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ACS Omega
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ACS Omega
2470-1343
American Chemical Society

10.1021/acsomega.4c05375
Article
Divergent Annulation Modes of (Z)-4-Aryl-4-oxo-2-(pyridin-2-yl)but-2-enenitrile and Methyl Nitroacetate: Selective Access to 2-Acyl-4H-quinolizin-4-one, Isoxazole, and 2-Acylindolizine
Lee Sunhee
Kim Woojin
https://orcid.org/0000-0002-0849-5517
Kim Ikyon *
College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, Republic of Korea
* Email: ikyonkim@yonsei.ac.kr. Tel.: +82 32 749 4515. Fax: +82 32 749 4105.
24 08 2024
10 09 2024
9 36 3812638141
08 06 2024
20 08 2024
10 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/).

Three different annulation modes of (Z)-4-aryl-4-oxo-2-(pyridin-2-yl)but-2-enenitrile in the reaction with methyl nitroacetate were discovered, allowing selective access to diverse heterocycles such as quinolizin-4-one, isoxazole, and indolizine with unique substitution patterns in good yields. Ease of operation, good chemical yields, and good functional group tolerance of our protocol enabled us to rapidly construct a number of synthetic analogs based on each scaffold under three reaction conditions.

National Research Foundation of Korea 10.13039/501100003725 NRF-2018R1A6A1A03023718 National Research Foundation of Korea 10.13039/501100003725 NRF-2020R1A2C2005961 document-id-old-9ao4c05375
document-id-new-14ao4c05375
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pmcIntroduction

As part of our ongoing research on annulative functionalization assembly of novel N-fused heterocycles,1 we recently described a modular approach to a wide variety of 2-acyl-3-aminoindolizines 2 by way of 1 utilizing pyridine-2-acetonitrile, (hetero)arylglyoxal, and TMSCN as building blocks (Scheme 1a).2 In order to install an ester moiety at the C3 site of the resulting indolizine 3, methyl nitroacetate was employed instead of TMSCN (Scheme 1b). We expected that Michael addition of methyl nitroacetate to the intermediate 1 would provide A which would undergo cyclization to give B. Final loss of proton and HNO2 from B would occur to afford the indolizine 3.3 In the course of our study with this aim, however, we discovered that three different types of compounds were obtained as major products from the reaction of 1 with methyl nitroacetate depending on the reaction conditions (Scheme 1c). Divergent approaches to several heterocycles from common intermediates are efficient ways to maximize structural diversity,4 which can be achieved by changing either the reacting partners5 or reaction conditions.6 As the substitution patterns around the core skeletons synthesized in this study are unknown in the literature even if each basic structure is well-known, we decided to investigate the divergent annulation of the common intermediate 1 and methyl nitroacetate under three different reaction conditions, which we wish to describe here.

Scheme 1 Use of 1 for the Synthesis of N-Fused Heterocycles

Results and Discussion

From our previous experience on the synthesis of 2 from 1, we began our optimization study with 1a, methyl nitroacetate (1.5 equiv), and piperidinium acetate (1 equiv) in THF at 100 °C (entry 1, Table 1). Surprisingly, the anticipated indolizine 3a was not detected from the reaction mixture. Rather, 4a (87%) and 5a (11%) were isolated. X-ray crystallographic analysis firmly established the chemical structure of each compound (Figures 1 and 2).7 When DBU (1 equiv) was used as a base, the same trend was observed (entry 2). Use of MeOH as a solvent with piperidinium acetate (1 equiv) provided 4a in 92% yield along with 5a (7%) (entry 3). Interestingly, when the reaction was carried out with Et3N (1 equiv), isoxazole 5a was isolated as a major product (entry 4). Brief screening of the solvent and the reaction temperature led us to identify that 5a was isolated in 86% yield after the reaction in toluene at 60 °C for 8 h (entries 5–7). Neither 3a nor 4a was detected under these conditions. Without any catalyst, only 5a was isolated in 53% yield upon heating a reaction mixture of 1a and methyl nitroacetate in THF at 100 °C (entry 8). In contrast, the reaction in hexafluoroisopropanol (HFIP)8 afforded indolizine 3a as a major product (entries 9 and 10). To our delight, we were able to find that 3a was produced in 80% yield upon exposure of the reaction mixture in HFIP to microwave heating conditions (120 °C, 30 min) (entry 11).

Table 1 Optimization Study for the Synthesis of 4aa

entry	catalyst (equiv)	solvent	temperature (°C)	time (h)	yield (%)b	
3a	4a	5a	
1	piperidinium acetate (1)	THF	100	1	0	87	11	
2	DBU (1)	THF	100	1	0	91	8	
3	piperidinium acetate (1)	MeOH	100	1	0	92	7	
4	Et3N (1)	THF	100	4	0	26	60	
5	Et3N (1)	MeOH	80	2	0	16	78	
6	Et3N (1)	toluene	80	2	0	0	63	
7	Et3N (1)	toluene	60	8	0	0	86	
8	 	THF	100	16	0	0	53	
9	 	HFIP	25	52	55	0	4	
10	 	HFIP	60	5	56	0	11	
11	 	HFIP	120c	0.5	80	0	8	
a A solution of 1a (30 mg, 0.13 mmol), methyl nitroacetate (1.5 equiv), and catalyst in solvent (2 mL) was heated at the indicated temperature for the indicated time.

b Isolated yield (%).

c Microwave heating was used.

Figure 1 Chemical structure of 4a.

Figure 2 Chemical structure of 5a.

Having found the optimal conditions for selective synthesis of 3–5, the reaction scope was examined with various substrates 1 and methyl nitroacetate (Tables 2–4). In the presence of piperidinium acetate (1 equiv) as a mild catalyst, a wide variety of 2-acyl-4H-quinolizin-4-ones 4 were readily accessed in good yields indicating that functional groups such as alkyl, alkoxy, and halogen are well tolerated under these conditions (Table 2). The isoxazoles 5 were obtained as minor products under these conditions. Although several synthetic approaches to 4H-quinolizin-4-ones have been known in the literature,9 the one with a cyano group at the C1 site and an acyl motif at the C2 site has not been disclosed yet, to the best of our knowledge. Moreover, most known methods require multistep sequence, harsh conditions, and/or expensive metal catalysts.

Table 2 Synthesis of 4a,b

a A mixture of 1 (0.13 mmol, 1 equiv), methyl nitroacetate (1.5 equiv), and piperidinium acetate (1 equiv) in MeOH (2 mL) was heated at 100 °C.

b Isolated yield (%).

As synthesis of the isoxazole 5a was favored in the presence of Et3N in toluene at 60 °C, several substrates 1 and methyl nitroacetate were exposed to the same conditions to give the corresponding isoxazoles 5 in good yields and the results are outlined in Table 3.

Table 3 Synthesis of 5a,b

a A mixture of 1 (0.13 mmol, 1 equiv), methyl nitroacetate (1.5 equiv), and Et3N (1 equiv) in toluene (2 mL) was heated at 60 °C.

b Isolated yield (%).

As illustrated in Scheme 2, formation of 2-acyl-4H-quinolizin-4-one 4 would be explained by nucleophilic acyl substitution at the ester in C by the pyridinyl nitrogen to give the amide D. Subsequent loss of HNO2 would give rise to 4. For the synthesis of isoxazole 5,10 elimination of HCN and tautomerization in Michael adduct E is proposed to occur to afford F which would undergo cyclization to furnish G. Final loss of H2O in G would lead to 5.

Scheme 2 Proposed Mechanisms for the Synthesis of 4 and 5

Finally, the synthesis of indolizines 3 from the reactions of 1 with methyl nitroacetate in HFIP at 120 °C was investigated as shown in Table 4. Under microwave heating conditions, the expected indolizines 3 were isolated as major products along with the isoxazoles 5 as minor ones. The structure of compound 3b was determined through X-ray crystallographic analysis (Figure 3).11 Notably, indolizines bearing one cyano group and two different acyl motifs at the C1–C3 positions have not been reported yet.

Table 4 Synthesis of 3a,b

a A mixture of 1 (0.13 mmol, 1 equiv) and methyl nitroacetate (1.5 equiv) in HFIP (2 mL) was heated at 120 °C (microwave heating for 0.5 h).

b Isolated yield (%).

c Reaction at 100 °C.

Figure 3 Chemical structure of 3b.

Scale-up experiments with 1a (300 mg) proceeded well under three different conditions to give 3a, 4a, and 5a in good yields (Scheme 3). When ethyl nitroacetate was used instead of methyl nitroacetate, the same results were observed; the reaction in the presence of Et3N in toluene gave the isoxazole 6 in 72% yield whereas the one in HFIP furnished the indolizine 7 as a major product. When benzoylnitromethane was allowed to react with 1a in HFIP, the corresponding isoxazole 8 was isolated as a major product along with a small amount of the indolizine 9. Use of malononitrile in the reaction with 1a in the presence of piperidinium acetate in MeOH at 100 °C provided 10 having a cyano and an amino group at the C4 and C5 site, respectively.12

Scheme 3 Scale-Up and Applications

In addition, postmodification experiments of the resulting products (3, 4, and 5) demonstrated the feasibility of expanding the heterocyclic chemical space associated with these scaffolds (Scheme 4). Exposure of 3a to hydrazine in EtOH allowed construction of the pyridazine ring to give 11.13 While partial reduction of 4a with H2 and Pd/C provided 12 and 13,14 treatment of 4a with NBS installed Br at the C3 site, delivering 14 in 96% yield.15 Suzuki-Miyaura coupling of 14 with 4-methoxyphenylboronic acid afforded a highly functionalized 2-acyl-4H-quinolizin-4-one 15. Hydrolysis of 4b under basic conditions produced the amide 16 in an excellent yield.16 Reduction of 5a with NaBH4 gave the diol 17 in 94% yield.

Scheme 4 Derivatization

In summary, three divergent pathways in the annulation process of (Z)-4-aryl-4-oxo-2-(pyridin-2-yl)but-2-enenitrile with methyl nitroacetate were discovered to provide ready access to three distinctive skeletons in good to excellent yields. Simple synthetic elaboration of these scaffolds was further demonstrated enabling facile expansion of these heterocyclic chemical space. We believe that three heterocyclic scaffolds with unique substitution patterns described here should be helpful in finding new biologically active compounds in medicinal chemistry. Along this line, biological evaluation of these compounds is underway and the results will be communicated soon.

Experimental Section

General Methods

Reagents and starting materials were obtained from commercial suppliers and used directly without further purification. “Concentrated” refers to the removal of volatile solvents through rotary evaporation. “Dried” refers to treating the material with anhydrous magnesium sulfate, followed by filtration. Flash chromatography was conducted using silica gel (230–400 mesh) with hexanes, ethyl acetate, and dichloromethane as the eluents. The progression of all the reactions was monitored by thin-layer chromatography on 0.25 mm silica plates (F-254) and visualized under UV light. Melting points were determined with a capillary melting point apparatus. 1H and 13C NMR spectra were recorded on a 400 MHz NMR spectrometer and the data were reported as chemical shifts, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; p, pentet; m, multiplet), coupling constants in hertz (Hz), and number of protons. High-resolution mass spectrometry (HRMS) was performed using electrospray ionization (ESI) and a Q-TOF mass analyzer. X-ray crystallographic analyses of compounds 3b, 4a, and 5a were carried out with a SuperNova, Dual, Cu at home/near, AtlasS2 diffractometer.

General Procedure for the Synthesis of 3

A solution of 1a (30 mg. 0.13 mmol) and methyl nitroacetate (18.0 μL, 1.5 equiv) in HFIP (2 mL) was heated at 120 °C (microwave heating was used) for 0.5 h. After concentration in vacuo, the crude residue was purified by silica gel column chromatography (hexane:ethyl acetate:dichloromethane = 30:1:2) to afford 3a (31.6 mg, 80%) as a white solid and 5a (3.2 mg, 8%) as a white solid.

Scale-Up Experiment

Reaction with 1a (300 mg, 1.3 mmol) under the same conditions gave 3a (296.7 mg, 75%) and 5a (48.1 mg, 12%).

Methyl 2-Benzoyl-1-cyanoindolizine-3-carboxylate (3a)

White solid, mp: 147.8–148.2 °C (31.6 mg, 80%); 1H NMR (400 MHz, CDCl3) δ 9.56 (d, J = 6.8 Hz, 1H), 7.84 (t, J = 7.2 Hz, 3H), 7.61 (t, J = 7.2 Hz, 1H), 7.51–7.44 (m, 3H), 7.16 (t, J = 6.8 Hz, 1H), 3.56 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.5, 160.0, 139.8, 137.4, 136.9, 136.6, 134.0, 129.5, 128.7, 128.3, 127.1, 117.9, 116.1, 113.5, 84.5, 51.7; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C18H13N2O3 305.0921, found 305.0920.

Methyl 1-Cyano-2-(4-methylbenzoyl)indolizine-3-carboxylate (3b)

White solid, mp: 199.2–199.9 °C (33.9 mg, 82%); 1H NMR (400 MHz, (CD3)2CO) δ 9.57 (dt, J = 7.2, 0.8 Hz, 1H), 7.92 (dt, J = 8.8, 1.2 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.69–7.64 (m, 1H), 7.40–7.34 (m, 3H), 3.55 (s, 3H), 2.42 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.1, 160.1, 145.1, 139.7, 137.2, 134.1, 129.7, 129.4, 128.3, 127.0, 117.8, 116.0, 113.6, 112.7, 84.4, 51.7, 21.8; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C19H15N2O3 319.1077, found 319.1075. Dissolution of the compound in a mixed solvent (ethyl acetate:EtOH, 1:1) and slow evaporation of the solvent at room temperature afforded the crystal 3b for X-ray crystallographic analysis.

Methyl 1-Cyano-2-(3,4-dimethoxybenzoyl)indolizine-3-carboxylate (3c)

White solid, mp: 147.8–148.2 °C (39.8 mg, 84%); 1H NMR (400 MHz, CDCl3) δ 9.57 (d, J = 7.2 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 1.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.22 (dd, J = 8.4, 1.6 Hz, 1H), 7.15 (t, J = 6.8 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 3.97 (s, 3H), 3.95 (s, 3H), 3.64 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 189.0, 160.2, 154.2, 149.3, 139.7, 137.3, 123.0, 128.4, 127.0, 126.1, 117.8, 116.0, 113.6, 112.8, 110.1, 109.9, 84.5, 56.14, 56.10, 51.9; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C20H17N2O5 365.1132, found 365.1134.

Methyl 2-(2-Naphthoyl)-1-cyanoindolizine-3-carboxylate (3d)

White solid, mp: 169.8–170.2 °C (32.2 mg, 70%); 1H NMR (400 MHz, CDCl3) δ 9.61 (d, J = 7.2 Hz, 1H), 8.20 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.96–7.84 (m, 4H), 7.63 (t, J = 7.2 Hz, 1H), 7.57–7.47 (m, 2H), 7.19 (t, J = 6.8 Hz, 1H), 3.53 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.5, 160.1, 139.8, 137.1, 136.0, 134.1, 132.41, 132.36, 129.8, 129.1, 128.8, 128.4, 127.9, 127.1, 126.9, 124.0, 117.9, 116.1, 113.5, 112.9, 84.6, 51.8; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C22H15N2O3 355.1077, found 355.1087.

Methyl 2-(4-Chlorobenzoyl)-1-cyanoindolizine-3-carboxylate (3e)

White solid, mp: 159.2–159.9 °C (27.3 mg, 62%); 1H NMR (400 MHz, CDCl3) δ 9.56 (d, J = 7.2 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 7.2 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.17 (t, J = 7.2 Hz, 1H), 3.59 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 189.2, 159.9, 140.6, 139.8, 136.3, 135.0, 130.8, 129.1, 128.3, 127.2, 117.9, 116.2, 113.4, 112.7, 84.4, 51.8; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C18H12ClN2O3 339.0531, found 339.0532.

Methyl 2-(3-Chlorobenzoyl)-1-cyanoindolizine-3-carboxylate (3f)

White solid, mp: 166.2–166.9 °C (24.7 mg, 56%); 1H NMR (400 MHz, CDCl3) δ 9.56 (d, J = 7.2 Hz, 1H), 7.83 (d, J = 7.2 Hz, 2H), 7.71 (d, J = 7.6 Hz, 1H), 7.61–7.57 (m, 1H), 7.49 (dd, J = 8.0, 7.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H), 3.60 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 189.2, 159.8, 139.8, 138.2, 136.1, 135.1, 133.9, 130.1, 129.2, 128.3, 127.6, 127.3, 118.0, 116.3, 113.3, 112.8, 84.4, 51.8; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C18H12ClN2O3 339.0531, found 339.0532.

Methyl 2-(4-Bromobenzoyl)-1-cyanoindolizine-3-carboxylate (3g)

White solid, mp: 182.3–182.9 °C (34.9 mg, 70%); 1H NMR (400 MHz, CDCl3) δ 9.55 (d, J = 7.2 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.8 Hz, 2H), 7.47 (t, J = 8.8 Hz, 1H), 7.16 (t, J = 6.8 Hz, 1H), 3.59 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 189.5, 159.8, 139.8, 136.3, 135.4, 132.1, 130.9, 129.4, 128.3, 127.2, 117.9, 116.2, 113.4, 112.7, 84.4, 51.8; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C18H12BrN2O3 383.0026, found 383.0039.

Methyl 1-Cyano-2-(furan-2-carbonyl)indolizine-3-carboxylate (3h)

Orange solid, mp: 160.5–160.8 °C (26.0 mg, 68%); 1H NMR (400 MHz, CDCl3) δ 8.50 (d, J = 4.8 Hz, 1H), 7.97 (d, J = 7.2 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.55 (s, 1H), 7.31 (dd, J = 7.6, 4.8 Hz, 1H), 7.15 (d, J = 2.8 Hz, 1H), 6.54–6.52 (m, 1H), 3.91 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 187.0, 168.4, 159.2, 154.9, 153.0, 150.2, 147.2, 144.9, 137.0, 125.2, 121.8, 119.1, 116.2, 112.7, 87.7, 53.2; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C16H11N2O4 295.0713, found 295.0702.

2-Ethyl 3-Methyl 1-Cyanoindolizine-2,3-dicarboxylate (3i)

White solid, mp: 157.8–158.2 °C (30.1 mg, 85%); 1H NMR (400 MHz, CDCl3) δ 9.45 (d, J = 7.2 Hz, 1H), 7.77 (d, J = 9.2 Hz, 1H), 7.40 (t, J = 9.2 Hz, 1H), 7.10 (t, J = 7.2 Hz, 1H), 4.48 (q, J = 7.2 Hz, 2H), 3.93 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.8, 160.2, 139.2, 129.9, 128.2, 126.8, 118.0, 116.1, 113.6, 113.2, 84.5, 62.4, 52.2, 14.2; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C14H13N2O4 273.0870, found 273.0858.

Methyl 2-Benzoyl-3-cyanopyrrolo[1,2-a]quinoline-1-carboxylate (3j)

White solid, mp: 156.2–156.9 °C (27.2 mg, 59%); 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J = 8.8 Hz, 1H), 7.86 (d, J = 7.6 Hz, 3H), 7.70–7.63 (m, 4H), 7.58 (t, J = 7.6 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 3.57 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.0, 161.7, 139.5, 136.9, 134.4, 133.9, 132.8, 129.52, 129.49, 129.4, 128.8, 128.7, 126.5, 125.4, 120.4, 118.7, 115.6, 113.5, 87.2, 52.6; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C22H15N2O3 355.1077, found 355.1078.

General Procedure for the Synthesis of 4

A solution of 1a (30 mg. 0.13 mmol), methyl nitroacetate (18.0 μL, 1.5 equiv), and piperidinium acetate (18.9 mg, 1.0 equiv) in methanol (2 mL) was heated at 100 °C for 1 h. After concentration in vacuo, the crude residue was purified by silica gel column chromatography (hexane:ethyl acetate:dichloromethane = 5:1:2) to give 4a (32.8 mg, 92%) as a yellow solid and 5a (2.8 mg, 7%) as a white solid.

Scale-Up Experiment

Reaction with 1a (300 mg, 1.3 mmol) under the same conditions furnished 4a (313.8 mg, 88%) and 5a (32.1 mg, 8%).

2-Benzoyl-4-oxo-4H-quinolizine-1-carbonitrile (4a)

Yellow solid, mp: 195.8–196.5 °C (32.8 mg, 92%); 1H NMR (400 MHz, CDCl3) δ 9.27 (d, J = 7.2 Hz, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.91–7.88 (m, 2H), 7.84 (t, J = 7.2 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.2 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H), 6.59 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.3, 156.7, 149.7, 146.4, 135.6, 134.7, 134.4, 130.4, 129.0, 128.9, 124.0, 117.5, 115.2, 107.6, 83.3; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C17H11N2O2 275.0815, found 275.0807. Dissolution of the compound in a mixed solvent (dichloromethane:ethyl acetate:EtOH, 1:1:1) and slow evaporation of the solvent at room temperature gave the crystal 4a for X-ray crystallographic analysis.

2-(4-Methylbenzoyl)-4-oxo-4H-quinolizine-1-carbonitrile (4b)

Yellow solid, mp: 147.8–148.2 °C (30.7 mg, 82%); 1H NMR (400 MHz, CDCl3) δ 9.26 (d, J = 6.8 Hz, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.84 (t, J = 7.6 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.34 (t, J = 6.8 Hz, 1H), 7.29 (d, J = 8.0 Hz, 2H), 6.56 (s, 1H), 2.43 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.9, 156.7, 150.1, 146.3, 146.1, 135.6, 131.9, 130.6, 129.6, 128.9, 123.9, 117.6, 115.3, 107.4, 83.2, 21.9; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C18H13N2O2 289.0972, found 289.0967.

2-(4-Methoxybenzoyl)-4-oxo-4H-quinolizine-1-carbonitrile (4c)

Yellow solid, mp: 218.9–219.5 °C (34.8 mg, 88%); 1H NMR (400 MHz, CDCl3) δ 9.28 (d, J = 6.8 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.4 Hz, 2H), 7.84 (t, J = 8.0 Hz, 1H), 7.34 (t, J = 6.8 Hz, 1H), 6.97 (d, J = 8.8 Hz, 2H), 6.58 (s, 1H), 3.89 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.7, 164.9, 156.7, 150.5, 146.3, 135.4, 133.0, 128.9, 127.4, 123.9, 117.4, 115.3, 114.2, 107.3, 83.4, 55.7; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C18H13N2O3 305.0921, found 305.0920.

2-(3,4-Dimethoxybenzoyl)-4-oxo-4H-quinolizine-1-carbonitrile (4d)

Yellow solid, mp: 247.2–247.6 °C (34.7 mg, 80%); 1H NMR (400 MHz, CDCl3) δ 9.30 (d, J = 7.2 Hz, 1H), 8.14 (d, J = 9.2 Hz, 1H), 7.84 (dd, J = 8.8, 7.2 Hz, 1H), 7.63 (s, 1H), 7.40–7.32 (m, 2H), 6.87 (d, J = 8.4 Hz, 1H), 6.61 (s, 1H), 3.97 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.7, 156.7, 154.9, 150.5, 149.6, 146.3, 135.4, 129.0, 127.5, 126.9, 123.9, 117.4, 115.3, 110.9, 109.9, 107.4, 83.5, 56.3, 56.1; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C19H15N2O4 335.1026, found 335.1046.

4-Oxo-2-(3,4,5-trimethoxybenzoyl)-4H-quinolizine-1-carbonitrile (4e)

Yellow solid, mp: 208.2–208.6 °C (34.6 mg, 73%); 1H NMR (400 MHz, CDCl3) δ 9.31 (d, J = 7.2 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.89–7.83 (m, 1H), 7.39–7.34 (m, 1H), 7.17 (s, 2H), 6.62 (s, 1H), 3.97 (s, 3H), 3.88 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.0, 156.6, 153.2, 150.0, 146.4, 144.2, 135.5, 129.3, 129.0, 124.0, 117.5, 115.1, 108.1, 107.3, 83.4, 61.1, 56.5; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C20H17N2O5 365.1132, found 365.1136.

2-(2-Naphthoyl)-4-oxo-4H-quinolizine-1-carbonitrile (4f)

Yellow solid, mp: 214.1–214.6 °C (37.5 mg, 89%); 1H NMR (400 MHz, CDCl3) δ 9.34 (d, J = 7.2 Hz, 1H), 8.33 (s, 1H), 8.19 (d, J = 9.2 Hz, 1H), 8.08 (dd, J = 8.8, 1.6 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.92 (t, J = 7.2 Hz, 2H), 7.89–7.85 (m, 1H), 7.69–7.64 (m, 1H), 7.58 (t, J = 7.2 Hz, 1H), 7.38 (td, J = 7.2, 1.2 Hz, 1H), 6.70 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.2, 156.7, 150.1, 146.4, 136.3, 135.5, 133.7, 132.2, 131.8, 129.8, 129.6, 129.2, 129.0, 128.0, 127.2, 124.5, 124.1, 117.5, 115.2, 107.7, 83.5; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C21H13N2O2 325.0972, found 325.0960.

2-(4-Fluorobenzoyl)-4-oxo-4H-quinolizine-1-carbonitrile (4g)

Yellow solid, mp: 236.0–236.8 °C (25.1 mg, 66%); 1H NMR (400 MHz, (CD3)2SO) δ 9.23 (d, J = 6.8 Hz, 1H), 8.11–8.02 (m, 4H), 7.58 (t, J = 6.4 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H), 6.59 (s, 1H); 13C{1H} NMR (100 MHz, (CD3)2SO) δ 191.9, 166.4 (J = 253.0 Hz), 156.8, 149.8, 146.7, 137.7, 133.9 (J = 10.0 Hz), 131.7 (J = 3.0 Hz), 129.5, 123.7, 118.9, 116.8 (J = 22.0 Hz), 116.2, 106.2, 81.4; 19F NMR (376 MHz, (CD3)2SO) δ −102.8; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C17H10FN2O2 293.0721, found 293.0717.

2-(2-Fluorobenzoyl)-4-oxo-4H-quinolizine-1-carbonitrile (4h)

Yellow solid, mp: 216.5–217.4 °C (23.6 mg, 62%); 1H NMR (400 MHz, CDCl3) δ 9.26 (d, J = 6.8 Hz, 1H), 8.17 (d, J = 8.8 Hz, 1H), 7.84 (t, J = 7.6 Hz, 2H), 7.68–7.62 (m, 1H), 7.36–7.31 (m, 2H), 7.16 (t, J = 10.0 Hz, 1H), 6.61 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 189.8, 161.6 (J = 256.0 Hz), 157.1, 149.9, 146.4, 136.2 (J = 9.0 Hz), 135.4, 131.6, 128.9, 124.9 (J = 4.0 Hz), 124.2, 124.1, 117.5, 116.8 (J = 21.0 Hz), 115.2, 107.6 (J = 2.0 Hz), 82.4; 19F NMR (376 MHz, CDCl3) δ −111.0; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C17H10FN2O2 293.0721, found 293.0724.

2-(3-Chlorobenzoyl)-4-oxo-4H-quinolizine-1-carbonitrile (4i)

Yellow solid, mp: 194.2–194.9 °C (30.9 mg, 77%); 1H NMR (400 MHz, (CD3)2SO) δ 9.23 (d, J = 7.2 Hz, 1H), 8.13–8.05 (m, 2H), 7.96 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.60–7.55 (m, 1H), 6.61 (s, 1H); 13C{1H} NMR (100 MHz, (CD3)2SO) δ 192.3, 156.8, 149.1, 146.8, 137.7, 136.8, 135.1, 134.5, 131.6, 130.1, 129.5, 129.3, 123.8, 118.9, 116.2, 106.5, 81.4; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C17H10ClN2O2 309.0425, found 309.0435.

2-(4-Bromobenzoyl)-4-oxo-4H-quinolizine-1-carbonitrile (4j)

Yellow solid, mp: 254.2–254.8 °C (34.0 mg, 74%); 1H NMR (400 MHz, CDCl3) δ 9.30 (d, J = 7.2 Hz, 1H), 8.17 (d, J = 9.2 Hz, 1H), 7.87 (t, J = 7.2 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.37 (t, J = 7.2 Hz, 1H), 6.59 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.3, 156.6, 149.2, 146.4, 135.7, 133.2, 132.4, 131.7, 130.4, 129.1, 124.1, 117.6, 115.1, 107.4, 83.1; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C17H10BrN2O2 352.9920, found 352.9919.

2-(Furan-2-carbonyl)-4-oxo-4H-quinolizine-1-carbonitrile (4k)

Yellow solid, mp: 175.5–176.0 °C (20.6 mg, 60%); 1H NMR (400 MHz, CDCl3) δ 9.28 (d, J = 7.2 Hz, 1H), 8.18 (d, J = 8.8 Hz, 1H), 7.85 (t, J = 8.0 Hz, 1H), 7.78–7.76 (m, 1H), 7.38–7.33 (m, 2H) 6.80 (s, 1H), 6.68–6.56 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 178.6, 156.8, 150.7, 149.1, 148.1, 146.4, 135.5, 128.9, 124.2, 122.8, 117.6, 115.1, 113.2, 107.9, 83.2; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C15H9N2O3 265.0608, found 265.0594.

Ethyl 1-Cyano-4-oxo-4H-quinolizine-2-carboxylate (4l)

Yellow solid, mp: 205.2–205.9 °C (32.3 mg, 92%); 1H NMR (400 MHz, CDCl3) δ 9.24 (d, J = 5.6 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 7.83 (t, J = 6.8 Hz, 1H), 7.33 (t, J = 7.2 Hz, 1H), 7.09 (s, 1H), 4.47 (q, J = 7.2 Hz, 2H), 1.44 (t, J = 7.6 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.3, 157.0, 146.4, 140.5, 135.3, 128.9, 124.4, 117.7, 115.6, 109.6, 83.9, 63.0, 14.0; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C13H11N2O3 243.0764, found 243.0763.

2-Benzoyl-7-methoxy-4-oxo-4H-quinolizine-1-carbonitrile (4m)

Yellow solid, mp: 256.6–257.2 °C (19.4 mg, 49%); 1H NMR (400 MHz, CDCl3) δ 8.83 (s, 1H), 8.11 (d, J = 9.6 Hz, 1H), 7.91 (d, J = 7.6 Hz, 2H), 7.67 (t, J = 7.2 Hz, 1H), 7.62 (dd, J = 9.6, 2.0 Hz, 1H), 7.52 (t, J = 7.6 Hz, 2H), 6.61 (s, 1H), 4.01 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.4, 156.3, 152.6, 148.1, 142.5, 134.63, 134.60, 130.6, 130.4, 128.9, 124.8, 115.4, 109.2, 107.0, 83.8, 56.6; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C18H13N2O3 305.0921, found 305.0922.

General Procedure for the Synthesis of 5

A solution of 1a (30 mg. 0.13 mmol), methyl nitroacetate (18.0 μL, 1.5 equiv), and Et3N (18.1 μL, 1 equiv) in toluene (2 mL) was heated at 60 °C for 8 h. After the solvent was evaporated under reduced pressure, the crude residue was purified by silica gel column chromatography (hexane:ethyl acetate:dichloromethane = 10:1:2) to afford 5a (34.5 mg, 86%) as a white solid.

Scale-Up Experiment

Reaction with 1a (300 mg, 1.3 mmol) under the same conditions gave 5a (288.6 mg, 71%).

Methyl 4-Benzoyl-5-(pyridin-2-yl)isoxazole-3-carboxylate (5a)

White solid, mp: 140.1–140.5 °C; 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 4.8 Hz, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.90–7.86 (m, 2H), 7.81 (td, J = 8.0, 1.6 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.29–7.25 (m, 1H), 3.85 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 188.4, 167.7, 159.2, 155.0, 150.1, 144.9, 137.1, 137.0, 133.6, 129.2, 128.6, 125.0, 121.5, 117.2, 53.1; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C17H13N2O4 309.0870, found 309.0866. Dissolution of the compound in a mixed solvent (ethyl acetate:EtOH, 1:1) and slow evaporation of the solvent at room temperature afforded the crystal 5a for X-ray crystallographic analysis.

Methyl 4-(4-Methylbenzoyl)-5-(pyridin-2-yl)isoxazole-3-carboxylate (5b)

White solid, mp: 152.8–153.2 °C; 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 4.4 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.81 (dd, J = 8.0, 1.2 Hz, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.30–7.27 (m, 1H), 7.23 (d, J = 8.0 Hz, 2H), 3.85 (s, 3H), 2.40 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 188.0, 167.6, 159.2, 155.0, 150.2, 144.9, 144.6, 137.0, 134.7, 129.4, 129.3, 125.0, 121.5, 117.4, 53.1, 21.8; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C18H15N2O4 323.1026, found 323.1028.

Methyl 4-(4-Methoxybenzoyl)-5-(pyridin-2-yl)isoxazole-3-carboxylate (5c)

White solid, mp: 147.8–148.3 °C; 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J = 4.8 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 9.2 Hz, 2H), 7.79 (td, J = 8.0, 1.6 Hz, 1H), 7.27 (t, J = 4.8 Hz, 1H), 6.90 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.9, 167.4, 164.0, 159.3, 155.0, 150.2, 145.0, 136.9, 131.6, 130.3, 125.0, 121.5, 117.4, 113.9, 55.5, 53.1; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C18H15N2O5 339.0975, found 339.0985.

Methyl 4-(3,4-Dimethoxybenzoyl)-5-(pyridin-2-yl)isoxazole-3-carboxylate (5d)

White solid, mp: 158.9–159.4 °C; 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 4.8 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.80 (td, J = 7.6, 1.6 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.30–7.27 (m, 1H), 7.26–7.22 (m, 1H), 6.77 (d, J = 8.4 Hz, 1H), 3.96 (s, 3H), 3.91 (s, 3H), 3.87 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.9, 167.5, 159.3, 155.0, 153.9, 150.3, 149.2, 145.0, 137.0, 130.5, 125.1, 125.0, 121.6, 117.2, 110.0, 109.9, 56.1, 56.0, 53.2; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C19H17N2O6 369.1081, found 369.1091.

Methyl 5-(Pyridin-2-yl)-4-(3,4,5-trimethoxybenzoyl)isoxazole-3-carboxylate (5e)

White solid, mp: 162.2–162.8 °C; 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 4.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.82 (td, J = 7.6, 1.6 Hz, 1H), 7.32–7.27 (m, 1H), 7.12 (s, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 3.80 (s, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 187.1, 167.7, 159.3, 155.1, 153.1, 150.3, 144.9, 143.1, 137.0, 132.2, 125.1, 121.7, 117.0, 106.6, 60.9, 56.2, 53.3; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C20H19N2O7 399.1187, found 399.1209.

Methyl 4-(2-Naphthoyl)-5-(pyridin-2-yl)isoxazole-3-carboxylate (5f)

White solid, mp: 155.5–155.9 °C; 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 4.0 Hz, 1H), 8.25 (s, 1H), 8.09 (dd, J = 8.4, 1.6 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.79 (td, J = 7.6, 1.6 Hz, 1H), 7.62–7.56 (m, 1H), 7.53–7.48 (m, 1H), 7.25–7.21 (m, 1H), 3.83 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 188.4, 167.8, 159.2, 155.1, 150.2, 144.9, 137.0, 135.9, 134.7, 132.4, 131.7, 129.7, 128.7, 128.6, 127.8, 126.7, 125.0, 124.2, 121.5, 117.3, 53.2; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C21H15N2O4 359.1026, found 359.1040.

Methyl 4-(4-Fluorobenzoyl)-5-(pyridin-2-yl)isoxazole-3-carboxylate (5g)

White solid, mp: 148.9–149.5 °C; 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 4.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.92–7.86 (m, 2H), 7.80 (t, J = 8.0 Hz, 1H), 7.29–7.23 (m, 1H), 7.12–7.05 (m, 2H), 3.86 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 186.9, 167.7, 166.0 (J = 254.0 Hz), 159.2, 154.9, 150.1, 144.8, 137.1, 133.7 (J = 3.0 Hz), 131.8 (J = 10.0 Hz), 125.1, 121.5, 116.9, 115.8 (J = 22.0 Hz), 53.2; 19F NMR (376 MHz, CDCl3) δ −104.1; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C17H12FN2O4 327.0776, found 327.0785.

Methyl 4-(2-Fluorobenzoyl)-5-(pyridin-2-yl)isoxazole-3-carboxylate (5h)

White solid, mp: 99.5–100.2 °C; 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 4.0 Hz, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.79 (t, J = 7.6 Hz, 1H), 7.55–7.47 (m, 1H), 7.27 (t, J = 6.8 Hz, 2H), 7.01 (t, J = 8.8 Hz, 1H), 3.88 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 184.5, 167.2, 161.9 (J = 257.0 Hz), 159.4, 154.5, 150.0, 145.0, 137.0, 135.2 (J = 9.0 Hz), 131.2, 125.8 (J = 9.0 Hz), 125.0, 124.3 (J = 4.0 Hz), 121.3, 119.5, 116.6 (J = 22.0 Hz), 53.2; 19F NMR (376 MHz, CDCl3) δ −111.4; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C17H12FN2O4 327.0776, found 327.0777.

Methyl 4-(4-Chlorobenzoyl)-5-(pyridin-2-yl)isoxazole-3-carboxylate (5i)

White solid, mp: 190.1–190.8 °C; 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 4.8 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.85–7.79 (m, 3H), 7.41 (d, J = 8.8 Hz, 2H), 7.31–7.27 (m, 1H), 3.88 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 187.2, 167.8, 159.2, 154.9, 150.1, 144.7, 140.0, 137.1, 135.6 130.5, 129.0, 125.2, 121.4, 116.8, 53.2; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C17H12ClN2O4 343.0480, found 343.0492.

Methyl 4-(3-Chlorobenzoyl)-5-(pyridin-2-yl)isoxazole-3-carboxylate (5j)

White solid, mp: 188.6–189.2 °C; 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 4.8 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.87 (s, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.30–7.27 (m, 1H), 3.88 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 187.1, 167.9, 159.1, 154.9, 150.1, 144.6, 138.7, 137.1, 134.9, 133.5, 129.9, 128.9, 127.4, 125.2, 121.4, 116.7, 53.3; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C17H12ClN2O4 343.0480, found 343.0477.

Methyl 4-(4-Bromobenzoyl)-5-(pyridin-2-yl)isoxazole-3-carboxylate (5k)

White solid, mp: 201.3–201.9 °C; 1H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 3.6 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.31–7.27 (m, 1H), 3.88 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 187.4, 167.8, 159.2, 154.9, 150.1, 144.7, 137.1, 136.0, 132.0, 130.6, 128.9, 125.2, 121.4, 116.8, 53.2; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C17H12BrN2O4 386.9975, found 386.9973.

Methyl 4-(4-Cyanobenzoyl)-5-(pyridin-2-yl)isoxazole-3-carboxylate (5l)

White solid, mp: 178.2–178.8 °C; 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J = 4.4 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.84 (t, J = 7.2 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.29 (t, J = 5.2 Hz, 1H), 3.89 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 187.0, 168.1, 159.1, 154.9, 150.0, 144.4, 140.2, 137.2, 132.5, 129.4, 125.4, 121.4, 118.0, 116.5, 116.3, 53.3; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C18H12N3O4 334.0822, found 334.0819.

Methyl 4-(5-Bromothiophene-2-carbonyl)-5-(pyridin-2-yl)isoxazole-3-carboxylate (5m)

White solid, mp: 126.2–126.9 °C; 1H NMR (400 MHz, CDCl3) δ 8.53–8.51 (m, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.84 (td, J = 7.6, 1.6 Hz, 1H), 7.34–7.30 (m, 1H), 7.16 (d, J = 4.0 Hz, 1H), 7.03 (d, J = 4.0 Hz, 1H), 3.93 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 179.0, 168.0, 159.0, 154.7, 150.3, 145.7, 144.6, 137.1, 134.1, 131.4, 125.3, 123.9, 121.6, 116.1, 53.3; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C15H10BrN2O4S 392.9539, found 392.9535.

4-Ethyl 3-Methyl 5-(Pyridin-2-yl)isoxazole-3,4-dicarboxylate (5n)

White solid, mp: 147.8–148.2 °C; 1H NMR (400 MHz, CDCl3) δ 8.71 (d, J = 4.8 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.87 (td, J = 7.6, 1.2 Hz, 1H), 7.41 (dd, J = 7.6, 4.8 Hz, 1H), 4.46 (q, J = 7.2 Hz, 2H), 4.01 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.4, 161.5, 159.3, 154.5, 150.2, 144.9, 137.0, 125.4, 122.4, 111.8, 62.2, 53.3, 14.0; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C13H13N2O5 277.0819, found 277.0822.

Methyl 4-Benzoyl-5-(5-methoxypyridin-2-yl)isoxazole-3-carboxylate (5o)

White solid, mp: 185.2–185.8 °C; 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J = 2.8 Hz, 1H), 7.90 (d, J = 8.8 Hz, 1H), 7.88–7.85 (m, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.24 (dd, J = 8.8, 3.2 Hz, 1H), 3.838 (s, 3H), 3.836 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 188.7, 167.8, 159.3, 156.6, 154.9, 138.4, 137.4, 137.3, 133.5, 129.2, 128.6, 122.4, 120.3, 115.7, 55.7, 53.1; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C18H15N2O5 339.0975, found 339.0979.

Methyl 4-Benzoyl-5-(5-bromopyridin-2-yl)isoxazole-3-carboxylate (5p)

White solid, mp: 132.2–132.8 °C; 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 2.0 Hz, 1H), 7.95 (dd, J = 8.4, 2.4 Hz, 1H), 7.86 (d, J = 8.4 Hz, 3H), 7.59 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.2 Hz, 2H), 3.86 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 188.1, 166.7, 160.2, 159.0, 155.1, 151.4, 143.2, 139.7, 136.9, 133.8, 129.1, 128.7, 122.6, 122.4, 53.2; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C17H12BrN2O4 386.9975, found 386.9976.

Methyl 4-Benzoyl-5-(quinolin-2-yl)isoxazole-3-carboxylate (5q)

White solid, mp: 144.2–144.7 °C; 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 1H), 7.62–7.57 (m, 1H), 7.54 (d, J = 6.4 Hz, 3H), 7.45 (t, J = 7.6 Hz, 2H), 3.90 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 188.6, 167.8, 159.3, 155.2, 147.6, 144.3, 137.44, 137.39, 133.5, 130.3, 129.7, 129.1, 128.6, 128.1, 128.0, 127.5, 117.9, 53.2; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C21H15N2O4 359.1026, found 359.1027.

Synthesis of 6

A solution of 1a (30 mg. 0.13 mmol), ethyl nitroacetate (17.2 μL, 1.5 equiv), and Et3N (18.1 μL, 1.0 equiv) in toluene (2 mL) was heated at 60 °C for 8 h. After concentration in vacuo, the crude residue was purified by silica gel column chromatography (hexane:ethyl acetate:dichloromethane = 10:1:2) to give 6 (30.2 mg, 72%) as a white solid.

Ethyl 4-Benzoyl-5-(pyridin-2-yl)isoxazole-3-carboxylate (6)

White solid, mp: 90.1–90.6 °C (30.2 mg, 72%); 1H NMR (400 MHz, CDCl3) δ 8.43–8.39 (m, 1H), 7.96 (d, J = 7.6 Hz, 1H), 7.90–7.86 (m, 2H), 7.80 (td, J = 8.0, 2.0 Hz, 1H), 7.60–7.54 (m, 1H), 7.43 (t, J = 8.0 Hz, 2H), 7.27 (td, J = 4.8, 1.2 Hz, 1H), 4.29 (q, J = 6.8 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 188.5, 167.7, 158.6, 155.2, 150.2, 144.9, 137.2, 137.0, 133.6, 129.2, 128.6, 125.0, 121.5, 117.1, 62.6, 13.7; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C18H15N2O4 323.1026, found 323.1026.

Synthesis of 7

A solution of 1a (30 mg. 0.13 mmol) and ethyl nitroacetate (17.2 μL, 1.5 equiv) in HFIP (2 mL) was heated at 120 °C (microwave heating was used) for 0.5 h. After concentration under reduced pressure, the crude residue was purified by silica gel column chromatography (hexane:ethyl acetate:dichloromethane = 30:1:2) to afford 7 (32.7 mg, 79%) as a white solid and 6 (5.0 mg, 12%) as a white solid.

Ethyl 2-Benzoyl-1-cyanoindolizine-3-carboxylate (7)

White solid, mp: 177.1–177.7 °C (32.7 mg, 79%); 1H NMR (400 MHz, CDCl3) δ 9.58 (d, J = 6.8 Hz, 1H), 7.88–7.84 (m, 2H), 7.82 (d, J = 8.8 Hz, 1H), 7.61 (t, J = 7.2 Hz, 1H), 7.49–7.43 (m, 3H), 7.15 (td, J = 6.8, 0.8 Hz, 1H), 4.06 (q, J = 7.2 Hz, 2H), 0.83 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.5, 159.6, 139.8, 136.8, 136.7, 133.9, 129.6, 128.6, 128.3, 127.0, 117.8, 116.0, 113.6, 112.8, 84.3, 61.1, 13.3; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C19H15N2O3 319.1077, found 319.1092.

Synthesis of 8 and 9

A solution of 1a (30 mg. 0.13 mmol) and benzoylnitromethane (32.7 mg, 1.5 equiv) in HFIP (2 mL) was heated at 120 °C (microwave heating was used) for 0.5 h. After concentration under reduced pressure, the crude residue was purified by silica gel column chromatography (hexane:ethyl acetate:dichloromethane = 30:1:2) to give 8 (28.0 mg, 61%) as a white solid and 9 (3.6 mg, 8%) as a brown gum.

(5-(Pyridin-2-yl)isoxazole-3,4-diyl)bis(phenylmethanone) (8)

White solid, mp: 139.6–140.4 °C (28.0 mg, 61%); 1H NMR (400 MHz, CDCl3) δ 8.44–8.41 (m, 1H), 8.29–8.26 (m, 2H), 7.97 (d, J = 8.0 Hz, 1H), 7.93–7.88 (m, 2H), 7.81 (td, J = 8.0, 1.6 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.56–7.49 (m, 3H), 7.41 (t, J = 8.0 Hz, 2H), 7.27 (td, J = 4.8, 0.8 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 188.9, 184.4, 166.8, 161.1, 150.2, 145.0, 137.3, 136.9, 135.1, 134.4, 133.4, 130.7, 129.2, 128.6, 128.5, 125.0, 121.6, 118.1; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C22H15N2O3 355.1077, found 355.1087.

2,3-Dibenzoylindolizine-1-carbonitrile (9)

Brown gum (3.6 mg, 8%); 1H NMR (400 MHz, CDCl3) δ 9.59 (d, J = 7.2 Hz, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.55 (t, J = 7.2 Hz, 1H), 7.43 (t, J = 7.2 Hz, 1H), 7.37–7.32 (m, 3H), 7.29 (d, J = 7.6 Hz, 2H), 7.21 (t, J = 7.6 Hz, 3H), 7.11 (t, J = 7.6 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 189.8, 186.6, 139.8, 137.7, 137.0, 133.3, 132.4, 129.4, 128.9, 128.8, 128.5, 128.3, 128.2, 128.0, 121.9, 118.1, 116.8, 113.7, 86.2; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C23H15N2O2 351.1128, found 351.1125.

Synthesis of 10

A solution of 1a (10 mg. 0.04 mmol), malononitrile (4.2 mg, 1.5 equiv), and piperidinium acetate (6.2 mg, 1.0 equiv) in methanol (1 mL) was heated at 100 °C for 1 h. After concentration under the reduced pressure, the crude residue was purified by silica gel column chromatography (hexane:ethyl acetate:dichloromethane = 2:1:2) to afford 10 (10.0 mg, 78%) as a yellow gum.

4-Amino-2-benzoyl-2H-quinolizine-1,3-dicarbonitrile (10)

Yellow gum (10.0 mg, 78%); 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 6.8 Hz, 1H), 7.69 (d, J = 9.2 Hz, 1H), 7.62–7.53 (m, 5H), 7.18 (t, J = 8.4 Hz, 1H), 6.78 (t, J = 6.8 Hz, 1H), 6.50 (s, 1H), 5.96 (s, 1H), 4.80 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.2, 138.0, 130.2, 129.8, 126.8, 126.3, 124.2, 124.1, 118.0, 117.8, 115.4, 115.0, 113.9, 93.0, 81.4, 35.5; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C18H13N4O 301.1084, found 301.1153.

Synthesis of 11

A solution of 3a (30 mg. 0.1 mmol) in ethanol (2 mL) was added hydrazine hydrate (3.1 μL, 2.0 equiv) at 0 °C. After being heated at 100 °C for 19 h, the reaction mixture was cooled to room temperature. The precipitated solid was filtered and washed with hexane to afford 11 (14.2 mg, 51%) as a yellow solid.

4-Oxo-1-phenyl-3,4-dihydropyridazino[4,5-b]indolizine-10-carbonitrile (11)

Yellow solid, mp: 365.1–365.9 °C (14.2 mg, 51%); 1H NMR (400 MHz, (CD3)2SO) δ 13.28 (s, 1H), 9.62 (d, J = 6.8 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.79–7.68 (m, 3H), 7.55 (t, J = 3.2 Hz, 3H), 7.38 (t, J = 7.2 Hz, 1H); 13C{1H} NMR (100 MHz, (CD3)2SO) δ 154.5, 142.6, 142.4, 134.6, 130.4, 129.9, 129.4, 128.9, 128.7, 125.5, 118.4, 117.6, 116.1, 114.6, 75.8; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C17H11N4O 287.0927, found 287.0929.

Synthesis of 12 and 13

A solution of 4a (30 mg. 0.1 mmol) and 10% Pd/C (5 mg) in ethyl acetate (2 mL) was stirred under H2 balloon atmosphere at rt for 24 h. The catalyst was removed by filtration and washed with ethyl acetate (4 mL). After concentration of the filtrate under reduced pressure, the crude residue was purified by silica gel column chromatography (hexane:ethyl acetate:dichloromethane = 5:1:2) to give 12 (21.3 mg, 70%) as a yellow oil and 13 (8.3 mg, 27%) as a white solid.

8-Benzoyl-6-oxo-1,3,4,6-tetrahydro-2H-quinolizine-9-carbonitrile (12)

Yellow oil (21.3 mg, 70%); 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 8.4 Hz, 2H), 7.66 (t, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 2H), 6.50 (s, 1H), 4.02 (t, J = 6.0 Hz, 2H), 3.16 (d, J = 6.8 Hz, 2H), 2.03 (p, J = 6.4 Hz, 2H), 1.93 (p, J = 6.8 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.9, 161.1, 157.8, 147.6, 134.7, 134.4, 130.3, 128.9, 116.8, 114.8, 88.9, 43.5, 28.5, 21.5, 17.9; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C17H15N2O2 279.1128, found 279.1123.

8-(Hydroxy(phenyl)methyl)-6-oxo-1,3,4,6-tetrahydro-2H-quinolizine-9-carbonitrile (13)

White solid, mp: 90.2–90.9 °C (8.3 mg, 27%); 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 7.2 Hz, 2H), 7.40–7.31 (m, 3H), 6.83 (s, 1H), 5.80 (s, 1H), 4.00–3.85 (m, 2H), 3.07–2.90 (m, 3H), 1.98–1.89 (m, 2H), 1.88–1.80 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 162.3, 156.3, 154.1, 139.9, 128.8, 127.5, 115.6, 113.0, 89.7, 73.3, 43.0, 28.2, 21.6, 18.0; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C17H17N2O2 281.1285, found 281.1282.

Synthesis of 14

A solution of 4a (30 mg. 0.1 mmol) and N-bromosuccinimide (38.9 mg, 2.0 equiv) in DMF (0.5 mL) was stirred at rt for 1 h. The reaction mixture was diluted with dichloromethane (3 mL) and washed with water (10 mL). The water layer was extracted with dichloromethane (3 mL) one more time. The organic layers were dried over MgSO4 and concentrated under reduced pressure to afford 14 (37.1 mg, 96%) as a yellow solid.

2-Benzoyl-3-bromo-4-oxo-4H-quinolizine-1-carbonitrile (14)

Yellow solid, mp: 122.8–123.2 °C (37.1 mg, 96%); 1H NMR (400 MHz, CDCl3) δ 9.35 (d, J = 7.6 Hz, 1H), 8.09 (d, J = 8.8 Hz, 1H), 7.94–7.90 (m, 2H), 7.90–7.85 (m, 1H), 7.69 (t, J = 7.2 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H), 7.41 (td, J = 7.2, 1.2 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.7, 154.2, 151.2, 144.8, 135.5, 135.2, 133.3, 130.0, 129.4, 129.3, 123.7, 118.2, 114.2, 99.9, 83.5; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C17H10BrN2O2 352.9920, found 352.9903.

Synthesis of 15

To a solution of 14 (10 mg, 0.03 mmol), 4-methoxyphenylboronic acid (4.7 mg, 1.1 equiv), and Na2CO3 (9.0 mg, 3.0 equiv) in a mixed solvent (water:ethanol:toluene = 1:2:2, 1 mL) was added tetrakis(triphenylphosphine)palladium (2.0 mg, 0.06 equiv) under N2 balloon atmosphere. The reaction mixture was purged by nitrogen for 5 min and then heated at 60 °C for 2 h. The reaction mixture was concentrated under reduced pressure, diluted with dichloromethane (2 mL), and washed with water (1 mL). The water layer was extracted with dichloromethane (2 mL) one more time. The organic layers were dried over MgSO4 and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (hexane:ethyl acetate:dichloromethane = 3:1:2) to give 15 (8.4 mg, 74%) as a yellow solid.

2-Benzoyl-3-(4-methoxyphenyl)-4-oxo-4H-quinolizine-1-carbonitrile (15)

Yellow solid, mp: 182.2–182.8 °C (8.4 mg, 74%); 1H NMR (400 MHz, CDCl3) δ 9.34 (d, J = 7.2 Hz, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.82–7.76 (m, 1H), 7.74–7.69 (m, 2H), 7.50 (d, J = 7.2 Hz, 1H), 7.37–7.29 (m, 3H), 7.24 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 8.8 Hz, 2H), 3.71 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.4, 159.4, 157.2, 148.8, 145.0, 134.73, 134.66, 134.3, 131.7, 129.6, 129.2, 128.7, 125.4, 123.6, 118.8, 117.2, 115.4, 113.7, 83.1, 55.1; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C24H17N2O3 381.1234, found 381.1231.

Synthesis of 16

A solution of 4b (20 mg. 0.07 mmol) and 40% aqueous NaOH solution (0.2 mL) in ethanol (0.8 mL) was stirred at rt for 10 min. The reaction mixture was concentrated under reduced pressure to give the crude residue, which was acidified with aq. 15 % HCl solution (3 mL). Filtration and drying gave 16 as a yellow solid (21.0 mg, 99%).

2-(4-Methylbenzoyl)-4-oxo-4H-quinolizine-1-carboxamide (16)

Yellow solid, mp: 254.3–254.9 °C (21.0 mg, 99%); 1H NMR (400 MHz, (CD3)2SO) δ 9.07 (s, 1H), 9.04 (d, J = 7.2 Hz, 1H), 8.80 (d, J = 8.8 Hz, 1H), 7.94–7.88 (m, 1H), 7.42–7.37 (m, 3H), 7.17 (d, J = 8.0 Hz, 2H), 7.05 (s, 1H), 6.12 (s, 1H), 2.28 (s, 3H); 13C{1H} NMR (100 MHz, (CD3)2SO) δ 167.8, 161.4, 158.5, 140.8, 138.9, 137.8, 135.2, 129.3, 128.6, 126.0, 121.6, 117.6, 101.0, 99.5, 86.5, 21.1; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C18H15N2O3 307.1077, found 307.1074.

Synthesis of 17

A solution of 5a (30 mg. 0.1 mmol) and NaBH4 (3.7 mg, 2.0 equiv) in ethanol (1 mL) was stirred at rt. After 24 h, the mixture was quenched with saturated NH4Cl (2 mL) and the organic solvent was evaporated in vacuo. After concentration under reduced pressure, the crude residue was diluted with dichloromethane (2 mL) and washed with water (1 mL). The water layer was extracted with dichloromethane (2 mL) one more time. The organic layers were dried over MgSO4 and concentrated under reduced pressure to afford 17 (25.8 mg, 94%) as a white solid.

(3-(Hydroxymethyl)-5-(pyridin-2-yl)isoxazol-4-yl)(phenyl)methanol (17)

White solid, mp: 115.1–115.9 °C (25.8 mg, 94%); 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J = 4.8 Hz, 1H), 7.98 (d, J = 8.0 Hz, 1H), 7.87 (td, J = 8.0, 1.6 Hz, 1H), 7.56 (s, 1H), 7.38 (d, J = 7.2 Hz, 2H), 7.34 (dd, J = 7.6, 6.0 Hz, 1H), 7.25–7.16 (m, 3H), 6.29 (s, 1H), 4.69–4.59 (m, 2H), 3.23 (s, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 163.8, 162.6, 148.6, 146.4, 142.7, 138.0, 128.4, 127.5, 126.1, 124.4, 122.3, 120.8, 66.5, 56.1; HRMS (ESI-QTOF) m/z [M + H]+ calcd for C16H15N2O3 283.1077, found 283.1079.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.4c05375.1H and 13C NMR spectra of synthesized compounds and CIF files for 3b, 4a, and 5a (PDF)

Supplementary Material

ao4c05375_si_001.pdf

The authors declare no competing financial interest.

Acknowledgments

Financial support from the National Research Foundation of Korea (NRF-2018R1A6A1A03023718 and NRF-2020R1A2C2005961) is acknowledged. We also thank Professors Kyungsoo Oh and Hun Young Kim (Chung-Ang University) for helpful discussions.
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