Suzuki-Miyaura coupling of heteroaryl boronic acids and vinyl chlorides

Article abstract of DOI:10.1039/c1cc15990a

A protocol for the Suzuki-Miyaura coupling of heteroaryl boronic acids and vinyl chlorides that minimizes protodeboronation is described. A combination of catalytic amounts of Pd(OAc)₂ and SPhos in conjunction with CsF in isopropanol effectivel

Full text of DOI:10.1039/c1cc15990a

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COMMUNICATION
Suzuki-Miyaura coupling of heteroaryl boronic acids and vinyl chlorideswz
Ashish Thakur, Kainan Zhang and Janis Louie*
Received 26th September 2011, Accepted 28th October 2011
DOI: 10.1039/c1cc15990a
A protocol for the Suzuki-Miyaura coupling of heteroaryl boronic
acids and vinyl chlorides that minimizes protodeboronation is
described. A combination of catalytic amounts of Pd(OAc)2 and
SPhos in conjunction with CsF in isopropanol effectively affords a
variety of coupled products. Surprisingly, a dramatic temperature
dependence in product selectivity was observed.
heteroaryltrifluoroborates in the coupling with the aryl/hetero-
aryl halides.7b,c However, these potassium trifluoroborate salts
are themselves prepared from boronic acids in moderate to good
yields.7b
Recently, we became interested in preparing vinyl indole 1a via a
Suzuki-Miyaura coupling (eqn (1)). Unfortunately, known proto-
cols afforded either low yields or no desired product (1a). Specifi-
cally, when 1 and a were subjected to Fu’s Pd2dba3/PCy3 catalytic
system,3 complete protodeboronation to free indole (1a0) occurred
Since the first report in 1979, the Suzuki-Miyaura coupling
reaction has emerged as one of the most powerful C–C bond
forming methodologies and is extensively utilized in the syntheses
of natural products, pharmaceuticals, and materials.1,2 Low
catalyst loadings, flexibility of compatible functional groups,
commercial availability of organoboron reagents, relative ease of
product separation, and low toxicity of boron by-products have
led its prominence in both academic and industrial research.2d–f
In recent years, significant progress has been made in the
Suzuki-Miyaura coupling of heteroaryl boronic acids and
aryl/heteroaryl halides. For example, Fu demonstrated the
use of a Pd2dba3/PCy3 catalytic system to couple N-heteroaryl
boronic acids with aryl and N-heteroaryl chlorides in good to
excellent yields.3 Undoubtedly, the Buchwald group has made
tremendous contributions to this field by designing sterically-
hindered, electron-rich biarylmonodentate phosphine ligands
such as SPhos and XPhos that, when combined with catalytic
amounts of Pd(0), efficiently couple heteroaryl boronic acids
with both aryl and heteroaryl chlorides.4
1
exclusively. Some product was obtained (46% yield by H NMR
spectroscopy) utilizing Buchwald’s conditions (i.e., 2 mol%
Pd(OAc)2, 4 mol% SPhos, K3PO4, n-butanol, 100 1C).4d However,
the remaining boronic acid a was completely protodeboronated.
Alternatively, the more stable potassium trifluoroborate salt of
boronic acid 1 was synthesized and subjected to Molander’s
conditions (i.e., 2 mol% Pd(OAc)2, 4 mol% RuPhos, 2 equiv.
Na2CO3, EtOH, 85 1C).7b Unfortunately, a 1 : 1 mixture of
coupling product 1a and protodeboronated indole 1a0 was again
obtained. Furthermore, attempts to isolate the coupling product 1a
proved futile as it co-elutes with 1a0 during chromatographic
separation. As such, we began to evaluate an unconventional
approach of using the heteroaryl boronic acid as the limiting
reagent. Herein we describe an effective protocol for the Suzuki-
Miyaura coupling of heteroaryl boronic acids and vinyl chlorides.
Using Buchwald’s conditions as a guide, we evaluated whether
a change in base, solvent, or temperature would result in higher
product yields (eqn (1), Table 1). Initially, when K3PO4 and
n-butanol were substituted for Cs2CO3 and toluene, a 1.1 : 1
mixture of product 1a to protodeboronated 1a0 was obtained.
Replacement of Cs2CO3 with CsF as the base led to a slight
increase in the product ratio (i.e., 1.9 : 1, entry 2). Although
switching from toluene to t-butanol led to a decrease in selectivity
(entry 3), the use of isopropanol as the solvent afforded a 3 : 1
ratio in favour of the desired 1a (entry 4). Surprisingly, lowering
the reaction from 110 1C to 100 1C resulted in an, albeit slight,
increase in selectivity (entry 5). Further investigation revealed a
dramatic temperature dependence (entries 4–9). Excellent selec-
tivity of the coupling product over protodeboronated product
was obtained when the reaction was run at 85 1C (entry 7). An
increase or decrease of the reaction temperature by as little as
5 1C led to lower selectivities (entries 6 and 8).8 Further optimization
led to these reactions conditions: 2 mol% Pd(OAc)2, 4 mol%
SPhos, 1.4 equiv. CsF, isopropanol (0.2 M), 3–10 h.
Despite these reports, the Suzuki-Miyaura coupling of
heteroaryl boronic acids and vinyl chlorides is largely
unexplored.5,6 One of the challenges associated with heteroaryl
boronic acids is their propensity to protodeboronate in the
presence of base and polar protic solvents.4a,7a,b The instability
of these boronic acids has led to the conventional approach of
using excess amounts (>1.2 equiv.) of these transmetallating
reagents while using the other electrophilic coupling partner as
the limiting reagent. Furthermore, the protodeboronation is
enhanced by the slow oxidative addition of vinyl chlorides
leading to low yields of the desired coupling product. Molander
has developed methods that utilize more stable potassium
Department of Chemistry, University of Utah, 315 South 1400 East,
Salt Lake City, UT 84112, USA. E-mail: louie@chem.utah.edu;
Fax: +1 (801) 581-8433; Tel: +1 (801) 581-7309
w This article is part of the ChemComm ‘Advances in catalytic C–C
bond formation via late transition metals’ web themed issue.
z Electronic supplementary information (ESI) available: characterization
data and NMR spectra of characterized compounds. See DOI: 10.1039/
c1cc15990a
With optimized conditions in hand, the coupling of other hetero-
aryl boronic acids and vinyl chlorides was explored. A particularly
challenging heteroaryl boronic acid that is known for fast
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 203–205 203

Table 1 Various reaction parameters for the Suzuki-Miyaura couplinga
with N-heteroaromatics like pyrimidines, which can potentially bind
[Pd] and kill its catalytic activity, worked efficiently in excellent yields
(4a, 5a, 5b, 5d). Additionally, both quinoline and isoquinoline
boronic acids were also coupled in moderate to good yields
(6a, 6e, 7e). The coupling with (Z)-2-chloro-2-butene afforded the
vinyl heteroaryl compounds with retention of stereochemistry
(6e, 7e). Five-membered heteroaryl boronic acids were also demon-
strated to couple effectively in good to excellent yields (8d, 9c).
Gratifyingly, this coupling is scalable and was successfully
applied to gram scale quantities of benzofuran-2-boronic acid
and 3-chloro-5,5-dimethylcyclohex-2-en-1-one to afford the
desired product (2c) in 83% yield (eqn (2)).
Ratiob
1a : 1a0
Entry
Base
Solvent
Temp. (1C)
1
2
3
4
5
6
7
8
9
Cs2CO3
CsF
CsF
CsF
CsF
CsF
CsF
Toluene
Toluene
110
110
110
110
100
90
85
80
75
1.1 : 1
1.9 : 1
1.5 : 1
3 : 1
3.3 : 1
10 : 1
16.7 : 1
11.1 : 1
6.7 : 1
tButanol
Isopropanol
Isopropanol
Isopropanol
Isopropanol
Isopropanol
Isopropanol
(2)
CsF
CsF
a
Reaction conditions: 1 (1 equiv., 0.2 M), a (1.2 equiv.), 5 mol%
b
Pd(OAc)2, 10 mol% SPhos. Ratio 1a : 1a0 determined by 1H NMR
spectroscopy.
In conclusion, we have developed an efficient catalytic
system to couple challenging heteroaryl boronic acids and
vinyl chlorides. This coupling takes the advantage of using
heteroaryl boronic acids as the limiting reagent. In addition,
we found that the ratio of protodeboronation to coupled
product was highly dependent on reaction temperature.
protodeboronation, N-Boc-indole-2-boronic acid,4a,7b was success-
fully coupled with both unactivated cyclic and acyclic vinyl chlorides
to yield vinyl indoles in high yields (1a, 1b, Table 2). Similarly,
benzofuran-2-boronic acid and benzothiophene-2-boronic acid
afforded the desired products (2a, 2b, 2c, 3c). Notably boronic acid
Table 2 Suzuki-Miyaura coupling of heteroaryl boronic acids and vinyl chloridesa
a
Reaction conditions: 1 equiv. heteroaryl boronic acid (0.2 M),1.2 equiv. vinyl chloride, 2 mol% Pd(OAc)2, 4 mol% SPhos, Isopropanol, 85 1C.
b
c
d
Product was contaminated with very low amounts of protodeboronated indole 1a0 (see ESIz). 4 mol% Pd(OAc)2/SPhos was used. 1.1 equiv.
e
of vinyl chloride was used. Retention of stereochemistry was observed as determined by NOESY-1D spectroscopy.
c
204 Chem. Commun., 2012, 48, 203–205
This journal is The Royal Society of Chemistry 2012

We gratefully acknowledge Cephalon, Inc. for support of this
research.
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(f) T. E. Barder, S. D. Walker, J. D. Martinelli and
S. L. Buchwald, J. Am. Chem. Soc., 2005, 127, 4685–4696.
5 For briefly explored coupling of activated vinyl chlorides
and heteroaryl boronic acids, see: (a) R. Rossi, F. Bellina and
M. Lessi, Tetrahedron, 2011, 67, 6969–7025; (b) L. M. Geary and
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Notes and references
1 (a) N. Miyaura, K. Yamada and A. Suzuki, Tetrahedron Lett., 1979, 20,
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2 (a) N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457–2483;
(b) K. C. Nicolaou, P. G. Bulger and D. Sarlah, Angew. Chem. Int.
Ed., 2001, 40, 4442–4489; (c) S. R. Chemler, D. Trauner and
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(d) S. Kotha, K. Lahiri and D. Kashinath, Tetrahedron, 2002, 58,
9633–9695; (e) N. Miyaura, Top. Curr. Chem., 2002, 219, 11–59;
(f) J.-P. Corbet and Gerard Mignani, Chem. Rev., 2006, 106, 2651–2710.
3 N. Kudo, M. Perseghini and G. C. Fu, Angew. Chem., Int. Ed.,
2006, 45, 1282–1284.
4 (a) T. Kinzel, Y. Zhang and S. L. Buchwald, J. Am. Chem. Soc.,
2010, 132, 14073–14075; (b) R. Martin and S. L. Buchwald, Acc.
Chem. Res., 2008, 41, 1461–1473; (c) K. Billingsley and
S. L. Buchwald, Angew. Chem., Int. Ed., 2008, 47, 4695–4698;
(d) K. Billingsley and S. L. Buchwald, J. Am. Chem. Soc., 2007,
129, 3358–3366; (e) K. Billingsley, K. W. Anderson and
6 For an example of unactivated vinyl chloride and heteroaryl boronic
acid, see: G.-R. Peh, E. A. B. Kantchev, J.-C. Er and J. Y. Ying,
Chem.–Eur. J., 2010, 16, 4010–4017.
7 (a) C. A. Fleckenstein and H. Plenio, J. Org. Chem., 2008, 73,
3236–3244; (b) G. A. Molander, B. Canturk and L. E. Kennedy,
J. Org. Chem., 2009, 74, 973–980; (c) G. A. Molander, S. L. J. Trice
and S. D. Dreher, J. Am. Chem. Soc., 2010, 132, 17701–17703.
8 We currently do not know the reason for the dramatic temperature
effect on product yields. We found, not surprisingly, that proto-
deboronation of 1 occurs within 30 min at 80 1C in the presence of
only base. As such, the high yield of product 1a at 85 1C does not
seem to be due to a simple correlation between the rate of cross
coupling and the rate of protodeboronation. We are investigating
other possible reasons for the observed temperature effect.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 203–205 205