
==== Front
J Org Chem
J Org Chem
jo
joceah
The Journal of Organic Chemistry
0022-3263
1520-6904
American Chemical Society

39177357
10.1021/acs.joc.4c01152
Note
Preparation of 4-Allenyloxazolines from (Z)-2-En-4-yn-1-ol via Propargyl/Allenyl Isomerization
https://orcid.org/0009-0003-1387-8285
Hung Shi-Heng
Wang Yu-Min
Liu Yi-Hung
https://orcid.org/0000-0002-0544-006X
Liu Shiuh-Tzung *
Department of Chemistry, National Taiwan University, Taipei 106, Taiwan
* E-mail: stliu@ntu.edu.tw.
23 08 2024
06 09 2024
89 17 1276212768
09 05 2024
16 08 2024
31 07 2024
© 2024 The Authors. Published by American Chemical Society
2024
The Authors
https://creativecommons.org/licenses/by/4.0/ Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).

A novel method for the preparation of 4-allenyl-oxazolines 2 is described via the reaction of 2-en-4-yn-1-ols 1 with trichloroacetonitrile in the presence of DBU. Reaction proceeds through the nucleophilic attack of OH functionality in 1 to CCl3CN followed by cyclization, propargyl/allene isomerization, and protonation. In this investigation, it is noticed that propargyl/allene isomerization is sensitive to the substituents.

National Science and Technology Council 10.13039/100020595 NSTC112-2113-M-002-023 document-id-old-9jo4c01152
document-id-new-14jo4c01152
ccc-price
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pmcThe development of synthetic methods for the construction of allenyl heterocycles has been an attractive subject due to the ability of these heterocycles to engage in cyclization with the allenylic moieties.1 Furthermore, quite a few natural products and pharmaceutical molecules embody an allenyl moiety with pendant heterocycles.2 Oxazolines are one of the common heterocycles and are useful compounds serving as building blocks in organic synthesis, polymers and as pharmaceuticals.3 However, there are a number of reports concerning allenyl-oxazolidinones,4 but few with allenyl-oxazoline.5

One of the approaches leading to oxazoline rings is the reaction of an allylic alcohol with trichloroactonitrile (Scheme 1A).6 The initial nucleophilic attack of the oxygen center on the nitrile generates the imidate anion I, which subsequently undergoes a 5-exo closure with the iodiranium moiety in II to give the oxazoline product. Although the transformation of 1,3-enynes into allyenyl systems is well-documented,7 we imagined that substituted (Z)-2-en-4-yn-1-ol III might be useful to grant the 4-allenyl oxazolines (Scheme 1B). Presumably, reaction of III with CCl3CN gives intermediate IV, which undergoes propargyl/allenyl isomerization, followed by protonation to reach the final product. However, there is a possibility for the protonation taking place with the initially generated propargylic intermediate IV and resulting in the formation of a propargyl-substituted oxazoline.4c

Scheme 1 Preparation of Oxazolines from Reaction of Allyl Alcohol with CCl3CN

2-En-4-yn-1-ols are useful synthetic intermediates and could be prepared by addition to chalcone followed by acid-catalyzed isomerization as reported in our early works.8 This investigation began with the reaction of 1a with trichloroacetonitrile in the presence of DBU in dichloromethane at ambient temperature (eq 1). To our delight, the desired compound 2a was obtained in 43%. Compound 2a was characterized by NMR and ESI-MS spectroscopy. ESI-HRMS gives a signal at [M + H]+m/z = 502.0318, consistent with the molecular formula of C26H19Cl4NO. Three unique signals for Ha ∼ Hc in 1H NMR appeared at δ 6.93 (d, J = 2.3 Hz), 5.84 (d, J = 7.9 Hz) and 5.29 (dd, J = 7.9, 2.3 Hz). Based on the NOE effect between Ha and Hb as well as the coupling constants,6c the relative configurations along the oxazoline ring and allenylic hydrogen were assigned as shown in the structure 2a (eq 1). The trans-fashion between Hb and Hc was further confirmed by X-ray crystallography on the hydrolysis product (see below).1

Optimization of reaction conditions for better production of 2a was screened (Table 1). Running the reaction in CH2Cl2 without the addition of molecular sieves did not provide the desired product (entry 2), indicating the interference of moisture in the reaction. Screening various amounts of reagent and base (entries 3–7), it was found that the combination of CCl3CN (2 equiv) and DBU (1.5 equiv) provided a quantitative yield, which appears to be the best choice (entry 5). Reaction without the presence of DBU or the use of a catalytic amount of DBU provided unsatisfactory results (entry 7–8), indicating that the base is essential for the reaction. Other bases and solvents were also screened (entries 10–13), but the results were no better than the conditions shown in entry 5.

Table 1 Reaction Optimizationa

entry	CCl3CN (equiv)	Base (equiv)	Solvent	Yield (%)b	
1	1.5	DBU (1.5)	CH2Cl2	53 (43)	
2c	1.5	DBU (1.5)	CH2Cl2	0	
3	1.0	DBU (1.5)	CH2Cl2	50	
4	1.0	DBU (1.0)	CH2Cl2	38	
5	2.0	DBU (1.5)	CH2Cl2	99 (96)	
6	2.0	DBU (1.0)	CH2Cl2	82	
7	2.0	DBU (0.2)	CH2Cl2	28	
8	2.0	–	CH2Cl2	0	
9	2.0	DBU (1.5)	toluene	84	
10	2.0	Pyridine (1.5)	CH2Cl2	NR	
11	2.0	tBuOK (1.5)	CH2Cl2	d	
12	2.0	KOAc	CH2Cl2	d	
13	2.0	KOH	CH2Cl2	d	
a Reaction condition: 1a (0.2 mmol), CCl3CN, 4 Å MS and Base in 1 mL DCM were stirred at ambient temperature for 24 h.

b NMR isolated yields given in parentheses.

c No molecular sieve.

d Complicated mixture

With the optimized conditions, we next studied the reaction scope with various substituents on the substrates (Table 2). Reactions of various substituted aryl groups at R2 in 2-en-4-yn-1-ols (1a–1f) with CCl3CN in the presence of DBU gave the cyclized products 2a–2f in excellent yields except for the nitro substituent at the para position of the R2 group. Presumably, the strong electron withdrawing nature slows down the nucleophilic attack toward the nitrile substrate. However, when R1 groups are in various natures of substituents, the reactivity leading to the desired allenyl-oxazolines is completely different. When R1 is a p-fluorophenyl group in 1g, the reaction proceeded smoothly to grant the expected product 2g in 94% yield, and reactant 1h (R1 = p-bromophenyl) behaved similarly, giving 2h in 98% yield. To our surprise, substrate 1i (R1 = p-nitrophenyl) did undergo the formation of oxazoline ring but did not form the allenyl product. Apparently, the isomerization of propargyl into the allenyl group did not take place; instead, the propargyl intermediate underwent the abstraction of chlorinium ion from CCl3CN to generate 3 as the major product.9 For substrates with R1 = p-MeC6H4 or p-MeOC6H4 in 1j–1k, reactions went into a complicated mixture and were not able to identify the product. Possibly, the electron-donating nature makes C=C less electrophilic, thus inhibiting the nucleophilic attack for the ring formation. This observation was also found in compound 1p with the o-tolyl group (R1 = o-MeC6H4). Interestingly, when R1 is a methyl group, substrate 1l went through a different pathway giving amide 4 in 64% yield. We assumed that the initial imidate anion was not able to undergo nucleophilic ring formation. Alternatively, Overman rearrangement followed by tautomerization took place to give 4 as the final product (Scheme 2).10 Finally, the reactivity of two substrates with a different substituent at the R3 position was investigated. As a TMS group seated at R3, the reaction proceeded similarly to that of 1i, but providing a protonation product 5, not a chloride. The trimethylsilyl is known to be a good inductive electron releasing group,11 which increases the basicity of propargyl anion to accept a proton. When R3 came to be a butyl group, the reaction went to a mixture of unidentified compounds. Besides 1l (R3 = Ph), when the R3 group is a p-methylphenyl group in 1o, the expected product 2o was obtained in 33% yield, similar to that for 2d. For gram scale reactions, substrates 1a (1.076 g) and 1h (1.044 g) were subjected to the reaction under the optimized conditions to give 2a (1.449 g) and 2h (0.910 g) in yields of 96% and 78%, respectively, showing the practicality and applicability of the developed method.

Scheme 2 Pathway Leading to Compound 4

Table 2 Reaction Scopea

a Reaction conditions: A solution of 1 (0.2 mmol), DBU (1.5 equiv) and CCl3CN (2 equiv) and 4 Å MS in 1 mL CH2Cl2 was stirred at room temperature for 24 h. Isolated yield.

b Complicated mixture.

Hydrolysis of 2-(trichloromethyl)-4,5-dihydrooxazoles leading to trichloroacetamido-alcohols is a well-documented reaction.12 We selected several compounds 2 for hydrolysis under acidic conditions (Table 3). All reactions provided the desired products quantitatively and all obtained compounds are in solid form. Particularly, crystal structures of both 6c and 6h were obtained. Figure 1 illustrates the ORTEP plot of the molecule. The relative configuration at both C4 and C5 are consistent with the proposed structure by NMR spectroscopic analysis. Crystallographic details and an ORTEP plot of 6c are deposited in the Supporting Information.

Figure 1 ORTEP plot of 6h (30% probability ellipsoids)

Table 3 Hydrolysis of 2 under Acidic Conditionsa

Reactant	R1	R2	Product	Yield (%)	
2a	p-ClC6H4	m-MeC6H4	6a	99	
2b	p-ClC6H4	p-FC6H4	6b	99	
2c	p-ClC6H4	p-ClC6H4	6c	99	
2h	p-BrC6H4	p-MeC6H4	6h	99	
a Reaction conditions: A solution of 2 (0.2 mmol) and p-toluenesulfonic acid (0.2 mmol) in a mixture of MeCN (1.6 mL) and H2O (0.4 mL) was stirred at rt under nitrogen atmosphere for 0.5 h; isolated yield.

A possible reaction pathway is illustrated in Scheme 3. Nucleophilic attack of 1 with CCl3CN in the presence of DBU gives the intermediate Int-1, where R2 is seated at the pseudo equatorial position. This conformation is more stable than that of Int-2 with R2 in a pseudo axial position, which may cause the steric interaction with the alkynyl group. Intramolecular ring closure followed by propargyl/allenyl isomerization leads to Int-1′, which accepts a proton to give the final product 2.

Scheme 3 Possible Reaction Pathway

In summary, we have disclosed an efficient method to prepare 4-allenyl-oxazolines from readily accessible 2-en-4-yn-1-ols. Although there is a limitation of substituents in the molecules, it offers an easy way to prepare the desired allene-heterocycles. From the study of the reaction scope, we found that the nature of substituents affects the propargyl/allene isomerization dramatically. In our opinion, theoretical study of the reaction pathway including the activation energy might be the possible way to understand this query and is currently under investigation.

Experimental Section

General Information

1H and 13C NMR spectra were recorded in a 400 MHz or 800 MHz spectrometer in CDCl3 referenced to TMS. All chemicals were commercially purchased and used without further purification. Flash chromatography was performed using silica gel 230–400 mesh. Chalcone derivatives were prepared according to the literature procedure. In cases of known compounds, their spectral data were compared with the literature values. Melting points were determined on a Fargo MP-1D instrument. Unless otherwise noted, all the reactions were performed without any special precautions. Compounds 1 were prepared according to our previously reported method8 and spectral data are deposited in SI.

General Procedure for Preparation of 2

A solution of pent-2-en-4-yn-1-ols 1 (0.2 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 45 μL, 0.3 mmol, 1.5 equiv) and 4 Å MS in CH2Cl2 (1 mL) was stirred for 10 min. Trichloroacetonitrile (40 μL, 0.4 mmol, 2 equiv) was then added, and the reaction mixture was stirred at ambient temperature overnight. Saturated NaHCO3aqueous solution (10 mL) was added to quench the reaction. Upon extraction with Et2O (15 mL × 2), the organic extracts were washed with water (15 mL), brine (15 mL), dried over MgSO4 and concentrated. The residue was chromatographed on silica gel with an elution of dichloromethane/hexane.

4-(1-(4-Chlorophenyl)-3-phenylpropa-1,2-dien-1-yl)-5-(m-tolyl)-2-(trichloromethyl)-4,5-dihydrooxazole (2a). Pale-yellow oil (96.6 mg, 96%). Eluent: hexane/CH2Cl2 (10:1). 1H NMR (400 MHz, CDCl3): δ 7.52 (d, J = 8.6 Hz, 2H), 7.39–7.36 (m, 4H), 7.34–7.30 (m, 3H), 7.27 (d, J = 7.7 Hz, 1H), 7.20–7.18 (m, 1H), 7.13–7.10 (m, 1H), 7.05–7.04 (m, 1H), 6.93 (d, J = 2.3 Hz, 1H), 5.84 (d, J = 7.9 Hz, 1H), 5.29 (dd, J = 7.9, 2.3 Hz, 1H), 2.30 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 206.2, 162.3, 142.2, 138.8, 138.3, 133.6, 132.4, 132.3, 129.8, 128.9, 128.8, 128.2, 128.1, 127.1, 126.7, 122.9, 109.8, 102.3, 89.4, 74.7(2C), 21.2. HRMS (ESI-TOF) m/z [M + H]+ Calcd for C26H20Cl4NO: 502.0294, found 502.0318.

4-(1-(4-Chlorophenyl)-3-phenylpropa-1,2-dien-1-yl)-5-(p-fluorophenyl)-2-(trichloromethyl)-4,5-dihydrooxazole (2b). Pale-yellow oil (89.3 mg, 88%). Eluent: hexane/CH2Cl2 (10:1). 1H NMR (400 MHz, CDCl3): δ 7.50 (dd, J = 8.6, 1.3 Hz, 2H), 7.41–7.26 (m, 10H), 7.08 (t, J = 8.6 Hz, 2H), 6.94 (br, 1H), 5.86 (dd, J = 7.6, 1.2 Hz, 1H), 5.27 (dd, J = 7.6, 1.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 206.1, 163.0 (d, 2JC–F = 248.6 Hz), 134.2, 133.8, 132.3 (d, 4JC–F = 2.5 Hz) 129.0, 128.9, 128.2, 128.1, 128.0 (d, 3JC–F = 8.3 Hz), 127.1, 116.1, 115.9, 109.7, 102.4, 88.7, 86.4, 74.8(2C); 19F NMR (375 MHz, CDCl3): δ −111.8. HRMS (ESI-TOF) m/z [M + H]+ Calcd for C25H17Cl4FNO: 506.0043, found: 506.0058.

4-(1-(4-Chlorophenyl)-3-phenylpropa-1,2-dien-1-yl)-5-(p-chlorophenyl)-2-(trichloromethyl)-4,5-dihydrooxazole (2c). Yellow oil (93.2 mg, 89%). Eluent: hexane/CH2Cl2 (10:1). 1H NMR (400 MHz, CDCl3): δ 7.50 (d, J = 8.6 Hz, 2H), 7.39–7.32 (m, 10H), 7.22 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 2.3 Hz, 1H), 5.84 (d, J = 7.6 Hz, 1H), 5.25 (dd, J = 7.6, 2.3 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 206.1, 162.2, 136.9, 135.0, 133.8, 132.2(2C), 129.2, 128.9, 128.9, 128.2, 128.1, 127.2, 127.1, 109.6, 102.4, 88.5, 74.8(2C). HRMS (ESI-TOF) m/z [M + H]+ Calcd for C25H17Cl5NO: 521.9747, found 521.9753.

4-(1-(4-Chlorophenyl)-3-phenylpropa-1,2-dien-1-yl)-5-(p-methoxyphenyl)-2-(trichloromethyl)-4,5-dihydrooxazole (2d). Pale-yellow oil (88.3 mg, 85%). Eluent: hexane/CH2Cl2 (10:1). 1H NMR (400 MHz, CDCl3): δ 7.47 (d, J = 8.6 Hz, 2H), 7.38–7.36 (m, 4H), 7.33–7.30 (m, 3H), 7.23 (d, J = 8.8 Hz, 2H), 6.92–6.90 (m, 3H), 5.81 (d, J = 7.5 Hz, 1H), 5.29 (dd, J = 7.5, 2.2 Hz, 1H), 3.84 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 206.2, 162.4, 160.2, 133.6, 132.4(2C), 130.3, 128.9, 128.8, 128.1, 128.0, 127.7, 127.1, 114.4, 109.9, 102.2, 89.6, 74.5(2C), 55.3; HRMS (ESI-TOF) m/z [M + H]+ Calcd for C26H20Cl4NO2: 518.0243, found 518.0244.

4-(1-(4-Chlorophenyl)-3-phenylpropa-1,2-dien-1-yl)-5-(3,5-dimethoxyphenyl)-2-(trichloromethyl)-4,5-dihydrooxazole (2e). Pale-yellow oil (96.7 mg, 88%). Eluent: hexane/CH2Cl2 (10:1). 1H NMR (400 MHz, CDCl3): δ 7.53 (d, J = 8.6 Hz, 2H), 7.38–7.37 (m, 4H), 7.35–7.32 (m, 3H), 6.92 (d, J = 2.3 Hz, 1H), 6.46 (t, J = 2.2 Hz, 1H), 6.43 (d, J = 2.2 Hz, 2H), 5.82 (d, J = 7.3 Hz, 1H), 5.30 (dd, J = 7.3, 2.3 Hz, 1H), 3.72 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3): δ 206.2, 162.2, 161.2, 140.9, 133.7, 132.3, 132.3, 128.9, 128.8, 128.2, 128.1, 127.1, 110.0, 103.4, 102.3, 101.0, 89.1, 74.7(2C), 55.2; HRMS (ESI-TOF) m/z [M + H]+ Calcd for C27H22Cl4NO3, 548.0348, found 548.0363.

4-(1-(4-Chlorophenyl)-3-phenylpropa-1,2-dien-1-yl)-5-(p-nitrophenyl)-2-(trichloromethyl)-4,5-dihydrooxazole (2f). Yellow oil (39.5 mg, 37%). Eluent: hexane/CH2Cl2 (10:1). 1H NMR (400 MHz, CDCl3): δ 8.23 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 7.42–7.37 (m, 5H), 7.35 (d, J = 8.6 Hz, 2H), 6.98 (d, J = 2.2 Hz, 1H), 5.99 (d, J = 7.8 Hz, 2H), 5.25 (d, J = 7.8, 2.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 206.1, 162.1, 148.1, 145.3, 134.0, 131.9 (2C), 129.1, 128.9, 128.5, 128.2, 127.1, 126.4, 124.2, 109.4, 102.7, 87.5, 75.0(2C); HRMS (ESI-TOF) m/z [M + H]+ Calcd for C25H17Cl4N2O3: 532.9988, found 532.9981.

4-(1-(4-Fluorophenyl)-3-phenylpropa-1,2-dien-1-yl)-5-(p-methylphenyl)-2-(trichloromethyl)-4,5-dihydrooxazole (2g). Pale-yellow oil (87.6 mg, 90%). Eluent: hexane/CH2Cl2 (10:1). 1H NMR (400 MHz, CDCl3): δ 7.52 (dd, J = 8.8, 5.3 Hz, 2H), 7.37–7.31 (m, 5H), 7.22–7.18 (m, 4H), 7.04 (t, J = 8.7 Hz, 2H), 6.89 (d, J = 2.0 Hz, 1H), 5.83 (d, J = 7.4 Hz, 1H), 5.29 (7.4, 2.0 Hz, 1H), 2.38 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 206.0, 162.3, 139.1, 135.5, 132.6, 129.9, 129.6, 128.8, 128.6, 128.5, 127.9, 127.1, 126.0, 115.7, 115.5, 109.9, 102.0, 89.5, 74.9, 21.1; 19F NMR (375 MHz, CDCl3): δ −114.7. HRMS (ESI-TOF) m/z [M + H]+ Calcd for C26H20Cl3FNO: 486.0589, found 486.0591.

4-(1-(4-Bromophenyl)-3-phenylpropa-1,2-dien-1-yl)-5-(p-methylphenyl)-2-(trichloromethyl)-4,5-dihydrooxazole (2h). Pale-yellow oil (107.3 mg, 98%). Eluent: hexane/CH2Cl2 (10:1). 1H NMR (400 MHz, CDCl3): δ 7.48 (d, J = 8.8 Hz, 2H), 7.42 (d, J = 8.8 Hz, 2H), 7.39–7.30 (m, 5H), 7.20 (s, 4H), 6.91 (d, J = 2.2 Hz, 1H), 5.84 (d, J = 7.4 Hz, 1H), 5.30 (dd, J = 7.4, 2.2 Hz, 1H), 2.39 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 206.5, 162.7, 139.5, 135.7, 133.2, 132.6, 132.1, 130.0, 129.2, 128.7, 128.4, 127.4, 126.4, 122.1, 110.3, 102.7, 89.9, 74.9 (2C), 21.5; HRMS (ESI-TOF) m/z [M + H]+ Calcd for C26H20Cl3BrNO: 545.9788, found 545.9745.

4-(1-(4-Chlorophenyl)-3-(p-tolyl)propa-1,2-dien-1-yl)-5-(p-tolyl)-2-(trichloromethyl)-4,5-dihydrooxazole (2o). Light yellow oil (34.1 mg, 33%). Eluent: hexane/CH2Cl2 (10:1).1H NMR (400 MHz, CDCl3): δ7.43 (d, J = 8.6 Hz, 2H), 7.26 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.1 Hz, 2H), 7.17–7.12 (m, 6H), 6.85 (d, J = 2.1 Hz, 1H), 5.78 (d, J = 7.4 Hz, 1H), 5.23 (dd, J = 7.4 Hz, J = 2.1 Hz, 1H), 2.35 (s, 3H), 2.34 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 206.1, 139.1, 138.1 (2C), 135.6, 133.5, 132.7, 129.7 (2C), 129.4, 128.8, 128.2, 127.1, 126.0, 109.8, 102.2, 89.6, 86.6, 74.8, 21.3, 21.2. HRMS (ESI-TOF) m/z [M + H]+ Calcd for C27H22Cl4NO: 516.0450, found 516.0448.

4-(1-Chloro-1-(4-nitrophenyl)-3-phenylprop-2-yn-1-yl)-5-(p-tolyl)-2-(trichloromethyl)-4,5-dihydrooxazole (3). Yellow oil (87.7 mg, 80%). Eluent: hexane/CH2Cl2 (10:1). 1H NMR (400 MHz, CDCl3): δ 8.29 (d, J = 9.0 Hz, 2H), 8.03 (d, J = 9.0 Hz, 2H), 7.63–7.61 (m, 2H), 7.50–7.38 (m, 5H), 7.29 (d, J = 8.0 Hz, 2H), 6.34 (d, J = 5.4 Hz, 1H), 4.92 (d, J = 5.4 Hz, 1H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 164.8, 148.0, 145.4, 139.2, 135.7, 132.1, 129.8, 128.8, 128.4, 125.9, 123.4, 120.6, 91.6, 87.9, 86.2, 85.0, 83.5, 67.3, 21.2; HRMS (ESI-TOF) m/z [M + H]+ Calcd for C26H19Cl4N2O3: 547.0144, found 547.0158. The isotope pattern with Cl4 also agreed with theoretical analysis (see SI).

2,2,2-Trichloro-N-(3-methyl-5-phenyl-1-(p-tolyl)pent-1-en-4-yn-3-yl)acetamide (4). Off-white solid. (65.1 mg, 80%). Eluent: hexane/CH2Cl2 (9:1). mp 142–143 °C. 1H NMR (400 MHz, CDCl3): δ 7.55–7.53 (m, 2H), 7.38–7.36 (m, 5H), 7.17 (d, J = 7.8 Hz, 2H), 7.00 (d, J = 15.8 Hz, 1H), 6.99 (br, 1H), 6.50 (d, J = 15.8 Hz, 1H), 2.37 (s, 3H), 2.02 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3): δ 159.7, 138.1, 133.0, 131.8, 131.3, 129.2, 128.7, 128.2, 127.8, 126.8, 122.0, 87.9, 85.4, 54.6 (2C), 27.5, 21.1; HRMS (ESI-TOF) m/z [M + H]+ Calcd for C21H19Cl3NO: 406.0527, found 406.0538.

4-(1-(4-Chlorophenyl)-3-(trimethylsilyl)prop-2-yn-1-yl)-5-(p-tolyl)-2-(trichloromethyl)-4,5-dihydrooxazole (5). Yellow oil (81.9 mg, 82%). Eluent: hexane/CH2Cl2 (9:1). 1H NMR (400 MHz, CDCl3): δ 7.40 (d, J = 8.7 Hz, 2H), 7.36 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 7.0 Hz, 2H), 6.79 (d, J = 8.0 Hz, 2H), 5.74 (d, J = 5.6 Hz, 1H), 4.41 (t, J = 5.6 Hz, 1H), 4.35 (d, J = 5.6 Hz, 1H), 2.32 (s, 3H), 0.25 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3): δ 163.0, 138.3, 136.3, 134.7, 133.6, 129.5, 129.4, 128.8, 124.8, 101.4, 92.0, 86.4, 79.8 (2C), 42.8, 21.0, −0.1; HRMS (ESI-TOF) m/z [M + H]+ Calcd for C23H24Cl4NOSi: 498.0376, found 498.0382.

General Procedure for Hydrolysis of 2

To a solution of 4-allenyl-2-oxazoline 2 (0.2 mmol) in acetonitrile (1.2 mL) under a N2 atmosphere was added a solution of para-toluenesulfonic acid (1 equiv) in 0.8 mL of MeCN/H2O (v/v = 1:1). The reaction was stirred at ambient temperature for 0.5 h. A saturated NaHCO3 aqueous solution (10 mL) followed by ether (10 mL) was added. The organic portion was separated, and the aqueous portion was extracted with Et2O (10 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over MgSO4 and concentrated. The residue was purified by flash chromatography with elution of EtOAc/hexane to give the desired product.

2,2,2-Trichloro-N-(3-(4-chlorophenyl)-1-hydroxy-5-phenyl-1-(m-tolyl)penta-3,4-dien-2-yl)acetamide (6a). Off-white sold (103.2 mg, 99%). Eluent: EtOAc: hexane (1:9). mp 164–165 °C. 1H NMR (400 MHz, CDCl3): δ 7.36–7.25 (m, 10H), 7.23 (d, J = 6.9 Hz, 1H), 7.17 (d, J = 5.4 Hz, 1H), 7.14 (d, J = 7.7 Hz, 1H), 7.07 (s, 1H), 7.02 (d, J = 7.4 Hz, 1H), 6.68 (d, J = 2.6 Hz, 1H), 5.11 (dt, J = 8.9, 2.6 Hz, 1H), 4.97 (br, 1H), 2.23 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 205.9, 161.6, 140.2, 138.6, 134.1, 133.3, 132.8, 129.4, 129.4, 129.3, 128.9, 128.3, 128.3, 127.4, 126.7, 123.1, 109.7, 101.7, 72.9 (2C), 56.5, 21.7. HRMS (ESI-TOF) m/z [M + Na]+ Calcd for C26H21Cl4NO2Na: 542.0219, found 542.0200.

2,2,2-Trichloro-N-(3-(4-chlorophenyl)-1-hydroxy-5-phenyl-1-(p-fluorophenyl)penta-3,4-dien-2-yl)acetamide (6b). Off-white sold (104.0 mg, 99%). Eluent: EtOAc: hexane (1:9). mp 161–162 °C. 1H NMR (400 MHz, CDCl3): δ 7.45 (d, J = 8.6 Hz, 2H), 7.43–7.30 (m, 10H), 7.04 (t, J = 8.6 Hz, 2H), 6.80 (d, J = 2.6 Hz, 1H), 5.23 (dt, J = 9.1, 2.6 Hz, 1H), 5.11 (br, 1H), 2.44 (d, J = 3.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 205.5, 162.5 (d, 1JC–F = 245.9 Hz), 161.4, 135.7 (d, 4JC–F = 2.7 Hz), 134.0, 132.8, 132.3, 129.1, 129.0, 128.1, 127.9, 127.4 (d, 3JC–F = 8.2 Hz), 127.0, 115.5 (d, 2JC–F = 21.7 Hz), 109.3, 101.5, 92.3, 72.0, 56.2; HRMS (ESI-TOF) m/z [M + Na]+ Calcd for C25H18Cl4FNO2Na: 545.9968, found 545.9945.

2,2,2-Trichloro-N-(3-(4-chlorophenyl)-1-hydroxy-5-phenyl-1-(p-chlorophenyl)penta-3,4-dien-2-yl)acetamide (6c). Off-white sold (107.2 mg, 99%). Eluent: EtOAc: hexane (1:9). mp 168–169 °C. 1H NMR (400 MHz, CDCl3): δ 7.45–7.28 (m, 14H), 6.80 (d, J = 2.8 Hz, 1H), 5.20 (dt, J = 8.9, 2.8 Hz, 1H), 5.07 (br, 1H), 2.47 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 205.5, 161.4, 138.4, 134.1, 134.0, 132.7, 132.2, 129.1, 129.0, 128.7, 128.1, 127.9, 127.1, 127.0, 109.2, 101.5, 92.3, 72.0, 56.0. HRMS (ESI-TOF) m/z [M + H]+ Calcd for C25H18Cl5NO2Na: 561.9672, found 561.9650.

2,2,2-Trichloro-N-(3-(4-bromophenyl)-1-hydroxy-5-phenyl-1-(p-tolyl)penta-3,4-dien-2-yl)acetamide (6h). Off-white sold (112.0 mg, 99%). Eluent: EtOAc: hexane (1:9). mp 180–181 °C. 1H NMR (400 MHz, CDCl3): δ 7.52 (d, J = 8.5 Hz, 2H), 7.43–7.33 (m, 7H), 7.34–7.24 (m, 3H), 7.16 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 2.5 Hz, 1H), 5.20 (dt, J = 8.9, 2.5 Hz, 1H), 5.06 (d, J = 1.8 Hz, 1H), 2.36 (s, 3H), 2.34 (br, 1H); 13C{1H} NMR (100 MHz, CDCl3): δ 205.5, 161.3, 138.0, 137.1, 133.1, 133.0, 132.0, 129.3, 128.9, 128.7, 128.3, 127.9, 127.1, 125.6, 121.9, 109.5, 101.4, 92.5, 72.4, 56.2, 21.1. HRMS (ESI-TOF) m/z [M + Na]+ Calcd for C26H20BrCl3NO2Na: 585.9713, found 585.9702.

Crystallography

Crystals of 6c and 6h suitable for X-ray determination were obtained by recrystallization from diethyl ether/hexane solutions. Data were collected at room temperature on a Bruker D8 Venture diffractometer. The structure was solved using the SHELXS-97 program13 and refined using the SHELXL-97 program14 by full-matrix least-squares on F2 values.

Data Availability Statement

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

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.4c01152.ORTEP plot of 6c, crystal data of 6c and 6h, and spectra for all new compounds (1H NMR and 13C NMR) (PDF)

Supplementary Material

jo4c01152_si_001.pdf

The authors declare no competing financial interest.

Acknowledgments

We thank the National Science and Technology Council of Taiwan for financial support (NSTC112-2113-M-002-023). We also thank Instrumentation Center (NTU), Ministry of Science and Technology Taiwan for the assistance in X-ray crystallography. The mass spectrometry technical research services from NTU Consortia of Key Technologies for mass measurement is acknowledged.
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