Pd-catalyzed oxidative cross-coupling of N-tosylhydrazones with arylboronic acids

Abstract

The Pd-catalyzed reaction of N-tosylhydrazones and arylboronic acids provides olefin derivatives. This oxidative cross-coupling is suggested to proceed through a migratory insertion process of a Pd carbene intermediate.

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Pd-catalyzed cross-coupling reactions of diazo compounds have recently emerged as a new type of cross-coupling reaction.^1–4 We have reported a Pd-catalyzed cross-coupling reaction of α-diazocarbonyl compounds with boronic acids, which affords α,β-unsaturated carbonyl compounds in high yields.^1e The reaction presumably proceeds through a migratory insertion process of the Pd carbene intermediate.⁵ To further extend the scope of this cross-coupling reaction, we conceived to employ diazo compounds that do not bear electron withdrawing substituents as the substrates in this reaction. Diazo compounds without electron withdrawing groups are usually unstable and thus difficult to handle. The recently developed methods of in situ generation of diazo compounds have largely circumvented this problem. Treatment of N-tosylhydrazones with base is the most widely practised method for this purpose.⁶ The reaction conditions are compatible with the Pd-catalyzed cross-coupling reaction, as demonstrated by Barluenga and co-workers’ reports on a Pd-catalyzed reaction of N-tosylhydrazones with aryl bromides in the presence of lithium tert-butoxide,^1b,c and by our own recent report on the Pd-catalyzed reaction of N-tosylhydrazones with benzyl halides.^2c As a continuation, we report in this communication the Pd-catalyzed oxidative cross-coupling of N-tosylhydrazone with aromaticboronic acids.

Initially, the cross-coupling reaction between acetophenone N-tosylhydrazone 1a and phenyl boronic acid2a was carried out under various conditions. From the mechanistic rational (vide infra), the cross-coupling reaction starts from the transmetallation of boronic acid to the Pd(II) catalyst.⁷ At the end of the reaction, a Pd(0) species is released, which needs to be oxidized in order to regenerate the Pd(II) catalyst. Initially, Ag₂CO₃ was employed as the oxidant. Thus, with Pd(PPh₃)₄ as catalyst and LiO^tBu as base, the reaction of N-tosylhydrazone 1a and boronic acid2a in dioxane at 70 °C affords 1,1-diphenylethylene3a in 16% yield (Table 1, entry 1). Further optimization of the reaction was focused on the search for a suitable oxidant. A number of oxidants such as Ag₂CO₃, ^tBuOO^tBu, KBrO₃, CuCl₂ and Cu(OAc)₂ were screened and none of them was efficient for the reaction (entries 2–6). To our delight, we observed that the combination of CuCl and oxygen under balloon pressure was effective and promoted the reaction in moderate to high yield (entry 7).

Table 1 Conditions of Pd-catalyzed reaction of 1a and 2a^a

Entry	Oxidant (% mol)	Base (equiv.)	Solvent	Yield (%)^b
a Reaction conditions: 1a (0.25 mmol), 2a (0.75 mmol), Pd(PPh3)4 (5 mol%), solvent (2 mL). b Isolated yield. c In an atmosphere of O2 : N2 = 1 : 4.
1	Ag2CO3 (200)	LiO^tBu (3)	Dioxane	16
2	^tBuOO^tBu (200)	LiO^tBu (3)	Dioxane	10
3	^tBuOO^tBu (300)	LiO^tBu (3)	Dioxane	13
4	Cu(OAc)2 (200)	LiO^tBu (4)	Dioxane	Trace
5	CuCl2 (200)	LiO^tBu (4)	Dioxane	Trace
6	KBrO3 (150)	LiO^tBu (5)	Dioxane	8
7	O2, CuCl (20)	LiO^tBu (4)	Dioxane	47
8	O2, CuCl (20)	LiO^tBu (4)	Toluene	34
9	O2, CuCl (20)	LiO^tBu (4)	MeCN	22
10	O2, CuCl (10)	LiO^tBu (5)	DMSO	7
11	O2, CuCl (20)	LiO^tBu (5)	Dioxane	68
12	O2, CuCl (10)	LiO^tBu (5)	Dioxane	71
13	O2, CuBr (20)	LiO^tBu (5)	Dioxane	60
14	O2, CuCl2 (20)	LiO^tBu (5)	Dioxane	64^c
15	O2, CuI (20)	LiO^tBu (5)	Dioxane	13
16	O2, CuOTf (10)	LiO^tBu (5)	Dioxane	26

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Next, we observed that solvent significantly affected this coupling reaction. Toluene, MeCN and DMSO were tested, but they were all less effective as compared with dioxane (entries 8–10). To further optimize the reaction, some copper salts were examined.† We found that both Cu(II) and Cu(I) could work for the reaction (entries 13–16). For CuCl, the molar percentage could be reduced to 10%, affording the highest yield (entry 12). Since the base used in the reaction also plays an important role, several bases such as KO^tBu, NaO^tBu, Cs₂CO₃, were also examined. However, they are all less efficient compared with LiO^tBu. Finally, we studied different palladium catalysts.† Although either Pd(0) or Pd(II) catalysts could catalyze the cross-coupling reaction, none of them exceeded the simple Pd(PPh₃)₄. Thus, the optimized reaction conditions were as follows: 1a (0.25 mmol), 2a (0.75 mmol), Pd(PPh₃)₄ (5 mol%), CuCl (10 mol%), LiO^tBu (1.25 mmol), in dioxane at 70 °C.

A series of substituted acetophenone N-tosylhydrazones 1a–i and arylboronic acids 2a–e were examined under the optimal reaction conditions. As shown in Table 2, the reaction gave moderate to good yields in most cases. The results do not show a significant electronic effect in this reaction. Since the homocoupling of arylboronic acids is inevitable as a side reaction,⁸ in all cases 3 equiv. of arylboronic acids were needed in order to completely transform the N-tosylhydrazones to the products.

Table 2 Pd(PPh₃)₄-catalyzed reactions of 1a–i and 2a–e^a

Entry	1, Ar^1	2, Ar^2	t/h	Yield (3, %)^b
a Reaction conditions: 1a–i (0.25 mmol), 2a–e (0.75 mmol), Pd(PPh3)4 (5 mol%), CuCl (10 mol%), LiO^tBu (1.25 mmol), dioxane (2 mL), 70 °C. b Yield of isolated product after chromatography. c The product and by-product biphenyl were inseparable on a column. The yield was determined by ^1H NMR. d The product and by-product 4,4′-dimethylbiphenyl were inseparable on a column. The yield was determined by ^1H NMR.
1	1a, C6H5	2a, C6H5	7	3a, 71^c
2	1a, C6H5	2b, p-MeOC6H4	7	3b, 70
3	1a, C6H5	2c, m-ClC6H4	7	3c, 47
4	1b, p-MeC6H4	2a, C6H5	6.5	3d, 70^c
5	1b, p-MeC6H4	2b, p-MeOC6H4	10	3e, 71
6	1b, p-MeC6H4	2d, p-MeC6H4	10	3f, 67^d
7	1c, p-ClC6H4	2a, C6H5	9	3g, 52
8	1c, p-ClC6H4	2b, p-MeOC6H4	8	3h, 67
9	1d, m-MeOC6H4	2a, C6H5	8.5	3i, 57
10	1d, m-MeOC6H4	2d, p-MeC6H4	7	3j, 68
11	1e, p-MeOC6H4	2a, C6H5	7	3b, 67
12	1e, p-MeOC6H4	2b, p-MeOC6H4	7	3k, 76
13	1e, p-MeOC6H4	2c, m-ClC6H4	7	3l, 40
14	1e, p-MeOC6H4	2d, p-MeC6H4	7	3e, 82
15	1e, p-MeOC6H4	2e, m-MeC6H4	7	3m, 71
16	1f, 3,4-Me2C6H3	2a, C6H5	9	3n, 57^c
17	1g, 3,5-Me2C6H3	2a, C6H5	7	3o, 63^c
18	1g, 3,5-Me2C6H3	2b, p-MeOC6H4	9	3p, 30
19	1h, p-CF3C6H4	2b, p-MeOC6H4	6	3q, 64
20	1i, p-NCC6H4	2a, C6H5	5	3r, 51

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The reaction could be extended to hydrazone substrates bearing substituents other than a methyl group. Thus, the Pd-catalyzed reaction of 4a–g and 2a,b under identical reaction conditions afforded 5a–h in good yields in most cases (Scheme 1).

Scheme 1 Pd-catalyzed reaction of 4a–g with 2a,b.

A plausible mechanism for this Pd-catalyzed oxidative coupling is proposed in Scheme 2. The reaction is initiated by the oxidation of the CuCl to Cu(II) species by oxygen, which then oxidize Pd(0) to Pd(II) species. Transmetallation of the Pd(II) species with the arylboronic acid affords arylpalladium species A, which reacts with the in situ generated diazo substrate to give Pd carbene complex B. Migratory insertion of the aryl group to the carbenic carbon of the Pd carbene species affords the intermediate C.^1–5 Finally, β-hydride elimination of C affords the product and regenerates the Pd(0) species in the presence of base.

Scheme 2 Possible reaction pathways.

However, the possibility exists that the Pd carbene is generated directly from Pd(II) and the diazo substrate. The formation of the olefin product may be due to the 1,2-H shift of the Pd carbene intermediate and subsequent Heck–Mizoroki-type reaction.^9,10 To confirm this possible pathway, styrene6 and phenyl boronic acid2a were reacted under the identical conditions (eqn (1)). Only a trace amount of 1,2-diphenylethylene7 was observed and no 1,1-diphenylethylene could be detected in the ¹H NMR spectrum of the crude product. Consequently, this pathway can be excluded.

To gain further insight into the reaction mechanism, we examined the kinetic isotope effect (KIE) of the reaction (Scheme 3). At first, intermolecular competition was carried out with d₃-deuterated N-tosylhydrazone 8 and 1a. The competition reaction gave 3b and 9 in equal amount (k_H/k_D = 1.0). On the other hand, the intramolecular competition experiment with d₁-deuterated N-tosylhydrazone 10 gave a KIE of 2.54. The significant KIE in the β-hydride elimination step and lack of KIE for the overall reaction (intermolecular competition) clearly suggest that β-hydride elimination is not in the rate determining step. It is noted that the KIE value observed in the intramolecular competition is comparable to those reported for β-hydride elimination in Pd-catalyzed reactions.¹¹ Thus, the KIE results are in accordance with the proposed reaction mechanism shown in Scheme 2.

Scheme 3 Kinetic isotopic effect experiment.

In conclusion, we have reported the first oxidative cross-coupling reaction between N-tosylhydrazone and arylboronic acids. This study shows that the coupling of N-tosylhydrazone and arylboronic acids under oxidative conditions can compete with the oxidative homocoupling of arylboronic acids, which indicates that the interaction of arylpalladium species with diazo substrates and the subsequent processes are both highly efficient. This study further demonstrates the generality of the transformations based on Pd carbene processes.

The project was supported by the NSFC (Grant No. 20832002, 20772003, 20821062) and 973 Program (No. 2009CB825300).

Notes and references

1. (a) K. L. Greenman, D. S. Carter and D. L. Van Vranken, Tetrahedron, 2001, 57, 5219; (b) J. Barluenga, P. Moriel, C. Valdés and F. Aznar, Angew. Chem., Int. Ed., 2007, 46, 5587; (c) J. Barluenga, M. Tomás-Gamasa, P. Moriel, F. Aznar and C. Valdés, Chem.–Eur. J., 2008, 14, 4792; (d) R. Kudirka and D. L. Van Vranken, J. Org. Chem., 2008, 73, 3585; (e) C. Peng, Y. Wang and J. Wang, J. Am. Chem. Soc., 2008, 130, 1566.
2. (a) K. L. Greenman and D. L. Van Vranken, Tetrahedron, 2005, 61, 6438; (b) W.-Y. Yu, Y.-T. Tsoi, Z. Zhou and A. S. C. Chan, Org. Lett., 2009, 11, 469; (c) Q. Xiao, J. Ma, Y. Yang, Y. Zhang and J. Wang, Org. Lett., 2009, 11, 4732.
3. (a) S. K. J. Devine and D. L. Van Vranken, Org. Lett., 2007, 9, 2047; (b) S. K. J. Devine and D. L. Van Vranken, Org. Lett., 2008, 10, 1909; (c) R. Kudirka, S. K. J. Devine, C. S. Adams and D. L. Van Vranken, Angew. Chem., Int. Ed., 2009, 48, 3677.
4. S. Chen and J. Wang, Chem. Commun., 2008, 4198.
5. For reports on the migratory insertion process of stable Pd carbene species, see: (a) A. C. Albéniz, P. Espinet, R. Manrique and A. Pérez-Mateo, Angew. Chem., Int. Ed., 2002, 41, 2363; (b) M. Bröring, C. D. Brandt and S. Stellwag, Chem. Commun., 2003, 2344; (c) D. Solé, L. Vallverdú, X. Solans, M. Font-Bardia and J. Bonjoch, Organometallics, 2004, 23, 1438; (d) A. C. Albéniz, P. Espinet, R. Manrique and A. Pérez-Mateo, Chem.–Eur. J., 2005, 11, 1565; (e) A. C. Albéniz, P. Espinet, A. Pérez-Mateo, A. Nova and G. Ujaque, Organometallics, 2006, 25, 1293.
6. J. R. Fulton, V. K. Aggarwal and J. de Vicente, Eur. J. Org. Chem., 2005, 1479.
7. For selected reviews on Pd-catalyzed coupling reactions with arylboronic compounds, see: (a) A. Suzuki, Acc. Chem. Res., 1982, 15, 178; (b) N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457; (c) N. Miyaura, J. Organomet. Chem., 2002, 653, 54; (d) N. Miyaura, in Advances in Metal Organic Chemistry, ed. L. S. Liebeskind, J AI, London, 1998, vol. 6, p. 187; (e) A. Suzuki, in Metal-Catalyzed Cross-Coupling Reactions, ed. F. Diederich and P. J. Stang, Wiley-VCH, New York, 1998, ch. 2; (f) N. Miyaura, Top. Curr. Chem., 2002, 219, 11.
8. For examples of Pd-catalyzed homocoupling of arylboronic compounds under oxidative conditions, see: (a) H. Yoshida, Y. Yamaryo, J. Ohshita and A. Kunai, Tetrahedron Lett., 2003, 44, 1541; (b) S. Punna, D. D. Diaz and M. G. Finn, Synlett, 2004, 2351; (c) C. Zhou and R. C. Larock, J. Org. Chem., 2006, 71, 3184; (d) A. Christian, C. Chama and J. Anny, Eur. J. Org. Chem., 2008, 4567.
9. For a recent report on the 1,2-H shift of Rh(II) carbenes, see: F. Xiao and J. Wang, J. Org. Chem., 2006, 71, 5789.
10. For examples, see: (a) X. Du, M. Suguro, K. Hirabayashi and A. Mori, Org. Lett., 2001, 3, 3313; (b) P.-A. Enquist, J. Lindh, P. Nilsson and M. Larhed, Green Chem., 2006, 8, 338; (c) K. S. Yoo, C. H. Yoon and K. W. Jung, J. Am. Chem. Soc., 2006, 128, 16384.
11. (a) E. Keinan, S. Kumar, V. Dangur and J. Vaya, J. Am. Chem. Soc., 1994, 116, 11151; (b) M. R. Netherton and G. C. Fu, Angew. Chem., Int. Ed., 2002, 41, 3910; (c) D. R. Chrisope, P. Beak and W. H. Saunders, Jr., J. Am. Chem. Soc., 1988, 110, 230; (d) J. M. Takacs, E. C. Lawson and F. Clement, J. Am. Chem. Soc., 1997, 119, 5956.

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Footnote

† Electronic supplementary information (ESI) available: Experimental details and characterization data. See DOI: 10.1039/b925590g

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