A highly efficient catalyst-free protocol for C-H bond activation: Sulfamidation of alkyl aromatics and aldehydes

Article abstract of DOI:10.1039/c2cc31258a

A catalyst-free protocol has been developed for amidation of alkyl aromatics and aldehydes using TsNBr₂via a nitrene transfer process in the presence of a base in excellent yield within a short time. The reaction was found to be selective for secondary and tertiary benzylic C-H bonds and C-H bonds of aldehydic groups.

Full text of DOI:10.1039/c2cc31258a

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COMMUNICATION
A highly efficient catalyst-free protocol for C–H bond activation:
sulfamidation of alkyl aromatics and aldehydesw
Arun Jyoti Borah and Prodeep Phukan*
Received 20th February 2012, Accepted 11th April 2012
DOI: 10.1039/c2cc31258a
a
A catalyst-free protocol has been developed for amidation of
alkyl aromatics and aldehydes using TsNBr2 via a nitrene
transfer process in the presence of a base in excellent yield
within a short time. The reaction was found to be selective for
secondary and tertiary benzylic C–H bonds and C–H bonds of
aldehydic groups.
Table 1 Amidation of ethyl benzene using TsNBr2
Entry TsNBr2 (mmol) Solvent Temp/1C Time/h Yieldb (%)
1
2
3
4
5
6
1
1
1
1.2
1
EtOAc RT
EtOAc 80
EtOAc 80
EtOAc 80
MeCN 80
24
4
15
4
12
15
NR
84
84
78
NR
48
Direct N-functionalization of saturated C–H bonds is considered
as a frontier of organic chemistry due to its potential for achieving
synthetically and biologically attractive amino functionality.1
Nitrene transfer reaction is an attractive tool for introducing
such a functionality in the presence of a transition metal
catalyst.1 This field pioneered by Breslow2 has progressed
considerably over the last few years. Iminoiodane derivatives,
such as ArIQNTs, have been the most commonly employed
reagent in combination with several transition-metal catalysts,
including those based on Rh,3 Ru,4 Mn,5 Ag,6 Cu7 and Zn.8 In
view of the limitations with the use of hypervalent iodine
reagents, efforts have been made for development of new
nitrene transfer sources. Thus C–H amidation using in situ
generated iminoiodane using PhI(OAc)2 has been shown to be
catalyzed by Ru,9,10 Mn,10 Rh11 and Ag12 complexes with
sulfonamides, sulfamates or carbamates as nitrene precursors.
This field of oxidative amidation process has been boosted by the
advent of several metal free protocols and new aminating agents
very recently.13 Other nitrene sources such as chloramine-T,7a,14
bromamine-T,15 tosyloxycarbamates16 and azides17 have also
been employed for amidation reaction in the presence of a
metal catalyst.
1
CCl4
80
a
Reaction conditions: ethyl benzene (1 mmol), solvent (3 mL),
b
N2 atmosphere. Isolated yield. NR: no reaction.
complexes for amidation of aldehydes.20 NHC catalyzed
amidation of aldehydes has been reported by Seayad et al.21
A few other oxidative methods are also known in the literature
for amidation of aldehydes.22
Recently, we found that N,N-dibromo-p-toluene-sulfonamide
(TsNBr2) is a very reactive and efficient reagent for various
organic transformations.23 In this communication, we report a
highly efficient amidation reaction of benzylic and aldehydic
C–H bonds using TsNBr2 without any catalyst.
Initially we have examined the C–H amidation reaction for
alkyl aromatics. The evaluation of the C–H amidation reac-
tion using TsNBr2 as the nitrene source was carried out using
ethyl benzene as the model substrate (Table 1). The reaction
was carried out by adding TsNBr2 (1 mmol) to a mixture of
ethylbenzene (1 mmol) and K2CO3 (3 mmol) in ethyl acetate
(3 mL) under an inert atmosphere.z Initial attempt at room
temperature (Table 1, entry 1) did not produce the desired
amidated product even after 24 h of reaction. However, the
reaction at 80 1C (bath temperature) in a tightly capped
Schlenk tube produced the corresponding amidated product in
84% yield after 4 h of reaction. Notably no 11-C–H insertion
product was detected in this case. Longer reaction time did not
improve the yield of the reaction (Table 1, entry 3).
Direct transformation of aldehydes into amides is another
important subject in organic synthesis owing to the prevalence
of amide linkage in a variety of bioactive compounds. However,
there are limited efforts in the literature in this direction. An
oxidative C–N bond forming process from aldehydes by using
TsNH2 in the presence of a Rh catalyst and PhI(OC(O)tBu)2
as the oxidant has been reported.18 Chan et al. reported a
nitrene insertion into an aldehydic C–H bond using different
iminoiodanes in the presence of a Ru, Cu or Fe catalyst.19 Seo
and Marks reported the use of homoleptic lanthanide amido
Then, the reaction was studied by increasing the amount of
TsNBr2 to 1.2 equivalents. However, the yield of the reaction
did not improve. Further the use of CCl4 as the solvent in the
reaction also had no effect on the yield. The reaction in
acetonitrile did not proceed at all. Finally, the use of
1 equivalent of TsNBr2 (based on the substrate) was found
Department of Chemistry, Gauhati University, Guwahati 781014,
Assam, India. E-mail: pphukan@yahoo.com
w Electronic supplementary information (ESI) available: NMR and
MS spectral data. See DOI: 10.1039/c2cc31258a
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5491–5493 5491

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a
Table 2 Amidation of alkyl aromatics using TsNBr2
amidated in the presence of the primary one. The attempt for
amidation of the allylic C–H bond led to the formation of
aziridine as the exclusive product perhaps due to more facile
p-insertion of nitrene.23e Attempts for amidation of saturated
alkanes such as isooctane, 4-methyl cyclohexane and hetero-
cycles such as THF and dioxane were also unsuccessful under
these conditions.
Entry
1
Substrate
Product
Time/h
Yieldb (%)
84
4
6
6
5
2
3
4
80
80
81
The success of the benzylic C–H insertion reactions
encouraged us to extend the nitrene insertion reaction to acyl
C–H bonds of aldehydes (Table 3). Initial reaction with
benzaldehyde as a substrate under the same reaction conditions
a
Table 3 Amidation of aldehydes using TsNBr2
Entry
Substrate
Product
Time/h
3
Yieldb (%)
85
5
6
7
5
5
8
78
89
64
1
2
3
4
5
6
3
3
3
3
3
84
80
88
78
80
8c
5
5
5
80
85
88
9c
10c
11c
3
7
92
75
12c
a
Reaction conditions: substrate (1 mmol), TsNBr2 (1 mmol), K2CO3
b
7
3
3
3
3
88
84
80
89
c
(3 mmol), ethyl acetate (3 mL), 80 1C. Isolated yield. Reaction
under solvent-free conditions using 0.5 mL of the reactant.
8
to be the most suitable for optimum yield of the aminated
product.
9
After evaluating the suitable reaction conditions for amida-
tion of ethyl benzene, the process was extended to a variety of
substrates (Table 2). It is apparent from Table 2 that different
kinds of substrates undergo amidation reaction at the benzylic
position in excellent yield with a short reaction time. In the
case of 1-(1-bromoethyl)benzene, the reaction produces a
substituted (N-tosyl)-amino product (Table 2, entry 6) with
substitution of Br, which was confirmed by analysis of NMR
and mass spectra. In the case of cumene, amidation was
observed at the benzylic 31-C–H bond (Table 2, entry 7).
With a view of expanding the scope of the reaction we
attempted amidation of toluene with TsNBr2. Though the
reaction failed in ethyl acetate, under solvent free conditions
the reaction yielded nearly 80% of the expected sulfamidate
product (Table 2, entry 8). In the case of 4-ethyl toluene
selective amidation at 21-benzylic C–H bond was observed
(Table 2, entry 11). The same result was observed for p-cymene
also (Table 2, entry 12), where the tertiary C–H bond was
10
11
12
13
3
3
90
89
4
4
79
87
14
a
Reaction conditions: substrate (1 mmol), TsNBr2 (1 mmol), K2CO3
b
(3 mmol), ethyl acetate (3 mL), 80 1C. Isolated yield.
c
5492 Chem. Commun., 2012, 48, 5491–5493
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produced the corresponding sulfonamide in 82% yield after
3 h of reaction.
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aromatic and aliphatic aldehydes (Table 3). These reactions
afforded the corresponding acylsulfonamides in very good
yield. Initially, various substituted benzaldehydes were tested
for this reaction, which produced high yield of the product
irrespective of the substituents present on the benzene ring.
The reaction was further extended to aliphatic aldehydes such
as n-octanal and isobutyraldehyde and was found to be equally
efficient. We observed exclusive formation of acylsulfonamides
in the case of amidation of p-tolualdehyde (Table 3, entry 10)
and 3-phenyl propionaldehyde (Table 3, entry 14). However,
our attempts for amidation of pyridine 3-carboxaldehyde,
4-hydroxybenzaldehyde, 4-(tert-butyldimethyl)silyloxy benzalde-
hyde were unsuccessful.
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from N,N-dibromo-p-toluene sulfonamide in the presence of
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In conclusion, an efficient protocol has been developed for
direct amidation of benzylic and acyl C–H bonds using
TsNBr2 via a nitrene transfer process. The amidation process
is very facile at 80 1C without a catalyst in the presence of
K2CO3. The reaction is fast, easy to handle and applicable to
various benzylic substrates to give corresponding aminated
products in high yield. Moreover, this metal free protocol
is highly regioselective for secondary and tertiary benzylic
C–H bonds. Selective amidation of aldehydic C–H bonds
was also observed.
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Financial support from DST (Grant No. SR/S1/OC-43/2011),
India, is gratefully acknowledged. AJB thanks UGC for a
research fellowship. We thank NEHU, Shillong, for MS data.
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Notes and references
z General procedure: to a mixture of substrate (1 mmol) and K2CO3
(3 mmol) in dry EtOAc (3 mL), in a Schlenk tube, TsNBr2 (1 mmol)
was added under a N2 atmosphere. The tube was then tightly capped
and heated at 80 1C. After completion of the reaction, water was added
and the reaction mixture was extracted with EtOAc. The organic layer
was separated, dried (Na2SO4) and evaporated. The crude product was
purified by column chromatography using a petroleum ether and ethyl
acetate mixture as eluent (4 : 1). Under solvent free conditions, 0.5 mL
of substrate was taken for the reaction.
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 5491–5493 5493