I₂-catalyzed one-pot synthesis of pyrrolo[1,2-a]quinoxaline and imidazo[1,5-a]quinoxaline derivatives via sp³ and sp² C–H cross-dehydrogenative coupling

Abstract

An efficient I₂-catalyzed cascade coupling protocol was developed for the synthesis of pyrrolo[1,2-a]quinoxaline and imidazo[1,5-a]quinoxaline derivatives via sp³ and sp² C–H cross-dehydrogenative coupling. A nontoxic, readily available catalyst, I₂, and an oxidant, DMSO, were used in this metal-free process. The target compounds were obtained in good-to-excellent yields with a broad substrate scope.

---

Cross-dehydrogenative coupling (CDC) has recently emerged as an ideal method for the formation of carbon–carbon (C–C)¹ and carbon–heteroatom (C–X)² bonds. Because of its substantial benefits for organic synthesis, this approach has garnered significant attention from the chemical community. However, most of the studied CDC methods suffer from expensive and detrimental metal precursors, harsh reaction conditions, critical product isolation procedures, and unsatisfactory product yields, thus limiting their use in green chemistry. Therefore, it is highly desirable to develop a convenient and efficient approach for CDC.

DMSO has received significant attention since it was first reported in 1957 as an oxidant.³ DMSO is an inexpensive, nontoxic, and readily available oxidant for various organic transformations under mild and convenient reaction conditions.⁴

Although acid catalysis remains the most widely used type of catalysis, it suffers from serious health and safety problems. Therefore, the development of a safe and atom-efficient acid-catalyzed organic process is one of the most important challenges in green chemistry. I₂ is a mild, inexpensive, nontoxic, and readily available Lewis acid with enhanced utility in several organic transformations.⁵ Moreover, most I₂-catalyzed reactions involve multicomponent or domino reaction sequences,⁶ and forming several bonds in a single operation is one of the important synthetic goals for molecular diversity and complexity.

Recently, pyrrolo[1,2-a]quinoxaline and imidazo[1,5-a]quinoxaline derivatives have received considerable attention for their biological activities such as 5-HTR affinities,⁷ anticancer,⁸in vitro antiparasitic,⁹ and potential nonpeptide glucagon receptor antagonist activities.¹⁰

Consequently, many synthetic protocols have been developed to synthesize pyrrolo[1,2-a]quinoxaline or imidazo[1,5-a]quinoxaline derivatives. Reeves et al. reported the synthesis of these tricyclic compounds in N-methylpyrrolidone (NMP) from 1H-pyrrole-2-carbaldehyde and 2-iodoaniline in the presence of CuI and sparteine (Scheme 1a).^11a Hulme and co-worker reported a multicomponent reaction for the synthesis of imidazo[1,5-a]quinoxaline derivatives from isonitrile, 2-oxo-2-phenylacetaldehyde, and tert-butyl(2-aminophenyl)carbamate via multiple steps (Scheme 1b).^11b Pereira and Thiéry developed a one-pot reaction for synthesizing pyrrolo[1,2-a]quinoxalines from 1-(2-nitrophenyl)pyrroles and various alcohols using excess of iron powder and HCl (Scheme 1c).^11c Kundu et al. reported the diversity-oriented synthesis of indoloquinoxalines from 1-(2-nitroaryl)-2-alkynylindoles and NaN₃ in hexamethylphosphoramide (HMPA) using CuI as the catalyst (Scheme 1d).^11d However, these methods suffer from some disadvantages such as complex manipulation^11b and the use of hazardous substrates^11b,d or transition-metal catalysts.^11a,c,d

Scheme 1 Previous work.

We have been developing the direct synthesis of heterocyclic systems using tandem reactions.¹² Herein, we report a cascade coupling protocol for the synthesis of pyrrolo[1,2-a]quinoxaline and imidazo[1,5-a]quinoxaline derivatives using I₂ as the catalyst and DMSO as the oxidant via sp³ and sp² C–H CDC (Scheme 2).

Scheme 2 This work.

The reaction conditions were optimized using acetophenone 1a and tryptamine 2a as the model substrates, and the results are summarized in Table 1. First, several types of solvents were investigated under a N₂ atmosphere; no product was detected until DMSO was used (Table 1, entries 1–6). Then, several types of iodide reagents such as N-iodosuccinimide (NIS), KI, and tetrabutylammonium iodide (TBAI) were screened; no desired product was obtained (Table 1, entries 7–9). The dosages of I₂ were also investigated, 20 mol% I₂ resulted in 87% yield, while 15 mol% I₂ significantly lowered the yield (Table 1, entries 6 and 10–15). Furthermore, a small amount of water and air did not significantly affect the reaction (Table 1, entries 16 and 17). Low yield (3aa) was obtained when 1a and 2a were added simultaneously (Table 1, entry 18).

Table 1 Optimization of reaction conditions for the one-pot synthesis of 3a^a,f

Entry	Additive (mol%)	Solvent	Yield^b (%)
a Reaction conditions: 1a (0.5 mmol), additive, and solvent (2 mL), in a sealed tube at 120 °C under a N2 atmosphere for 6 h, and then adding 2a (0.5 mmol). b Yield of the isolated product. c 1% water content. d Under air. e Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), I2 (20 mol%), and solvent (2 mL), in a sealed tube at 120 °C under an air atmosphere for 6 h. f DMF = N,N-dimethylformamide, DMA = N,N-dimethylacetamide, OX = o-xylene, NMP = N-methylpyrrolidone, DMSO = dimethyl sulfoxide.
1	I2 (100)	DMF	N.D.
2	I2 (100)	DMA	N.D.
3	I2 (100)	OX	N.D.
4	I2 (100)	PhCl	N.D.
5	I2 (100)	NMP	N.D.
6	I2 (100)	DMSO	85
7	NIS (20)	DMSO	Trace
8	KI (20)	DMSO	N.D.
9	TBAI (20)	DMSO	N.D.
10	I2 (120)	DMSO	83
11	I2 (80)	DMSO	85
12	I2 (60)	DMSO	87
13	I2 (40)	DMSO	87
14	I 2 (20)	DMSO	87
15	I2 (15)	DMSO	80
16	I2 (20)	DMSO^c	86
17	I 2 (20)	DMSO	87
18^e	I2 (20)	DMSO	75

---

With the optimized reaction conditions, the substrate scope of this method was investigated. As shown in Table 2, diverse aromatic ketones 1a–l were investigated in the reaction with 2-(1H-pyrrol-1-yl)aniline 2a; the corresponding products were obtained in good-to-excellent yields. The yields increased in the presence of electron-donating substituents on the aryl ring. Low yields were obtained when electron-withdrawing substituents were present on the aryl ring. Notably, heterocycles such as 1-(thiophen-2-yl)ethanone and 1-(benzodioxol-5-yl)ethanone also participated in the reaction, affording the corresponding products 3al and 3ai in 85% and 86% yields, respectively. Moreover, sterically hindered 2-acetylnaphthalene and 1-acetylnaphthalene also furnished the desired products 3aj and 3ak in 81% and 85% yields, respectively.

Table 2 Substrate scope of 1^a

a Reaction conditions: 1 (0.5 mmol), I₂ (20 mol%), and solvent (2 mL), in a sealed tube at 120 °C under a N₂ atmosphere for 6 h, and then adding 2 (0.5 mmol).

---

Next, the substrate scope of 2-(1H-pyrrol-1-yl)aniline 2b–d was investigated, and the results are shown in Table 3. The target compounds were obtained in good yields. The yields decreased in the presence of electron-withdrawing substituents on the benzene ring attached to 2-(1H-pyrrol-1-yl)aniline 2, while the electron-donating substituents did not affect the yields of the corresponding products.

Table 3 Substrate scope of 1^a

a Reaction conditions: 1 (0.5 mmol), I₂ (20 mol%), and solvent (2 mL), in a sealed tube at 120 °C under a N₂ atmosphere for 6 h, and then adding 2 (0.5 mmol).

---

Then, the substrate scope of 2-(1H-imidazol-1-yl)aniline and 2-(1H-indol-1-yl)aniline 2e–i were investigated; the corresponding products were obtained in good-to-excellent yields. Interestingly, considerable yields (3ea and 3ej) were obtained when 2-(1H-imidazol-1-yl)aniline 2e was used. This result could not be achieved in a previous study.¹³ Disappointingly, 3ja and 3ka could not be obtained by this method (Table 4).

Table 4 Substrate scope of 2e–j^a

a Reaction conditions: 1 (0.5 mmol), I₂ (20 mol%), and solvent (2 mL), in a sealed tube at 120 °C under a N₂ atmosphere for 6 h, and then adding 2 (0.5 mmol).

---

To elucidate the mechanism of the reaction, several control experiments were conducted (Scheme 3). In the absence of I₂, possible intermediate 1aa reacted with 2a, affording 3aa in good yield. The target molecule 3aa was also obtained from possible intermediate 1ac by reacting with 2a in the presence of I₂.

Scheme 3 Control experiments.

Based on the above control experiments, a possible mechanism for this reaction is shown in Scheme 4. First, the reaction of acetophenone 1a and I₂ affords α-iodoketone 1aa and HI. Then, the oxidation of α-iodoketone 1aa with DMSO affords phenylglyoxal 1ac,¹⁴ thus releasing by-products HI and dimethyl sulfide. Then, the I₂-catalyzed cyclization of phenylglyoxal 1ac with 2-(1H-pyrrol-1-yl)aniline 2a affords 4-benzoylpyrrolo[1,2-a]quinoxaline 3aa. Finally, the oxidation of the by-product HI with DMSO affords I₂, thus releasing H₂O and dimethyl sulfide and completing the catalytic cycle.

Scheme 4 Proposed mechanism.

An eco-friendly method was developed for the synthesis of pyrrolo[1,2-a]quinoxaline and imidazo[1,5-a]quinoxaline derivatives via sp³ and sp² C–H CDC. A nontoxic, readily available catalyst, I₂, and an oxidant, DMSO, were used. This metal-free method has a broad substrate scope, and the target compounds were obtained in good-to-excellent yields. Studies on the application of this method to the synthesis of pharmaceutical compounds are in progress.

Acknowledgements

We are grateful to the National Science Foundation of China (No. 21172131) and the State Key Laboratory of Natural and Biomimetic Drugs of Peking University (No. K20140208) for financial support to this research.

Notes and references

1. (a) C. J. Li, Acc. Chem. Res., 2009, 42, 335; (b) Z. Li and C. J. Li, J. Am. Chem. Soc., 2006, 128, 56; (c) Z. Li and C. J. Li, J. Am. Chem. Soc., 2005, 127, 6968; (d) Z. Li and C. J. Li, J. Am. Chem. Soc., 2005, 127, 3672; (e) Z. Li and C. J. Li, Org. Lett., 2004, 6, 4997; (f) Z. Li and C. J. Li, J. Am. Chem. Soc., 2004, 126, 11810; (g) Y. Z. Li, B. J. Li, X. Y. Lu, S. Lin and Z. J. Shi, Angew. Chem., Int. Ed., 2009, 48, 3817; (h) B. J. Li, S. L. Tian, Z. Fang and Z. J. Shi, Angew. Chem., Int. Ed., 2008, 47, 1115; (i) W. Shi, C. Liu and A. W. Lei, Chem. Soc. Rev., 2011, 40, 2761; (j) C. He, S. Guo, J. Ke, J. Hao, H. Xu, H. Y. Chen and A. W. Lei, J. Am. Chem. Soc., 2012, 134, 5766; (k) M. Gao, C. He, H. Y. Chen, R. P. Bai, B. Cheng and A. W. Lei, Angew. Chem., Int. Ed., 2013, 125, 7096.
2. (a) C. G. Espino, K. W. Fiori, M. Kim and J. DuBois, J. Am. Chem. Soc., 2004, 126, 15378; (b) K. W. Fiori and J. DuBois, J. Am. Chem. Soc., 2007, 129, 562; (c) M. Kim, J. V. Mulcahy, C. G. Espino and J. DuBois, Org. Lett., 2006, 8, 1073; (d) C. G. Liang, F. Robert-Peillard, C. Fruit, P. Müller, R. H. Dodd and P. Dauban, Angew. Chem., Int. Ed., 2006, 45, 4641; (e) H. Lebel and K. Huard, Org. Lett., 2007, 9, 639; (f) R. P. Reddy and H. M. L. Davies, Org. Lett., 2006, 8, 5013; (g) Y. P. Zhu, M. C. Liu, Q. Cai, F. C. Jia and A. X. Wu, Chem. – Eur. J., 2013, 19, 10132.
3. N. Kornblum, J. W. Powers, G. J. Anderson, W. J. Jones, H. O. Larson, O. Levand and W. M. Weaver, J. Am. Chem. Soc., 1957, 79, 6562.
4. (a) F. Jia, Y. Zhu, M. Liu, M. Lian, Q. Gao, Q. Cai and A. Wu, Tetrahedron, 2013, 69, 7038; (b) Z. Fei, Y. Zhu, M. Liu, F. Jia and A. Wu, Tetrahedron Lett., 2013, 54, 1222; (c) Y. Zhu, Z. Fei, M. Liu, F. Jia and A. Wu, Org. Lett., 2013, 15, 378; (d) Y. Zhu, F. Jia, M. Liu and A. Wu, Org. Lett., 2013, 14, 4414; (e) Y. Zhu, M. Liu, F. Jia, J. Yuan, Q. Gao, M. Lian and A. Wu, Org. Lett., 2013, 14, 3392; (f) W. Ge and Y. Wei, RSC Adv., 2013, 3, 10817; (g) W. Ge, X. Zhu and Y. Wei, Green Chem., 2012, 14, 2066; (h) Y. Ashikari, A. Shimizu, T. Nokami and J. Yoshida, J. Am. Chem. Soc., 2013, 135, 16070.
5. (a) Y. F. Liao, P. C. Jiang, S. P. Chen, H. G. Qi and G. J. Deng, Green Chem., 2013, 15, 3302; (b) P. Katrun, C. Mueangkaew, M. Pohmakotr, V. Reutrakul, T. Jaipetch, D. Soorukram and C. Kuhakarn, J. Org. Chem., 2014, 79, 1778; (c) A. K. Verma, V. Rustagi, T. Aggarwal and A. P. Singh, J. Org. Chem., 2010, 75, 7691; (d) H. A. Du, X. G. Zhang, R. Y. Tang and J. H. Li, J. Org. Chem., 2009, 74, 7844; (e) Z. He, H. Li and Z. Li, J. Org. Chem., 2010, 75, 4636; (f) C. Masdeu, E. Gomez, N. A. O. Williams and R. Lavilla, Angew. Chem., Int. Ed., 2007, 46, 3043; (g) B. Quiclet-Sire and S. Z. Zard, Chem. Commun., 2006, 1831; (h) N. K. Downer-Riley and Y. A. Jackson, Tetrahedron, 2007, 63, 10276; (i) F. Shibahara, A. Kitagawa, E. Yamaguchi and T. Murai, Org. Lett., 2006, 8, 5621.
6. (a) L. Y. Zeng and C. Cai, J. Comb. Chem., 2010, 12, 35; (b) P. Zalavadiya, S. Tala, J. Akbari and H. Joshi, Arch. Pharm., 2009, 342, 469; (c) H. S. Wang and J. E. Zeng, Chin. J. Chem., 2008, 26, 175; (d) M. Kidwai and P. Mothsra, Tetrahedron Lett., 2006, 47, 5029; (e) L. Y. Zeng and C. Cai, Org. Biomol. Chem., 2010, 8, 4803; (f) X. S. Wang, Q. Li, J. R. Wu and S. J. Tu, J. Comb. Chem., 2009, 11, 433; (g) X. S. Wang, Q. Li, J. Zhou and S. J. Tu, J. Heterocycl. Chem., 2009, 46, 1222; (h) X. S. Wang, J. Zhou, M. Y. Yin, K. Yang and S. J. Tu, J. Comb. Chem., 2010, 12, 266; (i) A. T. Khan, M. M. Khan and K. K. R. Bannuru, Tetrahedron, 2010, 66, 7762.
7. (a) H. Prunier, S. Rault, J. C. Lancelot, M. Robba, P. Renard, P. Delagrange, B. Pfeiffer, D. H. Caignard, R. Misslin and M. Hamon, J. Med. Chem., 1997, 40, 1808; (b) S. Butini, R. Budriesi, M. Hamon, E. Morelli, S. Gemma, M. Brindisi, G. Borrelli, E. Novellino, I. Fiorini, P. Ioan, A. Chiarini, A. Cagnotto, T. Mennini, C. Fracasso, S. Caccia and G. Campiani, J. Med. Chem., 2009, 52, 6946.
8. G. Moarbess, C. Deleuze-Masquefa, V. Bonnard, S. Gayraud-Paniagua, J. R. Vidal, F. Bressolle, F. Pinguet and P. A. Bonnet, Bioorg. Med. Chem., 2008, 16, 6601.
9. J. Guillon, E. Mouray, S. Moreau, C. Mullie, I. Forfar, V. Desplat, S. Belisle-Fabre, N. Pinaud, F. Ravanello, A. Le-Naour, J. M. Leger, G. Gosmann, C. Jarry, G. Deleris, P. Sonnet and P. Grellier, Eur. J. Med. Chem., 2011, 46, 2310.
10. J. Guillon, P. Dallemagne, B. Pfeiffer, P. Renard, D. Manechez, A. Kervran and S. Rault, Eur. J. Med. Chem., 1998, 33, 293.
11. (a) J. T. Reeves, D. R. Fandrick, Z. Tan, J. J. Song, H. Lee, N. K. Yee and C. H. Senanayake, J. Org. Chem., 2010, 75, 992; (b) F. D. Moliner and C. Hulme, Org. Lett., 2012, 14, 1354; (c) M. F. Pereira and V. Thiéry, Org. Lett., 2012, 14, 4754; (d) S. Samala, R. K. Arigela, R. Kant and B. Kundu, J. Org. Chem., 2014, 79, 2491.
12. (a) A. P. Huang, Y. M. Chen, Y. G. Zhou, W. Guo, X. D. Wu and M. Chen, Org. Lett., 2013, 15, 5480; (b) Y. M. Zhao, Y. M. Wu, J. Jia, D. J. Zhang and C. Ma, J. Org. Chem., 2012, 77, 8501; (c) B. C. Yang, X. Y. Niu, Z. X. Huang, C. H. Zhao, Y. Liu and C. Ma, Tetrahedron, 2013, 69, 8250; (d) B. C. Yang, Z. X. Huang, H. G. Guan, X. Y. Niu, Y. Q. Li, S. Fang and C. Ma, Tetrahedron Lett., 2013, 54, 5994; (e) X. Y. Niu, B. C. Yang, Y. Q. Li, S. Fang, Z. X. Huang, C. X. Xie and C. Ma, Org. Biomol. Chem., 2013, 11, 4102; (f) Y. L. Liu, C. J. Zhan, B. C. Yang, X. Q. Cao and C. Ma, Synlett, 2013, 111; (g) Y. L. Liu, C. X. Chu, A. P. Huang, C. J. Zhan, Y. Ma and C. Ma, ACS Comb. Sci., 2011, 13, 547; (h) S. Fang, X. Y. Niu, B. C. Yang, Y. Q. Li, X. M. Si, L. Feng and C. Ma, ACS Comb. Sci., 2014, 16, 328; (i) S. Fang, X. Y. Niu, Z. Y. Zhang, Y. Sun, X. M. Si, C. C. Shan, L. Wei, A. Q. Xu, L. Feng and C. Ma, Org. Biomol. Chem., 2014, 12, 6895.
13. A. K. Verma, R. R. Jha, V. K. Sankar, T. Aggarwal, R. P. Singh and R. Chandra, Eur. J. Org. Chem., 2011, 6998.
14. Q. H. Gao, S. Liu, X. Wu and A. X. Wu, Org. Lett., 2014, 16, 4582.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5qo00124b

---