Metal-free C-3 alkylation of imidazopyridines with xanthates and convenient access to alpidem and zolpidem

Abstract

A metal-free process for the C-3 alkylation of imidazopyridines has been developed. Various alkylation products including alkyl ester-, cyano-, ketone- and amide-substituted imidazopyridines were prepared in good yields. With this method, a highly efficient and concise formal synthesis of alpidem (A) and zolpidem (B) has been completed.

---

Imidazo[1,2-a]pyridines have attracted significant interest among the medicinal chemistry community because of their diverse biological activities, for example, antiviral, antitumor, antibacterial, anti-inflammatory, hypnotic, etc.¹ Some marketed drugs like alpidem (A),² zolpidem (B),³ saripidem (C),⁴ minodronic acid (D),⁵ zolimidine (E),⁶ olprinone (F),⁷ etc., contain this scaffold (Fig. 1). Consequently, remarkable progress has been made by various groups,⁸ including our group,⁹ on the synthesis of imidazo[1,2-a]pyridine derivatives through a C3-H functionalization strategy. For instance, Jiang et al. disclosed an inexpensive copper(I) catalytic system for the efficient direct arylation of substituted imidazo[1,2-a]pyridines with aryl iodides, aryl bromides and triflates.^8a Later, Cao and co-workers reported a ruthenium-catalyzed C-3 oxidative olefination of imidazo[1,2-a]pyridines.^8b Very recently, the methods for the formation of C-heteroatom bonds were also achieved, e.g., C-3 fluorination,^8d phosphonation,^8e sulfenylation^8f,8g,9 and thiocyanation^8h (Scheme 1a). However, the cross coupling of sp³(C)- and sp²(C)- hybridized C–H bonds to synthesize various alkylated imidazo[1,2-a]pyridines are much less common,¹⁰ though these derivatives are nonbenzodiazepine GABA potentiators.

Fig. 1 Clinical drugs with imidazopyridine backbone.

Scheme 1 Design approach for alkylated imidazopyridines.

Xanthate-based radical addition reactions developed by Zard and co-workers are powerful tools for the construction C–C bonds without utilizing potentially toxic metal agents.¹¹ Recently, we have also accounted a number of efficient methods for the synthesis of oxindole derivatives through N-arylacrylamides with xanthates.¹² On the other hand, the C-3 position of the imidazo[1,2-a]pyridines moiety is electronrich, which enables it to be attacked by electrophiles or radicals. Based on our recent work in xanthate-based radical chemistry (Scheme 1b), we envisaged that the imidazo[1,2-a]pyridines could be functionalized at the C-3 position by xanthates. Herein we report a direct and efficient method on C-3 alkylation of imidazo[1,2-a]pyridines with xanthates (Scheme 1c).

Initially, 2-phenylimidazo[1,2-a]pyridine 1a was selected to react with xanthate 2a in the presence of 1.5 equiv of dilauroyl peroxide (DLP) at 84 °C for 12 h.¹² To our delight, the desired product 3a was isolated in 45% yield (Table 1, entry 1). Encouraged by this result, the further optimization of the reaction conditions was performed. Several oxidants, including TBHP, H₂O₂, K₂S₂O₈, DTBP, were thoroughly examined, and the DLP remained as the best one (Table 1, entries 1–5). The solvent screening results revealed that DCE was the best choice (Table 1, entries 6–10). By altering the temperature to 120 °C, the yield of 3a was slightly reduced due to the instability of DLP at high temperature (Table 1, entry 11). Happily, the yield of 3a was obviously improved when increasing the amount of 2a and DLP (Table 1, entries 12 and 13). Therefore, the best reaction conditions were concluded as follows: 2-phenylimidazo[1,2-a]pyridine 1a (0.16 M), xanthate 2a (2.5 equiv), DLP (oxidant, 2.5 equiv) in DCE at 84 °C in an open flask.

Table 1 Optimization of reaction conditions^a

Entry	Oxidant	Temp (°C)	Solvent	Yield^b (%)
a Reaction conditions: 1a (0.3 mmol, 1 eq.), 2a (0.45 mmol, 1.5 eq.), oxidant (0.45 mmol, 1.5 eq.), solvent (5 mL), 12 h.b Isolated yields.c NR = no reaction.d 2a (2.0 eq.), oxidant (2.0 eq.).e 2a (2.5 eq.), oxidant (2.5 eq.).
1	DLP	84	DCE	45
2	TBHP	84	DCE	21
3	H2O2	84	DCE	NR^c
4	K2S2O8	84	DCE	NR
5	DTBP	84	DCE	12
6	DLP	100	Dioxane	26
7	DLP	60	EA	NR
8	DLP	65	THF	32
9	DLP	80	CH3CN	19
10	DLP	130	C6H5Cl	25
11	DLP	120	DCE	31
12^d	DLP	84	DCE	64
13^e	DLP	84	DCE	73

---

With the optimal reaction conditions in hand, we turned our attention toward the scope of the reaction, and the results are summarized in Table 2. The impact of substitutes of the imidazo[1,2-a]pyridine was first to be investigated. It is apparent that the property and the position of substituents did not obviously effect on the reaction (Table 2, 3b–3m). Imidazo[1,2-a]pyridines bearing electron-donating and withdrawing groups at 2-aryl ring, such as, 1b (4-Me), 1c (4′-OMe), 1d (4′-Cl) and 1e (2′-Cl), gave the corresponding products (3b–3e) in 69–75% yields, respectively. Even 2-thiophene imidazo[1,2-a]pyridine was also gave the product 3f in 70% yield. Imidazo[1,2-a]pyridines substituted with a methyl group at C-6 (1i), C-7 (1h) and C-8 (1g) gave the desired products (3g–3i) in 73–81% yields. Some functional groups at different positions on the pyridine ring were also compatible in the present reaction, including C–F bond, C–Cl bond and C–OBn (3j–3m), which could be further transformed to other useful functional groups. Furthermore, the application of our present protocol for alkylation of other heterocyclic compounds were also suitable to provide product (3n and 3o) in 75% and 81% yields, respectively. Next, a number of xanthates (2b–2e) bearing alkyl ester, ketone, and cyano functional groups were subjected to react with 1a under the conditions, affording the corresponding products 3p–3s in 65–79% yields.

Table 2 Reaction scope for the synthesis of^a

Entry	Substrate 1	Xanthate 2	Product 3	Yield (%)	Entry	Substrate 1	Xanthate 2	Product 3	Yield (%)
a Reaction conditions: 1 (0.3 mmol, 1 eq.) 2 (0.75 mmol, 2.5 eq.), DLP (0.75 mmol, 2.5 eq.), solvent (5 mL), 12 h.
1		2a		73	12		2a		76
2		2a		72	13		2a		81
3		2a		75	14		2a		75
4		2a		72	15		2a		81
5		2a		69	16		2b		75
6		2a		70	17		2c		79
7		2a		81	18		2d		65
8		2a		73	19		2e		79
9		2a		75	20		2f		81
10		2a		80	21		2g		71
11		2a		73

---

To demonstrate the utility of this method, we successfully prepared the drugs alpidem A and zolpidem B through the reaction of 1p and 1q with xanthates containing amide group 2f and 2g, respectively, under our optimized conditions in 81% and 71% yields.

To confirm that this chemistry proceeds through radical-based mechanism, the reaction of 1a and 2a was repeated in the presence of radical scavenger 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) under the standard reaction conditions. As expected, no desired product was obtained after 1 eq. of TEMPO was added and the starting material 1a was fully recovered.

Based on these results and previous observations,^8e,8h,12 a possible mechanism is proposed in Scheme 2. Initially, xanthate 2a reacts with DLP to give radical 4, which would promptly add to imidazo[1,2-a]pyridine 1a to generate radical species 5. Subsequently, this intermediate undergoes oxidation to produce imidazo[1,2-a]pyridine cation 6. De-protonation of 6 would generate the final product 3a.

Scheme 2 Plausible reaction pathway.

Conclusions

In summary, we have developed a metal-free regioselective C-3 alkylation of imidazopyridines with xanthates. The transformation proceeded in good yields and tolerated a wide range of functional groups. Using this novel synthetic method, a high efficient and concise formal syntheses of alpidem A and zolpidem B have been accomplished. Further application to other heterocyclic systems is underway.

Acknowledgements

This work is supported by National Natural Science Foundation of China (No. 21372019).

Notes and references

1. (a) A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven and R. J. K. Taylor, Comprehensive Heterocyclic Chemistry III, Elsevier, Oxford, 2008; (b) A. R. Katritzky, Y. J. Xu and H. Tu, J. Org. Chem., 2003, 68, 4935; (c) M. Lhassani, O. Chavignon, J. M. Chezal, J. C. Teulade, J. P. Chapat, R. Snoeck, G. Andrei, J. Balzarini, E. D. Clercq and A. Gueiffier, Eur. J. Med. Chem., 1999, 34, 271; (d) C. Enguehard-Gueiffier and A. Gueiffier, Mini-Rev. Med. Chem., 2007, 7, 888; (e) K. S. Gudmundsson, S. D. Boggs, J. G. Catalano, A. Svolto, A. Spaltenstein, M. Thomson, P. Wheelan and S. Jenkinson, Bioorg. Med. Chem. Lett., 2009, 19, 6399; (f) R. Gladsz, Y. Adriaenssens, H. D. Winter, J. Joossens, A. M. Lambeir, K. Augustyns and P. V. Veken, J. Med. Chem., 2015, 58, 9238.
2. (a) A. Berson, V. Descatoire, A. Sutton, D. Fau, B. Maulny, N. Vadrot, G. Feldmann, B. Berthon, T. Tordjmann and D. Pessayre, J. Pharmacol. Exp. Ther., 2001, 299, 793; (b) T. Okubo, R. Yoshikawa, S. Chaki, S. Okuyama and A. Nakazato, Bioorg. Med. Chem., 2004, 12, 423.
3. (a) S. Z. Langer, S. Arbilla, J. Benavides and B. Scatton, Adv. Biochem. Psychopharmacol., 1990, 46, 61; (b) B. Du, A. Shan, Y. Zhang, X. Zhong, D. Chen and K. Cai, Am. J. Med. Sci., 2014, 347, 178.
4. D. J. Sanger, Behav. Pharmacol., 1995, 6, 116.
5. L. A. Sorbera, J. Castaner and P. A. Leeson, Drugs Future, 2002, 27, 935.
6. (a) D. Belohlavek and P. Malfertheiner, Scand. J. Gastroenterol., Suppl., 1979, 54, 44; (b) L. Almirante, L. Polo, A. Mugnaini, E. Provinciali, P. Rugarli, A. Biancotti, A. Gamba and W. Murmann, J. Med. Chem., 1965, 8, 305.
7. K. Mizushige, T. Ueda, K. Yukiiri and H. Suzuki, Cardiovasc. Drug Rev., 2002, 20, 163.
8. (a) H. Cao, H. Y. Zhang, Y. G. Lin, X. L. Lin, Z. D. Du and H. F. Jiang, Org. Lett., 2012, 14, 1688; (b) H. Zhan, L. Zhao, N. Li, L. Chen, J. Liu, J. Liao and H. Cao, RSC Adv., 2014, 4, 32013; (c) J. Koubachi, S. El Kazzouli, S. Berteina-Raboin, A. Mouaddib and G. Guillaumet, Synthesis, 2008, 2537; (d) P. Liu, Y. Y. Gao, W. J. Gu, Z. Y. Shen and P. P. Sun, J. Org. Chem., 2015, 80, 11559; (e) M. Yadav, S. Dara, V. Saikam, M. Kumar, S. K. Aithagani, S. Paul, R. A. Vishwakarma and P. P. Singh, Eur. J. Org. Chem., 2015, 6525; (f) C. Ravi, D. C. Mohan and S. Adimurthy, Org. Lett., 2014, 16, 2798; (g) M. A. Hiebel and S. Berteina-Raboin, Green Chem., 2015, 17, 937; (h) D. S. Yang, K. L. Yan, W. Wei, G. Q. Li, S. L. Lu, C. X. Zhao, L. J. Tian and H. Wang, J. Org. Chem., 2015, 80, 11073; (i) C. C. Wang, S. Lei, H. Cao, X. S. Qiu, J. Y. Liu, H. Deng and C. J. Yan, J. Org. Chem., 2015, 80, 12725; (j) K. Monir, A. K. Bagdi, M. Ghosh and A. Hajra, J. Org. Chem., 2015, 80, 1332.
9. X. H. Huang, S. C. Wang, B. W. Li, X. Wang, Z. M. Ge and R. T. Li, RSC Adv., 2015, 5, 22654.
10. Vanadium catalyst C3-aminomethylation of imidazopyridines, see: P. Kaswan, A. Porter, K. Pericherla, M. Simone, S. Peters, A. Kumar and B. DeBoef, Org. Lett., 2015, 17, 5208.
11. For selected review of Zard’s work, see: (a) J. Axon, L. Boiteau, J. Boivin, J. E. Forbes and S. Z. Zard, Tetrahedron Lett., 1994, 35, 1719; (b) T. M. Ly, B. Quiclet-Sire, B. Sortais and S. Z. Zard, Tetrahedron Lett., 1999, 40, 1533; (c) T. Kaoudi, B. QuicletSire, S. Seguin and S. Z. Zard, Angew. Chem., Int. Ed., 2000, 39, 747; (d) N. Charrier, D. Gravestock and S. Z. Zard, Angew. Chem., Int. Ed., 2006, 45, 6520; (e) Z. B. Liu, L. Qin and S. Z. Zard, Org. Lett., 2014, 16, 2704; (f) P. Salomon and S. Z. Zard, Org. Lett., 2014, 16, 2926.
12. (a) S. C. Wang, X. H. Huang, B. W. Li, Z. M. Ge, X. Wang and R. T. Li, Tetrahedron, 2015, 71, 1869; (b) S. C. Wang, X. H. Huang, Y. Z. Wen, Z. M. Ge, X. Wang and R. T. Li, Tetrahedron, 2015, 71, 8117.

---

Footnotes

† Electronic supplementary information (ESI) available: Experimental procedures, copies of the ¹H and ¹³C NMR spectra. See DOI: 10.1039/c6ra09046j

‡ These authors contributed equally to this research.

---