Heterogeneous versus homogeneous copper(II) catalysis in enantioselective conjugate-addition reactions of boron in water

Article abstract of DOI:10.1002/asia.201300997

We have developed Cu^II-catalyzed enantioselective conjugate-addition reactions of boron to α,β-unsaturated carbonyl compounds and α,β,γ,δ-unsaturated carbonyl compounds in water. In contrast to the previously reported Cu^I catalysis that required organic solvents, chiral Cu^II catalysis was found to proceed efficiently in water. Three catalyst systems have been exploited: cat. 1: Cu(OH)₂ with chiral ligand L1; cat. 2: Cu(OH)₂ and acetic acid with ligand L1; and cat. 3: Cu(OAc)₂ with ligand L1. Whereas cat. 1 is a heterogeneous system, cat. 2 and cat. 3 are homogeneous systems. We tested 27 α,β-unsaturated carbonyl compounds and an α,β-unsaturated nitrile compound, including acyclic and cyclic α,β-unsaturated ketones, acyclic and cyclic β,β- disubstituted enones, acyclic and cyclic α,β-unsaturated esters (including their β,β-disubstituted forms), and acyclic α,β-unsaturated amides (including their β,β-disubstituted forms). We found that cat. 2 and cat. 3 showed high yields and enantioselectivities for almost all substrates. Notably, no catalysts that can tolerate all of these substrates with high yields and high enantioselectivities have been reported for the conjugate addition of boron. Heterogeneous cat. 1 also gave high yields and enantioselectivities with some substrates and also gave the highest TOF (43 200 h^-1) for an asymmetric conjugate-addition reaction of boron. In addition, the catalyst systems were also applicable to the conjugate addition of boron to α,β,γ, δ-unsaturated carbonyl compounds, although such reactions have previously been very limited in the literature, even in organic solvents. 1,4-Addition products were obtained in high yields and enantioselectivities in the reactions of acyclic α,β,γ,δ-unsaturated carbonyl compounds with diboron 2 by using cat. 1, cat. 2, or cat. 3. On the other hand, in the reactions of cyclic α,β,γ,δ-unsaturated carbonyl compounds with compound 2, whereas 1,4-addition products were exclusively obtained by using cat. 2 or cat. 3, 1,6-addition products were exclusively produced by using cat. 1. Similar unique reactivities and selectivities were also shown in the reactions of cyclic trienones. Finally, the reaction mechanisms of these unique conjugate-addition reactions in water were investigated and we propose stereochemical models that are supported by X-ray crystallography and MS (ESI) analysis. Although the role of water has not been completely revealed, water is expected to be effective in the activation of a borylcopper(II) intermediate and a protonation event subsequent to the nucleophilic addition step, thereby leading to overwhelmingly high catalytic turnover. Copyright

Full text of DOI:10.1002/asia.201300997

FULL PAPER
DOI: 10.1002/asia.201300997
Heterogeneous versus Homogeneous Copper(II) Catalysis in
Enantioselective Conjugate-Addition Reactions of Boron in Water
Taku Kitanosono, Pengyu Xu, and Shu Kobayashi*[a]
¯
Abstract: We have developed CuII-cat-
alyzed enantioselective conjugate-addi-
tion reactions of boron to a,b-unsatu-
rated carbonyl compounds and a,b,g,d-
unsaturated carbonyl compounds in
water. In contrast to the previously re-
ported CuI catalysis that required or-
ganic solvents, chiral CuII catalysis was
found to proceed efficiently in water.
Three catalyst systems have been ex-
ploited: cat. 1: Cu(OH)2 with chiral
ligand L1; cat. 2: Cu(OH)2 and acetic
acid with ligand L1; and cat. 3: Cu-
cat. 3 showed high yields and enantio-
selectivities for almost all substrates.
Notably, no catalysts that can tolerate
all of these substrates with high yields
and high enantioselectivities have been
reported for the conjugate addition of
boron. Heterogeneous cat. 1 also gave
high yields and enantioselectivities
with some substrates and also gave the
highest TOF (43200 hꢀ1) for an asym-
metric conjugate-addition reaction of
boron. In addition, the catalyst systems
were also applicable to the conjugate
addition of boron to a,b,g,d-unsaturat-
ed carbonyl compounds, although such
reactions have previously been very
limited in the literature, even in organ-
ic solvents. 1,4-Addition products were
obtained in high yields and enantiose-
lectivities in the reactions of acyclic
pounds with diboron 2 by using cat. 1,
cat. 2, or cat. 3. On the other hand, in
the reactions of cyclic a,b,g,d-unsatu-
rated carbonyl compounds with com-
pound 2, whereas 1,4-addition products
were exclusively obtained by using
cat. 2 or cat. 3, 1,6-addition products
were exclusively produced by using
cat. 1. Similar unique reactivities and
selectivities were also shown in the re-
actions of cyclic trienones. Finally, the
reaction mechanisms of these unique
conjugate-addition reactions in water
were investigated and we propose ste-
reochemical models that are supported
by X-ray crystallography and MS (ESI)
analysis. Although the role of water
has not been completely revealed,
water is expected to be effective in the
activation of a borylcopper(II) inter-
mediate and a protonation event subse-
quent to the nucleophilic addition step,
thereby leading to overwhelmingly
high catalytic turnover.
ACHTUNGTRENNUNG(OAc)2 with ligand L1. Whereas cat. 1
is a heterogeneous system, cat. 2 and
cat. 3 are homogeneous systems. We
tested 27 a,b-unsaturated carbonyl
compounds and an a,b-unsaturated ni-
trile compound, including acyclic and
cyclic a,b-unsaturated ketones, acyclic
and cyclic b,b-disubstituted enones,
acyclic and cyclic a,b-unsaturated
esters (including their b,b-disubstituted
forms), and acyclic a,b-unsaturated
amides (including their b,b-disubstitut-
ed forms). We found that cat. 2 and
a,b,g,d-unsaturated
carbonyl
com-
Keywords: asymmetric catalysis
·
boron · conjugate addition · copper ·
heterogeneous catalysis
Introduction
compounds has led to the emergence of a facile and
straightforward method for this reaction.[2] Based on seminal
independent reports of CuI-catalyzed conjugate borylation
by Hosomi and co-workers[3] and Miyaura and co-workers,[4]
Yun and co-workers disclosed an enantioselective procedure
for the CuI-catalyzed conjugate-borylation reaction, fol-
lowed by several catalytic asymmetric conjugate-addition re-
actions of boron by using CuI with chiral ligands.[5] Further-
more, other metal-catalyzed[6] and metal-free[7] enantioselec-
tive conjugate-addition reactions of boron to a,b-unsaturat-
ed carbonyl and related compounds have also been report-
ed.[8]
Enantioenriched a-chiral boron derivatives are an important
ꢀ
class of compounds and their C B linkages can be trans-
ꢀ
ꢀ
ꢀ
formed into C O, C N, and C C bonds through the 1,2-mi-
gration of intermediate “ate” complexes with appropriate
nucleophiles with retention of their stereogenic centers.[1]
The enantioselective conjugate addition of boron to a,b-un-
saturated carbonyl and related compounds provides one of
the most-efficient routes to chiral organoboron compounds
and the growing interest in enantioenriched organoboron
On the other hand, whereas all of those reactions were
carried out in organic solvents, Santos and co-workers re-
ported a CuII-catalyzed racemic conjugate-borylation reac-
tion in water in 2012.[9] In the same year, we reported
a chiral-Cu(OH)2-catalyzed enantioselective conjugate-addi-
tion reaction of boron to a,b-unsaturated carbonyl com-
pounds and nitriles in water.[10] This work arose from our
[a] T. Kitanosono, P. Xu, Prof. Dr. S. Kobayashi
Department of Chemistry, School of Science
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax : (+81)3-5684-0634
E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201300997.
1
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Shu¯ Kobayashi et al.
Table 1. Effect of the copper salt.
findings on metal-hydroxide catalysis in aqueous media. We
developed further organic reactions in water, but we en-
countered a serious issue: Many achiral and chiral catalysts
rapidly decomposed in the presence of even small amounts
of water. To address this issue, we searched for water-com-
patible catalysts and found that various metal hydroxides,
such as Zn(OH)2, Cu(OH)2, and Bi(OH)3, were stable in
water and catalyzed the addition reactions of allylboronates
and allenylboronates to aldehydes and acylhydrazones in
aqueous media.[11] In these reactions, it was found that ex-
change processes that involved metal hydroxides were cru-
cial for promoting the reactions. Accordingly, we assumed
a similar exchange process from the B atom of bis(pinacola-
Entry
Cu salt
Yield [%]
e.r.
1[a]
2[a,b]
3
4
5
Cu(OH)2
Cu(OH)2
84
95
94
71
90:10
99.5:0.5
95.5:4.5
80.5:19.5
77:23
CuN
CuCl2
CuBr2
to)diboron (B2ACHTUNGTRENNUNG(pin)2) to a second element and, as a result,
82
we developed enantioselective 1,4-addition reactions of di-
boron to a,b-unsaturated carbonyl compounds and nitriles
catalyzed by Cu(OH)2, acetic acid, and a chiral 2,2’-bipyri-
dine ligand in water.[10]
6
7
8
9
10
11
Cu
CuSO4
Cu(OTf)2
Cu(OSO3C12H25)2
Cu(acac)2
CuO
G
54
62
89
62
83:17
82.5:17.5
84.5:15.5
77:23
90.5:9.5
–
96
n.r.[c]
After this discovery, we continued to investigate chiral
CuII catalysis in water because: 1) Whereas CuI catalysis is
common in organic solvents, this reaction was the first ex-
ample of an enantioselective conjugate addition of boron in
water by using a CuII catalyst.[12] 2) We used acetic acid as
an additive and high yields and enantioselectivities were ob-
tained. However, the role of acetic acid remained unclear.
Through our investigation of several CuII salts, we found
that the use of Cu(OH)2 alone and the combined use of
equimolar amounts of Cu(OH)2 and acetic acid created
completely different catalyst systems, that is, heterogeneous
and homogeneous catalyst systems, respectively. In addition,
the two catalyst systems showed different catalytic activities
in enantioselective conjugate-addition reactions of boron to
a,b-unsaturated carbonyl compounds and a,b,g,d-unsaturat-
ed carbonyl compounds in water. Herein, we report the de-
tails of our investigation.
[a] Data taken from Ref. [9]. [b] 6 mol% AcOH was added. [c] n.r.=no
reaction.
chiral catalyst that consisted of Cu(OSO3C12H25)2, a com-
bined Lewis acid–surfactant-combined catalyst (LASC), and
ligand L1 has been reported to catalyze the enantioselective
ring-opening reactions of meso-epoxides with aniline and
indole derivatives in water;[16] however, it did not exhibit su-
perior performance over Cu(OH)2 (Table 1, entry 9).
Whereas CuACHTUNGRTNEUNG(acac)2 (acac=acetylacetone) gave the product
in 96% yield with 81% ee (Table 1, entry 10), the reaction
did not proceed at all by using CuO (Table 1, entry 11). b-
borylated product 3a was successfully converted into b-hy-
droxy ketone 4a or b-amino ketone 5a through subsequent
oxidation or substitution reactions (Scheme 1).
Results and Discussion
Effect of CuII Compounds
First, we reacted chalcone 1a with B2ACTHNUTRGNEUNG(pin)2 2 in the presence
of various CuII salts and chiral 2,2’-bipyridine L1[13] in water
(Table 1). Although all of the materials (substrates 1a and 2,
Cu(OH)2, and chiral ligand L1) were almost insoluble in
water, the desired product was obtained in 83% yield with
81% ee by using 5 mol% Cu(OH)2 and 6 mol% ligand L1
(Table 1, entry 1). Whilst organic solvents prevented the cat-
alysis, the reaction completely failed to give the desired
adduct when performed without any solvent (neat condi-
tions).[14] The yield and enantioselectivity were improved by
adding 6 mol% of acetic acid to this system (Table 1,
entry 2). The use of CuII acetate resulted in a slightly lower
enantioselectivity, but it was still at a high level (Table 1,
entry 3). The acetate anion was expected to function as an
activator of compound 2.[4b,15] Next, we examined various
CuII salts. With more-Lewis-acidic CuII salts, the yields and
enantioselectivities were lower (Table 1, entries 4–8). A
Scheme 1. Transformations of b-borylated compound 3a.
Heterogeneous and Homogeneous Catalysts
During the screening of various CuII salts, we noted that,
whereas the reaction mixture was heterogeneous for the
system in Table 1, entry 1, the catalyst systems in Table 1,
entries 2–8 and 10 were almost homogeneous. Photographs
at several stages of the reactions with Cu(OH)2 (Table 1,
entry 1) and CuACTHNUTRGNE(UNG OAc)2 (Table 1, entry 3) are shown in
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Shu¯ Kobayashi et al.
Figure 1. In the reactions with Cu(OH)2, a light-blue hetero-
geneous system that consisted of Cu(OH)2, ligand L1, and
compound 1a in water was observed (Figure 1, top row,
a and b). After the addition of compound 2, the color imme-
89% yield with an e.r. of 95.5:4.5. We concluded that
Cu(OH)2 created a heterogeneous catalyst system and that
CuACTHNUTRGEN(UGN OAc)2 created a homogeneous catalyst system.
In terms of the color of the reaction mixture, we found
that a brown color indicated the formation of the product,
which indicated that the Cu(OH)2-catalyzed reaction pro-
ceeded faster than the Cu
firm this theory, we performed a preliminary kinetic study
on the Cu(OH)2- and Cu(OAc)2-catalyzed conjugate-addi-
ACHTUNGERTN(NUNG OAc)2-catalyzed reaction. To con-
AHCTUNGTRENNUNG
tion reactions in water. The profiles of the reactions be-
tween compounds 1a and 2 in the presence of Cu(OH)2 and
ligand L1 or CuACHTNUTRGNEUNG(OAc)2 and ligand L1 are shown in Figure 2.
Figure 1. Photographs of the reactions by using Cu(OH)2 (top) and Cu-
ACHTUNGTRENNUNG(OAc)2 (bottom): a) Prepared catalyst solution with ligand L1, b) just
after the addition of compound 1a, and c) 2 min, d) 15 min, e) 30 min,
and f) 60 min after the addition of compound 2.
diately turned brown (Figure 1, top row, c). The brown color
darkened after 15 min (Figure 1, top row, d) and the same
color was maintained, even after 30 min and 60 min
(Figure 1, top row, e and f). At all stages, the systems
seemed to be heterogeneous. On the other hand, a light-
blue homogeneous solution was formed by combining Cu-
Figure 2. Profiles of the reactions catalyzed by Cu(OH)2 and CuACHTUNGTRENNUNG(OAc)2.
The reaction with Cu(OH)2 proceeded much faster than
that with Cu(OAc)2. It is very interesting that a heterogene-
AHCTUNGTRENNUNG
A
ous catalyst was more active than a homogeneous catalyst in
this case.
Next, we tested three catalyst systems, that is, cat. 1 (het-
erogeneous): Cu(OH)2 (5 mol%) and ligand L1 (6 mol%);
cat. 2 (homogeneous): Cu(OH)2 (5 mol%), acetic acid
(6 mol%), and ligand L1 (6 mol%); and cat. 3 (homogene-
addition of compounds 1a and 2 (both were solid and nei-
ther were soluble in water during the initial stage), the same
color was initially maintained (Figure 1, bottom row, b and
c), then gradually turned brown (Figure 1, bottom row, d–f).
Because the starting materials and the product (3a) were
not soluble in water, some insoluble material existed in the
reaction mixture; however, the catalyst seemed to be dis-
solved.
To confirm the heterogeneity and homogeneity of these
catalysts, a filtration test was performed. In the presence of
Cu(OH)2 (5 mol%) and ligand L1 (6 mol%), compound 1a
was combined with compound 2 in water. After 10 min, the
reaction mixture was filtered. The filtrate was analyzed and
no Cu was detected by ICP analysis.[17] Then, compounds 1a
and 2 were added to the filtrate and we confirmed that no
reaction occurred. On the other hand, when Cu(OH)2
(5 mol%), acetic acid (6 mol%), and ligand L1 (6 mol%)
were combined, the mixture was almost dissolved and a ho-
mogeneous system was formed, which we assumed to be
ous): CuACTHNURGTNEUNG(OAc)2 (5 mol%) and ligand L1 (6 mol%) (homo-
geneous), in the conjugate-addition reactions of 27 sub-
strates, including acyclic and cyclic a,b-unsaturated ketones,
b,b-disubstituted enones, and a,b-unsaturated esters, amides,
and nitriles (Scheme 2).
In general, the combined system of Cu(OH)2, acetic acid,
and ligand L1 (cat. 2) afforded the highest yields and enan-
tioselectivities among the three systems. The combination of
CuACTHUNTRGENNG(U OAc)2 and ligand L1 (cat. 3) also showed high yields
and enantioselectivities for most substrates. Notably, these
catalyst systems were applicable to various types of a,b-un-
saturated carbonyl compounds and nitriles, including acyclic
and cyclic a,b-unsaturated ketones, acyclic and cyclic b,b-
disubstituted enones, acyclic and cyclic a,b-unsaturated
esters (including their b,b-disubstituted forms), acyclic a,b-
unsaturated amides (including their b,b-disubstituted forms),
and a,b-unsaturated nitriles. No previous catalysts tolerated
all of these substrates with high yields and enantioselectivi-
ties. The heterogeneous catalyst system, which consisted of
Cu(OH)2 and ligand L1 (cat. 1), showed relatively lower
yields and enantioselectivities for many substrates. In partic-
a complex of Cu(OH)
ACHTUNGTRENNUNG(OAc)2 (5 mol%) and ligand L1 (6 mol%) were combined,
a similar homogeneous system was formed. These homoge-
neous systems remained, even after the addition of sub-
strates 1a and 2. After 2 h, the reaction mixture was filtered
and compounds 1a and 2 were added to the filtrate. The re-
action proceeded well to afford the desired compound in
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Shu¯ Kobayashi et al.
Scheme 2. Enantioselective conjugate addition of boron with three catalytic systems: [a] 20 mol% AcOH was added; [b] 1.6 equivalents of compound 2
were employed; [c] data taken from Ref. [10].
ular, low yields and enantioselectivities were observed for
cyclic substrates. On the other hand, high yields and enan-
tioselectivities were obtained for acyclic a,b-unsaturated
esters; in the reactions with cinnamyl esters, the yields and
enantioselectivities were highest among the three catalyst
systems. In all cases, we isolated a-chiral boron compounds;
however, for simplicity and, in particular, to determine the
enantioselectivity, the reaction mixtures were treated direct-
ly with NaBO3 to convert them into their corresponding al-
cohols. We also confirmed that there was no loss of enantio-
selectivity during the conversion of compound 3 into com-
pound 4. For synthesis purposes, the formation of enantioen-
riched tertiary alcohols, which are readily prepared from
b,b-disubstituted a,b-unsaturated carbonyl compounds, is
valuable. In the reaction of compound 1k, 0.005 mol% Cu-
AHCTUNGRTEG(NNUN OAc)2 could be used efficiently in a gram-scale experiment
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Shu¯ Kobayashi et al.
Scheme 3. Gram-scale synthesis.
Scheme 5. Conjugate addition of boron to a,b,g,d-unsaturated dienones
and dienoesters.
without any loss of enantioselectivity (Scheme 3, 1.08 g,
96% yield, e.r. 90.5:9.5).
Acyclic a,b,g,d-Unsaturated Dienones
We also performed turnover frequency (TOF) experi-
ments for the reaction between compounds 1a with 2. In the
presence of 0.005 mol% of the three catalyst systems de-
scribed herein, compound 1a was treated with compound 2
in water for 15 min (Scheme 4). TOFs of 17600 h[9] and
First, the reaction of acyclic a,b,g,d-unsaturated dienone 6a
with compound
2 was performed in the presence of
Cu(OH)2 and L1 (cat. 1) in water. The 1,4-addition product
(7aa) was exclusively obtained in 81% yield with an e.r. of
88.5:11.5 (Table 2, entry 1). The yield and enantioselectivity
were improved if the reaction was performed by using
Cu(OH)2, acetic acid, and ligand L1 (cat. 2; Table 2, entry 2)
or CuACTHNURGTEN(UGN OAc)2 and L1 (cat. 3; Table 2, entry 3). The allylbor-
ane product was also isolated without any loss of yield or
enantioselectivity. On the other hand, CuCl2, CuSO4, and
CuACHTNUTRGENNG(U OTf)2 afforded much-lower enantioselectivities (Table 2,
entries 4–6). Notably, in all cases, only 1,4-addition products
Table 2. Addition reactions to acyclic dienones and dienolates.
Scheme 4. Turnover-frequency test.
12800 h were obtained by using cat. 2 and cat. 3, respective-
ly, with high enantioselectivities. The TOF reached 43200 h
by using cat. 1, which is the highest reported value for an
asymmetric conjugate-addition reaction of boron, although
the enantioselectivity was slightly lower.
Entry
6
Cu salt
Yield [%] e.r.[a]
Whereas CuI catalysis in organic solvents has been the
most-extensively examined system for the enantioselective
conjugate addition of boron, this CuII procedure in water
tolerates a wider range of substrates and is expected to be
a more-expedient and environmentally benign method be-
cause it does not require the use of organic solvents.
1
Cu(OH)2 (Cat A)
Cu(OH)2 (Cat B)
CuACTHUNTRGENNG(U OAc)2 (Cat C) 91
CuCl2
CuSO4
81 (7aa)
93
88.5:11.5
2[b]
3
93.5:6.5
93.5:6.5
79.5:20.5
67:33
70.5:29.5
92:8
4
5
6
7
42
37
92
87 (7ba)
Cu
N
Cu(OH)2 (Cat A)
Cu(OH)2 (Cat B)
CuACTHUNTRGENNG(U OAc)2 (Cat C) 91
8[b]
9
87
95.5:4.5
95.5:4.5
a,b,g,d-Unsaturated Dienones and Dienoesters
10
Cu(OH)2 (Cat A)
Cu(OH)2 (Cat B)
83 (7ca)
87
92.5:7.5
96:4
95:5
11[b]
12
The enantioselective conjugate addition of boron to a,b,g,d-
unsaturated carbonyl compounds provides a direct approach
to enantiomerically enriched carbonyl-containing allylbor-
Cu
N
13
Cu(OH)2 (Cat A)
Cu(OH)2 (Cat B)
CuACTHUNTRGENNG(U OAc)2 (Cat C) 81
75 (7da)
85
91.5:8.5
95.5:4.5
95:5
14[b]
15
ꢀ
anes, which are useful allylating agents and whose C B
ꢀ
ꢀ
ꢀ
bonds can be transformed into C O, C N, or C C bonds
with retention of the stereogenic centers (Scheme 5). How-
ever, examples of such conjugate-addition reactions are very
limited and, to the best of our knowledge, only one example,
which was conducted in an organic solvent, has been repor-
ted.[5c] Thus, we wondered whether a chiral-CuII-catalyzed
conjugate-addition reaction to a,b,g,d-unsaturated dienones
could occur in water.[18]
16
Cu(OH)2 (Cat A)
Cu(OH)2 (Cat B)
CuACTHUNTRGENNG(U OAc)2 (Cat C) 90
86 (7ea)
91
95:5
99:1
97:3
17[b]
18
19
Cu(OH)2 (Cat A)
Cu(OH)2 (Cat B)
CuACTHUNTRGENNG(U OAc)2 (Cat C) 84
73 (7 fa)
86
87.5:12.5
94.5:5.5
91.5:8.5
20[b]
21
22
Cu(OH)2 (Cat A)
Cu(OH)2 (Cat B)
CuACTHUNTRGENNG(U OAc)2 (Cat C) 81
67 (7ga)
83
86:14
92:8
91:9
23[b]
24
[a] ee value of the major adduct; [b] 6 mol% AcOH was added.
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Shu¯ Kobayashi et al.
Table 3. Addition to b-substituted cyclic dienones.
7a were obtained and no 1,6-addition products
(7b) were produced. We tested other acyclic
a,b,g,d-unsaturated acyclic carbonyl compounds.
Whilst the same trend in enantioselectivity was ob-
served for dienone 6b (Table 2, entries 7–9), dien-
oester 6c also exclusively afforded the 1,4-addition
product with high enantioselectivity (Table 2, en-
tries 10–12). Acyclic dienones that contained
methyl substituents at the b position are known to
be amenable to 1,6-addition, presumably because
of a reluctance to react at the b position.[19] Howev-
er, the reaction of sterically congested dienone 6d
and dienoester 6e exclusively furnished their corre-
sponding 1,4-adducts (7da and 7ea) with high
enantioselectivities (Table 2, entries 13–18). Fur-
thermore, d-methyl- and n-butyl-substituted dien-
ones (6 f and 6g) also reacted smoothly to afford
their corresponding 1,4-adducts (7 fa and 7ga) with
high enantioselectivities (Table 2, entries 19–24).
Notably, 1,4-addition products 7a were exclusively
obtained, regardless of the use of heterogeneous or
homogeneous catalysts and the substituent pattern
of the acyclic a,b,g,d-unsaturated dienones and di-
enoates, and no 1,6-addition products (7b) were
produced in all cases.
Entry
8
Cu salt
Yield [%]
Ratio 9a[a]/9b
e.r. 9a/9b
1
Cu(OH)2 (Cat A)
Cu(OH)2 (Cat B)
81
92
94
49
37
81
69
87
92
43
77
84
84
21
32
22
39
77
81
18
<1/>99
>99/<1
>99/<1
69/31
56/44
91/9
<1/>99
>99/<1
>99/<1
65/35
<1/>99
>99/<1
>99/<1
73/27
69/31
82/18
<1/>99
>99/<1
>99/<1
53/47
–/88:12
93.5:6.5/–
95.5:4.5/–
66:34/51.5:48.5
57:43/50.5:49.5
72.5:27.5/49.5:50.5
–/94.5:5.5
94:6/–
94.5:5.5/–
2[b]
3
Cu
N
8a
4
5
6
7
CuCl2
CuSO4
Cu
N
Cu(OH)2 (Cat A)
Cu(OH)2 (Cat B)
8[b]
9
8b
8c
8d
Cu
N
10
11
12[b]
13
14
15
16
17
18b
19
20
CuCl2
Cu(OH)2 (Cat A)
Cu(OH)2 (Cat B)
64.5:35.5/53:47
–/90.5:9.5
96.5:3.5/–
Cu
N
96:4/–
CuCl2
CuSO4
67:33/50:50
59:41/50.5:49.5
76.5:23.5/49.5:50.5
–/66.5:33.5
91:9/–
Cu
N
Cu(OH)2 (Cat A)
Cu(OH)2 (Cat B)
Cu
N
80.5:19.5/–
53.5:46.5/50.5:49.5
CuCl2
Cyclic a,b,g,d-unsaturated Dienones
[a] The E/Z ratio of compound 9a was always about 1:1, irrespective of the geometry
of
the
dienone.
[b] 6 mol%
AcOH
was
added.
Cyclic dienones have also served as acceptors in
conjugate-addition reactions. Several reports on
the copper-catalyzed 1,6-conjugate addition of or-
ganometallic reagents to cyclic dienones have ap-
peared,[18] although the 1,6-conjugate addition of
boron has remained unexplored. Several copper(-
II) salts were closely examined in the reaction of
six-membered cyclic dienone 8a (Table 3). To our
astonishment, a simple swap of counteranions was
found to switch the regioselectivity between 1,4-
and 1,6-additions. That is, 1,6-adduct 9aa was ex-
clusively formed in the presence of cat. 1 (Cu(OH)2 and
ligand L1) with good enantioselectivity (Table 3, entry 1),
whereas the 1,4-addition pathway exclusively took place
when cat. 2 (Cu(OH)2, acetic acid, and ligand L1) or cat. 3
the nucleophile or chiral ligand has never been reported in
asymmetric Michael additions. The sterically congested elec-
trophilic site at the d position of compound 8b did not shift
the preference of Cu(OH)2 for 1,6-addition (Table 3,
entry 7). Both five- and seven-membered cyclic dienones
served as efficient substrates and showed the same switch in
regioselectivity as six-membered ones (Table 3, entries 11,
13, 17, and 19). In the previously reported examples, the re-
gioselectivity of the asymmetric conjugate-addition reactions
to cyclic dienones depended upon the nature of the nucleo-
phile, chiral ligand, and solvent.[18a–c,f] The general trend for
1,6-addition in the reaction of organometallic reagents has
appeared to be difficult to overcome. In addition, few cata-
lytic methods are available for direct and stereoselective
functionalization at the remote d position.[21]
(CuACHTUNGTRENNUNG(OAc)2 and ligand L1) was used as the catalyst with high
enantioselectivity (Table 3, entries 2 and 3). Notably, the
corresponding allylborane and homoallylborane were also
isolated without any loss of yield and enantioselectivity.
Moreover, the 1,4- and 1,6-addition pathways competed
with each other in the presence of other copper(II) salts,
such as CuCl2, CuSO4, and CuACHTNUTRGENNUG(OTf)2 (Table 3, entries 4–6).
In these cases, both the 1,4- and 1,6-modes afforded quite-
low levels of enantioselectivity. The E/Z ratio of the g,d-
olefin did not have any influence on the reactivity and selec-
tivity of this reaction. These results suggested that a 1,4-ad-
dition pathway seemed to be somewhat predominant, in
spite of the construction of a quaternary asymmetric carbon
center. To the best of our knowledge, the dependence of re-
gioselectivity on simple inorganic counteranions and not on
Typically, chiral copper catalysts for the reactions between
organometallic or silylboron reagents with cyclic dienones
furnish b,g-unsaturated 1,6-addition adducts through the ki-
netic protonation of dienolate intermediates.[19,18a] The iso-
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Shu¯ Kobayashi et al.
merization of these de-conjugated adducts is known to
easily lead to fully re-conjugated adducts. Nevertheless, we
verified that our aqueous procedure furnished a thermody-
namically favorable conjugated product through performing
a reaction in D2O (Scheme 6). Indeed, deuteration of the di-
enolate that was derived from compound 8a took place ex-
clusively at the g position.
exclusively provided 1,4-adduct 9ha in high yields with high
enantioselectivities (Table 4, entries 2 and 3).
Proposed Reaction Mechanism
In Cu
tion of a (pin)B Cu
termediate, which would be produced from the reaction be-
tween Cu(OAc)2/L1 and compound 2. Because no reaction
occurred without ligand L1, the ligand that was coordinated
to Cu(OAc)2 might have promote the release of the acetate
anion from Cu(OAc)2, which reacted with compound 2 to
ACHTUNGRTEN(NUNG OAc)2/L1-catalyzed reactions, we assumed the forma-
ꢀ
AHCTUNGTRENN(GUN OAc)·L1 (10) complex as a reactive in-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
form a borate and then complex 10. Water (solvent) may
also assist the formation of complex 10. We have already in-
vestigated the crystallographic structure of the CuBr2/L1
complex, which adopted a square-pyramidal structure, in
which two nitrogen atoms and only one of the oxygen atoms
of ligand L1 were attached onto the CuII atom in a tridentate
manner.[16] Indeed, this reaction did not require both hy-
droxy groups; a chiral catalyst that was composed of
Cu(OH)2 and ligand L2, in which one hydroxy group was
protected by a methyl group (Figure 3a), afforded almost
the same result in the reaction between compounds 1a with
2 (82% yield, e.r. 88.5:11.5; cf. Table 1, entry 1).
Scheme 6. Deuteration of cyclic dienone 8a in D2O.
Other cyclic dienones 8e and 8g did not react with dibor-
on 2 at the d position, even in the presence of Cu(OH)2,
presumably because of steric effects in the nucleophilic ad-
dition step.[22] Although dienone 8 f exhibited reactivity at
the d position, the reaction produced appreciable amounts
of several by-products that could not be separated.[23]
Cyclic Trienone
We further investigated the addition of compound 2 to trien-
one 8h, which contained an additional electrophilic site at
the terminal position (Table 4). Whereas the use of CuCl2
Table 4. Addition to cyclic trienones.
Figure 3. a) Structure of ligand L2 and b) structural model of the chiral
borylcopper(II) complex that was formed with ligand L1 (10).[a] The
counteranion and hydrogen atoms are omitted for clarity. Color code:
blue N, red O, yellow B, green Cu.
Entry Cu salt
Yield [%] 9ha/9hb/9hc e.r.
1
Cu(OH)2 (cat. A)
71
<1:74:26
86:14 (9hb),
73:27 (9hc)
96:4 (9ha)
2[a]
3
Cu(OH)2 (cat. B)
Cu(OAc)2 (cat. C)
86
87
>99:<1:<1
>99:<1:<1 95.5:4.5 (9ha)
The stereochemical model of compound 10, based on the
X-ray structure of the CuBr2/L1 complex, is shown in
Figure 3. We assumed the coordination of one hydroxy
group of ligand L1 to the Cu atom and the other hydroxy
group to the B atom. The reaction of compound 10 with
a,b-unsaturated carbonyl compounds may occur through the
interaction between the CuII atom and the carbonyl group
(presumably through the p electrons of the C=O bond). The
G
[a] 6 mol% AcOH was added.
resulted in the formation of a messy mixture that could not
be separated, the desired addition products were obtained
in the presence of Cu(OH)2 and CuACHTNUTRGNEUNG(OAc)2. 1,6-Adduct 9hb
and 1,8-adduct 9hc were obtained by using cat. 1 (Cu(OH)2
and ligand L1) with moderate selectivity (Table 4, entry 1).
No 1,4-adduct (9ha) was obtained and, notably, functionali-
zation at the most-remote z position was achieved. On the
other hand, homogeneous systems cat. 2 (Cu(OH)2, acetic
ꢀ
polarization of the Cu B bond towards the boron atom
could facilitate this interaction. The direction of the carbon-
yl interaction may be determined by the steric bulkiness of
compound 10 and the a,b-unsaturated carbonyl compounds
(Figure 4; compound 1a is used as a model example). The
acid, and ligand L1) and cat. 3 (CuACTHNUTRGNEUNG(OAc)2 and ligand L1)
7
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Shu¯ Kobayashi et al.
II
ꢀ
Historically, much attention has been paid to Cu 2,2’-bi-
pyridine (bpy) complexes and extensive studies in both the
solid state and in solution have been described.[26] Electron
paramagnetic resonance (EPR) spectroscopic analysis indi-
cated that a dimeric bis-m-hydroxide cation, [CuACHTUNGTRENNUNG(bpy)ACHTUNGTRENNUNG(m-
OH)]22+, was favored in aqueous solution.[28a] An insoluble
polymeric m-hydroxide is known to be a stable structure
(Figure 6). Because some chiral induction was demonstrat-
Figure 4. Plausible mechanistic pathway for the enantioselection.
steric bulkiness of the two tert-butyl groups in compound 10
may give rise to an enantiofacial preference for the accessi-
ble Si face, consistent with the observed sense of chiral in-
duction. The CuII enolate that is formed after the nucleo-
philic addition step is in equilibrium between the C-enolate
and the O-enolate. The well-established CuI pathway prefers
the C-enolate, which can interact with the vacant pz orbital
of the boron atom, whereas the CuII pathway is presumed to
favor the O-enolate, because of its unsatisfied d orbital. A
tentative model of the intermediate is shown in Figure 5.
Figure 6. Polymeric m-hydroxide Cu species.
ed, ligand L1 should coordinate to the polymeric Cu species
in a tridentate manner. As shown in Figure 7, in the reaction
of cyclic dienone 8a with compound 2, one Cu atom acti-
ꢀ
vates the carbonyl group of compound 8a and another Cu
Figure 7. Plausible intermediate structures in the Cu(OH)2- and Cu-
AHCTUNGRTEN(NGUN OAc)2-catalyzed reactions of cyclic dienone 8a.
Figure 5. Possible intermediate model from the MS (ESI) analysis; the
chalcone skeleton is shown in brown.
B bond attacks compound 8a through a 1,6-addition path-
way. 1,4-Addition may be sterically unfavorable; however,
We were able to successfully monitor this intermediate by
under CuACTHGNUTRENNU(G OAc)2 catalysis, smooth 1,4-addition is possible,
using MS (ESI) analysis. Substrates 1a and 2 were added to
even in the reaction of compound 8a.
a homogeneous solution of CuACHTUNRGTNEUNG(OAc)2 and ligand L1 in
aqueous THF and the reaction solution was analyzed by MS
(ESI). A strong peak at m/z 726.3265 was detected, which
Conclusions
corresponded to [L1+CuB
pattern. When trienone 6b was employed instead of com-
pound 1a, the corresponding peak at [L1+CuB
(pin)+6b]+
(pin)+1a]+ based on the isotope
ACHTUNGTRENNUNG
We have reported CuII-catalyzed enantioselective conjugate-
addition reactions of boron to a,b-unsaturated carbonyl
compounds and a,b,g,d-unsaturated carbonyl compounds in
water. In contrast to the previously reported CuI catalysis
that only proceeded in organic solvents, we have demon-
strated chiral CuII catalysis in water. We have developed
three catalyst systems: cat. 1: Cu(OH)2 with chiral ligand
L1; cat. 2: Cu(OH)2 and acetic acid with ligand L1; and
AHCTUNGTRENNUNG
was also detected. These results indicate that the reaction
pathway based upon CuII catalysis involves the formation of
a key complex between the enone and the borylcopper spe-
cies that is generated through s-metathesis.
Rapid protonation subsequent to the nucleophilic addi-
tion step afforded the product in water.[24] The reaction of
compound 1a with compound 2 in D2O resulted in exclusive
deuteration, thus indicating that water enabled the rapid
protonation.[25] Kinetic isotope effects were explored with
D2O by following the same procedure. A small isotope
effect confirmed that the rate-determining step did not in-
volve the protonation/deuteration of an enolate intermedi-
ate.[26,27]
cat. 3: CuACTHNUGTRENUNG(OAc)2 with ligand L1. We have shown that,
whereas cat. 1 is a heterogeneous system, cat. 2 and cat. 3
are homogeneous systems. Interestingly, the reaction pro-
ceeded faster with the heterogeneous systems than with the
homogeneous system. We tested 27 a,b-unsaturated carbon-
yl compounds and an a,b-unsaturated nitrile compound, in-
cluding acyclic and cyclic a,b-unsaturated ketones, acyclic
and cyclic b,b-disubstituted enones, acyclic and cyclic a,b-
unsaturated esters (including their b,b-disubstituted forms),
On the other hand, a catalyst that was formed from
Cu(OH)2 and ligand L1 exhibited heterogeneous behavior.
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Shu¯ Kobayashi et al.
127.5, 128.0, 128.3, 128.4, 133.6, 136.6, 143.0, 200.1 ppm; HPLC (Dialcel
Chiralpak IA; n-hexane/iPrOH, 90:10; flow rate 0.5 mLminꢀ1): tR =
9.2 min (S, minor), tR =12.5 min (R, major).
and acyclic a,b-unsaturated amides (including their b,b-dis-
ubstituted forms). Catalyst systems cat. 2 and cat. 3 showed
high yields and enantioselectivities for almost all of the sub-
strates; the TOFs reached 17600 and 12800 hꢀ1, respectively.
Notably, no catalysts that cover all of these substrates with
such high yields and enantioselectivities have been reported
for conjugate-addition reactions of boron, even in organic
solvents. Heterogeneous cat. 1 also gave high yields and
enantioselectivities for some substrates and the highest TOF
(43200 hꢀ1) for an asymmetric conjugate-addition reaction
of boron was achieved. For some substrates, higher yields
and/or enantioselectivities were obtained by using cat. 1
than those that were obtained by using cat. 2 or cat. 3; how-
ever, in general, the yields and enantioselectivities were
higher by using cat. 2 or cat. 3 than with cat. 1. Moreover,
the catalyst systems were also applicable to the conjugate
addition of boron to a,b,g,d-unsaturated carbonyl com-
pounds, although such conjugate-addition reactions have
previously been very limited in the literature. 1,4-Addition
products were obtained in high yields and enantioselectivi-
ties in the reactions of acyclic a,b,g,d-unsaturated carbonyl
compounds with diboron 2 by using cat. 1, cat. 2, or cat. 3.
On the other hand, in the reactions of cyclic a,b,g,d-unsatu-
rated carbonyl compounds with compound 2, whereas 1,4-
addition products were exclusively obtained with cat. 2 or
cat. 3, 1,6-addition products were exclusively produced with
cat. 1. Similar unique reactivities and selectivities were also
shown in the reactions of cyclic trienones. Finally, the reac-
tion mechanism of these unique conjugate-addition reac-
tions of boron in water was investigated and we proposed
stereochemical models that were supported by X-ray crystal-
lography and MS (ESI) analysis. Although the role of water
has not been completely revealed in this investigation, water
is expected to be effective in the activation of a borylcop-
per(II) intermediate and a protonation event subsequent to
the nucleophilic addition step, thereby leading to over-
whelmingly high catalytic turnover. The role of CuII and
water will be elucidated in more detail in due course.
Typical Experimental Procedure for the Oxidation Step
After the reaction of compound 1a with compound 2 had been complet-
ed, the reaction mixture was filtered and rinsed with THF (3 mL). Then,
an excess amount of NaBO3·4H2O (488 mg) was added and the mixture
was stirred at RT for 4 h. The aqueous layer was extracted with EtOAc
(3ꢁ20 mL) and the combined organic layers were dried over anhydrous
Na2SO4. After concentrating under reduced pressure, the crude mixture
was purified by preparative TLC (n-hexane/EtOAc, 4:1) to afford the de-
27
sired product (4a, 84.6 mg, quantitative yield) as a colorless oil. ½aꢁD
=
+69.3 (c=0.84, CHCl3); 1H NMR (500 MHz): d=3.37 (d, J=5.8 Hz,
2H), 5.35 (t, J=6.0 Hz, 1H), 7.28–7.48 (m, 7H), 7.56–7.59 (m, 1H),
7.95 ppm (d, J=7.0 Hz, 2H); 13C NMR (125 MHz): d=47.4, 70.0, 120.7,
127.5, 128.0, 128.3, 128.4, 133.6, 136.6, 143.0, 200.1 ppm; HPLC (Dialcel
Chiralcel OD-H; n-hexane/iPrOH, 85:15; flow rate: 0.7 mLminꢀ1): tR =
14.4 min (S, minor), tR =16.3 min (R, major).
Typical Procedure for the Turnover-Frequency Study
Chiral 2,2’-bipyridine L1 (0.079 mg, 0.006 mol%) was added to an aque-
ous solution (2 mL) of Cu(OH)2 (0.020 mg, 0.005 mol%). After stirred
vigorously for 15 min at RT, the resultant mixture was allowed to cool to
58C. Then, chalcone 1a (83.2 mg, 0.4 mmol) and B2ACTHNUTRGNE(UNG pin)2 (2, 121.8 mg,
0.48 mmol) were added successively at the same temperature. After stir-
ring for 15 min, the reaction mixture was filtered and rinsed with THF
(3 mL). Then, an excess amount of NaBO3·4H2O (488 mg) was added
and the mixture was stirred at RT for 4 h. The aqueous layer was extract-
ed with EtOAc (3ꢁ20 mL) and the combined organic layers were dried
over anhydrous Na2SO4. After concentrating under reduced pressure, the
crude mixture was purified by preparative TLC (n-hexane/EtOAc, 4:1)
to afford the desired product (4a, 48.7 mg, 54% yield) as a colorless oil.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research from
the Japan Society for the Promotion of Science (JSPS), the Global COE
Program, the University of Tokyo, MEXT (Japan), and the Japan Science
Technology Agency (JST). T.K. thanks the JSPS for a Research Fellow-
ship for Young Scientists. The authors also thank Dr. Masaharu Ueno
and Toshimitsu Endo (University of Tokyo) for their contributions
during the initial stage of this work.
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Experimental Section
Typical Procedure for the Chiral-Cu(OH)2-Catalyzed Enantioselective
Conjugate-Addition Reaction of Boron to a,b-Unsaturated Carbonyl
Compounds in Water
An aqueous solution of acetic acid (24 mm, 1 mL) was added to an aque-
ous solution (1 mL) of Cu(OH)2 (2.0 mg, 5 mol%) and chiral 2,2’-bipyri-
dine L1 (7.9 mg, 6 mol%). After stirred vigorously for 1 h at RT, the re-
sultant mixture was allowed to cool to 58C. Then, chalcone 1a (81.9 mg,
0.4 mmol) and B2ACHTUNGTRENNUNG(pin)2 (2, 121.8 mg, 0.48 mmol) were added successively
at the same temperature. After stirring for 12 h, the reaction mixture was
filtered and rinsed with EtOAc. The aqueous layer was extracted with
EtOAc (3ꢁ20 mL) and the combined organic layers were dried over an-
hydrous Na2SO4. After concentrating under reduced pressure, the crude
mixture was purified by preparative TLC (n-hexane>/EtOAc, 4:1) to
afford the desired product (3a, 127.9 mg, 95% yield) as a colorless oil.
½aꢁ2D6 =ꢀ36.5 (c=0.76, CDCl3); 1H NMR (500 MHz): d=1.06 (s, 6H),
1.14 (s, 6H), 2.80 (t, J=6.0 Hz, 1H), 3.39 (d, J=2.9, 5.8 Hz, 1H), 3.54 (d,
J=2.9, 5.8 Hz, 1H), 7.28–7.48 (m, 7H), 7.56–7.59 (m, 1H), 7.95 ppm (d,
J=7.0 Hz, 2H); 13C NMR (125 MHz): d=25.1, 44.4, 70.0, 83.6, 120.7,
9
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Shu¯ Kobayashi et al.
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ˇ
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Received: July 27, 2013
Published online: && &&, 0000
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Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

FULL PAPER
Heterogeneous Catalysis
Taku Kitanosono, Pengyu Xu,
Shu¯ Kobayashi*
&&&& — &&&&
Heterogeneous versus Homogeneous
Copper(II) Catalysis in Enantioselec-
tive Conjugate-Addition Reactions of
Boron in Water
Et (II) brute? Enantioselective addi-
tion reactions of bis(pinacolato)di-
boron to multifarious unsaturated
compounds are catalyzed by chiral
copper(II) complexes. The use of
Cu(OH)2 acts as a heterogeneous cata-
lyst, whereas Cu
ous.
ACHTUNGRTEN(NGNU OAc)2 is homogene-
11
&
&
Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ