NBS-mediated synthesis of β-keto sulfones from benzyl alcohols and sodium arenesulfinates

Article abstract of DOI:10.1016/j.tet.2019.05.010

An efficient synthetic route towards the synthesis of β-keto sulfones has been developed from secondary benzyl alcohols using N-bromosuccinimide (NBS). The present protocol utilizes NBS as oxidant as well as brominating agent, readily accessible benzyl alcohols and sodium arenesulfinates as the sulfonylating reagent under mild conditions. The control experiments revealed that the reaction proceeds via oxidation of alcohol to ketone, α-bromination of ketone and nucleophilic substitution by sodium arenesulfinate. Furthermore, the efficiency of the methodology was tested with a gram scale reaction and also shown the synthetic utility.

Full text of DOI:10.1016/j.tet.2019.05.010

Accepted Manuscript
NBS-mediated synthesis of β-keto sulfones from benzyl alcohols and sodium
arenesulfinates
Madithedu Muneeswara, Nallappan Sundaravelu, Govindasamy Sekar
PII:
S0040-4020(19)30528-9
https://doi.org/10.1016/j.tet.2019.05.010
TET 30331
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 27 December 2018
Revised Date: 30 April 2019
Accepted Date: 6 May 2019
Please cite this article as: Muneeswara M, Sundaravelu N, Sekar G, NBS-mediated synthesis of
β-keto sulfones from benzyl alcohols and sodium arenesulfinates, Tetrahedron (2019), doi: https://
doi.org/10.1016/j.tet.2019.05.010.
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NBS-Mediated Synthesis of β-Keto Sulfones
from Benzyl Alcohols and Sodium
Arenesulfinates
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Madithedu Muneeswara, Nallappan Sundaravelu and Govindasamy Sekar *
Department of Chemistry Indian Institution of Technology Madras, Chennai-600036, Tamilnadu, India.

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Tetrahedron
journal homepage: www.elsevier.com
NBS-mediated synthesis of β-keto sulfones from benzyl alcohols and sodium
arenesulfinates
Madithedu Muneeswara, Nallappan Sundaravelu and Govindasamy Sekar
Department of Chemistry, Indian Institute of Technology Madras, Chennai, Tamil Nadu, 600 036, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient synthetic route towards the synthesis of β-keto sulfones has been developed from
secondary benzyl alcohols using N-bromosuccinimide (NBS). The present protocol utilizes NBS
as oxidant as well as brominating agent, readily accessible benzyl alcohols and sodium
arenesulfinates as the sulfonylating reagent under mild conditions. The control experiments
revealed that the reaction proceeds via oxidation of alcohol to ketone, α-bromination of ketone
and nucleophilic substitution by sodium arenesulfinate. Furthermore, the efficiency of the
methodology was tested with a gram scale reaction and also shown the synthetic utility.
Available online
Keywords:
NBS
β-keto sulfones
Sulfonylation
Oxidation
2009 Elsevier Ltd. All rights reserved
.
Benzyl alcohols
1. Introduction
Compounds containing sulfonyl (-SO2-) functional group have
wide range of applications in medicines, material sciences and
modern organic synthesis as versatile synthetic intermediates.1,2
For instance, β-keto sulfones exhibit biological activities like
antibacterial, antifungal and were found as inhibitors of 11β-
hydroxy steroid dehydrogenase type 1.4, 3c β-Keto sulfones act as
key intermediates in Michael5 and Knoevenagel reactions.6 They
are versatile precursors in synthesis of alkenes,7 alkynes,8
allenes,9
aziridines,10
chalcones,11
2,3-dihydrofurans,12
5b
epoxides,13 functionalized 4H-pyrans,14,
α-halo methyl
sulfones,15 ketones,16 triazoles17 and vinyl sulfones.18
Additionally, optically active β-hydoxy sulfones have been
synthesized from β-keto sulfones.19
Due to their importance, considerable efforts have been made
to synthesize β-keto sulfones. In general, β-keto sulfones are
synthesized by alkylation of sodium sulfinate salts with α-halo
ketones (Scheme 1a),20 acylation of alkyl sulfones with
carboxylic acid derivatives like acid chlorides, esters or N-acyl
benzotriazoles (Scheme 1b),21 and oxidation of β-keto sulfides or
β-hydroxy sulfones with stoichiometric amount of oxidizing
agents (Scheme 1c).22
Recently, radical sulfonylation has gained attention as a useful
strategy for the synthesis of β-keto sulfones. General strategies to
synthesize β-keto sulfones involve the reactions of various
sulfonylation reagents with alkenes23 or activated alkenes24 and
Scheme 1. Previous and present approaches for the synthesis
of β-keto sulfones
alkynes (Scheme 1d).25 Ketones also have been used for the
———
Corresponding author. e-mail: gsekar@iitm.ac.in

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synthesis of β-keto sulfones (Scheme 1e). For instance, in 2006,
Varma and co-workers reported a hypervalent iodine catalyzed
synthesis of β-keto sulfones from ketones via alkylation of
sodium sulfinates with in situ generated α-tosyloxy ketones
(Scheme 1e).26 In 2014, Sreedhar et al. developed a method to
generate β-keto sulfones from ketones and iodosulfones in the
presence of a base (Scheme 1a).27 In 2015, Li et al. described a
Cu-catalyzed protocol for the construction of β-keto sulfones
from ketones and sodium sulfinates via radical pathway (Scheme
1e).28 Recently, Tang et al. reported a HBr/DMSO catalyzed
synthesis of β-keto sulfones from ketones and sodium
sulfinates.28b
5,5-dimethylhydantoin (DBDMH) 2d were tested. NCS 2b gave
trace amount of the product (entry 14), NIS 2c did not afford the
product (entry 15) and DBDMH 2d provided the product in 71%
yield (entry 16).
From the optimization studies, the use of NBS (2.0 equiv.) as
oxidant as well as brominating agent and p-toluenesulfinate (1.1
equiv.) in THF-DMSO solvent system at room temperature was
found to be the optimal reaction condition to the protocol (entry
5).
Table 1. Optimization of reaction conditions for β-keto
sulfones synthesisa
Despite significant efforts made in this area, many of them
generally require excess amount of sulfonylating reagents,
external oxidants, also involved the use of ketones which
generally need to be synthesized from two steps and expensive
precursors like styrenes, alkynes, and harsh reaction conditions.
Ketones can be prepared by oxidation of easily accessible
secondary alcohols in one step as demonstrated in the manuscript
as well. Therefore, the development of alternative and new
efficient methods to synthesize the β-keto sulfones with
economic precursors and mild reaction conditions is highly
desirable. Our group is interested in developing halogen reagent
mediated transformations and also functionalizing easily
accessible secondary benzyl alcohols.28c-28e Herein we report
NBS-mediated synthesis of β-keto sulfones from easily
accessible secondary benzyl alcohols and green sulfonylating
reagent such as sodium arenesulfinate salts (Scheme 1f).
Entry
N-Haloimide
Solvent
S1/S2
Time
Yieldb
(%)
(2.0 equiv.)
min/h
1
2
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NCS
NIS
MeCN:DMSO
DMF:DMSO
acetone:DMSO
H2O:DMSO
THF:DMSO
dioxane:DMSO
THF:DMF
5 h
5 h
40
46
3
6 h
21
4
6 h
0
2. Results and discussion
5
50 min
3 h
94
6
35
Optimization of the reaction conditions was carried out with 1-
phenylpropanol 1a as model substrate and NBS 2a as the oxidant
as well as brominating agent. Initial reaction was carried out in
acetonitrile solvent and a reddish brown color reaction mixture
faded out upon stirring for 10 min at room were provided
temperature to obtain the intermediate α-bromo ketone 3a, to
which 1.1 equiv. of p-toluenesulfinate 4a was added. To our
disappointment, the reaction gave trace amount of the product,
β-keto sulfone 5a. Then, other solvents like DMF, DMSO, THF
and acetone were also tested. They gave trace amount of the
product.
7
3 h
72
8
THF:MeCN
THF:acetone
THF:H2O
3 h
60
9
6 h
26
10
11
12
13
14
15
16
6 h
trace
trace
trace
trace
trace
nr
THF:PEG
6 h
DMSO:DMSO
DMSO:THF
THF:DMSO
THF:DMSO
THF:DMSO
4 h
1 h
Next, we decided to add a co-solvent before the
addition of the p-toluenesulfinate to enhance it solubility. DMSO
was added as co-solvent to the reaction mixture of 1a and NBS in
MeCN after 10 min and followed by the addition of p-
toluenesulfinate, and stirred at room temperature for 5 h. To our
delight, the β-keto sulfone 5a resulted in 40% yield (Table 1,
entry 1). When DMF-DMSO co-solvent was used, 5a obtained in
46% yield (entry 2). Whereas in acetone-DMSO, the product was
obtained in 21% yield (entry 3). In the case of H2O-DMSO,
product did not form (entry 4). Interestingly, when THF-DMSO
solvent system was tested, the reaction completed in 50 min to
give β-keto sulfone 5a in 94% yield (entry 5). Instead of THF-
DMSO, dioxane-DMSO was examined and the product obtained
in 35% only after 3 h (entry 6). The use of THF-DMF was found
be inferior to THF-DMSO system as it resulted 5a in 72% yield
(entry 7). Whereas, in the THF-MeCN and THF-acetone the
product was obtained in 60% and 26% yields respectively
(entries 8 and 9). Other solvent systems such as THF-H2O, THF-
PEG, DMSO and DMSO-THF provided trace amount of the
product (entries 10-13).
6 h
6 h
DBDMH
1 h
71
aReaction conditions: 0.7 mmol of 1a, 2.0 equiv. of 2 stirred for 10 min in (1
mL) of solvent 1 at rt then solvent 2 (1 mL) and followed by this p-
TolSO2Na 1.1 equiv. were added. bIsolated yield.
With the optimized reaction conditions in hand, the scope of
the methodology was investigated with substituted secondary
benzyl alcohols and the results are summarized in Table 2.
Substrate with moderate electron-rich group like methyl at para
position, 4-methyl-1-phenylpropanol 1b afforded the product 5b
in 92% yield (entry 2). However, the sterically hindered ortho-
isomer 1c gave the product in 36% yield (entry 3). Halo
substituted secondary benzyl alcohols afforded the products in
moderate to good yields. 4-Chloro-1-phenylpropanol 1d yielded
81% of 5d (entry 4) and 3-fluoro-1-phenylpropanol afforded 56%
of 5f (entry 6). Due to steric hindrance, ortho-bromo substituted
secondary benzyl alcohol 2-bromo-1-phenylpropanol 1e failed to
produce the α-bromo ketone 3 and hence, the product was not
Next, the reactivity of other N-haloimides, such as N-
chlorosuccinimide 2b, N-iodosuccinimide 2c and 1,3-dibromo-

3
isolated (entry 5). Substrate containing electron withdrawing
group like CF3 at meta-position, 3-trifluoromethyl-1-
phenylpropanol 1g proceeded with moderate yield 45% of the
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Table 2. Substrate scope for the synthesis of β-keto sulfonesa
aReaction conditions: 0.7 mmol of 1a, 2.0 equiv. of 2, stirred for 10 min in 1
mL of THF at rt follwed by DMSO 1 mL and ArSO2Na 1.1 equiv. were
added. bIsolated yield, cFormation of 1 to 3 were allowed for 15 min.
dFormation of 1 to 3 were allowed for 20 min. eNBS was added in 2 portions
with 5 min time interval. fBefore addition of PhSO2Na reaction miture was
cooled on ice bath.
product 5g (entry 7). Similarly, substrate with electron-
withdrawing nitro group 4-nitrro-1-phenylpropanol 1h did not
afford the corresponding product 5h (entry 8). Sterically hindered
1,2- diphenylethan-1-ol 1i also afforded the product 5i in
moderate yield 61% (entry 9). When the reaction was performed
with 1-naphthylpropanol 1j, it did not afford the product (entry
10). When 1-phenylpentanol 1k was used as the substrate the
product 5k was isolated in 85% yield (entry 11).
Next, the effect of other secondary benzylic alcohols was
studied. The reaction with 1-phenylethanol 1l provided 81% of
the product 5l (entry 12). In the case of 4-methyl-1-phenylethanol
1m, 84% of the corresponding product 5m was isolated (entry
13). Similarly, halo substituted secondary benzylic alcohols like
4-chloro-1-phenylethanol 1n and 4-bromo-1-phenylethanol 1o

4
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were afforded the β-keto sulfones 5n and 5o in 79% and 70%
tosylprop-2-en-1-one
9
in 85% yield via Knoevenagel
yields, respectively (entries 14 and 15).
condensation (Scheme 3d).
The reaction of secondary benzylic alcohols with sodium
benzenesulfinate provided comparable results to those of p-
toluenesulfinate. 1-Phenylpropanol 1a when reacted with sodium
benzenesulfinate gave 75% of corresponding product 5p (entry
16). 4-Methyl-1-phenylpropanol 1b afforded the product 5q in
71% yield (entry 17). Halo substituted secondary benzylic
alcohols such as 4-chloro-1-phenylpropanol 1d and 3-f1uoro-1-
phenylpropanol 1f were rendered the β-keto sulfones 5r and 5s in
65% and 51% yields, respectively (entries 18 and 19). In the case
of 1-phenylpentanol 1k as the substrate the product 5t was
obtained in 79% yield (entry 20). 1-Arylethanols also gave good
yields when reaction was performed with sodium
benzenesulfinate. 4-Methyl-1-phenylethanol 1m and 4-chloro-1-
phenylethanol 1n provided the corresponding products 5u 79%
and 5v 62% in yields, respectively (entries 21 and 22). Next, the
scope of reaction was studied with different sodium sulfinates by
reacting with 1-phenylpropanol 1a. Substituted sodium
To gain insight into the reaction pathway, some control
experiments were carried out (Scheme 4). The reaction of 1a with
NBS 2a gave the α-bromo ketone 3a in 90% yield (Scheme 4a).
Further to understand the formation of α-bromo ketone 3a from
1a, a reaction was performed with molecular bromine (Scheme
4b). No product formation confirms that NBS oxidizes the
alcohol 1a to ketone not molecular bromine. Next, a reaction of
propiophenone 10 with NBS was carried out and the formation of
3a was not observed (Scheme 4c). When 10 was reacted with
molecular bromine, the α-bromo ketone 3a was resulted in 79%
yield (Scheme 4d). This results reveals that bromine generated in
situ could react with 10 to give α-bromo ketone 3a. Next, the
reaction of α-bromo propiophenone 3a and p-toluenesulfinate 4a
by nucleophilic substitution afforded the β-keto sulfone 5a in
97% yield (Scheme 4e).
t
benzenesulfinates bearing substituents like OMe, Bu, Cl and Br
at para-position gave desired products in very good yields (5w-
5z.
Scheme 2. Gram-scale reaction of 1a
To test the efficiency of the transformation, a gram-scale
reaction was performed with 7.5 mmol of 1-phenylpropanol 1a
and 15 mmol of NBS 2a in 10 mL of THF, which resulted 3a in
10 min To which 10 mL of DMSO solvent was added, followed
by the addition of 8.25 mmol of p-toluenesulfinate provided the
product 5a in 92% yield (1.99 g). The shorter reaction time and
good yield of product show that the method is practically viable
(Scheme 2).
Scheme 4. Control experiments
Scheme 3. Synthetic utility of β-keto sulfones
Further, β-keto sulfone 5a was reduced to β-hydroxy sulfone 6
in 90% yield using NaBH4 (Scheme 3a). Next, 5l was also
derivatized to corresponding α-bromo β-keto sulfone 7 in 62%
yield using KBr/H2O2 (Scheme 3b). Further, β-keto sulfone 5l
was transformed into corresponding oxime 8 in 83% yield
(Scheme 3c). Then, 5l was converted into (E)-1,3-diphenyl-2-
Scheme 5. Plausible reaction pathway

5
Based on the control experiments, a plausible reaction
pathway is proposed (Scheme 5). Initially, NBS 2a reacts with
alcohol 1a to form hypobromite intermediate 12. Followed by
this step, the removal of HBr from 12 gives propiophenone 10.
Meanwhile, molecular bromine forms from the reaction of NBS
and HBr.29 Next, in situ generated molecular bromine reacts
with 10 to give α-bromo ketone 3a. Finally, α-bromo ketone 3a
by nucleophilic displacement with p-toluenesulfinate furnishes
the product β-keto sulfone 5a.
7.33 (m, 3H), 7.45-7.50 (m, 1H), 7.63-7.65 (m, 3H), 7.79 (d,
ACCEPTED MANUSCRIPT
J=9.5 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 13.1, 21.6, 65.3,
115.8 (d, 22.6 Hz), 121.0 (d, 21.4 Hz), 125.1 (d, 3.1 Hz), 129.6,
129.8, 130.4 (d, 7.5 Hz), 132.8, 138.3 (d, 6.4 Hz), 145.5, 162.7
(d, 247.1 Hz), 191.5; FTIR (KBr): 3074, 2941, 1679, 1580, 1493,
1444, 1313, 1146, 848, 756, 665 cm-1; HRMS (m/z): [M+Na]+
calcd. for C16H15FSO3Na: 329.0623; found: 329.0620.
4.4. 1-(3-Trifluoromethyl)phenyl-2-tosylpropan-1-one 5g
45% yield (112 mg), white solid, mp = 97-99 °C; Rf = 0.5 (in
20% ethyl acetate: hexanes); 1H NMR (500 MHz, CDCl3): δ 1.57
(d, J = 7.0 Hz, 3H), 2.42 (s, 3H), 5.14 (q, J = 7.0 Hz, 1H), 7.30
(d, J = 8.0 Hz, 2H), 7.62-7.65 (m, 3H), 7.84 (d, J = 8.0 Hz, 1H),
8.15 (s, 1H), 8.19 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz,
CDCl3): δ 12.8, 21.6, 65.2, 123.5 (q, 271 Hz), 125.8 (q, 3.6 Hz),
129.6, 129.7, 130.5 (q, 3.3 Hz), 131.5 (q, 33 Hz), 132.4, 132.9,
136.8, 145.7, 191.5; FTIR (KBr): 3071, 2952, 1686, 1486, 1447,
1328, 1131, 816, 763 cm-1; HRMS (m/z): [M+H]+ calcd. for
C17H16F3SO3: 357.0772; found: 357.0771.
3. Conclusions
A mild, efficient, metal-free and external oxidant free method
was developed for the synthesis of β-keto sulfones from easily
accessible secondary benzyl alcohols as precursors and green
sodium arenesulfinates as the sulfonylating reagents using NBS
as oxidant as well as brominating agent at room temperature.
Various substituted secondary benzyl alcohols were screened and
they resulted in the corresponding β-keto sulfones in good to
excellent yields. The control experiments disclosed that the
reaction proceeded via oxidation of alcohol to ketone, α-
bromination of ketone and followed by nucleophilic
displacement by sodium arenesulfinate. Practicality of the
protocol was shown by a gram-scale reaction with a very good
yield of product in a short reaction time. Further synthetic utility
of the product was also demonstrated.
Acknowledgments
G. S. thanks IIT Madras for the IRDA project (CHY/17-
18/686 847/RFIR/GSEK). M. M. thanks the University Grants
Commission (UGC), New Delhi for the Senior Research
Fellowship and N. S. thanks the Council of Scientific and
Industrial Research (CSIR), New Delhi for the Senior Research
Fellowship.
4. Experimental section
4.1 General procedure for the synthesis of β-keto sulfones 5
References
An oven dried reaction tube containing secondary
benzyl alcohol 1 (0.7 mmol) was charged with NBS 2a (2.0
equiv.) under open atmosphere and allowed to stir for a few min.
at room temperature. 1 mL of THF was added after the
generation of brown color gas (bromine), which resulted in a
reddish brown color mixture, then reaction tube was closed with
glass stopper. The formation of α-bromo ketone 3 was monitored
by TLC and the fadeout of reddish brown color was observed in
10-15 min. Then, DMSO was added to the reaction mixture and
followed by the addition of 1.1 equiv. p-toluenesulfinate. After
the reaction was allowed to stir for 50 min-1.5 h at room
temperature (see the time given in Table 2 for the respective
examples). After complete consumption of reactants (progress of
the reaction was monitored by TLC), the reaction mixture was
washed with 10 mL of sat. NaHCO3 solution and extracted using
ethyl acetate (3 x 20 mL). The combined organic layer was dried
over anhydrous Na2SO4 and concentrated under reduced pressure.
The crude residue was purified by column chromatography on
silica gel (hexanes:ethyl acetate = 8:2) to give pure β-keto
sulfone 5.
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4.2. 1-(2-Methyl)phenyl-2-tosylpropan-1-one 5c
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20% ethyl acetate: hexanes); 1H NMR (500 MHz, CDCl3): δ 1.59
(d, J = 7.0 Hz, 3H), 2.46 (s, 3H), 2.47 (s, 3H), 5.04 (q, J = 7.0
Hz, 1H), 7.28-7.30 (m, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.42 (t, J
= 7.0 Hz, 1H), 7.70-7.73 (m, 3H); 13C NMR (125 MHz, CDCl3):
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133.7, 137.0, 139.3, 145.2, 195.4; FTIR (KBr): 3057, 2980,
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(d, J=8.5 Hz, 3H), 2.44 (s, 3H), 5.08 (q, J=8.5 Hz, 1H), 7.29-

6
ACCEPTED MANUSCRIPT
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