Palladium catalyzed Suzuki cross-coupling of benzyltrimethylammonium salts via C–N bond cleavage

Abstract

A palladium catalyzed Suzuki cross-coupling for construction of Csp³–Csp² bond via Csp³–N bond activation of benzyltrimethyl-ammonium salt is described. This reaction not only offered a highly efficient approach to diarylmethanes but also paved the way for the application of benzyltrimethylammonium salts in the palladium catalyzed cross coupling reactions.

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Palladium catalyzed cross-coupling reactions between various electrophiles and nucleophilic metal reagents are highly practical methodologies for C–C bond formation.¹ They are one of the significant accomplishments of last century's chemistry and their significance has been recognized by the 2010 Nobel Prize in Chemistry. Among these cross coupling reactions, the Suzuki reaction, the coupling between organoborane reagents and electrophiles, is the most popular one because of the inherent advantages of organoboron reagents, such as air- and moisture-stability, good functional group tolerance, low toxicity and wide availability. A variety of electrophiles such as aryl halides,² triflates,³ mesylates/tosylates,⁴ esters,⁵ ethers,⁶ and phosphates⁷ have been developed for this reaction. Very recently, the transition metal catalyzed Suzuki coupling reactions involving the C–N bonds cleavage have attracted much attentions.⁸ Quaternary ammonium salts⁹ are the most important C–N bond containing electrophiles due to their wide availability and high reactivity. Macmillan and co-workers reported the first Ni catalyzed Suzuki cross-couplings of aryltrimethylammoniums.⁸ⁱ Watson extended this concept to benzyltrimethyl ammoniums and realized the stereospecific preparation of enantioenriched diarylethanes.^8j However, both cases involved the using of air and moisture sensitive Ni catalysts which limited their practical application. Compared with Ni catalyzed reactions carried out under inert atmosphere, palladium catalyzed coupling reactions are relatively easy to handle. However, the palladium catalyzed cross-coupling reactions involving C–N bond cleavage of quaternary ammonium salts remained rare. Recent studies demonstrated that palladium could be used as valid catalyst for cross-coupling reaction of quaternary ammonium salts. Wang and co-workers reported a palladium catalyzed C–H arylation of oxazoles with aryltrimethyl-ammonium salts.¹⁰ Reeves developed the palladium catalyzed cross-coupling between aryltrimethyl-ammonium salts and Grignard reagents.¹¹ However, palladium catalyzed Suzuki cross-coupling of quaternary ammonium salts is still kept untouched. In addition, considering the diversity of palladium catalyzed organic transformations, establishment of robust palladium catalyst systems for activating the C–N bond of quaternary ammonium salts would be valuable for exploring their application in organic synthesis. In such context, we herein reported the first palladium catalyzed Suzuki coupling with benzyltrimethylammoniums as the electrophile partner.

Diarylmethane derivatives have been widely used in pharmaceuticals and materials (Fig. 1).¹² Very recently, Rhee disclosed that the synthesis of diarylmethanes could be accomplished by palladium catalyzed Suzuki cross-coupling of N,N-ditosylbenzylamines¹³via C–N bond activation. We envisioned that palladium catalyzed Suzuki cross-coupling of benzylammonium salts with aryl boronic acids would be an effective approach to diarylmethanes. It is initiated by investigating the crossing coupling of 4-cyanophenyl boronic acid with benzylammonium salt 1a, which is readily prepared quantitatively via methylation of 4-cyano-N,N-dimethylbenzylamine. As shown in Table 1, the reaction is sensitive to ligand. Only the monodentate PPh₃ ligand afforded moderate yield of target diarylmethane accompanied by significant amount of homo coupling product of boronic acid when PdCl₂ was used as the catalyst. Although further screening of palladium catalysts did not offer any improvement, a dramatic solvent affect was observed (Table 1, entries 13–18). In particularly, homo coupling of boronic acid, the notorious issue of Suzuki cross-coupling, could be suppressed significantly by using ethanol as the solvent. We were delighted to observe that the homo coupling could be suppressed completely when more ethanol was used (Table 1, entry 19). In turn, the yield of cross coupling product was increased up to quantitative. The similar reaction efficiencies were observed when potassium phenyltrifluoroborate and phenylboronic acid pinacol ester were used as the boron reagent (Table 1, entry 20 & 21).

Fig. 1 Drugs containing diarylmethane motif.

Table 1 Optimization of reaction conditions^a

Entry	Catalyst (3 mol%)	Ligand (10 mol%)	Solvent	Yield^b (%)
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (3 mol%), ligand (10 mol%) and Na2CO3 (2 equiv.) in solvent (1 mL) at 100 °C. Mixture: toluene : DMSO = 9 : 1. b GC yield, isolated yield was indicated parentheses. c EtOH (3 mL). d Potassium phenyltrifluoroborate was used in place of boronic acid. e Phenylboronic acid pinacol ester as the boron reagent.
1	PdCl2	—	Mixture	—
2	PdCl2	dppf	Mixture	—
3	PdCl2	dppp	Mixture	—
4	PdCl2	Xantphos	Mixture	Trace
5	PdCl2	PPh3	Mixture	67(65)
6	Pd(acac)2	PPh3	Mixture	65
7	Pd2(dba)3	PPh3	Mixture	63
8	Pd(TFA)2	PPh3	Mixture	57
9	PdCl2(PPh3)2	PPh3	Mixture	55
10	Pd(PPh3)4	PPh3	Mixture	54(50)
11	PdCl2(dppf)2	PPh3	Mixture	50
12	Pd(OAc)2	PPh3	Mixture	20
13	PdCl2	PPh3	PhMe	34
14	PdCl2	PPh3	DMSO	18
15	PdCl2	PPh3	DMF	54
16	PdCl2	PPh3	CH3CN	43
17	PdCl2	PPh3	THF	32
18	PdCl2	PPh3	EtOH	75
19^c	PdCl2	PPh3	EtOH	99(98)
20^d	PdCl2	PPh3	EtOH	97
21^e	PdCl2	PPh3	EtOH	96

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With the optimized reaction conditions in hand, we next set out to evaluate the generality of benzylammonium salts with 4-cyanophenyl boronic acid as a model substrate. As shown in Scheme 1, a broad substrate scope of benzylammonium salts was observed. It seems that the electronic effect and the steric effect of the substituents on the benzylammonium salts have little effect on the reaction efficiency. No matter electron-donating (3b–f) or -withdrawing (3g–j) groups on the phenyl ring of benzylammonium salts, good to excellent yields were obtained. The ortho methyl substituent could be tolerated (3b). Notably, the C–N bond could be selectively cleaved in the presence of ether (3e & 3f), fluoro (3g) and chloro (3h) groups albeit bromo and iodo-substituted benzylammonium salts did not offer the target cross coupling products.

Scheme 1 Palladium-catalyzed reaction of 4-cyanophenyl boronic acid with various benzylammonium salts. Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), PdCl₂ (3 mol%), PPh₃ (10 mol%) and Na₂CO₃ (0.4 mmol) in ethanol (3 mL) at 100 °C for 18–24 h. Isolated yields were given.

The substrate scope of boronic acids had also been investigated and the results are summarized in Scheme 2. Moderate electron-withdrawing and -donating groups were tolerated while their stronger congeners cause slight decrease in yield. Even the steric demanding 2,6-dimethyl substituents were tolerated (3aa). It is noted that a series of functional groups such as carbonate (3ag), aldehyde (3ai) and ester (3aj) were compatible. In addition, diarylmethanes containing heterocycles such as pyridine (3ak), furan (3al) and thiophene (3am) could also be prepared by this method. Styrylboronic acid also proceeded smoothly to furnish the cross coupling product in excellent yield (3ao). No evidence of Heck coupling was observed when (4-vinylphenyl)boronic acid was employed as the substrate (3an). Interestingly, for some cases (3a–d, 3f–i), we could get the same products with that of Scheme 1 from different set of starting materials by employing the standard reaction conditions. This advantage will be more prominent when one of the starting material is more expensive or not available.

Scheme 2 Palladium-catalyzed reaction of 1-(4-cyanophenyl)-N,N,N-trimethylmethanaminium trifluoromethanesulfonate reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), PdCl₂ (3 mol%), PPh₃ (10 mol%) and Na₂CO₃ (0.4 mmol) in ethanol (3 mL) at 100 °C for 18–24 h. Isolated yields were given.

A significant functional group orthogonality to chloride, fluoride, ether and amine for benzylammonium salts as well as boronic acids was observed in this methodology. For example, the chloro group was kept intact in both cases (3h) and thus affording an opportunity for further functionalization. This feature was exemplified by sequential Suzuki-cross couplings (Scheme 3).

Scheme 3 Sequential Suzuki crossing couplings.

A plausible reaction mechanism was proposed in Scheme 4. The oxidative addition of Pd(0) A formed in situ, with benzyltrimethylammonium salt 1 produced C–Pd complex B with the release of trimethylamine. Followed by a transmetalation with boronic acid, the palladium complex B afforded a new complex D, which upon reductive elimination furnished the cross coupling product 3.

Scheme 4 Proposed reaction mechanism.

In summary, we have developed the first palladium catalyzed Suzuki cross-coupling reaction of quaternary ammonium salts. This reaction represented the first example of palladium catalyzed Csp³–Csp² coupling of benzyltrimethylammonium salts via C–N bond activation. It not only offered an effective synthetic strategy to diarylmethane derivatives but also paved the way for the unprecedented palladium catalyzed cross-coupling of benzyltrimethyl ammonium salts. Further application of the catalyst system to other palladium catalyzed cross-coupling reactions of benzyltrimethyl ammonium salts are undergoing in our laboratory and the results will be reported in due course.

Acknowledgements

This work is supported by the National Natural Science Foundation of China (21462023, 21562026) and the Natural Science Foundation of Jiangxi Province (20143ACB20007, 20161BAB203085).

References

1. C. C. C. Johansson Seechurn, M. O. Kitching, T. J. Colacot and V. Snieckus, Angew. Chem., Int. Ed., 2012, 51, 5062.
2. (a) X. Bei, H. W. Turner, W. H. Weinberg, A. S. Guram and J. L. Petersen, J. Org. Chem., 1999, 64, 6797; (b) J. P. Wolfe, R. A. Singer, B. H. Yang and S. L. Buchwald, J. Am. Chem. Soc., 1999, 121, 9550; (c) G. A. Grasa, A. C. Hillier and S. P. Nolan, Org. Lett., 2001, 3, 1077; (d) N. E. Leadbeater and M. Marco, Org. Lett., 2002, 4, 2973; (e) G. A. Molander and B. Biolatto, Org. Lett., 2002, 4, 1867; (f) O. Navarro, R. A. Kelly and S. P. Nolan, J. Am. Chem. Soc., 2003, 125, 16194; (g) N. Marion, O. Navarro, J. Mei, E. D. Stevens, N. M. Scott and S. P. Nolan, J. Am. Chem. Soc., 2006, 128, 4101; (h) K. Billingsley and S. L. Buchwald, J. Am. Chem. Soc., 2007, 129, 3358; (i) R. Martin and S. L. Buchwald, Acc. Chem. Res., 2008, 41, 1461.
3. A. F. Littke, C. Dai and G. C. Fu, J. Am. Chem. Soc., 2000, 122, 4020.
4. (a) M. K. Lakshman, P. F. Thomson, M. A. Nuqui, J. H. Hilmer, N. Sevova and B. Boggess, Org. Lett., 2002, 4, 1479; (b) H. N. Nguyen, X. Huang and S. L. Buchwald, J. Am. Chem. Soc., 2003, 125, 11818; (c) K. W. Quasdorf, M. Riener, K. V. Petrova and N. K. Garg, J. Am. Chem. Soc., 2009, 131, 17748.
5. (a) D. Bouyssi, V. Gerusz and G. Balme, Eur. J. Org. Chem., 2002, 2445; (b) H. Tatamidani, F. Kakiuchi and N. Chatani, Org. Lett., 2004, 6, 3597; (c) B.-T. Guan, Y. Wang, B.-J. Li, D.-G. Yu and Z.-J. Shi, J. Am. Chem. Soc., 2008, 130, 14468.
6. (a) M. Tobisu, T. Shimasaki and N. Chatani, Angew. Chem., Int. Ed., 2008, 47, 4866; (b) B. M. Rosen, K. W. Quasdorf, D. A. Wilson, N. Zhang, A.-M. Resmerita, N. K. Garg and V. Percec, Chem. Rev., 2011, 111, 1346; (c) M. Tobisu and N. Chatani, Acc. Chem. Res., 2015, 48, 1717; (d) D.-G. Yu, B.-J. Li and Z.-J. Shi, Acc. Chem. Res., 2010, 43, 1486; (e) D.-G. Yu, B.-J. Li, S.-F. Zheng, B.-T. Guan, B.-Q. Wang and Z.-J. Shi, Angew. Chem., Int. Ed., 2010, 49, 4566; (f) K. Huang, D.-G. Yu, S.-F. Zheng, Z.-H. Wu and Z.-J. Shi, Chem.–Eur. J., 2011, 17, 786.
7. (a) U. S. Larsen, L. Martiny and M. Begtrup, Tetrahedron Lett., 2005, 46, 4261; (b) L. Pedzisa, I. W. Vaughn and R. Pongdee, Tetrahedron Lett., 2008, 49, 4142.
8. (a) K. Ouyang, W. Hao, W. X. Zhang and Z. Xi, Chem. Rev., 2015, 115, 12045; (b) T. Saeki, E.-C. Son and K. Tamao, Org. Lett., 2004, 6, 617; (c) J. Liu and M. J. Robins, Org. Lett., 2004, 6, 3421; (d) K. R. Buszek and N. Brown, Org. Lett., 2007, 9, 707; (e) Z. Peng, G. Hu, H. Qiao, P. Xu, Y. Gao and Y. Zhao, J. Org. Chem., 2014, 79, 2733; (f) Y. Zhao and V. Snieckus, Org. Lett., 2014, 16, 3200; (g) J. Liu and M. J. Robins, Org. Lett., 2005, 7, 1149; (h) M. L. Duda and F. E. Michael, J. Am. Chem. Soc., 2013, 135, 18347; (i) S. B. Blakey and D. W. C. MacMillan, J. Am. Chem. Soc., 2003, 125, 6046; (j) P. Maity, D. M. Shacklady-McAtee, G. P. A. Yap, E. R. Sirianni and M. P. Watson, J. Am. Chem. Soc., 2013, 135, 280; (k) D. M. Shacklady-McAtee, K. M. Roberts, C. H. Basch, Y. G. Song and M. P. Watson, Tetrahedron, 2014, 70, 4257; (l) S. Ueno, N. Chatani and F. Kakiuchi, J. Am. Chem. Soc., 2007, 129, 6098; (m) T. Koreeda, T. Kochi and F. Kakiuchi, J. Am. Chem. Soc., 2009, 131, 7238; (n) M.-K. Zhu, J.-F. Zhao and T.-P. Loh, Org. Lett., 2011, 13, 6308; (o) N. A. Weires, E. L. Baker and N. K. Garg, Nat. Chem., 2016, 8, 75; (p) P. Anbarasan, H. Neumann and M. Beller, Angew. Chem., Int. Ed., 2011, 50, 519; (q) T. N. Uehara, J. Yamaguchi and K. Itami, Asian J. Org. Chem., 2013, 2, 938; (r) M.-B. Li, Y. Wang and S.-K. Tian, Angew. Chem., Int. Ed., 2012, 51, 2968; (s) M. Tobisu, K. Nakamura and N. Chatani, J. Am. Chem. Soc., 2014, 136, 5587.
9. (a) E. Wenkert, A. L. Han and C. J. Jenny, Chem. Commun., 1988, 975; (b) L. G. Xie and Z. X. Wang, Angew. Chem., Int. Ed. Engl., 2011, 50, 4901; (c) W. J. Guo and Z. X. Wang, Tetrahedron, 2013, 69, 9580; (d) X. Yang and Z.-X. Wang, Organometallics, 2014, 33, 5863; (e) X. Q. Zhang and Z. X. Wang, Org. Biomol. Chem., 2014, 12, 1448; (f) J. Hu, H. Sun, W. Cai, X. Pu, Y. Zhang and Z. Shi, J. Org. Chem., 2016, 81, 14; (g) H. Zhang, S. Hagihara and K. Itami, Chem.–Eur. J., 2015, 21, 16796; (h) T. Moragas, M. Gaydou and R. Martin, Angew. Chem., Int. Ed., 2016, 55, 5053; (i) Y. Z. Lei, R. Zhang, L. J. Wu, Q. Wu, H. Mei and G. X. Li, Appl. Organomet. Chem., 2014, 28, 310; (j) H. J. Davis, M. T. Mihai and R. J. Phipps, J. Am. Chem. Soc., 2016, 138, 12759; (k) X.-Q. Zhang and Z.-X. Wang, J. Org. Chem., 2012, 77, 3658; (l) D. Wu, J.-L. Tao and Z.-X. Wang, Org. Chem. Front., 2015, 2, 265.
10. F. Zhu, J. L. Tao and Z. X. Wang, Org. Lett., 2015, 17, 4926.
11. J. T. Reeves, D. R. Fandrick, Z. Tan, J. J. Song, H. Lee, N. K. Yee and C. H. Senanayake, Org. Lett., 2010, 12, 4388.
12. (a) A. V. Cheltsov, M. Aoyagi, A. Aleshin, E. C.-W. Yu, T. Gilliland, D. Zhai, A. A. Bobkov, J. C. Reed, R. C. Liddington and R. Abagyan, J. Med. Chem., 2010, 53, 3899; (b) S. Messaoudi, A. Hamze, O. Provot, B. Tréguier, J. Rodrigo De Losada, J. Bignon, J.-M. Liu, J. Wdzieczak-Bakala, S. Thoret, J. Dubois, J.-D. Brion and M. Alami, ChemMedChem, 2011, 6, 488; (c) B. Liegault, J.-L. Renaud and C. Bruneau, Chem. Soc. Rev., 2008, 37, 290.
13. S. Yoon, M. C. Hong and H. Rhee, J. Org. Chem., 2014, 79, 4206.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c7ra02549a

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