Copper-mediated annulation of 2-(1-arylvinyl) anilines and aryl nitrosos towards 2,3-diaryl-2H-indazoles

Abstract

A copper-mediated annulation of 2-(1-substituted vinyl) anilines and aryl nitrosos is developed for the synthesis of 2,3-diaryl pyrazoles. Compared with previously reported sequential azobenzene C–H ortho-acylation, reduction and cyclization procedures towards such frameworks, no external reductant was required during this cyclization, where the vinyl served as a formal innate reductant. Moreover, in this procedure, no selectivity was involved in the case of Ar¹ ≠ Ar².

---

2H-Indazoles are remarkable potential medicines against a variety of diseases.¹ However, compared with thermodynamically favored 1H-analogues,² the development of methodologies to access 2H-indazole was far below expectations. Coarctate cyclization reactions required a high reaction temperature (160–200 °C) towards 2H-indazoles.³ To circumvent it, Lindenschmidt developed a palladium-catalyzed cascade reaction of 1-chloro-2-phenylethynylbenzene and phenylhydrazine leading to 2H-pyrazoles.⁴ Almost at the same time, Knochel disclosed the reaction of 2-chloromethylarylzinc and aryldiazonium to generate polyfunctional 2H-indazoles.⁵ Afterwards, Driver demonstrated an iron(II)-catalyzed intramolecular transformation of azides with methyl oximes,⁶ and Genung achieved a mild, one-pot condensation–cadogan reductive cyclization to access 2H-indazoles.⁷ Nevertheless, the development of both new reaction substrates and methodologies towards such frameworks remained highly desirable in organic chemistry.

Besides, Shi has reported the [3 + 2] cycloaddition of arynes and sydnones in 2010 to access 2H-indazoles.⁸ And Lee achieved the construction of this motif via the reaction of diazos with 2-iodoazobenzenes.⁹ Recently, Wang developed the synthesis of 2H-indazoles by sequential acylation of azo compounds (or their derivatives), followed by cyclization at the cost of stoichiometric reductants such as NaBH₄ and Zn.¹⁰ Subsequently, similar procedures were independently achieved by Ellman¹¹ and Wang,¹² wherein an external reductant was not required since the intermediate before cyclization was a low oxidation state alcohol rather than a ketone via ortho C–H acylation of azobenzene. Since a vinyl group could serve as a precursor of diol, we expect a similar intermediate whereby the appropriate oxidation of 2-vinyl in azobenzene could furnish the ring closure to construct 2H-indazole frameworks, where nitroso compounds were employed.¹³ Such a procedure shows several advantages: (1) the potential starting material 2-(1-arylvinyl) aniline is readily available by either the reaction of terminal alkyne and aniline,¹⁴ or the reaction between 2-iodoaniline and phenacylamine N-Ts hydrazone;¹⁵ (2) no additional external reductant is required; and (3) in comparison with the procedure starting with benzyne and azobenzene, no regional selectivity is involved.

Initially, we tested the reaction of 2-(1-phenylvinyl) aniline 1a with nitrosobenzene 2a in the presence of Cu(acac)₂ and di-tert-butyl peroxide (DTBP) in DMSO under O₂ at 130 °C (Table 1, entry 1). To our delight, 2,3-diphenyl-2H-indazoles 3aa were isolated in 12% yield. On replacing Cu(acac)₂ with Cu(OAc)₂, the yield dramatically increased to 60% (Table 1, entry 2), while CuCl₂ did not work at all (Table 1, entry 3). Other cooxidants, such as K₂S₂O₈ and p-benzoquinone (BQ) were much less effective than DTBP (Table 1, entries 4 and 5). 3aa could be obtained in 45% without any cooxidant (Table 1, entry 6). This result encouraged us to employ O₂ as the terminal cooxidant. In this case, the yield increased substantially with the increasing loading of Cu(OAc)₂ (Table 1, entries 7–9), and the yield increased to 75% when 2.0 equivalents of Cu(OAc)₂ were added (Table 1, entry 9). However, a further increase of the loading of the catalyst didn't give higher yield (Table 1, entry 10). To investigate the solvent effects on reaction efficiency, DMF, DMAc, xylene and PhCF₃ were employed. However, they were all inferior to DMSO, generating 3aa in 25%, 10%, 46% and 40% yields, respectively (Table 1, entry 9). On varying either the atmosphere (air or N₂) or the reaction temperature (80, 100 or 120 °C) all the efficiencies decreased (Table 1, entry 11). No reaction took place in the absence of Cu(OAc)₂ (Table 1, entry 12). No 3aa was detected when Cu(OAc)₂ was replaced with OsO₄ (2.0 equiv.), (NH₄)₂S₂O₈ (2.0 equiv.) and H₂O₂ (2.0 equiv.) (Table 1, entries 13–15). Interestingly, NaIO₄ worked well, giving 3aa in 62% yield (Table 1, entry 16).

Table 1 Screening the optimized reaction conditions^a

Entry	[Cu](equiv.)	Cooxidant	Yield^b (%)
a Reaction conditions: 2-(1-phenylvinyl)aniline 1a (0.1 mmol), nitrosobenzene 2a (0.25 mmol), copper, cooxidant (2.0 equiv.), in DMSO (2 mL), under O2, 130 °C, 15 h. b Isolated yield. c DMF (2 mL). d DMAc (2 mL). e Xylene (2 mL). f PhCF3 (2 mL). g In air. h Under N2. i At 80 °C. j At 100 °C. k At 120 °C.
1	Cu(acac)2(0.2)	DTBP	12
2	Cu(OAc)2(0.2)	DTBP	60
3	CuCl2(0.2)	DTBP	<5
4	Cu(OAc)2(0.2)	K2S2O8	<5
5	Cu(OAc)2(0.2)	BQ	15
6	Cu(OAc)2(0.2)	—	45
7	Cu(OAc)2(0.1)	—	37
8	Cu(OAc)2(1.0)	—	63
9	Cu(OAc)2(2.0)	—	75, 25^c, 10^d, 46^e, 40^f
10	Cu(OAc)2(2.5)	—	73
11	Cu(OAc)2(2.0)	—	67^g, 38^h, 49^i, 61^j, 68^k
12	—	—	<5
13	—	OsO4	<1
14	—	(NH4)2S2O8	<1
15	—	H2O2	<1
16	—	NaIO4	62

---

Once the optimized conditions were established, the scope of 2-(1-arylvinyl) anilines were studied (Fig. 1). As expected, this procedure was applicable to a series of 2,3-diaryl-2H-pyrazoles, providing the corresponding products in moderate to good yields (3aa–3ja, 38%–80%). All the products except 3aa were hard to access via the previously reported procedures starting from azobenzenes and aryne owing to their regioselectivity. Thus, this method represents an exceedingly practical complement to access 2,3-diaryl-2H-pyrazoles. Pleasingly, functional groups, such as methyl, methoxy, bromo, chloro and fluoro were all well tolerated under the standard conditions, providing facile handles for potentially further functionalization. Notably, R′ of Ar² on ortho-, meta- and para-positions were all studied, providing corresponding 2H-pyrazole derivatives in 53%–80% yields (3ia and 3ka–3ra). However, the hindrance on the 2-phenyl and 4-position of the product had some effect on the reaction efficiency, as 3ia and 3ja were isolated in 53% and 38% yields, respectively. Unfortunately, the attempt to access 2-phenyl-3-methyl-2H-pyrazoles was failed.

Fig. 1 Substrate scope of 2-(1-substituted vinyl)anilines. Reaction conditions: 2-(1-phenylvinyl)aniline 1 (0.1 mmol), nitrosobenzene 2a (0.25 mmol) and Cu(OAc)₂ (2.0 equiv.) in DMSO (2 mL) under O₂, 130 °C, 15 h. ^a Cu(OAc)₂ (0.2 equiv.).

Meanwhile, the scope of nitrosobenzenes was studied, as shown in Fig. 2. Once again, the diversity of the product further increased as the procedure produced 2,3-diaryl-2H-pyrazoles with varied groups on 3-phenyl (methyl, tert-butyl, chloro, bromo) in moderate to good yields (45%–65%, 3ab–3ag). In the cases of 3ia, 3ja and 3ab, the formation of 3-aryl indole byproducts via aza-Wacker-type cyclization may account for the slightly low yields.

Fig. 2 Substrate scope of nitrosos. Reaction conditions: 2-(1-phenylvinyl)aniline 1a (0.1 mmol), aryl nitroso 2 (0.25 mmol) and Cu(OAc)₂ (2.0 equiv.) in DMSO (2 mL) under O₂, 130 °C, 15 h.

More experiments were conducted to gain some insights into this transformation. First, some potential intermediates (4–6) were prepared and subjected to the reaction, respectively (Scheme 1). The reaction of 4 and nitrosobenzene, as well as the reaction of 5 under a standard procedure did not lead to the desired product (Scheme 1, eqn (1) and (2)). Thus, 4 and 5 were unlikely the intermediates in this transformation. However, 3aa was obtained in 28% yield when diol 6 was employed under a standard procedure, along with a byproduct (Fw = 286) in 37% yield (Scheme 1, eqn (3)). The MS, ¹H NMR and ¹³C NMR were all consistent with the structure of O-3aa (Scheme 1, eqn (3)), which may be derived from the oxidation of 3aa by O₂. In most cases, trace byproducts with one more oxygen formula weight were detected by GC-MS (see the ESI† for details). Further studies revealed that both Cu(OAc)₂ and O₂ were required in this reaction to ensure the transformation towards the final product.

Scheme 1 Preliminary mechanistic studies.

Based on these experimental results, a proposed mechanism was outlined in Scheme 2. Firstly, the addition of amino to nitroso followed by the elimination of H₂O produces aryl azo 8.^16,17 Then, the oxidation of vinyl by Cu(OAc)₂ and/or O₂ provides the diol intermediate 7. Secondly, similar to Ellman's procedure,¹¹ the intra- molecular S_N reaction furnishes the ring closure and leads to intermediate 9. Finally, 9 undergoes the retro-Friedel–Crafts reaction to deliver 2,3-diphenyl-2H-indazoles along with formaldehyde.¹⁸ Copper may also take part in this step. Alternatively, an intermolecular oxyamination of 8 to 9 is also reasonable.¹⁹

Scheme 2 Plausible reaction pathway.

Conclusions

In conclusion, we have developed a copper-mediated annulation of 2-(1-arylvinyl) anilines with aryl nitrosos towards 2,3-aryl-2H-Indazoles. The reaction involves: (1) the reaction of amine and nitroso towards azo; (2) the key step whereby the appropriate oxidation of vinyl to diol as a low oxidation state intermediate rather than a ketone; and (3) the intramolecular S_N reaction of hydroxyl attacked by azo furnishing C–N bond formation with ring closure to construct the framework of 2,3-aryl-2H-indazoles. In comparison with the previously reported sequential azobenzene C–H ortho-acylation, reduction and cyclization procedures towards such frameworks, no regional selectivity was involved and no external reductant was required during the cyclization step, where the vinyl served as a formal innate reductant.

Acknowledgements

We thank the National Natural Science Foundation of China (no. 21272028, 21572025 and 21672028), “Innovation & Entrepreneurship Talents” Introduction Plan of Jiangsu Province, the Natural Science Foundation for Colleges and Universities of Jiangsu Province (no. 16KJB150002 and 15KJA150001), the Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology (BM2012110) and the Advanced Catalysis and Green Manufacturing Collaborative Innovation Center, Changzhou University for financial supports.

Notes and references

1. For reviews: (a) M. J. Haddadin, W. E. Conrad and M. J. Kurth, Mini-Rev. Med. Chem., 2012, 12, 1293; (b) A. Schmidt, A. Beutler and B. Snovydovych, Eur. J. Org. Chem., 2008, 4073; (c) D. D. Gaikwad, A. D. Chapolikar, C. G. Devkate, K. D. Warad, A. P. Tayade, R. P. Pawar and A. J. Domb, Eur. J. Med. Chem., 2015, 90, 707; (d) A. Thangadurai, M. Minu, S. Wakode, S. Agrawal and B. Narasimhan, Med. Chem. Res., 2012, 21, 1509.
2. For selected recent examples: (a) C.-Y. Chen, G. Tang, F. He, Z. Wang, H. Jing and R. Faessler, Org. Lett., 2016, 18, 1690; (b) B. C. Wray and J. P. Stambuli, Org. Lett., 2010, 12, 4576; (c) X. Xiong, Y. Jiang and D. Ma, Org. Lett., 2012, 14, 2552; (d) H.-J. Liu, S.-F. Hung, C.-L. Chen and M.-H. Lin, Tetrahedron, 2013, 69, 3907; (e) J. Yu, J. W. Lim, S. Y. Kim, J. Kim and J. N. Kim, Tetrahedron Lett., 2015, 56, 1432; (f) X. Tang, H. Gao, J. Yang, W. Wu and H. Jiang, Org. Chem. Front., 2014, 1, 1295; (g) T. Zhang and W. Bao, J. Org. Chem., 2013, 78, 1317; (h) R. C. Wheeler, E. Baxter, I. B. Campbell and S. J. F. MacDonald, Org. Process Res. Dev., 2011, 15, 565; (i) Q. Wang and X. Li, Org. Lett., 2016, 18, 2102; (j) L. Li, H. Wang, S. Yu, F. Yang and X. Li, Org. Lett., 2016, 18, 3662.
3. (a) B. S. Young, R. Herges and M. M. Haley, Chem. Commun., 2012, 48, 9441; (b) D. B. Kimball, T. J. R. Weakley and M. M. Haley, J. Org. Chem., 2002, 67, 6395; (c) D. B. Kimball, A. G. Hayes and M. M. Haley, Org. Lett., 2000, 2, 382.
4. N. Halland, M. Nazaré, O. R'Kyek, J. Alonso, M. Urmann and A. Lindenschmidt, Angew. Chem., Int. Ed., 2009, 48, 6879.
5. B. Haag, Z. Peng and P. Knochel, Org. Lett., 2009, 11, 4270.
6. B. J. Stokes, C. V. Vogel, L. K. Urnezis, M. Pan and T. G. Driver, Org. Lett., 2010, 12, 2884.
7. N. E. Genung, L. Wei and G. E. Aspnes, Org. Lett., 2014, 16, 3114.
8. C. Wu, Y. Fang, R. C. Larock and F. Shi, Org. Lett., 2010, 12, 2234.
9. W.-S. Yong, S. Park, H. Yun and P. H. Lee, Adv. Synth. Catal., 2016, 358, 1958.
10. (a) H. Li, P. Li, H. Tan and L. Wang, Chem. – Eur. J., 2013, 19, 14432; (b) H. Li, P. Li, Q. Zhao and L. Wang, Chem. Commun., 2013, 49, 9170; (c) H. Li, P. Li and L. Wang, Org. Lett., 2013, 15, 620.
11. J. R. Hummel and J. A. Ellman, J. Am. Chem. Soc., 2015, 137, 490.
12. X. Geng and C. Wang, Org. Lett., 2015, 17, 2434.
13. For the transformations of unsaturated compounds with nitroso compounds, please see: (a) X.-H. Yang, R.-J. Song and J.-H. Li, Adv. Synth. Catal., 2015, 357, 3849; (b) T. Shen, Y. Yuan and N. Jiao, Chem. Commun., 2014, 50, 554; (c) F. Chen, X. Huang, X. Li, T. Shen, M. Zou and N. Jiao, Angew. Chem., Int. Ed., 2014, 53, 10495; (d) Y. Liu, J.-L. Zhang, R.-J. Song, P.-C. Qian and J.-H. Li, Angew. Chem., Int. Ed., 2014, 53, 9017; (e) U. Dutta, S. Maity, R. Kancherla and D. Maiti, Org. Lett., 2014, 16, 6302; (f) P. Gao, H.-X. Li, X.-H. Hao, D.-P. Jin, D.-Q. Chen, X.-B. Yan, X.-X. Wu, X.-R. Song, X.-Y. Liu and Y.-M. Liang, Org. Lett., 2014, 16, 6298; (g) Y. Lin, W. Kong and Q. Song, Org. Lett., 2016, 18, 3702; (h) G. C. Senadi, B. S. Gore, W.-P. Hu and J.-J. Wang, Org. Lett., 2016, 18, 2890.
14. (a) Z. Zhang, L.-L. Liao, S.-S. Yan, L. Wang, Y.-Q. He, J.-H. Ye, J. Li, Y.-G. Zhi and D.-G. Yu, Angew. Chem., Int. Ed., 2016, 55, 7068; (b) K. Sasano, J. Takaya and N. Iwasawa, J. Am. Chem. Soc., 2013, 135, 10954; (c) L. Wang, J. Ferguson and F. Zeng, Org. Biomol. Chem., 2015, 13, 11486; (d) A. Arienti, F. Bigi, R. Maggi, E. Marzi, P. Moggi, M. Rastelli, G. Sartori and F. Tarantola, Tetrahedron, 1997, 53, 3795; (e) J. Ferguson, F. L. Zeng, N. Alwis and H. Alper, Org. Lett., 2013, 15, 1998.
15. (a) D. P. Ojha and K. R. Prabhu, J. Org. Chem., 2012, 77, 11027; (b) D. Ganapathy and G. Sekar, Org. Lett., 2014, 16, 3856. For reviews on the N-tosyl hydrazine, see: (c) Y. Zhang and J. Wang, Top. Curr. Chem., 2012, 327, 239; (d) A. P. Jadhav, D. Ray, V. U. B. Rao and R. P. Singh, Eur. J. Org. Chem., 2016, 2369; (e) Z. Liu and J. J. Wang, Org. Chem., 2013, 78, 10024; (f) Z. Liu, Y. Zhang and J. Wang, Chin. J. Org. Chem., 2013, 33, 687; (g) Q. Xiao, Y. Zhang and J. Wang, Acc. Chem. Res., 2013, 46, 236; (h) Z. Shao and H. Zhang, Chem. Soc. Rev., 2012, 41, 560.
16. For reviews on the synthetic application of nitroso, please see: (a) D. B. Huple, S. Ghorpade and R.-S. Liu, Adv. Synth. Catal., 2016, 358, 1348; (b) P. Merino, T. Tejero, I. Delso and R. Matute, Synthesis, 2016, 653; (c) B. Maji and H. Yamamoto, Bull. Chem. Soc. Jpn., 2015, 88, 753; (d) S. Huang, H. Huo, W. Li and R. Hong, Chin. J. Org. Chem., 2012, 32, 1776; (e) A. V. Malkov, Chem. Heterocycl. Compd., 2012, 48, 39; (f) M. Baidya and H. Yamamoto, Synthesis, 2013, 1931.
17. (a) R. Zhao, C. Tan, Y. Xie, C. Gao, H. Liu and Y. Jiang, Tetrahedron Lett., 2011, 52, 3805; (b) T. H. L. Nguyen, N. Gigant, S. Delarue-Cochin and D. Joseph, J. Org. Chem., 2016, 81, 1850.
18. For the Friedel–Crafts reactions of indoles, please see: (a) C. W. Downey, C. D. Poff and A. N. Nizinski, J. Org. Chem., 2015, 80, 10364; (b) J. A. Joule, Sci. Synth., 2001, 10, 361.
19. For copper-promoted oxyamination of alkenes, please see: (a) F. C. Sequeira and S. R. Chemler, Org. Lett., 2012, 14, 4482; (b) S. Ren, S. Song, L. Ye, C. Feng and T.-P. Loh, Chem. Commun., 2016, 52, 10373; (c) M. Noack and R. Göttlich, Chem. Commun., 2002, 536.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6qo00540c

---