Synthesis of poly-functionalized imidazoles via vinyl azides annulation

Abstract

An efficient annulation of vinyl azides with activated imines has been developed for the synthesis of poly-functionalized imidazole derivatives. This reaction includes thermal decomposition of vinyl azides to 2H-azirines, nucleophilic attack of 2H-azirines with activated imines and subsequent cyclization to desired imidazoles.

---

Functionalized imidazoles are very important in natural products, pharmaceuticals, and materials science. They constitute platforms for biologically active molecules,¹ chemical ligands² and advanced materials.³ In every application of imidazoles, the substitution pattern of the imidazole ring is of importance as it impacts on both the chemical and physical properties of the resultant molecules. Therefore, various synthetic methods have been developed, such as the functionalization of already constructed imidazole rings⁴ and other cascade reactions involving cycloaddition reactions of activated isocyanides,⁵ reaction of amidines with α-haloketones^6a,b or nitroallylic acetates.^6c Despite these advances, the development of efficient strategies for the construction of poly-functionalized imidazoles is highly desirable.

Vinyl azides have long proved to be versatile building blocks in the synthesis of nitrogen-containing heterocycles. Our group and others have reported the utility in the construction of azaheterocycles, such as anilines,^7a pyrrolo[1,2-a]pyrazine,^7b 4-aminopyridines,^7c pyrazoles,^7d imidazoles^7e or other heterocycles.^7f–j

The continued interest in electrophilic reactivity of vinyl azides motivated us to investigate the reaction of vinyl azides with activated imines. We began our studies using vinyl azide (1a) with ethoxyimidate as a model reaction. The ethoxyimidates were usually prepared from nitriles through a Pinner reaction.⁸ Unexpectedly, the reaction failed to proceed under the Michael addition conditions previously reported (Table 1, entries 1–6).⁷ To our surprise, the reaction proceeded when using EtOH as solvent in the presence of Et₃N (1.0 equiv.) under the 110 °C for 10 h (Table 1, entry 8). The main product was then characterized as 3a in 30% yield. It was found that the reaction could also lead to the formation of 3a in 32% yield without the addition of base (Table 1, entry 9). The low yields were due to the decomposition of vinyl azides.

Table 1 Optimization of reaction conditions^a

Entry	Base	Solvent	LG	T/°C	t/h	Yield^b/%
a Unless otherwise specified, reactions were performed in a sealed tube using 1a (0.1 mmol) and 2 (0.11 mmol) in various solvents (1.0 mL) at different temperature in the presence or absence of the additive (0.1 mmol) for a period of time.b Isolated yields are the means from two independent experiments.c No reaction.
1	Et3N	DMF	OEt	25	10	nr^c
2	Et3N	DMF	OEt	60	10	Trace
3	Et3N	EtOH	OEt	25	10	nr^c
4	t-BuOK	EtOH	OEt	25	10	nr^c
5	Cs2CO3	EtOH	OEt	25	10	nr^c
6	K2CO3	EtOH	OEt	25	10	nr^c
7	Et3N	EtOH	OEt	80	10	Trace
8	Et3N	EtOH	OEt	110	10	30
9	—	EtOH	OEt	110	8	32
10	—	DMF	OEt	110	8	37
11	—	Toluene	OEt	110	8	22
12	—	t-BuOH	OEt	110	8	92
13	—	t-BuOH	Ot-Bu	110	8	10
14	—	t-BuOH	SCH3	110	8	90
15	—	t-BuOH	OEt	110	1	23
16	—	t-BuOH	OEt	110	4	48
17	—	t-BuOH	OEt	110	10	91

---

In order to improve the yields, we screened other solvents including t-BuOH, DMF and toluene, t-BuOH was found to be favor for this reaction with higher yield of 92% (Table 1, entry 12 vs. entries 9–11). Additionally, the inductive effect of the leaving groups was tested in this reaction. It was surprising to find that only 10% of the desired product was obtained from the t-BuO-substituted imidate, while the formation of product 3a proceeded in near quantitative yield from vinyl azide (1a) with ethyoxyimidate (Table 1, entry 12 vs. entry 13). Gratifyingly, the analogues thioimidate⁹ gave the desired product 3a in the yield of 90% (Table 1, entry 14). These results showed the importance in the selection of the leaving groups. After optimization of the reaction conditions, an acceptable yield of 92% was obtained in t-BuOH at 110 °C for 8 h (Table 1, entry 12). When the reaction was performed for 10 h, the yields did not show significant difference (Table 1, entry 12 vs. entry 17). But when the reaction times were shorten to 1 h or 4 h, the yield of 3a decreased to 23% and 48%, respectively.

On the basis of our initial results outlined above, we explored the reaction scope. The electronic effects of the substituents adjacent to the vinyl azide 1 were examined. The reaction showed tolerance for various R₁ and R₂ groups of vinyl azides 1 (Table 2, 3a–3u, except 3h and 3j). For example, when vinyl azides were substituted at the aryl ring (R₁) with H or Br, the desired product 3a and 3g were obtained in near quantitative yields of 92% and 93%, respectively. Vinyl azide with heterocycle substituent also smoothly reacted with imidate and provided the desired product 3i in 55% yield. However, when H was substituted at the R₁ position of vinyl azide 1, the desired product 3j was obtained in trace (<5%). It may be due to the instability of aziridine formed in situ. Instead of the ester group at the R₂ position, vinyl azides substituted with carbonyl group or amide group were also tested in this reaction conditions to give the corresponding products in 28%, 95% and 90% yields, respectively (3k–3m). Moreover, the chemical reactivity of leaving groups (–OEt, –SCH₃) on the activated imines 2 was evaluated with various substituted vinyl azides. Imidate and thioamidium reacted with vinyl azides in a similar fashion and the reaction proceeded well, affording the imidazoles in moderate to good yields (Table 2). Additionally, aliphatic substitution as well as bearing an activated methylene on the R₃ position of activated imines (2) were compatible for the tandem cyclization (Table 2, 3o–3q, 3s and 3u).

Table 2 Imidazole formation from tandem addition/cyclization of vinyl azides 1 and activated imines 2^a

a Reaction conditions: vinyl azides 1 (1.0 equiv.) and activated imines 2 (1.1 equiv.) in t-BuOH heated in a sealed tube (110 °C). Yields shown are those of the isolated products.

---

The structures of the products synthesized in this study were characterized from their ¹H NMR, ¹³C NMR spectroscopies and HRMS analysis. The structure of compound 3g was further confirmed by X-ray analysis (Fig. 1) (ESI†).

Fig. 1 X-Ray crystal structure of 3g.

Based on the results of the study, we supposed that the reaction may proceed through 2H-azirines involving tandem cyclization. To this end, we prepared the 2H-aziridine (A)¹⁰ by thermolysis of vinyl azide 1a.¹¹ To our expectation, the reaction of 2H-aziridine (A) with ethoxyimidate proceeded well at room temperature to give the desired product 3a (Scheme 1). This result finally supported our hypothesis.

Scheme 1 Control experiments.

Accordingly, we proposed a mechanism for this tandem cyclization as shown in Scheme 2. Firstly, vinyl azides 1 can be transformed to the corresponding 2H-aziridines in situ by thermal elimination of N₂.¹⁰ The reaction may proceed through the addition of activated imines 2 to the imino carbon of 2H-aziridine, following by the intramolecular nucleophilic attack following with the ring opening of the strained three-membered ring to obtain the imidazole 3.

Scheme 2 Proposed reaction mechanism for the construction of poly-functionalized imidazoles 3.

In summary, we have developed a concise approach for the synthesis of poly-functionalized imidazoles by tandem annulation of vinyl azides and activated imines, such as imidate or thioamidium. An attractive concept for the synthesis of imidazoles is the utilization of the ring strain and chemical reactivity of 2H-azirines. Aldehyde groups and halide substituents were compatible with the developed reaction conditions, thus providing convenient handles for further functionalization.

Acknowledgements

This project was supported from the National Natural Science Foundation of China (no. 81273356 and 81473074), National Science & Technology Major Projects for "Major New Drugs Innovation and Development" of China (2014ZX09304002-007), the Program for Zhejiang Leading Team of S&T Innovation Team (2011R50014), and Arthritis & Chronic Pain Research Institute, USA, to Y. Yu; National Natural Science Foundation of China (no. 81402778) and the Fundamental Research Funds for the Central Universities (no. 2015QNA7029) to W. Chen; the China Postdoctoral Science Foundation Funded Project (2015M570520) to J. Shao.

Notes and references

1. For the biological application of imidazoles, see: (a) G. J. Atwell, J. Fan, K. Tan and W. A. Denny, J. Med. Chem., 1998, 41, 4744; (b) P. B. Koswatta and C. H. Lovely, Nat. Prod. Rep., 2011, 28, 511; (c) F. V. Lali, A. E. Hunt, S. J. Turner and B. M. J. Foxwell, J. Biol. Chem., 2000, 275, 7395; (d) R. R. Wexler, W. J. Greenlee, J. D. Irvin, M. R. Goldberg, K. Prendergast, R. D. Smith and P. B. M. W. M. Timmermans, J. Med. Chem., 1996, 39, 625; (e) S. Riduan and Y. Zhang, Chem. Soc. Rev., 2013, 42, 9055.
2. For publications on imidazole coordination chemistry, see: (a) Y. Sunatsuki, Y. Motoda and N. Matsumoto, Coord. Chem. Rev., 2002, 226, 199; (b) Y. Sunatsuki, R. Kawamoto, K. Fujita, H. Maruyama, T. Suzuki, H. Ishida, M. Kojima, S. Iijima and N. Matsumoto, Coord. Chem. Rev., 2010, 254, 1871; (c) K. M. Lancaster, J. B. Gerken, A. C. Durrell, J. H. Palmer and H. B. Gray, Coord. Chem. Rev., 2010, 254, 1803.
3. (a) T. Iwamura and S. Nakamura, Polymer, 2013, 54, 4161; (b) S. Yuan, Y. Deng and D. Sun, Chem.–Eur. J., 2014, 20, 1.
4. C. Sämann, E. Coya and P. Knochel, Angew. Chem., Int. Ed., 2014, 53, 1430.
5. (a) R. V. A. Orru and V. G. Nenajdenko, Isocyanide Chemistry, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2012, p. 109; (b) A. V. Lygin and A. de Meijere, Angew. Chem., Int. Ed., 2010, 49, 9094; (c) A. V. Gulevich, A. G. Zhdanko, R. V. A. Orru and V. G. Nenajdenko, Chem. Rev., 2010, 110, 5235; (d) U. Schöllkopf, Angew. Chem., Int. Ed. Engl., 1977, 16, 339.
6. (a) H. Bredereck, R. Gompper and D. Hayer, Chem. Ber., 1959, 92, 338; (b) T. J. Donohoe, M. A. Kabeshov, A. H. Rathi and I. E. D. Smith, Org. Biomol. Chem., 2012, 10, 1093; (c) T. Kumar, D. Verma, R. F. S. Menna-Barreto, W. O. Valenca, E. N. da Silva Júnior and I. N. N. Namboothiri, Org. Biomol. Chem., 2015, 13, 1996.
7. (a) S. Liu, W. Chen, J. Luo and Y. Yu, Chem. Commun., 2014, 50, 8539; (b) W. Chen, M. Hu, J. Wu, H. Zou and Y. Yu, Org. Lett., 2010, 12, 3863; (c) J. Shao, W. Yu, Z. Shao and Y. Yu, Chem. Commun., 2012, 48, 2785; (d) G. Zhang, H. Ni, W. Chen, J. Shao, H. Liu, B. Chen and Y. Yu, Org. Lett., 2013, 15, 5967; selected references: (e) L. Xiang, Y. Niu, X. Pang, X. Yang and R. Yan, Chem. Commun., 2015, 51, 6598; (f) X. Zhu, Y.-F. Wang, F.-L. Zhang and S. Chiba, Chem.–Asian. J., 2014, 9, 2458; (g) S. Chiba, Chimia, 2012, 66, 377; (h) Y.-F. Wang, K. K. Toh, E. P. J. Ng and S. Chiba, J. Am. Chem. Soc., 2011, 133, 6411; (i) E. P. J. Ng, Y.-F. Wang and S. Chiba, Synlett, 2011, 783; (j) Y.-F. Wang and S. Chiba, J. Am. Chem. Soc., 2009, 131, 12570.
8. (a) V. K. Yadav and K. G. Babu, Eur. J. Org. Chem., 2005, 452; (b) R. Morgentin, F. Jung, M. Lamorlette, M. Maudet, M. Plé, P. Ménard, G. Pasquet and F. Renaud, Tetrahedron, 2009, 65, 757.
9. S. Caron, L. Wei, J. Douville and A. Ghosh, J. Org. Chem., 2010, 75, 945.
10. 2H-Aziridine (A), yellow oil; ¹H NMR (500 MHz, CDCl₃) δ 7.32 (m, 3H), 7.15–7.12 (m, 2H), 4.48 (m, 2H), 3.47 (s, 1H), 1.42 (t, J = 7.1 Hz, 3H).
11. (a) S. Chiba, Y.-F. Wang, G. Lapointe and K. Narasaka, Org. Lett., 2008, 10, 313; (b) Ǻ. S. Timén, E. Risberg and P. Somfai, Tetrahedron Lett., 2003, 44, 5339–5341.

---

Footnotes

† Electronic supplementary information (ESI) available. CCDC 1045551. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra07320k

‡ Jing Luo and Wenteng Chen contributed equally to this work.

---