Highly regio- and stereoselective synthesis of alkenylboronic esters by copper-catalyzed boron additions to disubstituted alkynes

Article abstract of DOI:10.1039/c0cc04496b

The copper-catalyzed addition of bis(pinacolato)diboron to internal alkynes in the presence of methanol generates alkenylboron compounds with high levels of regio- and stereoselectivities. The catalytic efficiency is increased by using monodentate phosphine ligands, especially P(p-tolyl)₃ and a range of internal alkynes was borylated in good yields. The Royal Society of Chemistry.

Full text of DOI:10.1039/c0cc04496b

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COMMUNICATION
Highly regio- and stereoselective synthesis of alkenylboronic esters by
copper-catalyzed boron additions to disubstituted alkynesw
Hye Ryung Kim and Jaesook Yun*
Received 19th October 2010, Accepted 24th December 2010
DOI: 10.1039/c0cc04496b
The copper-catalyzed addition of bis(pinacolato)diboron to internal
alkynes in the presence of methanol generates alkenylboron
compounds with high levels of regio- and stereoselectivities. The
catalytic efficiency is increased by using monodentate phosphine
ligands, especially P(p-tolyl)3 and a range of internal alkynes was
borylated in good yields.
bisphosphines or bulky N-heterocyclic carbene (NHC) ligands,
since the latter ligands exhibited low efficiencies in terms of
reactivity and regioselectivity.10 Keeping with a 1 : 1.2 ratio of
copper and ligand, we investigated the boron addition reaction in
1-phenyl-1-butyne with bis(pinacolato)diboron (1).
Nitrogen-based ligands11 such as pyridine (Table 1, entry 2)
did not offer sufficient reactivity. Phosphite ligands led the
reaction to completion with the formation of a small amount
of the other regioisomer (Table 1, entries 3 and 4). When
we switched ligands to the electron-donating and bulky
phosphine ligands, P(t-Bu)3 and P(o-tolyl)3, the reaction
proceeded to complete conversion, but again produced traces
of a different regioisomer (Table 1, entries 5 and 6). Finally,
the electron-donating and less bulky phosphine ligands gave
the best results (Table 1, entries 7–9) in terms of reactivity and
regioselectivity. Only syn-addition product was formed, and
no other regioisomers were detected. Tri-p-tolylphosphine was
chosen as an optimal ligand for further investigation.
Transition metal-catalyzed addition reactions of boron-containing
reagents to carbon–carbon multiple bonds have become
important strategies for the synthesis of organoboron
compounds.1,2 For example, catalytic hydroboration of alkynes
is one of the powerful means to afford alkenylboron compounds.
Transition metal-catalyzed hydroborations of terminal alkynes
using hydroboranes have provided 1-alkenylboronic esters with
good levels of regio- and stereoselectivities.3 However, there are
only few reports on the hydroboration of internal alkynes that
proceed with a high level of regioselectivity.4 In general, internal
alkynes are much less reactive than terminal alkynes, and highly
efficient regioselective boron addition to internal alkynes remains
challenging.5 For example, the hydroboration of 1-phenyl-1-
propyne with either catecholborane or pinacolborane produced
a mixture of regioisomers.4a,b,6 It was reported that a recent
Ir-catalyzed hydroboration of 1-phenyl-1-propyne by Suginome
et al.4e produced a mixture of stereo- and regioisomers.
The optimized reaction conditions were applied to other
internal aryl- and heteroaryl-substituted alkynes (Table 2).
Notably, in all cases when the substituent (R0) is 11 alkyl, 21
alkyl or phenyl, the boronate moiety was added to the
Table
various ligands
1
Catalytic diboron addition to 1-phenyl-1-butyne with
Herein, we report an efficient monophosphine–copper
catalytic system that allows for a regio- and stereoselective
addition of a boronate moiety and H to alkynes and synthetic
applications of products. Recently, we reported that a catalytic
addition of a diboron reagent to alkyno esters in the presence
of methanol7 produced b-borylated a,b-ethylenic esters with
copper–bisphosphine catalysts.8,9 Although the same system
worked well for a terminal alkyne, the catalytic conditions
resulted in poor conversion for internal aryl alkynes. Other
new catalytic systems for internal alkynes were developed
based on bis(1,3-disubstituted imidazoline-2-thione)–copper
complexes, but displayed limited substrate scope.10
Product ratiob
Entry Ligand
Time (h) Convn (%)a
Yield (%)c
Z-3aA Z-3aB
1d
2
3
4
5
6
7
8
9
IMS
Pyridine 24
P(OEt)3 24
P(Oi-Pr)3 24
P(t-Bu)3 24
P(o-tolyl)3
PPh3
PPhEt2
24
49
5
N.de
N.d
2
100
100
98
30
—
—
—
—
—
90
89
90
100
100
100
100
100
100
100
4
3
96
97
In initial experiments, we focused on the use of monodentate
ligands, sterically less encumbered ligands than bidentate
6
12
5
3
97
N.d
N.d
N.d
100
100
100
Department of Chemistry and Institute of Basic Science,
Sungkyunkwan University, Suwon 440-746, Korea.
E-mail: jaesook@skku.edu; Fax: +82-31-290-7075;
Tel: +82-31-299-4561
w Electronic supplementary information (ESI) available: Experimental pro-
cedures and characterization of all products. See DOI: 10.1039/c0cc04496b
P(p-tolyl)3
5
a
b
Conversion was determined by GC analysis. Ratio was determined
c
by GC analysis. Isolated yield. The data was taken from ref. 10.
d
e
IMS = 1,3-dimethylimidazoline-2-thione. Not detected.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 2943–2945 2943

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b-carbon to the aryl and both the boron and H were added in a
syn-fashion to yield only the (Z)-isomer. 1-Aryl-1-
propynes bearing fluoro-, bromo-, and cyano- groups on the
aryl ring and 2-(1-propynyl)-naphthalene afforded the corres-
ponding products in good yields with excellent regioselectivity
(Table 2, entries 1–4). Sterically demanding 2,6-dimethylphenyl-
substituted propyne (2f) produced the borylated product in
good yield (Table 2, entry 5). Functional groups on the arene
ring exerted electronic effects on the rate of reaction.
The 1-aryl-1-butyne substrate (2g) bearing a strong electron
donating group exhibited decreased reactivity and was converted
to the product slowly at room temperature, requiring a higher
temperature for completion (Table 2, entry 6). When the size of
the alkyl group of the internal alkynes increased from a 11 alkyl
to a 21 alkyl, it was necessary to use a slightly longer reaction
time and the regioselectivity was lowered to produce a mixture of
both regioisomers (Table 2, entries 9 and 10).12 Heteroaromatic
substituted internal alkynes were examined as well. Thienyl-
1-propyne (2l), 2-alkynylbenzoxzole (2m) and 2-(1-hexynyl)-
pyridine (2n) underwent the addition reaction with high
regio- and stereoselectivity (Table 2, entries 11–13).
Then, sterically demanding t-butyl substituted alkynes were
prepared and subjected to the borylation conditions (Table 3).
The reaction proceeded rather slowly, possibly due to steric
reasons. Electronic factors also affected the reaction rates,
leading the reactions of 4d and 4e to incompletion. Surprisingly,
in all cases, only a single isomer was obtained as the product in
which the boronate moiety was added at the a-carbon to the
aryl (5A), avoiding severe steric hindrance with the bulky
group. Furthermore, the anti-addition products13 were obtained
exclusively for aryl substituted alkynes (Table 3, entries 1–4).
The formation of trans-a-boryl products (E-5A) was again
proved in the following example (eqn (1)). Borylation of the
t-butyl alkyne having a 2-pyridyl substituent (4f) gave no
alkenylboron products, affording a mixture of 6 and 7. The
formation of 6 could be rationalized by a-borylation and
subsequent protodeboronation, and further borylation of the
alkene 6 led to the synthesis of 7. While b-borylated alkene
product with 2-pyridyl substituent (Z-3nB) seems stable under
the reaction conditions (Table 2, entry 13), the a-borylated
alkene product from 4f is not stable to protodeboronation.
Table 2 Copper-catalyzed boron additions to various internal aryl
alkynes with P(p-tolyl)3
a
Product ratiob
Z-3A
Z-3B
Entry Substrates
Time (h)
Yield (%)c
1
2
3
6
5
6
N.d.d 100
90
92
93
N.d.
N.d.
100
100
4
6
N.d.
100
92
ð1Þ
5
12
24
6
N.d.
N.d.
N.d.
100
100
100
89
90
90
Table 3 Copper-catalyzed borylation of internal alkynes having
sterically demanding t-butyl groupa
6e
7
Time
(h)
Convn
(%)b
Yield
Product (%)c
8
12
12
12
4
100
14
91
Entry Substrates
9
86
88f
82f
93
1d
2
20
20
100
100
E-5aA
E-5bA
91
92
10
11
20
80
N.d.
100
3
20
100
E-5cA
92
12
13
a
6
N.d.
N.d.
100
100
90
89
4d,e
5d
a
24
24
79
48
E-5dA
Z-5eA
62
37
12
A mixture of 4, B2pin2 (1; 1.1 equiv.), CuCl, P(p-tolyl)3, and MeOH
A mixture of 2, B2pin2 (1; 1.1 equiv.), CuCl, P(p-tolyl)3 and MeOH
(2 equiv.) in THF was stirred at ambient temperature under a nitrogen
b
atmosphere unless otherwise noted. Determined by GC analysis.
(2 equiv.) in THF was stirred at ambient temperature under a nitrogen
b
c
d
atmosphere. Determined by GC analysis. Isolated yield. Not
c
d
e
e
f
Isolated yields. Reaction was conducted at 50 1C. 10 mol%
copper was used.
detected. Reaction was conducted at 50 1C. Yield for an
inseparable isomeric mixture.
c
This journal is The Royal Society of Chemistry 2011
2944 Chem. Commun., 2011, 47, 2943–2945

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This work was supported by National Research Foundation
grants R01-2008-000-20332-0 (Mid-career Researcher
Program) and NRF-20090085824 (Basic Science Research
Program).
Notes and references
1 For reviews, see: (a) I. Beletskaya and C. Moberg, Chem. Rev.,
2006, 106, 2320–2354; (b) G. J. Irvine, M. J. G. Lesley, T. B.
Marder, N. C. Norman, C. R. Rice, E. G. Robins, W. R. Roper,
G. R. Whittell and L. J. Wright, Chem. Rev., 1998, 98, 2685–2722;
(c) M. Suginome, T. Matsuda, T. Ohmura, A. Seki and
M. Murakami, in Comprehensive Organometallic Chemistry III,
ed. R. Crabtree, M. Mingos and I. Ojima, Elsevier, Oxford, 2007,
vol. 10, pp. 725–787.
2 (a) P. V. Ramachandran and H. C. Brown, Organoboranes for
Syntheses, ACS symposium series 783, American Chemical
Society, Washington DC, USA, 2001; (b) A. Pelter, K. Smith and
H. C. Brown, Borane Reagents, Academic Press, New York, 1988.
3 (a) T. Ohmura, Y. Yamamoto and N. Miyaura, J. Am. Chem. Soc.,
2000, 122, 4990–4991; (b) S. Pereira and M. Srebnik, Organometallics,
1995, 14, 3127–3128; (c) S. Pereira and M. Srebnik, Tetrahedron Lett.,
1996, 37, 3283–3286; (d) Y. D. Wang, G. Kimball, A. S. Prashad and
Y. Wang, Tetrahedron Lett., 2005, 46, 8777–8780.
4 Formation of regioisomeric mixtures from internal alkynes via
hydroboration, see: (a) H. C. Brown and S. K. Gupta, J. Am.
Chem. Soc., 1972, 94, 4370–4371; (b) C. E. Tucker, J. Davidson
and P. Knochel, J. Org. Chem., 1992, 57, 3482–3485; (c) T. Konno,
J. Chae, T. Tanaka, T. Ishihara and H. Yamanaka, Chem.
Commun., 2004, 690–691; (d) X. He and J. F. Hartwig, J. Am.
Chem. Soc., 1996, 118, 1696–1702; (e) N. Iwadate and
M. Suginome, Org. Lett., 2009, 11, 1899–1902.
Scheme 1 Proposed reaction pathway.
Simple dialkyl alkynes other than 4e could be borylated
under our reaction conditions as well. However, the regio-
selectivity was not high in the absence of a t-butyl group.14
A possible catalytic cycle for the boron addition process
promoted by methanol is proposed in Scheme 1. A ligated
copper–boryl complex adds to the alkyne in a syn-fashion in
step I with boron addition at the b-carbon to the R when R0 is
not sterically bulky. Protonolysis of the C–copper bond by
MeOH produces the (Z)-alkenyl product in step II.15
The alkenylboronic ester products obtained in this study are
useful intermediates for the stereospecific synthesis of various
diarylalkenes (Scheme 2). The coupling of 4-fluorophenyl
alkenylborane Z-3bB, and bromobenzene and that of 9 and
1-bromo-4-fluorobenzene produced the isomeric diarylalkenyl
products 8 and 10 as a single isomer, respectively. In addition,
the Suzuki–Miyaura coupling of 9 and 6-bromo-2,2,3,3-tetra-
hydro-1,1,4,4-tetramethylnaphthalene (11) produced temarotene16
(12) without a loss of geometrical purity.
5 For a regiospecific nickel-catalyzed hydroboration of thioalkynes,
see: I. D. Gridnev, N. Miyaura and A. Suzuki, Organometallics,
1993, 12, 589–592.
6 The ratios of isomers obtained by using catecholborane and
pinacolborane were 73 : 27 and 85 : 15, respectively, in favor of
the boron addition at the less hindered site.
7 S. Mun, J.-E. Lee and J. Yun, Org. Lett., 2006, 8, 4887–4889.
8 J.-E. Lee, J. Kwon and J. Yun, Chem. Commun., 2008, 733–734.
9 For other copper-catalyzed reactions of alkynes with diboron reagents,
see: (a) K. Takahashi, T. Ishiyama and N. Miyaura, J. Organomet.
Chem., 2001, 625, 47–53; (b) Y. Lee, H. Jang and A. H. Hoveyda,
J. Am. Chem. Soc., 2009, 131, 18234–18235; (c) V. Lillo, M. R. Fructos,
In summary, we have developed an efficient copper catalytic
system for the boron addition to internal alkynes that
produces hydroborylated compounds regioselectively. A range
of internal alkynes reacted to provide alkenylboron
compounds with high degrees of regio- and stereoselectivities
in the presence of a copper–phosphine catalyst. The catalytic
efficiency was greatly improved by using electron-
donating, monodentate phosphine ligands. Further studies
are under way.
J. Ramı
´
P. J. Perez and E. Ferna
rez, A. A. C. Braga, F. Maseras, M. M. Dı
ndez, Chem.–Eur. J., 2007, 13, 2614–2621.
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az-Requejo,
´
´
10 H. R. Kim, I. G. Jung, K. Yoo, K. Jang, E. S. Lee, J. Yun and
S. U. Son, Chem. Commun., 2010, 46, 758–760.
11 (i-Pr)2NH, Et3N, and 1,10-phenanthroline gave less than 20%
conversion in 24 h.
12 For the isopropyl substrate (2k), the regioselectivity can be improved
to 95 : 5 by using a bulky NHC–Cu complex, (IPr)CuCl (IPr = 1,3-
bis(2,6-diisopropylphenyl)-imidazol-2-ylidene). Investigation of the
effect of ligands on the regioselectivity in more detailis in progress.
13 The structures were characterized by NOE experiments. For an
anti-addition example in organocuprate addition, when R is t-Bu,
see: (a) J. M. Gil and D. Y. Oh, J. Org. Chem., 1999, 64,
2950–2953; (b) E. J. Corey and J. A. Katzenellenbogen, J. Am.
Chem. Soc., 1969, 91, 1851–1852.
14 For example, 2-hexyne afforded products in a regioisomeric
mixture (B4 : 1, 70% isolated yield) in favor of boron addition
at the less hindered methyl site with P(OEt)3 as the ligand. P(OEt)3
exhibited a better reactivity than did the phosphine ligand for
simple dialkyl alkynes. See Supporting information for detailsw.
15 The anti-addition products (E-5) may be formed by protonolysis
after the geometrical isomerization of the cis-adduct in step I to
trans-adduct due to steric hindrance through a zwitterionic form,
see: (a) I. Ojima, N. Clos, R. J. Donovan and P. Ingallina,
Organometallics, 1990, 9, 3127–3133; (b) C.-H. Jun and
R. H. Crabtree, J. Organomet. Chem., 1993, 447, 177–187.
16 L. Deloux, M. Srebnik and M. Sabat, J. Org. Chem., 1995, 60,
3276–3277.
Scheme 2 Synthetic application of alkenylboron products; synthesis
of trisubstituted diarylalkenes via Suzuki–Miyaura coupling.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 2943–2945 2945