Enantioselective Formal C?H Conjugate Addition of Acetanilides to β-Substituted Acrylates by Chiral Iridium Catalysts

Article abstract of DOI:10.1002/chem.201604962

The Ir-catalyzed enantioselective reaction of substituted acetanilides with β-substituted α,β-unsaturated esters provided chiral 3,3-disubstituted propanoates in high yield with good-to-excellent enantiomeric excess (up to 99 % ee). This transformation, i

Full text of DOI:10.1002/chem.201604962

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Title: Enantioselective Formal C-H Conjugate Addition of Acetanilides
to beta-Substituted Acrylates by Chiral Iridium Catalysts
Authors: Takanori Shibata, Masamichi Michino, Hisaki Kurita, Yu-ki
Tahara, and Kyalo Stephen Kanyiva
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To be cited as: Chem. Eur. J. 10.1002/chem.201604962
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Enantioselective Formal C-H Conjugate Addition of Acetanilides
β
to -Substituted Acrylates by Chiral Iridium Catalysts
Takanori Shibata,*[a],[b] Masamichi Michino,[a] Hisaki Kurita,[a] Yu-ki Tahara,[a] and Kyalo Stephen
Kanyiva[c]
Dedication ((optional))
Abstract: The Ir-catalyzed enantioselective reaction of substituted
acetanilides with β-substituted α,β-unsaturated esters gave chiral
3,3-disubstituted propanoates in high yield with good to excellent
enantiomeric excess (up to 99% ee). The present transformation
initiated by sp2 C-H bond activation is the first example of
enantioselective formal C-H conjugate addition to β-substituted α,β-
unsaturated carbonyl compounds. The starting materials are
commercially available and/or readily accessible.
derivatives with various vinyl ethers (Scheme 1b).[11,12] Another
approach involved formal C-H conjugate addition of
benzoxazoles to α-substituted acrylates.[13] Against this
background, we report here an enantioselective formal C-H
conjugate addition to β-substituted α,β-unsaturated esters
(Scheme 1d). The Ir-catalyzed enantioselective reaction of
acetanilides with crotonates gives chiral ortho-phenylene-
tethered δ-amino acid derivatives.
The direct conversion of ubiquitous C-H bonds is an ideal
transformation in organic synthesis.[1] In particular, a catalytic
and enantioselective reaction initiated by C-H bond cleavage is
a target of aggressive research in asymmetric synthesis. A
clear-cut approach to the creation of central chirality is the
enantioselective activation of a secondary sp3 C-H bond, and Yu
reported the chiral Pd-catalyzed sp3 C-H bond activation of
cyclopropanes with boron reagents using a carbamoyl directing
group.[2,3] We previously reported the chiral Ir-catalyzed sp3 C-H
alkylation of alkyl amines with various alkenes using a pyridyl
directing group for the preparation of chiral secondary
amines.[4a,b] We further used this enantioselective C-H alkylation
strategy for the synthesis of γ-amino acid derivatives with the
use of γ-lactams as substrates.[4c]
(a) Branch-selective C-H alkylation of indoles using styrenes and norbornene
R2
NR'
Me
Me
Ph
chiral cat.
+
∗
∗
∗
N
R
N
Bz
N
N
Ar
R1
Boc
H
42% ee by Ir
96% ee by Ir
87% ee by Co
(Yoshikai)10
(Shibata)8
(Hartwig)9
(b) Branch-selective C-H alkylation of benzamide using vinyl ethers
O
R1
O
R1
chiral Ir cat.
>99% ee
(Nishimura)11
NHMs
Me
NHMs
+
OR2
∗
OR2
(c) Formal C-H conjugate addition of benzoxazoles to α-substituted acrylates
R1
R1
R2
∗
R2
96% ee
(Rovis)13
CO2Et
N
O
N
O
chiral Rh cat.
+
CO2Et
(d) This work: formal C-H conjugate addition of anilides to β-substituted acrylates
R1
R1
Another attractive protocol for the creation of central chirality is
the hydroarylation of an alkene initiated by sp2 C-H bond
activation. Since Murai’s pioneering work,[5] chiral Rh-catalyzed
intramolecular reactions have been comprehensively studied by
Bergman and Ellman: hydroarylation of various alkenes
generated stereogenic centers.[6,7] Regarding the intermolecular
reaction, the branch-selective C2 C-H alkylation of an indole is a
typical strategy: the first example of the Ir-catalyzed C-H
alkylation of N-benzylindole with styrene[8] was followed by the
Ir-catalyzed alkylation with norbornene[9] and the Co-catalyzed
C-H alkylation of 3-iminoindole[10] (Scheme 1a). For compounds
other than indole derivatives, Nishimura recently reported the Ir-
catalyzed branch-selective C-H alkylation of benzamide
NHAc
NHAc
chiral Ir cat.
CO2Me
+
R2
∗
CO2Me
R2
1a-e
Scheme 1. Enantioselective intermolecular C-H alkylation with
alkenes initiated by sp2 C-H bond activation
Although many examples of sp2 C-H alkylation with alkenes
have been reported,[1,14] there are few examples with electron-
deficient olefins, such as α,β-unsaturated carbonyl compounds,
which are fascinating because of their potential to provide
synthetically useful alkylated compounds.[15,16] Among them, the
reactions of α,β-unsaturated esters, namely formal C-H
conjugated addition, has recently been a hot topic.[17] However,
there is no example of an enantioselective variant to β-
substituted α,β-unsaturated carbonyl compounds.
[a]
Prof. Dr. T. Shibata, M. Michino, H. Kurita
Department of Chemistry and Biochemistry
School of Advanced Science and Engineering
Waseda University, 3-4-1 Okubo, Shinjuku, Tokyo 169-8555 (Japan)
E-mail: tshibata@waseda.jp
[b]
[c]
Prof. Dr. T. Shibata
JST, ACT-C, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012 (Japan)
Dr. K. S. Kanyiva
International Center for Science and Engineering Programs (ICSEP)
Waseda University, 3-4-1 Okubo, Shinjuku, Tokyo 169-8555 (Japan)
We chose (3’-methyl)acetanilide (1a) and (E)-methyl crotonate
(2a) as model substrates and conducted the reaction in the
presence of various chiral Ir catalysts, which were prepared in
situ from [Ir(cod)2]OTf and chiral diphosphine ligands.[18] As a
result, 2,3-bis(diphenylphosphino)butane (CHIRAPHOS) gave
alkylated product 3aa in good yield and ee, and 5,5'-
Supporting information for this article is available on the WWW
under http://www.angewandte.org
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bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole
(SEGPHOS)
9c
Me (1a)
72
>99 (3aa)
85
realized almost perfect enantioselectivity, albeit in low yield due
[a] The reaction was conducted under the neat conditions. [b]
Alkene 2a (1 equiv) was used. [a] The chiral Ir catalyst (2
mol%) was used.
to the low conversion of substrate 1a.[19]
H
Me
N
Me
Since the enantioselectivity still had room for improvement, we
further examined the reaction conditions using SEGPHOS
analogues (Table 2). When we used the preliminarily prepared
Ir-SEGPHOS catalyst, the yield remained low even under neat
conditions (entries 1 and 2). Among SEGPHOS analogues,
O
O
Me
NH
[Ir(cod)2]OTf + chiral ligand
(10 mol%)
1a
Me
+
dioxane, 120 °C, 24 h
CO2Me
Me
CO2Me
Me
3aa
(S,S)-CHIRAPHOS: 76%, 85% ee
(S)-SEGPHOS: 13%, 98% ee
2a
DIFLUORPHOS showed
a drastic increase in conversion
(4 equiv)
(entries 3-5), and the yield reached 50% under prolongation of
the reaction time (entry 6). Two equivalent amounts of alkene 2a
gave comparable results.
Scheme 2. Preliminary results of the enantioselective reaction of
anilide 1a with 2a.
Table 2: Screening of SEGPHOS analogues in the enantioselective
reaction of anilide 1a with 2a.
We next investigated the effect of an amide directing group
using preliminarily prepared Ir-CHIRAPHOS catalysts, which
were purified by column chromatography[20] (Table 1). In addition
to propionamide 1b, more bulky isobutyramide 1c gave almost
the same results as acetamide 1a (entries 1-3). In contrast, the
electronic effect was significant, and the reaction of
phenylacetamide 1d or trifluoroacetamide 1e did not proceed at
all (entries 4 and 5). We determined that acetamide 1a could be
used as a standard substrate. When we used a longer reaction
time, the amide was completely consumed, and quantitative
yield was achieved without a loss of ee (entry 6). Comparable
results were obtained even under solvent-free conditions (entry
7). When exactly a stoichiometric amount of alkene 2a was used,
the yield was still high (entry 8). It is noteworthy that only 2 mol%
of the catalyst achieved the quantitative yield without loss of ee
(entry 9).
[Ir(cod){(S)-ligand}]OTf
(10 mol%)
1a
+
2a
3aa
dioxane, 120 °C, time
(4 equiv)
Entry
Liganda
Time [h] Yield [%]
ee [%]
1
2b
3
SEGPHOS
SEGPHOS
24
24
24
24
24
72
72
22
25
16
16
43
50
48
97
97
98
95
98
97
97
DM-SEGPHOS
SYNPHOS
4
5
DIFLUORPHOS
DIFLUORPHOS
DIFLUORPHOS
6
7c
[a] DM-SEGPHOS: 5,5'-bis[di(3,5-xylyl)phosphine]-4,4'-bi-1,3-
benzodioxole, SYNPHOS: 6,6'-bis(diphenylphosphino)-2,2',3,3'-
tetrahydro-5,5'-bi-1,4-benzodioxin, DIFLUORPHOS: 5,5'-
bis(diphenylphosphino)-2,2,2',2'-tetrafluoro-4,4'-bi-1,3-
benzodioxole. [b] Under neat conditions. [c] Crotonate 2a (2
equiv) was used.
Table 1: Screening of amide directing groups in the enantioselective
reaction of anilides 1a-1e with (E)-methyl crotonate (2a)
O
R
H
N
[Ir(cod){(S,S)-chiraphos}]OTf
Me
R
Me
NH
(10 mol%)
2a
(4 equiv)
+
O
dioxane, 120 °C, time
CO2Me
1a-1e
Me
3aa-3ea
We used cationic Ir–CHIRAPHOS or –DIFLUORPHOS catalyst
to investigate the substrate scope of mono- and disubstituted
acetanilides (Table 3). Regarding the 3 position, both electron-
donating and –withdrawing groups were tolerable, and chiral
ortho-phenylene-tethered δ-amino acids derivatives 3fa-3la were
obtained with good to excellent ee (entries 1-6). 3,4-
Disubstituted acetanilides 1i and 1j were also transformed into
the corresponding C-H alkylated products 3ia and 3ja,
respectively (entries 7-9). The Ir–DIFLUORPHOS catalyst
realized excellent ee, but resulted in low yield due to low
conversion, except for (3’-methoxy)acetanilide (1f) (entry 2). The
substituent at the 2 position had a significant effect: while the
reaction of (2’-methyl)acetanilide (1k) with the Ir-CHIRAPHOS
catalyst proceeded with high enantioselectivity (91% ee), that of
(2’-chloro)acetanilide (1m) did not proceed at all (entries 10-13).
When the parent acetanilide (1n) was subjected to the standard
Entry
R
Time [h]
Yield [%] ee [%]
1
2
Me (1a)
Et (1b)
24
24
24
24
24
72
72
72
79 (3aa)
66 (3ba)
76 (3ca)
NR
84
81
81
-
3
i-Pr (1c)
Bn (1d)
CF3 (1e)
Me (1a)
Me (1a)
Me (1a)
4
5
NR
-
6
>99 (3aa)
>99 (3aa)
85 (3aa)
85
85
85
7a
8b
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conditions, the inseparable mixture of mono- and dialkylated
products was obtained, but the selective formation of 3na was
achieved by the use of exactly a stoichiometric amount of alkene
2a (entries 14 and 15).
Table 4: Substrate scope of β-substituted α,β-unsaturated esters 2
in the reaction with acetamide 1a
[Ir(cod){(S,S)-chiraphos}]OTf
or
[Ir(cod){(S)-difluorphos}]OTf
Me
NHAc
CO2R2
R1
3ab-3af
R1
(10 mol%)
1a
+
CO2R2
2b-2f
(4 equiv)
dioxane, 120 °C, 72 h
Table 3: Substrate scope of substituted acetanilides 1 in the reaction
with methyl crotonate (2a)
[Ir(cod){(S,S)-chiraphos}]OTf
Entry
Alkene
Liganda Yield [%]
ee [%]
or
2
R
R
3
[Ir(cod){(S)-difluorphos}]OTf
NHAc
CO2Me
NHAc
(10 mol%)
2a
(4 equiv)
+
Me
1
2
A
B
>99 (3ab)
72b (3ab)
85
97
4
dioxane, 120 °C, 72 h
CO2(i-Pr)
CO2(t-Bu)
1f-1n
Me
3fa-3na
2b
2c
2d
Me
3
A
ND
-
Entry
R
Liganda Yield [%]
ee [%]
1
2
3-OMe (1f)
3-OMe (1f)
3-Cl (1g)
A
B
A
B
A
B
A
B
A
A
A
B
A
A
B
90 (3fa)
60 (3fa)
89 (3ga)
11 (3ga)
62 (3ha)
12 (3ha)
98 (3ia)
16 (3ia)
64 (3ja)
88 (3ka)
85 (3la)
13 (3la)
ND
84
98
81
96
78
94
85
98
81
91
90
97
4
5
6
7
8
9
A
B
A
B
A
B
88 (3ad)
41 (3ad)
78 (3ae)
31 (3ae)
51 (3af)
39 (3af)
80
98
80
99
80
99
n-C5H11
CO2Me
Ph
3
CO2Me
2e
4
3-Cl (1g)
5
3-CF3 (1h)
3-CF3 (1h)
3,4-Me2 (1i)
3,4-Me2 (1i)
3-Cl-4-Me (1j)
2-Me (1k)
2-MeO (1l)
2-MeO (1l)
2-Cl (1m)
H (1n)
MeO2C
CO2Me
6
(E)-2f
CO2Me
7
MeO2C
10
A
34 (3af)
73
8
(Z)-2f
[a] A: CHIRAPHOS, B: DIFLUORPHOS. [b] NMR yield.
9
10
11
12
13
14b
15b
As a preliminary study of the reaction mechanism, the reaction
of 1a was conducted in the presence of D2O (Scheme 3). Under
alkene-free conditions, excellent H/D exchange occurred at both
ortho positions of the amide group, which means that C-H bond
cleavage is not regioselective. In the reaction with alkene 2a,
both the expected α-position and the β-position with respect to
the ester moiety of product 3aa were partly deuterated.
80 (3na)
33 (3na)
86
96
H (1n)
[a] A: CHIRAPHOS, B: DIFLUORPHOS. [b] Alkene 2a (1
96%-D
equiv) was used.
[Ir(cod){(S,S)-chiraphos}]OTf
H/D
(10 mol%)
D2O (10 equiv)
Me
NHAc
H/D
Table 4 shows the reaction of 1a with various β-substituted α,β-
unsaturated esters 2b-2f. The ester moiety greatly affected the
results: while an isopropyl ester gave good results, a tert-butyl
ester did not (entries 1-3). n-Pentyl and phenyl-substituted
acrylates 2d and 2e were also good acceptors, and 3,3-
disubstituted propanoates 3ad and 3ae were obtained with good
to excellent ee (entries 4-7). Dimethyl fumarate (E)-2f also
reacted with acetanilide 1a to give chiral 2-arylsuccinate 3af
(entries 8 and 9). The reaction of dimethyl maleate gave 3af in
lower yield and ee, but the major enantiomer was the same as
that derived from dimethyl fumarate (entry 10).
1a
dioxane, 120 °C, 72 h
1a-D
85%-D
H/D
96%-D
86%-D
H/D
35%-D
Me
NHAc
Me
NHAc
H/D
same as above
1a
+
+
2a
CO2Me
Me H/D
(4.0 equiv)
85%-D
17%-D
3aa-D: 65%
1a-D: 31%
Scheme 3. Reaction of 1a in the presence of D2O without or with
alkene 2a
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