Copper-catalyzed asymmetric allylic substitution of allyl phosphates with aryl- and alkenylboronates

Article abstract of DOI:10.1002/anie.201103581

The asymmetric allylic substitution of allyl phosphates with aryl- and alkenylboronates catalyzed by a copper/N-heterocyclic carbene complex was developed and the substitution products were obtained with high enantioselectivity (see scheme). To account for the observed influence of the reaction parameters a possible catalytic cycle for this process was proposed. Copyright

Full text of DOI:10.1002/anie.201103581

Communications
DOI: 10.1002/anie.201103581
Asymmetric Catalysis
Copper-Catalyzed Asymmetric Allylic Substitution of Allyl Phosphates
with Aryl- and Alkenylboronates**
Ryo Shintani,* Keishi Takatsu, Momotaro Takeda, and Tamio Hayashi*
Catalytic asymmetric allylic substitution with organometallic
reagents is one of the efficient ways of constructing enan-
tioenriched chiral compounds by the formation of a new
carbon–carbon bond. Although a significant number of
reports have been made on this reaction, particularly using
chiral copper complexes as catalysts,[1] the organometallic
reagents that can be employed are mostly limited to highly
reactive ones, such as Grignard,[2] diorganozinc,[3] and tri-
organoaluminum reagents.[4] In contrast, the use of milder
nucleophiles, such as organoboronic acid derivatives, has been
much less explored despite their availability, stability, and
ease of handling.[5] In fact, the asymmetric substitution of
simple allylic electrophiles with organoboronic acids has been
addressed only in the context of nickel-catalyzed reactions
with moderate enantioselectivity,[6] and rhodium-catalyzed
reactions using cis-2-butene-1,4-diol derivatives as sub-
strates.[7,8] In addition to the limited number of methods,
most of the organometallic nucleophiles that have been
employed in asymmetric allylic substitution reactions are
alkylmetals; the successful employment of aryl nucleophiles
has begun to appear only recently.[2d–f,3a,4c,6–9] Herein we
describe the development of a copper/N-heterocyclic carbene
complex catalyzed asymmetric allylic substitution of allyl
phosphates with aryl- and alkenylboronic acid esters to
construct both tertiary and quaternary carbon stereocenters
with high regio- and enantioselectivity.[10]
Table 1: A study of the base and ligand used in the copper-catalyzed
asymmetric allylic substitution of 1a with 4-methoxyphenylboronate.
Entry Ligand
salt
Base
Yield of
2a/
ee of
2a+3a [%][a]
3a[b]
2a [%][c]
1
2
(S)-4a
(S)-4a
(S)-4a
(S)-4b
(S,S)-4c
(S,S)-4d
KOtBu 95
NaOtBu 92
NaOMe 91
NaOMe 85
NaOMe 92
NaOMe 92
NaOMe 75
NaOMe 68
41:59 56
86:14 32
78:22 48
86:14 76
3[d]
4[d]
5
97:3
99:1
99:1
94:6
91
92
81
78
6
7[e,f] (S,S)-4d
8[f]
(S,S)-4e
[a] Yield of the isolated product. [b] Determined by 1H NMR spectros-
copy. [c] Determined by HPLC on a Chiralpak AS-H column with hexane/
2-propanol=95:5 after converting 2a into alcohol 5a by hydroboration/
oxidation. [d] The reaction was conducted for 40 h. [e] 4-Methoxyphe-
nylboronic acid pinacol ester was used as the nucleophile. [f] The
reaction was conducted for 30 h. THF=tetrahydrofuran.
In 2010, two research groups independently reported that
arylboronic acid esters are competent nucleophiles in copper-
catalyzed allylic substitution reactions using achiral cata-
lysts.[11] Based on this precedent, as well as our recent success
in the copper-catalyzed asymmetric addition of organoboro-
nates using Mauduit-type chiral N-heterocyclic carbene
(NHC) ligands,[12,13] we initially conducted the reaction of
cinnamyl phosphate (1a) with 4-methoxyphenylboronic acid
neopentylglycol ester in the presence of CuCl (5 mol%),
chiral NHC salt (S)-4a (5.5 mol%),[12a] and KOtBu
(2.0 equiv) in THF at 308C (Table 1, entry 1). Under these
reaction conditions, the reaction proceeded smoothly to give a
41:59 mixture of the g-substitution product 2a and the a-
substitution product 3a in 95% combined yield; the thus
obtained 2a had a moderate ee value of 56%.[14] We
subsequently found that the choice of metal alkoxide base
had a significant impact on the reaction outcome. For
example, when NaOtBu was used there was a higher
selectivity toward 2a over 3a (86:14), but the enantioselec-
tivity of 2a became significantly lower (Table 1, entry 2). On
the other hand, the reaction with NaOMe resulted in
preferential formation of 2a (2a/3a = 78:22) with 48% ee
(Table 1, entry 3). On the basis of these results, we decided to
employ NaOMe as the base in investigations to examine the
effect of different chiral NHC ligands. As shown in entry 4
(Table 1), the change of substitutent on the ligand tether from
tert-butyl to phenyl ((S)-4b)[12a] improved both the g selectiv-
ity (86:14) and enantioselectivity (76% ee), and even higher
selectivities were observed when using a tether derived from
[*] Dr. R. Shintani, Dr. K. Takatsu, M. Takeda, Prof. Dr. T. Hayashi
Department of Chemistry, Graduate School of Science
Kyoto University, Sakyo, Kyoto 606-8502 (Japan)
E-mail: shintani@kuchem.kyoto-u.ac.jp
thayashi@kuchem.kyoto-u.ac.jp
[**] Support has been provided in part by a Grant-in-Aid for Young
Scientists (B), the Ministry of Education, Culture, Sports, Science,
and Technology (Japan). K.T. thanks the JSPS for a fellowship.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103581.
8656
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 8656 –8659

trans-1-amino-2-indanol ((S,S)-4c;[12b] Table 1, entry 5). The
highest regio- and enantioselectivities were realized when the
2,6-dimethylphenyl group on (S,S)-4c was changed to a 9-
anthryl group ((S,S)-4d;[12b] Table 1, entry 6). The reaction
with 4-methoxyphenylboronic acid pinacol ester as the
nucleophile, in place of neopentylglycol ester, also led to
the formation of 2a with high regioselectivity, but the yield
and the enantioselectivity was somewhat lower (Table 1,
entry 7). Also, the use of the NHC salt (S,S)-4e, which has a
methoxy group instead of a hydroxy group ((S,S)-4c), slightly
diminished the regioselectivity (94:6), and the yield and
enantioselectivity were lower (Table 1, entry 8).
(Table 2, entries 7 and 8). With regard to the g substituent of
the allyl phosphates, various aryl groups including 2-naphthyl
and 3-thienyl groups are tolerated in the reaction with
phenylboronate, and the corresponding 1-(hetero)aryl-1-
phenyl-2-propenes are obtained in high yield with uniformly
high regio- and enantioselectivities (Table 2, entries 9–14).
Highly regio- and enantioselective preparation of 1,1-diaryl-
2-propenes having substituents on both of the aryl groups is
also possible, as exemplified in entry 15 (Table 2). In addition
to these cinnamyl phosphate derivatives, g-alkylated or g-
silylated allyl phosphates are also suitable substrates for the
present catalysis and give products 2 with high regioselectivity
and with moderate to good enantioselectivity (Table 2,
entries 16–19).
Under the reaction conditions in which (S,S)-4d was used
as the ligand precursor, several arylboronic acid neopentyl-
glycol esters can react with cinnamyl phosphate 1a to give
products 2 with high regio- and enantioselectivities (Table 2,
As demonstrated in Table 1, both regio- and enantiose-
lectivity in the product formation are highly dependent on the
nature of the metal alkoxide base, and the ester portion of the
organoboronate as well as the hydroxy tether of the ligand
also affected the reaction outcome. Although no conclusive
evidence about the mechanism has been obtained to date, on
the basis of these experimental results and a recent report by
Nakamura and co-workers on the copper-catalyzed asym-
Table 2: Investigation of the substrate scope for the copper-catalyzed
asymmetric allylic substitution of 1 with organoboronates.
metric allylic substitutions using diorganozinc reagents,[3b]
a
possible catalytic cycle for the present catalysis using Cu/
(S,S)-4d is illustrated in Scheme 1. A mixture of CuCl, (S,S)-
4d, and NaOMe generates the chelated copper(I)/NHC
complex A,[15] which undergoes transmetalation with organo-
boronate to give organocopper(I) species B.[10d,11b,12] Inter-
action of NaOMe with the pendant boron atom of inter-
mediate B would form intermediate C. The sodium moiety of
Entry
1
R’
Product Yield of
2+3 [%][a]
2/3[b] ee of
2 [%][b]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
4-MeOC6H4
4-MeC6H4
4-ClC6H4
(S)-2a
(S)-2b
(S)-2c
92
99:1 92
99:1 91
98:2 93
96:4 91
>99:1 94
99:1 94
85:15 93
99:1 73
99:1 91
97:3 90
99:1 91
>99:1 93
99:1 91
98:2 89
>99:1 96
99:1 68
>99:1 85
>99:1 85
>99:1 84
93
88
89
91
92
93
84
93
93
92
95
90
90
84
87
93
4-MeO2CC6H4 (S)-2d
3-MeC6H4
2-naphthyl
3-thienyl
(S)-2e
(S)-2 f
(S)-2g
1-cyclohexenyl (R)-2h
9
1b Ph
(R)-2b
(R)-2c
(R)-2e
(R)-2i
(R)-2 f
(R)-2g
(R)-2j
(R)-2k
(S)-2l
10
11
12
13
14
15[d]
16
17
18
19
1c
1e
1i
1 f
1g Ph
1i
1k
1l
1m Ph
1n Ph
Ph
Ph
Ph
Ph
2-naphthyl
Ph
Ph
(S)-2m 83
(R)-2n 74
[a] Yield of the isolated product. [b] Determined by 1H NMR spectros-
copy. [c] Determined by HPLC using a chiral stationary phase with
hexane/2-propanol after converting 2 into alcohol 5 by hydroboration/
oxidation. [d] The reaction was conducted for 40 h. Cy=cyclohexyl.
entries 1–6). Heteroaryl- and alkenylboronates can also be
employed to give the substitution products in high yield,
although either the regio- or enantioselectivity decreases
Scheme 1. A possible catalytic cycle for the copper-catalyzed allylic
substitution of allyl phosphates with organoboronates.
Angew. Chem. Int. Ed. 2011, 50, 8656 –8659
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8657

Communications
C guides the orientation of the allyl phosphate in the
Keywords: allylic substitution · asymmetric catalysis · boron ·
copper · N-heterocyclic carbenes
.
subsequent oxidative addition to the organocopper center,
thus giving the allylcopper(III) species D[3b] along with the
formation of sodium diethyl phosphate and trialkoxyborane.
Reductive elimination of D then gives the substitution
product, and copper(I) complex A is regenerated. The step
from C to D of this catalytic cycle is presumably the regio- and
stereodetermining step, and this scheme can explain why the
selectivities are strongly dependent on the base, the boronic
ester, and the hydroxy tether of the ligand.
Having established a copper-catalyzed asymmetric allylic
substitution of g-monosubstituted allyl phosphates with
organoboronates, we applied this method to the construction
of quaternary carbon stereocenters by using g,g-disubstituted
allyl phosphates.[3a,4c-e,16] As shown in Table 3, entry 1, the
[1] For reviews, see: a) C. A. Falciola, A. Alexakis, Eur. J. Org.
Chem. 2008, 3765; b) K. Guerts, S. P. Fletcher, A. W. van Zijl,
A. J. Minnaard, B. L. Feringa, Pure Appl. Chem. 2008, 80, 1025;
c) A. Alexakis, J. E. Bꢀckvall, O. Pꢁmies, M. Diꢂguez, Chem.
Rev. 2008, 108, 2796.
[2] For recent examples, see: a) C. A. Falciola, A. Alexakis, Angew.
Chem. 2007, 119, 2673; Angew. Chem. Int. Ed. 2007, 46, 2619;
b) C. A. Falciola, K. Tissot-Croset, H. Reyneri, A. Alexakis,
Adv. Synth. Catal. 2008, 350, 1090; c) L. Carosi, D. G. Hall,
Angew. Chem. 2007, 119, 6017; Angew. Chem. Int. Ed. 2007, 46,
5913; d) K. B. Selim, K. Yamada, K. Tomioka, Chem. Commun.
2008, 5140; e) K. B. Selim, Y. Matsumoto, K. Yamada, K.
Tomioka, Angew. Chem. 2009, 121, 8889; Angew. Chem. Int. Ed.
2009, 48, 8733; f) K. B. Selim, H. Nakanishi, Y. Matsumoto, Y.
Yamamoto, K. Yamada, K. Tomioka, J. Org. Chem. 2011, 76,
1398; g) W. Lçlsberg, S. Ye, H.-G. Schmalz, Adv. Synth. Catal.
2010, 352, 2023.
Table 3: Copper-catalyzed asymmetric allylic substitution of 6 with
arylboronates.
[3] For recent examples, see: a) M. A. Kacprzynski, T. L. May, S. A.
Kazane, A. H. Hoveyda, Angew. Chem. 2007, 119, 4638; Angew.
Chem. Int. Ed. 2007, 46, 4554; b) N. Yoshikai, K. Miura, E.
Nakamura, Adv. Synth. Catal. 2009, 351, 1014; c) T. Jennequin, J.
Wencel-Delord, D. Rix, J. Daubignard, C. Crꢂvisy, M. Mauduit,
Synlett 2010, 1661.
[4] For recent examples, see: a) Y. Lee, K. Akiyama, D. G. Gilling-
ham, M. K. Brown, A. H. Hoveyda, J. Am. Chem. Soc. 2008, 130,
446; b) K. Akiyama, F. Gao, A. H. Hoveyda, Angew. Chem.
2010, 122, 429; Angew. Chem. Int. Ed. 2010, 49, 419; c) F. Gao, Y.
Lee, K. Mandai, A. H. Hoveyda, Angew. Chem. 2010, 122, 8548;
Angew. Chem. Int. Ed. 2010, 49, 8370; d) F. Gao, K. P. McGrath,
Y. Lee, A. H. Hoveyda, J. Am. Chem. Soc. 2010, 132, 14315;
e) J. A. Dabrowski, F. Gao, A. H. Hoveyda, J. Am. Chem. Soc.
2011, 133, 4778.
[5] For a review of transition-metal-catalyzed allylic substitution
reactions with organoboron reagents, see: F. C. Pigge, Synthesis
2010, 1745.
[6] a) K.-G. Chung, Y. Miyake, S. Uemura, J. Chem. Soc. Perkin
Trans. 1 2000, 15; b) H. Chen, M.-Z. Deng, J. Organomet. Chem.
2000, 603, 189.
Entry Ar
Product Yield of 7 [%][a] 7/8[b]
ee of 7 [%][c]
1
2
3
4
4-MeOC6H4 (S)-7a
4-ClC6H4
3-MeC6H4
2-naphthyl
90
84
89
95
>99:1 86
96:4 86
>99:1 90
>99:1 89
(S)-7b
(S)-7c
(S)-7d
[a] Yield of the isolated product. [b] Determined by 1H NMR spectros-
copy. [c] Determined by HPLC using a chiral stationary phase with
hexane/2-propanol after converting 7 into alcohol 9 by hydroboration/
oxidation.
[7] a) T. Miura, Y. Takahashi, M. M. Murakami, Chem. Commun.
2007, 595; b) B. Yu, F. Menard, N. Isono, M. Lautens, Synthesis
2009, 853.
[8] Rhodium-catalyzed asymmetric allylic substitution reactions
based on 1,4-addition or desymmetrization strategies have also
been reported: a) L. Dong, Y.-J. Xu, L.-F. Cun, X. Cui, A.-Q. Mi,
Y.-Z. Jiang, L.-Z. Gong, Org. Lett. 2005, 7, 4285; b) M. Lautens,
C. Dockendorff, K. Fagnou, A. Malicki, Org. Lett. 2002, 4, 1311;
c) F. Menard, T. M. Chapman, C. Dockendorff, M. Lautens, Org.
Lett. 2006, 8, 4569; d) F. Menard, D. Perez, D. S. Roman, T. M.
Chapman, M. Lautens, J. Org. Chem. 2010, 75, 4056.
[9] An iridium-catalyzed asymmetric allylic substitution with aryl-
zinc reagents has been reported: D. Polet, X. Rathgeb, C. A.
Falciola, J.-B. Langlois, S. E. Hajjaji, A. Alexakis, Chem. Eur. J.
2009, 15, 1205.
[10] For examples of copper-catalyzed carbon–carbon bond-forming
reactions using organoboronic acid derivatives, see: a) R. Wada,
K. Oisaki, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 2004, 126,
8910; b) R. Wada, T. Shibuguchi, S. Makino, K. Oisaki, M.
Kanai, M. Shibasaki, J. Am. Chem. Soc. 2006, 128, 7687; c) D.
Tomita, M. Kanai, M. Shibasaki, Chem. Asian J. 2006, 1, 161;
d) T. Ohnishi, M. Nishiura, Z. Hou, Angew. Chem. 2008, 120,
5876; Angew. Chem. Int. Ed. 2008, 47, 5792; e) J. Takaya, S.
Tadami, K. Ukai, N. Iwasawa, Org. Lett. 2008, 10, 2697; f) Y.
Yamamoto, N. Kirai, Y. Harada, Chem. Commun. 2008, 2010;
reaction of compound 6 with 4-methoxyphenylboronate
smoothly proceeded in the presence of Cu/(S,S)-4d to give
g-substitution product 7a exclusively with reasonably high
enantioselectivity (86% ee). Similarly, several other arylboro-
nates can also be employed, giving 2,2-diaryl-3-butenes 7 in
high yield with up to 90% ee (Table 3, entries 2–4).
In summary, we have developed a copper/N-heterocyclic
carbene catalyzed asymmetric allylic substitution of allyl
phosphates with organoboronates to give the g-substitution
products with high enantioselectivity. We have also proposed
a catalytic cycle to explain the observed influence of the
reaction parameters. Future studies will be directed toward
mechanistic investigations to establish the detailed catalytic
cycle and to understand the origin of the stereoselectivity in
the present catalysis.
Received: May 25, 2011
Published online: July 26, 2011
8658
www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 8656 –8659

g) Y. Yamamoto, N. Kirai, Org. Lett. 2008, 10, 5513; h) H. Zheng,
Q. Zhang, J. Chen, M. Liu, S. Cheng, J. Ding, H. Wu, W. Su, J.
Org. Chem. 2009, 74, 943; i) H. Ohmiya, U. Yokobori, Y. Makida,
M. Sawamura, J. Am. Chem. Soc. 2010, 132, 2895; a copper-
catalyzed asymmetric allylic substitution reaction with diboron
has been reported: j) H. Ito, S. Ito, Y. Sasaki, K. Matsuura, M.
Sawamura, J. Am. Chem. Soc. 2007, 129, 14856.
Chem. 2005, 690, 5237; c) D. Martin, S. Kehrli, M. d’Augustin, H.
Clavier, M. Mauduit, A. Alexakis, J. Am. Chem. Soc. 2006, 128,
8416; d) S. Kehrli, D. Martin, D. Rix, M. Mauduit, A. Alexakis,
Chem. Eur. J. 2010, 16, 9890.
[14] An NHC salt structurally very similar to (S)-4a has been
reported to be highly effective for the copper-catalyzed asym-
metric substitution of allyl phosphates with diethylzinc; see
reference [3c].
[15] A related silver complex has been reported; see reference [3c].
[16] a) C. A. Luchaco-Cullis, H. Mizutani, K. E. Murphy, A. H.
Hoveyda, Angew. Chem. 2001, 113, 1504; Angew. Chem. Int.
Ed. 2001, 40, 1456; b) M. A. Kacprzynski, A. H. Hoveyda, J. Am.
Chem. Soc. 2004, 126, 10676; c) A. O. Larsen, W. Leu, C. N.
Oberhuber, J. E. Campbell, A. H. Hoveyda, J. Am. Chem. Soc.
2004, 126, 11130; d) J. J. Van Veldhuizen, J. E. Campbell, R. E.
Giudici, A. H. Hoveyda, J. Am. Chem. Soc. 2005, 127, 6877.
[11] a) H. Ohmiya, N. Yokokawa, M. Sawamura, Org. Lett. 2010, 12,
2438; b) A. M. Whittaker, R. P. Rucker, G. Lalic, Org. Lett. 2010,
12, 3216.
[12] a) R. Shintani, K. Takatsu, T. Hayashi, Chem. Commun. 2010,
46, 6822; b) K. Takatsu, R. Shintani, T. Hayashi, Angew. Chem.
2011, 123, 5662; Angew. Chem. Int. Ed. 2011, 50, 5548.
[13] a) H. Clavier, L. Coutable, J.-C. Guillemin, M. Mauduit,
Tetrahedron: Asymmetry 2005, 16, 921; b) H. Clavier, L.
Coutable, L. Toupet, J.-C. Guillemin, M. Mauduit, J. Organomet.
Angew. Chem. Int. Ed. 2011, 50, 8656 –8659
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 8659