Sterically demanding aryl–alkyl Suzuki–Miyaura coupling

Abstract

Efficient sterically demanding aryl–alkyl Suzuki–Miyaura coupling between di-ortho-substituted aryl halides and secondary alkylboronic acids has been achieved with a Pd-AntPhos catalyst that has shown high reactivity and a broad substrate scope with unprecedented steric hindrance. The methodology has facilitated the synthesis of molecular gears such as by cross-coupling.

---

Despite the recent advances in the area of aryl–aryl Suzuki–Miyaura coupling reactions,^1,2 the development of efficient aryl–alkyl cross-couplings is more challenging and has been relatively unexplored.³ In contrast to the sp²-hybridized arylboronic acids, the sp³-hybridized alkylboronic acids are relatively bulkier and slower for transmetallation. Moreover, the presence of β-hydrogen in alkylboronic acid allows the β-hydride elimination pathway and facilitates the reduction of aryl halides during cross-coupling (Fig. 1). The formation of the β-hydride elimination–reduction side-product increases significantly with growing steric bulk on the substrates. The development of sterically demanding aryl–alkyl Suzuki–Miyaura coupling remains a significant challenge, particularly of di-ortho-substituted aryl halide substrates. Herein we report an efficient method for Suzuki–Miyaura coupling between di-ortho-substituted aryl halides and secondary alkylboronic acids, and a cross-coupling product was formed for the first time between di-ortho-secondary-alkyl aryl bromides and cyclic alkylboronic acids. The methodology has facilitated the synthesis of molecular gears such as hexaalkylbenzenes by cross-coupling.

Fig. 1 Pd-catalyzed sterically demanding aryl–alkyl coupling and the β-hydride elimination–reduction side pathway.

The steric and electronic properties of the phosphorus ligands have a significant impact on the reactivity and outcome of palladium-catalyzed cross-coupling reactions.⁴ During our study on sterically hindered aryl–aryl Suzuki–Miyaura coupling,⁵ we observed the excellent reactivity of ligand 1 (BI-DIME) and ligand 2 (AntPhos)⁶ for tetra-ortho-substituted biaryl coupling. In particular, an interesting coordination between the Pd center and the anthracenyl moiety of AntPhos was revealed in the X-ray structure of the Pd(0)-AntPhos complex. Although there is no information on whether such coordination still exists during the catalytic cycle of cross-coupling, the coordination ability of the rigid anthracenyl moiety should make the formation of G unfavorable (Fig. 1) during the aryl–alkyl cross-coupling and thus inhibit the β-hydride elimination–reduction pathway. We thus envisioned that AntPhos would be advantageous for sterically demanding aryl–alkyl Suzuki–Miyaura coupling and further broaden the synthetic utility of Suzuki–Miyaura coupling (Fig. 2).

Fig. 2 Ligands for sterically demanding aryl–alkyl cross-couplings.

While most known palladium catalysts are applied only for the coupling between mono-ortho-substituted aryl halides and secondary alkylboronic acids or the coupling between di-ortho-substituted aryl halides and primary alkylboronic acids, only two examples⁷ are available for the coupling between di-ortho-substituted aryl halides and secondary alkylboronic acids or zinc reagents with a limited substrate scope. We applied ligands 1 and 2 for the Suzuki–Miyaura coupling between 2,4,6-triisopropylphenyl bromide and cyclohexylboronic acid, an extremely sterically demanding and unexplored cross-coupling system. The reactions were performed under nitrogen at 110 °C in toluene for 12 h at 1 mol% palladium loading. To our delight, the desired coupling product was isolated in 31% yield with BI-DIME (1) as the ligand along with the reduction side-product 7 (Table 1, entry 1). The yield increased significantly when AntPhos (2) was applied as the ligand (entries 2). Elevation of the reaction temperature by using xylenes as the solvent provided 6 in 63% isolated yield. To the best of our knowledge, this is the most sterically demanding aryl–alkyl cross-coupling product to date. To investigate whether other commercially available ligands are also applicable, a series of mono- or bis-phosphorus ligands were also employed for comparison (entries 4–12). Except that S-Phos provided a low yield (3%, entry 8) of 6, no other ligands were applicable for this system, indicating the uniqueness and power of AntPhos for the success of this reaction.

Table 1 Cross-coupling between 2-bromo-1,3,5-trimethylbenzene and cyclohexylboronic acid

Entries^a	Ligand	Conv.^b (%)	Yield of 6^c (%)	7 (%)
a The reactions were performed in toluene under nitrogen at 110 °C for 24 h in the presence of 1 mol% Pd(OAc)2 and 2 mol% ligand with K3PO4 as the base unless otherwise specified. b Conversions were analyzed by reversed phase HPLC on a C-18 column. c Isolated yields. d The reaction was run in xylenes at 140 °C for 12 h.
1	1 (BI-DIME)	100	31	69
2	2 (AntPhos)	100	58	42
3^d	2	100	63	37
4	DPPF	54	0	54
5	DPPE	100	0	98
6	DPPP	100	0	97
7	DPPB	100	0	98
8	S-Phos	100	3	97
9	X-Phos	46	0	46
10	Ru-Phos	52	0	52
11	PCy3	100	0	97
12	PPh3	83	0	83

---

We then looked into the substrate scope of this sterically hindered cross-coupling reaction. As can be seen in Table 2, a series of di-ortho-substituted aryl bromides were successfully coupled with 3-, 4-, 5-, and 6-membered cyclic alkyl boronic acids with a Pd-AntPhos catalyst to form the corresponding coupling products in good to excellent yields (70–99%). In general, the yields followed the trend of the ring size of the cyclic alkyl boronic acids: 3 > 4 > 5 > 6 (entries 12, 14, 16 vs.Table 1, entry 3). High yields were achieved on reactions with cyclopropyl boronic acids (entries 15 and 16 due to its relatively small size as well as its inability to undergo the β-hydride elimination pathway). The β-hydride elimination–reduction side-product formation became more severe with the increase of the ring size, as indicated by diminished coupling yields. The reactions proceeded well with di-ortho-methyl, ethyl, or isopropyl substituents (entries 1, 5, 6, and 13–16). 9-Anthracenyl, 2-methylnaphthyl bromide, and 2-methoxynaphthyl bromide were also applicable (entries 2–4 and 7–9). Functionalities such as methoxy, nitro, and cyano groups were well tolerable (entries 9–11). When isopropylboronic acid was employed to couple with 2-bromo-1,3,5-trimethylbenzene, the major product was unfortunately the n-propyl substituted arene (entry 17) derived from isomerization-coupling. No formation of tert-butyl substituted arene was observed when tert-butylboronic acid was used as the starting material.

Table 2 Sterically hindered aryl–alkyl cross-couplings

Entry^a	Aryl halide	Boronic acid	Product	Yield^b (%)
a Unless otherwise specified, the reactions were carried in toluene under nitrogen at 110 °C for 24 h in the presence of 1 mol% Pd(OAc)2 and 2 mol% AntPhos with K3PO4 as the base. b Isolated yields. c The reactions were run in xylenes at 140 °C for 12 h. d The major coupling product is n-propyl arene (82%), along with isopropyl arene (6%) and the reduction side-product (12%).
1				92
2^c				74
3				82
4				70
5^c				80
6				93
7				80
8				87
9				75
10				79
11^c				79
12				81
13				92
14				90
15				99
16				99
17^d				6/82

---

In order to gain kinetic insight into this cross-coupling methodology, the coupling of 2-bromo-5-methoxy-1,3-dimethylbenzene (8) and cyclohexylboronic acid (5) was performed in xylenes in the presence of 1 mol% Pd(OAc)₂ and 2 mol% AntPhos, monitored by ReactIR. As shown in Scheme 1, the amount of bromide 8 and the coupling product 9 was easily traced by their IR absorbance at 1163 cm⁻¹ and 1149 cm⁻¹ (symmetrical C–O–C bond stretching), respectively. The reaction proceeded rapidly when the reaction temperature was elevated over 80 °C and bromide 8 was completely consumed in only 25 min at 130 °C, demonstrating the high reactivity of the Pd-AntPhos catalyst for this reaction. The desired product 9 was isolated in 82% yield, along with 15% reduction side-product.

Scheme 1 Reaction profile of the cross-coupling between 2-bromo-5-methoxy-1,3-dimethylbenzene (8) and cyclohexylboronic acid (5) by ReactIR: (a) 3D-FTIR profiles. (b) Component profiles.

Hexaalkylbenzenes are molecular gears⁸ that have unique static and dynamic behaviors due to restricted rotation of each substituent on the benzene ring. These compounds are traditionally accessed by trimerization of disubstituted alkynes,⁹ and a few reports are available on their syntheses by metal-catalyzed cross-coupling.¹⁰ We believe that this methodology provides a facile and versatile method to synthesise these interesting compounds. Thus, the coupling of 1,3,5-tribromo-2,4,6-tricyclopentylbenzene (10) with cyclopropylboronic acid provided the coupling product 11 in 90% yield (Scheme 2). In a similar manner, 1,3,5-tricyclopentyl-2,4,6-trimethylbenzene (13) can be synthesized from 1,3,5-tribromo-2,4,6-trimethylbenzene (12) and cyclopentaneboronic acid in 87% yield by using this methodology. Such structures, which are difficult to access by cyclotrimerization of alkynes, could provide interesting physical organic properties.

Scheme 2 Synthesis of “molecular gears” by Suzuki–Miyaura coupling.

In summary, efficient sterically demanding aryl–alkyl Suzuki–Miyaura couplings between di-ortho-substituted aryl halides and secondary alkylboronic acids have been achieved with a Pd-AntPhos catalyst that has shown a high reactivity and a broad substrate scope with unprecedented steric hindrance. The unique structure of AntPhos plays a major role in its reactivity and allows overcoming the β-hydride elimination–reduction side pathway. The methodology has been applied successfully for efficient synthesis of molecular gears such as hexaalkylbenzenes by cross-coupling. A further study on sterically demanding aryl–alkyl Suzuki–Miyaura coupling and the application of the Pd-AntPhos catalyst in broadening the scope of metal-catalyzed cross-coupling is currently ongoing in our laboratory.

Notes and references

1. Selected reviews: (a) A. Suzuki, J. Organomet. Chem., 1999, 576, 147; (b) N. Miyaura, Top. Curr. Chem., 2002, 219, 11; (c) N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457; (d) N. Miyaura, Top. Curr. Chem., 2002, 219, 11; (e) J. Hassan, M. Sévignon, C. Gozzi, E. Schulz and M. Lemaire, Chem. Rev., 2002, 102, 1359; (f) S. Kotha, K. Lahiri and D. Kashinath, Tetrahedron, 2002, 58, 9633; (g) A. F. Littke and G. C. Fu, Angew. Chem., Int. Ed., 2002, 41, 4176; (h) F. Bellina, A. Carpita and R. Rossi, Synthesis, 2004, 2419; (i) K. C. Nicolaou, P. G. Bulger and D. Sarlah, Angew. Chem., Int. Ed., 2005, 44, 4442; (j) F. Alonso, I. P. Beletskaya and M. Yus, Tetrahedron, 2008, 64, 3047; (k) Metal-Catalyzed Cross-Coupling Reactions, ed. A. de Meijere and F. Diederich, Wiley-VCH, Weinheim, 2004, vol. 2; (l) Modern Arylation Methods, ed. L. Ackermann, Wiley-VCH, Weinheim, 2009; (m) C. C. C. J. Seechurn, M. O. Kitching, T. J. Colacot and V. Snieckus, Angew. Chem., Int. Ed., 2012, 51, 5062; (n) R. J. Lundgren and M. Stradiotto, Chem.–Eur. J., 2012, 18, 9758; (o) S. M. Wong, C. M. So and F. Y. Kwong, Synlett, 2012, 1132.
2. Recent papers on aryl–aryl Suzuki–Miyaura couplings: (a) W. Shen, Tetrahedron Lett., 1997, 38, 5575; (b) A. F. Littke and G. C. Fu, Angew. Chem., Int. Ed., 1998, 37, 3387; (c) A. F. Littke, C. Dai and G. C. Fu, J. Am. Chem. Soc., 2000, 122, 4020; (d) A. Zapf, A. Ehrentraut and M. Beller, Angew. Chem., Int. Ed., 2000, 39, 4153; (e) J. P. Stambuli, R. Kuwano and J. F. Hartwig, Angew. Chem., Int. Ed., 2002, 41, 4746; (f) C. A. Fleckenstein and H. Plenio, Chem.–Eur. J., 2007, 13, 2701; (g) C. A. Fleckenstein and H. Plenio, J. Org. Chem., 2008, 73, 3236; (h) C. M. So, C. P. Lau and F. Y. Kwong, Angew. Chem., Int. Ed., 2008, 47, 8059; (i) C. M. So, W. K. Chow, P. Y. Choy, C. P. Lau and F. Y. Kwong, Chem.–Eur. J., 2010, 16, 7996; (j) S. C. To and F. Y. Kwong, Chem. Commun., 2011, 47, 5079; (k) W. Tang, N. D. Patel, G. Xu, X. Xu, J. Savoie, S. Ma, M.-H. Hao, S. Keshipeddy, A. G. Capacci, X. Wei, Y. Zhang, J. Gao, W. Li, S. Rodriguez, B. Lu, N. Yee and C. H. Senanayake, Org. Lett., 2012, 14, 2258; (l) G. Xu, W. Fu, G. Liu, C. H. Senanayake and W. Tang, J. Am. Chem. Soc., 2014, 136, 570.
3. For a recent review: (a) R. Jana, T. P. Pathak and M. S. Sigman, Chem. Rev., 2011, 111, 1417. Recent papers on aryl–alkyl Suzuki–Miyaura couplings: (b) N. Kataoka, Q. Shelby, J. P. Stambuli and J. F. Hartwig, J. Org. Chem., 2002, 67, 5553; (c) A. van den Hoogenband, J. H. M. Lange, J. W. Terpstra, M. Koch, G. M. Visser, M. Visser, T. J. Korstanje and J. T. B. H. Jastrzebski, Tetrahedron Lett., 2008, 49, 4122; (d) S. Imao, B. W. Glasspoole, V. S. Laberge and C. M. Crudden, J. Am. Chem. Soc., 2009, 131, 5024; (e) T. Ohmura, T. Awano and M. Suginome, Chem. Lett., 2009, 38, 664; (f) T. Ohmura, T. Awano and M. Suginome, J. Am. Chem. Soc., 2010, 132, 13191; (g) D. L. Sandrock, L. Jean-Gérard, C.-y. Chen, S. D. Dreher and G. A. Molander, J. Am. Chem. Soc., 2010, 132, 17108; (h) J. C. H. Lee, R. McDonald and D. G. Hall, Nat. Chem., 2011, 3, 894; (i) T. Awano, T. Ohmura and M. Suginome, J. Am. Chem. Soc., 2011, 133, 20738; (j) G. A. Molander and S. R. Wisniewski, J. Am. Chem. Soc., 2012, 134, 16856.
4. (a) G. Liu, G. Xu, R. Luo and W. Tang, Synlett, 2013, 2465; (b) R. Martin and S. L. Buchwald, Acc. Chem. Res., 2008, 41, 1461.
5. (a) W. Tang, A. G. Capacci, X. Wei, W. Li, A. White, N. D. Patel, J. Savoie, J. J. Gao, S. Rodriguez, B. Qu, N. Haddad, B. Z. Lu, D. Krishnamurthy, N. K. Yee and C. H. Senanayake, Angew. Chem., Int. Ed., 2010, 49, 5879; (b) Q. Zhao, C. Li, C. H. Senanayake and W. Tang, Chem.–Eur. J., 2013, 19, 2261.
6. For the application of AntPhos for sterically demanding Miyaura borylation, see: W. Tang, S. Keshipeddy, Y. Zhang, X. Wei, J. Savoie, N. D. Patel, N. K. Yee and C. H. Senanayake, Org. Lett., 2011, 13, 1366.
7. (a) S. D. Dreher, P. G. Dormer, D. L. Sandrock and G. A. Molander, J. Am. Chem. Soc., 2008, 130, 9257; (b) C. Han and S. L. Buchwald, J. Am. Chem. Soc., 2009, 131, 7532.
8. (a) J. Siegel, A. Gutierrez, W. B. Schweizer, O. Ermer and K. Mislow, J. Am. Chem. Soc., 1986, 108, 1569; (b) H. Iwamura and K. Mislow, Acc. Chem. Res., 1988, 21, 175.
9. (a) S. Kotha, E. Brahmachary and K. Lahiri, Eur. J. Org. Chem., 2005, 4741; (b) F. Fabris, L. Zambrini, E. Rosso and O. De Lucchi, Eur. J. Org. Chem., 2004, 3313.
10. Y. Yu, A. D. Bond, P. W. Leonard, U. J. Lorenz, T. V. Timofeeva, K. P. C. Vollhardt, G. D. Whitener and A. A. Yakovenko, Chem. Commun., 2006, 2572.

---

Footnote

† Electronic supplementary information (ESI) available: Detailed procedures of cross-coupling reactions, characterization data, and spectra. See DOI: 10.1039/c4qo00024b

---