Base-free Ni-catalyzed Suzuki-type cross-coupling reactions of epoxides with boronic acids

Abstract

A Ni-catalyzed Suzuki-type cross-coupling of boronic acids with epoxides without an exogenous base and with broad substrate scope has been developed. The product selectivity of styrenyl epoxides is different from that of previous work. This methodology uses readily available starting materials to access a range of substituted alcohols, which are valuable feedstock chemicals.

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Transition metal-catalyzed Suzuki–Miyaura cross-couplings of organoboron compounds with organic electrophiles are among the most vital C–C bond-forming reactions in organic and medicinal synthesis. These transformations generally require the addition of a stoichiometric amount of exogenous base.¹ This requirement restricts the functional-group compatibility of the reaction.² Epoxides are crucial electrophiles in organic synthesis because they are readily available and highly useful for ring-opening reactions with various carbon-based nucleophiles.³ The alcohol products obtained from the ring-opening reactions of epoxides are valuable feedstock chemicals that play vital roles in synthetic and medicinal chemistry. Over the past few decades, various ring-opening reactions of epoxides with carbon-based nucleophiles, such as strongly nucleophilic organolithium reagents and Grignard reagents, have been investigated.^4,5 Organoboron compounds are usually readily available and have a broad functional-group tolerance.⁶ In this context, Doyle reported nickel-catalyzed cross-coupling of styrenyl epoxides with arylboronic acids and obtained rearrangement products (Scheme 1a).⁷ Unfortunately, the use of the strong base K₃PO₄ was incompatible with many functional groups in this reaction. Recently, Fu realized the Cu-catalyzed cross-coupling of epoxides with organoboron compounds (Scheme 1b).⁸ The 1,2-disubstituted epoxides and alkenyl-boron are incompatible substrates. Unfortunately, using the strong base LiO^tBu also proved to be incompatible with many polar functional groups.

Scheme 1 Suzuki-type cross-coupling reactions of epoxides.

Recently, nickel-catalyzed cross-coupling reactions have attracted great attention because of the low cost of nickel catalysts, and their excellent functional-group tolerance.⁹ To date, nickel-catalyzed Suzuki-type cross-coupling reactions of ubiquitous alkyl epoxides has not been reported. In this communication, we report an example of a Ni-catalyzed Suzuki-type cross-coupling of boronic acids with epoxides (Scheme 1c). In addition to monosubstituted and 1,1-disubstituted epoxides, 1,2-disubstituted epoxides also gave products with good reaction yields. Alkenyl boronic acids also undergo coupling to generate homoallylic alcohols. The selectivity of aromatic epoxides is different from Doyle's and Fu's work. The selectivity of the ring-opening reaction is excellent. This reaction does not use an exogenous base and has better substrate compatibility. This methodology utilizes readily available and inexpensive epoxides, and boronic acids to access a diverse array of synthetically valuable alcohols, which are valuable feedstock chemicals in synthetic and medicinal chemistry.

We began our study by selecting phenylboronic acid (1a) and cyclohexene oxide (2a) as the model reaction substrates (Table 1). On the basis of recent studies on the cross-coupling reaction of epoxides with organoboron compounds, we first examined analogous catalytic conditions with an exogenous base for the ring-opening coupling. Unfortunately, only a trace amount of the coupling product was observed (entry 1). Next, we tested other bases, such as K₃PO₄, K₂CO₃, LiOMe, NaOAc, and Et₃N, to see whether they could accelerate the reaction. However, the reaction yield was still very low (see ESI†). We then used other solvents instead of N,N-dimethylacetamide (entry 5). However, the yields of the desired product remained very poor. Unexpectedly, under the same reaction conditions, we removed the exogenous base and obtained a moderate reaction yield (entry 6 vs. entry 1). In the absence of an exogenous base, we found that alcoholic solvents gave better reaction yields. Finally, we obtained the optimal reaction conditions after screening a series of alcoholic solvents (entry 9). Using other nickel catalysts, such as NiI₂ and NiCl₂(PPh₃)₂, significantly reduced the reaction yield (entry 10 and 11) compared to that of entry 9. Switching the ligand to 1,10-phenanthroline also decreased the reaction yield (entries 12). A control experiment indicated that the reaction completely shut down without the addition of a catalyst (entry 13). The use of phenylboronic acid ester instead of phenylboronic acid generated only a trace amount of the desired product (see ESI†).

Table 1 Optimization of the reaction conditions

Entry^a	Catalyst	Ligand	Base	Solvent	Yield% (d.r.)
a 1a (0.5 mmol), 2a (0.25 mmol), base (1.5 equiv.) in 0.8 mL solvent at 70 °C for 20 h. b No catalyst. The yield was determined by GC using Benzophenone as internal standard. The d.r. ratio was determined by GC.
1	NiBr2·diglyme	dtbpy	LiO^tBu	DMAc	Trace
2	NiBr2·diglyme	dtbpy	K3PO4	DMAc	2
3	NiBr2·diglyme	dtbpy	K2CO3	DMAc	19(7.5 : 1)
4	NiBr2·diglyme	dtbpy	LiOMe	DMAc	6(8 : 1)
5	NiBr2·diglyme	dtbpy	K2CO3	THF	16(7 : 1)
6	NiBr2·diglyme	dtbpy	—	DMAc	30(8 : 1)
7	NiBr2·diglyme	dtbpy	—	HO^tBu	47(9 : 1)
8	NiBr2·diglyme	dtbpy	—	^iPrOH	65(8.5 : 1)
9	NiBr 2 ·diglyme	dtbpy	—	EtOH	89(9 : 1)
10	NiI2	dtbpy	—	EtOH	29(8 : 1)
11	NiCl2(PPh3)2	dtbpy	—	EtOH	20(7 : 1)
12	NiBr2·diglyme	Phen	—	EtOH	25(8 : 1)
13^b	—	dtbpy	—	EtOH	0

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With optimized conditions in hand, we next evaluated the scope of the Suzuki-type cross-coupling of epoxides (Table 2). Many of the substituted boronic acids coupled with epoxides in moderate to good yields. Both electron-rich and electron-poor boronic acids afforded the desired products. Importantly, many functional groups are readily tolerated, including trifluoromethyl (3b, 3e), fluoride (3d), ester (3j), amide (3v, 3w), and ketal (3u). Even more reactive groups, such as aldehyde (3l), ketone (3h, 3i, 3o), were compatible in the reaction. These functional group is incompatible with Fu's method. Acyclic epoxides including monosubstituted, 1,1-disubstituted and 1,2-disubstituted epoxides also gave products with good reaction yields. Some functional groups, such as cyano (3n), ketone (3o, 3p), trifluoromethoxy (3q), are readily tolerated. Other cyclic epoxides (3t, 3u, 3v, 3w) can also participate in the coupling reaction. Benzofuran (3m) group can also be present in the reaction. The position of the substituent on the boronic acid does not affect the reaction. The configuration of the major isomer of 3g was determined by X-ray diffraction.

Table 2 Scope of the base-free Suzuki-type reaction of epoxides

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Transition metal-catalyzed Suzuki-type cross-coupling of alkenyl boron with alkyl epoxides has not been realized. The reaction can also be extended to alkenyl boronic acids. Alkenyl boronic acids underwent the reaction with a diverse array of substituted epoxides in high yields (Table 3). Therefore, the reaction can provide access to a diverse array of substituted homoallylic alcohols, which are valuable structural motifs in organic chemistry.

Table 3 Scope of alkenyl boron acid

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In the case of styrenyl epoxides, Doyle's work obtained rearrangement products,⁷ and Fu's work obtained a linear product.⁸ However, this work obtains the branched-chain products (Table 4). Moreover, the selectivity of this reaction is excellent; many of the substituted boronic acids coupled with styrenyl epoxides in good yields. Many functional groups are readily tolerated, including fluoride (5c), ketone (5d), cyano (5e), amide (5f), and chloride (5h). Alkenyl boronic acids underwent the reaction with styrenyl epoxides to give products in high yields. Even base-sensitive hydroxyl functional groups (5j) was compatible in the reaction. Therefore, this work complements the selectivity of the Suzuki-type reaction of styrenyl epoxides. The 1,1-disubstituted styrenyl epoxides, such as 2-methyl-2-phenyloxirane, cannot participate in this reaction.

Table 4 Scope of styrenyl epoxides

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Vinyl epoxide is a special type of epoxide, which is characterized by the conjugated reactivity of the epoxide and carbon–carbon double bond. Because of its unique structural features, vinyl epoxide can carry out S_N2 and S_N2′-type ring-opening/coupling reactions.¹⁰ We performed a reaction using alkenyl boronic acid with vinyl epoxide, which generated both the S_N2 and S_N2′-type products (Scheme 2). Therefore, this methodology can provide access to some special substituted homoallylic alcohols.

Scheme 2 Example of vinyl epoxide.

To demonstrate the scalability of the base-free Ni-catalyzed Suzuki-type cross-coupling of boronic acids with epoxides, we performed the reaction on a gram scale, which afforded the product in 85% yield (Scheme 3). Product 5a was efficiently transformed into 4-phenylisochromane through an Oxa-Pictet–Spengler reaction.

Scheme 3 A gram-scale reaction and derivatization of product.

The monoalkyl-substituted chiral epoxide reacted smoothly at the less-substituted carbon center under the standard reaction conditions and obtained the desired products with almost no loss of enantiomeric excess (Scheme 4).

Scheme 4 Example of chiral epoxide.

The mechanism of the reaction was investigated through several experiments. First, we observed the product in 61% yield when using iodohydrin instead of the epoxide and in the absence of sodium iodide. Using an epoxide starting material and in the absence of NaI, no production was observed. These results indicated that the epoxy group goes through a β-iodohydrin intermediate process.¹¹ Then, we performed the reaction with an epoxide carrying a pendant homoallyl group. In this case, only the ring-closure isomer was isolated (Scheme 5, eqn (1)).¹² Furthermore, the (R)-styrene oxide was used to study the stereochemistry, which led to a racemic product in 75% isolated yield (Scheme 5, eqn (2)). The above observations are consistent with a radical-type mechanism for the epoxides.¹³

Scheme 5 Support experiments for the mechanism.

In summary, we report an example of a Ni-catalyzed Suzuki-type cross-coupling of boronic acids with epoxides without an exogenous base. A variety of substituted epoxides are suitable reaction substrates. Alkenyl boronic acids also undergo coupling to generate homoallylic alcohols. The selectivity of aromatic epoxides is different from that of previous work. This Ni-catalyzed Suzuki-type cross-coupling reaction of epoxides has a wider range of substrate types than previous work. This reaction does not require the use of an exogenous base and has good functional-group compatibility. This methodology provides access to a diverse array of substituted alcohols, which are valuable feedstock chemicals in synthetic and medicinal chemistry.

This work was supported by 2017qd11, 16030801108 and KJ2019A0635.

Conflicts of interest

There are no conflicts to declare.

Notes and references

1. (a) R. Jana, T. P. Pathak and M. S. Sigman, Chem. Rev., 2011, 111, 1417–1492; (b) A. H. Cherney, N. T. Kadunce and S. E. Reisman, Chem. Rev., 2015, 115, 9587–9652; (c) F.-S. Han, Chem. Soc. Rev., 2013, 42, 5270–5298; (d) A. Suzuki, Angew. Chem., Int. Ed., 2011, 50, 6722–6737; (e) A. J. J. Lennox and G. C. Lloyd-Jones, Angew. Chem., Int. Ed., 2013, 52, 7362–7370; (f) K. C. Nicolaou, P. G. Bulger and D. Sarlah, Angew. Chem., Int. Ed., 2005, 44, 4442–4489.
2. (a) C. A. Malapit, J. R. Bour, C. E. Brigham and M. S. Sanford, Nature, 2018, 563, 100–104; (b) L. Chen, D. R. Sanchez, B. Zhang and B. P. Carrow, J. Am. Chem. Soc., 2017, 139, 12418–12421; (c) T. J. A. Graham and A. G. Doyle, Org. Lett., 2012, 14, 1616–1619.
3. (a) P. Crotti and M. Pineschi, Aziridines and Epoxides in Organic Synthesis, Wiley-VCH Verlag GmbH & Co. KGaA, 2006, pp. 271–313; (b) V. V. Fokin and P. Wu, Aziridines and Epoxides in Organic Synthesis, Wiley-VCH Verlag GmbH & Co. KGaA, 2006, pp. 443–477; (c) P. A. S. Lowden, Aziridines and Epoxides in Organic Synthesis, Wiley-VCH Verlag GmbH & Co. KGaA, 2006, pp. 399–442; (d) H. Ohno, Aziridines and Epoxides in Organic Synthesis, Wiley-VCH Verlag GmbH & Co. KGaA, 2006, pp. 37–71; (e) B. Olofsson and P. Somfai, Aziridines and Epoxides in Organic Synthesis, Wiley-VCH Verlag GmbH & Co. KGaA, 2006, pp. 315–347; (f) C. Molinaro and T. F. Jamison, J. Am. Chem. Soc., 2003, 125, 8076–8077; (g) Y. Ikeda, H. Yorimitsu, H. Shinokubo and K. Oshima, Adv. Synth. Catal., 2004, 346, 1631; (h) B. P. Woods, M. Orlandi, C.-Y. Huang, M. S. Sigman and A. G. Doyle, J. Am. Chem. Soc., 2017, 139, 5688–5691; (i) X.-Y. Lu, J.-S. Li, S.-Q. Wang, Y.-J. Zhu, Y.-M. Li, L.-Y. Yan, J.-M. Li, J.-Y. Wang, H.-P. Zhou and X.-T. Ge, Chem. Commun., 2019, 55, 11123–11126; (j) K. L. Jensen, E. A. Standley and T. F. Jamison, J. Am. Chem. Soc., 2014, 136, 11145–11152; (k) D. K. Nielsen, C.-Y. Huang and A. G. Doyle, J. Am. Chem. Soc., 2013, 135, 13605–13609; (l) C.-Y. Huang and A. G. Doyle, J. Am. Chem. Soc., 2012, 134, 9541–9544.
4. C.-Y. Huang and A. G. Doyle, Chem. Rev., 2014, 114, 8153–8198.
5. (a) M. Alam, C. Wise, C. A. Baxter, E. Cleator and A. Walkinshaw, Org. Process Res. Dev., 2012, 16, 435–441; (b) C. Bonini, L. Chiummiento, M. T. Lopardo, M. Pullez, F. Colobert and G. Solladie, Tetrahedron Lett., 2003, 44, 2695–2697.
6. For selected Suzuki-type cross-couplings (a) J. Zhou and G. C. Fu, J. Am. Chem. Soc., 2004, 126, 1340–1341; (b) F. González-Bobes and G. C. Fu, J. Am. Chem. Soc., 2006, 128, 5360–5361; (c) N. A. Weires, E. L. Baker and N. K. Garg, Nat. Chem., 2015, 8, 75–79; (d) J. Wang, T. Qin, T.-G. Chen, L. Wimmer, J. T. Edwards, J. Cornella, B. Vokits, S. A. Shaw and P. S. Baran, Angew. Chem., Int. Ed., 2016, 55, 9676–9679; (e) M. L. Duda and F. E. Michael, J. Am. Chem. Soc., 2013, 135, 18347–18349; (f) Y. Takeda, Y. Ikeda, A. Kuroda, S. Tanaka and S. Minakata, J. Am. Chem. Soc., 2014, 136, 8544–8547; (g) C. T. Yang, Z. Q. Zhang, Y. C. Liu and L. Liu, Angew. Chem., Int. Ed., 2011, 50, 3904; (h) X.-Y. Yu, Q.-Q. Zhou, P.-Z. Wang, C.-M. Liao, J.-R. Chen and W.-J. Xiao, Org. Lett., 2018, 20, 421–424; (i) J. C. Tellis, D. N. Primer and G. A. Molander, Science, 2014, 345, 433–436; (j) P. Maity, D. M. Shacklady-McAtee, G. P. A. Yap, E. R. Sirianni and M. P. Watson, J. Am. Chem. Soc., 2013, 135, 280–285.
7. D. K. Nielsen and A. G. Doyle, Angew. Chem., Int. Ed., 2011, 50, 6056.
8. X. Y. Lu, C. T. Yang, J. H. Liu, Z. Q. Zhang, X. Lu, X. Lou, B. Xiao and Y. Fu, Chem. Commun., 2015, 51, 2388–2391.
9. S. Z. Tasker, E. A. Standley and T. F. Jamison, Nature, 2014, 509, 299–309.
10. (a) J. He, J. Ling and P. Chiu, Chem. Rev., 2014, 114, 8037–8128; (b) J. Kjellgren, J. Aydin, O. A. Wallner, I. V. Saltanova and K. J. Szab’o, Chem. – Eur. J., 2005, 11, 5260; (c) J. P. Patterson, P. Cotanda, E. G. Kelley, A. O. Moughton, A. Lu, T. H. Epps 3rd and R. K. O'Reilly, Polym. Chem., 2013, 4, 2033; (d) X.-Y. Lu, J.-S. Li, J.-Y. Wang, S.-Q. Wang, Y.-M. Li, Y.-J. Zhu, R. Zhou and W.-J. Ma, RSC Adv., 2018, 8, 41561–41565.
11. (a) Y. Zhao and D. J. Weix, J. Am. Chem. Soc., 2013, 136, 48–51; (b) Y. Zhao and D. J. Weix, J. Am. Chem. Soc., 2015, 137, 3237–3240.
12. S. Teng, M. E. Tessensohn, R. D. Webster and J. S. Zhou, ACS Catal., 2018, 8, 7439–7444.
13. Hammett analysis of the reaction was undertaken: see ESI;† (a) X. Lu, B. Xiao, Z. Zhang, T. Gong, W. Su, J. Yi, Y. Fu and L. Liu, Nat. Commun., 2016, 7, 11129; (b) E. Richmond and J. Moran, Synthesis, 2018, 499–513; (c) X. Wang, Y. Dai and H. Gong, Top. Curr. Chem., 2016, 374, 43; (d) S. Joung, A. M. Bergmann and M. K. Brown, Chem. Sci., 2019 10.1039/C9SC04199K.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1967481. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c9cc08079a

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