Palladium-catalyzed Suzuki cross-couplings of N′-mesyl arylhydrazines via C–N bond cleavage

Abstract

An efficient palladium-catalyzed Suzuki cross-coupling reaction of N′-mesyl arylhydrazine with aryl boronic acid is described, which affords the corresponding biaryl compounds in high yields. This transformation proceeds through C–N bond cleavage under mild conditions.

---

Substituted biaryls are important structural motifs because of their presence in many natural products, pharmaceuticals, agrochemicals, and functional materials.¹ Thus, the development of new and efficient methods for synthesizing these structures is crucial to the work of organic chemistry, and several useful reactions have been developed over the last century.²

Transition-metal-catalyzed cross-coupling reactions are among the most powerful methods for the formation of (hetero)aryl–aryl bond.³ The Suzuki cross-coupling is, unarguably, of the greatest practical importance of these methods.⁴ Although aryl halides and pseudo-halides are the most commonly employed electrophilic partners, broadening the scope of electrophiles would be significant to practitioners of chemical synthesis. In recent years, metal-catalyzed cross-coupling reaction via C–N bond cleavage of arylhydrazine has attracted renewed interest in this reagent.⁵ This strategy utilizing arylhydrazine as arylating reagent has provided powerful methods for constructing biaryls^5a and aryl substituted olefins,^5b indoles,^5c ketones^5d and glycals.^5e Very recently, we developed a novel palladium-catalyzed Suzuki cross-coupling of N′-tosyl arylhydrazine, which also demonstrated its generality as a readily available and efficient coupling partner in a number of coupling reactions.⁶

Meanwhile, in view of the deficient atom-economy of N′-tosyl arylhydrazines as arylating reagents in the coupling procedure, to pursue other more economic and efficient coupling partners is necessary. N′-Mesyl arylhydrazines are relatively unreactive but atom-economic compared to the corresponding N′-tosyl arylhydrazines counterparts. However, to the best of our knowledge, no reports have appeared for the cross-coupling of N′-mesyl arylhydrazines with arylboronic acids. In this paper, as a continuation of our ongoing study on novel and green coupling processes,^6,7 we investigated whether or not the Suzuki reaction could be carried out by employing N′-mesyl arylhydrazines via C–N bond cleavage.

To verify our hypothesis, a set of experiments were carried out using N′-mesyl phenylhydrazine 1a and 4-methoxyphenyl boronic acid 2a as model substrates. Various conditions were screened and the results were summarized in Table 1. When 5 mol% of Pd(OAc)₂ was used as the palladium source and K₂CO₃ (2.0 equiv.) as the base, the reaction of 1a with 2a proceeded smoothly, and 73% yield of product 3a was achieved in MeOH at 60 °C (Table 1, entry 1). Encouraged by this result, we examined more Pd catalysts and found that PdCl₂(PPh₃)₂ was the best Pd source, affording 94% yield of the desired product 3a (Table 1, entry 3). Various bases were then screened for this reaction. However, none of them was more efficient than K₂CO₃ (Table 1, entries 5–9). Other solvents, such as EtOH, H₂O, DMSO, toluene and THF, were also investigated; however, moderate yields were obtained (Table 1, entries 10–14). In addition, the reaction temperature was examined and the results showed that 60 °C was the best choice (Table 1, entry 3 versus 15 and 16). Increasing the amount of Pd catalyst loading to 10 mol% resulted in a comparable yield (Table 1, entry 17 versus 3). However, a significant drop in yield was observed when 2 mol% of PdCl₂(PPh₃)₂ was used (Table 1, entry 18). Palladium catalyst is necessary for the cross-coupling and no product was observed in the absence of any Pd-catalyst (Table 1, entry 19).

Table 1 Influence of the reaction conditions in Suzuki cross-coupling of N′-mesyl phenylhydrazine 1a with 4-methoxyphenyl boronic acid 2a^a

Entry	Catalyst/base	Solvent	Yield (%)^b
a Reaction conditions: 1a (0.30 mmol), 2a (0.36 mmol), Pd catalyst (5 mol%), base (2.0 equiv.), solvent (2 mL), 60 °C, 4–8 h, under air.b Isolated yields.c At 80 °C.d At room temperature.e Pd catalyst (10 mol%).f Pd catalyst (2 mol%).
1	Pd(OAc)2/K2CO3	MeOH	73
2	PdCl2/K2CO3	MeOH	60
3	PdCl2(PPh3)2/K2CO3	MeOH	94
4	PdCl2(PhCN)2/K2CO3	MeOH	61
5	PdCl2(PPh3)2/Na2CO3	MeOH	70
6	PdCl2(PPh3)2/K3PO4	MeOH	54
7	PdCl2(PPh3)2/KF	MeOH	50
8	PdCl2(PPh3)2/KOAc	MeOH	45
9	PdCl2(PPh3)2/Et3N	MeOH	68
10	PdCl2(PPh3)2/K2CO3	EtOH	75
11	PdCl2(PPh3)2/K2CO3	H2O	37
12	PdCl2(PPh3)2/K2CO3	DMSO	55
13	PdCl2(PPh3)2/K2CO3	PhMe	48
14	PdCl2(PPh3)2/K2CO3	THF	35
15^c	PdCl2(PPh3)2/K2CO3	MeOH	79
16^d	PdCl2(PPh3)2/K2CO3	MeOH	58
17^e	PdCl2(PPh3)2/K2CO3	MeOH	87
18^f	PdCl2(PPh3)2/K2CO3	MeOH	63
19	—/K2CO3	MeOH	Trace

---

Then the scope of the Pd-catalyzed Suzuki cross-coupling of N′-mesyl arylhydrazines with aryl boronic acids was investigated (Table 2). For all cases, N′-mesyl arylhydrazines reacted with arylboronic acid 2 leading to the corresponding products 3 in good to excellent yields. Arylboronic acids with both electron-donating and electron-withdrawing groups attached to the aromatic ring were all good partners in this transformation. For example, N′-mesyl phenylhydrazines 1a reacted with 2e to provide the cross-coupling biaryl product in excellent yield (Table 2, entry 5). High yields could also be obtained for arylboronic acids 2c and 2d (Table 2, entries 3 and 4). In addition, 2b with ortho-substituent at aryl moiety also participated in the desired cross-coupling process, and slightly lower yield was obtained for its larger steric hindrance of methoxy substituent (Table 2, entry 2). Halogen substituents on phenyl rings (Table 2, entries 6–10) were observed to be tolerant in this reaction, indicating good chemoselectivity in contrast to the traditional Suzuki cross-coupling of aryl chloride and aryl fluoride. Arylboronic acids 2k–n with electron-withdrawing groups attached to the aromatic ring all could participate in the desired cross-coupling process smoothly (Table 2, entries 11–14). Not only aryl- but also heteroarylboronic acid gave high yield (Table 2, entry 15). Besides 1a, other substituted N′-mesyl arylhydrazines 1b–g were all effective in this kind of reaction (Table 2, entries 16–22). For instance, N′-mesyl arylhydrazines 1b and 1c with electron-donating groups could be employed in the coupling reaction in good yields (Table 2, entries 16, 17 and 22). Interestingly, 83% yield could be obtained with 1d even for its large steric hindrance of ortho-methyl substituent (Table 2, entry 18).

Table 2 Pd-catalyzed Suzuki cross-coupling of N′-mesyl arylhydrazines with arylboronic acids^a

Entry	1	2	Yield (%)^b
a Reaction conditions: 1 (0.30 mmol), 2 (0.36 mmol), PdCl2(PPh3)2 (5 mol%), K2CO3 (2.0 equiv.), MeOH (2 mL), 60 °C, 4–8 h, under air.b Isolated yields.
1			94
2	1a		65
3	1a		70
4	1a		76
5	1a		95
6	1a		88
7	1a		76
8	1a		75
9	1a		94
10	1a		80
11	1a		72
12	1a		73
13	1a		65
14	1a		77
15	1a		69
16		2a	85
17		2a	92
18		2a	83
19		2a	70
20		2a	76
21		2a	71
22	1c		76

---

In our previous work, compared with aryl bromide, N′-tosyl arylhydrazines proved to be more efficient and milder electrophiles (Scheme 1b).^6a Interestingly, for the palladium-catalyzed coupling reaction of bromo-substituted N′-mesyl arylhydrazines, a novel chemoselectivity could be observed, and the unexpected 4-methoxybiphenyl was obtained as the only cross-coupling product (Scheme 1a). From the two experiments, we can find that the series of aforementioned electrophiles in decreasing order of reactivity is: N′-tosyl arylhydrazine > aryl bromide > N′-mesyl arylhydrazine. This practical chemoselectivity can be used for the synthesis of some multi-aryl compounds by stepwise cross-coupling of N′-sulfonyl arylhydrazines and halides.

Scheme 1 Suzuki reactions of N′-sulfonyl arylhydrazine 1h and 1h′ with arylboronic acid 2a.

To explore the mechanism of this Suzuki reaction, we carried out two control experiments (Scheme 2). Compared with the standard conditions, a comparable yield was obtained under O₂ atmosphere, but a significant drop in yield was observed under N₂ atmosphere. From these results, it seems that the oxygen might play an important role as an oxidant in the coupling process.

Scheme 2 Control experiments.

Based on these results and the research findings from other groups, a possible mechanism for this Suzuki reaction via C–N bond cleavage has been proposed (Fig. 1).^6,8 Firstly, N′-mesyl arylhydrazine A was dehydrogenated in the presence of base and Pd(II)-catalyst to provide the aryl diazonium ion B, accompany with the in situ generation of Pd(0) active species. Then oxidative addition of diazonium ions to the Pd(0) gave the organopalladium intermediate C, which promoted the transmetallation of the arylboronic acid to form the diaryl-palladium species D. Finally reductive elimination of D afforded the corresponding biaryl product E and gave the Pd(0). Meanwhile, oxygen in the air regenerated the Pd(II)-catalyst.

Fig. 1 Proposed mechanism for the Suzuki cross-coupling of N′-mesyl arylhydrazine with aryl boronic acid.

In summary, we have described a novel C–N bond cleavage for the preparation of biaryl compounds by Pd-catalyzed Suzuki cross-coupling between N′-mesyl arylhydrazine and aryl boronic acid. Notably, N′-sulfonyl arylhydrazine as a readily available and stable electrophile demonstrated its significant chemo-selectivity in the Suzuki cross-coupling reaction. Efforts are underway to extend the scope of the reaction of N′-sulfonyl arylhydrazine.

Acknowledgements

This work was supported by PhD research startup foundation of Jiangxi University of Science and Technology (no. jxxjbs13021), and the Key Laboratory of Functional Small Organic Molecules, Ministry of Education.

Notes and references

1. (a) D. A. Horton, G. T. Bourne and L. M. Smythe, Chem. Rev., 2003, 103, 893; (b) O. Baudoin and F. Gueritte, Stud. Nat. Prod. Chem., 2003, 29, 355; (c) F. Bellina, A. Carpita and R. Rossi, Synthesis, 2004, 2419; (d) S. Lightowler and M. Hird, Chem. Mater., 2005, 17, 5538.
2. J. Hassan, M. Sevignon, C. Gozzi, E. Schulz and M. Lemaire, Chem. Rev., 2002, 102, 1359.
3. (a) Metal-Catalyzed Cross-Coupling Reactions, ed. F. Diederich and A. Meijere, Wiley-VCH, Weinheim, Germany, 2004; (b) J. Corbet and G. Mignani, Chem. Rev., 2006, 106, 2651; (c) E. Negishi, Bull. Chem. Soc. Jpn., 2007, 80, 233.
4. (a) N. Miyaura, Bull. Chem. Soc. Jpn., 2008, 81, 1535; (b) A. Suzuki, Angew. Chem., Int. Ed., 2011, 50, 6722.
5. (a) Z. Peng, G. Hu, H. Qiao, P. Xu, Y. Gao and Y. Zhao, J. Org. Chem., 2014, 79, 2733; (b) M.-K. Zhu, J.-F. Zhao and T.-P. Loh, Org. Lett., 2011, 13, 6308; (c) Y. Chen, S. Guo, K. Li, J. Qu, H. Yuan, Q. Hua and B. Chen, Adv. Synth. Catal., 2013, 355, 711; (d) Y. Su, X. Sun, G. Wu and N. Jiao, Angew. Chem., Int. Ed., 2013, 52, 9808; (e) Y. Bai, L. Mai, H. Kim, H. Liao and X.-W. Liu, J. Org. Chem., 2013, 78, 8821.
6. (a) J.-B. Liu, H. Yan, H.-X. Chen, Y. Luo, J. Weng and G. Lu, Chem. Commun., 2013, 49, 5268; (b) J.-B. Liu, L. Nie, H. Yan, L.-H. Jiang, J. Weng and G. Lu, Org. Biomol. Chem., 2013, 11, 8014; (c) J.-B. Liu, H.-P. Zhou and Y.-Y. Peng, Tetrahedron Lett., 2014, 55, 2872.
7. (a) Y.-Y. Peng, J.-B. Liu, X. Lei and Z. Yin, Green Chem., 2010, 12, 1072; (b) J.-B. Liu, H. Yan and G. Lu, Tetrahedron Lett., 2013, 54, 891.
8. (a) J. L. Kice and R. S. Gabrielsen, J. Org. Chem., 1970, 35, 1004; (b) C. D. Ritchie, J. D. Saltiel and E. S. Lewis, J. Am. Chem. Soc., 1961, 83, 4601; (c) N. Kamigata, A. Satoh, M. Yoshida and M. Kameyama, Bull. Chem. Soc. Jpn., 1989, 62, 605; (d) A. Furst, R. C. Berlo and S. Hooton, Chem. Rev., 1965, 65, 51; (e) D. M. Littrell, D. H. Bowers and B. J. Tatarchuk, J. Chem. Soc., Faraday Trans. 1, 1987, 83, 3271; (f) G.-Y. Huang, S.-M. Xu, G. Xu, L.-Y. Li and L.-F. Zhang, Trans. Nonferrous Met. Soc. China, 2009, 19, 389; (g) Y. Wang, Y.-F. Shi, Y.-B. Chen and L.-M. Wu, J. Solid State Chem., 2012, 191, 19.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra03421j

---