Cu(II)-catalyzed decarboxylation/elimination of N-arylsulfonyl amino acids to primary aryl sulfonamides

Article abstract of DOI:10.1080/00397911.2016.1202981

A novel protocol for CuO-catalyzed decarboxylation/elimination of N-arylsulfonyl amino acids was developed. It is the first example of using an accessible amino acid as an ammonia synthetic equivalent for the synthesis of primary aryl sulfonamides via oxidative decarboxylation/elimination reactions. The present protocol shows excellent functional group tolerance and provides an efficient method for the synthesis of primary aryl sulfonamides in excellent yields.

Full text of DOI:10.1080/00397911.2016.1202981

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Cu(II)-Catalyzed Decarboxylation/Elimination
of N-Arylsulfonyl Amino Acids to Primary Aryl
Sulfonamides
Liandi Zhou, Xiaokang Li, Wei Liu, Yongli Zhao & Junmin Chen
To cite this article: Liandi Zhou, Xiaokang Li, Wei Liu, Yongli Zhao & Junmin Chen (2016):
Cu(II)-Catalyzed Decarboxylation/Elimination of N-Arylsulfonyl Amino Acids to Primary Aryl
Sulfonamides, Synthetic Communications
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Date: 17 July 2016, At: 22:05

Cu(II)-Catalyzed decarboxylation/elimination of N-arylsulfonyl amino acids to primary
aryl sulfonamides
Liandi Zhou1, Xiaokang Li1,2, Wei Liu1, Yongli Zhao1, Junmin Chen1
1Department of Chemistry, Jiangxi Normal University, Nanchang, P. R. China, 2Key Laboratory
of Organo-pharmaceutical Chemistry, Gannan Normal University, Ganzhou, Jiangxi, China
Corresponding author to J. Chen: E-mail: jxnuchenjm@163.com
Abstract
A novel protocol for CuO-catalyzed decarboxylation/elimination of N-arylsulfonyl amino acids
was developed. It is the first example of using an accessible amino acid as an ammonia synthetic
equivalent for the synthesis of primary aryl sulfonamides via oxidative
decarboxylation/elimination reactions. The present protocol shows excellent functional group
tolerance and provides an efficient method for the synthesis of primary aryl sulfonamides in
excellent yields.
O
O
S
Me
Me
OH CuO (0.3 equiv)
O
O
S
NH2
N
H
Ar
Ar
DMSO
O
100 oC, 8h
2
1
15 examples, up to 98% yield
KEYWORDS: Copper, decarboxylation, elimination, amino acids, primary aryl sulfonamides
INTRODUCTION

Sulfonamides are an important structural motif because of their diverse biological properties.[1]
Particularly, they are employed widely in pharmaceutical research, such as β-secretase inhibitors
for Alzheimer's disease,[2] dipeptidyl peptidase IV inhibitors for diabetes,[3] insulin-like growth
factor receptor (IGF-IR), inhibitors for cancer,[4] HCV NS5B polymerase inhibitors for acute
hepatitis and chronic liver disease,[5] and as antibacterial agents.[6] The ability to serve as amide
surrogates, with unique physical properties, have made them ideal functional groups for the
development of novel peptidomimetics.[7] Other applications of sulfonamides include their use as
nitrogen protecting groups[8] and as useful synthetic intermediates or as key precursors for the
preparation of biologically important compounds.[9-11] Because of their significance, a number of
advancements in sulfonamide synthesis have been developed. Traditional methods for the
synthesis of primary amides rely on the treatment of sulfonyl halides with excess ammonia.[12]
Recently, Jiang and Song independently developed an efficient method to build up sulfonamides
between sodium sulfinates and amines under different oxidative conditions.[13,14] Very recently,
Azarifar reported a convenient procedure for direct synthesis of primary sulfonamides via the
reaction of sulfonyl chlorides with sodium cyanate as an inexpensive reagent under catalyst-free
conditions in water.[15] In addition, some novel modified methods have proposed the use of other
ammonia precursors for the conversion to the corresponding primary sulfonamides. For example,
Wang reported an elegant method of the synthesis of primary sulfonamides by reduction of
sulfonyl azides with metallic samarium and catalytic amount of iodine in good yields under
neutral and mild condition.[16] The deprotection of benzyl, allyl and alkyl groups is also a
classical method for the synthesis of primary sulfonamides from corresponding secondary
sulfonamides.[17-19] Despite these advances, development of an alternative method for the
construction of primary sulfonamides under mild conditions is still highly desirable.

Recently, transition-metal-catalyzed decarboxylative couplings have generated much interest in
the past few years because of its efficiency, selectivity, as well as convenience.[20] During the
numerous transformations, a large number of useful building blocks, such as biaryls,[21] aryl
ketones,[22] and vinyl arenes[23] were obtained. Recently, Tunge and Li independently reported the
decarboxylative coupling reaction of sp3- and sp-hybridized carbon atoms, a powerful strategy
for the formation of C-C bond through decarboxylation of ester derivatives (Scheme 1, a).[24,25]
Very recently, decarbonylation/dehydration reactions have been also studied and constitute a
useful tool in synthesis of olefins[26] (Scheme 1, b). Despite significant advances in
decarbonylation reactions, questions concerning decarbonylation/dehydration of amino acids was
less explored. Based on the previous work, we reasoned that the strategy used in the
abovementioned processes should also allow the conversion of amino acids 1 to imines via a
catalytic decarbonylative elimination reaction, followed by hydrolysis to afford the
corresponding primary sulfonamides 2 (Scheme 2). Herein, we wish to report a novel approach
to primary aryl sulfonamides from N-arylsulfonyl amino acids via Cu-catalyzed
decarboxylation/elimination of N-arylsulfonyl amino acids by using air as the sole oxidant.
RESULTS AND DISCUSSION
To evaluate the feasibility of this methodology, we chose N-phenyl sulfonyl amino acids 1 as a
model substrate (Table 1). Initially, a variety of accessible amino acids were examined as an
ammonia synthetic equivalent. Substrate 1a containing an glycine provided only trace amounts
of product 2a by using Cu(OAc)2 (1 equiv) as the oxidant and in DMSO at 100 oC for 8 h (Table
1, entry 1). To our delight, Substrate 1b containing an alanine can afford the corresponding
primary aryl sulfonamide in 54% yield (Table 1, entry 2). Remarkably, Substrate 1c containing a

2-methylalanine offered the corresponding product in 67% isolated yield (Table 1, entry 3). We
next evaluated various oxidants under the same reaction conditions; delightfully, Substrate 1c
had completely converted and gave the desired product in 98% yield by using CuO as an oxidant
(Table 1, entry 4), the using
CuSO4 as an oxidant only offered 46% yield (Table 1, entry 5). Notably, the reaction failed with
CuCl2, CuBr2, and CuI (Table 1, entries 6-8). Next, a multitude of solvents were screened in the
presence of CuO, DMF provided the desired product in 82% (Table 1, entry 9), whereas, xylene
and dioxane were ineffective and only trace amount of the product were obtained (Table 1,
entries 10, 11). Results of solvents screening indicated that DMSO was still the best choice
(Table 1, entry 4). In addition, the equivalent of the CuO was evaluated, we found that 0.3 equiv
of CuO was be sufficient to prompt the reaction without an apparent decrease in reaction yield
(Table 1, entries 12 and 13). Unfortunately, further reducing the loading of CuO to 0.1 equiv
only gave the desired product in 26% yield (Table 1, entry 14). Considering the oxidantion of
monovalent copper, we envisioned that whether using the catalytic amount of CuO can also
prompt the reaction by adding other oxidants. With this in mind, various oxidants were screened,
we found that the use of K2S2O8, 1,4-benzoquinone and O2 as oxidants were ineffective and the
yield of 2a was slightly improved (Table 1, entries 15-17); interestingly, 67% yield was obtained
by using AgOAc as the oxidant (Table 1, entry 18). Finally, we screened the reaction
temperatures and found that depression of the reaction temperature was harmful for the reaction,
the yield of 2a reduce to 41% at 80 oC and the reaction did not take place at 50 oC (Table 1,
entries 19 and 20). Furthermore, the control experiment showed that the copper as catalyst was
necessary to the success of the transformation (Table 1, entry 21). As our overall experimental

results demonstrate, the optimal reaction conditions involve the use of 0.3 equiv of CuO in 1.0
mL of DMSO for 0.5 mmol of 1c at 100 oC for 8h under an air atmosphere (Table 1, entry 13).
Next, we applied this catalytic system to various 1 to demonstrate the efficiency and scope of the
present method. The experiment showed that aryl sulfonamides amino acids 1 with an electron-
withdrawing and electron-donating group all gave the corresponding primary sulfonamides in
excellent yields (Table 2). For example, the substrates containing p-Me, p-MeO, p-CF3 and p-
NO2 afforded the corresponding primary sulfonamides in 95%, 85%, 89%, and 87% isolated
yield, respectively (Table 2, entries 2-5). As for different substitution patterns of arenes, meta-
substituted substrates all worked well in the reaction to give the desired products. For example,
substrate 1h bearing meta-substituent such as m-Me also proceeded well, and offered 86%
isolated yield (Table 2, entry 6), substrate 1i bearing ortho-substituent such as m-NO2 can afford
the corresponding products in quantitative yield (Table 2, entry 7). Gratefully, substrates bearing
ortho-substituent such as o-Me and o-Cl can afford the corresponding products in 93% and 89%
yields, respectively (Table 2, entries 8 and 9). The present conditions appear to be applicable to
3,5-disubstituted arylsulfonamides 1l and gave 85% yield (Table 2, entry 10). Notably,
heterocyclic substrate 1m also can participate the reaction and afford the desired product 2k in
excellent yield (Table 2, entry 11). As for the substrate 1n, very excellent reactivity was
exhibited and afforded the 2-phenyl phenyl sulfonamides products 2l in 88% yield (Table 2,
entry 12), which represents a significant class of promising bioactive compounds.26 Finally, the
N-benzoyl amino acids were also investigated under the present catalytic system; however, we
found that the N-benzoyl amino acids as substrates were ineffective in this protocol. Then,

various copper salts were tested. To our delight, moderate yields were obtained by using 0.3
equiv of CuCl2 as the oxidant (Table 2, entries 13-15).
CONCLUSION
In summary, an efficient protocol for the synthesis of primary aryl sulfonamides from easily
available N-arylsulfonyl amino acids has been developed. In the presence of 0.3 equiv of CuO,
facile decarbonylation/elimination of N-arylsulfonyl amino acids, followed by hydrolysis to
afford the corresponding primary amides was achieved at 100 °C in air. The present protocol
shows excellent functional group tolerance and provides an efficient method for the synthesis of
aryl sulfonamides in excellent yields. Further applications to the synthesis of biologically
important molecules and mechanistic studies are in progress.
EXPERIMENTAL
All reactions were carried out in air. Chemicals were purchased from Aldrich, Acros, or Alfa
Asar, and, unless otherwise noted, were used without further purification. Flash chromatography
was performed on silca gel (silca gel, 200-300 mesh). 1H NMR and 13C NMR spectra were
recorded on Bruker 400 MHz and Bruker 100 MHz spectrometers with d-DMSO as the solvent.
High-resolution mass spectral (HRMS) data were recorded on Bruker APEX IV Fourier
transform ion cyclotron resonance mass spectrometer using electrospray ionization (ESI).
General Procedure For Primary Aryl Sulfonamides 2.

A mixture of aryl sulfonyl amino acid 1 (0.5 mmol), CuO (0.15 mmol), and DMSO (0.5 mL) was
placed in a 25 mL round-bottom flask. The mixture was stirred for 8 h at 100 oC under air. Then,
the reaction mixture was cooled, diluted with ethyl acetate, filtered through Celite, and
concentrated in vacuo. The residue was purified by silica gel column chromatography with ethyl
acetate/ petroleum ether to afford the desired product 2.
Funding
We are grateful for the financial support from the National Natural Science Foundation of China
(51463002), the Science and Technology Planning Project of Jiangxi Province, China
(20142BAB203007).
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Table 1. Examination of reaction conditions
O
S
O
S
R
O
O
R
O
[Cu], oxidant
OH
NH2
N
H
solvent, temp.
Me
Me
2a
1
1a R1 = H; R2 = H
1b R1 = Me; R2 = H
1c R1 = Me; R2= Me
Entrya Substrate Cu
Oxidant
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
Yield of 2a (%)b
1
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuO
/
/
/
/
/
/
/
/
/
trace
54
1a
1b
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
2
3
67
4
98
5
CuSO4
CuCl2
CuBr2
CuI
46
6
trace
trace
trace
82
7
8
9
CuO
10
11
12c
13d
14e
15e
16e
CuO
/
Xylene
Dioxane
DMSO
DMSO
DMSO
DMSO
DMSO
trace
trace
98
/
CuO
CuO
/
CuO
/
97
CuO
/
26
CuO
K2S2O8
34
CuO
1,4-benzoquinone
42

17e
CuO
CuO
CuO
CuO
/
O2
DMSO
DMSO
DMSO
DMSO
DMSO
32
1c
1c
1c
1c
1c
18e
AgOAc
67
19d,f
20d,g
21d
/
/
/
41
trace
trace
aReaction conditions: N-phenylsulfonyl amino acids 1 (0.5 mmol), oxidant (1.0 mmol), solvent
(0.5 mL), at 100 oC for 8 h.
bIsolated yield.
c0.5 equiv of CuO was used.
d0.3 equiv of CuO was used.
e0.1 equiv of CuO was used.
fat 80 oC.
gat 50 oC

Table 2. Synthesis of primary sulfonamides from N-phenylsulfonyl amino acids
O
O
S
Me
Me
OH CuO (0.3 equiv)
O
O
S
NH2
N
H
Ar
Ar
DMSO
O
100 oC, 8h
2
1
Entrya
Substrate
Product
Yield/%b
97
O
O
Me
Me
OH
1
S
2a
N
H
O
Me
1c
O
S
Me
Me
OH
2
3
4
5
6
7
O
95
85
89
87
86
93
2b
2c
2d
1e
2f
N
H
O
1d
O
Me
Me
OH
O
S
N
H
O
MeO
F3C
1e
O
Me
O
O
Me
OH
S
N
H
O
1f
O
S
Me
Me
OH
N
H
O
O2N
Me
1g
O
S
Me
Me
OH
O
N
H
O
1h
O
Me
Me
OH
O
O2N
S
2g
N
H
O
1i

Me
O
S
Me
Me
OH
8
9
O
93
89
85
2h
2i
N
H
O
1j
Cl
O
S
Me
Me
OH
O
N
H
O
1k
O
Me
10
O
Me
OH
Cl
S
2j
N
H
O
1l
Cl
O
O
S
Me
11
12
Me
OH
88
91
2k
2l
N
H
S
O
1m
O
O
S
NH2
4-MeC6H4
1n
13c
14c
15c
O
Me
Me
OH
46
41
53
2m
2n
2o
N
H
O
1o
O
Me
Me
OH
N
H
O
Me
Cl
1p
O
Me
Me
OH
N
H
O
1q
aReaction conditions: N-phenylsulfonyl amino acids 1 (0.5 mmol), oxidant (0.3 mmol), solvent
(0.5 mL), at 100 oC for 8 h.
bIsolated yield.
c0.3 equiv of CuCl2 was used.

Scheme 1. Transition metal-catalyzed decarbonylation couplings and elimination reactions
R2
R1
R3
(a)
H
R2
cat.Pd
R1
OH
H
O
R1
R2
(b)

Scheme 2. Transition metal-catalyzed decarbonylation/elimination reactions
O
O
S
R
2
O
O
R
1
S
OH
cat. Cu
?
NH
2
N
H
Ar
Ar
O
O
O
R
2
2
1
S
N
R
1
Ar
via