Copper-catalyzed synthesis of 1,1-diborylalkanes through regioselective dihydroboration of terminal alkynes

Article abstract of DOI:10.1002/asia.201402458

The copper-catalyzed sequential hydroboration of terminal alkynes with pinacolborane to prepare 1,1-diborylalkanes directly from alkynes was studied. Protected propargyl amines, propargyl alcohol derivatives, and simple alkynes regioselectively produced t

Full text of DOI:10.1002/asia.201402458

COMMUNICATION
DOI: 10.1002/asia.201402458
Copper-Catalyzed Synthesis of 1,1-Diborylalkanes through Regioselective
Dihydroboration of Terminal Alkynes
Sumin Lee, Dingxi Li, and Jaesook Yun*[a]
Abstract: The copper-catalyzed sequential hydroboration of
terminal alkynes with pinacolborane to prepare 1,1-dibory-
lalkanes directly from alkynes was studied. Protected prop-
argyl amines, propargyl alcohol derivatives, and simple al-
kynes regioselectively produced the desired 1,1-diborylal-
kanes in good yields with a copper/xantphos catalyst.
kynes would efficiently provide 1,1-diboryl compounds with
more economical copper catalysts. While the copper-cata-
lyzed hydroboration of terminal alkynes has not previously
been reported, catalytic hydroborations of internal alkynes[9]
and the formal hydroboration of terminal alkynes[5b,10] with
a diboron reagent and methanol producing anti-Markovni-
kov products have been reported. Herein, we report a regio-
selective copper-catalyzed sequential hydroboration of ter-
minal alkynes including propargyl substrates and alkylal-
kynes, which constitutes a worthy alternative to the Rh-cata-
lyzed synthesis of 1,1-diborylalkane compounds.
We initiated our investigation with the copper-catalyzed
reaction of phenylacetylene and pinacolborane using 1,2-
bis(diphenylphosphino)benzene (dppbz) as the ligand,
which was an efficient ligand for the hydroboration of vinyl-
arenes.[7a,11] When 1.2 equivalents pinacolborane were used
in an attempt to prepare the monohydroboration product,
the reaction proceeded to partial conversion of the starting
alkyne and produced a mixture of mono- and diborylated
regioisomeric products. With an increase of pinacolborane
to 2.2 equivalents, a similar product distribution was ob-
served with complete conversion of the starting alkyne.
Analysis of the products indicated poor regioselectivity, with
a ratio of a- and b-hydroboration of approximately 1:1.[12]
Using CuCl and 4,5-bis(diphenylphosphino)-9,9-dimethyl-
xanthene (xantphos), however, the hydroboration resulted
in predominantly b-hydroboration products (b-m, b-d;
Scheme 1). In the absence of phosphine ligands, no reaction
was observed at room temperature, which indicated that the
Stereoselective catalytic hydroboration reactions have
proven to be valuable methods for the preparation of vari-
ous organoboron derivatives.[1] Multiborylated compounds,
including 1,1-diboryl compounds, are intriguing synthetic in-
termediates for further organic transformations, as evi-
denced by recent progress in their applications.[2] However,
previous hydroboration or diboration reactions have been
reported to generate multiborylated compounds as regioiso-
meric mixtures.[3] Only recently has the regio- and stereose-
lective synthesis of 1,1-diborylated compounds by hydrobo-
ration of appropriate alkenylboron derivatives been dis-
closed.[4,5] Since alkenylboronates can be prepared from al-
kynes via hydroboration, the synthesis of 1,1-diboryl com-
pounds directly from alkynes would be desirable and
convenient. To date, only a single report of such a transfor-
mation using a rhodium catalyst has appeared, from the Shi-
bata group.[6] A rhodium-based catalytic system produced
the desired products from arylalkynes; however, the forma-
tion of side-products through reduction of intermediate al-
kenylboronates was unavoidable even under optimized Rh/
dppb catalytic conditions (dppb=1,4-bis(diphenylphosphi-
no)butane). The ratio of regioisomeric 1,1-diboryl products
was highly variable depending on the rhodium/phosphine
catalyst.
À
hydroboration required a phosphine copper catalyst. Based
on the proposed mechanism of the copper-catalyzed hydro-
boration,[11] a-hydroboration products were expected to
form as a result of electronic control of the substrate react-
Recently, we reported that a phosphine-ligated copper(I)
catalyst was effective for the hydroboration of electrophilic
alkenes using pinacolborane (HBpin) as the hydroborating
reagent.[7] Since alkenylboronic esters can be prepared from
alkyne substrates,[8] we envisioned that two successive regio-
and stereoselective hydroboration reactions of terminal al-
[7a,13]
À
ing with the nucleophilic Cu H catalyst.
On the other
hand, the b-hydroboration product (b-m) would result from
steric interactions between the substrate and catalyst.
[a] S. Lee, D. Li, Prof. J. Yun
Department of Chemistry and Institute of Basic Science
Sungkyunkwan University
Suwon 440-746 (Korea)
Fax : (+82)31-290-7075
E-mail: jaesook@skku.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201402458.
Scheme 1. Hydroboration of phenylacetylene.
Chem. Asian J. 2014, 9, 2440 – 2443
2440
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemasianj.org
Jaesook Yun et al.
Table 2. Synthesis of 1,1-diboryl compounds via hydroboration.
To increase the regioselectivity of the first hydroboration
and for an overall more efficient synthesis, the substrate was
switched from an arylalkyne to less electronically biased
simple alkynes and propargylic alkynes. The hydroboration
of propargyl amide 1a was investigated by screening the
copper source, ligand, and base in the presence of pinacol-
borane at room temperature (Table 1). While CuTC/dppbz
Entry
1[c]
Alkyne
Yield [%][b]
80
1b
2[c]
3[d]
1c
1d
74
72
Table 1. Hydroboration of propargyl amide 1a.
4
1e
32
5
6
1 f
1g
n.r.[e]
83
Entry
Cu/L
CuTC[c]/dppbz
CuTC/PCy3
Base
Conversion [%][a]
Yield [%][b]
1
2
3
4
NaOtBu
NaOtBu
NaOtBu
NaOtBu
LiOtBu
K3PO4
92
63
32
100
100
100
60
14
30
7[f]
8[g]
1h
1i
56
63
CuCl/dppbz
CuCl/xantphos
CuCl/xantphos
CuCl/xantphos
66
5[d]
6
76
n.i.[e]
9[d,f]
10
1j
61
60
[a] Determined by GC analysis with an internal standard based on con-
sumption of 1a. [b] Yield of isolated 2a. [c] CuTC=copper(I) thiophene-
2-carboxylate [d] 2.2 equiv HBpin was used. [e] Not isolated. A 4:1 ratio
of 2a and monodeboronated product (2a’) was obtained by GC analysis
of the crude mixture.
1k
[a] The reaction was carried out with the combination of 5 mol% CuCl,
6 mol% xantphos, and 15 mol% NaOtBu in toluene using 2.2 equiv of pi-
nacolborane at room temperature for 24 h. [b] Yield of isolated 2.
[c] 2.4 equiv HBpin was used. [d] 10 mol% NaOtBu was used. [e] No re-
action. [f] The reaction temperature was 508C. [g] 5 mol% CuTC and
5 mol% NaOtBu were used. TBDMSO=tert-butyldimethylsilyloxy.
catalyst gave the desired product in moderate yield (Table 1,
entry 1), a copper/monophosphine catalyst gave the product
in low yield together with deboronated product (Table 1,
entry 2). Using CuCl/xantphos resulted in a superior conver-
sion to the product, which was isolated in 66% yield
(Table 1, entry 4). In contrast to the hydroboration of phe-
nylacetylene, a borylalkenyl intermediate was not detected
during this reaction. Replacement of NaOtBu with LiOtBu
gave a slightly increased isolated yield (Table 1, entry 5).
The reaction with less basic K3PO4 proceeded to complete
conversion, but deboronated product and impurities formed
along with the diborylated product.
diborylated products, which indicate that a sterically bulky
substituent does not impede the reaction.
Next, intermediate alkenylboronate compounds were pre-
pared in a separate step,[10,17] and these intermediates were
subjected to hydroboration at room temperature to assess
the efficiency of the copper/xantphos catalyst in the second
hydroboration step (Scheme 2). The reactions proceeded
smoothly at room temperature to afford the products with
With optimized reaction conditions including NaOtBu[14]
as base, the dihydroboration of various terminal alkynes was
examined (Table 2). The reaction of benzyl or methyl pro-
tected propargyl alcohols gave the desired products in good
yields without the detection of other regioisomeric products
(Table 2, entries 1 and 2). The reaction of silyl-protected
propargyl ether (1d) afforded the product in 72% yield, but
reaction of a propargyl ester (1e) gave a poor yield of prod-
uct, possibly due to SN2’ substitution[15] by the Cu H catalyst
À
instead of addition. Unprotected propargyl alcohol (1 f) was
not reactive under the reaction conditions.
Simple aliphatic alkynes were suitable substrates for the
reaction as well. For alkyl substituted substrates, the reac-
tion temperature was increased to 508C to obtain a better
yield of the target products.[16] Primary alkyl-substituted
compounds (1g–1i) afforded the desired products in moder-
ate to good yields. Secondary and tertiary alkyl-substituted
alkyne substrates (1j, 1k) also produced the corresponding
Scheme 2. Hydroboration of alkenylboronates.
Chem. Asian J. 2014, 9, 2440 – 2443
2441
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemasianj.org
Jaesook Yun et al.
was stirred for 10 min at room temperature. The alkyne substrate
(0.5 mmol) was added to the reaction mixture, and the reaction tube was
washed with toluene (0.5 mL), sealed, and stirred at room temperature.
The reaction was monitored by TLC and GC. After 24 h, the reaction
mixture was filtered through a pad of Celite and concentrated. The prod-
uct was purified by chromatography on silica gel.
excellent regioselectivity and high yield. The hydroboration
of simple alkenylboronates proceeded at room temperature
to form the product in high yield (Scheme 2 (1)). The ab-
sence of detectable intermediate alkenylboronates in the di-
hydroboration of alkyl-substituted alkynes (Table 2) togeth-
er with this result suggests that the first hydroboration is
less energetically favorable than the second hydroboration,
especially for alkylalkynes under the dihydroboration condi-
tions.
Acknowledgements
A possible catalytic cycle for the sequential hydroboration
of terminal alkynes is proposed in Scheme 3. A ligand-coor-
This research was supported by the Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded by
the Ministry of Education, Science, and Technology (2011-0009533,
2013R1A1A2058160).
À
dinated Cu H moiety, generated in situ from CuOtBu and
Keywords: alkynes
· copper · homogeneous catalysis ·
hydroboration · regioselectivity
[1] a) K. Burgess, M. J. Ohlmeyer, Chem. Rev. 1991, 91, 1179–1191;
b) C. M. Crudden, D. Edwards, Eur. J. Org. Chem. 2003, 4695–4712;
c) A.-M. Carroll, T. P. OꢁSullivan, P. J. Guiry, Adv. Synth. Catal.
2005, 347, 609–631; d) T. Hayashi, Y. Matsumoto, Y. Ito, Tetrahe-
dron: Asymmetry 1991, 2, 601–612; e) H. Doucet, E. Fernandez,
T. P. Layzell, J. M. Brown, Chem. Eur. J. 1999, 5, 1320–1330.
[2] a) K. Endo, T. Ohkubo, M. Hirokami, T. Shibata, J. Am. Chem. Soc.
2010, 132, 11033–11035; b) K. Endo, M. Hirokami, T. Shibata, J.
Org. Chem. 2010, 75, 3469–3472; c) K. Endo, T. Ohkubo, T. Shibata,
Org. Lett. 2011, 13, 3368–3371; d) J. C. H. Lee, R. McDonald, D. G.
Hall, Nat. Chem. 2011, 3, 894–899.
[3] a) D. J. Pasto, J. Am. Chem. Soc. 1964, 86, 3039–3047; b) P. Nguyen,
R. B. Coapes, A. D. Woodward, N. J. Taylor, J. M. Burke, J. A. K.
Howard, T. B. Marder, J. Organomet. Chem. 2002, 652, 77–85;
c) V. V. R. Rao, S. K. Agarwal, I. Mehrotra, D. Devaprabhakara, J.
Organomet. Chem. 1979, 166, 9–16; d) J. Ramꢂrez, A. M. Segarra,
E. Fernꢃndez, Tetrahedron: Asymmetry 2005, 16, 1289–1294.
[4] X. Feng, H. Jeon, J. Yun, Angew. Chem. Int. Ed. 2013, 52, 3989–
3992; Angew. Chem. 2013, 125, 4081–4084; 1,1-diboryl compounds
via conjugate borylation, see ref. [2d].
[5] For the synthesis of 1,2-diboryl compounds from alkenylboronates
via hydroboration, a) C. Wiesauer, W. Weissensteiner, Tetrahedron:
Asymmetry 1996, 7, 5–8; via formal hydroboration b) Y. Lee, H.
Jang, A. H. Hoveyda, J. Am. Chem. Soc. 2009, 131, 18234–18235;
c) H.-Y. Jung, J. Yun, Org. Lett. 2012, 14, 2606–2609.
[6] K. Endo, M. Hirokami, T. Shibata, Synlett 2009, 1331–1335.
[7] a) D. Noh, H. Chea, J. Ju, J. Yun, Angew. Chem. Int. Ed. 2009, 48,
6062–6064; Angew. Chem. 2009, 121, 6178–6180; b) D. Noh, S. K.
Yoon, J. Won, J. Y. Lee, J. Yun, Chem. Asian J. 2011, 6, 1967–1969.
[8] a) C. Gunanathan, M. Hçlscher, F. Pan, W. Leitner, J. Am. Chem.
Soc. 2012, 134, 14349–14352; b) C. E. Tucker, J. Davidson, P. Kno-
chel, J. Org. Chem. 1992, 57, 3482–3485; c) S. Pereira, M. Srebnik,
Tetrahedron Lett. 1996, 37, 3283–3286; d) H. C. Brown, S. K. Gupta,
J. Am. Chem. Soc. 1972, 94, 4370–4373.
Scheme 3. Proposed catalytic cycle for the copper-catalyzed sequential
hydroboration of alkynes.
pinacolborane, is considered as the active catalyst, and its
addition to the alkyne and subsequent transmetalation with
pinacolborane affords the hydroboration product I by steric
control. Subsequent hydroboration of the alkenyl prod-
uct produces the desired 1,1-diborylalkane product. Since
the hydroboration of isolated alkenylboronates produced
1,1-diborylated products as the only detectable isomer
(Scheme 2), it could be concluded that the initial hydrobora-
tion of the alkyne controls the overall regioisomeric product
distribution of the diborylated products. The examples in
Scheme 2 also provide an alternative stepwise access to 1,1-
diborylalkane products from arylalkynes, which are difficult
to obtain in pure regioisomeric form due to the moderate
regioselectivity of the first hydroboration of these substrates
under the copper-catalyzed conditions.
In summary, we have developed a sequential copper-cata-
lyzed hydroboration of terminal alkynes with pinacolborane
for the preparation of 1,1-diborylalkane compounds. Pro-
tected propargyl amines, propargyl alcohol derivatives, and
simple alkynes reacted to give the desired 1,1-diborylalkanes
in good yields and high regioselectivity. This current method
that utilizes copper catalysis constitutes an alternative to the
previously reported Rh/dppb catalyzed protocol.
[9] K. Semba, T. Fujihara, J. Terao, Y. Tsuji, Chem. Eur. J. 2012, 18,
4179–4184.
[10] a) J.-E. Lee, J. Kwon, J. Yun, Chem. Commun. 2008, 733–734; b) M.
Gao, S. B. Thorpe, W. L. Santos, Org. Lett. 2009, 11, 3478–3481.
[11] J. Won, D. Noh, J. Yun, J. Y. Lee, J. Phys. Chem. A 2010, 114,
12112–12115.
[12] The ratio was determined by NMR spectroscopic analysis of a crude
reaction mixture. The deboronated form of a-d (Y=H) was ob-
tained under the reaction conditions.
Experimental Section
À
A mixture of CuCl (2.5 mg, 0.025 mmol), NaOtBu (7.2 mg, 0.075 mmol),
and xantphos (17.4 mg, 0.03 mmol) in anhydrous toluene (1 mL) was
stirred for 15 min in a Schlenk tube under a nitrogen atmosphere. Pina-
colborane (160 mL, 1.1 mmol) was added to the reaction, and the mixture
[13] For in situ generation of Cu H from copper precursors with pinacol-
borane, see: a) D. Zhao, K. Oisaki, M. Kanai, M. Shibasaki, J. Am.
ˇ
ˇ
Chem. Soc. 2006, 128, 14440–14441; b) B. H. Lipshutz, Z. V. Bos-
kovic, D. H. Aue, Angew. Chem. Int. Ed. 2008, 47, 10183–10186;
ˇ
Chem. Asian J. 2014, 9, 2440 – 2443
2442
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.chemasianj.org
Jaesook Yun et al.
À
Angew. Chem. 2008, 120, 10337–10340; for reviews of Cu H cata-
119, 1677–1681; c) C. Zhong, Y. Sasaki, H. Ito, M. Sawamura,
Chem. Commun. 2009, 5850–5852.
lyzed reactions, see: c) C. Deutsch, N. Krause, B. H. Lipshutz,
Chem. Rev. 2008, 108, 2916–2927; d) S. Rendler, M. Oestreich,
Angew. Chem. Int. Ed. 2007, 46, 498–504; Angew. Chem. 2007, 119,
504–510.
[16] For example, reactions of 1h and 1j at room temperature for 24 h
gave products in lower yields, 26% and 48%, respectively.
[17] a) H. R. Kim, J. Yun, Chem. Commun. 2011, 47, 2943–2945; b) J.
Takagi, K. Takahashi, T. Ishiyama, N. Miyaura, J. Am. Chem. Soc.
2002, 124, 8001–8006.
[14] LiOtBu was less effective for simple alkynes and protected proparg-
yl alcohol derivatives.
[15] a) J. F. Daeuble, C. McGettigan, J. M. Stryker, Tetrahedron Lett.
1990, 31, 2397–2400; b) C. Deutsch, B. H. Lipshutz, N. Krause,
Angew. Chem. Int. Ed. 2007, 46, 1650–1653; Angew. Chem. 2007,
Received: April 30, 2014
Published online: June 24, 2014
Chem. Asian J. 2014, 9, 2440 – 2443
2443
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim