Base-Mediated Cascade Substitution–Cyclization of 2H-Azirines

Letter pubs.acs.org/OrgLett

Base-Mediated Cascade Substitution−Cyclization of 2H‑Azirines: Access to Highly Substituted Oxazoles Xiyan Duan,*,† Kun Yang,† Jun Lu,† Xianglei Kong,‡ Ning Liu,† and Junying Ma*,† †

School of Chemical Engineering & Pharmaceutics, Henan University of Science and Technology, Luoyang 471003, Henan, China State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China

‡

S Supporting Information *

ABSTRACT: A novel strategy to synthesize highly functionalized oxazoles has been successfully developed via a base-mediated intermolecular substitution between 2-acyloxy-2H-azirines and Nnucleophile or O-nucleophile with a subsequent ring expansion of a 2H-azirine intermediate. This method provides straightforward access to highly substituted oxazoles with high efficiency and excellent functional group compatibility under metal-free reaction conditions.

O

Katritzky9 have demonstrated novel strategies toward this challenge. However, these processes have some disadvantages, such as limited nucleophiles, harsh reaction conditions, and lower reaction yield.8,9 Very recently, our group has developed a potassium iodide-promoted nucleophilic substitution reaction between 2-acyloxy-2H-azirines and carboxylic acids.10 Encouraged by these results, we set out to see if a similar reaction would take place between 2-acyloxy-2H-azirines and other nucleophiles (O-nucleophile, N-nucleophile), which could result in the formation of a C−O or C−N bond via intermolecular nucleophilic substitution reaction. In this paper, we reveal a novel and efficient protocol for the synthesis of highly substituted oxazoles via base-mediated tandem substitution and ring expansion reaction from 2-acyloxy-2Hazirines (Scheme 1). In this process, a cascade reaction

xazoles have attracted considerable attention in medicinal and agrochemical fields as a ubiquitous structural motif with a wide range of biological properties such as antineoplastic, anti-inflammatory, antibiotic, and nervous system stimulant.1 As a consequence of their importance, significant effort has been devoted to the development of efficient methodologies for the preparation an oxazole moiety.2 However, many protocols suffer from drawbacks which include the need for toxic reagents, harsh reaction conditions, transition-metal catalysts, highly functionalized starting materials, and multistep operations. Therefore, new synthetic options for the direct and efficient construction of substituted oxazole are still in great demand. On the other hand, 2H-azirines represent a highly valuable class of precursors which could generate reactive intermediates such as vinyl nitrenes and nitrile ylides. Thus, 2H-azirines have been explored extensively in the synthesis of various Nheterocycles via strain-driven ring expansion.3 It is generally accepted that the thermolysis of 2H-azirine results in cleavage of the N−C2 bond providing a vinylnitrene intermediate followed by cyclization giving isoxazole as a final product.4 However, there are also several groups demonstrated that the 2H-azirines could subsequently undergo C2−C3 bond scission to yield nitrile ylides, followed by cyclization to the corresponding oxazoles.5 Recently, our group reported the KI/TBHP-mediated oxidative cross-coupling of enamines and carboxylic acid to give 2-acyloxy-2H-azirines.6 However, the reactivity of 2-acyloxy-2H-azirines under thermal conditions is virtually unexplored. Because the reaction of 2H-azirines with nucleophiles always involves the initial addition to the imine bond,7 the selective nucleophilic substitution of 2H-azirines to yield 2-substituted 2H-azirines or their derivatives remains a challenge in organic chemistry. Pioneering works by the groups of Melo8 and © 2017 American Chemical Society

Scheme 1. Base-Mediated Cascade Substitution−Cyclization of 2-Acyloxy-2H-azirines

Received: May 1, 2017 Published: June 13, 2017 3370

DOI: 10.1021/acs.orglett.7b01305 Org. Lett. 2017, 19, 3370−3373

Letter

Organic Letters occurred, where a N-nucleophile or O-nucleophile replaces the acyloxy moiety in the 2-acyloxy-2H-azirines first, and it is followed by a ring expansion to form highly substituted oxazoles. When the nucleophile is 2,2,2-trifluoroethanol, the reaction could proceed smoothly at room temperature, which provided trifluoroethoxylated oxazoles in good yield. An initial study using readily available 2-acyloxy-2H-azirine 1a and pyrazole 2a as reactants was conducted using potassium iodide in DMF at 100 °C for 5 h, which gave rise to a 35% yield of highly substituted oxazole product 3a (Table 1, entry 1). The

reaction between the 2H-azirine 1a and pyrazole 2a (Table 1, entry 3). When NaH (1 equiv) was used together with potassium iodide (KI, 1 equiv), the reaction was completed in 0.5 h with a negligible decrease in yield (Table 1, entry 4). To our delight, the reaction of 1a with 2a in the presence of 2 equiv of NaH in DMF under a nitrogen atmosphere furnished an improved yield of 3a (Table 1, entry 5). Instead of sodium hydride, the use of some other bases such as NaHCO3, NaOH, and Na2CO3 decreased the yields of 3a (Table 1, entries 6−8). Further screening showed that the yield of product 3a was dramatically decreased as the concentrations of substrate 1a and 2a in DMF were increased (Table 1, entry 9). When the reaction was carried out at a lower temperature (80 °C), the efficiency of this transformation decreased significantly (Table 1, entry 10). The result showed that the starting material decomposed when the reaction was carried out under the base condition at room temperature (Table 1, entry 11). Further solvent screening showed that other solvents such as DMSO, toluene, or CH3CN were not suitable (not shown). Having the optimal reaction conditions in hand, we then explored the functional group tolerance for the synthesis of various substituted oxazoles under the standard conditions (Scheme 2). R2 in 1 can be an aryl group bearing either an

Table 1. Optimization of Reaction Conditionsa

entry

promotor (equiv)

additives (equiv)

time (h)

yield (%)b

1 2 3 4 5c 6c 7c 8c 9c,d 10c,e 11c,f

KI (1) − − KI (1) − − − − − − −

− − NaH (1) NaH (1) NaH (2) NaHCO3 (2) NaOH (2) Na2CO3 (2) NaH (2) NaH (2) NaH (2)

5 5 0.5 0.5 0.5 1 1 2 0.5 0.5 0.5

35 20 57 54 70 41 51 49 33 32 decomposed

Scheme 2. Scope of the 2H-Azirinesa,b

a

Reaction conditions: pyrazole (1.2 mmol), NaH (2 mmol), 2acyloxy-2H-azirines 1a (1 mmol), DMF (5 mL), under air. bIsolated yields. cReaction conditions: pyrazole (1.2 mmol), NaH (2 mmol), 2acyloxy-2H-azirines 1a (1 mmol), DMF (5 mL), under N2. d Concentration: 1 mmol/mL. eTemperature: 80 °C. fRoom temperature.

structure of 3a was confirmed by X-ray crystallography (Figure 1). To our surprise, the tandem reaction also occurred and the desired product 3a was obtained in 20% yield in the absence of any catalyst (Table 1, entry 2). It was found that sodium hydride (1 equiv) could activate the nucleophilic substitution

a

Reaction conditions: pyrazole (1.2 mmol), NaH (2 mmol), 2acyloxy-2H-azirines 1a (1 mmol), DMF (5 mL), 100 °C, 2 h, under N2. bIsolated yields.

electron-donating or -withdrawing group such as p-MeO, p-Me, p-F, p-Cl, and p-Br. The corresponding products 3b−f were isolated in 41−61% yields. R3 can be either a chloro or trifluoromethyl substituent, and the corresponding products 3g−h were isolated in moderate yields. Moreover, the reaction worked well when there were two substituted aryl groups in 2acyloxy-2H-azirines 1 (3i, 79%). R2 can also be other aryl groups such as the naphthyl group (3j, 52%) or thiophene group (3k, 64%).

Figure 1. X-ray ORTEP illustration of compound 3a. 3371

DOI: 10.1021/acs.orglett.7b01305 Org. Lett. 2017, 19, 3370−3373

Letter

Organic Letters The utility of the protocol was further extended to the reaction of various 2-acyloxylated 2H-azirines (1b−g) with pyrazole 2a (Supporting Information, Scheme 6). When the R1position of 2-acyloxylated 2H-azirines 1 is attached to a phenyl ring, both an electron-withdrawing (F−) and electron-donating (Me− and MeO−) group at either the para- or meta- position (1b−d) are well tolerated to give the corresponding target compound 3a. It was found that substrate 1e could undergo the tandem reaction with pyrazole 2a to give the desired compound 3a in satisfactory yield. When R1 was an alkyl group (1f−g), the reaction gave the desired product 3a in lower yields. To further test the scope of the reaction, several Nnucleophiles 2 were examined as substrates to react with 2acyloxy-2H-azirine 1a under the optimized reaction conditions (Scheme 3). Both 1,2,4-1H-triazole and 1H-benzimidazole

Scheme 4. Substitution−Cyclization of 2H-Azirines 1 with 2,2,2-Trifluoroethanola,b

Scheme 3. Substitution−Cyclization of 2H-Azirines 1a with Other Nitrogenous Compoundsa,b

a

Reaction conditions: 2,2,2-trifluoroethanol (1.2 mmol), NaH (2 mmol), 2-acyloxy-2H-azirines 1 (1 mmol), DMF (5 mL), room temperature, 1 h, under N2. bIsolated yields.

converted to the corresponding products (5b−g) in satisfactory to good yields (Scheme 4). When R2 is the p-MeO phenyl group and R3 is chloro, the reaction also gave the desired product 5h in 85% yield. For substrates containing other rings in place of the phenyl ring, such as naphthalene and thiophene, the reaction proceeded efficiently to provide the corresponding products 5i and 5j in good yields. Then, the 2H-azirine 1a was chosen as a substrate to react with several alcohols (6a−g) under optimized reaction conditions (Supporting Information, Table 2). Disappointingly, alcohols (6a−g) failed to give their corresponding oxazoles (Table 2, entries 1−7). Further conditions screening showed that the reaction of substrate 1c and O-nucleophiles (6a−b) only delivered the corresponding azirines 7a and 7b in good yields (Supporting Information, Scheme 7). Treatment of 1c and 1,1,1,3,3,3-hexafluoro-2propanol 6c provided the corresponding azirine 7c in 57% yield. To explore the reaction mechanism, several control experiments were conducted. Both radical quenchers 2,2,6,6tetramethylpiperidine 1-oxyl (TEMPO) and 2,6-di-tert-butyl4-methylphenol (BHT) did not hamper the substitution− cyclization reaction between 2-acyloxy-2H-azirine 1a and pyrazole 2a, suggesting that the free radical mechanism is unlikely. When the amount of NaH was decreased to 0.5 equiv, the reaction of 2a with substrate 1a afforded a 25% yield of the 2substitued 2H-azirine 8a, in addition to the 4-substitued oxazoles product 3a in 35% yield and the recovered starting material 1a in 28% yield (Supporting Information, Scheme 8a). Treatment of 2-substituted 2H-azirine 8a with NaH (1 equiv) in DMF at 100 °C or room temperature led to product 3a in the yield of 76% and 72% respectively (Scheme 8b). In

a Reaction conditions: N-Nucleophile 2 (1.2 mmol), NaH (2 mmol), 2-acyloxy-2H-azirines 1 (1 mmol), DMF (5 mL), 100 °C, 2 h, under N2. bIsolated yields.

successfully reacted with 1a to afford 4a and 4b in good yields. When the N-nucleophile was changed to indazole, the reaction also proceeded smoothly to afford the desired product 4c in 40% yield. 5-Chlorobenzimidazole also could successfully react with 1a to afford a mixture of two regioselective products 4d and 4d′. Unfortunately, a series of other N-nucleophiles such as pyrrole, pyrrolidine, tetrazole, and 1-methylindole failed to afford the desired product under the same conditions (not shown). We next focused our attention on the substitution− cyclization reactions of 2-acyloxy-2H-azirines 1 with 2,2,2trifluoroethanol to provide 4-trifluoroethoxylated oxazoles 5 (Scheme 4). Screening of solvents, temperatures, and the ratio of reagents established the optimized conditions to be NaH (2 equiv) in DMF at room temperature and 1a and 2,2,2trifluoroethanol in a ratio of 1:1.2. Under standard reaction conditions, product 5a was obtained in 75% yield. The 2acyloxy-2H-azirine substrates bearing either electron-donating or -withdrawing substituents on the aromatic ring were all 3372

DOI: 10.1021/acs.orglett.7b01305 Org. Lett. 2017, 19, 3370−3373

Organic Letters

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addition, treatment of 2H-azirine 9a with sodium hydride at room temperature delivered the desired product 5a in excellent yield (Scheme 8c). These results indicated that the reaction sequence involves not only the intermolecular substitution but also a subsequent intramolecular ring expansion process. Interestingly, the intermediate 8a could be converted to 3a in DMF at 100 °C in poor yield during the prolonged reaction time in the absence of any other reactant or promotor (Scheme 8d). However, when the substrate was switched to 9a, no reaction occurred at either room temperature or high temperature (Scheme 8e). These experimental results suggest that the structure of 2H-azirine is a key factor of ring expansion of the 2H-azirine intermediate under the heating condition in the absence of any promoter. No reaction occurred when 8a was treated with 2a in DMF at room temperature. This result indicates that the pyrazole cannot promote the ring expansion (Scheme 8f). On the basis of experiment results and literature reports,10,11 a possible mechanistic pathway has been proposed using 1a and 2a as examples (Scheme 5). Under the basic conditions, a

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Xiyan Duan: 0000-0003-4882-0430 Xianglei Kong: 0000-0002-8736-6018 Notes

The authors declare no competing financial interest.

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REFERENCES

(1) (a) Kibriz, I. E.; Saçmaci, M.; Sahin, E.; Yildirim, I. P. Tetrahedron 2017, 73, 1795−1802. (b) Wu, X.; Geng, X.; Zhao, P.; Zhang, J.; Wu, Y.; Wu, A. Chem. Commun. 2017, 53, 3438−3441. (c) Wan, C.; Gao, L.; Wang, Q.; Zhang, J.; Wang, Z. Org. Lett. 2010, 12, 3902−3905. (2) (a) Zheng, Y.; Li, X.; Ren, C.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. J. Org. Chem. 2012, 77, 10353−10361. (b) Cheung, C. W.; Buchwald, S. L. J. Org. Chem. 2012, 77, 7526−7537. (c) Zheng, M.; Huang, L.; Huang, H.; Li, X.; Wu, W.; Jiang, H. Org. Lett. 2014, 16, 5906−5909. (d) Saito, A.; Taniguchi, A.; Kambara, Y.; Hanzawa, Y. Org. Lett. 2013, 15, 2672−2675. (e) Senadi, G. C.; Hu, W.-P.; Hsiao, J.-S.; Vandavasi, J. K.; Chen, C.-Y.; Wang, J.-J. Org. Lett. 2012, 14, 4478−4481. (f) Yang, D.-S.; Yan, K.-L.; Wei, W.; Tian, L.-J.; Shuai, Y.Y.; Li, R.-X.; You, J.-M.; Wang, H. Asian J. Org. Chem. 2014, 3, 969− 973. (g) Yang, D.-S.; Liu, P.; Zhang, N.; Wei, W.; Yue, M.; You, J.-M.; Wang, H. ChemCatChem 2014, 6, 3434−3439. (3) Loy, N. S. Y.; Singh, A.; Xu, X.; Park, C.-M. Angew. Chem., Int. Ed. 2013, 52, 2212−2216. (4) (a) Padwa, A.; Smolanoff, J.; Tremper, A. J. Org. Chem. 1976, 41, 543. (b) Padwa, A.; Smolanoff, J.; Tremper, A. J. Am. Chem. Soc. 1975, 97, 4682. (c) Isomura, K.; Ayabe, G.-I.; Hatano, S.; Taniguchi, H. J. Chem. Soc., Chem. Commun. 1980, 1252. (d) Wendling, L. A.; Bergman, R. G. J. Org. Chem. 1976, 41, 831. (e) Singh, B.; Zweig, A.; Gallivan, J. B. J. Am. Chem. Soc. 1972, 94, 1199. (f) Orton, E.; Collins, S. T.; Pimentel, G. C. J. Phys. Chem. 1986, 90, 6139. (g) Inui, H.; Murata, S. J. Am. Chem. Soc. 2005, 127, 2628. (h) Inui, H.; Murata, S. Chem. Lett. 2001, 30, 832. (i) Lopes, S.; Nunes, C. M.; GómezZavaglia, A.; Pinho e Melo, T. M. V. D.; Fausto, R. Tetrahedron 2011, 67, 7794−7804. (5) (a) Lopes, S.; Nunes, C. M.; Fausto, R.; Pinho e Melo, T. M. V. D. J. Mol. Struct. 2009, 919, 47−53. (b) Singh, B.; Ullman, E. F. J. Am. Chem. Soc. 1967, 89, 6911. (c) Isomura, K.; Hirose, Y.; Shuyama, H.; Abe, S.; Ayabe, G.; Taniguchi, H. Heterocycles 1978, 9, 1207. (6) Duan, X.; Kong, X.; Zhao, X.; Yang, K.; Zhou, H.; Zhou, D.; Zhang, Y.; Liu, J.; Ma, J.; Liu, N.; Wang, Z. Tetrahedron Lett. 2016, 57, 1446−1450. (7) Pinho e Melo, T. M. V. D.; Lopes, C. S. J.; Gonsalves, A. M. Tetrahedron Lett. 2000, 41, 7217−7220. (8) (a) Pinho e Melo, T. M. V. D.; Lopes, C. S. J.; Gonsalves, A. M. A. R.; Beja, A. M.; Paixão, J. A.; Silva, M. R.; Veiga, L. A. J. Org. Chem. 2002, 67, 66−71. (b) Pinho e Melo, T. M. V. D.; Cardoso, A. L.; Gonsalves, A. M. A. R. Tetrahedron 2003, 59, 2345−2351. (9) Katritzky, A. R.; Wang, M.; Wilkerson, C. R.; Yang, H. J. Org. Chem. 2003, 68, 9105−9108. (10) Duan, X.; Yang, K.; Liu, J.; Kong, X.; Liang, J.; Zhou, D.; Zhou, H.; Zhang, Y.; Liu, N.; Feng, S.; Gu, G.; Lu, J.; Song, N.; Zhang, D.; Ma, J. Adv. Synth. Catal. 2016, 358, 3161−3166. (11) Singh, B.; Ullman, E. F. J. Am. Chem. Soc. 1967, 89, 6911−6916.

Scheme 5. Proposed Reaction Mechanism

nucleophilic substitution reaction between substrate 1a and the pyrazole anion occurred and resulted in the formation of intermediate 8a.10 Sodium hydride reacted with a trace amount of water to generate sodium hydroxide. Then, the hydroxyl group would attack the imine bond of intermediate 8a to form intermediate B. Then, intermediate B might undergo an alkaline scission C2−C3 bond to generate intermediate C. Finally, the intramolecular substitution of intermediate C would lead to final product 3a.11 In summary, an efficient base-promoted cascade substitution−cyclization reaction of 2-acyloxy-2H-azirines has been initially developed. This transformation is the first example of NaH-mediated cascade substitution−cyclization of 2H-azirines with the O-nucleophile and N-nucleophile. Moreover, this novel method provides efficient access to highly substituted oxazole derivatives.

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Letter

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01305. Full experimental details and characterization data for all products (PDF) X-ray crystallographic files for compound 3a (CIF) 3373

DOI: 10.1021/acs.orglett.7b01305 Org. Lett. 2017, 19, 3370−3373