A facile noncatalytic pathway for the nitrene transfer process: Expeditious access to aziridines

Article abstract of DOI:10.1039/c0cc05387b

A fast and efficient method has been developed for generation of sulfonyl nitrene from N,N-dibromo-p-toluenesulfonamide (TsNBr₂) in the presence of a base without any catalyst. This method was applied to produce aziridines from different kinds of olefins within a short time in high yields. The Royal Society of Chemistry.

Full text of DOI:10.1039/c0cc05387b

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COMMUNICATION
A facile noncatalytic pathway for the nitrene transfer process:
expeditious access to aziridinesw
Indranirekha Saikia, Bishwapran Kashyap and Prodeep Phukan*
Received 6th December 2010, Accepted 5th January 2011
DOI: 10.1039/c0cc05387b
A fast and efficient method has been developed for generation
of sulfonyl nitrene from N,N-dibromo-p-toluenesulfonamide
(TsNBr2) in the presence of a base without any catalyst. This
method was applied to produce aziridines from different kinds of
olefins within a short time in high yields.
Scheme 1 Synthesis of aziridines using TsNBr2.
organic transformations.16 In this communication, we wish to
report an expeditious, noncatalytic route for the synthesis
of aziridines directly from olefins using TsNBr2 as a nitrene
source (Scheme 1).
Nitrenes are among the most fundamental reactive intermediates
in organic synthesis.1 Nitrene transfer reaction provides an
effective route for the construction of biologically important
molecules such as drugs and natural products.2 Consequently,
development of new synthetic methods for this reactive inter-
mediate is considered as the frontiers of organic synthesis.
Classical methods for generation of nitrenes are: thermal or
photochemical decomposition of hydrazoic acid, alkyl and aryl
azides, sulfonyl azides, azidoformates and cyanogen azide.1,3 In
the recent past, several nitrene sources were reported. The most
commonly employed nitrene source is PhIQNR that can also be
formed in situ by oxidizing sulfonamides or other amines with
PhI(OAc)2 or PhIO.2 However, due to some limitations in the
use of these iminoiodinanes, alternative nitrogen sources such as
chloramine-T (TsN(Cl)Na), bromamine-T (TsN(Br)Na) and
organic azides (RN3) were more recently investigated.2
During the course of our investigation, we found that
TsNBr2 is a strong source of the bromonium ion and liberation
of the bromonium ion from TsNBr2 is very facile. It is well
known that carbene can be generated by a-dehalogenation of
gem-dihalo compounds.17 We presumed that, analogous to
carbene formation, it should be possible to generate nitrene
from N,N-dibromo-p-toluenesulfonamide by debromination
in the presence of a base. With this view in mind, we have
carried out a reaction by adding a solution of TsNBr2 (1.2 equiv.)
in dichloromethane to a mixture of K2CO3 (2.5 equiv.) and
styrene (1 equiv.) in dichloromethane at room temperature.
The process was carried out under inert atmosphere and the
progress of the reaction was monitored by TLC. We observed
that the reaction is very fast and the corresponding aziridine
was isolated in 63% yield after 10 minutes of reaction. In order
to find out the best reaction condition, we have investigated
the effect of various solvents on the product yield (Table 1).
When acetonitrile was used as a solvent the reaction did not
produce the expected product after 10 minutes of reaction.
Further investigation on the reaction using ethyl acetate as a
solvent gave the best result of 84% isolated yield of the
corresponding aziridine. The reaction was also studied with
A very common and widely utilized nitrene insertion reaction
as a synthetic tool for achieving nitrogeneous molecules is the
synthesis of aziridines.2,4 Aziridines exhibit highly regio-
and stereoselective ring opening reactions which provide
a convenient entry to the stereoselective preparation of
functionalized amino compounds, heterocycles, and alkaloids.5
Among several approaches, metal-catalyzed aziridination of
alkenes with proper nitrene sources is the most widely utilized
method for the synthesis of the three-membered ring structure.2
Iminoiodinane derivatives such as [N-(p-tolylsulfonyl)imino]-
phenyliodinane (PhIQNTs)6 and its variants have been
extensively used as the nitrene source in the presence of several
transition metal catalysts including those based on Cu,7 Mn,8
Fe,9 Rh,10 Ru,11 Ag,12 and Au.13 Alternative nitrene sources
such as N-halo-sulfonamides,14 organic azides,15 etc. were also
used in the presence of a catalyst. Recently, we have found
that TsNBr2 is a very reactive and efficient reagent for various
Table 1 Influence of solvent and K2CO3 amount on the synthesis of
aziridine from styrenea
Entry
Solvent
K2CO3/mmol
Yieldb (%)
1
2
3
4.
5
6
DCM
2.5
2.5
2.5
1
1.5
3.5
63
CH3CN
EtOAc
EtOAc
EtOAc
EtOAc
Trace
84
25
40
84
Department of Chemistry, Gauhati University, Guwahati-781014,
Assam, India. E-mail: pphukan@yahoo.com
w Electronic supplementary information (ESI) available: NMR
spectral data. See DOI: 10.1039/c0cc05387b
a
Reaction conditions: styrene (1 mmol), TsNBr2 (1.2 mmol), solvent
b
(10 mL), rt, 10 min. Isolated yield.
c
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varying amount of K2CO3 (Table 1). Yields of the corresponding
aziridine were found to be lower when the amount of the base
was reduced, while increase of base amount could not improve
the yield. Finally, the use of 2.5 equiv. of K2CO3 was found to
be optimum for the best result.
After optimizing the reaction conditions, the process was
extended to a variety of olefins.z Results are summarized in
Table 2. Initially, we examined the reaction for different
styrenes. It can be seen from Table 2 that various styrenes
bearing functional groups reacted successfully to give the
corresponding aziridine in high yields within a short time.
After being successful in the case of styrenes, we extended the
procedure to various kinds of olefins such as indene, b-methyl
Scheme 2 Plausible mechanism of formation of aziridine.
styrene, cyclohexene, 1-octene, ethyl acrylate, cyclohexenone,
ethyl cinnamate, etc., which produced the corresponding
aziridine in high yields (Table 2). However, cyclohexenone
and ethyl cinnamate took longer time for completion of the
reaction. It is well known that nitrene p-insertion reaction is a
concerted process which imposes stereochemical consequences
in the product. We observed that when trans-b-methyl styrene
was subjected to aziridination reaction, the resultant product
exhibited trans-selectivity (Table 2, entry 5), while cis-b-methyl
styrene produced the product having cis-selectivity (Table 2,
entry 6). Similar trend of trans-selectivity was observed for
trans-3-hexene also (Table 2, entry 8).
a
Table 2 Aziridination of various alkenes with TsNBr2
Yieldb
Sl. No Substrate (a)
Product (b)
T/min (%)
1
10
84
Mechanistically, it is likely that analogous to carbene
formation reaction,17 there is a strong possibility of generation
of sulfonyl nitrene from N,N-dibromo-p-toluene sulfonamide
in the presence of K2CO3. Initial step of the reaction is the
abstraction of the Br+ ion by the base which subsequently
loses KBr to form the nitrene (Scheme 2). We observed that
the solution becomes very turbid at the end of the reaction
which is due to the precipitation of KBr. Formation of KBr
during the reaction was confirmed by a positive silver
nitrate test.
2
3
4
25
60
60
79
80
78
5
60
69c
To confirm the formation of the nitrene intermediate, we
have carried out an experiment to trap the nitrene intermediate
with benzene.18 When a mixture of N,N-dibromo-p-toluene
sulfonamide (1 equiv.) and K2CO3 (2 equiv.) was heated in dry
benzene at 150 1C for 6 h, corresponding 1-[(4-methylphenyl)-
sulfonyl]-1H-azepine (15) was formed in 22% yield along with
p-toluene sulfonamide (Scheme 3).
6
7
60
60
73d
74
To further confirm the formation of the nitrene intermediate,
we treated TsNBr2 with a phosphorous compound under the
same reaction conditions.19 When triphenyl phosphine was
reacted with TsNBr2, iminophosphorane 16b was formed in
80% yield (Table 3, entry 1) after 30 min of reaction. Similarly,
triethyl phosphite also produced the corresponding product
17b in high yield (Table 3, entry 2).
8
9
60
60
70e
76
10
11
60
60
80
78
One interesting observation we made during our investigation
is that, when a mixture of TsNBr2 and K2CO3 was stirred
in DMF at room temperature, the corresponding amidine,
N-[(dimethylamino)methylene]-4-methylbenzene-sulfonamide
(18), was obtained in quantitative yield. Similar to the Vilsmeier–
Haack reaction, this process might involve an iminium
intermediate species at the initial stage of the reaction due to
the interaction of TsNBr2 with DMF (Scheme 4). Since,
12
13
60
78
240
240
77
80
14
a
Reaction conditions: olefin (1 mmol), K2CO3 (2.5 mmol), TsNBr2
b
(1.2 mmol), EtOAc (10 mL), rt. Isolated yield. trans : cis = 6 : 1
d
c
e
cis : trans = 5 : 1. trans : cis = 4 : 1.
Scheme 3 Formation of azepine.
c
2968 Chem. Commun., 2011, 47, 2967–2969
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Table 3 Reaction of phosphorous compounds with TsNBr2
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PPh3
P(OEt)3
TsNQPPh3
TsNQP(OEt)3
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80
76
a
Isolated yield.
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Scheme 4 Formation of amidine from DMF.
TsNBr2 is an excellent source of Br+ species, formation of the
iminium ion is very likely. The presence of base facilitates
subsequent abstraction of the second Br+ ion to yield the
sulfonyl amidine derivative.
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In conclusion, an efficient protocol has been developed for
direct generation of sulfonyl nitrene from N,N-dibromo-p-
toluenesulfonamide which was further reacted with olefin to
form the corresponding aziridine. The aziridination process is
very facile in ethylacetate at room temperature without
a catalyst. The procedure is fast, easy to perform at room
temperature and applicable to various olefins to give
corresponding aziridines in high yield.
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Financial support from DST, India (Grant No. SR/S1/
RFPC-07/2006), is gratefully acknowledged. IS thanks to
CSIR and BK thanks to UGC for research fellowship. We
thank IIT-Guwahati and NEHU, Shillong, for analytical data
and reviewers for their valuable suggestions.
Notes and references
z General procedure: to a solution of olefin (1 mmol) and K2CO3
(2.5 mmol), in dry ethyl acetate (5 mL), a solution of TsNBr2
(1.2 mmol) in dry ethyl acetate (5 mL) was added dropwise under
nitrogen atmosphere at room temperature. After completion of the
reaction, an aqueous solution of 10% sodium thiosulfate (5 mL) was
added and the organic layer separated. After usual workup, the
crude product was purified by flash chromatography on silica gel
(230–400 mesh) with petroleum ether/ethyl acetate as eluent.
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c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 2967–2969 2969