ChemComm

View Article Online

COMMUNICATION View Journal

Base-free Ni-catalyzed Suzuki-type cross-coupling

Published on 26 November 2019. Downloaded by University of Reading on 12/3/2019 9:29:32 AM.

reactions of epoxides with boronic acids†

Cite this: DOI: 10.1039/c9cc08079a
Xiao-Yu Lu, *ab Lu-Yu Yan,a Jin-Song Li,a Jia-Mei Li,a Hai-pin Zhou,a
Received 15th October 2019, Run-Chuang Jiang,a Chuang-Chuang Liu,a Ran Lua and Rong Hua
Accepted 24th November 2019

DOI: 10.1039/c9cc08079a

rsc.li/chemcomm

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 sub-
stituted alcohols, which are valuable feedstock chemicals.

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, Scheme 1 Suzuki-type cross-coupling reactions of epoxides.
various ring-opening reactions of epoxides with carbon-based
nucleophiles, such as strongly nucleophilic organolithium
reagents and Grignard reagents, have been investigated.4,5 Organo- strong base LiOtBu also proved to be incompatible with many
boron compounds are usually readily available and have a broad polar functional groups.
functional-group tolerance.6 In this context, Doyle reported nickel- Recently, nickel-catalyzed cross-coupling reactions have
catalyzed cross-coupling of styrenyl epoxides with arylboronic acids attracted great attention because of the low cost of nickel
and obtained rearrangement products (Scheme 1a).7 Unfortunately, catalysts, and their excellent functional-group tolerance.9
the use of the strong base K3PO4 was incompatible with many To date, nickel-catalyzed Suzuki-type cross-coupling reactions
functional groups in this reaction. Recently, Fu realized the of ubiquitous alkyl epoxides has not been reported. In this
Cu-catalyzed cross-coupling of epoxides with organoboron com- communication, we report an example of a Ni-catalyzed Suzuki-
pounds (Scheme 1b).8 The 1,2-disubstituted epoxides and alkenyl- type cross-coupling of boronic acids with epoxides (Scheme 1c).
boron are incompatible substrates. Unfortunately, using the In addition to monosubstituted and 1,1-disubstituted epoxides,
1,2-disubstituted epoxides also gave products with good reaction
a
School of Materials and Chemical Engineering, ChuZhou University, yields. Alkenyl boronic acids also undergo coupling to generate
Chu Zhou, 239000, China. E-mail: xiaoyulu@mail.ustc.edu.cn homoallylic alcohols. The selectivity of aromatic epoxides is
b
School of Chemistry and Chemical Engineering, AnHui University,
different from Doyle’s and Fu’s work. The selectivity of the ring-
He Fei, 230601, China
† Electronic supplementary information (ESI) available. CCDC 1967481. For ESI
opening reaction is excellent. This reaction does not use an
and crystallographic data in CIF or other electronic format see DOI: 10.1039/ exogenous base and has better substrate compatibility. This
c9cc08079a methodology utilizes readily available and inexpensive epoxides,

This journal is © The Royal Society of Chemistry 2019 Chem. Commun.

 View Article Online

Communication ChemComm

Table 1 Optimization of the reaction conditions Table 2 Scope of the base-free Suzuki-type reaction of epoxides

Entrya Catalyst Ligand Base Solvent Yield% (d.r.)

1 NiBr2diglyme dtbpy LiOtBu DMAc Trace
2 NiBr2diglyme dtbpy K3PO4 DMAc 2
3 NiBr2diglyme dtbpy K2CO3 DMAc 19(7.5 : 1)
Published on 26 November 2019. Downloaded by University of Reading on 12/3/2019 9:29:32 AM.

4 NiBr2diglyme dtbpy LiOMe DMAc 6(8 : 1)

5 NiBr2diglyme dtbpy K2CO3 THF 16(7 : 1)
6 NiBr2diglyme dtbpy — DMAc 30(8 : 1)
7 NiBr2diglyme dtbpy — HOtBu 47(9 : 1)
i
8 NiBr2diglyme dtbpy — PrOH 65(8.5 : 1)
9 NiBr2diglyme dtbpy — EtOH 89(9 : 1)
10 NiI2 dtbpy — EtOH 29(8 : 1)
11 NiCl2(PPh3)2 dtbpy — EtOH 20(7 : 1)
12 NiBr2diglyme Phen — EtOH 25(8 : 1)
13b — dtbpy — EtOH 0
a
1a (0.5 mmol), 2a (0.25 mmol), base (1.5 equiv.) in 0.8 mL solvent at
70 1C for 20 h. b No catalyst. The yield was determined by GC using Benzo-
phenone as internal standard. The d.r. ratio was determined by GC.

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 con-
ditions 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†).
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 mono-
substituted, 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.
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.
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

Chem. Commun. This journal is © The Royal Society of Chemistry 2019


ChemComm
Table 3 Scope of alkenyl boron acid
Published on 26 November 2019. Downloaded by University of Reading on 12/3/2019 9:29:32 AM.
Table 4 Scope of styrenyl epoxides
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.
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 SN2 and SN20 -type ring-opening/coupling reactions.10
We performed a reaction using alkenyl boronic acid with vinyl
epoxide, which generated both the SN2 and SN2 0 -type products
(Scheme 2). Therefore, this methodology can provide access to
some special substituted homoallylic alcohols.
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
This journal is © The Royal Society of Chemistry 2019
View Article Online
Communication
Scheme 2 Example of vinyl epoxide.
Scheme 3 A gram-scale reaction and derivatization of product.
Scheme 4 Example of chiral epoxide.
product in 85% yield (Scheme 3). Product 5a was efficiently
transformed into 4-phenylisochromane through an Oxa-Pictet–
Spengler reaction.
The monoalkyl-substituted chiral epoxide reacted smoothly
at the less-substituted carbon center under the standard reac-
tion conditions and obtained the desired products with almost
no loss of enantiomeric excess (Scheme 4).
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
b-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
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
Scheme 5 Support experiments for the mechanism.
Chem. Commun.

Communication
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
Published on 26 November 2019. Downloaded by University of Reading on 12/3/2019 9:29:32 AM.
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
Chem. Commun.
View Article Online
ChemComm
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, DOI: 10.1039/C9SC04199K.
This journal is © The Royal Society of Chemistry 2019