Rhodium(i)-catalyzed mono-selective C-H alkylation of benzenesulfonamides with terminal alkenes

Article abstract of DOI:10.1039/c9cc05219d

The Rh(i)-catalyzed ortho-alkylation of benzenesulfonamides with alkenes with the aid of an 8-aminoquinoline directing group is reported. The reaction is applicable to a variety of benzenesulfonamide derivatives and various alkenes. Curiously, unactivated

Full text of DOI:10.1039/c9cc05219d

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DOI: 10.1039/C9CC05219D
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Rhodium(I)-Catalyzed Mono-Selective C‒H Alkylation of
Benzenesulfonamides with Terminal Alkenes
Supriya Rej and Naoto Chatani*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
The Rh(I)-catalyzed ortho-alkylation of benzenesulfonamides with unsaturated esters was reported by Ding and Peng.5c Mono-
alkenes with the aid of an 8-aminoquinoline group is reported. The selective alkenylation reaction with α,β-unsaturated esters was
reaction is applicable to
a variety of benzenesulfonamide reported when ortho-substituted benzenesulfonamides were
derivatives and various alkenes. Curiously, unactivated 1-alkenes used as a substrate.5d The reaction of benzenesulfonamides
were more reactive than activated alkenes. Deuterium labeling that contain no ortho-substitutient on the aryl ring consistently
experiments indicate that an unusual 1,2-H shift mechanism to provided double C‒H activated product. To the best of our
generate a carbene rhodium intermediate is involved.
knowledge, interms of alkylation C‒H mono-alkylation of
benzenesulfonamides with alkenes has not been explored.
Thus, a much more selective C‒H alkylation of sulfonamides
would be highly desirable.
Sulfonamide derivatives are frequent components of the
biologically active structural motifs due to their extensive
chemical and biological activities as drugs, such as azosemide,
celecoxib, and sulfamethoxazole.1-3 In the family of sulfonamide
derivatives, sultams also show high biological activities.3
Because of this, various research groups have focused on the
synthesis of sultams from sulfonamides via C‒H activation.4 In
2012, Cramer reported the Rh-catalyzed oxidative annulation of
N-acylated benzenesulfonamides with internal alkynes to afford
benzosultam derivatives (Scheme 1).4a Similarly, the Co-
O
O
S
N
H
N
O
O
O
S
O
R
n
S
R = alkyl, CO2R', aryl
N
HN
C6F5
N
This work
R
R
Co
Rh
R
R
n = 0, 1
2017
Volla,
Rao, 2017
C
Pd
R = aryl, CO2R'.
2011
Yu,
O
n
R
catalyzed
synthesis
of
benzosultams
from
S
O
HN
benzenesulfonamides and alkynes was independently reported
by Sundararaju,4b Whiteoak and Ribas,4c and Yang.4d Recently,
Volla4e and Rao4f independently reported the annulation of
benzenesulfonamides with allenes to give sultam derivatives.
However, the simple ortho-C‒H functionalization of
sulfonamides with alkenes has not been extensively explored.5
To the best of our knowledge, only two examples of the ortho-
C‒H alkenylation of benzenesulfonamides have been reported
to date. In 2011, Yu reported the Pd-catalyzed ortho-
H
DG
n = 0, 1
Ar
Rh, Co
Ar
O
O
R
S
DG
R
Rh
CO2R
O
S
O
N
R
Rh
CO2R
Ac
N
H
R
DG = Ac, 8-aminoquinoline
2012
O
O
Ar
Cramer,
Sundaraju,
Whiteoak and Ribas,
2016
S
2014
Wang and Li,
2015
N
Ac
2015
Yang,
CO2R
2014
Wang and Li,
Ding and Peng
2015
2014
alkenylation of N-perfluoroaryl-substituted sulfonamides.5a
complementary report by Wang and Li described the
[RhCp*Cl2]2-catalyzed double ortho-alkenylation of
A
Qu and Liu
Scheme
1 Literature reports and this work on the C‒H functionalization of
benzenesulfonamides with unsaturated hydrocarbons.
sulfonamides,5b in which the authors showed that the double
alkenylation product was formed only when styrene derivatives
were used, whereas a simultaneous cyclization proceeded
along with alkenylation in the case of α,β-unsaturated esters.
Almost the same time, a similar transformation using α,β-
In the growing field of chelation-assisted C‒H functionalization,6
we previously reported the Rh-catalyzed alkylation of aromatic
carboxamides with various alkene coupling partners7 by taking
advantage of an 8-aminoquinoline moiety as a directing group,
which was first introduced by Daugulis for Pd-catalyzed C‒H
arylation reactions.8 We also recently reported the Rh-catalyzed
C8-alkylation of naphthylamides with alkenes with the aid of a
picolinamide moiety as a directing group.9 Having a continuous
interest in Rh-catalyzed C‒H activation, and the difficulty in
controlling the alkylation of sulfonamides prompted us to
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita,
Osaka 565-0871, Japan
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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examine the mono-selective linear ortho-alkylation of alkylation took place only at the less-hindered C‒H bond,
benzenesulfonamides. Herein, we report the first example of irrespective of the electronic nature ofDtOhIe: 1s0u.1b03sV9tii/etCwu9eACrntCict0lse5.O2Tn1lh9inDee
the Rh(I)-catalyzed C‒H alkylation of benzenesulfonamides with ortho-substituted arylsulfonamide 1l gave the alkylated product
alkenes (Scheme 1). Curiously, it was found that the mechanism 2la only in moderate yield (46% yield), which could be due to
for the present reaction is different from that for C‒H alkylation steric repulsion between the ortho-methyl group and the
of carboxamides with alkenes.
sulfonamide moiety. Therefore, mono-selective alkylation
products were obtained in a high degree of selectivity in the
case of para-substituted sulfonamides (2aa-2ha). The
applicability of other alkenes for this C‒H alkylation of
sulfonamides were tested by using 1m as a model substrate.
Ethyl acrylate, benzyl acylate, and butyl acrylate all gave the
desired products 2mb-md in high yields. Even methyl vinyl
ketone was reactive, giving a good yield of the alkylated product
2me.8c However, when styrene was used, the corresponding
alkylated product 2if was formed in only a moderate yield,
accompanied by the alkenylated product, in a ratio of 86:14.
Table 1 Substrate scope for sulfonamides with activated alkenesa
0.9 mmol
5.0 mol %
0.6 mmol
R
O
S
O
O O
[Rh(OAc)(cod)]2
2,3-difluorobenzoic acid
Q
S
Q
Q
N
N
R
R
H
H
toluene 1.5 mL
160 °C, 24 h
1
0.3 mmol
2
R
2aa
2ba
2ca
2da
2ea
2fa
O
S
O
, R = Me 70% / 8% (8%)
, R = H 62% / 9% (8%)
O O
Q
S
N
O
N
, R = tBu 59% / 9% (n.d.)
, R = Ph 60% / 6% (11%)
, R = OMe 71% / 5% (9%)
H
H
R
R
N
H
, R = CN 47% / trace (19%)b
CO2Me
CO2Me
50% / 5% (32%)
Table 2 Substrate scope for sulfonamide with unactivated alkenesa
60% / trace (19%)c
2ga
, R = F
2ha
R'
1.5 mmol
5.0 mol %
0.6 mmol
Me
O
O
O
S
O
O
S
O
O
S
O
O O
[Rh(OAc)(cod)]2
2,3-difluorobenzoic acid
S
Q
Q
2ia
2ja
Q
Q
S
Q
,
R = Me 64% / n.d. (18%)
R = OMe 63% / n.d. (22%)
, R = CF3 51% / n.d. (10%)b
N
N
N
N
N
H
H
,
R
R
R
H
H
H
+
toluene 0.5 mL
160 °C, 24 h
2ka
1
0.3 mmol
R'
CO2Me
46% / n.a. (33%)
CO2Me
R'
2la
2 linear
2' branch
O
O
O
O
O O
S
O
O
O
O
O O
MeO
MeO
S
Q
MeO
MeO
S
Q
Me
Q
N
Me
S
Q
F3C
S
Q
MeO
MeO
S
Q
N
N
H
N
N
N
H
H
H
H
H
CO2R
COMe
64% / trace (29%)d
Ph
nBu
nBu
76%
(linear/branch = 77/23)
nBu
88%
(linear/branch = 75/25)
2ma
2mb
2mc
2md
, R = Me 74% / n.d. (12%)
, R = Et 73% / n.d. (15%)
, R = Bn 80% / n.d. (9%)
, R = Bu 70% / n.d. (20%)
57% / n.d. (20%)e
2ig
2kg
2mg
79%
(linear/branch = 76/24)
2me
2if
O
O
O
O
O
O
MeO
MeO
S
Q
MeO
MeO
S
Q
MeO
MeO
S
Q
aIsolated yield of alkylated product 2/side product 3 (bis-alkylated product).
Recovered starting materials are given in parentheses. b10 Mol % catalyst and 5
equiv of methyl acrylate were used. cMethyl acrylate (4 equiv) was used. dMethyl
vinyl ketone (5 equiv) was used. eStyrene (4 equiv) and the acid additive (3 equiv)
were used for 48 h; A mixture of alkylated and alkenylated product formed in a
ratio of 86:14
N
N
N
H
H
H
nDec
2mh
2mj
84%
(linear/branch = 78/22)
85%
(linear/branch = 74/26)
2mi
86%
(linear/branch = 80/20)
O
O
O
O
O
O
MeO
MeO
S
Q
MeO
MeO
S
Q
MeO
MeO
S
Q
N
N
N
We began our studies by investigating the reaction of the
sulfonamide 1a with methyl acrylate by varying the reaction
parameters with the goal of selectively producing the mono-
alkylation product 2aa (see SI). After extensive screening we
found that when 1a was reacted with 3 equivalents of methyl
acrylate in the presence of [Rh(OAc)(cod)]2 (5.0 mol%) and 2,3-
difluorobenzoic acid (2.0 equiv) at 160 °C for 24 h, the desired
product 2aa formed in 70% isolated yield along with the double
C‒H activated side product 3aa in 8% yield (see SI). With the
optimized reaction conditions in hand, the scope of the reaction
of sulfonamide derivatives with methyl acrylate as a coupling
partner was examined (Table 1). Benzenesulfonamide 1b gave
the product 2ba in 62%, along with 9% of bis-alkylated product.
Para-substituted benzenesulfonamides 1c-h also afforded the
desired products in moderate to good yields (47%-71%), along
with traces of the double C‒H activated side product. It should
be noted that 4-acetamidobenezene sulfonamide 1h selectively
gave 2ha with the acetamido group remaining intact.
Particularly, electron-deficient sulfonamides, such as 1f and 1g
showed poor reactivity under the optimized reaction
conditions. Hence, the use of a higher catalyst loading and/or
an excess amount of the alkene produced the desired products
2fa and 2ga in good yields. The reaction of meta-substituted aryl
sulfonamides, 1i-k with methyl acrylate selectively gave the
corresponding mono-alkylation products 2ja-2ka in which the
H
H
H
O
2mk
2ml
2mm
62% (31%)
(linear/branch = 75/25)
90%
(linear/branch = 75/25)
64%
(linear/branch = 79/21)
aIsolated yield of the product was given. The ratio of linear and branch isomer was
calculated from a crude NMR and given in parentheses. Recovered starting
material is given in parentheses.
Unactivated 1-alkenes also can be used as a coupling partner
(Table 2). It is noteworthy that the reactivity of unactivated
alkenes was even higher than that of acrylates and styrene.
Sulfonamides 1i, 1m, and even the electron withdrawing group
substituted sulfonamide 1k reacted smoothly with 1-hexene to
afford the products in very good yields. 1-Undecene,
allylcyclohexane,
5-methylhex-1-ene,
vinylcyclohexane,
allylbenzene, and hex-5-en-2-one afforded the desired product
2mh, 2mi, 2mj, 2mk, 2ml, and 2mm respectively, in good to
excellent yields.
To gain the mechanistic insights into the alkylation reaction,
deuterium labelling studies were carried out using deuterated
alkenes (Scheme 2). In the reaction of sulfonamide 1b with
styrene-d8, the product 5 was obtained, in which nearly one
proton had been incorporated in the x-position of the product,
2 | J. Name., 2012, 00, 1-3
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which may have originated from the ortho-C‒H proton of y-position (1.36 H) in linear product 11 which indicates that the
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sulfonamide (Scheme 2a). This result is consistent with our similar mechanism was followed even in unactivated 1-alkene
DOI: 10.1039/C9CC05219D
previous finding for Rh-catalyzed C‒H alkylation reactions with system (Scheme 2c). To verify the incorporation of the ortho-
alkenes.6n,7c,7e,7g,9 However, in the y-position of product 5, more C‒H bond of the benzenesulfonamide to the x-position of the
D incorporation (1.65 D) was observed (0.35 H) than at the x- product, reactions of the deuterated sulfonamide 1b-d5 with
position, which would only be possible if the D atom had shifted styrene were also performed (Scheme 2d). Although the D-
from the x-position to the y-position.7e
content is low in the product because of the fast H/D exchange
that occurred during the reaction at the ortho-position of the
starting amide (see SI), a D atom was found only at the x-
position of the product 13.
a)
5.0 mol %
0.6 mmol
[Rh(OAc)(cod)]2
D
2,3-difluorobenzoic
acid
O
S
O
y
D
x
+
N
D5
toluene 1.5 mL
160 °C, 12 h
H
D
N
O
O
O
O
1b
0.3 mmol
1.2 mmol
S
S
0.86 H
N
N
O
O
O
a
O
S
H
H
H
b
N
x
N
S
+
N
N
H
H
H
H
N
N
Rh(OCOR)
x
y
R
H
O
O
y
1.04 H
0.35 H
H
S
C6D5
N
O
O
a + b = 1.73 H
RCOOH
Rh
N
S
5
6
31%
55%
N
A
OCOR
+L
L = COD
- RCOOH
Rh
N
b)
5.0 mol %
0.6 mmol
[Rh(OAc)(cod)]2
2,3-difluorobenzoic
acid
x
y
H
y
H
H
94% D
O
O
S
O
S
O
F
H
D
x
+
R
N
N
toluene 1.5 mL
160 °C, 12 h
H
N
D
Rh
N
path a
94% D
1b
7
1.2 mmol
0.3 mmol
B
O
L
O
R
S
- L
N
H
y
(90% D)
D
O
O
O
O
O O
0.93 H
Rh
N
b
S
S
S
+
+
N
O
O
x
N
N
H
E
y
H
H
D
H
H
x
S
Rh
N
N
N
x
N
(89% D)
a
R
O
O
H
OCOR
y
1.08 H
7'
Rh
N
path b
S
Ar
H
x
H
G
N
a + b = 1.78 H
y
1.18 H
Rh
N
H
R
8
9
Ar = 4-tBuC6H4 28%
52%
H
R
C
y
H
H
D
O
S
O
x
c)
5.0 mol %
0.6 mmol
[Rh(OAc)(cod)]2
2,3-difluorobenzoic
acid
87%H
H
y
N
R
RCOOH
O
O
Rh
N
D
O
O
Me
S
+
C10H21
N
x
S
H
OCOR
toluene 0.5 mL
160 °C, 5 h
H
N
D
N
x
H
Rh
N
H
y
y
R
1i
10
0.6 mmol
0.2 mmol
ROCO
x
O
O
O
O
I
R
Me
S
Me
S
N
N
Scheme 3 Plausible catalytic cycle
H
H
y
x
N
N
x
y
C10H21
C10H21
We proposed a possible reaction mechanism based on the
above deuterium studies (Scheme 3). The first step involves the
complexation between Rh(I) and a bidentate sulfonamide to
form complex A, followed by the release of the carboxylic acid
to give Rh complex B (path a).10 Coordination of an alkene to B
generates C, in which a 1,2-hydrogen shift from the x-position
to the y-position proceeds to produce a rhodium carbene
complex D (a shift of one of the deuterium atoms from the x-
position to the y-position was observed, as shown in Scheme
2a-c).11 Oxidative addition of the ortho-C‒H bond to a Rh center
in D gives the five-membered rhodacycle complex E, which
undergoes a 1,2-hydride shift to afford complex F.12,13 Reductive
elimination followed by protonation gives the desired alkylated
product with the regeneration of Rh(I). In Scheme 2a, the
incorporation of a H atom (0.35H) at the y-position of the
product 5 was observed. However, if the reactions were to
proceed completely through path a, no H atom would be
incorporated at the y-position. This result prompted us to
consider the possibility that an alternative catalytic cycle is also
operative (path b in Scheme 3),7g,9 in which the oxidative
addition of the N‒H bond in A to a rhodium center proceeds to
form the metallacylce G.14 The coordination of an alkene to G
followed by the insertion of an alkene into a H-Rh bond in H
gives complex I. The successive release of the carboxylic acid
from I generates the carbene intermediate D. The involvement
of other minor path cannot rule out completely.
0.78 H
1.06 H
1.18 H 1.36 H
11
12
25%
47%
d)
5.0 mol %
0.6 mmol
[Rh(OAc)(cod)]2
2,3-difluorobenzoic
acid
75% D
D
O
O
75% D
D
y
S
x
+
Ph
N
H
toluene 1.5 mL
160 °C, 5 h
N
D
D
1.2 mmol
75% D
75% D
D
75% D
0.82 H
O
O
O
S
O
1b-d5
0.3 mmol
b
D
S
D
D
+
N
N
H
H
N
N
a
x
D
y
D
D
Ph
1.68 H
a + b = 1.53 H
1b-d5'
1.98 H
13
26%
54%
Scheme 2 Deuterium labelling experiments.
To examine this observation further, deuterated styrene
derivative 7 in which only the x-position is deuterated was used
(Scheme 2b). The reaction of 1b with 7 gave 8, with the
deuterium content at the y-position increased, clearly
suggesting that a D atom had shifted from the x-position to the
y-position. In the recovered starting materials 6 and 9, D-
incorporation was observed at the ortho-C‒H bond, which
indicates that the C‒H activation step is reversible. In addition,
only negligible H/D exchange was detected in the recovered
alkene 7’. Similarly, the alkylation reaction of 1i with the x,x’-
deuterated alkene 10 gave linear product 11, in which, a
significant amount of D-incorporation (0.64 D) was observed at
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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2014, 43, 6906–6919. (e) O. Daugulis, J. Roane and L. D. Tran,
We report herein the first example of the Rh-catalyzed, mono-
selective C‒H alkylation of benzenesulfonamides with alkenes
by taking advantage of a bidentate chelating system. Several
alkenes, including acrylate esters, methyl vinyl ketone, styrene,
and even unactivated 1-alkenes can be used as an alkylating
coupling partner. Deuterium studies revealed that the reaction
proceeds through an unusual catalytic cycle, in which a carbene
intermediate appears to be generated along with a 1,2-
hydrogen shift of the x-hydrogen of an alkene to the y-position,
as evidenced by deuterium labelling experiments (Scheme 2a-
c). Furthermore, to truly understand the unusual 1,2-H-shifting
mechanism for this reaction, DFT studies along with further
attempts to isolate reaction intermediates are ongoing in our
laboratory.
View Article Online
Acc. Chem. Res., 2015, 48, 1053–1064. (f) Z. Chen, B. Wang, J.
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R. Blieck, T. Dao-Huy, G. Pototschnig, P. Schaaf, T. Wiesinger,
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For papers from our group on the Rh-catalyzed alkylation of
benzamides, see: (a) K. Shibata and N. Chatani, Org. Lett.,
2014, 16, 5148–5151. (b) K. Shibata, T. Yamaguchi and N.
Chatani, Org. Lett., 2015, 17, 3584–3587. (c) K. Shibata and N.
Chatani, Chem. Sci., 2016, 7, 240–245. (d) Q. He, T. Yamaguchi
and N. Chatani, Org. Lett., 2017, 19, 4544–4547. (e) K. Shibata,
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Commun., 2017, 8, 1448–1455. (f) Q. He and N. Chatani, J.
Org. Chem., 2018, 83, 13587–13594. (g) T. Yamaguchi, S.
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Conflicts of interest
“There are no conflicts to declare”.
7
Acknowledgements
This work was supported by a Grant in Aid for Specially
Promoted Research by MEXT (No. 17H06091).
Notes and references
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8
9
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2
10 A stoichiometric reaction of sulfonamide 1b and
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4 | J. Name., 2012, 00, 1-3
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ChemComm
View Article Online
DOI: 10.1039/C9CC05219D
Journal Name
COMMUNICATION
Rhodium(I)-Catalyzed Mono-Selective C‒H Alkylation of
Benzenesulfonamides with Terminal Alkenes
Received 00th January 20xx,
Accepted 00th January 20xx
Supriya Rej and Naoto Chatani*
DOI: 10.1039/x0xx00000x
www.rsc.org/
O
S
O
O
S
O
H
y
N
x
Rh-catalyst
D
N
H
Ar
+
R
Ar
H
N
D
N
D
x
H
R = alkyl, CO2R', aryl
H
D
R
y
1,2-D shift
H
The Rh(I)-catalyzed ortho-alkylation of benzenesulfonamides with
alkenes with the aid of an 8-aminoquinoline group is reported. The
reaction is applicable to a variety of benzenesulfonamide derivatives
and various alkenes. Curiously, unactivated 1-alkenes were more
reactive than activated alkenes. Deuterium labeling experiments
indicate that an unusual 1,2-H shift mechanism to generate a
carbene rhodium intermediate is involved.
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita,
Osaka 565-0871, Japan. E-mail: chatani@chem.eng.osaka-u.ac.jp
‡ The authors contributed equally
† Electronic Supplementary Information (ESI) available: Experimental details and
Spectroscopic data. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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