A masked diboron in Cu-catalysed borylation reaction: Highly regioselective formal hydroboration of alkynes for synthesis of branched alkenylborons

Article abstract of DOI:10.1039/c4cc01757a

The use of a masked diboron as a boron source in the presence of a Cu-N-heterocyclic carbene (NHC) catalyst enables alkyl-, aryl-, heteroatom- and silyl-substituted terminal alkynes to undergo α-selective formal hydroboration to give diverse branched alkenylboron compounds exclusively. Synthetic potential of this α-selective hydroboration has been demonstrated by total synthesis of pharmaceutically significant bexarotene and LG100268. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01757a

Showcasing research from Dr Hiroto Yoshida, Department of
Applied Chemistry, Hiroshima University, Japan
As featured in:
A masked diboron in Cu-catalysed borylation reaction: Highly
regioselective formal hydroboration of alkynes for synthesis of
branched alkenylborons
A wide variety of terminal alkynes have been demonstrated to be
convertible into branched borylalkenes straightforwardly by the
Cu-catalyzed α-selective hydroboration with a masked diboron.
By utilizing the resulting branched borylalkene, pharmacologically
significant bexarotene and LG100268 can be conveniently
synthesized in good overall yields.
See Hiroto Yoshida et al.,
Chem. Commun., 2014, 50, 8299.
www.rsc.org/chemcomm
Registered charity number: 207890

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
A masked diboron in Cu-catalysed borylation
reaction: highly regioselective formal
hydroboration of alkynes for synthesis of
branched alkenylborons†
Cite this: Chem. Commun., 2014,
50, 8299
Received 8th March 2014,
Accepted 8th April 2014
Hiroto Yoshida,*ab Yuki Takemotoa and Ken Takakia
DOI: 10.1039/c4cc01757a
www.rsc.org/chemcomm
The use of a masked diboron as a boron source in the presence of a
Cu–N-heterocyclic carbene (NHC) catalyst enables alkyl-, aryl-,
heteroatom- and silyl-substituted terminal alkynes to undergo
a-selective formal hydroboration to give diverse branched alkenylboron
compounds exclusively. Synthetic potential of this a-selective hydro-
boration has been demonstrated by total synthesis of pharmaceutically
significant bexarotene and LG100268.
The development of new methods for accessing regio- and
stereodefined alkenylboron compounds has been one of the central
subjects in chemical synthesis,1 because it provides us convenient
and potent access to invaluable multisubstituted alkenes with con-
trolled geometry through carbon–carbon bond-forming processes
including Suzuki–Miyaura coupling,2 the Petasis reaction,3 transition
metal-catalysed conjugate addition,4 etc. One of the most
Fig. 1 Selected valuable compounds having a 1,1-disubstituted alkene moiety.
straightforward approaches to alkenylboron compounds would of terminal alkynes using bis(pinacolato)diboron and a copper
be hydroboration of alkynes,5 and the anti-Markovnikov addition complex, these methods are still not versatile unfortunately, because
to terminal alkynes commonly occurs to provide linear alkenyl- of the confined substrate scope of alkynes, the imperfect regioselec-
boron compounds with high b-selectivity, regardless of the tivity and the use of stoichiometric amounts of a copper complex
presence6 or absence7 of a transition metal catalyst (eqn (1)).
(the former case). In view of the fact that 1,1-disubstituted alkenes
are ubiquitous motifs in biologically and pharmacologically signifi-
cant molecules such as apoatropine,11 bexarotene,12 dehydro-a-
curcumene13 and isocombretastatin A-414 (Fig. 1), the development
of catalytic and truly a-selective hydroboration of terminal alkynes
with broad scope, which opens up a direct way to these valuable
classes of compounds, has been a long-sought goal.
(1)
In marked contrast, selective access to branched alkenylboron
compounds, regioisomers of linear ones, is narrow and laborious,
because the existing procedures require multistep operation by use
of preformed branched alkenyl anionic species8 or halides.9
Although Miyaura10a and Hoveyda10b reported on direct synthesis
of branched alkenylboron compounds via a-selective hydroboration
We have recently devoted our attention to developing copper-
catalysed borylation reactions of unsaturated carbon linkages15
involving alkenes, alkynes and arynes by use of bis(pinacolato)diboron
as a boron source, and accomplished diborylation,16a boryl-
stannylation16b and carboboration16c which enable previously
inaccessible organoboron compounds to be synthesized efficaciously.
The regiochemical outcomes of these reactions are definitively
governed by mode of addition of a borylcopper species, derived
from (pin)B–B(pin) and a copper(I) complex, across the unsaturated
C–C bonds, and anti-Markovnikov selectivities are usually observed
with terminal alkynes (and alkenes) as depicted in Scheme 1.
Similarly to the conventional uncatalysed hydroboration, one of
a Department of Applied Chemistry, Graduate School of Engineering,
Hiroshima University, Higashi-Hiroshima 739-8527, Japan.
E-mail: yhiroto@hiroshima-u.ac.jp; Fax: +81-82-424-5494; Tel: +81-82-424-7724
b ACT-C, Japan Science and Technology Agency, Japan
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization data. See DOI: 10.1039/c4cc01757a
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 8299--8302 | 8299

View Article Online
Communication
ChemComm
Table 1 Scope of Cu-catalysed a-selective hydroboration of terminal alkynes
Entry
1
Product
Yielda (%)
81
a : bb
Scheme 1 Cu-catalysed borylstannylation and carboboration of terminal
alkynes with anti-Markovnikov selectivity.
499 : 1
the chief factors affecting the orientation of the approaching
borylcopper species should be the Lewis acidic character of the
(pin)B moiety, which favours addition to the terminal carbons to
generate a more stable carbocationic transition state. We thus
hypothesized that diminishing the Lewis acidity of a boron
centre with appropriate substituents may alter the regiochemical
behaviour of a borylcopper species in the borylcupration step,
leading to Markovnikov selectivity. Herein we report that the
highly a-selective hydroboration of terminal alkynes with broad
scope is achievable by use of a masked diboron17 as a boron
source under copper catalysis.
2
3
99
92
499 : 1
499 : 1
We first carried out the reaction of phenylacetylene with a
diboron ((pin)B–B(dan)),18 one of whose boryl moiety was masked
with 1,8-diaminonaphthalene (dan),19 in THF in the presence of
a sterically congested N-heterocyclic carbene (NHC)-coordinated
copper complex ((SIPr)CuCl, 2 mol%),20 KOtBu and MeOH,21 and
observed that the B(dan) moiety was introduced with exclusive
a-selectivity to afford a branched borylstyrene (1a) in 81% yield
(Table 1, entry 1). ortho- and para-methoxy-substituted arylalkynes
were also facilely convertible into the respective a-borylstyrenes (1b
and 1c) in excellent yields (entries 2 and 3), being in marked contrast
to the Hoveyda’s results that a mixture of a- and b-borylalkenes was
produced (41 : 59 for ortho-methoxyphenylacetylene; 62 : 38 for para-
methoxyphenylacetylene).10b Although a small amount of a linear
borylalkene (10d) was formed exceptionally in the reaction of p-CF3-
phenylacetylene, the selectivity for a branched one (1d) was still
95% (entry 4). It should be noted that the present hydroboration
proceeded with the high degree of the a-selectivity, irrespective of
steric and electronic properties of terminal alkynes employed, giving
boryl-substituted aliphatic alkenes (1e and 1f), silylalkene (1g) and
allyl ether (1h) in high yields (entries 5–8). Furthermore, the high
functional group compatibility of the reaction was demonstrated by
use of 4-bromo-1-butyne, leaving the C–Br bond intact (1i, entry 9),
and the reaction was applicable to 1,7-octadiyne, both of whose triple
bonds underwent the a-selective hydroboration to give diborylation
product 1j (entry 10).
4
67
95 : 5
5
6
7
92
79
99
499 : 1
499 : 1
499 : 1
8
9
99
99
499 : 1
499 : 1
10c
95
499 : 1
a
b
c
Isolated yield. Ratio of products determined by 1H NMR. Reaction
Synthetic utility of the a-selective formal hydroboration has
been demonstrated by total synthesis of bexarotene (4), being
used to treat cutaneous T-cell lymphoma (Scheme 2).12 Thus, a
carried out with half the molar of an alkyne.
branched borylalkene (1k) was available as the sole product in conversion and regioselectivity. Unmasking of the B(dan) moiety of
97% yield by the formal hydroboration of the respective arylalkyne, 1k under acidic conditions provided 2,22 whose C–B(pin) bond was
where only 0.1 mol% catalyst loading was enough for excellent coupled with methyl 4-iodobenzoate in the presence of a palladium
8300 | Chem. Commun., 2014, 50, 8299--8302
This journal is ©The Royal Society of Chemistry 2014

View Article Online
ChemComm
Communication
Scheme 2 Total synthesis of bexarotene and LG100268.
catalyst to afford 3. Hydrolysis of the ester moiety of 3 finally gave acidic B(pin) moiety of (pin)B–B(dan) and the alkoxy moiety of
bexarotene (4) in 60% overall yield (4 steps, based on the alkyne). Cu–OR in the s-bond metathesis step. Subsequent insertion of
Similarly, the cross-coupling of 2 with ethyl 6-chloronicotinate an alkyne into the Cu–B(dan) bond which generates a b-boryl-
produced a 78% yield of diarylalkene (5).23 Subsequent cyclo- alkenylcopper species followed by protonation with MeOH
propanation with a sulfoxonium ylide, followed by hydrolysis of provides the hydroboration product with regeneration of
the resulting diarylcyclopropane (6) furnished LG100268 (7),24
high affinity, selective retinoid X receptor (RXR) agonist, in 53% masked B(dan) moiety19 in Cu–B(dan), the interaction between an
overall yield (5 steps, based on the alkyne). incoming terminal alkyne and the boron centre, which may be a
a
Cu–OR (Scheme 3). Owing to the diminished Lewis acidity of the
The present hydroboration would be triggered by exclusive contributory factor of anti-Markovnikov-type (b-selective) addition
formation of a borylcopper species, Cu–B(dan), which can be through a more stable carbocationic transition state (vide supra),25
rationally explained by selective interaction between the Lewis would be negligible in the borylcupration step. Therefore the
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun., 2014, 50, 8299--8302 | 8301

View Article Online
Communication
ChemComm
4 (a) T. Hayashi, Synlett, 2001, 879; (b) T. Hayashi and K. Yamasaki,
Chem. Rev., 2003, 103, 2829.
5 I. Beletskaya and A. Pelter, Tetrahedron, 1997, 53, 4957.
6 (a) S. Pereira and M. Srebnik, Tetrahedron Lett., 1996, 37, 3282;
(b) S. Pereira and M. Srebnik, Organometallics, 1995, 14, 3127;
(c) Y. D. Wang, G. Kimball, A. S. Prashad and Y. Wang, Tetrahedron
¨
¨
Lett., 2005, 46, 8777; (d) D. Mannig and H. Noth, Angew. Chem., Int.
Ed. Engl., 1985, 24, 878; (e) T. Ohmura, Y. Yamamoto and
N. Miyaura, J. Am. Chem. Soc., 2000, 122, 4990; ( f ) B. Sundararaju
and A. Fu¨rstner, Angew. Chem., Int. Ed., 2013, 52, 14050;
(g) N. Iwadate and M. Suginome, Org. Lett., 2009, 11, 1899.
7 (a) C. E. Tucker, J. Davidson and P. Knochel, J. Org. Chem., 1992,
57, 3482; (b) K. Shirakawa, A. Arase and M. Hoshi, Synthesis, 2004,
1814.
8 (a) C. Morrill, T. W. Funk and R. H. Grubbs, Tetrahedron Lett., 2004,
45, 7733; (b) W. J. Moran and J. P. Morken, Org. Lett., 2006, 8, 2413;
(c) F. Gao and A. H. Hoveyda, J. Am. Chem. Soc., 2010, 132, 10961.
9 J. Takagi, K. Takahashi, T. Ishiyama and N. Miyaura, J. Am. Chem.
Soc., 2002, 124, 8001.
10 (a) K. Takahashi, T. Ishiyama and N. Miyaura, J. Organomet. Chem.,
2001, 625, 47; (b) H. Jang, A. R. Zhugralin, Y. Lee and A. H. Hoveyda,
J. Am. Chem. Soc., 2011, 133, 7859.
11 M. Tavasli, D. O’Hagan, A. S. Batsanov, G. R. Foxon, R. F. Halliwell
and J. A. K. Howard, J. Chem. Soc., Perkin Trans. 1, 1999, 3455.
12 T. Illidge, C. Chan, N. Counsell, S. Morris, J. Scarisbrick, D. Gilson,
B. Popova, P. Patrick, P. Smith, S. Whittaker and R. Cowan, Br.
J. Cancer, 2013, 109, 2566.
13 J. R. Vyvyan, C. Loitz, R. E. Looper, C. S. Mattingly, E. A. Peterson
and S. T. Staben, J. Org. Chem., 2004, 69, 2461.
14 J. Aziz, E. Brachet, A. Hamze, J.-F. Peyrat, G. Bernadat, E. Morvan,
J. Bignon, J. Wdzieczak-Bakala, D. Desravines, J. Dubois, M. Tueni,
A. Yassine, J.-D. Brion and M. Alami, Org. Biomol. Chem., 2013,
11, 430.
15 (a) H. R. Kim, I. G. Jung, K. Yoo, K. Jang, E. S. Lee, J. Yun and
S. U. Son, Chem. Commun., 2010, 46, 758; (b) H. R. Kim and J. Yun,
Chem. Commun., 2011, 47, 2943; (c) Y. Lee and A. H. Hoveyda, J. Am.
Chem. Soc., 2009, 131, 3160; (d) Y. Sasaki, Y. Horita, C. Zhong,
M. Sawamura and H. Ito, Angew. Chem., Int. Ed., 2011, 50, 2778;
(e) K. Semba, T. Fujihara, J. Terao and Y. Tsuji, Chem. – Eur. J., 2012,
18, 4179; ( f ) W. Yuan and S. Ma, Org. Biomol. Chem., 2012, 10, 7266;
Scheme 3 Catalytic cycle for the Cu-catalysed hydroboration of alkynes.
´
´
(g) A. L. Moure, R. G. Arrayas, D. J. Cardenas, I. Alonso and
J. C. Carretero, J. Am. Chem. Soc., 2012, 134, 7219; (h) J. K. Park,
B. A. Ondrusek and D. T. McQuade, Org. Lett., 2012, 14, 4790.
16 (a) H. Yoshida, S. Kawashima, Y. Takemoto, K. Okada, J. Ohshita
and K. Takaki, Angew. Chem., Int. Ed., 2012, 51, 235; (b) Y. Takemoto,
H. Yoshida and K. Takaki, Chem. – Eur. J., 2012, 18, 14841;
(c) H. Yoshida, I. Kageyuki and K. Takaki, Org. Lett., 2013, 15, 952.
17 N. Iwadate and M. Suginome, J. Am. Chem. Soc., 2010, 132, 2548.
18 This diboron can readily be synthesized from (pin)B–B(pin) and
1,8-diaminonaphthalene. See ESI† for details.
19 The boryl moiety masked with the dan group becomes significantly
less Lewis acidic. See: (a) H. Noguchi, K. Hojo and M. Suginome,
J. Am. Chem. Soc., 2007, 129, 758; (b) H. Noguchi, T. Shioda, C.-M.
Chou and M. Suginome, Org. Lett., 2008, 10, 377; (c) N. Iwadate and
M. Suginome, Chem. Lett., 2010, 39, 558.
20 Although we did not conduct the reaction of a terminal alkyne
with other NHC ligands, SIPr turned out to exhibit the highest
regioselectivity in the hydroboration of an unsymmetrical internal
alkyne with (pin)B–B(dan), which will be reported in due course.
21 S. Mun, J.-E. Lee and J. Yun, Org. Lett., 2006, 8, 4887.
22 K. Sasaki and T. Hayashi, Angew. Chem., Int. Ed., 2010, 49, 8145.
23 The transformation of 2 into 5 using CuI instead of [(PPh3)CuCl]4
resulted in lower yield, because of aggregation of copper.
orientation of Cu–B(dan) should simply be controlled by steric
repulsion between a substituent on alkynes and the bulkier copper
moiety, which results in the sole introduction of the B(dan) moiety
into the internal carbon of terminal alkynes.
In conclusion, we have developed the first general a-selective
hydroboration by combining a masked diboron and (SIPr)CuCl
catalyst, which leads to the direct and potent method for
synthesizing diverse branched borylalkenes, irrespective of
the electronic and steric nature of terminal alkynes employed.
The resulting branched borylalkene has proven to be synthetically
useful for fabricating pharmacologically significant compounds
such as bexarotene and LG100268. Further studies on borylation
reactions using a masked diboron under copper catalysis as well as
on mechanistic details are in progress.
Notes and references
1 (a) Boronic Acids, ed. D. G. Hall, Wiley-VCH, Weinheim, 2011;
(b) G. A. Molander and N. Ellis, Acc. Chem. Res., 2007, 40, 275.
24 A. Mazumdar, D. Medina, F. S. Kittrell, Y. Zhang, J. L. Hill,
D. E. Edwards, R. P. Bissonnette and P. H. Brown, Cancer Prev.
Res., 2012, 5, 1195.
2 (a) N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457; 25 Although other factors (electronic properties of the ligand, coordination
(b) N. Miyaura, Top. Curr. Chem., 2002, 219, 11; (c) S. Kotha,
K. Lahiri and D. Kashinath, Tetrahedron, 2002, 58, 9633.
3 (a) N. A. Petasis, A. Goodman and I. A. Zavialov, Tetrahedron,
modes of alkynes to the copper, etc.) may also affect the regio-
selectivities of the borylcupration, we particularly focused on the
masking effect of the boron moiety in order to plainly rationalize the
different regiochemical outcomes in the reactions using (pin)B–
B(dan) or (pin)B–B(pin).
¨
1997, 53, 16463; (b) T. Koolmeister, M. Sodergren and M. Scobie,
Tetrahedron Lett., 2002, 43, 5965.
8302 | Chem. Commun., 2014, 50, 8299--8302
This journal is ©The Royal Society of Chemistry 2014