Copper-catalyzed β-boration of α,β-unsaturated carbonyl compounds: Rate acceleration by alcohol additives

Article abstract of DOI:10.1021/ol061955a

(Chemical Equation Presented) The efficient addition of bis(pinacolato)diboron to α/β-unsaturated carbonyl compounds with a copper-diphosphine catalyst has been carried out. A dramatic rate acceleration of the reaction was realized by adding alcohol additives. With use of this procedure, a variety of α,β-unsaturated carbonyl compounds including conjugated substrates at the acid oxidation level such as esters and nitrites were reacted to give to the corresponding β-boryl carbonyl compounds in high yields.

Full text of DOI:10.1021/ol061955a

ORGANIC
LETTERS
2006
Vol. 8, No. 21
4887-4889
Copper-Catalyzed
â-Boration of
r,â-Unsaturated Carbonyl Compounds:
Rate Acceleration by Alcohol Additives†
Soungyun Mun, Ji-Eon Lee, and Jaesook Yun*
Department of Chemistry and Institute of Basic Science, Sungkyunkwan UniVersity,
Suwon 440-746, Korea
jaesook@skku.edu
Received August 7, 2006
ABSTRACT
The efficient addition of bis(pinacolato)diboron to
r,
â
-unsaturated carbonyl compounds with a copper
−diphosphine catalyst has been carried
out. A dramatic rate acceleration of the reaction was realized by adding alcohol additives. With use of this procedure, a variety of
unsaturated carbonyl compounds including conjugated substrates at the acid oxidation level such as esters and nitriles were reacted to give
to the corresponding -boryl carbonyl compounds in high yields.
r,â-
â
Transition metal-catalyzed boration of unsaturated C-C
bonds is an attractive method to produce the organoboron
derivatives with defined regio- and stereochemistry and has
greatly expanded the potential application of boron deriva-
tives in synthetic organic chemistry.1 While the addition of
diboronates such as bis(pinacolato)diboron (1) and bis-
(catecholato)diboron to alkenes and alkynes has been ex-
tensively studied with Pd,2 Pt,3 and Rh4 catalysts, few
examples employing other metals have been reported.5
Recently, copper-catalyzed conjugate addition reactions of
bis(pinacolato)diboron to R,â-enones have been indepen-
dently reported by Hosomi et al.6 and Miyaura et al.7 and
applied to the synthesis of boronated amino acids as a key
synthetic step. These acids are potential therapeutic agents.8
Although the reported copper-catalyzed reaction systems
afford â-boryl enones in reasonable yields, these reactions
have some limitations; only enones among other R,â-
unsaturated carbonyl compounds are reactive and high
catalyst loadings (10-110 mol %) are often required. Herein,
we report an efficient â-boration method of various R,â-
† Dedicated to Professor Eun Lee on the occasion of his 60th birthday.
(1) For reviews, see: (a) Beletskaya, I.; Moberg, C. Chem. ReV. 1999,
99, 3435. (b) Irvine, G. J.; Lesley, M. J. G.; Marder, T. B.; Norman, N. C.;
Rice, C. R.; Robins, E. G.; Roper, W. R.; Whittell, G. R.; Wright, L. J.
Chem. ReV. 1998, 98, 2685. (c) Davison, M.; Hughes, A. K.; Marder, T.
B.; Wade, K. Contemporary Boron Chemistry; RSC: Cambridge, UK, 2000.
(d) Matteson, D. S. Stereodirected Synthesis with Organoboranes;
Springer: Berlin, Germany, 1995.
(4) (a) Morgan, J. B.; Miller, S. P.; Morken, J. P. J. Am. Chem. Soc.
2003, 125, 8702. (b) Nguyen, P.; Coapes, R. B.; Woodward, A. D.; Taylor,
N. J.; Burke, J. M.; Howard, J. A. K.; Marder, T. B. J. Organomet. Chem.
2002, 652, 77. (c) Dai, C.; Robins, E. G.; Scott, A. J.; Clegg, W.; Yufit, D.
S.; Howard, J. A. K.; Marder, T. B. Chem. Commun. 1998, 1983.
(5) (a) Baker, R. T.; Nguyen, P.; Marder, T. B.; Westcott, S. A. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1336. (b) Ram´ırez, J.; Corbera´n, R.; Sanau´,
M.; Peris, E.; Fernandez, E. Chem. Commun. 2005, 3056.
(6) Ito. H.; Yamanaka, H.; Tateiwa, J.; Hosomi, A. Tetrahedron Lett.
2000, 41, 6821.
(2) Pelz, N. F.; Woodward, A. R.; Burks, H. E.; Sieber, J. D.; Morken,
J. P. J. Am. Chem. Soc. 2004, 126, 16328.
(3) (a) Ishiyama, T.; Matsuda, N.; Miyaura, N.; Suzuki, A. J. Am. Chem.
Soc. 1993, 115, 11018. (b) Iverson, C. N.; Smith, M. R., III Organometallics
1997, 16, 2757. (c) Marder, T. B.; Norman, N. C.; Rice, C. R. Tetrahedron
Lett. 1998, 39, 155.
(7) Takahashi, K.; Ishiyama, T.; Miyaura, N. J. Organomet. Chem. 2001,
625, 47.
(8) Kabalka, G. W.; Das, B. C.; Das, S. Tetrahedron Lett. 2001, 42,
7145.
10.1021/ol061955a CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/23/2006

unsaturated carbonyl compounds with a copper-diphosphine
catalyst in the presence of alcohol additives.
decided to use alcohol additives as in the conjugate reduction
of R,â-unsaturated nitriles,10 hoping that the additives would
promote reaction rates by effectively protonating organo-
copper species12 generated by the addition of copper boryl
species to the ester. Indeed, addition of alcohols to the
reaction mixture led to an enhanced rate of reaction (entries
4 and 5). Methanol was a better additive than sterically bulky
t-BuOH. Both DPEphos ligand and MeOH additive were
necessary for an efficient reaction, as other monophosphine
ligands (entries 6 and 7) and the ligandless reaction (entry
8) resulted in incomplete conversion after 14 h.
For the past few years, our laboratory has engaged in the
development of the reduction reactions of ketones and R,â-
unsaturated carbonyl compounds catalyzed by copper-
phosphine complexes in the presence of stoichiometric
hydrosilanes.9 Recently, we have reported that complexes
of a copper salt and xanthene-based ligands such as Xant-
phos (9,9-dimethyl-4,6-bis(diphenylphosphino)xanthene) and
DPEphos (bis(2-diphenylphosphinophenyl)ether) are par-
ticularly efficient for the conjugate reduction of R,â-
unsaturated nitriles.10 On the basis of the observations that
the Xantphos-type ligands increased the nucleophilic reactiv-
ity of copper hydride species, we envisioned that similar
copper boryl complexes coordinated with those ligands would
be efficient for the catalytic â-boration of R,â-unsaturated
carbonyl compounds.
With an optimal reaction protocol using DPEphos ligand
and MeOH as additives, the catalytic â-boration of various
R,â-unsaturated carbonyl compounds was examined. As
shown in Table 2, a range of R,â-unsaturated substrates were
Initially, we examined the â-boration of (E)-ethyl crotonate
by using a catalytic amount of copper salt and ligand in the
presence of 1.1 equiv of bis(pinacolato)diboron (1) in THF
at room temperature. Catalytic â-boration of conjugated
carbonyl systems at the acid oxidation level is especially
challenging.7,11 For example, a stoichiometric amount of
copper salt and an elevated temperature were necessary for
the conjugate addition of the diboron to R,â-unsaturated
esters, giving the desired products only in moderate yields.7
As shown in Table 1, copper(I) chloride, a more easily
Table 2. Copper-Catalyzed â-Boration of Various Unsaturated
Carbonyl Compoundsa
time 3, yield
entry substrate
R
EWG
(h)
(%)b
1
2
3
4
5
6
7c
2a
2b
2c
2d
2e
2f
H
CH3
Ph
C(O)OEt
C(O)OEt 14.5
C(O)OEt 11
1.5
98
95
91
98
93
95
90
4-MeOC6H4
4-ClC6H4
Ph
3-methyl-2-
cyclohexen-1-one
Ph
C(O)OEt
3
C(O)OEt 16
C(O)CH3 14
14
Table 1. Catalytic Addition of Diboron (1) to (E)-Ethyl
Crotonate under Various Conditions
2g
8
9
2h
2i
CN
6.5
95
91d
Ph
P(O)OEt2 15
a Conditions: 3 mol % of CuCl, 3 mol % of DPEphos, 9 mol % of
NaOt-Bu, 1.1 equiv of 1, 2 equiv of MeOH, THF, room temperature.
b Isolated yield. c 5 mol % of catalyst was used. d GC yield.
base
(mol %)
additive
(equiv)
convn
(%)a
entry
CuX
ligand
1
2
3
4
5
6
7
8
Cu(OAc) DPEphos
26
30
48
82
>98
85
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
Xantphos NaOt-Bu (9)
DPEphos NaOt-Bu (9)
DPEphos NaOt-Bu (9) t-BuOH (2)
DPEphos NaOt-Bu (9) MeOH (2)
PBu3
PCy3
regioselectively borylated at room temperature in excellent
yields. Simple ethyl acrylate (2a), ethyl crotonate (2b), and
cinnamate (2c) afforded the corresponding products in high
yields (entries 1-3). The reaction of cinnamate derivatives
bearing an electron-donating group and an electron-
withdrawing group yielded products in excellent yields as
well (entries 4 and 5). Especially, substrate 2d with an
electron-donating methoxy group reacted faster than the
cinnamate itself. R,â-Unsaturated ketones (entries 6 and 7)
were borylated more efficiently under our optimal reaction
conditions than Hosomi’s conditions employing CuOTf and
PBu3. It is noteworthy that the present catalytic system is
tolerant of steric hindrance at the â-carbon and reacted with
NaOt-Bu (9) MeOH (2)
NaOt-Bu (9) MeOH (2)
NaOt-Bu (9) MeOH (2)
82
84
a Conversion was determined by GC analysis.
accessible Cu(I) salt than Cu(OAc), gave a slightly higher
conversion in the presence of NaOt-Bu (entry 1 vs 2) and
DPEphos performed better than Xantphos as ligands (entry
2 vs 3). However, all the reactions investigated proceeded
to a partial conversion and longer reaction times gave only
a small increase in conversion before decomposition. We
(11) In a Pt-catalyzed addition of bis(pinacolatodiboron) to R,â-unsatur-
ated esters, 3,4-addition products were obtained in moderate conversion,
see: Bell, N. J.; Cox, A. J.; Cameron, N. R.; Evans, J. S. O.; Marder, T.
B.; Duin, M. A.; Elsevier, C. J.; Baucherel, X.; Tulloch, A. A. D.; Tooze,
R. P. Chem. Commun. 2004, 1854.
(12) Hughes, G.; Kimura, M.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 11253.
(9) (a) Lee, D.; Yun, J. Tetrahedron Lett. 2004, 45, 5415. (b) Yun, J.;
Kim, D.; Yun, H. Chem. Commun. 2005, 5181. (c) Lee, D.; Kim, D.; Yun,
J. Angew. Chem., Int. Ed. 2006, 45, 2785.
(10) Kim, D.; Park, B.-M.; Yun, J. Chem. Commun. 2005, 1755.
4888
Org. Lett., Vol. 8, No. 21, 2006

sterically hindered â,â-disubstituted enone 2g that was inert
under Hosomi’s conditions (entry 7). Other R,â-unsaturated
nitriles and phosphonates13 were suitable substrates as well
(entries 8 and 9).
Scheme 2. A Proposed Mechanism
In preliminary experiments to show the utility of this
reaction protocol, the asymmetric â-boration of cinnamoni-
trile and subsequent oxidation14 were attempted by using
Josiphos as the chiral ligand (Scheme 1). These transforma-
Scheme 1. Application of â-Borylated Product
carbonyl compounds takes place. The resulting organocopper
species reacts with MeOH to yield the protonated product
and a copper alkoxide. The latter then regenerates the active
catalyst with diboron 1.
In summary, we disclose a highly efficient protocol for
the conjugate addition of bis(pinacolato)diboron to various
R,â-unsaturated carbonyl compounds by using the combina-
tion of catalytic amounts of CuCl, NaOt-Bu, and DPEphos
in the presence of methanol as additives. The addition of
MeOH was essential for the successful â-boration and
enhancement of the reaction scope. Future studies are aimed
at establishing the full scope of this method, investigation
of mechanistic issues, and the application of boron deriva-
tives to organic synthesis. Establishment of asymmetric
tertiary and quaternary stereocenter by this method is in
progress as well.
tions yielded â-hydroxy nitrile compound 415 of 82% ee in
84% overall yield, which could be further transformed to
other useful functionalities.
A possible catalytic cycle for the alcohol accelerated
â-boration process is shown in Scheme 2. Our current view
is that a diphosphine ligated copper boryl complex16 is the
key intermediate and its conjugate addition to R,â-unsaturated
(13) The â-borylated phosphonate 3i was unstable on SiO2, decomposing
into 2i and being eluted together as an inseparable mixture. For difficulties
of isolating phosphonoboronates, see: Pergament, I.; Srebnik, M. Org. Lett.
2001, 3, 217.
Acknowledgment. This work was supported by the
Faculty Research Fund 2005, Sungkyunkwan University.
(14) Farthing, C. N.; Marsden, S. P. Tetrahedron Lett. 2000, 41, 4235.
(15) (a) Suto, Y.; Kumagai, N.; Matsunaga, S.; Kanai, M.; Shibasaki,
M. Org. Lett. 2003, 5, 3147. (b) Liu, P. N.; Gu, P. M.; Wang, F.; Tu, Y. Q.
Org. Lett. 2004, 6, 169.
(16) For an isolated copper boryl complex, see: Laitar, D. S.; Muller,
P.; Sadighi, J. P. J. Am. Chem. Soc. 2005, 127, 17196.
Supporting Information Available: Experimental pro-
cedures and chracterization of the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL061955A
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