7-Oxa-4-thia-1-aza-bicyclo[3.2.1]octane 4,4-Dioxides: Mechanochemical Synthesis by Tandem Michael Addition–1,3-Dipolar Cycloaddition of Aldoximes and Evaluation of Antibacterial Activities

Article abstract of DOI:10.1002/ejoc.201701511

A solvent-free, green, and efficient mechanochemical method for the synthesis of a series of bridged bicyclo aza-sulfone derivatives, namely 7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane 4,4-dioxides through tandem Michael addition–1,3-dipolar cycloaddition of aldoximes was developed. Mechanochemical grinding/milling facilitates quick formation of aldoximes from corresponding aldehydes and hydroxylamine, which upon reaction with divinyl sulfone in a mixer mill affords 7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane 4,4-dioxide derivatives in good overall yields. The newly synthesized bicyclo aza-sulfone derivatives 4 were screened for antibacterial activities. Mostly bicyclo aza-sulfones derived from electron-rich aromatic aldehydes inhibit the growth of Mycobacterium smegmatis (mc²155) and those from aliphatic aldehydes the growth of Escherichia coli (DH5α) in moderate to good effect. However, butyraldehyde-derived compound 4r was very effective against both M. smegmatis and E. coli. The key advantages of this mechanochemical method are catalyst- and solvent-free conditions, shorter reaction time, and formation of a new series of 7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane 4,4-dioxide derivatives, which are good antibacterial agents against M. smegmatis and E. coli.

Full text of DOI:10.1002/ejoc.201701511

A Journal of
Accepted Article
Title: Mechanochemical synthesis of 7-oxa-4-thia-1-aza-
bicyclo[3.2.1]octane-4,4-dioxides via tandem Michael
addition-1,3-dipolar cycloaddition and their antibacterial
properties
Authors: Zigmee T. Bhutia, Avijit Das, Malabika Biswas, Amrita
Chatterjee, and Mainak Banerjee
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
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content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701511
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701511
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201701511
FULL PAPER
Mechanochemical
synthesis
of
7-oxa-4-thia-1-aza-
bicyclo[3.2.1]octane-4,4-dioxides via tandem Michael addition-1,3-
dipolar cycloaddition of aldoximes and evaluation of their
antibacterial activities
[
a]
[b]
[b]
[a]
[a]
Zigmee T. Bhutia, Avijit Das, Malabika Biswas, Amrita Chatterjee* and Mainak Banerjee*
Abstract: A solvent-free, green and efficient mechanochemical method for the synthesis of a series of bridged bicyclo aza-sulfone derivatives
viz. 7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-dioxides via tandem Michael addition-1,3-dipolar cycloaddition of aldoximes was developed.
Mechanochemical grinding/milling facilitates quick formation of aldoximes from corresponding aldehydes and hydroxylamine which upon
reaction with divinyl sulfone in a mixer-mill affords 7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-dioxide derivatives in good overall yields. The
newly synthesized bicyclo aza-sulfone derivatives (4) were screened for antibacterial activities. It was found that mostly bicyclo aza-sulfones
2
derived from electron rich aromatic aldehydes inhibit the growth of Mycobacterium smegmatis (mc -155) and that of aliphatic aldehydes inhibit
the growth of Escherichia coli (DH5) in moderate to good effect. However, butyraldehyde derived compound 4r was found to be very
effective against both M. smegmatis and E. coli. The key advantages of this mechanochemical method are catalyst- and solvent-free
condition, shorter reaction time, and the new series of 7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-dioxide derivatives are good antibacterial
agents against M. smegmatis and E. coli.
O
O
O
O
H
N
S
Introduction
(A)
OH
N
X
S
N
O
O
H3CO
O
OCH3
O
1,4-Thiazine-1,1-dioxide (or 4-aza-sulfones) is
a common
X = -CHO, -CH2OCH3
antibacterial activity[1g,h]
antiinflammatory activity[1d]
OH
substructure of many biologically active and pharmaceutically
O
[
1]
S
important molecules of natural as well as synthetic origin.
Compounds containing this moiety exhibit a wide range of
N
H
[
1d]
[1e.f]
biological activities including anti-inflammatory,
antiviral
N
[
1g,h]
and antibacterial activities
scaffolds like aza-bicyclo[3.2.1]octane
bicyclo[3.2.1]octane are ubiquitous among various bioactive
(Figure 1). On the other hand,
HCV polymerase NS5B
inhibitor
[
1e]
[
2]
O
N
and
oxa-aza-
[
3]
F
[
2,3]
N
N
compounds.
bicyclic sulfone
bicyclo[3.2.1]octane-4,4-dioxides are known in the literature
Of our interest, somewhat complex bridged
OH
(B)
N
Ar
(
C)
derivatives, viz. 7-oxa-4-thia-1-aza-
N
[4]
N
O
OR
but not much is known about their bioactivities. These sulfone
derivatives are mainly constructed by tandem Michael addition-
N
N
F3C
Ar = Ph, 2-Naph, 2-Pyr etc
R = Me
H
H
serotonin reuptake inhibitor[2g]
rapamycin (mTOR) inhibitors[3a]
1
,3-dipolar cycloaddition of oximes,
a
method separately
[
4a-d]
[4e,f]
reported by Griggs
and Padwa . While these conventional
Figure 1. Chemical structures of few relevant bioactive compounds: (A) 1,4-
thiazine-1,1-dioxides, (B) one with axa-bicyclo[3,2,1]octane skeleton and (C)
one with oxa-axa-bicyclo[3,2,1]octane skeleton.
methods are disadvantageous in terms of use of toxic solvents
and high temperature, only one “green method” is available
[
5]
involving reaction in aqueous micellar media.
In the present scenario, most of the large-scale chemical
processes use toxic organic solvents for various transformations
which account for 80–90% of the waste generated in a typical
sustainable and eco-friendly chemical processes, a significant
research effort is focused on solvent-free (or solvent-less)
[
6]
.[7]
pharmaceutical/fine chemical processes. In order to achieve
reactions In this direction, mechanochemical techniques have
gradually become a powerful tool in the paradigm of synthetic
[
8]
organic chemistry. In mechanochemical-organosynthesis the
chemical transformations are achieved either by milling in a ball-
[9,10]
[11,12]
mill
or by manual grinding
in a mortar-pestle. Both
methods have gained significant research interests for organic
transformations not only for solvent-free conditions but also for
time efficiency, cleaner and safer reaction profile, easy handling
etc. As a part of our ongoing interests in mechanochemical
[
[
[
a]
b]
*]
Department of Chemistry, BITS, Pilani, Goa Campus, Goa-
03726, India.
Department of Biological Sciences, BITS, Pilani, Goa Campus,
Goa- 403726, India.
4
[
13]
[13b,14]
Fax: +91-832-255-7031; Tel.: +91-832-2580-347 (M.B.), +91-832-
reactions
and nitrone cycloaddition chemistry,
we
2580-320 (A.C.); Email: mainak@goa.bits-pilani.ac.in (M.B.);
assumed that it is worthwhile to investigate the scope of
mechanochemical grinding/milling for the formation of somewhat
complex bridged heterobicyclic compounds via tandem Michael
amrita@goa.bits-pilani.ac.in (A.C.).
Supporting information for this article is given via a link at the end
of the document.
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201701511
FULL PAPER
addition-1,3-dipolar cycloadditions. We, herein, report an
environmentally benign synthetic route to 7-oxa-4-thia-1-aza-
bicyclo[3.2.1]octane-4,4-dioxides (4) from various aldehydes and
hydroxylamine via in situ formation of aldoximes followed by
Michael addition-1,3-dipolar cycloaddition. These compounds
were examined for antibacterial activities against acid-fast
Mycobacterium smegmatis, Gram-negative Escherichia coli and
Gram-positive Staphylococcus aureus.
the additive of choice for further reactions because of easy
separation of additive from the product by water wash and for
affording marginally better yields than other additives apart from
being a side product of the first step. In a separate study, the
milling condition was standardized by changing milling frequency,
the number of balls and amount of reaction mixture. The best
results were obtained by carrying out reactions in a 5 mL jar
(stainless steel) with two 7 mm balls for a quantity of 2 mmol of
an aldehyde with 5 times w/w of additive and milled at 30 Hz.
O
O
O
N
OH
N
S
R/Ar CHO
K CO
2 3
S
O
R/Ar
O
Table 1. Optimization of reaction condition for 7-oxa-4-thia-1-aza-
bicyclo[3.2.1]octane-4,4-dioxides.
1
MM/G
KCl (additive)
5-10 min Ar/R MM (30 Hz), 6-8 h
H
H
3
+
NH OH.HCl
or G
upto 12 h
80 °C,
2
OH
N
2
O
O
O
N
MeO
MeO
O
N
O
N
O
N
S
MeO
CHO
K2CO3
R/Ar
R/Ar
MM = mixer-milling
G = grinding
S
O
S
O
O
S
S
O
1a
+
milling
or
grinding
milling
or
H
O
O
H
O
H
H
H
O
OMe grinding
NH2OH.HCl
4a
5
2a
3a
4
not formed
[
a]
Entry
Solvent/
Additive
Meth
od
Time
of
Time
of
% of
3a
%
Yield
[
b]
[c,d]
Ar = aromatic: Ph, 4-MeOPh, 4-NO Ph etc.
2
R = alkyl: n-propyl, n-hexyl, n-heptyl etc.
oxime
format
ion
cyclo
additio
n (h)
isolat
ed
of 4a
[
e]
Scheme 1. General scheme for the of synthesis of 7-oxa-4-thia-1-aza
bicyclo[3.2.1]octane-4,4-dioxide derivatives (4).
(min)
1
2
3
4
5
6
neat
EtOH
neat
grinding
grinding
milling
05
12
12
12
12
6
55
51
33
40
--
15
20
30
20
42
15
05
Results and Discussion
05
At the beginning of our studies, the focus was on the
optimization of reaction conditions either by grinding in an
electrical mortar-pestle (Agate made) or by milling in a mixer-mill
SiO
SiO
2
2
grinding
milling
10
05
(
MM400) using 4-methoxybenzaldehyde (1a), hydroxylamine
hydrochloride and divinyl sulfone in a model reaction. K CO
2
3
2
Al O3
grinding
10
12
38
was used for the liberation of hydroxylamine from its HCl salt
during formation of aldoximes. It was observed that formation of
oxime is very fast for both methods. However, electrical grinding
under neat condition was not good enough for complete
conversion of oxime (2a) to intermediate nitrone (3a) even after
(neutral)
7
Al
O
2 3
milling
05
5
--
63
(neutral)
8
9
KCl
grinding
milling
05
05
05
05
12
6
35
--
23
71
20
70
12 h (Table 1, entry 1). Only presence of a very little amount of
KCl
product (4a) was observed in the reaction mixture after 12 h.
[
13c,15]
Next, liquid-assisted grinding (LAG)
by addition of EtOH
10
NaCl
NaCl
grinding
milling
12
6
34
--
(
(
0.5 mL per 1 mmol of 1a) was attempted for the same reaction
Table 1, entry 2). However, no significant change was observed
11
in the course of the reaction. Notably, the addition of solid
additives (such as SiO , Al , KCl etc.) was partly effective in
order to get the final compound (4a) only in low yields under
grinding condition (Table 1, entries 4, 6, 8, 10). In these cases,
oximes get converted to nitrones approximately after 6 h but 1,3-
dippolar cycloaddition remains sluggish (Table 1, entries 4, 6, 8,
[
a] 2 mmol of 1a was taken for reaction. [b] Additive taken was five time of
2
2 3
O
weight of the aldehyde. [c] Electric grinding at 110 rpm. [d] Mixer milling with 2
balls (7 mm) in 5 ml stainless steel jar at 30 Hz. [e] Nitrone (3a) was not
detected in TLC for entries 5, 7, 9, 11.
Although grinding in
a
mortar-pestle at ambient
temperature was not promising, attempts were made to use this
method for the formation of bridged bicyclo aza-sulfones (4) by
subsequent heating in
aldoximes derived from aromatic aldehydes were ground in the
presence of KCl in an electrical mortar-pestle upto 6 h for
complete formation of nitrones and the mortar was placed in a
sand-bath and heated at 80 °C for several hours with intermittent
hand-grinding (Table 2). However, the yield of the desired
product (4) was below satisfactory level. It was observed that
open-air heating generates a complex mixture of side products
10). On the other hand, milling with a solid additive was found
more suitable (Table 1, entry 5, 7, 9, 11) than milling under
neat condition (Table 1, entry 3). In case of silica gel (60-120
mesh) as the additive, some amount of aldehyde (1a) was
isolated. Presumably, acidic silica gel initiates partial hydrolytic
decomposition of the aldoxime 2a, which is the reason for the
lower yield of the final product. Although no significant difference
was observed in terms of yield of 4a in the presence of neutral
alumina or simple salts like KCl or NaCl, KCl was consider as
a sand-bath. Accordingly, selected
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European Journal of Organic Chemistry
10.1002/ejoc.201701511
FULL PAPER
(
along with 4) which could not be separated in pure form.
4-thia-1-aza-bicyclo[3.2.1]octane-4,4-dioxides
thoroughly characterized by H NMR, C NMR, ESI-MS and
(4)
were
1
13
However, in some cases (e.g. 4-bromo-benzaldehyde, 1k), a
significant amount of the di-nitrone intermediate was also
isolated and was confirmed by H NMR. Overall, grinding in
mortar-pestle was not found very suitable for the formation of
bridged sulfones (4). Therefore, further studies were carried out
in a Retsch MM400 mixer mill.
CHN analysis. The spectra were in good agreement with the
1
[4a-c,e,f,5]
reported values of the known compounds.
appearance of a doublet at around δ 4.5 ppm in H NMR (peak
of exo-H at C-6) and not in the range δ 2.4-2.7 ppm clearly
The
1
2 2
indicates the presence of –OCH – (and not aliphatic –CH –)
affirming formation of 7-oxa-bicyclo[3.2.1]octane ring system. In
1
3
C NMR corresponding carbon peak appeared at δ 68-70 ppm
Table 2. Synthesis of 8-aryl-7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-
dioxide derivatives by grinding followed by heating.
and not at the aliphatic zone. Similarly, for aldoximes derived
from aromatic aldehydes (e.g. 4a, 4b, 4m and others) the
benzylic proton (at C-8) appeared as a sharp singlet at around δ
OH
N
CHO
O
O
O
N
O
N
S
80 °C
6-8h
5.1-5.3 ppm similar to what was observed by Griggs and co-
K2CO3
S
O
[4a,b]
grinding
5-10 min
R
R
S
O
workers
during their study which unequivocally confirms the
grinding
6h
H
H
O
R
1
R
H
O
+
formation of the expected stereoisomer 4. All the other peaks
matched with the structure of 4 (and not 5). In general, the
method worked well with a variety of aliphatic, aromatic and
heteroaromatic aldehydes with similar efficacy. It was noticed
that the presence of electron donating group (EDG) (4a, 4c-f,
Table 3) or electron withdrawing group (EWG) (4h-n, Table 3) in
the aromatic ring does not have significant effect in the rate of
the reaction under mechanochemical condition. While it may be
presumed that the presence of EDG is helpful for Michael
addition step, 1,3-cycloaddtion determines overall rate of the
reaction which is indifferent by the presence of any substituent in
the aromatic ring. Even the reactions involving aliphatic
aldehydes with not much substituent effect took 4-5 h for
completion (4r-u, Table 3). However, the results indicated that
the yields of the final product may vary based on the
substituents present in the aromatic ring of the aldoximes
derived from aromatic aldehydes. The aldoximes with greater
electron-density produced the final product in higher yield (4a,
NH2OH.HCl
2
3
4
[
a,b]
Entry
R (1)
Heating
time (h)
%Yield
of 4
1
2
3
4
1a: 4-MeO
1b: H
6
6
6
8
4a: 40
4b: 38
[
c]
1h: 4-F
1k: 4-Br
4h: 35
[
c]
4k: 35
[
a] Grinding in electrical mortar pestle at 110 rpm with KCl (5 times w/w
as additive). [b] Isolated yield of
also isolated.
4. [c] About 15-20 % of dinitrone was
The versatility of the mechanochemical method was
established by carrying out several reactions under the
optimized reaction condition with a series of aromatic and
aliphatic aldehydes (1a-u) under milling condition (Table 3).
Each of the reactions was started by taking an aldehyde,
4c-g, Table 3) than the aldoximes with lower electron-density
(
4k-o, Table 3). Presumably, the electron donation ability of the
substituents in the aromatic ring helps to stabilize the
intermediate nitrone (3) reducing the possibility of some other
side reactions. Noticeably, relatively unstable heteroaromatic
aldehydes (such as furfuraldehyde) participated equally to afford
final product in good yields. The mechanochemical method was
found effective for several aliphatic aldehydes as starting
materials producing the desired product in comparable yields in
similar time period (4r-u, Table 3). From the above results the
following mechanistic pathway may be proposed (Figure 2).
2 3
hydroxylamine hydrochloride (1.1 equiv) and K CO (1.1 equiv)
in a 5 mL stainless steel jar with two stainless steel balls (7 mm
dia). The reaction mixture was milled at 30 Hz for 5-10 min. The
formation of intermediate aldoximes was monitored by TLC. It
often takes just 5 min for quantitative conversion to aldoximes.
Subsequently, divinyl sulfone (1.0 equiv) and KCl (5 times w/w
of 1) were added to the reaction mixture and it was further milled
at 30 Hz for several hours (Table 3). The reactions afforded 8-
aryl/alkyl-7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-dioxides
Mechanochemical
grinding/milling
allows
spontaneous
[
4a-c]
(
4) as the only isolable major product
and other possibility i.e.
formation of 7-aryl/alkyl-8-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-
condensation of aldehydes and hydroxylamine. The
corresponding aldoximes (2) get converted to nitrones by the
nucleophilic attack of oxime nitrogen to the Michael receptor,
[
4a-c]
4
al.
,4-dioxides (5) was not observed. Griggs et al.,
Padwa et
[
4e,f]
[5]
and Hota et al. separately reported that the nitrones (3)
1,4-diene (here divinyl sulfone). The nitrone may remain in two
derived from corresponding aldoximes (2) undergo 1,3-dipolar
cycloaddition in regio- and stereo-specific manner to afford
bridged heterocycles (4) only under different reaction conditions
pre-transition state conformers (3A or 3B). Presumably, kinetic
selection prefers conformer 3A over other with better non-
bonded interactions in the transition state(s), which precedes
cycloaddition. Moreover, conformer 3B may experience some
(
both conventional media and aqueous media). It seems that
similar pathway is followed under the mechanochemical
condition as well. The progress of the cycloaddition reaction was
monitored by TLC at regular intervals. It was observed that the
conversion of aldoximes (2a-u) to the bridged aza-sulfones (4a-
u) via formation of intermediate nitrone (3) is facile in terms of
yields (60-80%) and reaction time (4-8 h). All 8-aryl/alkyl-7-oxa-
torsional strain between H
A B
and H (Figure 2). Finally, a
comparison was drawn in between the existing methods
including (a) conventional reaction media reported by Griggs et
[
4a]
[5]
al., (b) micellar media by Hota et al. and the current
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European Journal of Organic Chemistry
10.1002/ejoc.201701511
FULL PAPER
Table 3. Mechanochemical synthesis of 8-aryl/alkyl-7-Oxa-4-thia-1-aza
bicyclo[3.2.1]octane-4,4-dioxide derivatives.
O
H
N
O
N
O
H
S
HONH2
2
O
S
O
R
H
O
O
N
O
N
H
R
S
OH
N
O
R
O
H
S
O
N
-H O
Michael
addition
H
O
H
O
O
R/Ar CHO
R/Ar
K2CO3
H
3A
HB
S
O
HA
X
R/Ar
O
1
a-u
S
O
R
2
MM (30 hz)
5-10 min
KCl
O
1
3B
Ar/R
H
H
+
H
MM (30 Hz)
NH2OH.HCl
2a-u 4-8 h
3a-u
4a-u
1,3-cycloaddition
R = aryl or alkyl
H
O
8
O
2
7
O
N
O
N
O
N
6
2
H
1
H CO
H C
1
3
N
6
3
3
3
N
R
R
S
O
S
O
5
S
O
S
O
O
O
5
S
H 7
4
8
H
O
4
O
O
O
4b, 5 h, 77%
4c, 5 h, 80%
4
4
a, 4.5 h, 71%
5
H C
H3C
O
3
O
N
O
N
Figure 2. Possible mechanistic pathway for synthesis of 7-oxa-4-thia-1-aza-
bicyclo[3.2.1]octane-4,4-dioxides.
N
N
S
O
H C
3
H C
3
S
O
S
O
O
O
O
O
O
4
d, 7 h, 81%
4e, 6 h, 78%
4f, 6.5 h, 71%
O
N
O
N
O
mechanochemical method in terms of reaction condition and
yields of a common product, 4b (Table 4). It is clear from table 4
that the mechanochemical method is far superior to other
methods in terms of yield (of 4b) and the rate of the reaction.
However, a direct comparison cannot be drawn as the current
method involves in-situ oxime formation followed by
cycloaddition, whereas, for other methods the information is
based on Michael addition-1,3-dipolar cycloaddition step only.
HO
F
Cl
N
S
S
S
O
O
O
O
4
g, 5.5 h, 76%
4h, 7 h, 77%
4i, 6.5 h, 74%
Br
Cl O
N
O
N
O
N
S
Br
S
S
O
O
O
O
O
O
4
j, 7.5 h, 70%
4k, 6.5 h, 68%
4l, 7 h, 65%
O N
NC
2
O
N
O
N
O
N
O2N
In vitro antibacterial study
S
S
S
O
O
O
O
O
O
4
m, 8 h, 65%
4n, 7 h, 60%
4o, 8 h, 66%
In modern days, bacterial pathogenic diseases like tuberculosis,
syphilis and anthrax cause major health problems to the humans.
O
N
O
O
N
S
O
N
S
As bacteria develop drug resistance synthesis and screening of
S
[16]
S
O
O
O
O
new antibacterial agents are essential.
At first, for in vitro
O
O
4
p, 4.5 h, 65%
4q, 6 h, 67%
4r, 4 h, 60%
antibacterial activity study, the synthesized 8-aryl/alkyl-7-Oxa-4-
O
O
O
N
thia-1-aza-bicyclo[3.2.1]octane-4,4-dioxide derivatives (4) were
N
S
N
S
screened for the inhibition zones against the bacteria by spot
S
O
[17]
(
)4
O
()5
O
()9
O
plate technique.
Selected compounds derived from aromatic,
O
O
4
s, 4 h, 68%
4t, 4 h, 71%
4u, 4.5 h, 75%
heteroaromatic and aliphatic aldehydes were treated with
different categories of bacterial strains viz. acid fast
2
Mycobacterium
smegmatis
(mc 155),
Gram-positive
All yields refer to isolated product.
Staphylococcus aureus (RN4220) and Gram-negative
Escherichia coli (DH5α) with Kanamycin as a standard drug.
Subsequently, more compounds of similar classes were tested
based on the initial results. The compounds which showed
strong inhibition zones were tested further for minimum inhibitory
Table 4. A comparison of formation of 4b by various methods
Method
Solvent
Xylene
water
Catalyst/
auxiliary
Condition
Yield
(%)
Ref.
[18]
concentrations (MICs)
by broth microdilution method. The
initial spot plate study showed that bridged bicyclo aza-sulfones
derived from aromatic aldehydes with electron donating groups
such as 4a, 4g and heteroaromatic aldehydes such as 4q
showed better inhibition activity against M. smegmatis (Table 5).
Whereas, compounds (4) derived from aromatic aldehydes with
strong electron withdrawing groups are not potential inhibitors of
M. smegmatis. However, this cannot be generalized as some
compounds with alkyl chain instead of aromatic rings at C-8 (e.g.
4r) showed good activities. Notably, only bridged sulfones with
alkyl chain at C-8 (4r-u) were found to inhibit E. coli with the best
antibacterial agent being 4s with MIC 15.6 µg mL-1 (Table 5).
[
a]
organic
media
none
140 °C, 6 h
55 °C,16 h
60
57
4a
5
(Grigg’s method)
[
a]
micellar
media
DBSA
(10
(Hota’s method)
mol%)
[
b]
mechanochemical
current work)
solvent-
free
KCl
MM (30 Hz),
5 h
77
-
(
[
[
a] Isolated yield of 4b for the reaction between oxime (2b) and divinyl sulfone.
b] Isolated yield (of 4b) over two-steps starting from aldehyde (1b).
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201701511
FULL PAPER
However, these compounds failed to show any appreciable
bioactivity against S aureus. Based on the initial results, SAR
studies may be envisaged on 7-oxa-4-thia-1-aza-bicyclo[3.2.1]-
octane-4,4-dioxides in future.
mechanochemical method for bridged bicyclo aza-sulfone
derivatives
a sustainable alternative to existing synthetic
methodologies. Furthermore, several of these 7-oxa-4-thia-1-
aza-bicyclo[3.2.1]octane-4,4-dioxides are reasonably good
antibacterial agents against M. smegmatis and E. coli.
Table 5. MICs of various bicyclo aza-sulfones (4) against Mycobacterium
smegmatis and Escherichia coli.
Experimental Section
Compounds
M. smegmatis
E. coli
(in µL/mL)
General information: All reagents were purchased from commercial
sources and were used without further purification. All solvents used
were of research grade. The milling experiments were performed in
Retsch MM-400 and grinding by electrical mortar pestle (Agate made,
Scientech instruments, India). The reactions were monitored by thin layer
chromatography (TLC) carried out on 0.25 mm silica gel aluminium
plates (60F-254) using UV light (254 nm) for visualization. Column
(in µL/mL)
4a
4b
4g
4k
4q
31.2
250
62.5
250
62.5
62.5
-
-
-
-
1
chromatography was performed using 60-120 mesh silica gel. H NMR
13
and C NMR spectra were recorded on Bruker Avance (400 MHz) with
tetramethylsilane (TMS) or solvent peak as internal standard. The
chemical shifts are reported in parts per million () units. Mass spectra
were recorded on Agilent Technologies 6460 triple quard LC/MS using
ESI as ion source. IR spectra were recorded in KBr pellets with IR Affinity
1, Shimadzu. CHN data were recorded using Vario MICRO elementar
CHNS analyzer.
-
-
4r
31.2
15.6
31.2
125
4s
Method for antibacterial activity screening: The agar diffusion
4t
-
[
17]
method
synthesized
Staphylococcus aureus (RN4220) and Mycobacterium smegmatis
was employed for analysing the antibacterial effect of the
compounds against Escherichia coli (DH5α),
4u
-
2
(
mc 155). 1.5% Agar powder was mixed with the respective selective
media, luria bertani broth (Hi-Media) for Escherichia coli, BACTO tryptic
soy broth (Becton, Dickinson and Company) for Staphylococcus aureus
and Middlebrook 7H9 broth base (HiMedia) for Mycobacterium
smegmatis, autoclaved and poured onto sterile Petri dishes. The
respective media were finally inoculated with freshly grown bacterial
cultures. Meanwhile, all the synthesized compounds were dissolved in
DMSO and 5 µL solution of each compound was spotted on the
Conclusion
In conclusion, we have developed a catalyst- and solvent-free,
cost-effective mechanochemical route for the synthesis of a
variety of 7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-dioxide
derivatives involving tandem Michael addition-1,3-dipolar
cycloaddition of aldoximes. Mechanochemical grinding or milling
promotes condensation of aldehydes and hydroxylamine within
few min. The corresponding aldoximes react with divinyl sulfone
o
inoculated plates. The spot tested plates were incubated at 37 C for 18
h for E. coli and S. aureus and 48 h for M. smegmatis. DMSO was also
screened for anti-bacterial effect in the same way. The compounds which
were found to produce a zone of inhibition were further screened for their
antibacterial activity by Broth Micro dilution method for the determination
in
a
mixer-mill in-situ to affords 7-oxa-4-thia-1-aza-
[
18]
of minimum inhibitory concentrations (MICs). 0.1 mL of the respective
liquid media was added to each of the 96 wells of a sterile microtiter plate.
Two columns were kept as negative controls: (a) broth only and (b) broth
and compound. Two fold dilutions of each compound were made in the
wells, thus a plate contained 0.98–500 µg/mL of different compounds and
of kanamycin (positive control). The inoculum was adjusted to McFarland
bicyclo[3.2.1]octane-4,4-dioxide derivatives (4) in good overall
yields. The methodology works fine with aliphatic, aromatic and
heteroaromatic aldehydes. Presence of electron withdrawing
and electron donating substituents in the aromatic ring of
aldoxime is insignificant in terms of yields and reaction time.
However, grinding in an electrical mortar-pestle was found not
suitable to get the final product in decent yields. The newly
synthesized bridged bicyclo aza sulfone derivatives (4) were
0.1 turbidity standard, and further diluted to the ratio of 1:20. Each well
was inoculated with 10 µL of the prepared inoculum and the plates were
o
incubated at 37 C for respective incubation time. Resazurin was added
to the wells at the end of the respective incubation period and incubated
for another 3 h to visualise the viability of the bacterial cells. All the
experiment was repeated thrice for better reproducibility of the data.
screened for antibacterial activities against acid-fast
Mycobacterium
2
smegmatis
(mc 155),
Gram-negative
Escherichia coli (DH5α) and Gram-positive Staphylococcus
aureus (RN4220). It was found that mostly sulfones derived from
aromatic aldehydes with electron donating groups inhibit growth
of M. smegmatis and that of aliphatic aldehydes inhibit growth of
E. coli in moderate to good effects. However, these compounds
do not show appreciable bioactivity against S. aureus. The
simplicity of this synthetic process and the use of
environmentally benign reaction conditions make this
General procedure for the mechanosynthesis of bicyclo aza-
sulfones: synthesis of 8-(4-methoxyphenyl)-7-oxa-4-thia-1-aza-
bicyclo[3.2.1]octane-4,4-dioxide (4a)
[
4a]
A 5 mL stainless steel milling vessel was charged with two steel balls (7
mm dia.), 1a (212 mg, 2 mmol), hydroxylammonium chloride (139 mg,
2.2 mmol) and K
2 3
CO (276 mg, 2.2 mmol). The vessel was closed and
milled at 30 Hz for 5 min for aldoximes formation. Divinyl sulfone (236 mg,
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201701511
FULL PAPER
1
2
mmol) and KCl (1.06 gm) were added and the reaction mixture was
148 °C; H NMR (400 MHz, CDCl
3
):  (ppm) 3.22-3.29 (m, 1H), 3.52-3.64
milled further for the time given in Table 3. The crude product was
triturated with a biphasic solution of EtOAc (10 mL) and water (20 mL).
The organic layer was separated and the aqueous layer was further
extracted with EtOAc (2 x 10 mL). The organic fractions were combined,
(m, 2H), 3.88-4.03 (m, 3H), 4.57 (d, J = 9.6 Hz, 1H), 5.81 (s, 1H), 7.50-
13
7.67 (m, 3H), 7.82-7.94 (m, 3H), 8.10 (d, J = 8.4 Hz, 1H); C NMR (100
MHz, CDCl ):  (ppm) 46.4, 54.2, 68.3, 68.7, 69.1, 122.4, 124.1, 125.6,
126.0, 127.2, 128.9, 129.2, 129.3, 131.1, 133.8; IR (KBr): 3057, 2945,
3
-
1
washed with brine solution and dried over anhydrous Na
2
SO
4
. The
2891, 1597, 1510, 1398, 1321, 1213, 1121, 972 cm ; ESI-MS: m/z 290
+
solvent was evaporated and the crude product was purified by column
[M + H] ; Anal. Calcd for C15
3
H15NO S: C, 62.26; H, 5.23; N, 4.84; S,
chromatography (silica gel, 60-120 mesh). Light yellow solid; yield 71%
11.08. Found: C, 62.29; H, 5.21; N, 4.79; S, 11.09.
1
(eluent 5% MeOH in CHCl
3
); m.p. 152-153 °C (lit. m.p. 155-156 °C ); H
NMR (400 MHz, CDCl
3
):  (ppm) 3.06-3.16 (m, 1H), 3.39-3.49 (m, 2H),
.77-3.93 (m, 3H), 3.83 (s, 3H), 4.52 (d, J = 9.2 Hz, 1H), 5.13 (s, 1H),
8
-(4-Hydroxyphenyl)-7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-
dioxide (4g): White solid; yield 76% (eluent 5% MeOH in CHCl ); m.p.
):  (ppm) 3.26-3.46 (m, 4H),
= 9.6 Hz, 1H), 4.42 (d, J = 9.6
3
6
3
13
1
.92 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H); C NMR (100 MHz,
):  (ppm) 45.9, 53.5, 55.3, 68.2, 69.3, 70.2, 114.3, 126.8, 128.5,
59.4; IR (KBr): 3072, 2994, 2886, 2839, 1614, 1516, 1313, 1177, 1121,
2
3
10-212 °C; H NMR (400 MHz, DMSO-d
.52-3.61 (m, 1H), 3.74 (dd, J = 6.0 Hz, J
6
CDCl
3
1
2
1
9
5
1
Hz, 1H), 5.00 (s, 1H), 6.74 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H),
-
1
+
13
4
70 cm ; ESI-MS: m/z 270 [M + H] ; Anal. Calcd for C12H15NO S: C,
9
6
1
6
.41 (s, 1H); C NMR (100 MHz, DMSO-d ):  (ppm) 45.7, 53.4, 68.1,
8.4, 70.0, 115.6, 127.5, 128.0, 157.2; IR (KBr): 3391, 2951, 2895, 1614,
520, 1454, 1317, 1290, 1233, 1119, 970 cm ; ESI-MS: m/z 256 [M +
3.52; H, 5.61; N, 5.20; S, 11.91. Found: C, 53.75; H, 5.64; N, 5.16; S,
1.92.
-1
+
H] ; Anal. Calcd for C11
4
H13NO S: C, 51.75; H, 5.13; N, 5.49; S, 12.56.
8
-Phenyl-7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-dioxide
Found: C, 51.66; H, 5.18; N, 5.54; S, 12.48.
[
4a,5]
(
4b):
White solid; yield 77% (eluent 5% MeOH in CHCl
3
); m.p. 166-
1
168 °C (lit. m.p. 170 °C); H NMR (400 MHz, CDCl ):  (ppm) 3.06-3.17
3
8-(4-Fluorophenyl)-7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-
(
m, 1H), 3.44 (ABq, JAB = 13.2 Hz, 2H), 3.77-3.91 (m, 3H), 4.51 (d, J =
dioxide (4h): Off white solid; yield 77% (eluent 5% MeOH in CHCl
3
); m.p.
):  (ppm) 3.06-3.15 (m, 1H), 3.38-
.47 (m, 2H), 3.76-3.89 (m, 3H), 4.50 (d, J = 9.2 Hz, 1H), 5.13 (s, 1H),
13
8

3
.8 Hz, 1H), 5.16 (s, 1H), 7.30-7.46 (m, 5H); C NMR (100 MHz, CDCl
3
):
1
2
3
7
06-208 °C; H NMR (400 MHz, CDCl
3
(ppm) 46.0, 53.5, 68.2, 69.2, 70.6, 125.6, 128.2, 128.9, 136.4; IR (KBr):
-
1
13
063, 2994, 2887, 1605, 1452, 1313, 1211, 1166, 1121, 970 cm ; ESI-
3
.05-7.11 (m, 2H), 7.36-7.45 (m, 2H); C NMR (100 MHz, CDCl ): 
+
MS: m/z 240 [M + H] ; Anal. Calcd for C11
5
3
H13NO S: C, 55.21; H, 5.48; N,
(ppm) 45.9, 53.5, 68.2, 69.2, 70.1, 115.9 (d, J = 21.6 Hz), 127.5 (d, J =
.85; S, 13.40. Found: C, 55.32; H, 5.45; N, 5.79; S, 13.47.
8
.1 Hz), 132.2 (d, J = 3.2 Hz), 162.5 (d, J = 245.7 Hz); IR (KBr): 3053,
-
1
2968, 2887, 1611, 1512, 1404, 1315, 1238, 1121, 972 cm ; ESI-MS: m/z
+
8
-(4-Methylphenyl)-7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-
258 [M + H] ; Anal. Calcd for C11
3
H12FNO S: C, 51.35; H, 4.70; N, 5.44; S,
dioxide (4c): Off white solid; yield 80% (eluent 5% MeOH in CHCl
3
); m.p.
):  (ppm) 2.35 (s, 3H), 3.05-3.14
m, 1H), 3.43 (ABq, JAB = 12.8 Hz, 2H), 3.76-3.91 (m, 3H), 4.48-4.52 (m,
12.46. Found: C, 51.45; H, 4.67; N, 5.41; S, 12.38.
1
180-182 °C; H NMR (400 MHz, CDCl
3
(
8-(4-Chlorophenyl)-7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-
13
1
H), 5.15 (s, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H);
):  (ppm) 21.1, 46.0, 53.5, 68.2, 69.3, 70.5, 125.5,
29.6, 133.5, 138.0; IR (KBr): 3042, 2941, 2897, 1516, 1409, 1319, 1290,
C
dioxide (4i): Off white solid; yield 74% (eluent 5% MeOH in CHCl
3
); m.p.
):  (ppm) 3.07-3.17 (m, 1H), 3.43
ABq, JAB = 13.0 Hz, 2H), 3.77-3.90 (m, 3H), 4.52 (d, J = 9.6 Hz, 1H),
NMR (100 MHz, CDCl
3
1
1
(
68-170 °C; H NMR (400 MHz, CDCl
3
1
1
-
1
+
221, 1117, 974 cm ; ESI-MS: m/z 254 [M + H] ; Anal. Calcd for
S: C, 56.90; H, 5.97; N, 5.53; S, 12.66. Found: C, 57.18; H,
13
5
4
2
2
.13 (s, 1H), 7.35-7.42 (m, 4H); C NMR (100 MHz, CDCl
5.9, 53.4, 68.2, 69.1, 70.1, 127.1, 129.1, 134.2, 134.9; IR (KBr): 3061,
3
):  (ppm)
12 3
C H15NO
-
1
6.04; N, 5.48; S, 12.59.
949, 2887, 1493, 1404, 1315, 1296, 1221, 1123, 972 cm ; ESI-MS: m/z
+
3
74 [M + H] ; Anal. Calcd for C11H12ClNO S: C, 48.26; H, 4.42; N, 5.12;
8-(4-Isopropylphenyl)-7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-
S, 11.71. Found: C, 48.32; H, 4.39; N, 5.11; S, 11.69.
dioxide (4d): White solid, yield 81% (eluent 4% MeOH in CHCl
3
); m.p.
1
2
2
3
32-234 °C; H NMR (400 MHz, CDCl ):  (ppm) 1.26 (d, J = 7.2 Hz, 6H),
.92 (sep, J = 7.2 Hz, 1H), 3.06-3.16 (m, 1H), 3.39-3.49 (m, 2H), 3.77-
3
8-(2-Chlorophenyl)-7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-
dioxide (4j): Light brown solid; yield 70% (eluent 5% MeOH in CHCl
3
);
):  (ppm) 3.10-3.20 (m, 1H),
.43-3.52 (m, 2H), 3.77-3.89 (m, 2H), 4.02 (dd, J = 2.8 Hz, J = 5.6 Hz,
H), 4.53 (d, J = 9.6 Hz, 1H), 5.35 (s, 1H), 7.28-7.42 (m, 3H), 7.65-7.71
.86 (m, 1H), 3.91-3.94 (m, 2H), 4.50-4.54 (m, 1H), 5.13 (s, 1H), 7.25 (d,
1
m.p. 140-142 °C; H NMR (400 MHz, CDCl
3
13
J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H); C NMR (100 MHz, CDCl
3
): 
3
1
1
2
(ppm) 23.93, 23.94, 33.8, 46.0, 53.6, 68.2, 69.2, 70.5, 125.5, 127.0,
1
9
5
1
33.8, 148.9; IR (KBr): 3035, 2957, 2887, 1514, 1418, 1312, 1240, 1123,
72 cm ; ESI-MS: m/z 282 [M + H] ; Anal. Calcd for C14H19NO S: C,
3
9.76; H, 6.81; N, 4.98; S, 11.40. Found: C, 59.89; H, 6.84; N, 4.95; S,
1.34.
13
(m, 1H); C NMR (100 MHz, CDCl
3
):  (ppm) 46.3, 53.7, 67.8, 68.1, 69.2,
-
1
+
1
1
27.4, 128.1, 129.7, 129.8, 131.7, 133.8; IR (KBr): 3067, 2945, 2893,
-1
+
474, 1441, 1319, 1207, 1123, 974 cm ; ESI-MS: m/z 274 [M + H] ; Anal.
12ClNO S: C, 48.26; H, 4.42; N, 5.12; S, 11.71. Found: C,
8.34; H, 4.47; N, 5.09; S, 11.80.
Calcd for C11
4
H
3
8
4
2
-(4-Dimethylaminophenyl)-7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-
,4-dioxide (4e):White solid, yield 78% (eluent 5% MeOH in CHCl
3
); m.p.
):  (ppm) 2.95 (s, 6H), 2.99-3.11
= 5.6 Hz, J
.6 Hz, 1H), 4.48 (d, J = 9.6 Hz, 1H), 5.07 (s, 1H), 6.69-6.72 (m, 2H),
8
-(4-Bromophenyl)-7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-
1
08-210 °C; H NMR (400 MHz, CDCl
3
dioxide (4k): Off white solid; yield 68% (eluent 5% MeOH in CHCl
3
); m.p.
):  (ppm) 3.08-3.17 (m, 1H), 3.44
ABq, JAB = 13.2 Hz, 2H), 3.78-3.90 (m, 3H), 4.53 (d, J = 8.8 Hz, 1H),
1
(m, 1H), 3.36-3.45 (m, 2H), 3.74-3.86 (m, 2H), 3.93 (dd, J
1
2
=
2
(
06-208 °C; H NMR (400 MHz, CDCl
3
9
7
6
1
13
.23-7.29 (m, 2H); C NMR (100 MHz, CDCl
8.2, 69.2, 70.4, 112.5, 123.8, 126.3, 150.2; IR (KBr): 3011, 2953, 2803,
616, 1526. 1358, 1221, 1123, 972 cm ; ESI-MS: m/z 283 [M + H] ; Anal.
S: C, 55.30; H, 6.43; N, 9.92; S, 11.36. Found: C,
5.36; H, 6.48; N, 9.86; S, 11.44.
3
):  (ppm) 40.5, 45.9, 53.6,
13
5
(
.12 (s, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H); C NMR
100 MHz, CDCl ):  (ppm) 45.9, 53.4, 68.2, 69.0, 70.1, 122.3, 127.5,
32.1, 135.4; IR (KBr): 3051, 2988, 2897, 1498, 1400, 1317, 1294, 1211,
3
-
1
+
1
1
Calcd for C13
5
H N O
18 2 3
-1
+
79
+
123, 974 cm ; ESI-MS: m/z 318 [M + H] (for Br), 320 [M + H] (for
8
1
3
Br); Anal. Calcd for C11H12BrNO S: C, 41.52; H, 3.80; N, 4.40; S, 10.08.
Found: C, 41.53; H, 3.76; N, 4.36; S, 10.06.
8
-Naphthayl-7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-dioxide
[
4e]
(
3
4f): Off white solid; yield 71% (eluent 5% MeOH in CHCl ); m.p. 146-
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201701511
FULL PAPER
+
8-(3-Bromophenyl)-7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-
ESI-MS: m/z 230 [M + H] ; Anal. Calcd for C
9 4
H11NO S: C, 47.15; H, 4.84;
dioxide (4l): Off white solid; yield 65% (eluent 5 % MeOH in CHCl
3
) m.p.
3
00-202 °C; H NMR (400 MHz, CDCl ):  (ppm) 3.09-3.19 (m, 1H), 3.38-
N, 6.11; S, 13.99. Found: C, 47.08; H, 4.86; N, 6.07; S, 13.89.
1
2
3
7
1
1
1
.49 (m, 2H), 3.76-3.91 (m, 3H), 4.51 (d, J = 9.6 Hz, 1H), 5.12 (s, 1H),
[5]
8-Propyl-7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-dioxide
(4r):
.24-7.28 (m, 1H), 7.36-7.38 (m, 1H), 7.46 (d, J = 8.0 Hz, 1 H), 7.65 (s,
White solid; yield 60% (eluent 3% MeOH in CHCl
3
); m.p. 109-111 °C (lit.
13
1
H); C NMR (100 MHz, CDCl
3
):  (ppm) 45.9, 53.4, 68.2, 69.0, 70.0,
m.p. 115 °C); H NMR (400 MHz, CDCl
3
):  (ppm) 0.98 (t, J = 7.2 Hz, 3H),
23.1, 124.2, 128.9, 130.5, 131.4, 138.5; IR (KBr): 3082, 2965, 2895,
1
2
=
4
1
.27-1.59 (m, 4H), 3.00-3.05 (m, 1H), 3.27-3.36 (m, 2H), 3.62-3.69 (m,
H), 3.92-3.95 (m, 1H), 4.17 (dd, J = 5.6 Hz, J = 9.6 Hz, 1H), 4.52 (d, J
10.0 Hz, 1H); C NMR (100 MHz, CDCl ):  (ppm) 13.6, 19.3, 33.8,
5.9, 53.6, 67.0, 68.8, 68.9; IR (KBr): 2972, 2866, 1460, 1325, 1217,
176, 1121, 1082, 964, 821 cm ; ESI-MS: m/z 206 [M + H] ; Anal. Calcd
S: C, 46.81; H, 7.37; N, 6.82; S, 15.62. Found: C, 46.92; H,
7.39; N, 6.88; S, 15.56.
-
1
+
566, 1474, 1317, 1223, 1123, 972 cm ; ESI-MS: m/z 318 [M + H] (for
1
2
7
9
+
81
13
3
Br), 320 [M + H] (for Br); Anal. Calcd for C11H12BrNO S: C, 41.52; H,
3
3.80; N, 4.40; 10.08. Found: C, 41.43; H, 3.84; N, 4.36; 10.14.
-
1
+
8
-(4-Nitrophenyl)-7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-dioxide
8 3
for C H15NO
[
4a,5]
(
4m):
Pale yellow solid; yield 65% (eluent 5% MeOH in CHCl
3
); m.p.
):  (ppm)
.35-3.37 (m, 1H), 3.43-3.53 (m, 2H), 3.62-3.69 (m, 2H), 4.48 (d, J = 10.0
1
236-238 °C (lit. m.p. 240 °C); H NMR (400 MHz, DMSO-d
6
3
8-Hexyl-7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-dioxide (4s): Off
1
Hz, 1H), 4.72 (dd, J
1
= 2.8 Hz, J
2
1
= 5.6 Hz, 1H), 5.34 (s, 1H), 7.75 (d, J =
white solid; yield 68% (eluent 3% MeOH in CHCl
NMR (400 MHz, CDCl ):  (ppm) 0.88 (t, J = 6.8 Hz, 3H), 1.28-1.40 (m,
H), 1.50-1.54 (m, 2H), 2.98-3.02 (m, 1H), 3.20-3.36 (m, 2H), 3.61-3.66
m, 2H), 3.86-3.89 (m, 1H), 4.13 (dd, J = 6.0 Hz, J = 9.6 Hz, 1H), 4.48
d, J = 9.6 Hz, 1H); C NMR (100 MHz, CDCl ):  (ppm) 14.0, 22.5, 26.0,
8.8, 31.6, 31.9, 45.9, 53.6, 67.0, 68.8, 69.1; IR (KBr): 2954, 2928, 2857,
3
); m.p. 89-91 °C; H
3
8
4
2
2
1
.4 Hz, 2H), 8.22-8.25 (m, 2H); C NMR (100 MHz, DMSO-d
5.6, 53.2, 67.6, 68.4, 69.8, 124.0, 128.0, 145.1, 147.4; IR (KBr): 3111,
6
):  (ppm)
3
8
-
1
972, 2845, 1604, 1516, 1419, 1350, 1231, 1123, 974 cm ; ESI-MS: m/z
(
(
1
2
+
85 [M + H] ; Anal. Calcd for C11
12 2
H N O
5
S: C, 46.47; H, 4.25; N, 9.85; S,
13
3
1.28. Found: C, 46.56; H, 4.19; N, 9.78; S, 11.19.
2
1
-
1
+
466, 1329, 1278, 1121, 959 cm ; ESI-MS: m/z 248 [M + H] ; Anal.
S: C, 53.41; H, 8.56; N, 5.66; S, 12.96. Found: C,
53.29; H, 8.60; N, 5.61; S, 12.88.
8-(3-Nitrophenyl)-7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-dioxide
Calcd for C11H21NO
3
(
4n): Pale yellow solid; yield 60% (eluent 5% MeOH in CHCl
86 °C; H NMR (400 MHz, DMSO-d
6
3
); m.p. 184-
):  (ppm) 3.35-3.37 (m, 1H), 3.44-
.53 (m, 2H), 3.63-3.72 (m, 2H), 4.48 (d, J = 10 Hz, 1H), 4.79 (dd, J
.8 Hz, J = 5.6 Hz, 1H), 5.34 (s, 1H), 7.67-7.71 (m, 1H), 7.91-7.94 (m,
H), 8.17-8.19 (m, 1H), 8.33 (s, 1H); C NMR (100 MHz, DMSO-d
1
1
3
2
1
1
=
8-Heptyl-7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-dioxide (4t): Off
1
2
white solid; yield 71% (eluent 3% MeOH in CHCl
NMR (400 MHz, CDCl ):  (ppm) 0.88 (t, J = 6.4 Hz, 3H), 1.23-1.38 (m,
0H), 1.52-1.57 (m, 2H), 2.97-3.02 (m, 1H), 3.20-3.36 (m, 2H), 3.60-3.65
m, 2H), 3.86-3.89 (m, 1H), 4.14 (dd, J = 6.0 Hz, J = 10.0 Hz, 1H), 4.82
d, J = 10.0 Hz, 1H); C NMR (100 MHz, CDCl ):  (ppm) 14.1, 22.6,
6.1, 29.08, 31.7, 31,9, 45.9, 53.6, 66.9, 68.8, 69.1; IR (KBr): 2961, 2922,
3
); m.p. 85-88 °C; H
13
6
): 
3
(ppm) 45.6, 53.2, 67.6, 68.5, 69.5, 121.6, 123.1, 130.5, 133.3, 139.9,
1
1
48.4; IR (KBr): 3071, 2990, 2897, 1528, 1354, 1313, 1223, 1123, 927
(
(
1
2
-
1
+
cm ; ESI-MS: m/z 285 [M + H] ; Anal. Calcd for C11
12 2 5
H N O S: C, 46.47;
13
3
H, 4.25; N, 9.85; S, 11.28. Found: C, 46.37; H, 4.30; N, 9.90; S, 11.19.
2
2
-
1
+
857, 1466, 1331, 1277, 1122, 961 cm ; ESI-MS: m/z 262 [M + H] ; Anal.
S: C, 55.14; H, 8.87; N, 5.36; S, 12.27. Found: C,
55.25; H, 8.92; N, 5.38; S, 12.20.
8-(3-Cyanophenyl)-7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-
Calcd for C12H23NO
3
dioxide (4o): Light yellow solid; yield 66% (eluent 5% MeOH in CHCl
3
);
):  (ppm) 3.10-3.19 (m, 1H),
.40-3.52 (m, 3H), 3.73-3.85 (m, 2H), 4.53 (d, J = 8.8 Hz, 1H), 5.19 (s,
1
m.p. 234-236 °C; H NMR (400 MHz, CDCl
3
3
1
6
2
8
(
-Undecanyl-7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-dioxide
4u): Off white solid; yield 75% (eluent 3% MeOH in CHCl ); m.p. 90-
):  (ppm) 0.89 (t, J = 7.2 Hz, 3H), 1.20-
.42 (m, 18H), 1.50-1.58 (m, 2H), 2.99-3.06 (m, 1H), 3.21-3.38 (m, 2H),
.61-3.67 (m, 2H), 3.89 (dd, J = 5.6 Hz, J = 8.4 Hz, 1H), 4.15 (dd, J
.8 Hz, J = 9.6 Hz, 1H), 4.49 (d, J = 9.6 Hz, 1H); C NMR (100 MHz,
):  (ppm) 14.1, 22.7, 26.1, 29.1, 29.27, 29.33, 29.43, 29.48, 29.55,
29.60, 31.9, 45.9, 53.6, 67.0, 68.8, 69.2; IR (KBr): 2955, 2920, 2851,
13
H), 7.60-7.71 (m, 4H); C NMR (100 MHz, CDCl
3
):  (ppm) 45.9, 53.4,
3
1
8.2, 68.9, 70.2, 112.4, 118.3, 126.7, 132.8, 141.4; IR (KBr): 3048, 2953,
9
1
3
5
2 °C; H NMR (400 MHz, CDCl
3
-
1
893, 2228, 1609, 1406, 1314, 1220, 1121, 974 cm ; ESI-MS: m/z 265
+
[
12 2 3
M + H] ; Anal. Calcd for C12H N O S: C, 54.53; H, 4.58; N, 10.60; S,
1
2
1
=
13
12.13. Found: C, 54.44; H, 4.59; N, 10.51; S, 12.05.
2
CDCl
3
8-Thiophene-7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-dioxide
-
1
+
(
2
4p): Off white solid; yield 65% (eluent 5% MeOH in CHCl
3
); m.p. 202-
):  (ppm) 3.08-3.16 (m, 1H), 3.41-3.53
= 2.8 Hz, J = 5.6 Hz, 1H), 4.17
2
= 9.6 Hz 1H), 4.57 (d, J = 9.6 Hz, 1H), 5.38 (s, 1H),
1472, 1327, 1287, 1119, 961 cm ; ESI-MS: m/z 318 [M + H] ; Anal.
Calcd for C16 S: C, 60.53; H, 9.84; N, 4.41; S, 10.10. Found: C,
1
04°C; H NMR (400 MHz, CDCl
3
H31NO
3
(
(
7
m, 2H), 3.76-3.84 (m, 1H), 4.03 (dd, J
dd, J = 5.6 Hz, J
.00-7.06 (m, 2H), 7.31 (J = 4.4 Hz, 1H); C NMR [100 MHz, DMSO-d
1
2
60.43; H, 9.86; N, 4.40; S, 10.05.
1
13
6
in
3
(1:1)]:  (ppm) 50.5, 58.1, 72.8, 73.2, 73.5, 129.1, 130.5, 131.8,
CDCl
Acknowledgments
1
9
4
2
44.8; IR (KBr): 3096, 2953, 2891, 1474, 1445, 1310, 1238, 1219, 1123,
70 cm ; ESI-MS: m/z 246 [M + H] ; Anal. Calcd for C H11NO S : C,
9 3 2
4.06; H, 4.52; N, 5.71; S, 26.14. Found: C, 44.14; H, 4.47; N, 5.68; S,
6.05.
-
1
+
M. B. thanks DST-SERB (project No. EMR/2016/002253) for
financial support and Z. T. B thanks DST-INSPIRE for INSPIRE
Fellowship.
8-Furan-7-oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-dioxide
(4q):
Pale yellow solid; yield 67% (eluent 5% MeOH in CHCl
3
); m.p. 152-
Keywords: Mechanochemistry, Solvent-free synthesis, Tandem
reaction, Regio- and stereo-specific cycloaddition, Antibacterial
activity.
1
1
(
(
6

54 °C; H NMR (400 MHz, CDCl
m, 2H), 3.72-3.81 (m, 1H), 4.13 (dd, J
dd, J = 6.0 Hz, J = 9.6 Hz, 1H), 4.59 (d, J = 9.6 Hz, 1H), 5.19 (s, 1H),
.39-6.41 (m, 2H) 7.40 (d, J = 1.6 Hz, 1H); C NMR (100 MHz, CDCl
(ppm) 46.0, 53.5, 66.38, 66.44, 69.3, 108.0, 110.8, 142.7, 149.1; IR
3
):  (ppm) 3.07-3.18 (m, 1H), 3.41-3.50
1
= 2.8 Hz, J = 6.0 Hz, 1H), 4.25
2
1
2
13
3
):
-
1
(KBr): 3136, 2980, 2899, 1601, 1508, 1400, 1325, 1227, 1126, 970 cm ;
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201701511
FULL PAPER
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European Journal of Organic Chemistry
10.1002/ejoc.201701511
FULL PAPER
Key Topic: Synthetic Method, Mechanochemistry
TOC:
An efficient mechanochemical method for the highly regio- and
stereo-selective synthesis of bridged bicyclo aza-sulfones viz. 7-
oxa-4-thia-1-aza-bicyclo[3.2.1]octane-4,4-dioxides by tandem
Michael addition-1,3-dipolar cycloaddition has been developed.
Some of these compounds are reasonably good antibacterial
agents against M. smegmatis and E. coli.
This article is protected by copyright. All rights reserved.