Formal [4 + 1] cycloaddition of in situ generated 1,2-diaza-1,3-dienes with diazo esters: facile approaches to dihydropyrazoles containing a quaternary center

Abstract

A Cu(II)/bisoxazoline ligand-promoted formal [4 + 1] cycloaddition of diazo esters with azoalkenes formed in situ has been developed. This strategy provides a potential protocol for the construction of dihydropyrazoles containing a quaternary center with good to excellent yields.

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The efficient construction of quaternary carbon centers has remained a crucial issue in organic synthesis.¹ Quaternary carbon centers are ubiquitous in various natural products, and pharmaceutically relevant compounds.² Although significant efforts have been devoted to the effective construction of quaternary centers in recent years,¹ new methodologies that could be advantageous in terms of functional-group tolerance, operational simplicity, and the use of easily obtained starting materials are still highly desired.

On the other hand, dihydropyrazoles represent a class of important heterocycles that occur in biologically active natural products and pharmaceuticals such as anti-amoebic, hypotensive, analgesic, anti-bacterial, anti-cancer, anti-depressant and nonsteroidal anti-inflammatory agents.³ Accordingly, great research efforts have been devoted toward their synthesis, and remarkable advances have been achieved in the construction of these nitrogen heterocycles. Representative synthetic strategies include formal [3 + 2] cycloaddition,⁴ [4 + 1] cycloaddition,⁵ catalytic asymmetric Fischer's pyrazoline synthesis via a sequential aza-Michael addition/cyclocondensation process,⁶ and photocatalytic radical cyclization.^7,8 In comparison with the more ubiquitous family of [3 + 2] cycloadditions, [4 + 1] cycloannulations are relatively underutilized in these target-directed five-membered aza-heterocycles construction.⁵ In 2012, Bolm and coworkers reported the first example of asymmetric synthesis of dihydropyrazoles by formal [4 + 1] cycloaddition of in situ derived azoalkenes and sulfur ylides (Scheme 1a).^5a Recently, diazo esters as 1,1-dipolar C1 synthons had also been utilized by the group of Favi to synthesize racemic dihydropyrazoles in a similar manner (Scheme 1b).^5b However, none of these investigations has explored the possibility of accessing dihydropyrazoles containing a quaternary center. Herein, we present a Cu(II)/bisoxazoline ligand-promoted formal [4 + 1] cycloaddition of diazo esters with azoalkenes formed in situ, affording dihydropyrazoles containing a quaternary center with good to excellent yields (Scheme 1c).

Scheme 1 Synthesis of dihydropyrazoles by formal [4 + 1] cycloaddition.

At the outset of this investigation, we employed hydrazone 1a and diazo ester 2a as the substrates (Table 1). Preliminary screening showed that the ligand has a remarkable effect on the reaction. For instance, the reaction with phosphine ligands gave the desired dihydropyrazole 3a in low yields (Table 1, entry 2–4). It was found that the reaction proceeded efficiently when bisoxazoline L6 was employed as ligand, leading to the desired product 3a in 98% yield (Table 1, entry 7). Subsequently, different bases and solvents were then explored (Table 1, entries 7–16), Na₂CO₃ and CH₂Cl₂ was the best choice.

Table 1 Optimization of reaction conditions^a

Entry	[Cu]	Ligand	Base	Solvent	Yield^b (%)
a Reaction was run under the following conditions: a solution of 1a (0.1 mmol), 2a (0.5 mmol), base (0.5 mmol), Cu cat. (10 mol%), and ligand (11 mol%) in anhydrous solvent (1 mL) was stirred at 40 °C under nitrogen atmosphere for 0.5 h.b Yields refer to isolated products.
1	CuCl2	None	Na2CO3	CH2Cl2	None
2	CuCl2	L1	Na2CO3	CH2Cl2	18
3	CuCl2	L2	Na2CO3	CH2Cl2	6
4	CuCl2	L3	Na2CO3	CH2Cl2	22
5	CuCl2	L4	Na2CO3	CH2Cl2	5
6	CuCl2	L5	Na2CO3	CH2Cl2	6
7	CuCl2	L6	Na2CO3	CH2Cl2	98
8	CuCl2	L6	K2CO3	CH2Cl2	15
9	CuCl2	L6	Cs2CO3	CH2Cl2	26
10	CuCl2	L6	NaOH	CH2Cl2	Trace
11	CuCl2	L6	KOtBu	CH2Cl2	Trace
12	CuCl2	L6	Et3N	CH2Cl2	Trace
13	CuCl2	L6	Na2CO3	THF	83
14	CuCl2	L6	Na2CO3	Toluene	Trace
15	CuCl2	L6	Na2CO3	CH3CN	5
16	CuCl2	L6	Na2CO3	Hexane	12

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With the optimized conditions in hand, we next explored the substrate scope of the heterodienes. A series of hydrazones 1a–l bearing electron-neutral, -deficient or -rich aromatic substituents were smoothly reacted with diazo ester 2a to give the corresponding dihydropyrazoles 3a–l in 76−98% yield (Table 2, entry 1–12). Also α-bromo N-benzoyl hydrazone 1o reacted well, and 88% yield were achieved (Table 2, entry 15). In contrast, 2-naphthyl-substituted hydrazone 1m and aliphatic hydrazone 1n only gave a small quantity of product 3m and 3n (Table 2, entry 13–14).

Table 2 Substrate scope for hydrazones^a

Entry	1	X	R^1	Yield^b of 3 (%)
a Reaction was run under the following conditions: a solution of 1 (0.1 mmol), 2a (0.5 mmol), Na2CO3 (0.5 mmol), CuCl2 (10 mol%), and L6 (11 mol%) in anhydrous CH2Cl2 (1 mL) was stirred at 40 °C under nitrogen atmosphere for 0.5 h.b Yields refer to isolated products.
1	1a	Cl	Ph	3a, 98
2	1b	Cl	2-Br–Ph	3b, 82
3	1c	Cl	2-F–Ph	3c, 78
4	1d	Cl	2-CH3–Ph	3d, 76
5	1e	Cl	3-Cl–Ph	3e, 93
6	1f	Cl	3-OCH3–Ph	3f, 92
7	1g	Cl	3-CH3–Ph	3g, 89
8	1h	Cl	4-Cl–Ph	3h, 98
9	1i	Cl	4-F–Ph	3i, 94
10	1j	Cl	4-OCH3–Ph	3j, 98
11	1k	Cl	4-NO2–Ph	3k, 92
12	1l	Cl	4-CH3–Ph	3l, 98
13	1m	Cl	2-Naphthyl	3m, trace
14	1n	Cl	n-Bu	3n, trace
15	1o	Br	Ph	3o, 88

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Next, the scope of the reaction was extended by conducting the reaction with various diazo esters (Table 3). Variation of the ester R² group (entries 1 and 2) had little influence on the yield of product 3. The significant steric effect of R¹ has been observed. Methyl and ethyl groups gave excellent results (entries 2–3), while the more bulky groups gave only a trace of products (entries 4–5).

Table 3 Substrate scope for diazo esters^a

Entry	2	R^1	R^2	Yield^b of 3 (%)
a Reaction was run under the following conditions: a solution of 1a (0.1 mmol), 2 (0.5 mmol), Na2CO3 (0.5 mmol), CuCl2 (10 mol%), and L6 (11 mol%) in anhydrous CH2Cl2 (1 mL) was stirred at 40 °C under nitrogen atmosphere for 0.5 h.b Yields refer to isolated products.
1	2a	Me	Bn	3a, 98
2	2b	Me	Et	3p, 98
3	2c	Et	Et	3q, 92
4	2d	Bn	Bn	3r, trace
5	2e	Ph	Et	3s, trace

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We next attempted to investigate asymmetric variant of this Cu(II)-catalyzed formal [4 + 1] cycloaddition reaction of diazo esters with azoalkenes formed in situ (Scheme 2). An extensive screening of chiral phosphine ligands (L7, L8), bisoxazoline ligands (L9–12) and different reaction conditions had been implemented. Unfortunately, only up to 5% ee was obtained when L12 was employed as chiral ligand, albeit with excellent yield (98%).

Scheme 2 The investigation on asymmetric [4 + 1] annulation reaction.

To show the synthetic potential of this strategy, we have carried out a gram scale synthesis of 3a (Scheme 3). Under the optimized reaction conditions, the reaction with 3 mmol of 1a proceeded smoothly with 5 equiv. of 2a, affording 1.07 g of 3a (90% yield).

Scheme 3 Reaction on the gram scale.

In summary, we have developed a Cu(II)/bisoxazoline ligand-promoted formal [4 + 1] cycloaddition of diazo esters with azoalkenes formed in situ, affording dihydropyrazoles containing a quaternary center with good to excellent yields. The reaction involves the use of stable, readily available starting materials and is operationally simple.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was financial supported by the National Natural Science Foundation of China (No. 21572183 and 21801208).

Notes and references

1. For selected reviews, see: (a) K. Fuji, Chem. Rev., 1993, 93, 2037–2066; (b) J. C. Douglas and L. E. Overman, Proc. Natl. Acad. Sci. U. S. A., 2004, 101, 5363–5367; (c) J. Christoffers and A. Baro, Quaternary Stereocenters-Challenges and Solutions for Organic Synthesis, Wiley-VCH, Weinheim, 2005; (d) B. M. Trost and C. Jiang, Synthesis, 2006, 369–396; (e) M. Shimizu, Angew. Chem., Int. Ed., 2011, 50, 5998–6000; (f) B. M. Wang and Y. Q. Tu, Acc. Chem. Res., 2011, 44, 1207–1222; (g) J. P. Das and I. Marek, Chem. Commun., 2011, 47, 4593–4623; (h) M. Büschleb, S. Dorich, S. Hanessian, D. Tao, K. B. Schenthal and L. E. Overman, Angew. Chem., Int. Ed., 2016, 55, 4156–4186.
2. (a) D. J. Newman and G. M. Cragg, J. Nat. Prod., 2012, 75, 311–335; (b) D. J. Newman and G. M. Cragg, J. Nat. Prod., 2016, 79, 629–661 and references within; (c) Y. Tu, C. Jeffries, H. Ruan, C. Nelson, D. Smithson, A. A. Shelat, K. M. Brown, X.-C. Li, J. P. Hester, T. Smillie, I. A. Khan, L. Walker, K. Guy and B. Yan, J. Nat. Prod., 2010, 73, 751–754.
3. (a) M. Kissane and A. R. Maguire, Chem. Soc. Rev., 2010, 39, 845–883; (b) C.-H. Küchenthal and W. Maison, Synthesis, 2010, 719–740; (c) A. Sahoo, S. Yabanoglu, B. N. Sinha, G. Ucar, A. Basu and V. Jayaprakash, Bioorg. Med. Chem. Lett., 2010, 20, 132–136; (d) M. Johnson, B. Younglove, L. Lee, R. LeBlanc, H. Holt Jr, P. Hills, H. Mackay, T. Brown, S. L. Mooberry and M. Lee, Bioorg. Med. Chem. Lett., 2007, 17, 5897–5901; (e) M. A. Ali and M. Shaharyar, Bioorg. Med. Chem., 2007, 15, 1896–1902; (f) J. H. M. Lange and C. G. Kruse, Curr. Opin. Drug Discovery Dev., 2004, 7, 498.
4. (a) S. Kanemasa and T. Kanai, J. Am. Chem. Soc., 2000, 122, 10710–10711; (b) R. Shintani and G. C. Fu, J. Am. Chem. Soc., 2003, 125, 10778–10779; (c) M. P. Sibi, L. M. Stanley and C. P. Jasperse, J. Am. Chem. Soc., 2005, 127, 8276–8277; (d) A. Suárez, C. W. Downey and G. C. Fu, J. Am. Chem. Soc., 2005, 127, 11244–11245; (e) T. Kano, T. Hashimoto and K. Maruoka, J. Am. Chem. Soc., 2006, 128, 2174–2175; (f) M. P. Sibi, L. M. Stanley and T. Soeta, Adv. Synth. Catal., 2006, 348, 2371–2375; (g) M. P. Sibi, L. M. Stanley and T. Soeta, Org. Lett., 2007, 9, 1553–1556; (h) L. Gao, G. S. Hwang, M. Y. Lee and D. H. Ryu, Chem. Commun., 2009, 5460–5462; (i) H. Suga, Y. Furihata, A. Sakamoto, K. Itoh, Y. Okumura, T. Tsuchida, A. Kakehi and T. Baba, J. Org. Chem., 2011, 76, 7377–7387; (j) T. Arai and Y. Ogino, Molecules, 2012, 17, 6170–6178; (k) T. Imaizumi, Y. Yamashita and S. Kobayashi, J. Am. Chem. Soc., 2012, 134, 20049–20052; (l) M. Rueping, M. S. Maji, H. B. Kücük and I. Atodiresei, Angew. Chem., Int. Ed., 2012, 51, 12864–12868; (m) G. Wang, X. Liu, T. Huang, Y. Kuang, L. Lin and X. Feng, Org. Lett., 2013, 15, 76–79; (n) A. L. Gerten, M. C. Slade, K. M. Pugh and L. M. Stanley, Org. Biomol. Chem., 2013, 11, 7834–7837; (o) T. Arai, Y. Ogino and T. Sato, Chem. Commun., 2013, 49, 7776–7778; (p) T. Hashimoto, Y. Takiguchi and K. Maruoka, J. Am. Chem. Soc., 2013, 135, 11473–11476; (q) M. Hori, A. Sakakura and K. Ishihara, J. Am. Chem. Soc., 2014, 136, 13198–13201; (r) X. Hong, H. B. Kücük, M. S. Maji, Y.-F. Yang, M. Rueping and K. N. Houk, J. Am. Chem. Soc., 2014, 136, 13769–13780; (s) X. Wang, Y.-m. Pan, X.-c. Huang, Z.-y. Mao and H.-s. Wang, Org. Biomol. Chem., 2014, 12, 2028–2032; (t) D.-Y. Zhang, L. Shao, J. Xu and X.-P. Hu, ACS Catal., 2015, 5, 5026–5030.
5. (a) J.-R. Chen, W.-R. Dong, M. Candy, F.-F. Pan, M. Jörres and C. Bolm, J. Am. Chem. Soc., 2012, 134, 6924–6927; (b) O. A. Attanasi, L. D. Crescentini, G. Favi, F. Mantellini, S. Mantenuto and S. Nicolini, J. Org. Chem., 2014, 79, 8331–8338; (c) Z. Wang, Y. Yang, F. Gao, Z. Wang, Q. Luo and L. Fang, Org. Lett., 2018, 20, 934–937.
6. (a) H. Yanagita and S. Kanemasa, Heterocycles, 2007, 71, 699–709; (b) S. Müller and B. List, Angew. Chem., Int. Ed., 2009, 48, 9975–9978; (c) S. Müller and B. List, Synthesis, 2010, 2010, 2171–2178; (d) O. Mahé, I. Dez, V. Levacher and J.-F. Brière, Angew. Chem., Int. Ed., 2010, 49, 7072–7075; (e) N. R. Campbell, B. Sun, R. P. Singh and L. Deng, Adv. Synth. Catal., 2011, 353, 3123–3128; (f) M. Fernández, E. Reyes, J. L. Vicario, D. Badía and L. Carrillo, Adv. Synth. Catal., 2012, 354, 371–376; (g) O. Mahé, I. Dez, V. Levacher and J.-F. Brière, Org. Biomol. Chem., 2012, 10, 3946–3954.
7. (a) X.-Q. Hu, J.-R. Chen, Q. Wei, F.-L. Liu, Q.-H. Deng, A. M. Beauchemin and W.-J. Xiao, Angew. Chem., Int. Ed., 2014, 53, 12163–12167; (b) Q. Wei, J.-R. Chen, X.-Q. Hu, X.-C. Yang, B. Lu and W.-J. Xiao, Org. Lett., 2015, 17, 4464–4467; (c) J. Cheng, P. Xu, W. Li, Y. Cheng and C. Zhu, Chem. Commun., 2016, 52, 11901–11904; (d) Q.-Q. Zhao, J. Chen, D.-M. Yan, J.-R. Chen and W.-J. Xiao, Org. Lett., 2017, 19, 3620–3623; (e) J.-m. Yu, G.-P. Lu and C. Cai, Chem. Commun., 2017, 53, 5342–5345.
8. For other methods for synthesis of dihydropyrazoles, see: (a) C. B. Tripathi and S. Mukherjee, Org. Lett., 2014, 16, 3368–3371; (b) X. Wu, M. Wang, G. Zhang, Y. Zhao, J. Wang and H. Ge, Chem. Sci., 2015, 6, 5882–5890; (c) M.-N. Yang, D.-M. Yan, Q.-Q. Zhao, J.-R. Chen and W.-J. Xiao, Org. Lett., 2017, 19, 5208–5211; (d) J. Zhao, M. Jiang and J.-T. Liu, Org. Chem. Front., 2018, 5, 1155–1159.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures and compound characterisation data, including X-ray crystal structures of 3h. CCDC 1840892. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c8ra08909d

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