Cl2 to furnish compound Z/E-3fj (106 mg, 56% (73:27 Z/E)).

Z-3fj

(77.2 mg, 41% (82:18 dr) mixture of isomer) as a brown sticky-gum. 1H NMR (400 MHz, CDCl3) δ 7.97 (dd, J = 8.4, 1.6 Hz, 2H, Ar–H, major), 7.66 (d, J = 8.4 Hz, 1H, Ar–H, major), 7.56–7.43 (m, 5H, Ar–H, major), 6.55 (s, 1H, =CHCOPh, minor), 6.50 (s, 1H, =CHCOPh, major), 5.80 (s, 1H, ArCHO, major), 2.13 (s, 3H, N=CCH3, major), 1.71 (s, 3H, CH3, minor), 1.70 (s, 3H, CH3, major). 13C{1H} NMR (100 MHz, CDCl3) δ 188.4 (COPh, major), 177.2 (COO, minor), 176.9 (COO, major), 164.7 (=CO, major), 164.6 (N=CCH3, major), 164.58 (=CO, minor), 163.2 (N=CCH3, minor), 140.8 (major), 140.6 (minor), 139.6 (minor), 139.5 (major), 137.9 (minor), 137.7 (major), 133.3 (major), 132.0 (major), 131.9 (minor), 130.34 (major), 130.32 (minor), 128.5 (minor), 128.3 (2C, major), 127.9 (minor), 127.8 (2C, major), 122.9 (major), 122.88 (major), 122.8 (minor), 122.3 (minor), 93.2 (=CHCOPh, minor), 92.8 (=CHCOPh, major), 87.8 (ArCHO, minor), 87.2 (ArCHO, major), 71.8 (C, minor), 71.4 (C, major), 19.8 (CH3, minor), 19.1 (CH3, major), 15.1 (N=CCH3, major), 14.9 (N=CCH3, minor). IR (UATR) νmax 3061, 2937, 1822 (CO), 1730 (CO), 1655 (C=N), 1599, 1587, 1567, 1232 cm–1. HRMS (ESI) calcd. for C21H16ClNNaO4 [M + Na]+: 404.0660, found 404.0665.

E-3fj

(29.0 mg, 15%) as a brown sticky-gum. 1H NMR (300 MHz, CDCl3) δ 9.40 (d, J = 8.4 Hz, 1H, Ar–H), 8.04–7.94 (m, 2H, Ar–H), 7.59–7.42 (m, 5H, Ar–H), 6.81 (s, 1H, =CHCOPh), 5.65 (s, 1H, ArCHO), 2.16 (s, 3H, N=CCH3), 1.69 (s, 3H, CH3). 13C{1H} NMR (75 MHz, CDCl3) δ 189.3 (COPh), 177.5 (COO), 169.1 (=CO), 164.1 (N=CCH3), 143.2, 139.7, 138.4, 132.2, 130.9, 130.2, 129.7, 128.5 (2C), 127.9 (2C), 122.0, 98.3 (=CHCOPh), 85.0 (ArCHO), 71.5 (C), 19.1 (CH3), 15.1 (N=CCH3). IR (UATR) νmax 3063, 2928, 2853, 2200, 1824 (CO), 1743 (CO), 1663 (C=N), 1601, 1588, 1575, 1465, 1448, 1426, 1376 cm–1. HRMS (ESI) calcd. for C21H17ClNO4 [M + H]+: 382.0841, found 382.0843.

(Z)-4-(6-Fluoro-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-2,4-dimethyloxazol-5(4H)-one (Z-3gj) and (E)-4-(6-Fluoro-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-2,4-dimethyloxazol-5(4H)-one (E-3gj)

Following the general procedure, using compound 1g (128 mg, 0.51 mmol, 1 equiv), l-alanine 4j (69.6 mg, 0.78 mmol, 1.5 equiv), NaOAc (47.9 mg, 0.58 mmol, 5 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by column chromatography on silica gel using 2–50% EtOAc in CH2Cl2 to furnish compound Z/E-3gj (44.4 mg, 24% (>99:1 Z/E)).

Z-3gj

(44.4 mg, 24%) as a brown solid. Mp 152.0–153.5 °C. 1H NMR (300 MHz, CDCl3) 8.04–7.92 (m, 2H, Ar–H), 7.72 (dd, J = 8.4, 4.8 Hz, 1H, Ar–H), 7.58–7.40 (m, 3H, Ar–H), 7.30–7.12 (m, 2H, Ar–H), 6.47 (s, 1H, =CHCOPh), 5.80 (s, 1H, ArCHO), 2.14 (s, 3H, N=CCH3), 1.70 (s, 3H, CH3). 13C{1H} NMR (75 MHz, CDCl3) δ 188.4 (COPh), 176.9 (COO), 164.9 (=CO), 164.62 (d, 1JC–F = 252.0 Hz, CF), 164.59 (N=CCH3), 141.6 (d, 3JC–F = 9.3 Hz), 139.6, 131.9, 130.7, 128.3 (2C), 127.8 (2C), 123.8 (d, 3JC–F = 9.8 Hz), 117.8 (d, 2JC–F = 23.7 Hz), 110.0 (d, 2JC–F = 24.8 Hz), 92.4 (d, 6JC–F = 1.4 Hz, =CHCOPh), 87.2 (d, 4JC–F = 2.9 Hz, ArCHO), 71.4 (C), 19.2 (CH3), 15.1 (N=CCH3). 19F{1H} NMR (376 MHz, CDCl3) δ – 109.47. IR (UATR) νmax 3064, 2959, 1820 (CO), 1802 (CO), 1682 (C=N), 1653, 1592, 1575, 1481, 1447, 1376 cm–1. HRMS (ESI) calcd. for C21H17FNO4 [M + H]+: 366.1136, found 366.1128.

(Z)-4-(6-Methoxy-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-2,4-dimethyloxazol-5(4H)-one (Z-3hj) and (E)-4-(6-Methoxy-3-(2-oxo-2-phenylethylidene)-1,3-dihydroisobenzofuran-1-yl)-2,4-dimethyloxazol-5(4H)-one (E-3hj)

Following the general procedure, using compound 1h (132 mg, 0.50 mmol, 1 equiv), l-alanine 4j (67.0 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv), the crude product was purified by short-pad silica gel eluted with 5–15% EtOAc in CH2Cl2 to furnish compound Z/E-3hj (56.0 mg, 30% (60:40 Z/E)), and minor product was decomposed in a further purification process.

Z-3hj

(33.9 mg, 18%) as a brown sticky-gum. 1H NMR (300 MHz, CDCl3) 7.97(dd, J = 8.8, 1.6 Hz, 2H, Ar–H), 7.64 (d, J = 8.4 Hz, 1H, Ar–H), 7.53–7.40 (m, 3H, Ar–H), 7.04 (dd, J = 8.4, 2.0 Hz, 1H, Ar–H), 6.94 (d, J = 2.0 Hz, 1H, Ar–H), 6.43 (s, 1H, =CHCOPh), 5.77 (s, 1H, ArCHO), 3.88 (s, 3H, Ar−OCH3), 2.14 (s, 3H, N=CCH3), 1.71 (s, 3H, CH3). 13C{1H} NMR (75 MHz, CDCl3) δ 188.5 (COPh), 177.0 (COO), 166.3 (=CO), 164.4 (N=CCH3), 162.7, 141.6, 140.0, 131.6, 128.2 (2C), 127.8 (2C), 127.0, 123.3, 116.5, 107.4, 91.2 (=CHCOPh), 87.3 (ArCHO), 71.4 (C), 55.8 (Ar–OCH3), 19.2 (CH3), 15.1 (N=CCH3). IR (UATR) νmax 3060, 2939, 1807 (CO), 1739 (CO), 1546, 1487, 1229 cm–1. HRMS (ESI) calcd. for C22H19NNaO5 [M + Na]+: 400.1155, found 400.1153.

(Z)-4-Benzyl-4-(3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2-phenyloxazol-5(4H)-one (Z-3′ag) and (E)-4-Benzyl-4-(3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2-phenyloxazol-5(4H)-one (E-3′ag)

Following the general procedure, using compound 1a (86.7 mg, 0.50 mmol, 1 equiv), dl-phenylalanine 4g (124 mg, 0.75 mmol, 1.5 equiv), Et3N (0.08 mL, 0.55 mmol, 1.1 equiv), and Bz2O (227 mg, 1.01 mmol, 2 equiv) in CH3CN (0.24 mL), the crude product was purified by column chromatography on silica gel using 2–10% EtOAc in CH2Cl2 to furnish compound Z/E-3′ag (97.3 mg, 46% (71:29 Z/E)).

Z-3′ag

(69.2 mg, 33% (71:29 dr) mixture of isomer) as a brown sticky-gum. 1H NMR (300 MHz, CDCl3) δ 7.81–7.75 (m, 2H, Ar–H, major), 7.72–7.67 (m, 2H, Ar–H, minor), 7.62–7.12 (m, 12H, Ar–H, major), 6.02 (s, 1H, ArCHO, major), 6.01 (s, 1H, ArCHO, minor), 5.81 (s, 1H, =CHCOCH3, minor), 5.73 (s, 1H, =CHCOCH3, major), 3.60 (AB q, J = 13.5 Hz, 2H, CH2Ph, major), 3.47 (AB q, J = 13.2 Hz, 2H, CH2Ph, minor), 2.57 (s, 3H, =CHCOCH3, minor), 2.51 (s, 3H, =CHCOCH3, major). 13C{1H} NMR (75 MHz, CDCl3) δ 197.4 (COCH3, minor), 197.1 (COCH3, major), 175.9 (COO, minor), 175.5 (COO, major), 164.9 (=CO, minor), 164.7 (=CO, major), 162.4 (N=CPh, major), 161.4 (N=CPh, minor), 138.6 (major), 134.1 (major), 133.8 (minor), 133.2 (major), 132.91 (minor), 132.87 (major), 131.7 (minor), 131.5 (major), 130.3 (2C, major), 130.2 (2C, minor), 129.9 (major), 129.8 (minor), 128.8 (2C, major), 128.6 (2C, minor), 128.3 (2C, major), 128.2 (2C, minor), 127.9 (2C, major), 127.8 (2C, minor), 127.6 (major), 127.5 (minor), 124.9 (major), 124.8 (minor), 122.5 (major), 122.1 (major), 121.9 (minor), 99.3 (=CHCOCH3, minor), 98.9 (=CHCOCH3, major), 88.0 (ArCHO, minor), 87.1 (ArCHO, major), 77.1 (C, minor), 76.9 (C, major), 39.8 (CH2Ph, major), 39.3 (CH2Ph, minor), 31.1 (=CHCOCH3, minor), 31.0 (=CHCOCH3, major). IR (UATR) νmax 3063, 3034, 2922, 1817 (CO), 1633 (C=N), 1602, 1495, 1467 cm–1. HRMS (ESI) calcd. for C27H22NO4 [M + H]+: 424.1543, found 424.1538.

E-3′ag

(28.1 mg, 13% (85:15 dr) mixture of isomer) as a pale-yellow sticky-gum. 1H NMR (300 MHz, CDCl3) δ 9.32 (d, J = 7.8 Hz, 1H, Ar–H, major), 7.82–7.76 (m, 2H, Ar–H, major), 7.68–7.62 (m, 2H, Ar–H, minor), 7.59–7.52 (m, 1H, Ar–H, major), 7.52–7.46 (m, 1H, Ar–H, major), 7.46–7.39 (m, 4H, Ar–H, major), 7.39–7.30 (m, 1H, Ar–H, major), 7.25–7.14 (m, 4H, Ar–H, major), 6.31 (s, 1H, ArCHO, minor), 6.17 (s, 1H, ArCHO, major), 5.82 (s, 1H, =CHCOCH3, major), 3.55 (s, 2H, CH2Ph, major), 3.43 (AB q, J = 13.2 Hz, 2H, CH2Ph, minor), 2.32 (s, 3H, =CHCOCH3, minor), 2.22 (s, 3H, =CHCOCH3, major). 13C{1H} NMR (75 MHz, CDCl3) δ 196.5 (COCH3, minor), 196.4 (COCH3, major), 176.4 (COO, minor), 175.7 (COO, major), 168.4 (=CO, minor), 168.2 (=CO, major), 162.3 (N=CPh, major), 161.4 (N=CPh, minor), 141.3 (minor), 141.1 (major), 133.2 (major), 133.0 (major), 132.8 (minor), 132.3 (major), 132.1 (minor), 131.9 (major), 130.4 (2C, major), 130.3 (2C, minor), 129.8 (major), 129.7 (minor), 129.0 (minor), 128.8 (2C, major), 128.6 (2C, minor), 128.3 (2C, major), 128.2 (major), 128.0 (2C, major), 127.9 (2C, minor), 127.5 (major), 125.2 (major), 124.9 (minor), 121.6 (major), 121.1 (minor), 102.0 (=CHCOCH3, minor), 101.6 (=CHCOCH3, major), 85.5 (ArCHO, minor), 84.4 (ArCHO, major), 77.2 (C, minor), 76.9 (C, major), 39.9 (CH2Ph, major), 39.4 (CH2Ph, minor), 32.0 (=CHCOCH3, minor), 31.9 (=CHCOCH3, major). IR (UATR) νmax 3033, 2925, 1818 (CO), 1777 (CO), 1650 (C=N), 1608, 1591, 1578, 1496, 1467, 1452 cm–1. HRMS (ESI) calcd. for C27H22NO4 [M + H]+: 424.1543, found 424.1536.

Mechanistic Investigation

(4R)-4-(Hydroxy(2-(3-oxobut-1-yn-1-yl)phenyl)methyl)-2-phenyloxazol-5(4H)-one (5a)

To a suspension of compound 1a (172 mg, 1.00 mmol, 1 equiv), hippuric acid 4a (269 mg, 1.50 mmol, 1.5 equiv), NaOAc (41.0 mg, 0.50 mmol, 0.5 equiv) and Ac2O (0.47 mL, 5.00 mmol, 5 equiv) were added in a sealed tube and stirred at 60 °C for 1 h. The reaction mixture was allowed to cool to room temperature and then quenched with sat. Na2CO3 (5 mL) and extracted with CH2Cl2 (3 × 10 mL). Combined organic layers were washed with sat. Na2CO3 until pH = 7, followed by water and brine, dried over anh. Na2SO4, and concentrated to give a yellow-brown solid. The crude product was purified by precipitation with cooled EtOH, filter off solid, and washed with cooled EtOH and hexane to afford desired product 5a (186 mg, 56%) as a pale-yellow solid. Mp 168.8–170.1 °C. 1H NMR (300 MHz, CDCl3) δ 8.77–8.69 (m, 1H, Ar–H), 8.16 (dd, J = 7.0, 1.5 Hz, 2H, Ar–H), 7.65–7.48 (m, 6H, Ar–H), 5.62 (br t, J = 7.2 Hz, 1H, ArCHOH), 5.10 (d, J = 7.2 Hz, 1H, – OH), 2.49 (overlapped, 4H, COCH3 and CHN=). 13C{1H} NMR (75 MHz, CDCl3) δ 205.8 (COCH3), 166.8 (COO), 161.8 (N=CPh), 149.9, 146.6, 137.8, 133.0, 132.8, 130.0, 129.0, 128.9 (2C), 128.15, 128.10 (2C), 125.7, 124.9, 74.7 (ArCHOH), 60.4 (CHN=), 32.8 (COCH3). IR (UATR) νmax 3326 (OH), 2926, 1781 (CO), 1711 (CO), 1656 (C=N) cm–1. HRMS (ESI) calcd. for C20H15NNaO4 [M + Na]+: 356.0893, found 356.0900.

(Z)-3-(2-Oxopropylidene)-1,3-dihydroisobenzofuran-1-yl Acetate (6a)

Following the general procedure, compound 1a (87.0 mg, 0.50 mmol, 1 equiv), NaOAc (45.0 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv) were stirred at 80 °C for 4 h. The crude product was purified by column chromatography on silica gel using 20–30% EtOAc in hexane to afford compound 6a (53.8 mg, 46%) as a pale-yellow solid (1H NMR data identical to that in the literature).19a

4-(2-(3-(N-Acetylacetamido)-3-benzyl-4-oxooxetan-2-yl)phenyl)but-3-yn-1-yl Acetate (9)

Following the general procedure, using compound 1i(28) (121 mg, 0.69 mmol, 1 equiv), dl-phenylalanine 4g (172 mg, 1.04 mmol, 1.5 equiv), NaOAc (63.9 mg, 0.78 mmol, 1.1 equiv), and Ac2O (0.33 mL, 3.45 mmol, 5 equiv), the crude product was purified by column chromatography on silica gel using 2% EtOAc in CH2Cl2 to furnish compound 9 (95.9 mg, 32%) as a pale-yellow sticky-gum. 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J = 6.0 Hz, 1H, Ar–H), 7.46 (d, J = 6.0 Hz, 1H, Ar–H), 7.42–7.24 (m, 2H, Ar–H), 7.22–7.15 (m, 3H, Ar–H), 7.04–6.96 (m, 2H, Ar–H), 6.66 (s, 1H, ArCHO), 4.36 (t, J = 6.0 Hz, 2H, OCH2CH2), 3.33 (d, J = 12.0 Hz, 1H, CHHPh), 2.30 (t, J = 7.5 Hz, 2H, (≡CCH2), 2.69 (d, J = 12.0 Hz, 1H, CHHPh), 2.07 (s, 3H, CH3CO), 2.00 (s, 3H, CH3CO), 1.99 (s, 3H CH3COO). 13C{1H} NMR (75 MHz, CDCl3) δ 177.9 (COO), 171.0 (CH3COO), 168.5 (CO), 162.1 (CO), 136.8, 133.3, 132.1, 130.2 (2C), 128.5, 128.3, 128.2, 128.1 (2C), 127.3, 123.7, 91.6 (C ≡ ), 79.7 (C ≡ ), 77.9 (C), 74.7 (ArCHO), 62.3 (OCH2), 38.9 (CH2Ph), 20.8 (CH3), 20.7 (CH3), 20.2 (≡CCH2), 14.7 (OCOCH3). IR (UATR) νmax 3256, 3077, 3051, 2995, 2931, 1759 (CO), 1634, 1486, 1419, 1361 cm–1. HRMS (ESI) calcd. for C26H26NO6 [M + H]+: 448.1755, found 448.1746.

(Z)-6-Fluoro-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl Acetate (6c)

Following the general procedure, compound 1c (95.1 mg, 0.50 mmol, 1 equiv), l-proline 4k (86.4 mg, 0.75 mmol, 1.5 equiv), NaOAc (45.7 mg, 0.55 mmol, 1.1 equiv), and Ac2O (0.24 mL, 2.50 mmol, 5 equiv) were stirred at 80 °C for 3 h. The crude product was purified by chromatography on silica gel using 15% EtOAc in hexane to furnish compound 6c (38.4 mg, 31%) as a brown solid. Mp 130.0–131.0 °C. 1H NMR (300 MHz, CDCl3) δ 7.59 (dd, JH–H = 8.1 Hz and JH–F = 4.5 Hz, 1H, Ar–H), 7.55 (s, 1H, Ar–H), 7.31–7.25 (m, 1H, Ar–H), 7.23 (s, 1H, ArCHO), 5.76 (s, 1H, =CHCOCH3), 2.49 (s, 3H, =CHCOCH3), 2.20 (s, 3H, CH3). 13C{1H} NMR (75 MHz, CDCl3) δ 197.1 (COCH3), 169.4 (COO), 164.9 (d, 1JC–F = 252.6 Hz, CF), 161.4 (=CO), 140.4 (d, 3JC–F = 9.5 Hz), 129.3 (d, 4JC–F = 2.3 Hz), 123.6 (d, 3JC–F = 9.5 Hz), 118.9 (d, 2JC–F = 23.9 Hz), 110.8 (d, 2JC–F = 24.7 Hz), 100.4 (d, 6JC–F = 1.7 Hz, =CHCOCH3), 98.2 (d, 4JC–F = 2.8 Hz, ArCHO), 31.0 (=CHCOCH3), 20.9 (CH3). 19F{1H} NMR (376 MHz, CDCl3) δ – 109.14. IR (UATR) νmax 3256, 3077, 3051, 2995, 2931, 1759 (CO), 1634, 1486, 1419, 1361 cm–1. HRMS (ESI) calcd. for C13H11FNaO4 [M + Na]+: 273.0534, found 273.0539.

Hydrolysis and Oxidation of Indeno[2,1-c]pyran-3-one 2a

N-(1-Methyl-3,9-dioxo-3,9-dihydroindeno[2,1-c]pyran-4-yl)benzamide (10)

Compound 2a (37.5 mg, 0.10 mmol, 1 equiv) was treated with 5% KOH in EtOH (0.18 mL) and stirred at room temperature (26 °C) for 5 min. The reaction mixture was quenched with 2 N HCl (0.20 mL) and extracted with CH2Cl2 (3 × 5 mL). Combined organic layers were washed with water and brine and dried over anh. Na2SO4 and concentrated to give an orange yellow solid which was further used in the next step without purification. The crude reaction was dissolved with CH2Cl2 (1.5 mL), and PCC was added (32.0 mg, 0.15 mmol, 1.5 equiv) and stirred at room temperature (26 °C) for 1.5 h. After completion, the mixture was filtered through a short silica gel column, eluent with CH2Cl2, and then the solvent was removed. The residue was purified by column chromatography on silica gel using 40% EtOAc in hexane to afford the compound 10 (14.2 mg, 43% (2 steps)) as a pale-yellow solid. Mp 278.6–280.0 °C. 1H NMR (300 MHz, CDCl3) δ 8.28 (br s, 1H, – NH), 8.10–7.80 (m, 3H, Ar–H), 7.80–7.40 (m, 6H, Ar–H), 2.74 (s, 3H, =CCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 187.9 (CO), 165.8 (=CO), 161.5 (CO), 161.1 (COO), 141.4, 139.0, 138.7, 134.8, 132.9, 132.1, 129.0 (2C), 128.1, 127.8 (3C), 124.0, 113.6, 113.5, 16.6 (CH3). IR (UATR) νmax 3324, 3238, 1735 (CO), 1709 (CO), 1659 (CO), 1504, 1473 cm–1. HRMS (ESI) calcd. for C20H13NNaO4 [M + Na]+: 354.0737, found 354.0735.

Ethyl (E)-2-Benzamido-2-(2-(1-hydroxyethyl)-1H-inden-1-ylidene)acetate (11)

To a suspension of compound 2a (38.0 mg, 0.10 mmol, 1 equiv) in EtOH (1.5 mL) NaBH4 (15.0 mg, 0.40 mmol, 4 equiv) was added and stirred at room temperature (26 °C) for 18 h. The reaction mixture was quenched with water (1 mL) and extracted with EtOAc (3 × 5 mL). Combined organic layers were washed with water and brine, dried over anh. Na2SO4, and concentrated to give yellow oil. The residue was purified by PTLC using 30% EtOAc in hexane to afford the compound 11 (15.0 mg, 41%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 11.53 (br s, 1H, – NH), 8.00 (dd, J = 7.2, 1.6 Hz, 2H, Ar–H), 7.56–7.50 (m, 1H, Ar–H), 7.47–7.39 (m, 3H, Ar–H), 7.22–7.10 (m, 3H, Ar–H), 6.73 (s, 1H, ArCH=), 4.92–4.83 (m, 1H, CH3CHOH), 4.64–4.49 (m, 2H, OCH2CH3), 2.74 (d, J = 8.0 Hz, 1H, – OH), 1.63 (d, J = 6.8 Hz, 3H, CH3CHOH), 1.43 (t, J = 7.2 Hz, 3H, OCH2CH3). 13C{1H} NMR (100 MHz, CDCl3) δ 165.9 (CO), 165.1 (COO), 140.9, 140.2, 135.2, 132.5, 132.3, 130.4, 129.9, 128.7 (2C), 128.0 (2C), 127.1, 125.6, 123.7, 122.0, 121.5, 66.0 (CH3CHOH), 62.4 (OCH2CH3), 21.5 (CH3CHOH), 13.7 (OCH2CH3). IR (UATR) νmax 3380 (OH), 3069, 2933, 1719 (CO), 1658 (CO), 1610, 1324, 1272 cm–1. HRMS (ESI) calcd. for C22H21NNaO4 [M + Na]+: 386.1363, found 386.1367.

4-Benzyl-4-(6-fluoro-3-(2-oxopropyl)-1,3-dihydroisobenzofuran-1-yl)-2-methyloxazol-5(4H)-one (12)

A suspension of compound Z-3cg (75.8 mg, 0.2 mmol, 1 equiv) and Pd/C (10.8 mg, 0.10 mmol, 50 mol %) in EtOAc (5 mL) was stirred at room temperature (25 °C) under H2 atmosphere (40 bar). After being stirred for 24 h, the palladium catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to give the crude product, which was further purified by column chromatography on silica gel using 50% EtOAc in hexane to furnish compound 12 (40.4 mg, 53% (72:28 dr) mixture of isomer) as a pale-yellow viscous oil. 1H NMR (400 MHz, CDCl3) δ 7.31–7.10 (m, 6H, Ar–H, major), 7.04 (t, J = 8.6 Hz, 1H, Ar–H, major), 6.95 (d, J = 8.4 Hz, 1H, Ar–H, major), 6.84 (d, J = 8.4 Hz, 1H, Ar–H, minor), 5.71–5.63 (m, 1H, ArCHCH2, major), 5.51 (s, 1H, ArCHO, major), 5.48 (s, 1H, ArCHO, minor), 3.33 (AB q, J = 13.4 Hz, 2H, CH2Ph, minor), 3.36 (AB q, J = 13.2 Hz, 2H, CH2Ph, major), 3.14 (dd, J = 16.4, 8.0 Hz, 1H, ArCHCHH, major), 2.87 (dd, J = 16.4, 4.8 Hz, 1H, ArCHCHH, major), 2.32 (s, 3H, COCH3, minor), 2.30 (s, 3H, COCH3, major), 2.05 (s, 3H, N=CCH3, major), 1.77 (s, 3H, N=CCH3, minor). 13C{1H} NMR (100 MHz, CDCl3) δ 206.9 (COCH3, minor), 206.6 (COCH3, major), 177.7 (COO, minor), 176.7 (COO, major), 163.3 (N=CCH3, major), 162.7 (d, 1JC–F = 244.6 Hz, CF, major), 162.6 (d, 1JC–F = 244.7 Hz, CF, minor), 161.6 (N=CCH3, minor), 138.31 (d, 3JC–F = 8.4 Hz, major), 138.26 (d, 3JC–F = 8.2 Hz, minor), 137.58 (major), 137.56 (minor), 133.8 (minor), 133.4 (major), 130.3 (2C, major), 130.2 (2C, minor), 128.2 (2C, major), 128.1 (2C, minor), 127.4 (major), 127.3 (minor), 123.1 (d, 3JC–F = 8.9 Hz, major), 123.0 (d, 3JC–F = 7.9 Hz, minor), 116.4 (d, 2JC–F = 23.1 Hz, major), 116.1 (d, 2JC–F = 23.0 Hz, minor), 109.4 (d, 2JC–F = 24.2 Hz, major), 108.8 (d, 2JC–F = 24.0 Hz, minor), 85.5 (ArCHO, minor), 85.4 (ArCHO, major), 79.93 (ArCHCH2, major), 79.88 (ArCHCH2, minor), 77.8 (C, minor), 77.76 (C, major), 50.7 (ArCHCH2CO, major), 50.6 (ArCHCH2CO, minor), 39.6 (CH2Ph, minor), 39.4 (CH2Ph, major), 31.1 (COCH3, minor), 30.8 (COCH3, major), 14.8 (N=CCH3, major), 14.4 (N=CCH3, minor). 19F{1H} NMR (376 MHz, CDCl3) δ – 117.10 (major), – 117.14 (minor). IR (UATR) νmax 3368, 3031, 2924, 2875, 1713 (CO), 1615, 1519, 1489, 1431, 1402, 1364 cm–1. HRMS (ESI) calcd. C22H20FNNaO4 for [M + Na]+: 404.1269, found 404.1272.

Ethyl (Z)-2-Acetamido-2-(6-fluoro-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-3-phenylpropanoate (Z-13)

Compound Z-3cg (76.0 mg, 0.20 mmol) was treated with 5% KOH in EtOH (0.33 mL) and stirred at room temperature (25 °C) for 5 min. The reaction mixture was quenched with 2 N HCl (0.20 mL) and extracted with CH2Cl2 (3 × 5 mL). Combined organic layers were washed with water and brine, dried over anh. Na2SO4, and concentrated in vacuo. The crude product was purified by precipitation with CH2Cl2 in EtOAc to afford the compound Z-13 (84.3 mg, 99%) as a white solid. Mp 195.0–195.5 °C. 1H NMR (300 MHz, CDCl3) δ 7.53 (dd, JH–H = 8.4 Hz and JH–F = 4.8 Hz, 1H, Ar–H), 7.39 (dd, J = 8.4, 2.1 Hz, 1H, Ar–H), 7.32–7.24 (m, 3H, Ar–H), 7.19 (td, J = 8.4, 2.1 Hz, 1H, Ar–H), 7.13–7.03 (m, 2H, Ar–H), 6.67 (s, 1H, ArCHO), 6.54 (br s, 1H, – NH), 5.66 (s, 1H, =CHCOCH3), 4.03 (q, J = 7.2 Hz, 2H, OCH2CH3), 4.02 (d, J = 12.5 Hz, 1H, CHHPh), 3.42 (d, J = 12.5 Hz, 1H, CHHPh), 2.43 (s, 3H, =CHCOCH3), 1.97 (s, 3H, CH3CONH), 0.99 (t, J = 7.2 Hz, 3H, OCH2CH3). 13C{1H} NMR (75 MHz, CDCl3) δ 197.0 (CO), 170.0 (CONH), 168.9 (COO), 164.6 (d, 1JC–F = 251.0 Hz, CF), 164.3 (=CO), 143.3 (d, 3JC–F = 9.6 Hz), 134.1, 130.1 (d, 4JC–F = 2.1 Hz), 129.7 (2C), 128.6 (2C), 127.6, 123.1 (d, 3JC–F = 9.5 Hz), 117.3 (d, 2JC–F = 23.9 Hz), 111.7 (d, 2JC–F = 25.1 Hz), 98.2 (=CHCOCH3), 86.8 (d, 4JC–F = 2.9 Hz, ArCHO), 68.2 (C), 62.4 (OCH2CH3), 37.3 (CH2Ph), 30.9 (=CHCOCH3), 23.9 (NHCOCH3), 13.6 (OCH2CH3). 19F{1H} NMR (376 MHz, CDCl3) δ – 109.96. IR (UATR) νmax 3282 (NH), 3034, 2930, 1727 (CO), 1683 (CO), 1632 (CO), 1615, 1482, 1371, 1264, 1257 cm–1. HRMS (ESI) calcd. C24H24FNNaO5 for [M + Na]+: 448.1531, found 448.1522.

(Z)-N-(1-(6-Fluoro-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2-phenyl-1-(4-tosyloxazol-5-yl)ethyl)acetamide (Z-14)

A suspension of compound Z-3cg (75.9 mg, 0.20 mmol, 1 equiv) and TosMIC (78.2 mg, 0.40 mmol, 2 equiv) in CH2Cl2 (0.1 M) was added with NaH (22.1 mg, 0.50 mmol, 2.5 equiv) and stirred at room temperature (26 °C) for 1 h. The reaction mixture was quenched with water (0.50 mL) and extracted with CH2Cl2 (3 × 5 mL). Combined organic layers were washed with water and brine and dried over anh. Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 50% EtOAc in hexane to afford the compound Z-14 (55.0 mg, 48%) as a white solid. Mp 224.0–225.0 °C. 1H NMR (300 MHz, CDCl3) δ 9.20 (br s, 1H, – NH), 7.67 (s, 1H, OCH=N), 7.38 (dd, JH–H = 8.6 Hz and JH–F = 4.5 Hz, 1H, Ar–H), 7.31 (d, J = 8.4 Hz, 2H, Ar–H), 7.25–7.03 (m, 8H, Ar–H and ArCHO), 6.79–6.73 (m, 2H, Ar–H), 5.63 (s, 1H, =CHCOCH3), 4.55 (AB q, J = 13.8 Hz, 1H, CHHPh), 3.78 (AB q, J = 13.8 Hz, 1H, CHHPh), 2.61 (s, 3H, =CHCOCH3), 2.41 (s, 3H, CH3), 2.27 (s, 3H, NHCOCH3). 13C{1H} NMR (75 MHz, CDCl3) δ 197.0 (CO), 171.3 (CONH), 164.8 (d, 1JC–F = 253.0 Hz, CF), 164.2, 150.1, 149.2 (OCH=N), 145.7, 142.4 (d, 3JC–F = 9.4 Hz), 140.0, 135.0, 134.9, 129.8 (2C), 129.4 (2C), 129.0 (d, 4JC–F = 2.1 Hz), 128.5 (2C), 128.2 (2C), 127.2, 123.6 (d, 3JC–F = 9.6 Hz), 117.8 (d, 2JC–F = 23.9 Hz), 110.4 (d, 2JC–F = 24.8 Hz), 98.5 (=CHCOCH3), 86.9 (d, 4JC–F = 2.6 Hz, ArCHO), 66.3 (C), 38.7 (CH2Ph), 31.1 (=CHCOCH3), 24.3 (NHCOCH3), 21.7 (CH3). 19F{1H} NMR (376 MHz, CDCl3) δ – 108.49. IR (UATR) νmax 3305 (NH), 3066, 2959, 2872, 1680 (CO), 1638 (CO), 1618, 1597, 1521, 1481, 1456 cm–1. HRMS (ESI) calcd. C31H27FN2NaO6S for [M + Na]+: 597.1466, found 597.1475.

Ethyl (Z)-2-Acetamido-2-(6-fluoro-3-(2-oxo-1-phenylpropylidene)-1,3-dihydroisobenzofuran-1-yl)-3-phenylpropanoate (15:15′)

A suspension of compound Z-13 (132 mg, 0.30 mmol, 1 equiv) and 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.07 mL, 0.30 mmol, 1 equiv) in CH3CN (3 mL, 0.1 M) was added with CsF (228 mg, 1.5 mmol, 5 equiv) and stirred at 80 °C for 21 h. The resulting mixture was filtrated through short-pad silica gel, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel using 15–80% EtOAc in hexane to furnish compounds 15:15′ (77.8 mg, 51% (65:35 dr))

15

(47.3 mg) as a white solid. Mp. 199.4–201.1 °C. 1H NMR (300 MHz, CDCl3) δ 7.50–7.41 (m, 3H, Ar–H), 7.32–7.23 (m, 3H, Ar–H), 7.21–7.14 (m, 2H, Ar–H), 7.11–7.04 (m, 2H, Ar–H), 6.98 (dd, J = 8.0, 2.0 Hz, 1H, Ar–H), 6.81 (s, 1H, ArCHO), 6.72 (td, J = 8.8, 2.2 Hz, 1H, Ar–H), 6.51 (br s, 1H, – NH), 5.91 (dd, JH–H = 8.9 Hz and JH–F = 5.0 Hz, 1H, Ar–H), 4.29 (AB q, J = 13.8 Hz, 1H, CHHPh), 4.04 (dq, J = 10.8, 7.2 Hz, 1H, OCHHCH3), 3.87 (dq, J = 10.8, 7.2 Hz, 1H, OCHHCH3), 3.76 (AB q, J = 13.5 Hz, 1H, CHHPh), 2.75 (s, 3H, =CCOCH3), 2.12 (s, 3H, NHCOCH3), 1.13 (t, J = 7.1 Hz, 3H, OCH2CH3). 13C{1H} NMR (75 MHz, CDCl3) δ 197.3 (CO), 170.4 (CONH), 169.9 (COO), 163.6 (d, 1JC–F = 252.1 Hz, CF), 162.6, 143.4, 135.8, 135.0, 131.0 (2C), 129.8 (d, 4JC–F = 2.4 Hz), 129.7 (2C), 129.2 (2C), 128.5 (2C), 128.0, 127.8 (d, 3JC–F = 9.2 Hz), 127.3, 116.7 (d, 2JC–F = 22.9 Hz), 115.7 (d, 6JC–F = 1.6 Hz), 109.8 (d, 2JC–F = 23.6 Hz), 83.4 (d, 4JC–F = 2.9 Hz, ArCHO), 68.0 (C), 62.7 (OCH2CH3), 36.9 (CH2Ph), 32.6 (=CCOCH3), 24.5 (NHCOCH3), 13.8 (OCH2CH3). 19F{1H} NMR (376 MHz, CDCl3) δ – 110.72. IR (UATR) νmax 3311 (NH), 3060, 3032, 2983, 1737 (CO), 1674 (CO), 1647 (CO), 1605, 1595, 1497, 1475, 1456, 1443, 1365 cm–1. HRMS (ESI) calcd. C30H28FNNaO5 for [M + Na]+: 524.1844, found 524.1849.

15′

(30.5 mg) as a white solid. Mp. 200.0–201.5 °C. 1H NMR (400 MHz, CDCl3) δ 7.49–7.41 (m, 3H, Ar–H), 7.35–7.24 (m, 4H, Ar–H), 7.16–7.06 (m, 4H, Ar–H), 6.76 (t, J = 8.4 Hz, 1H, Ar–H), 6.70 (s, 1H, ArCHO), 6.57 (br s, 1H, – NH), 5.91 (dd, JH–H = 8.8 Hz and JH–F = 4.8 Hz, 1H, Ar–H), 4.10–4.00 (m, 3H, OCH2CH3 and CHHPh), 3.46 (AB q, J = 12.6 Hz, 1H, CHHPh), 2.52 (s, 3H, =CCOCH3), 2.01 (s, 3H, NHCOCH3), 0.99 (t, J = 7.2 Hz, 3H, OCH2CH3). 13C{1H} NMR (100 MHz, CDCl3) δ 197.2 (CO), 170.1 (CONH), 169.1 (COO), 163.7 (d, 1JC–F = 251.3 Hz, CF), 161.9, 144.3 (d, 3JC–F = 9.4 Hz), 135.8, 134.3, 131.0 (2C), 130.1 (d, 4JC–F = 2.4 Hz), 129.7 (2C), 129.2 (2C), 128.6 (2C), 128.0, 127.6 (d, 3JC–F = 10.0 Hz), 127.5, 116.4 (d, 2JC–F = 22.9 Hz), 115.6 (d, 6JC–F = 1.6 Hz), 110.9 (d, 2JC–F = 24.8 Hz), 85.2 (d, 4JC–F = 2.8 Hz, ArCHO), 68.5 (C), 62.4 (OCH2CH3), 37.0 (CH2Ph), 32.3 (=CCOCH3), 24.0 (NHCOCH3), 13.6 (OCH2CH3). 19F{1H} NMR (376 MHz, CDCl3) δ – 111.23. IR (UATR) νmax 3319 (NH), 3059, 2983, 2930, 1733 (CO), 1670 (CO), 1591, 1542, 1497, 1474, 1457, 1444, 1367 cm–1. HRMS (ESI) calcd. C30H28FNNaO5 for [M + Na]+: 524.1844, found 524.1842.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.4c03842.Crystallographic data of molecular structure of compound Z-3ag (CIF)

Crystallographic data of molecular structure of compound E-3cg (CIF)

Crystallographic data of molecular structure of compound Z-13 (CIF)

Crystallographic data of molecular structure of compound 15 (CIF)

Experimental details, characterization data, and 1H and 13C{1H} NMR and HRMS data of all the compounds (PDF)

Supplementary Material

ao4c03842_si_001.cif

ao4c03842_si_002.cif

ao4c03842_si_003.cif

ao4c03842_si_004.cif

ao4c03842_si_005.pdf

The authors declare no competing financial interest.

Acknowledgments

This work was supported by the Thailand Science Research and Innovation (TSRI), Grant Number FRB660044/0240 Project code 180874 for Chulabhorn Royal Academy and Grant Number 48296/4691996 for Chulabhorn Research Institute. The authors would like to thank Center of Excellence on Environmental Health and Toxicology (EHT), OPS, Ministry of Higher Education, Science, Research and Innovation for their excellent technical support.
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b Beck J. J. ; Chou S.-C. The Structural Diversity of Phthalides from the Apiaceae. J. Nat. Prod. 2007, 70 , 891–900. 10.1021/np0605586.17477571
c Ernst-Russell M. A. ; Chai C. L. L. ; Wardlaw J. H. ; Elix J. A. Euplectin and Coneuplectin, New Naphthopyrones from the Lichen Flavoparmelia euplecta. J. Nat. Prod. 2000, 63 , 129–131. 10.1021/np9903245.10650094
d Mueller D. ; Davis R. A. ; Duffy S. ; Avery V. M. ; Camp D. ; Quinn R. J. Antimalarial Activity of Azafluorenone Alkaloids from the Australian Tree Mitrephora diversifolia. J. Nat. Prod. 2009, 72 , 1538–1540. 10.1021/np900247f.19591451
e Zhang W. ; Liu Z. ; Li S. ; Lu Y. ; Chen Y. ; Zhang H. ; Zhang G. ; Zhu Y. ; Zhang G. ; Zhang W. ; Liu J. ; Zhang C. Fluostatins I–K from the South China Sea-Derived Micromonospora rosaria SCSIO N160. J. Nat. Prod. 2012, 75 , 1937–1943. 10.1021/np300505y.23136829
f Kwon Y.-J. ; Sohn M.-J. ; Kim C.-J. ; Koshino H. ; Kim W.-G. Flavimycins A and B, Dimeric 1,3-Dihydroisobenzofurans with Peptide Deformylase Inhibitory Activity from Aspergillus flavipes. J. Nat. Prod. 2012, 75 , 271–274. 10.1021/np200720v.22329646
g Luan Y. ; Wei H. ; Zhang Z. ; Che Q. ; Liu Y. ; Zhu T. ; Mándi A. ; Kurtan T. ; Gu Q. ; Li D. Eleganketal A, a Highly Oxygenated Dibenzospiroketal from the Marine-Derived Fungus Spicaria elegans KLA03. J. Nat. Prod. 2014, 77 , 1718–1723. 10.1021/np500458a.24967847
h Luo X. ; Lin X. ; Salendra L. ; Pang X. ; Dai Y. ; Yang B. ; Liu J. ; Wang J. ; Zhou X. ; Liu Y. Isobenzofuranones and Isochromenones from the Deep-Sea Derived Fungus Leptosphaeria sp. SCSIO 41005. Mar. Drugs 2017, 15 , 204 10.3390/md15070204.28661451
i Tang Y.-T. ; Wu J. ; Yu Y. ; Bao M.-F. ; Tan Q.-G. ; Schinnerl J. ; Cai X.-H. Colored Dimeric Alkaloids from the Barks of Erythrina variegata and Their Neuroprotective Effects. J. Org. Chem. 2021, 86 , 13381–13387. 10.1021/acs.joc.1c01489.34546728
j Garcellano R. C. ; Moinuddin S. G. A. ; Young R. P. ; Zhou M. ; Bowden M. E. ; Renslow R. S. ; Yesiltepe Y. ; Thomas D. G. ; Colby S. M. ; Chouinard C. D. ; Nagy G. ; Attah I. K. ; Ibrahim Y. M. ; Ma R. ; Franzblau S. G. ; Lewis N. G. ; Aguinaldo A. M. ; Cort J. R. Isolation of Tryptanthrin and Reassessment of Evidence for Its Isobaric Isostere Wrightiadione in Plants of the Wrightia Genus. J. Nat. Prod. 2019, 82 , 440–448. 10.1021/acs.jnatprod.8b00567.30295480
Synthesis of indenopyrans for selected publications, see:

a Morrell A. ; Antony S. ; Kohlhagen G. ; Pommier Y. ; Cushman M. Synthesis of benz[d]indeno[1,2-b]pyran-5,11-diones: Versatile intermediates for the design and synthesis of topoisomerase I inhibitors. Bioorg. Med. Chem. Lett. 2006, 16 , 1846–1849. 10.1016/j.bmcl.2006.01.008.16442283
b Diac A. P. ; Tepeş A.-M. ; Soran A. ; Grosu I. ; Terec A. ; Roncali J. ; Bogdan E. Indenopyrans–synthesis and photoluminescence properties. Beilstein J. Org. Chem. 2016, 12 , 825–834. 10.3762/bjoc.12.81.27340473
c Johnson K. F. ; Schneider E. A. ; Schumacher B. P. ; Ellern A. ; Scanlon J. D. ; Stanley L. M. Rhodium-Catalyzed Enantioselective Intramolecular Hydroacylation of Trisubstituted Alkenes. Chem. Eur. J. 2016, 22 , 15619–15623. 10.1002/chem.201603880.27572933
d Godfrey N. A. ; Schatz D. J. ; Pronin S. V. Twelve-Step Asymmetric Synthesis of (−)-Nodulisporic Acid C. J. Am. Chem. Soc. 2018, 140 , 12770–12774. 10.1021/jacs.8b09965.30261724
e Thomas W. P. ; Pronin S. V. New Methods and Strategies in the Synthesis of Terpenoid Natural Products. Acc. Chem. Res. 2021, 54 , 1347–1359. 10.1021/acs.accounts.0c00809.33596652
f Hassan A. A. ; Brase S. ; Aly A. A. ; Mohamed N. K. ; El-Haleem L. E. A. ; Nieger M. Stereoselective synthesis of homochiral paracyclophanylindenofuranylimidazo[3.3.3]propellanes. Monatsh. Chem. 2021, 152 , 1571–1579. 10.1007/s00706-021-02853-0.
g Wu P. ; Zhang Y. ; Cheng Y. Sequential Ag(I) Salt and Chiral N-Heterocyclic Carbene Catalysis Enables Enantioselective and Diastereoselective Construction of Complex Heterocyclic Molecules and the Switch of Stereoselectivity. J. Org. Chem. 2022, 87 , 2779–2796. 10.1021/acs.joc.1c02703.35041426
h Hazra G. ; Mishra G. ; Dandela R. ; Thirupathi B. A Method to Access Highly Functionalized Dibenzobicyclo[3.2.1]octadienones: Application to the Construction of the 6/6/5/6/6 Carbon Skeleton of Rubialatin A. J. Org. Chem. 2022, 87 , 11925–11938. 10.1021/acs.joc.2c00340.35475607
For selected publications, see:

a Ondeyka J. G. ; Helms G. L. ; Hensens O. D. ; Goetz M. A. ; Zink D. L. ; Tsipouras A. ; Shoop W. L. ; Slayton L. ; Dombrowski A. W. ; Polishook J. D. ; Ostlind D. A. ; Tsou N. N. ; Ball R. G. ; Singh S. B. Nodulisporic Acid A, a Novel and Potent Insecticide from a Nodulisporium Sp. Isolation, Structure Determination, and Chemical Transformations. J. Am. Chem. Soc. 1997, 119 , 8809–8816. 10.1021/ja971664k.
b Hensens O. D. ; Ondeyka J. D. ; Dombrowski A. W. ; Ostlind D. A. ; Zink D. L. Isolation and structure of nodulisporic acid A1 and A2, novel insecticides from a Nodulisporium Sp. Tetrahedron Lett. 1999, 40 , 5455–5458. 10.1016/S0040-4039(99)01064-3.
c Singh S. B. ; Ondeyka J. G. ; Jayasuriya H. ; Zink D. L. ; Ha S. N. ; Dahl-Roshak A. ; Greene J. ; Kim J. A. ; Smith M. M. ; Shoop W. L. ; Tkacz J. S. Nodulisporic Acids D-F: Structure, Biological Activities, and Biogenetic Relationships. J. Nat. Prod. 2004, 67 , 1496–1506. 10.1021/np0498455.15387649
Biological activities of nodulisporic acid, see:

a Ondeyka J. G. ; Dahl-Roshak A. M. ; Tkacz J. S. ; Zink D. L. ; Zakson-Aiken M. ; Shoop W. L. ; Goetz M. A. ; Singh S. B. Nodulisporic Acid B, B1, and B2: A Series of 1′-Deoxy-nodulisporic Acids from Nodulisporium sp. Bioorg. Med. Chem. Lett. 2002, 12 , 2941–2944. 10.1016/S0960-894X(02)00621-2.12270179
b Ondeyka J. G. ; Byrne K. ; Vesey D. ; Zink D. L. ; Shoop W. L. ; Goetz M. A. ; Singh S. B. Nodulisporic Acids C, C1, and C2: A Series of D-Ring-Opened Nodulisporic Acids from the Fungus Nodulisporium sp. J. Nat. Prod. 2003, 66 , 121–124. 10.1021/np020339u.12542359
de Jesus A. E. ; Steyn P. S. ; van Heerden F. R. ; Vleggaar R. Structure Elucidation of the Janthitrems, Novel Tremorgenic Mycotoxins from Penicillium janthinellum. J. Chem. Soc. Perkin Trans. I. 1984, 697–701. 10.1039/p19840000697.
Belofsky G. N. ; Gloer J. B. ; Wicklow D. T. ; Dowd P. F. Antiinsectan Alkaloids: Shearinines A-C and a New Paxilline Derivative from the Ascostromata of Eupenicillium Shearii. Tetrahedron 1995, 51 , 3959–3968. 10.1016/0040-4020(95)00138-X.
Smetanina O. F. ; Kalinovsky A. I. ; Khudyakova Y. V. ; Pivkin M. V. ; Dmitrenok P. S. ; Fedorov S. N. ; Ji H. ; Kwak J.-Y. ; Kuznetsova T. A. Indole Alkaloids Produced by a Marine Fungus Isolate of Penicillium janthinellum Biourge. J. Nat. Prod. 2007, 70 , 906–909. 10.1021/np060396d.17555349
Rukachaisirikul V. ; Rodglin A. ; Sukpondma Y. ; Phongpaichit S. ; Buatong J. ; Sakayaroj J. Phthalide and Isocoumarin Derivatives Produced by an Acremonium sp. Isolated from a Mangrove Rhizophora apiculate. J. Nat. Prod. 2012, 75 , 853–858. 10.1021/np200885e.22524636
Lin G. ; Chan S. S.-K. ; Chung H.-S. ; Li S.-L. Chemistry and Biological Activities of Naturally Occurring Phthalides. Studies in Natural Products Chemistry 2005, 32 , 611–669. 10.1016/S1572-5995(05)80065-1.
Mitsuhashi H. ; Muramatsu T. ; Nagai U. ; Nakano T. ; Ueno K. Studies on the Constituents of Umbelliferae Plants. VIII. Distribution of Alkylphthalides in Umbelliferae Plants. Chem. Pharm. Bull. 1963, 11 , 1317–1319. 10.1248/cpb.11.1317.
(Z)-3-Butylidenephthalide from Ligusticum porter, see:

a León A. ; Toscano R. A. ; Tortoriello J. ; Delgado G. Phthalides and other constituents from Ligusticum porteri; sedative and spasmolytic activities of some natural products and derivatives. Nat. Prod. Res. 2011, 25 , 1234–1242. 10.1080/14786419.2010.534735.21797735
b Brindis F. ; Rodríguez R. ; Bye R. ; González-Andrade M. ; Mata R. (Z)-3-Butylidenephthalide from Ligusticum porteri, an α-Glucosidase Inhibitor. J. Nat. Prod. 2011, 74 , 314–320. 10.1021/np100447a.20879744
Kwon J.-H. ; Ahn Y.-J. Acaricidal Activity of Butylidenephthalide Identified in Cnidium officinale Rhizome against Dermatophagoides farinae and Dermatophagoides pteronyssinus (Acari: Pyroglyphidae). J. Agric. Food Chem. 2002, 50 , 4479–4483. 10.1021/jf020293a.12137464
Deng S. ; Chen S.-N. ; Yao P. ; Nikolic D. ; van Breemen R. B. ; Bolton J. L. ; Fong H. H. S. ; Farnsworth N. R. ; Pauli G. F. Serotonergic Activity-Guided Phytochemical Investigation of the Roots of Angelica sinensis. J. Nat. Prod. 2006, 69 , 536–541. 10.1021/np050301s.16643021
For selected publications, see:

a Zhang J. ; Han X. An Unexpected Addition of Acetic Acid to ortho-Electron-Deficient Alkynyl-Substituted Aryl Aldehydes Catalyzed by Palladium(II) Acetate. Adv. Synth. Catal. 2014, 356 , 2465–2470. 10.1002/adsc.201301170.
b Zhang R. ; Zhu H. ; Meng X. ; Cao Z. ; Chen G. ; Tian L. ; Sun X. ; You J. Base-Mediated Domino Reaction of ortho-Carbonylated Alkynyl Substituted Arenealdehydes with Indoles: Access to Indole Functionalized Isobenzofurans. Eur. J. Org. Chem. 2017, 2017 , 2615–2620. 10.1002/ejoc.201700050.
c Mancuso R. ; Mehta S. ; Gabriele B. ; Salerno G. ; Jenks W. S. ; Larock R. C. A Simple and Mild Synthesis of 1H-Isochromenes and (Z)-1-Alkylidene1,3-dihydroisobenzofurans by the Iodocyclization of 2-(1-Alkynyl)benzylic Alcohols. J. Org. Chem. 2010, 75 , 897–901. 10.1021/jo902333y.20043652
d Son E. C. ; Kim S. Y. ; Kim S.-G. Squaramide-Catalyzed Asymmetric Intramolecular Oxa-Michael Reaction of α,β-Unsaturated Carbonyls Containing Benzyl Alcohol: Construction of Chiral 1-Substituted Phthalans. J. Org. Chem. 2021, 86 , 6826–6839. 10.1021/acs.joc.1c00715.33904749
e Wei L.-L. ; Wei L.-M. ; Lin P.-Y. ; Chen C.-C. ; Pan W.-B. ; Wu M.-J. Palladium(0)-catalyzed 5-exo-dig O-cyclization/coupling of ethyl 3-(2-alkynylphenyl)-3-oxopropanoates with aryl iodides to 1,3-dihydroisobenzofurans. Tetrahedron Lett. 2015, 56 , 6629–6632. 10.1016/j.tetlet.2015.10.040.
f Sreenivasulu C. ; Satyanarayana G. Time and Temperature Dependent Palladium-Catalyzed Stereo- and Regioselective Alkoxy-arylation of Triple Bonds: Synthesis of (E)/(Z)-1,1-Disubstituted-3-(1-Phenylalkylidene)-1,3-dihydroisobenzofurans. J. Org. Chem. 2021, 86 , 8182–8196. 10.1021/acs.joc.1c00666.34097385
Tang R.-Y. ; Li J.-H. PdCl2-Catalyzed Domino Reactions of 2-Alkynylbenzaldehydes with Indoles: Synthesis of Fluorescent 5H-Benzo[b]carbazol-6-yl Ketones. Chem. Eur. J. 2010, 16 , 4733–4738. 10.1002/chem.201000133.20349473
Mariaule G. ; Newsome G. ; Toullec P. Y. ; Belmont P. ; Michelet V. Silver-Catalyzed Domino Hydroarylation/Cycloisomerization Reactions of ortho-Alkynylbenzaldehydes: An Entry to Functionalized Isochromene Derivatives. Org. Lett. 2014, 16 , 4570–4573. 10.1021/ol5021256.25133776
Zhu H. ; Cao Z. ; Meng X. ; Tian L. ; Chen G. ; Sun X. ; You J. Acid-mediated domino reaction of ortho-carbonylated alkynyl-substituted arylaldehydes with phenols: Rapid access to fused indeno[2,1-c]chromen-7-one derivatives. Tetrahedron 2017, 73 , 3310–3315. 10.1016/j.tet.2017.04.041.
Worayuthakarn R. ; Deesiri S. ; Chainok K. ; Wannarit N. ; Ruchirawat S. ; Thasana N. Highly Regioselective Tandem Reaction of Ene-Yne-Oxazolones Induced by H-Phosphonates: Construction of Phosphinylindane Derivatives. J. Org. Chem. 2021, 86 , 9360–9383. 10.1021/acs.joc.1c00609.34213338
For selected publications, see:

a Allinger N. L. ; Wang G. L. ; Dewhurst B. B. Some Kinetic and Mechanistic Studies of the Dakin-West Reaction. J. Org. Chem. 1974, 39 , 1730–1735. 10.1021/jo00925a029.
b Godfrey A. G. ; Brooks D. A. ; Hay L. A. ; Peters M. ; McCarthy J. R. ; Mitchell D. Application of the Dakin-West Reaction for the Synthesis of Oxazole-Containing Dual PPARα/γ Agonists. J. Org. Chem. 2003, 68 , 2623–2632. 10.1021/jo026655v.12662031
c Misra N. C. ; Ila H. 4-Bis(methylthio)methylene-2-phenyloxazol-5-one: Versatile Template for Synthesis of 2-Phenyl-4,5-functionalized Oxazoles. J. Org. Chem. 2010, 75 , 5195–5202. 10.1021/jo100941f.20670028
Data of minor product E-3ag was collected by using Et3N as a base under EPA conditions (Table 2, entry 10). (E)-4-Benzyl-2-methyl-4-(3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)oxazol-5(4H)-one (E-3ag) (81:19 dr (mixture of isomer)) as a brown sticky-gum. 1H NMR (300 MHz, CDCl3) δ 9.48–9.40 (m, 1H, Ar−H, major), 7.58–7.40 (m, 3H, Ar−H, major), 7.30–7.12 (m, 5H, Ar−H, major), 6.28 (s, 1H, =CHCOCH3, minor), 6.18 (s, 1H, =CHCOCH3, major), 5.75 (s, 1H, ArCHO, minor), 5.74 (s, 1H, ArCHO, major), 3.41 (s, 2H, CH2Ph, major), 3.40 (AB q, J = 13.2 Hz, 2H, CH2Ph, minor), 2.30 (s, 3H, =CHCOCH3, minor), 2.27 (s, 3H, =CHCOCH3, major), 1.96 (s, 3H, N=CCH3, major), 1.72 (s, 3H, N=CCH3, minor). 13C{1H} NMR (75 MHz, CDCl3) δ 196.3 (COCH3, major), 176.0 (COO, major), 168.1 (=CO, major), 163.7 (N=CCH3, major), 141.1 (minor), 141.0 (major), 133.2 (minor), 132.9 (major), 132.2 (major), 132.0 (minor), 131.9 (major), 130.3 (2C, major), 130.2 (2C, minor), 129.8 (major), 129.6 (minor), 128.24 (2C, major), 128.19 (major), 128.06 (minor), 127.5 (major), 127.4 (minor), 121.5 (major), 120.6 (minor), 101.9 (=CHCOCH3, minor), 101.3 (=CHCOCH3, major), 85.1 (ArCHO, minor), 84.3 (ArCHO, major), 76.9 (C, minor), 76.5 (C, major), 39.5 (CH2Ph, minor), 38.9 (CH2Ph, major), 31.9 (=CHCOCH3, major), 14.6 (N=CCH3, major), 14.2 (N=CCH3, minor). IR (UATR) νmax 3034, 2928, 1820 (CO), 1681 (CO), 1608, 1509, 1577, 1496, 1466, 1456, 1432, 1384 cm–1. HRMS (ESI) calcd. for C22H19NNaO4 [M + Na]+: 384.1206, found 384.1206.

Data of minor product E-3cg was collected from gram scale synthesis of 3cg. (E)-4-Benzyl-4-(6-fluoro-3-(2-oxopropylidene)-1,3-dihydroisobenzofuran-1-yl)-2-methyloxazol-5(4H)-one (E-3cg) (57 mg, 78:22 dr (mixture of isomer)) as a pale-yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.39 (dd, JH-H = 8.9 Hz and JH-F = 5.3 Hz, 1H, Ar−H, major), 7.31–7.14 (m, 6H, Ar−H, major), 7.11 (dd, J = 8.1, 2.1 Hz, 1H, Ar−H, major), 7.00 (dd, J = 8.0, 2.0 Hz, 1H, Ar−H, minor), 6.25 (s, 1H, =CHCOCH3, minor), 6.15 (s, 1H, =CHCOCH3, major), 5.70 (s, 1H, ArCHO, major), 3.39 (AB q, J = 13.2 Hz, 2H, CH2Ph, major), 3.34 (AB q, J = 13.2 Hz, 2H, CH2Ph, minor), 2.30 (s, 3H, =CHCOCH3, minor), 2.27 (s, 3H, =CHCOCH3, major), 1.98 (s, 3H, N=CCH3, major), 1.79 (s, 3H, N=CCH3, minor). 13C{1H} NMR (100 MHz, CDCl3) δ 196.6 (COCH3, minor), 196.5 (COCH3, major), 176.4 (COO, minor), 175.8 (COO, major), 167.3 (=CO, major), 164.6 (d, 1JC-F = 253.0 Hz, CF, major), 164.1 (N=CCH3, major), 163.1 (N=CCH3, minor), 144.0 (d, 3JC-F = 9.1 Hz, minor), 143.8 (d, 3JC-F = 9.3 Hz, major), 132.9 (minor), 132.7 (major), 130.7 (d, 3JC-F = 9.5 Hz, major), 130.6 (minor), 130.4 (2C, major), 130.3 (2C, minor), 128.5 (d, 4JC-F = 1.9 Hz, major), 128.4 (2C, major), 128.3 (2C, minor), 127.7 (major), 127.6 (minor), 117.4 (d, 2JC-F = 22.2 Hz, major), 117.2 (d, 2JC-F = 22.2 Hz, minor), 109.1 (d, 2JC-F = 24.8 Hz, major), 108.4 (d, 2JC-F = 24.6 Hz, minor), 101.6 (d, 6JC-F = 2.0 Hz, =CHCOCH3, minor), 101.0 (d, 6JC-F = 1.2 Hz, =CHCOCH3, major), 84.7 (d, 4JC-F = 3.4 Hz, ArCHO, minor), 83.9 (d, 4JC-F = 2.8 Hz, ArCHO, major), 77.2 (C, minor), 76.4 (C, major), 39.3 (CH2Ph, minor), 39.1 (CH2Ph, major), 31.9 (=CHCOCH3, major), 14.7 (N=CCH3, major), 14.4 (N=CCH3, minor). 19F{1H} NMR (376 MHz, CDCl3) δ – 108.21 (minor), – 108.54 (major). IR (UATR) νmax 3034, 2929, 1824 (CO), 1678 (CO), 1615, 1583, 1496, 1478, 1456, 1432, 1385 cm–1. HRMS (ESI) calcd. for C22H18FNNaO4 [M + Na]+: 402.1112, found 402.1116.

Melhado A. D. ; Luparia M. ; Toste F. D. Au(I)-Catalyzed Enantioselective 1,3-Dipolar Cycloadditions of Münchnones with Electron-Deficient Alkenes. J. Am. Chem. Soc. 2007, 129 , 12638–12639. 10.1021/ja074824t.17900190
Wang J. ; Zhu H.-T. ; Chen S. ; Luan C. ; Xia Y. ; Shen Y. ; Li Y.-X. ; Hua Y. ; Liang Y.-M. Electrophilic Cyclization and Intermolecular Acetalation of 2-(4-Hydroxybut-1-yn-1-yl)benzaldehydes: Synthesis of Diiodinated Diepoxydibenzo[c,k][1,9]dioxacyclohexadecine. J. Org. Chem. 2017, 82 , 10641–10649. 10.1021/acs.joc.7b01646.28862460
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a van Leusen A. M. ; Hoogenboom B. E. ; Siderius H. A Novel and Efficient Synthesis of Oxazoles from Tosylmethylisocyanide and Carbonyl Compounds. Tetrahedron Lett. 1972, 13 , 2369–2372. 10.1016/S0040-4039(01)85305-3.
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c Kumar K. TosMIC: A Powerful Synthon for Cyclization and Sulfonylation. ChemistrySelect 2020, 5 , 10298–10328. 10.1002/slct.202001344.
Liu J. ; Tang S. ; Zhao M. ; Huai J. ; Yu J. ; Zhao J. ; Li P. Reactivity of Vinyl Epoxides/Oxetanes/Cyclopropanes toward Arynes: Access to Functionalized Phenanthrenes. ACS Omega 2021, 6 , 35852–35865. 10.1021/acsomega.1c06166.34984314
