Rhodium-catalyzed asymmetric addition of arylboroxines to β-alkoxyacrylate esters

Article abstract of DOI:10.1039/c1cc14150c

Asymmetric addition of arylboroxines to β-alkoxyacrylate esters proceeded in the presence of a rhodium complex coordinated with a chiral diene ligand to give high yields of β-alkoxy-β-arylcarboxylic acid esters with very high enantioselectivity.

Full text of DOI:10.1039/c1cc14150c

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COMMUNICATION
Rhodium-catalyzed asymmetric addition of arylboroxines to
b-alkoxyacrylate estersw
Takahiro Nishimura,* Atsuyuki Kasai, Makoto Nagaosa and Tamio Hayashi*
Received 11th July 2011, Accepted 29th July 2011
DOI: 10.1039/c1cc14150c
Asymmetric addition of arylboroxines to b-alkoxyacrylate esters
proceeded in the presence of a rhodium complex coordinated with
a chiral diene ligand to give high yields of b-alkoxy-b-arylcarboxylic
acid esters with very high enantioselectivity.
Rhodium-catalyzed asymmetric addition of organoboron
reagents to a,b-unsaturated carbonyl compounds is a powerful
tool to construct a stereogenic carbon center,1 because a wide
Scheme 2 Asymmetric addition to b-phthaliminoacrylate esters.
variety of aryl- and alkenyl groups can be introduced into the
b-position in high yields and high enantioselectivity.2 Most
studies so far have focused on the addition to a,b-unsaturated
carbonyl compounds substituted with alkyl or aryl groups at
the b-position, while the addition to those substituted with
heteroatoms has been less developed.3–5 The rhodium-catalyzed
addition of arylboronic acids to a,b-unsaturated carbonyl
compounds proceeds via an oxa-p-allylrhodium intermediate,
which then undergoes hydrolysis to give a hydroarylation
product I (Scheme 1).6 On the other hand, in the addition
to a,b-unsaturated carbonyl compounds bearing a strongly
electronegative atom such as nitrogen or oxygen at the b-position,
b-elimination from the oxa-p-allylrhodium intermediate giving a
substitution product II becomes a problem as a competitive
reaction,7 and the preferential hydrolysis of the oxa-p-allyl-
rhodium intermediate is important for the selective formation
of the addition product. Recently, we reported rhodium-catalyzed
asymmetric addition of arylboronic acids to b-phthaliminoacry-
late esters (Scheme 2). The reaction was successfully carried out
by use of a hydroxorhodium/chiral diene catalyst giving b-aryl-
b-N-phthaloylamino acid esters in high yields with high enantio-
selectivity, while elimination of phthalimide was observed in
the reaction with a bisphosphine ligand (binap) or KOH as
a base.8
Chiral b-hydroxy- and b-alkoxy carboxylic acid derivatives
are important structural components in natural products and
pharmaceuticals, and a number of methods to access b-alkoxy
carbonyl compounds in a stereoselective manner have been
reported in the aldol reaction9 and the oxa-Michael reaction.10,11
Our straightforward approach to synthesize chiral b-alkoxy
carboxylic acid derivatives is focusing on the rhodium-catalyzed
asymmetric conjugate arylation of b-alkoxyacrylate esters. Here
we report the asymmetric addition of arylboroxines to b-alkoxy-
acrylate esters, which are readily available from propiolic acid
esters and alcohols.12 The reaction giving chiral b-alkoxy-
b-arylcarboxylic acid esters with extremely high enantioselec-
tivity is realized by use of a rhodium/chiral diene catalyst.
We found that the catalytic activity of a rhodium complex
for the reaction of b-alkoxyacrylate esters is higher with a
diene ligand than with a bisphosphine ligand (Table 1). Thus,
treatment of tert-butyl 3-isopropoxypropenoate (1a) with
phenylboroxine (2m) (2.5 equiv. of B) in the presence of
Scheme 1 Rhodium-catalyzed addition to a,b-unsaturated carbonyl
compounds.
6
[Rh(OH)((R)-binap)]2 (3 mol% of Rh) in 1,4-dioxane/H2O
(9 : 1) at 30 1C for 3 h, which is one of the best catalytic
conditions in the asymmetric addition of arylboronic acids
to a,b-unsaturated carbonyl compounds,6 gave the addition
product 3am in 6% yield, where most of the phenylboroxine
(2m) was consumed to give benzene by protodeborylation
(entry 1). The yield of the addition product 3am was low
(5%) even in the reaction in the presence of KOH (40 mol%)
Department of Chemistry, Graduate School of Science,
Kyoto University, Sakyo, Kyoto 606-8502, Japan.
E-mail: tnishi@kuchem.kyoto-u.ac.jp, thayashi@kuchem.kyoto-u.ac.jp;
Fax: +81 75 753 3988; Tel: +81 75 753 3983
w Electronic supplementary information (ESI) available: Experimental
procedures and compound characterization data. See DOI: 10.1039/
c1cc14150c
c
10488 Chem. Commun., 2011, 47, 10488–10490
This journal is The Royal Society of Chemistry 2011

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Table 1 Rhodium-catalyzed addition of phenylboroxine (2m) to 1a
with over 99.5% ee and a small amount (2%) of methyl
3,3-diphenylpropanoate (4bm) (entry 7). The reactions of
2,6-dimethylphenyl ester 1c and 2,6-dimethoxyphenyl ester
1d proceeded with complete conversion to give the corres-
ponding addition products 3cm and 3dm in 90 and 97% yield,
respectively (entries 8 and 9), where the chemoselectivity was
high in the reaction of 1d (3dm/4dm = 97%/3%) (entry 9).
The enantioselectivities observed for 3cm and 3dm were
extremely high (499.5% ee). The reaction was also catalyzed
by rhodium complexes coordinated with Ph-tfb* (L3) or Bn-tfb*
(L4), but their catalytic activities and stereoselectivities were lower
than those observed with the ferrocene-substituted diene L2
(entries 10 and 11). The reaction was not catalyzed at all by
[Rh(OH)(binap (L1))]2 under the same reaction conditions (entry
12). Phenylboronic acid can be used as well as phenylboroxine
(2m) to give 3dm with the same high chemo- and enantioselec-
tivity (entry 13). The absolute configuration of 3dm obtained with
(S,S)-L2 was assigned to be S by analogy with (S)-3im (vide infra).
The present catalytic system can be applied to the asym-
metric addition of several arylboroxines to b-alkoxyacrylates
with all extremely high enantioselectivity (Table 2). Aryl
groups (2m–2t) having a variety of substituents were success-
fully introduced at the b position of the b-isopropoxyacrylate
1d giving the corresponding addition products (3dm–3dt) in
high yields with over 99.5% ee (entries 1–8). The addition of
phenylboroxine (2m) to b-alkoxyacrylates where the alkoxy
groups are cyclohexyloxy (1e), ethoxy (1f), methoxy (1g),
benzyloxy (1h), and p-methoxybenzyloxy (1i) gave the corres-
ponding addition products 3em–3im with over 99.5% ee
(entries 9–13).16
Entry 1 L and conditions Conv.b (%) 3b (%)
4b (%) eec (%)
d
1
1a L1
1a L1
1a cod
1a cod
1a cod
1a L2
1b L2
1c L2
1d L2
1d L3
1d L4
1d L1
1d L2
A
A
A
B
C
C
C
C
C
C
C
C
C
8
19
45
25
38
92
89
100
100
91
6 (3am)
5 (3am)
27 (3am) 12
o1
—
—
—
—
—
98
d
2e
3
2 (6)f
4
5
6
7
8
9
10
11
12
13g
18 (3am)
30 (3am)
3
2
82 (3am) 10
86 (3bm)
90 (3cm) 10
97 (3dm)
78 (3dm) 11
77 (3dm)
o1 (3dm) 0
96 (3dm)
2
499.5
499.5
499.5
99.2
3
87
o1
9
94
—
d
100
3
499.5
a
Reaction conditions: 1 (0.200 mmol), (PhBO)3 (2m) (0.167 mmol),
[Rh(OH)L]2 (3 mol% of Rh) at 30 1C for 3 h. Conditions A: the
reaction in dioxane/H2O (9 : 1; 0.8 mL). Conditions B: the reaction
in CH2Cl2/MeOH (1 : 1; 0.8 mL). Conditions C: the reaction in
CH2Cl2/MeOH (1 : 1; 0.8 mL) in the presence of Et3N (0.20 mmol).
The b-alkoxy-b-arylcarboxylic acid esters obtained here
with almost perfect enantioselectivity can be converted into
b
A conversion of 1 and yields of 3 and 4 were determined by
c
1H NMR. The ee was determined by HPLC analysis with chiral
d
stationary phase columns. Not determined. Performed in the pre-
Table 2 Asymmetric addition of arylboroxine 2 to 1a
e
f
sence of KOH (40 mol%) at 60 1C. The value in parentheses is an
yield of t-butyl cinnamate. PhB(OH)2 (0.50 mmol) was used instead
of (PhBO)3; cod: cycloocta-1,5-diene.
g
at 60 1C (entry 2). The b-alkoxyacrylate ester was prone to
eliminate the alkoxy group during the present rhodium-
catalyzed reaction to give tert-butyl cinnamate (6%) and
tert-butyl 3,3-diphenylpropanoate (4am: 2%), which is the
phenylation product of tert-butyl cinnamate formed by
elimination of the isopropoxy group. On the other hand, the
use of [Rh(OH)(cod)]2 gave 27% yield of 3am and 12% of 4am
(entry 3). The selectivity giving the addition product 3am
was higher in the solvent system of CH2Cl2/MeOH (1 : 1)
(3am/4am = 18%/3%) (entry 4), and the addition of triethyl-
amine (1.0 equiv.) increased the chemoselectivity (3am/4am =
30%/2%) (entry 5). Chiral diene ligands13,14 based on
tetrafluorobenzobarrelenes (tfb)15 displayed a high catalytic
activity and enantioselectivity. Thus, the reaction of 1a in the
presence of [Rh(OH)((S,S)-Fc-tfb* (L2))]2 (Fc; ferrocenyl)15a
(3 mol% of Rh) gave the 1,4-addition product 3am in 82%
yield, whose ee was 98% (entry 6). The formation of 10%
yield of the diphenylation product 4am was also observed. The
ester group of 1 had a significant influence on both the
reactivity and selectivity (entries 7–9). The addition to
methyl ester 1b gave the addition product 3bm in 86% yield
Entry
1
Ar (2)
Yieldb (%)
eec (%)
1
2
3
4
1d
1d
1d
1d
1d
1d
1d
1d
1e
1f
Ph (2m)
95 (3dm)
91 (3dn)
96 (3do)
94 (3dp)
91 (3dq)
90 (3dr)
68 (3ds)
90 (3dt)
92 (3em)
87 (3fm)
75 (3gm)
88 (3hm)
88 (3im)
499.5
499.5
499.5
499.5
499.5
499.5
499.5
499.5
499.5
499.5
499.5
499.5
499.5
2-MeC6H4 (2n)
3-MeC6H4 (2o)
4-MeC6H4 (2p)
4-MeOC6H4 (2q)
4-ClC6H4 (2r)
4-CF3C6H4 (2s)
2-Naphthyl (2t)
Ph (2m)
Ph (2m)
Ph (2m)
Ph (2m)
Ph (2m)
5d
6e
7f
8
9
10
11
12
13
1g
1h
1i
a
Reaction conditions: 1 (0.200 mmol), (PhBO)3 (2) (0.167 mmol),
[Rh(OH)(L2)]2 (3 mol% of Rh), Et3N (0.20 mmol), MeOH (0.40 mL),
b
c
CH2Cl2 (0.40 mL) at 30 1C for 3 h. Isolated yield of 3. Determined
by HPLC analysis with chiral stationary phase columns. Performed
e
with (4-MeOC6H4BO)3 (0.200 mmol). For 12 h. For 24 h.
d
f
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 10488–10490 10489

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some functionalized compounds without loss of their enantio-
meric purity (eqn (1)–(3)). Thus, basic hydrolysis of 3dm gave
the corresponding b-isopropoxycarboxylic acid 5 in 86%
yield (eqn (1)), and the reduction of 3dm by treatment with
(i-Bu)2AlH gave alcohol 6 in 96% yield (eqn (2)). Treatment
of b-p-methoxybenzyloxycarboxylic acid ester 3im with 2,3-
dichloro-5,6-dicyano-p-benzoquinone (DDQ), followed by
basic hydrolysis gave b-hydroxycarboxylic acid (S)-8, whose
absolute configuration was determined by comparison of its
specific rotation with the value reported previously (eqn (3)).17
7 In most examples of addition of carbon nucleophiles to b-alkoxy-
a,b-unsaturated carbonyl compounds, the formation of substitu-
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´
In summary, we have developed a rhodium-catalyzed asym-
metric addition of arylboroxines to b-alkoxyacrylate esters
giving b-alkoxy-b-arylcarboxylic acid esters in high yields with
very high enantioselectivity, which was realized by use of a
rhodium/chiral diene catalyst.
12 M.-J. Fan, G.-Q. Li and Y.-M. Liang, Tetrahedron, 2006, 62, 6782.
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¨
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10490 Chem. Commun., 2011, 47, 10488–10490
This journal is The Royal Society of Chemistry 2011