Solvent free one-pot multi-component synthesis of β-azaarene substituted ketones via a Sn-catalyzed C(sp³)–H functionalization of 2-alkylazaarenes

Abstract

A tin-catalyzed solvent free one-pot multi-component cascade reaction strategy for the direct Michael addition/C(sp³)–H functionalization of 2-alkylazaarenes with aldehydes and ketones via an aldol reaction has been developed. This is the first report and provides cost effective new access to potent biologically/medicinally important azaarene derivatives with high atom economy.

---

The C(sp²)–H and C(sp³)–H bond activation/functionalization as well as C–C bond formation has emerged as a key strategy to construct complex structured biologically active compounds.¹ Direct C(sp³)–H bond activation/functionalization of 2-alkyl azaarenes using a transition metal catalyst² has been well documented by various research groups. Nonetheless, a complement to the transition metal catalyst method, a Lewis acid catalyzed C(sp³)–H bond activation/functionalization of 2-alkyl azaarenes, has been reported by Kanai et al. as shown in their previous work^3b (Scheme 1). Even though, significant progress has been achieved for C–H bond functionalization of 2-azaarenes using Michael addition,³ alkylation reaction,⁴ aldol reaction,⁵ nucleophilic addition reaction for C–C, C–N and other heteroatom bond formation,⁶ however, all these strategies are limited to single step reactions as shown in the previous work (Scheme 1). To the best of our knowledge, so far Kumar et al.⁷ have reported a multi-component protocol for the synthesis of alkyl azaarene pyridinium zwitterions via iodine mediated C–H activation of a 2-alkyl azaarene. Therefore, the development of C(sp³)–H bond activation/functionalization of the methyl groups of azaarenes using a single step multi-substrate protocol by implementing a cascade sequential scaffold strategy has not been explored so far (present work, Scheme 1), which is very interesting and an exciting research area in modern-day organic chemistry.⁸

Scheme 1 Metal-catalyzed C–H functionalization of azaarenes.

Azaarenes derivatives are not only ubiquitous motifs in a wide range of alkaloid/natural products but are also potent precursors of biological/pharmaceutical active compounds (Fig. 1).^9,11c Also 2-(azaaryl) methanes as the core structural constituents of heterocyclic compounds along with benzimidazole, benzoxazole, benzothiazole, pyridine, and piperazine moieties have been attracted world-wide because of their huge application in therapeutic,¹² as well as being pharmacophores in library design and drug discovery.¹³ Hence, the development of solvent-free, more efficient, cost effective, environmentally sustainable methodologies to construct its structural units with the concept of high atom economy is a real challenge in organic synthesis. As part of our ongoing research program on the development of the C(sp³)–H functionalization of 2-methyl azaarenes and (2-azaaryl)methanes^10a and one-pot multi-component reaction (MCR) strategy^10b,c for organic synthesis, we herein report a cascade sequential scaffold strategy for an atom-economic, solvent free, and efficient synthesis of β-azaarene substituted ketones via a tin catalyzed one-pot multi-component reaction (MCR) protocol for the C(sp³)–H bond activation/functionalization of 2-alkyl azaarenes, as shown in the present work (Scheme 1).

Fig. 1 Selected β-azaarene substituted biologically active compounds.

In order to test the possibility of our MCR hypothesis, acetophenone 1a, benzaldehyde 2a and 2-methyl benzothiazole 3a were chosen as model substrates to optimize the reaction conditions. Initially, the screening of various Lewis acid catalysts such as ZnCl₂, Cu(OAC)₂, FeCl₃, AlCl₃, and CuCl₂ was performed by reacting acetophenone (1 mmol) 1a, benzaldehyde (1 mmol) 2a and 2-methyl benzothiazole (1 mmol) in the presence and absence of 5 mL of DMF as a solvent using 20 mol% catalyst at 120 °C, for 24 h (Table 1). However, in the presence of the DMF solvent, the formation of the desired product 4a was not observed using ZnCl₂, Cu(OAC)₂, FeCl₃, AlCl₃, and CuCl₂ as catalysts, whereas the InCl₃, SnCl₂·2H₂O, and DTP/SiO₂ catalysts provided 4a in 25, 38 and 16% yields, respectively (entries 2–4). Due to the highest performance of the SnCl₂·2H₂O catalyst compared to the other catalysts in DMF, the screening of other solvents such as 1,4-dioxane, toluene, DCE, DMSO, and NMP has also been carried out. Unfortunately, the desired product formation was not observed. Therefore, the performance of the Lewis acid catalysts were examined in the absence of DMF solvent. The Cu(OAC)₂, FeCl₃, AlCl₃, and CuCl₂ catalysts do not show any sign of catalytic activity. Moreover, the SnCl₂·2H₂O catalyst (entry 7) exhibited excellent performance compared to the ZnCl₂, InCl₃, and DTP/SiO₂ catalysts (entry 4, 6, 8) under the solvent free reaction conditions. Results on the catalyst screening reveal that the SnCl₂·2H₂O catalyst shows excellent performance at 120 °C in 24 h under solvent free reaction conditions.

Table 1 Comparison of the results between previous research work and present research work

Entry	Catalyst	Solvent	Yield (%)
a Reaction conditions: 2-methyl benzothiazole (1 mmol), benzaldehyde (1 mmol), acetophenone (1 mmol), catalyst (20 mol%), solvent (5 mL). 90–120 °C for 24 h.b Isolated yield.c DTP/SiO2 100 mg catalyst.
Previous work
1	Sc(OTf)3	PhCl	60–96
Present work: optimization of the reaction conditions^a
2	InCl3	DMF	25^b
3	SnCl2·2H2O	DMF	38^b
4^c	DTP/SiO2	DMF	16^b
5	ZnCl2	—	41^b
6	InCl3	—	65^b
7	SnCl2·2H2O	—	72^b
8^c	DTP/SiO2	—	40^b

---

With the optimized reaction conditions in hand, we then explored the substrate scope of the MCR protocol for the synthesis of β-azaarene substituted ketones. To explore the substrate scope of the one-pot multi-component reaction through a cascade process for the synthesis of β-azaarene substituted ketones via Sn-catalyzed C(sp³)–H bond activation/functionalization of various azaarenes, initially the reactivity of various acetophenones was tested with benzaldehyde and 2-methyl benzothiazole; the results are shown in Table 2. To our surprise, acetophenone as well as acetophenones bearing electron-withdrawing and electron-releasing functional groups at the ortho, meta, or para position of aryl ring reacted smoothly with benzaldehyde and 2-methylbenzothiazole and afforded the corresponding desired products in moderate to good yield (entries 4a–4d). Amazingly, the disubstituted acetophenones such as 2-bromo-4-methoxyacetophenone, 2,4-dichloroacetophenone, and 4-isobutyl acetophenone also reacted well with benzaldehyde and 2-methylbenzothiazole, and delivered the desired products in good yields ranging from 82–74% (entries 4e–4g). However, the results from a cyclic ketone reveal that the 1-indanone is less reactive and provided a moderate yield (64%) in a longer reaction time (entry 4h). Due to encouraging results on the substituted acetophenones, the reactivity of different substituted benzaldehydes and their electronic effects were examined. An electron rich substrates such as 4-methoxybenzaldehyde, 3,4-dimethoxybenzaldehyde, and piperonal were reacted well with acetophenone and 2-methylbenzothiazole, under optimized reaction conditions and furnished the corresponding desired compounds in good yields (entries 4i–4k). Also electronically poor aldehydes such as 4-chlorobenzaldehyde and 4-nitrobenzaldehyde were well tolerated to the optimized reaction conditions and delivered their corresponding desired products (Table 1 entry 4l and 4m) in good yields.

Table 2 Substrate scope of substituted acetophenone and benzaldehyde^a,b

a Reactions were conducted with 2-methylbenzothiazole (1 mmol), acetophenone (1 mmol), benzaldehyde (1 mmol), SnCl₂·2H₂O (20 mol%) in solvent free conditions at 120 °C for 24 h.b The yields indicated are the isolated yields by column chromatography.

---

Interestingly, 3-phenoxy benzaldehyde, neutral naphthaldehyde and heterocyclic 2-thiophene carboxylate reacted smoothly with acetophenone and 2-methylbenzothiazole and furnished the desired products in good (72–81%) yields (entries 4n–4p). The results in Table 2 reveal that electron withdrawing and electron releasing substituents on the aryl ring of acetophenone, as well as aldehydes play a key role, and that the yields obtained were very much dependent on substituents. The ortho, or para substituents on aryl rings provided higher yields compared to meta substituents.

Because of the excellent performance of MCR protocols using substituted acetophenones, substituted aldehydes and 2-methylbenzothiazole, we were keen to investigate the Sn-catalyzed C(sp³)–H bond activation/functionalization of 2-chloro-4-methylpyridine. Therefore acetophenone, aldehyde and 2-chloro-4-methylpyridine were reacted under optimized reaction conditions, unfortunately, the reaction failed to deliver the expected compound 4a; nonetheless we end up with an unexpected α-arylated acetophenone product 5a in 74% yield (Scheme 2).

Scheme 2 Sn-catalyzed C–H functionalization of 2-chloro-4-methyl pyridine.

To gain further insight into the mechanism, various control experiments were performed (Scheme 3). A result from the controlled experiments reveals that the mechanism involves enone formation.

Scheme 3 Control experiments.

As per previous research reported in the literature,^3b,6a–c and also based on the controlled experiment results, a plausible reaction mechanism scenario for one-pot multi-component cascade strategies via aldol condensation, sp³ C–H functionalization or a Michael addition process is outlined in Scheme 4. Initially, a Sn-catalyzed condensation of an aldehyde with a ketone is followed by an in situ elimination of water which provides an enone (I). Meanwhile, a Sn-catalyzed in situ generated enamine (II) is formed from 2-alkylazarenes. The enone (I) reacts with enamine (II), which is facilitated through C–H functionalization or Michael addition to generate the corresponding intermediate (III) followed by rearrangement to give the final corresponding desired product (IV).

Scheme 4 Plausible mechanisms for the synthesis of β-azaarenes substituted ketones.

Conclusions

In conclusion, we have developed a Sn-catalyzed solvent free one-pot multi-component cascade reaction strategy for the direct Michael addition/C(sp³)–H functionalization of 2-alkylazaarenes with aldehydes and ketones via an aldol reaction for the synthesis of biologically relevant novel 4-(benzo(d)thiazol-2-yl)-1,3-diphenylbutan-1-one and azaarenes containing other derivatives. The developed method is an efficient, mild, atom-economical, and one-pot multi-component cascade reaction via aldol condensation, C–H functionalization or a Michael addition. This strategy allows C(sp³)–H functionalization in a one-pot cascade process to rationalize the complex molecule synthesis. Further applications of these newly developed methods for other substrates and the synthesis of biologically active compounds are underway in our research group.

Acknowledgements

We are grateful for the financial support from the CSIR-India (JRF and SRF fellowships to S. S. C. and M. Y. P.). The authors also thank Dr V. V. Ranade, Chair of CE-PD for his encouragement and support.

Notes and references

1. For recent selected sp² (C–H) and sp³ (C–H) activation, see: (a) G. Rouquet and N. Chatani, Angew. Chem., Int. Ed., 2013, 52, 11726; (b) X. Li, L. He, H. Chen, W. Wu and H. Jiang, J. Org. Chem., 2013, 78, 3636; (c) P. B. Arockian, C. Bruneau and P. H. Dixneuf, Chem. Rev., 2012, 112, 5879; (d) J. Wencel-Delord, T. Drcge, F. Liu and F. Glorius, Chem. Soc. Rev., 2011, 40, 4740; (e) G. Song, F. Wang and X. Li, Chem. Soc. Rev., 2012, 41, 3651; (f) C. Tsukano, M. Okuno and Y. Takemoto, Angew. Chem., Int. Ed., 2012, 124, 2817. For C–H activation in natural product synthesis, see: (g) D. Y. K. Chen and S. W. Youn, Chem.–Eur. J., 2012, 18, 9452; (h) J. Yamaguchi, A. D. Yamaguchi and K. Itami, Angew. Chem., Int. Ed., 2012, 51, 8960.
2. For recent selected C–H activation on azaarenes: (a) L. Xu, Z. Shao, L. Wang and J. Xiao, Org. Lett., 2014, 16, 796; (b) S. Lou, D. Xu, D. Shen, Y. Wang, Y. Liu and Z. Xu, Chem. Commun., 2012, 48, 11993; (c) T. Niwa, H. Yorimitsu and K. Oshima, Angew. Chem., Int. Ed., 2007, 46, 2643; (d) R. Shang, Z. Yang, Y. Wang, S. Zhang and L. Liu, J. Am. Chem. Soc., 2010, 132, 14391.
3. (a) B. Qian, D. Shi, L. Yang and H. Huang, Adv. Synth. Catal., 2012, 354, 2146; (b) H. Komai, T. Yoshino, S. Matsunaga and M. Kanai, Org. Lett., 2011, 13, 1706.
4. (a) G. Song, Y. Su, X. Gong, K. Han and X. Li, Org. Lett., 2011, 13, 1968; (b) T. Niwa, H. Yorimitsu and K. Oshima, Org. Lett., 2007, 9, 2373; (c) P. M. Burton and J. A. Morris, Org. Lett., 2010, 12, 5359.
5. (a) R. Niu, J. Xiao, T. Liang and X. Li, Org. Lett., 2012, 14, 676; (b) J. J. Jin, H. Y. Niu, G. R. Qu, H. M. Guo and J. S. Fossey, RSC Adv., 2012, 2, 5968; (c) F. F. Wang, C. P. Luo, Y. Wang, G. Deng and L. Yang, Org. Biomol. Chem., 2012, 10, 8605.
6. (a) Y. Yan, K. Xu, Y. Fang and Z. Wang, J. Org. Chem., 2011, 76, 6849; (b) H. Komai, T. Yoshino, S. Matsunaga and M. Kanai, Synthesis, 2012, 44, 2185; (c) M. Rueping and N. Tolstoluzhsky, Org. Lett., 2011, 13, 1095; (d) B. S. Qian, G. J. Shao, Q. Zhu, L. Yang, C. Xia and H. Huang, J. Am. Chem. Soc., 2010, 132, 3650; (e) B. Qian, P. Xie, Y. Xie and H. Huang, Org. Lett., 2011, 13, 2580; (f) J. Y. Liu, H. Y. Niu, S. Wu, G. R. Qu and H. M. Guo, Chem. Commun., 2012, 48, 9723.
7. (a) A. Kumar, G. Gupta and S. Srivastava, Org. Lett., 2011, 13, 6366; (b) A. Kumar, L. P. Gupta and M. Kumar, RSC Adv., 2013, 3, 18771.
8. (a) V. P. Mehta, J.-A. García-López and M. F. Greaney, Angew. Chem., Int. Ed., 2014, 126, 1555; (b) A. Pinto, L. Neuville and J. Zhu, Angew. Chem., Int. Ed., 2007, 46, 3291; (c) L. Guo, F. Zhang, W. Hu, L. Lia and Y. Jia, Chem. Commun., 2014, 50, 3299; (d) S. Rakshit, F. W. Patureau and F. Glorius, J. Am. Chem. Soc., 2010, 132, 9585; (e) T. K. Hyster and T. Rovis, J. Am. Chem. Soc., 2010, 132, 10565.
9. W. Frohner, L. A. Lopez-Garcia, S. Neimanis, N. Weber, J. Navratil, F. Maurer, A. Stroba, H. Zhang, R. M. Biondi and M. Engel, J. Med. Chem., 2011, 54, 6714–6723.
10. (a) S. A. R. Mulla, M. Y. Pathan and S. S. Chavan, RSC Adv., 2013, 3, 20281; (b) S. S. Chavan, M. Y. Pathan, S. H. Thorat, R. G. Gonnade and S. A. R. Mulla, RSC Adv., 2015, 5, 81103; (c) S. A. R. Mulla, T. A. Salama, M. Y. Pathan, S. M. Inamdar and S. S. Chavan, Tetrahedron Lett., 2013, 54, 672.
11. (a) A. R. Katritzky, C. A. Ramsden, E. F. V. Scriven and R. J. K. Taylor, Comprehensive Heterocyclic Chemistry, Elsevier, Oxford, 2008, vol. 7; (b) L. C. Campeau and K. Fagnou, Chem. Soc. Rev., 2007, 36, 1058; (c) J. P. Michael, Nat. Prod. Rep., 2005, 22, 627; (d) G. D. Henry, Tetrahedron, 2004, 60, 6043.
12. (a) A. O. Plunkett, Nat. Prod. Rep., 1992, 9, 491; (b) I. N. Houpis, A. Molina, J. Lynch, R. A. Reamer, R. P. Volante and P. J. Reider, J. Org. Chem., 1993, 58, 3176; (c) W. Frohner, L. A. Lopez-Garcia, S. Neimanis, N. Weber, J. Navratil, F. Maurer, A. Stroba, H. Zhang, R. M. Biondi and M. Engel, J. Med. Chem., 2011, 54, 6714.
13. D. Best and H. W. Lam, J. Org. Chem., 2014, 79, 831.

---

Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, and copies of the ¹H and ¹³C NMR spectra of all products. See DOI: 10.1039/c5ra20728b

---