Chiral tetrafluorobenzobarrelenes as effective ligands for rhodium-catalyzed asymmetric 1,4-addition of arylboroxines to β,β-disubstituted α,β-unsaturated ketones

Article abstract of DOI:10.1002/anie.201000467

(Chemical Equotion Present) Lock, Stock and Two Smoking Barrelenes: The rhodium-catalyzed 1,4-addition of readily available arylboronic acid anhydrides to simple β,β-disubstituted α,βunsaturated ketones creates quaternary carbon stereocenters with high enantiomeric excesses using a chiral tetrafluorobenzobarrelene ligand.

Full text of DOI:10.1002/anie.201000467

Angewandte
Chemie
DOI: 10.1002/anie.201000467
Asymmetric Catalysis
Chiral Tetrafluorobenzobarrelenes as Effective Ligands for
Rhodium-Catalyzed Asymmetric 1,4-Addition of Arylboroxines to
b,b-Disubstituted a,b-Unsaturated Ketones**
Ryo Shintani,* Momotaro Takeda, Takahiro Nishimura, and Tamio Hayashi*
The catalytic asymmetric 1,4-addition of organometallic
reagents to b,b-disubstituted a,b-unsaturated compounds
offers a straightforward way of constructing all-carbon
quaternary stereocenters.[1,2] Although some copper-cata-
lyzed processes have appeared in combination with highly
reactive nucleophiles, such as diorganozinc,[3] Grignard,[4] and
triorganoaluminum reagents,[5] the use of air-stable, easily
handled organoboronic acid derivatives would be desirable in
view of the mildness of the reaction conditions. Unfortu-
nately, however, applicable substrates have so far been
limited to a,b-unsaturated pyridyl sulfones[6] and 3-substi-
tuted maleimides[7] under rhodium catalysis. Herein, we
describe that simple b,b-disubstituted a,b-unsaturated
ketones can now be employed as substrates for the rho-
dium-catalyzed 1,4-addition of arylboroxines (arylboronic
acid anhydrides) and that highly efficient asymmetric catal-
ysis can be realized by using a chiral tetrafluorobenzobarre-
lene as the ligand.
ities were achieved, the synthetic drawback of this process
was that tetraarylborates were required to promote the
reaction, and more readily available organoboronic acids
and organoboronates could not be effectively employed as
the nucleophile.
To solve this methodological problem, we decided to
reinvestigate the reaction conditions for the phenylation of
3-methyl-2-cyclohexen-1-one (1a) and found that [{Rh(OH)-
(cod)}2] (5 mol% Rh) could effectively catalyze the addition
of air-stable and readily available phenylboroxine[10] at 608C
in anhydrous dioxane to give 1,4-adduct 2aa in 78% yield
(1.2m initial concentration of 1a; Table 1, entry 1).[11] The use
of [{RhCl(cod)}2] in place of [{Rh(OH)(cod)}2] as the catalyst
did not promote the reaction (Table 1, entry 2), but the in situ
generation of [{Rh(OH)(cod)}2] from [{RhCl(cod)}2] by
treating it with KOH successfully produced 2aa in 73%
yield (Table 1, entry 3). Furthermore, no reaction was
observed with a rhodium bis(phosphine) complex, such as
As a partial solution to the use of simple b,b-disubstituted
a,b-enones in the asymmetric 1,4-addition of air-stable
organoboron nucleophiles, we recently reported a rhodium-
catalyzed asymmetric 1,4-addition of sodium tetraarylborates
in the presence of chiral diene ligand (R)-L1,[8] as illustrated
in Equation (1).[9] Although high yields and enantioselectiv-
Table 1: Rhodium-catalyzed 1,4-addition of phenylboroxine to 3-methyl-
2-cyclohexen-1-one (1a): Optimization.
Entry Rhodium catalyst
Base (mol%) Yield [%][a] ee [%][b]
1
2
3
4
5
6
7
8
9
[{Rh(OH)(cod)}2]
[{RhCl(cod)}2]
[{RhCl(cod)}2]
[{Rh(OH)(binap)}2]
[{RhCl((R)-L1)}2]
[{RhCl((R)-L1)}2]
[{RhCl((R)-L1)}2]
[{Rh(OH)((R,R)-Bn-tfb*)}2] none
[{Rh(OH)((R,R)-Ph-tfb*)}2] none
none
none
KOH (7.5)
none
78
0[c]
73
0[c]
0[c]
–
–
–
–
–
KOH (7.5)
Cs2CO3 (15) 10[c]
Cs2CO3 (100) 48
–
[d]
90 (R)
99 (R)
99 (R)
98 (R)
97 (R)
94
99
70
92
10
11
[{RhCl((R,R)-Bn-tfb*)}2]
[{RhCl((R,R)-Ph-tfb*)}2]
KOH (7.5)
KOH (7.5)
[*] Dr. R. Shintani, M. Takeda, Dr. T. Nishimura, Prof. Dr. T. Hayashi
Department of Chemistry, Graduate School of Science
Kyoto University, Sakyo, Kyoto 606-8502 (Japan)
Fax: (+81)75-753-3988
[a] Yield of isolated product. [b] Determined by chiral HPLC on a
Chiralcel OJ-H column with hexane/2-propanol=95:5. [c] Determined by
1H NMR spectroscopy of the crude material. [d] Not determined. cod=
1,5-cyclooctadiene,
phosphine).
binap=1,1’-binaphthalene-2,2’-diylbis(diphenyl-
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 Scientific
Research (S) (19105002), the Ministry of Education, Culture, Sports,
Science, and Technology (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201000467.
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Communications
[{Rh(OH)(binap)}2] as the catalyst (Table 1, entry 4). On the
enones give the opposite enantiomers as the major product,
which indicates that the catalyst efficiently recognizes the
olefin geometry of the substrates (Table 2, entry 4 versus
entry 6). With regard to the nucleophilic component, a
sterically and electronically diverse array of aryl groups can
be installed onto enone 1a in uniformly high yield (81–97%)
with excellent enantioselectivity (99%; Table 2, entries 7–12).
To gain some insight into the mechanism, we conducted a
reaction of 1a with phenylboroxine in the presence of
[{Rh(OH)(cod)}2] as the catalyst and the reaction was
quenched with [D4]acetic acid instead of water [Eq. (2)].
basis of these results and our previous success in the addition
of sodium tetraarylborates, we attempted to develop its
asymmetric analogue by using [{RhCl((R)-L1)}2] as the
catalyst; however, no 2aa product was obtained with KOH
as a base (Table 1, entry 5). Changing the base from KOH to
Cs2CO3 afforded 2aa in up to 48% yield with 90% ee
(Table 1, entries 6 and 7), but further improvement could not
be achieved with this rhodium complex.
We successively examined chiral tetrafluorobenzobarre-
lene (tfb*) ligands[12–15] because their hydroxorhodium com-
plexes can be isolated as stable compounds[12e] and they are
known to display high catalytic activity in other related
asymmetric addition reactions.[12] To our delight, both
[{Rh(OH)((R,R)-Bn-tfb*)}2]
and
[{Rh(OH)((R,R)-Ph-
tfb*)}2] did effectively promote the reaction of 1a with
phenylboroxine to give 2aa in 94 and 99% yield, respectively,
with excellent enantioselectivity (99% ee; Table 1, entries 8
and 9). The reaction also proceeded well using catalysts
generated in situ from reaction of their corresponding
chlororhodium complexes with KOH, but the yields became
somewhat lower (70–92%, 97–98% ee; Table 1, entries 10
and 11).
Various cyclic enones were then reacted with phenyl-
boroxine using [{Rh(OH)((R,R)-Ph-tfb*)}2] as the catalyst to
give the corresponding b-phenylketones in high yields and
enantioselectivities (70–99% yield, 98–99% ee; Table 2,
entries 1–3). Furthermore, acyclic enones also reacted suc-
cessfully under the same conditions (78–82% yield; Table 2,
entries 4–6), although the enantioselectivities were somewhat
lower (81–86% ee). It is worthy to note that (E) and (Z)-
Under these conditions, product 2aa was obtained in 77%
yield with 85% deuterium incorporation only at the
a-position adjacent to the quaternary carbon stereocenter
(d.r. = 6.7:1); this result indicates that the primary product
during the catalysis exists as a form of enolate, which is
protonated upon aqueous work-up. On the basis of this result,
a proposed catalytic cycle of the reaction of 1a with phenyl-
boroxine is illustrated in Figure 1.[1d] Thus, phenylrhodium
Table 2: Rhodium-catalyzed asymmetric 1,4-addition of arylboroxines to
b,b-disubstituted a,b-unsaturated ketones 1: Scope.
Figure 1. Proposed catalytic cycle for the rhodium-catalyzed 1,4-addi-
tion of phenylboroxine to 1a. [Rh]=[{Rh(diene)}].
species A, initially generated by transmetalation between
phenylboroxine and a hydroxorhodium complex, undergoes
insertion of 1a to give oxa-p-allylrhodium intermediate B.
Direct transmetalation of this intermediate with phenylbor-
oxine regenerates phenylrhodium A along with the formation
of boron enolate C,[16] which becomes 2aa after addition of
water at the end of the reaction.
We also carried out the reaction of 1a with phenyl-
boroxine in the presence of both [{Rh(OH)(cod)}2] and
[{Rh(OH)((R,R)-Ph-tfb*)}2] (2.5 mol% Rh for each), and
found that product 2aa was obtained in 90% yield with 79%
ee (R) [Eq. (3)]. Because [{Rh(OH)(cod)}2] gives racemic
2aa, and [{Rh(OH)((R,R)-Ph-tfb*)}2] gives 2aa with 99% ee
(R), the rhodium complex with the (R,R)-Ph-tfb* ligand is
approximately four times more active than the complex with
the cod ligand, assuming that these complexes work as
Entry
1
Ar
t [h] Product Yield [%][a] ee [%][b]
1
2
3
4
5
6
7
8
9
1a
1b
1c
(E)-1d
(E)-1e
(Z)-1d
1a
1a
1a
1a
1a
Ph
Ph
Ph
Ph
Ph
24
48
48
60
60
60
48
24
24
24
24
48
(R)-2aa 99
(R)-2ba 88
(R)-2ca 70
(S)-2da 82
(S)-2ea 80[c]
(R)-2da 78
(R)-2ab 81
(R)-2ac 94
(R)-2ad 97
(R)-2ae 85
(R)-2af 87
(R)-2ag 95
99
99
98
86
81
86
99
99
99
99
99
99
Ph
4-MeOC6H4
4-FC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
2-naphthyl[d]
10
11
12
1a
[a] Yield of isolated product. [b] Determined by chiral HPLC with hexane/
2-propanol. [c] Determined by 1H NMR spectroscopy against an internal
standard after chromatographic purification. [d] 1.2 equivalents B.
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dꢄAugustin, M. Humam, A. Alexakis, R. Taras, S. Gladiali,
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((R,R)-Ph-tfb*)}2] could be attributed to the acceleration of
transmetalation and insertion steps owing to the electron-
withdrawing nature of (R,R)-Ph-tfb*.[17]
In summary, we have developed a rhodium-catalyzed 1,4-
addition of arylboroxines to b,b-disubstituted a,b-unsaturated
ketones. Highly efficient asymmetric catalysis has also been
described to create quaternary carbon stereocenters by
employing a chiral tetrafluorobenzobarrelene as the ligand.
Future studies will explore further expansion of the substrate
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Experimental Section
General procedure for Table 2: A solution of [{Rh(OH)((R,R)-Ph-
tfb*)}2] (9.0 mg, 18 mmol Rh), enone 1 (0.36 mmol), and arylboroxine
(0.72 mmol) in dioxane (0.30 mL) was stirred for 24–60 h at 608C, and
the reaction was quenched with water (50 mL). The mixture was
passed through a pad of silica gel with EtOAc and the solvent was
removed under vacuum. The residue was purified by preparative TLC
on silica gel to afford 1,4-adduct 2.
Received: January 26, 2010
Published online: April 13, 2010
Keywords: arylboroxine · asymmetric catalysis · diene ligands ·
.
ketones · rhodium
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