Benzosulfones as photochemically activated sulfur dioxide (SO2) donors

Article abstract of DOI:10.1039/c4ob02466d

Sulfur dioxide (SO₂) is a gaseous environmental pollutant which is routinely used in industry as a preservative and antimicrobial. Recent data suggests that SO₂ may have value as a therapeutic agent. However, due to its gaseous nature, localizing SO₂ generation is challenging. Herein, various 1,3-dihydrobenzo[c]thiophene 2,2-dioxides (benzosulfones) were prepared as candidates for photochemically activated sulfur dioxide (SO₂) generation. These compounds were found to be stable in buffer but were photolysed upon irradiation with UV light to generate SO₂. Our data indicates that photolysis of benzosulfones depends on substituents, and that the presence of electron donating groups results in an enhanced yield of SO₂. This journal is

Full text of DOI:10.1039/c4ob02466d

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: S. Malwal and H.
Chakrapani, Org. Biomol. Chem., 2014, DOI: 10.1039/C4OB02466D.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/obc

Page 1 of 8
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C4OB02466D
Journal Name
RSCPublishing
ARTICLE
Benzosulfones as Photochemically Activated Sulfur
Dioxide (SO2) Donors
Cite this: DOI: 10.1039/x0xx00000x
Satish R. Malwal and Harinath Chakrapani*
Sulfur dioxide (SO2) is a gaseous environmental pollutant which is routinely used in
industry as a preservative and antimicrobial. Recent data suggests that SO2 may have value
as a therapeutic agent. However, due to its gaseous nature, localizing SO2 generation is
challenging. Herein, various 1,3-dihydrobenzo[c]thiophene 2,2-dioxides (benzosulfones)
were prepared as candidates for photochemically activated sulfur dioxide (SO2) generators.
These compounds were found to be stable in buffer but were photolysed upon irradiation
with UV light to generate SO2. Our data indicates that photolysis of benzosulfones depended
on substituents and the presence of electron donating groups resulted in enhanced yield of
SO2.
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
Recently we showed that 2,4-dinitrophenylsulfonamides
were activated by biological thiols in physiological pH to
generate SO2 (Scheme 1).19 A number of these derivatives were
Sulfur dioxide (SO2) a colorless pollutant gas that enters the
atmosphere primarily from volcanic eruptions and combustion
of fossil fuels.1 Chronic exposure to SO2 can cause respiratory
and various cardiovascular diseases.2-6 After inhalation, SO2 is
hydrated to form its derivatives sulfite and bisulfite7, 8 which
are known to cause oxidative damage to biomacromolecules.9-12
In contrast, SO2 is used as an antimicrobial agent in wine
also found to have Mycobacterium tuberculosis
(Mtb)
inhibitory activity.20 Compounds that were better at generating
SO2 in a short period were superior inhibitors of Mtb suggesting
an important role for SO2 (Scheme 1).20
making,13 and as a preservative and antioxidant in the food and
pharmaceutical industry.14,
Barring some individual cases,
15
SO2 is well tolerated by most people. SO2 is also presumably
produced endogenously during metabolism of sulfur containing
amino acids and oxidation of hydrogen sulfide.16 Much of its
biological effects, however remain unclear and require further
investigation. In order to study the role of SO2, we have to rely
on gaseous SO2 or complex formulations of sulfite and
bisulfite.4, 17, 18 These sources neither offer scope for localizing
SO2 delivery nor are they capable of controlling rate of SO2
generation.
Scheme 2. Benzosultines as temperature dependent SO2 donors.
However, as thiols themselves are targets for modification
by SO2, other methods for activation to produce SO2 are
necessary. Another approach that we recently reported was to
use benzosultines as SO2 donors.21 These compounds undergo a
retro Diels-Alder reaction to produce SO2 with half-lives
ranging from a few minutes to an hour.21 Benzosultines showed
SO2 like activity in a DNA cleavage assay suggesting potential
applications for molecular biological assays (Scheme 2).21
However, using only heat as a trigger for SO2 generation might
hinder site-directed delivery applications for this series of
compounds. Hence SO2 donors which are stable at room
temperature but require a trigger that is not a biological thiol
are desirable but yet unavailable. Furthermore, recently the use
of SO2 as a reagent in synthesis has assumed importance with
methodologies being developed using small molecule sources
of SO2.22 Taken together, developing new small molecule-
based methodologies for generating SO2 may have chemical as
well as biological applications.
Scheme 1. 2,4‐Dinitrophenylsulfonamides are thiol‐activated SO2 donors.
Department of Chemistry, Indian Institute of Science Education and
Research, Pune, Maharashtra, 411 008 India.
E-mail: harinath@iiserpune.ac.in; Tel: +91 20 2590 8090
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
This journal is © The Royal Society of Chemistry 2013
J. Name., 2013, 00, 1‐3 | 1

Organic & Biomolecular Chemistry
Page 2 of 8
View Article Online
ARTICLE
Journal Name
DOI: 10.1039/C4OB02466D
Photochemical approaches are frequently used to localize and 4c were then reduced by Zn/HCOONH4 to give sulfones 5a
entities including drugs.23-25 Here, a compound is designed to and 5b with an electron donating amino group.29
be activated by light to generate the drug in situ and such
approaches find use in photodynamic therapy. The ability to donating or withdrawing group, starting from phthalide, using a
control the timing, location and dosage of delivery are key reported procedure we synthesized in three steps (Scheme 4).
advantages to using photochemical methods for drug delivery. This aldehyde was treated with various Grignard reagents to
We considered benzosulfones (Figure 1) as possible candidates produce 10a 10i using reported methods (Table 1). Attempts to
In order to study the effect of aryl substituent with electron
9
-
for light activated sulfur dioxide donors. These scaffolds synthesize the 4-nitrophenyl derivative using this methodology
provide structural handles to modulate SO2 generation and can failed. Hence, starting from 2-bromotoluene, 10j was prepared
be classified in three series. First, substituents on the aryl ring in five steps as described in Scheme 5.
of the benzosulfone (A) can be varied to modulate
Using a reported two-step sequence involving m-CPBA
electronically the SO2 release profile. Second, in series B an oxidation followed by sulfuryl chloride mediated cyclization,
aryl ring on the α-position of the sulfonyl functional group the thioether 10a was converted to its corresponding
would offer opportunities to perturb SO2 generation. Finally, benzosultine 11a. Refluxing this benzosultine in acetonitrile
steric effects on photolysis could be studied by studying series gave 12a presumably through a retro Diels-Alder reaction
C.
followed by an in situ chelotropic addition of SO2.21
When this two step sequence was attempted to prepare the
2-methoxy derivative 11b, we instead isolated the benzosulfone
12b presumably due to the poor stability of the sultine under
the reaction conditions (Table 1). A similar observation was
recorded for the 4-methoxy derivative and we isolated 12f as
the major product (Table 1). Previously, rates of retro Diels-
Alder reactions of 1-aryl-benzosultines were recorded and
Figure 1. Benzosulfones that are proposed to be studied in this work.
Hammett analysis yielded a -value of 
0.621 suggesting that
electron donating groups accelerated retro Diels-Alder reaction.
Our observation is consistent with this result. Benzosulfones
Results and discussion
12c-12e and 12g-12j were synthesized from the corresponding
Benzosulfones (series A) containing electron donating or
withdrawing group on the aromatic ring were synthesized as
described in Scheme 3. Ortho xylene 1a was dibrominated by 2
equivalents of NBS,26 to give 2a. Treatment of 2a with 2-
hydroxymethane sulfinate (rongalite) gave cyclic sulfinate ester
benzosultines, which in turn were prepared from the thioethers
through the two-step oxidation/cyclization process (Table 1).
Compound 12h was found to be crystalline and X-ray
diffraction analysis showed that the sulfone ring was puckered
and the aryl ring was nearly perpendicular to the sulfonyl
functional group (Figure 2). This result is consistent with
previous computational energy minimization studies that
3a 27
This sultine was refluxed in acetonitrile wherein a retro
.
Diels-Alder followed by in situ chelotropic addition of SO2
gave the sulfone 4a (Scheme 3).28 Similarly nitro sulfones 4b
and 4c were prepared starting from 1b and 1c. Compounds 4b
indicate a similar geometry for 11a 21
.
Br
O
HO
S
O
O
O
NBS, Bz2O2
ONa
ACN reflux
Zn, NH4COOH
O
O
S
S
S
O
0°C, 6h,
DMF
60-80%
12 h, CCl4
Reflux
70-90%
R2
DCM: MeOH
1:1, 12h RT
85-90%
24h, 50-70%
R2
R2
R2
R2
R1
R1
R1
R1 Br
2a-2c
R1
1a
3a
4a
5a
; R1 = NH2, R2 = H
; R1 = H, R2 = H
; R1 = R2 = H
; R1 = H, R2 = H
1b; R1 = NO2, R2 = H
1c; R1 = H, R2 = NO2
3b; R1 = NO2, R2 = H
3c; R1 = H, R2 = NO2
4b; R1 = NO2, R2 = H
4c; R1 = H, R2 = NO2
5b; R1 = H, R2 = NH2
Scheme 3. General scheme for synthesis of benzosultines.
Scheme 4. General scheme for synthesis of precursors to benzosultines.
2 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 2012

Page 3 of 8
Journal Name
Organic & Biomolecular Chemistry
View ArticAle ROnTliInCeLE
DOI: 10.1039/C4OB02466D
Scheme 5. Synthesis of 10j
.
Scheme 7. Synthesis of 1,1‐dimethyl sulfone.
Table 1. Synthesis of 1-aryl benzosulfones
oxidized to sulfoxide by m-CPBA, followed by sulfuryl
chloride mediated cyclization to give sultine 21, which was
converted to the benzosulfone 22
.
Entry Ar
Thioether Sultine
Sulfone
Scheme 6. Synthesis of sulfone with methyl substituent on 1‐position.
1
2
3
4
5
6
7
8
Ph
2-OMePh 10b
2-NO2Ph 10c
3-OMePh 10d
3-CNPh 10e
4-OMePh 10f
10a
11a
11bc
11c
11d
11e
11fc
11g
11h
11i
12a
12b
12c
12d
12e
12f
12g
12h
12i
The above derivatives were exposed to photolytic
conditions in phosphate buffer and % SO2 generated was
quantified as sulfate by ion chromatography equipped with ion
conductivity detector.31 When sulfone 4a was irradiated for 10
min, 49% of SO2 was generated (Table 2, entry 1). Under
similar conditions, when 4a was stirred in buffer no
decomposition or SO2 was seen. In the presence of an electron
withdrawing nitro group as in the cases of 4b and 4c, the yields
of SO2 were significantly lower giving 30% and 12% SO2,
respectively, after 10 min (Table 2, entries 2-3). In the cases of
5a and 5b, where an electron donating amino group was
present, the yield of SO2 was significantly higher than what we
obtained for 4a (Table 2, entry 4-5). In 1 h, nearly quantitative
SO2 yield was obtained for 4a, 5a and 5b (Table 2, entries 1, 4
and 5) whereas the yields were diminished in the cases of 4b
and 4c. A SO2 yield of 80% was recorded during photolysis of
4c after 4 h (Table 2, entry 3). Hence it appears that an electron
donating group on the fused aromatic ring increases efficiency
of photolysis.
4-MePh
4-FPh
4-CNPh
4-NO2Ph
10g
10h
10i
9
10
10j
11j
12j
a: 1. m-CPBA, 0 °C, DCM, 2 h; 2. SO2Cl2, 0°C DCM, 45 min. b ACN, reflux. cNot
isolated
Next, in order to understand the effect of aryl substituent on
α-position, 12a-12j were irradiated (Table 2, entries 6-15). The
introduction of a phenyl ring at 1-position resulted in increased
SO2 yield with 12a giving nearly 84% of SO2 after 10 min
(Table 1, entry 7). When a strong or mild electron donating
Figure 2. X‐ray crystal structure of 12h
In order to study the effect of alkyl substituent on 1-position
of sulfone we synthesized the methyl derivative (Scheme 6).
Sulfone 4a alkylated at 1-position using butyl lithium and
methyl iodide30 to give α-methyl derivative 18. Next, 1,1-
dimethyl-1,4-dihydrobenzo[d][1,2]oxathiine 3-oxide 21 was
prepared starting from phthalide (Scheme 7). Thioether 20 was
group was present on the
-aryl ring, similar SO2 yields was
obtained after 10 and 60 min suggesting no major electronic
effect on photolysis of these 1-aryl benzosulfones (Table 2).
Previously, benzosulfones have been reported to undergo
photolysis in organic media when irradiated with UV light
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1‐3 | 3

Organic & Biomolecular Chemistry
Page 4 of 8
View Article Online
ARTICLE
Journal Name
DOI: 10.1039/C4OB02466D
through a radical mechanism to produce cyclobutene as the alkyl group marginally enhanced yields of SO2 as compared to
major product.32 Thus, the stability of the radical should dictate 4a
.
the propensity of the benzosulfone to undergo photolysis. Our
In summary, we report a series of benzosulfones that
results indicate that photolysis is sensitive to substituent effects. undergo photolysis to generate SO2 in physiological pH. The
Among the benzosulfones 4a 4c and 5a 5b electron yields of SO2 can be modulated by altering substituent pattern.
-
-
,
withdrawing groups appear to hinder photolysis while the The possibility of using these compounds for localized delivery
electron donating amino groups promoted photolysis. Singh and of SO2 is being explored.
coworkers reported that the radical constants for para
substituted toluenes were in the order of NH2>NO2 supporting Experimental
that the formation of the benzylic radical containing an amino
substituent was favoured.33, 34
General
All chemicals were purchased from commercial sources and
Table 2. Results of photolysis of benzosulfones prepared in this study
used as received unless stated otherwise. All reactions were
conducted in nitrogen atmosphere. THF was dried using a
Entry Compd
% SO2, 10 mina
% SO2, 60 mina
sodium wire and distilled before use. Dichloromethane (DCM)
and acetonitrile (ACN) were pre-dried over calcium hydride
and then distilled under reduced pressure. Column
chromatography was performed using Merck silica gel (60-
120/100–200 mesh) as the solid support. 1H and 13C NMR
spectra were recorded on a JEOL 400 MHz (or 100 MHz for
13C) spectrometer using either residual solvent signals as an
internal reference or with tetramethylsilane (TMS) as an
internal standard. Chemical shifts (δ) are reported in ppm and
1
2
3
4
5
6
7
8
4a
4b
4c
5a
5b
12a
12b
12c
12d
12e
12f
12g
12h
12i
12j
18
49
30
12
72
81
84
90
58
79
81
79
80
77
77
51
66
62
98
75
43 (80)b
100
100
97(88)c
100
96
9
100
97
96
97
93
99
100
95
coupling constants (J) in Hz. High-resolution mass spectra
10
11
12
13
14
15
16
17
(HRMS) were obtained using a HRMS-ESI-Q-Time of Flight
LC/MS (Synapt G2, Waters). Infrared spectra (IR) were
obtained using NICOLET 6700 FT-IR spectrophotometer using
a KBr disc. Melting points were measured using a VEEGO
melting point apparatus in open glass capillary and values
reported are uncorrected. Photolysis was carried out in an Ace
photochemical reactor equipped with a 450 W lamp. Ion
chromatography was conducted using a Metrohm 882 Compact
IC plus instrument (Metrohm A Supp 5-250/4.0 mm, column).
94
22
a% SO2 was determined in acetonitrile/pH 7.4 Buffer as SO42- using an ion
chromatography, unless and otherwise mentioned. bThe yield of SO2
produced after 4 h is reported in paranthesis. c% SO2 was determined in
Ethanol/pH 7.4 Buffer as SO32-/SO42- using an ion chromatography.
Compounds 4a 36
12c-12e 21 12g-12i 21
and our data were consistent with reported spectral data.
,
4c 37
,
,
5b 37
,
7-9
,
10a-10i 21
,
11a-11i21 12a 21
,
,
1538 and 18 30
, were previously reported
In the presence of an additional aromatic ring, as in the case
of 12a, the yield of SO2 during photolysis is significantly
higher when compared with 4a (Table 2). This observation
could be rationalized by stabilization afforded by extended
conjugation of the additional aryl ring at the 1-position to
stabilize the radical.35 However, changing substituents on this
aryl ring did not significantly alter photolysis yields except in
the cases of a NO2 substituent being present on the 2- or 4-
position of 1-phenyl ring i.e. 12c and 12j, wherein decreased
yield of SO2 after 10 min was observed (Table 2, entries 8 and
15). However, in all the aforementioned cases, we obtained
excellent yields of SO2 after 1 h. This result indicates a
diminished electronic substituent effect on photolysis possibly
due to a transition state devoid of any partial charges. Lastly, in
order to test the suitability of these SO2 donors for molecular
biology studies we carried out the photolysis in ethanolic
buffer. The yield of SO2 under these conditions was 88%.
General procedure A: NBS bromination.26 To a solution of
of o-xylene or substituted o-xylene (0.050 mol) in dry CCl4 (25
mL), N-bromosuccinamide (0.100 mol) and benzoyl peroxide
(0.010 mol) were added portionwise at room temperature. The
reaction mixture was refluxed until the starting material was
completely consumed (TLC analysis). The reaction mixture
was cooled gradually to room temperature and filtered. The
resulting filtrate was concentrated under reduced pressure to
give crude product. The crude was used for next step without
further purification.
General procedure B: Formation of cyclic sulfinate ester
(sultine) by reaction with rongalite.27 To a solution of 1,2-
bis(bromomethyl)-3-nitrobenzene or 1,2-bis(bromomethyl)-4-
nitrobenzene (0.032 mol) in dry DMF (10 mL), sodium
hydroxymethanesulfinate
hydrate
(0.130
mol)
and
tetrabutylammonium bromide (0.0064 mol) were added
portionwise at 0 °C. The reaction mixture was stirred at room
temperature for 6 h. To the reaction mixture, water was added
and extracted in ethyl acetate. The combined organic layer was
dried on Na2SO4 and filtered. The resulting filtrate was
In order to understand the role of alkyl substituent on 1-
position we conducted the irradiation experiment with 18 and
22 (Table 2, entries 16-17). In both cases, the presence of an
4 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 2012

Page 5 of 8
Journal Name
Organic & Biomolecular Chemistry
View ArticAle ROnTliInCeLE
DOI: 10.1039/C4OB02466D
concentrated under reduced pressure to give crude product. The (m, 5H), 6.87 (d,
J
= 6.8 Hz, 2H), 6.19 (s, 1H), 3.80 (s, 3H),
crude was used for next step without further purification.
3.77 (d, J = 8.9 Hz, 1H), 3.72 (d, J = 8.9 Hz, 1H), 2.90 (s, 1H),
General procedure C: Conversion of sultine to sulfone.28
The solution of sultine (conc. varied from 0.05 M to 0.5 M) in
acetonitrile was refluxed for appropriate time until TLC
analysis showed complete conversion to sulfone. The reaction
mixture was cooled gradually to room temperature and
concentrated under reduced pressure to give crude product. The
crude was purified by silica gel flash column chromatography
using EtOAc/PE (1:4) as the eluant to produce sulfone. The
1.36 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 158.9, 142.5,
130.9, 128.2, 128.1, 127.9, 127.7, 116.1, 114.8, 113.8, 72.4,
55.3, 43.5, 33.5, 33.7; HRMS (ESI-TOF): C19H24O2S [M+Na]+
: 339.1395. Found [M+Na]+ : 339.1392.
1-(2-methoxyphenyl)-1,3-dihydrobenzo[c]thiophene
2,2-
dioxide (12b). Formed as a product while preparing 11b
according to general procedure for synthesis of sultine in
reference 21. Starting from 10b (1.0 g, 3.16 mmol), 12b (0.58
g, 66%) was isolated as a white solid: mp 179-180 °C; FTIR
(νmax, cm-1): 1601, 1587, 1493, 1471, 1306, 1297, 1252, 1203,
1135, 1104; 1H NMR (400 MHz, CDCl3): δ 7.42-7.34 (m, 4H),
sulfones 4a
, 4b, 4c, 12a, 12c, 12d, 12e, 12g, 12h, 12i and 12j
were prepared according to this procedure.
4-nitro-1,3-dihydrobenzo[c]thiophene 2,2-dioxide (4b).
Prepared according general procedure C. Starting from 3b (1.5
g, 7.04 mmol) in ACN (15 mL, 24h reflux), 4b (0.80 g, 53%)
was isolated as a yellow solid: mp 177-178 °C; FTIR (νmax, cm-
7.14 (d,
J = 7.0 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.93-6.89 (m,
1
1): 3000, 1525, 1453, 1389, 1355, 1310, 1137 ; H NMR (400
1H), 6.79 (d,
J
= 7.1 Hz, 1H), 6.05 (s, 1H), 4.38 (s, 2H), 3.92 (s,
3H); 13C NMR (100 MHz, CDCl3): δ 158.7, 135.9, 131.4,
MHz, DMSO-d6): δ 8.20 (d,
J = 8.2 Hz, 1H), 7.83 (d, J = 7.6
Hz, 1H), 7.70-7.66 (m, 1H), 4.87 (s, 2H), 4.67 (s, 2H); 13C
NMR (100 MHz, DMSO-d6): δ 145.9, 135.9, 132.6, 129.8,
128.5,124.5, 56.4, 55.2; HRMS (ESI-TOF): C8H7NO4S
[M+Na]+ : 235.9993. Found [M+Na]+ : 235.9993.
130.6, 129.8, 129.0, 128.9, 126.8, 125.8, 120.8, 120.7, 111.2,
65.7, 56.0, 55.5; HRMS (ESI-TOF): C15H14O3S [M+Na]+
:
297.0561. Found [M+Na]+ : 297.0565; Anal. Calcd. for
C15H14O3S: C, 65.67; H, 5.14; S, 11.69. Found: C, 65.01; H,
4.81; S, 11.50.
4-amino-1,3-dihydrobenzo[c]thiophene 2,2-dioxide (5a).29
To a solution of 4-nitro-1,3-dihydrobenzo[c]thiophene 2,2-
dioxide 4b (0.230 g, 1.07 mmol) in DCM:MeOH (25 mL, 1:1),
activated zinc powder (0.700 g, 10.7 mmol) and ammonium
formate (0.270 g, 10.7 mmol) were added portionwise at room
temperature. The reaction mixture was stirred at room
temperature for 3 h. To reaction mixture 10 mL of water was
added and extracted in ethyl acetate (3×10 mL). The combined
organic layer was dried on Na2SO4 and filtered. The resulting
filtrate was concentrated under reduced pressure to produce 5a
1-(4-methoxyphenyl)-1,3-dihydrobenzo[c]thiophene
2,2-
dioxide (12f). Formed as a product while preparing 11f
according to general procedure for synthesis of sultine in
reference 1. Starting from 10f (1.0 g, 3.16 mmol), 12f (0.266 g,
30%) was isolated as a white solid: mp 121-122 °C; FTIR (νmax
,
cm-1): 2932, 1610, 1512, 1456, 1317, 1272, 1252, 1194, 1178,
1
1134; H NMR (400 MHz, CDCl3): δ 7.43-7.37 (m, 3H), 7.19
(d,
J = 8.7 Hz, 2H), 7.11 (d, J = 8.0 Hz, 1H), 6.95 (d, J = 11.6
Hz, 2H), 5.43 (s, 1H), 4.41 (s, 2H), 3.82 (s, 3H); 13C NMR (100
MHz, CDCl3): δ 160.5, 136.1, 131.7, 131.0, 129.1, 129.0,
126.7, 125.9, 121.9, 114.5, 71.2, 55.4, 55.0; HRMS (ESI-TOF):
C15H14O3S [M+Na]+ : 297.0561. Found [M+Na]+ : 297.0566;
Anal. Calcd. for C15H14O3S: C, 65.67; H, 5.14; S, 11.69. Found:
C, 65.18; H, 5.08; S, 11.12.
( 0.180 g, 91%) as a yellow solid: mp 187-188 °C; FTIR (νmax
,
cm-1): 3452, 3362, 2922, 1636, 1589, 1480, 1307, 1201; H
NMR (400 MHz, DMSO-d6): δ 7.05(m, 1H), 6.59 (d, = 8.0
1
J
Hz, 1H), 6.51 (d,
J = 7.4 Hz, 1H), 5.29 (s, 2H), 4.37 (s, 2H),
4.18 (s, 2H) ; 13C NMR (100 MHz, DMSO-d6):): δ 145.6,
133.0, 129.2, 115.9, 113.8, 113,36, 56.9, 54.2 ; HRMS (ESI-
TOF): C8H9NO2S [M+H]+ : 184.0432. Found [M+H]+
184.0431
:
(2-(bromomethyl)phenyl)(4-nitrophenyl)methanone (16). To
a solution of (4-nitrophenyl)(o-tolyl)methanol 15 (3.25 g,
13.36 mmol) in dry DCM (25 mL), activated MnO2 (5.80 g,
66.8 mmol) was added portionwise at 0 °C. The reaction
mixture was stirred at room temperature for 6 h. To the reaction
mixture, 20 mL of DCM was added and filtered through a celite
bed. The resulting filtrate was dried on Na2SO4 and
concentrated under reduced pressure to give (4-nitrophenyl)(o-
tolyl)methanone (2.95 g, 93%) as a brown solid. The crude was
used for next step without further purification. To a solution of
(4-nitrophenyl)(o-tolyl)methanone (1.77 g, 7.3 mmol) in dry
CCl4 (40 mL), NBS (1.78 g, 7.3 mmol) and benzoyl peroxide
(2-(tert-butylthiomethyl)
phenyl)
(2-methoxyphenyl)
methanol (10b). Prepared according to general procedure in
reference 21. Starting from
9 (1.0 g, 4.80 mmol), 10b (1.4 g,
93% yield) was isolated as a colorless oil: FTIR (νmax, cm-1):
3584, 2959, 1598, 1487, 1460, 1440, 1291, 1245, 1165, 101 6;
1H NMR (400 MHz, CDCl3): δ 7.32-7.25 (m, 4H), 7.21-7.19
(m, 2H), 6.98-6.94, (m, 1H), 6.87 (dd,
J = 0.6, 8.2 Hz, 1H),
6.50 (s, 1H), 3.92 (d, = 11.2 Hz, 1H), 3.77 (s, 3H), 3.75 (d,
J
J
= 12.0 Hz, 1H), 1.37 (s, 9H); 13C NMR (100 MHz, CDCl3): δ
156.6, 141.7, 135.1, 131.2, 130.3, 128.6, 127.7, 127.6, 127.5,
120.7, 110.4, 67.3, 55.4, 43.3, 30.7, 30.6; HRMS (ESI-TOF):
C19H24O2S [M+Na]+ : 339.1395. Found [M+Na]+ : 339.1384.
(2-((tert-butylthio)methyl)phenyl)(4-methoxyphenyl)
(0.26 g, 1.5 mmol) were added
portionwise at room
temperature. The reaction mixture was refluxed until starting
material was completely consumed (TLC analysis). The
reaction mixture was cooled gradually to room temperature and
filtered. The resulting filtrate was concentrated under reduced
pressure to give the crude product. The crude was purified by
silica gel column chromatography using EA/PE (1:9) as the
eluant to produce 16 (0.86 g, 37%) as a pale yellow solid: mp
124-125 °C; FTIR (νmax, cm-1): 1665, 1600, 1517, 1345, 1294,
methanol (10f). Prepared according to general procedure in
reference 21. Starting from
9 (1.0 g, 4.80 mmol), 10f (0.87 g,
87%) was isolated as a colorless oil: FTIR (νmax, cm-1): 3421,
1
2959, 2361, 1610, 1510, 1458, 1364, 1249, 1171, 1034; H
NMR (400 MHz, CDCl3): δ 7.34, (d, J = 5.6 Hz, 1H), 7.29-7.20
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1‐3 | 5

Organic & Biomolecular Chemistry
Page 6 of 8
View Article Online
ARTICLE
Journal Name
DOI: 10.1039/C4OB02466D
1269; 1H NMR (400 MHz, CDCl3): δ 8.32 (d,
J
= 8.9 Hz, 2H), The combined ethyl acetate layer was dried on Na2SO4 and
7.98 (d,
J = 8.4 Hz, 2H), 7.57-7.51 (m, 2H), 7.41-7.31 (m, 1H), filtered. The resulting filtrate was concentrated under reduced
7.33-7.31 (m, 1H), 4.73 (s, 2H); 13C NMR (100 MHz, CDCl3): pressure to give the crude product. The crude material was used
δ 195.7, 150.4, 142.3, 138.3, 136.9, 131.8, 131.5, 131.3, 129.8, for next step without further purification. To a solution of the
128.1, 123.7, 30.2. HRMS (ESI-TOF): C14H10BrNO3 [M+Na]+: sulfoxide (0.89 g, 2.56 mmol) in DCM (25 mL), sulfuryl
341.9742. Found [M+Na]+: 341.9740.
chloride (0.34 mL, 3.8 mmol, in 5 mL DCM) was added
(2-((tert-butylthio)methyl)phenyl)(4-nitrophenyl)methanone dropwise at 0 °C during 5 min. The reaction mixture was stirred
(17). To solution of (2(bromomethyl) phenyl)(4- at 0 °C for 45 min. After completion of reaction, 10 mL of
a
nitrophenyl)methanone 16 (1.3 g, 4.0 mmol) in dry DMF (25 water was added and the resulting mixture was extracted with
mL), sodium 2-methylpropane-2-thiolate (0.5 g, 4.6 mmol, DCM (2×15 mL). The combined DCM layer was dried on
solution in 5 mL dry DMF) was added dropwise in 5 min. The Na2SO4 and filtered. The resulting filtrate was concentrated on
reaction mixture was stirred at room temperature for 5 h. To the a rotary evaporator (bath temperature maintained at 0-5 °C)
reaction mixture 300 mL of water was added and extracted in under reduced pressure to give the crude oil. The crude was
ethyl acetate (3×25 mL). The combined organic layer was dried purified by silica gel flash column chromatography using
on Na2SO4 and filtered. The resulting filtrate was concentrated EA/PE (1:4) as the eluant (Note: the eluant was cooled to 5-10
under reduced pressure to give the crude product. The crude °C before chromatography) to produce 11j (0.51 g, 69%) as a
was purified by silica gel column chromatography using EA/PE white solid: mp 129-130 °C; FTIR (νmax, cm-1):1615, 1573,
1
(1:9) as the eluant to produce 17 (0.84 g, 63 %) as a yellow 1540, 1524, 1488, 1456, 1347; H NMR (400 MHz, CDCl3):
solid: mp 120-121 °C; FTIR (νmax, cm-1): 1663, 1600, 1518, major isomer, δ 8.31 (d,
J
= 8.6 Hz, 2H), 7.60 (d,
= 8.7 Hz, 2H), 7.47-7.38 (m, 1H), 7.32-7.25 (m, 2H), 6.70 (d,
= 8.7, 2H), 7.50-7.44 (m, 2H), 7.32-7.23 (m, 1H), 6.36 (s, 1H), 4.63 (d, = 15.5 Hz, 1H), 3.70 (d, J = 15.5
J
= 8.6 Hz,
1346, 1268; 1H NMR (400 MHz, CDCl3): δ 8.30 (d,
2H), 7.98 (d,
J
J = 7.7 Hz,
J
J
2H), 3.93 (s, 2H), 1.21 (s, 9H); 13C NMR (100 MHz, CDCl3): δ Hz, 1H); 13C NMR (100 MHz, CDCl3): for mixture of isomers
196.0, 150.2, 142.7, 138.7, 137.5, 131.3, 131.2, 129.2, 126.5, δ 148.3, 145.3, 144.1, 136.5, 134.5, 131.5, 130.2, 130.0, 129.4,
123.8, 123.5, 43.2, 30.5, 30.4. HRMS (ESI-TOF): C18H19NO3S 129.1, 128.6, 128.1, 126.6, 126.5, 126.2, 124.2, 124.0, 80.2,
[M+Na]+: 352.0983. Found [M+Na]+: 352.0980.
(2-((tert-butylthio)methyl)phenyl)(4-nitrophenyl)methanol
73.3, 57.7, 55.8; HRMS (ESI-TOF): C14H11NO4S [M+K]+:
328.0046. Found [M+K]+: 328.0043.
(10j). To a solution of (2-((tert-butylthio)methyl) phenyl)(4- 1-(4-nitrophenyl)-1,3-dihydrobenzo[c]thiophene 2,2-dioxide
nitrophenyl)methanone 17 (0.27 g, 0.8 mmol) in dry THF (25 (12j). Prepared according to general procedure C. Starting from
mL), sodium borohydride (0.03 g, 1.0 mmol) was added 1-(4-nitrophenyl)-1,4-dihydrobenzo[d][1,2]oxathiine 3-oxide
portionwise at room temperature. The reaction mixture was 11j (0.10 g, 0.345 mmol ) in ACN (5 mL, 5 h reflux), 12j
stirred at room temperature for 8 h. To the reaction mixture, 5 (0.085 g, 85%) was isolated as a white solid: mp 191-192 °C;
mL of water was added and extracted in ethyl acetate (2×15 FTIR (νmax, cm-1): 1519, 1333, 1323, 1180, 1147; 1H NMR
mL). The combined organic layer was dried on Na2SO4 and (400 MHz, CDCl3): δ 8.28 (d,
J
= 8.7 Hz, 2H), 7.47-7.40 (m,
= 7.3 Hz, 1H), 5.58 (s, 1H), 4.51 (d, = 15.6 Hz,
= 15.6 Hz, 1H), ; 13C NMR (100 MHz, CDCl3):
filtered. The resulting filtrate was concentrated under reduced 5H), 7.07 (d,
pressure to give the crude product. The crude was purified by 1H), 4.46 (d,
J
J
J
silica gel column chromatography using EA/PE (1:4) as the δ 148.6, 137.6, 134.7, 131.5, 131.0, 129.8, 129.4, 126.5, 126.2,
eluant to produce 10j (0.22 g, 81 %) as a yellow oil; FTIR 124.1, 71.0, 55.6; HRMS (ESI-TOF): C14H11NO4S [M+K]+
:
1
(νmax, cm-1): 3404, 2960, 1600, 1521, 1346, 1162; H NMR 328.0046. Found [M+K]+ : 328.0040.
(400 MHz, CDCl3): δ 8.21 (d,
Hz, 2H), 7.33 (dd, = 1.6, 7.4 Hz, 1H), 7.29-7.20 (m, 2H), 7.07 of 2-((tert-butylthio)methyl)benzoic acid
(dd, = 1.5, 7.4 Hz, 1H), 6.26 (d, = 3.0 Hz, 1H), 3.87 (d, in 5 mL methanol, few drops of conc. H2SO4 were added at 0
11.0 Hz, 1H), 3.79 (d, = 11.0 Hz, 1H), 3.45 (d, = 3.9 Hz, °C. The reaction mixture was refluxed for 5 h. The reaction
J = 8.9 Hz, 2H), 7.60 (d, J
= 8.6 Methyl 2-(tert-butylthiomethyl)benzoate (19).39 To a solution
J
7 (0.8 gm, 3.5 mmol)
J
J
J =
J
J
1H), 1.39 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 150.6, 147.1, mixture was cooled gradually to room temperature and
141.5, 135.3, 131.3, 129.2, 128.7, 128.2, 127.4, 123.5, 72.1, concentrated under reduced pressure on a rotory evaporator to
44.0, 31.0, 30.7. HRMS (ESI-TOF): C18H21NO3S [M+K]+: give a crude material. To this crude 5 mL of water was added
370.0879. Found [M+K]+: 370.0876.
and extracted in ethyl acetate (3×15 mL). The combined
1-(4-nitrophenyl)-1,4-dihydrobenzo[d][1,2]oxathiine 3-oxide organic layer was dried on Na2SO4 and filtered. The resulting
(11j). To a solution of (2-((tert-butylthio)methyl)phenyl)(4- filtrate was concentrated under reduced pressure to the give
nitrophenyl)methanol 10j (0.85 g, 2.5 mmol) in dry THF (25 crude product. The crude was purified by silica gel column
mL),
m-CPBA (0.95 eq. solution in 5 mL THF) was added chromatography using EA/PE (1:9) as the eluant to give 19
dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 (0.620 g, 73%) as a sticky oil : FTIR (νmax, cm-1): 3441, 2959,
h. The reaction mixture was gradually warmed to room 1723, 1434, 1364, 1266, 1163, 1116, 1076; 1H NMR (400
temperature and concentrated under reduced pressure on a MHz, CDCl3): δ 7.86 (d,
J = 7.4 Hz, 1H), 7.44.-7.42 (m, 2H),
rotory evaporator to give a white sticky mass. To this crude 7.30-7.25 (m, 1H), 4.18 (s, 2H), 3.91 (s, 3H), 1.35 (s, 9H). 13C
material satd. aq. NaHCO3 solution (15 mL) was added and NMR (100 MHz, CDCl3): δ 167.9, 140.3, 131.8, 131.3, 130.8,
resulting mixture was washed with ethyl acetate (3×25 mL). 129.9, 126.9, 52.2, 43.1, 31.3, 30.9. HRMS (ESI-TOF):
6 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 2012

Page 7 of 8
Journal Name
Organic & Biomolecular Chemistry
View ArticAle ROnTliInCeLE
DOI: 10.1039/C4OB02466D
Calculated C13H18O2S [M+Na]+: 261.0925. Found [M+Na]+: The
261.0927.
solution
of
1,1-dimethyl-1,4-dihydrobenzo[d][1,2]
oxathiine 3-oxide 21 (0.300 g, 1.52 mmol ) in 5 mL dry toluene
2-(2-(tert-butylthiomethyl)phenyl)propan-2-ol (20).40 To a was heated at 135 °C oil bath temperature for 24 h in sealed
solution of Methyl 2-(tert-butylthiomethyl)benzoate 19 (0.9 gm, tube. The reaction mixture was cooled gradually to room
3.78 mmol) in diethyl ether (10 mL), methyl magnesium temperature and concentrated under reduced pressure on rotory
bromide (10 mL, 1.0 M in butyl ether, 9.45 mmol) was added evaporator to give the crude product. The crude was purified by
dropwise at 0 °C. The reaction mixture was gradually warmed silica gel flash column chromatography using EA/PE (1:4) as
to room temperature and refluxed for 2 h. The reaction mixture the eluant to give 22 (0.165 g, 55%) as a brown solid: mp 108-
was cooled gradually to room temperature. The reaction 109 °C; FTIR (νmax, cm-1): 2925, 1463, 1304, 1209, 1189,
mixture was quenched with satd. aq. NH4Cl solution (5 mL). 1127, 1105 ; 1H NMR (400 MHz, CDCl3): δ 7.41-7.26 (m, 4H),
The aqueous phase was extracted with ethyl acetate (3 × 25 4.30 (s, 2H), 1.64 (s, 6H); 13C NMR (100 MHz, CDCl3): δ
mL). The combined organic layer was dried on Na2SO4 and 142.5, 129.1, 128.8, 128.4, 126.0, 123.5, 63.5, 52.8, 22.7;
concentrated under reduced pressure to get a crude oil. The HRMS (ESI-TOF): C10H12O2S [M+H]+: 197.0636. Found
crude was purified by silica gel column chromatography using [M+H]+ : 197.0645.
EA/PE (1:4) as the eluant to give 20 (0.47 g, 52%) as a sticky General procedure for photolysis. A 1 mM stock solution of
oil: FTIR (νmax, cm-1): 3447, 2970, 1723, 1488, 1458, 1364, compound was prepared in acetonitrile or ethanol. Using this
1
1163, 953; H NMR (400 MHz, CDCl3): δ 7.31-7.28 (m, 2H), stock solution, 250 mL of 100 µM solution was prepared in
7.20-7.17 (m, 2H), 4.17 (s, 2H), 1.66 (s, 6H), 1.41 (s, 9H). 13C ACN or ethanol /PB, pH 7.4 (% of ACN or ethanol varies from
NMR (100 MHz, CDCl3): δ 146.4, 134.5, 133.3, 127.2, 127.1, 30 to 40%). The above solution was irradiated at 37 °C using
126.6, 74.6, 43.4, 32.6, 32.4, 30.8. HRMS (ESI-TOF): 450 W broad-spectrum UV lamp (operating range of 200-400
Calculated C14H22OS [M+Na]+: 261.1289. Found [M+Na]+: nm), in an immersion assembly. (principal wavelengths: 365
261.1289.
nm, 313 nm and 253 nm). After intervals of 10 and 60 min, the
3-oxide lamp was switched off and after 30 min an aliquot of the
2-(2-((tert- reaction mixture was injected in an ion chromatograph
1,1-dimethyl-1,4-dihydrobenzo[d][1,2]oxathiine
(21).
To
a
solution
of
butylthio)methyl)phenyl)propan-2-ol 20 (0.84 g, 3.52 mmol) in equipped with conductivity detector. SO2 was quantified as
2- 41
dry THF (25 mL),
m .
-CPBA (0.95 eq. in 5 mL THF) was added SO32-/SO4
dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 Acknowledgements
h. The reaction mixture was gradually warmed to room The authors thank IISER Pune and the Department of Science
temperature and concentrated under reduced pressure on rotory and Technology (SR/FT/CS-89/2010) and the Department of
evaporator to give a white sticky mass. To this crude material, Biotechnology, India (BT/PR6798/MED/29/636/2012) for
satd. aq. NaHCO3 solution (15 mL) was added and resulting financial support. H.C. acknowledges an Innovative Young
mixture was washed with ethyl acetate (3×25 mL). The Biotechnologist
Award
(BT/05/IYBA/2011).
S.R.M.
combined organic layer was dried on Na2SO4 and filtered. The acknowledges a research fellowship from Council for Scientific
resulting filtrate was concentrated under reduced pressure to and Industrial Research (CSIR).
give the crude product. The crude was used for next step Notes and references
1.
2.
3.
S. E. Manahan, Environmental Chemistry 5th Ed.; Lewis
Publishers: Michigan, 1991.
without further purification. To a solution of the sulfoxide (0.89
g, 3.49 mmol) in dry DCM (25 mL), sulfuryl chloride (0.565
mL, 7.0 mmol, in 15 mL DCM) was added dropwise at 0 °C
during 5 min. The reaction mixture was stirred at 0 °C for 45
minutes. To the reaction mixture, 10 mL of water was added
and the resulting mixture was extracted with DCM (2×15 mL).
The combined DCM layer was dried on Na2SO4 and filtered.
The resulting filtrate was concentrated on a rotary evaporator
under reduced pressure to give crude oil. The crude was
purified by silica gel flash column chromatography using
EA/PE (1:4) as the eluant to produce 21 (0.475 g, 68 %) as a
white solid: mp 63-64 °C; FTIR (νmax, cm-1): 3440, 2978, 2360,
1493, 1449, 1382, 1363, 1238, 1184, 1104, 869; 1H NMR (400
K.-B. Min, J.-Y. Min, S.-I. Cho and D. Paek, Inhal. Toxicol.
,
2008, 20, 435-444.
J.-Y. Min, K.-B. Min, S.-I. Cho and D. Paek, Int. J. Cardiol.
2009, 133, 119-121.
,
4.
5.
R. Li, Z. Meng and J. Xie, Toxicol. Lett., 2007, 175, 71-81.
D. Liao, Y. Duan, E. A. Whitsel, Z.-j. Zheng, G. Heiss, V. M.
Chinchilli and H.-M. Lin, Am. J. Epidemiol., 2004, 159, 768-
777.
P. J. M. Koken, W. T. Piver, F. Ye, A. Elixhauser, L. M. Olsen
and C. J. Portier, Environ. Health Perspect., 2003, 111, 1312-
1317.
6.
7.
8.
9.
Z. Meng, Inhal. Toxicol., 2003, 15, 181-195.
X. Shi, J. Inorg. Biochem., 1994, 56, 155-165.
A. F. Gunnison, Food and Cosmetics Toxicology, 1981, 19
667-682.
X. L. Shi and Y. Mao, Biochem. Biophys. Res. Commun.
1994, 205, 141-147.
,
,
10.
11.
12.
MHz, CDCl3): δ 7.40-7.27 (m, 3H), 7.18 (d,
J = 7.3 Hz, 1H),
4.04 (d, = 14.6 Hz, 1H), 3.85 (d, = 14.6 Hz, 1H), 1.86 (s,
J
J
D. Wu and Z. Meng, Arch. Environ. Contam. Toxicol., 2003,
45, 423-428.
E. Rencüzoǧullari, H. B. İla, A. Kayraldiz and M. Topaktaş,
Mutat. Res., 2001, 490, 107-112.
C. S. Ough and E. A. Crowell, J. Food Sci., 1987, 52, 386-388.
L. A. Komarnisky, R. J. Christopherson and T. K. Basu,
Nutrition, 2003, 19, 54-61.
3H), 1.62 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 140.1, 131.5,
128.6, 127.8, 124.6, 122.2, 82.8, 54.6, 32.1, 31.5; HRMS (ESI-
TOF): Calculated C10H12O2S [M+H]+: 197.0636. Found
[M+H]+: 197.0636.
13.
14.
1,1-dimethyl-1,3-dihydrobenzo[c]thiophene 2,2-dioxide (22).
15.
B. J. Freedman, Br. J. Dis. Chest, 1980, 74, 128-134.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1‐3 | 7

Organic & Biomolecular Chemistry
Page 8 of 8
View Article Online
ARTICLE
Journal Name
DOI: 10.1039/C4OB02466D
16.
17.
M. H. Stipanuk, Annu. Rev. Nutr., 2004, 24, 539-577.
V. Nimet İzgüt-Uysal, V. Küçükatay, M. Bülbül, R. Tan, P.
Yargıçoğlu and A. Ağar, Food Chem. Toxicol., 2005, 43, 599-
605.
18.
19.
20.
21.
22.
H. Niknahad and P. J. O’Brien, Chem.−Biol. Interact., 2008,
174, 147-154.
S. R. Malwal, D. Sriram, P. Yogeeswari, V. B. Konkimalla and
H. Chakrapani, J. Med. Chem., 2012, 55, 553-557.
S. R. Malwal, D. Sriram, P. Yogeeswari and H. Chakrapani,
Bioorg. Med. Chem. Lett., 2012, 22, 3603-3606.
S. R. Malwal, M. Gudem, A. Hazra and H. Chakrapani, Org.
Lett., 2013, 15, 1116-1119.
P. Bisseret and N. Blanchard, Org. Biomol. Chem., 2013, 11
,
5393-5398.
23.
24.
B. Moses and Y. You, Med. Chem., 2013,
S. K. Choi, M. Verma, J. Silpe, R. E. Moody, K. Tang, J. J.
3, 192-198.
Hanson and J. R. Baker Jr, Bioorg. Med. Chem., 2012, 20
,
1281-1290.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
C. Alvarez-Lorenzo, L. Bromberg and A. Concheiro,
Photochem. Photobiol., 2009, 85, 848-860.
D. A. Favor, D. S. Johnson, J. J. Powers, T. Li and R.
Madabattula, Tetrahedron Letters, 2007, 48, 3039-3041.
M. D. Hoey and D. C. Dittmer, J. Org. Chem., 1991, 56, 1947-
1948.
W. F. Jarvis, M. D. Hoey, A. L. Finocchio and D. C. Dittmer,
J. Org. Chem., 1988, 53, 5750-5756.
D. C. Gowda, B. Mahesh and S. Gowda, Indian J. Chem. Sec B
2001, 40 B, 75-77.
T. Durst, M. Lancaster and D. J. H. Smith, J. Chem. Soc.,
Perkin Trans. 1, 1981, 1846-1848.
S. R. Malwal, D. Sriram, P. Yogeeswari, V. B. Konkimalla and
H. Chakrapani, J. Med. Chem., 2011, 55, 553-557.
M. P. Cava, R. H. Schlessinger and J. P. Van Meter, J. Am.
Chem. Soc., 1964, 86, 3173-3174.
N. K. Singh, P. L. A. Popelier and P. J. O’Malley, Chem. Phys.
Lett., 2006, 426, 219-221.
K. Tokumura, H. Nosaka and T. Ozaki, Chem. Phys. Lett.
1990, 169, 321-325.
,
M. B. Smith and J. March, John Wiley
Publication, New Jersey, 2007.
& Sons, Inc.
T. Durst and L. Tétreault-Ryan, Tetrahedron Lett., 1978, 19
,
2353-2354.
G. A. Tashbaev, Russ. Chem. Bull., Int. Ed., 2005, 54, 437-
440.
C. Qin, H. Wu, J. Cheng, X. a. Chen, M. Liu, W. Zhang, W. Su
and J. Ding, J.Org. Chem., 2007, 72, 4102-4107.
V. Divya, R. O. Freire and M. L. P. Reddy, Dalton Trans.
2011, 40, 3257-3268.
,
F. Galaud and W. D. Lubell, Biopolymers, 2005, 80, 665-674.
Previous reports show the formation of cyclobutene as a
byproduct (see ref 32 and 42). In aqueous buffer, however, we
were unable to characterize the organic byproduct.
42.
Y. Odaira, K. Yamaji and S. Tsutsumi, Bull. Chem. Soc. Jpn.
1964, 37, 1410-1412.
,
8 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 2012