Copper triflate/t-BuOOAc-catalyzed amidation of allylic and benzylic acetates with sulfonamides

Article abstract of DOI:10.1016/j.tetlet.2008.02.135

A copper triflate/t-BuOOAc-catalyzed amidation of allylic and benzylic acetates has been developed which is suitable for the coupling of a wide variety of functionalized sulfonamide nucleophiles with acetate electrophiles. The methodology allows for the amidation of benzylic substrates which are not further activated by an additional adjacent alkene or alkyne, enabling simple allylic acetates and primary benzylic acetates to be used as reaction partners.

Full text of DOI:10.1016/j.tetlet.2008.02.135

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2495–2498
Copper triflate/t-BuOOAc-catalyzed amidation of allylic
and benzylic acetates with sulfonamides
David A. Powell *, Guillaume Pelletier
Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Que´bec, Canada H9H 3L1
Received 5 February 2008; revised 20 February 2008; accepted 22 February 2008
Available online 29 February 2008
Abstract
A copper triflate/t-BuOOAc-catalyzed amidation of allylic and benzylic acetates has been developed which is suitable for the coupling
of a wide variety of functionalized sulfonamide nucleophiles with acetate electrophiles. The methodology allows for the amidation of
benzylic substrates which are not further activated by an additional adjacent alkene or alkyne, enabling simple allylic acetates and
primary benzylic acetates to be used as reaction partners.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Copper; Amidation; Sulfonamide; Allylic acetate; Benzylic acetate
Methodologies which enable mild and selective C–N
bond formation are of tremendous importance in organic
synthesis as they facilitate the construction of complex
naturally occurring and pharmacologically active mole-
cules.1 Advancements have led to the development of a
considerable variety of methodologies for the introduction
of an amine functionality; however, given the importance
of this transformation, further explorations into differential
methodologies will serve to supplement these existing tools.
Recently, a variety of Lewis acid2 and Brønsted acid3-
catalyzed methodologies for the amidation of benzylic
and allylic alcohols have been disclosed.4 Predominant
among these examples are the use of benzylic alcohols
which are further activated by an adjacent alkene or
alkyne. In contrast, few examples of nucleophilic substitu-
tion for the synthesis of allylic or primary benzylic amides
have been disclosed.2b,c During the course of our studies on
the copper-catalyzed amidation of allylic and benzylic C–H
bonds,5 we demonstrated that a postulated benzyl acetate
intermediate can be amidated with a sulfonamide under
the influence of copper(II) trifluoromethanesulfonate cata-
lyst. Herein, we disclose our explorations into the scope
and utility of this transformation which proceeds with
benzylic and allylic acetate substrates.6,7
Table 1
Reaction parameters in the copper triflate/t-BuOOAc-catalyzed amidation
Me
OR
Me
O
O
5 mol % copper catalyst
10 mol % oxidant
O
O
S
N
Ph
+
S
H
H2N
Ph
ClCH2CH2Cl, 60 ºC, 16 h
(1.5 equiv)
Entry
R
Catalyst
Oxidant
None
t-BuOOAc None
None
Additive
Yielda
(%)
1
2
3
4
5
6
7
Ac
Ac
Ac
Ac
Ac
H
None
None
Cu(OTf)2
Cu(OTf)2
None
None
<5
<5
35
t-BuOOAc None
93
CuCl2 or Cu(OAc)2 t-BuOOAc None
Cu(OTf)2
Cu(OTf)2
<5
18b
<5
t-BuOOAc None
t-BuOOAc 2,6-Di-tert-
butylpyridine
Ac
(15 mol %)
8
9
Ac
Ac
10 mol % TfOH
1 mol % TfOH
None
None
None
None
31
52
a
*
Isolated yield after column chromatography.
Determined by 1H NMR analysis of the unpurified reaction mixture.
Corresponding author. Tel.: +1 514 428 3098; fax: +1 514 428 4900.
E-mail address: david_powell2@merck.com (D. A. Powell).
b
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.02.135

2496
D. A. Powell, G. Pelletier / Tetrahedron Letters 49 (2008) 2495–2498
Table 2
Scope of the copper triflate/t-BuOOAc-catalyzed amidation of allylic and benzylic acetates with sulfonamides
Entry
1
Acetate
Sulfonamide
Product
Temperature (°C)
Timea (h)
Yieldb (%)
93
Me
OAc
Me
O
O
O O
S
S
60
6
N
Ph
H2N
Ph
H
Me
OAc
CO2Me
Me
CO2Me
O
O
S
O
O
S
2
3
4
60
60
60
6
6
54
90
66
H2N
N
H
Me
Me
OAc
O
O
O
O
S
S
H2N
N
H
OCH3
Cl
OCH3
Cl
Me
OAc
Me
O
O
O
S
O
S
H2N
N
16
H
OCH3
MeO2C
MeO2C
OCH3
O
O
OAc
S
O
O
HN
Ph
5
25
6
83
S
H2N
Ph
O
O
S
OAc
Ph
HN
O
O
S
6
7
25
25
16
6
79
78
Ph
H2N
Br
Br
Me
OAc
Me
O
O
O
O
S
N
SiMe3
S
S
H
H2N
SiMe3
H3CO
H3CO
O
O
OAc
S
O
O
S
HN
S
8
9
25
25
16
6
76
63
H2N
H3C
H3C
O
O
O
S
O
S
Me
Me
OAc
N
Ph
N
Ph
H
Me
MeO
MeO
O
O
O
S
O
S
OAc
10
11
60
25
16
16
76
86
N
Ph
N
H
Ph
Me
O
O
O
O
S
S
H2N
N
H
OAc
Cl
Cl
O
O
Me
OAc
O
O
O
H
H
S
N
H
Me
S
12
13
25
25
60
1
16
16
89c
86
N
H
Me
Me
H
O
S
O
OAc
N
Ph
O
Me
Me
Me
S
N
H
Ph
N
N
SO2Ph
SO2Ph
O
O
O O
S
S
OAc
N
H
N
Me
14
40
Me
Me
a
Reaction times are not optimized.
Isolated yield.
A single diastereomer was isolated and the stereochemistry determined to be exo by 1H NOE studies.
b
c

D. A. Powell, G. Pelletier / Tetrahedron Letters 49 (2008) 2495–2498
2497
Investigation into the reaction parameters which
influence the amidation protocol was explored for the
representative reaction of 1-phenylethyl acetate and benz-
enesulfonamide (Table 1).
pared to 93% when conducted on a 3 mmol scale (Table 2,
entry 1).
To gain further insight into the mechanism of this trans-
formation, we explored the reaction of a chiral benzylic
acetate (Eq. 1) under the copper triflate/t-BuOOAc catalyst
system. Amidation under standard conditions resulted in a
the formation of a racemic product, consistent with a
benzylic cation intermediate.15
Critical to this transformation is the use of catalytic
quantities of both the copper(II) trifluoromethanesulfonate
(triflate) catalyst and tert-butylperacetate oxidant which
affords the amidation product in 93% yield (entry 4). Sig-
nificantly lower yields are obtained in the absence of the
oxidant (entry 3), or with other copper salts (entry 5).
Reaction of 1-phenylethanol under the optimized condi-
tions yielded less than 20% of the amidation product as
determined by 1H NMR analysis of the unpurified reaction
mixture (entry 6).
O
O
S
HN
Ph
OAc
5 mol % Cu(OTf)2
10 mol % -BuOOAc
O
O
t
+
S
H2N
Ph
ClCH2CH2Cl,
25 ºC, 2 h
66% yield
0% ee
>95% ee
(1.5 equiv)
The proclivity of metal triflates to generate protic
acids8 and the previous reports on Brønsted acid-cata-
lyzed nucleophilic substitutions of benzylic alcohols9
prompted us to further investigate the role of the copper
triflate/t-BuOOAc catalyst system. Importantly, in the
presence of an excess of 2,6-di-tert-butylpyridine
(15 mol %), the desired amidation product is not obtained
(entry 7).10 Amidation of the benzylic acetate does occur
in the presence of triflic acid (entries 8 and 9), suggesting
that Lewis acid-assisted Brønsted acid-catalysis11 is oper-
ating in the copper triflate/t-BuOOAc protocol. The lower
yield and concomitant formation of multiple secondary
products, which interfere with product purification, dem-
onstrate the superiority of the copper triflate/t-BuOOAc
systems over triflic acid catalysts as a means to achieve
this transformation.12
ð1Þ
ð2Þ
Me
O
O
5 mol % Cu(OTf)2
O
O
S
10 mol % t-BuOOAc
N
Ph
+
S
H
H2N
Ph
ClCH2CH2Cl,
60 ºC, 16 h
26% yield
(1.5 equiv)
In the related reactions of benzylic alcohols, symmetri-
cal ethers (e.g., bis(1-phenylethyl) ether) have been
observed as intermediates.2g,4a Similar products have not
been detected in our copper triflate/t-BuOOAc-catalyzed
amidation procedure; however, we have observed small
amounts of styrene derivatives in the crude reaction mix-
ture, resulting from the elimination of acetic acid from
the benzylic acetate electrophile.
Having established reaction conditions for the amida-
tion of 1-phenylethyl acetate, we then investigated the
range of allylic and benzylic acetate and sulfonamide cou-
pling partners which could be employed (Table 2). Most
reactions occur at room temperature, although some allylic
and benzylic acetates require heating to 60 °C to achieve
full conversion. Arylsulfonamides with either electron-
withdrawing or electron-donating substituents serve as
suitable reaction components (entries 2 and 3), although
lower yields are observed with the more electron-deficient
sulfonamides.13
In addition to arylsulfonamides, 2° sulfonamides
(entries 9 and 10, 12–14), heteroarylsulfonamides (entry
8) and alkylsulfonamides (entries 6 and 7) can be utilized,
including the readily cleaved trimethylsilylethylsulfona-
mide14 (entry 7). The more sterically hindered 1-arylphenyl-
propyl acetate (entry 9) and the primary indole methyl
acetate (entry 13) underwent facile amidation at room tem-
perature. Notably, this methodology is also suitable for the
amidation of allylic acetates (entries 10–12), including the
tricyclic deca-4,8-dien-3-yl acetate (entry 12), which affor-
ded the amidation product as a single diastereomer.
The reaction has been conducted on a 10-fold larger
scale without compromising either the yield or the opera-
tional simplicity of the procedure. Reaction of 1-phenyl-
ethyl acetate and benzenesulfonamide on a 30 mmol scale
afforded the amidation product in 89% yield (6.94 g) com-
To investigate the possibility of whether an elimination–
hydroamidation mechanism was operating,16 we explored
the reaction of styrene with benzenesulfonamide under
the copper triflate/t-BuOOAc catalysts system. This affor-
ded the amidation product in significantly lower yield
(Eq. 2). While the lower yield of the amidation product
obtained with styrene versus 1-phenylethyl acetate does
not exclude a mechanism whereby amidation proceeds
via acetic acid elimination followed by hydroamidation,
we propose that the reaction more likely proceeds via a
direct trapping of an allylic or benzylic cation with the
sulfonamide nucleophile.17
In summary, we have developed a copper triflate/t-
BuOOAc-catalyzed amidation of allylic and benzylic ace-
tates which is suitable with a wide variety of functionalized
sulfonamide nucleophiles and acetate electrophiles. The
methodology allows for the amidation of benzylic sub-
strates which are not further activated by an additional
adjacent alkene or alkyne, enabling simple allylic acetates
and primary benzylic acetates to be used as substrates.
Acknowledgements
We thank Natural Science and Engineering Research
Council (NSERC) of Canada for an undergraduate
research award to G.P. We also thank Dr. Austin Chen

2498
D. A. Powell, G. Pelletier / Tetrahedron Letters 49 (2008) 2495–2498
Synthesis 2004, 1581–1584; (c) Rubin, M.; Gevorgyan, V. Org. Lett.
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for valuable discussions and NOE NMR experiments, and
Dr. Jason Burch and Dr. Ernest Lee for their insights.
7. For several representative examples of transition metal-catalyzed
allylic and benzylic aminations with acetate or carboxylate electro-
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8. For selected examples where protons have been implicated as active
catalysts in Lewis acid-mediated reactions, see: (a) Wabnitz, T. C.;
Yu, J.-Q.; Spencer, J. B. Chem. Eur. J. 2004, 10, 484–493; (b) Liu, P.
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2008.02.135.
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