A simple method for the synthesis of sulfonic esters

Article abstract of DOI:10.1080/00397911.2020.1794657

An efficient and simple approach for the direct synthesis of aryl and heteroaryl sulfonic esters was developed using DMS and DES as alkoxysulfonylation reagents. The reaction is operationally simple and scalable. This protocol does not require solvent, expensive catalysts, base, ligand additives or other reagents. A wide range of sulfonic esters were synthesized in moderate to good chemical yields. This method has the advantage of low cost, facile and tolerated a wide range of substrates.

Full text of DOI:10.1080/00397911.2020.1794657

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
A simple method for the synthesis of sulfonic
esters
Bharath Kumar Goud Bhatthula , Janardhan Reddy Kanchani , Veera Reddy
Arava & Subha Marata Chenna Subbarao
To cite this article: Bharath Kumar Goud Bhatthula , Janardhan Reddy Kanchani , Veera Reddy
Arava & Subha Marata Chenna Subbarao (2020): A simple method for the synthesis of sulfonic
esters, Synthetic Communications, DOI: 10.1080/00397911.2020.1794657
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https://doi.org/10.1080/00397911.2020.1794657
A simple method for the synthesis of sulfonic esters
Bharath Kumar Goud Bhatthulaa, Janardhan Reddy Kanchania,b, Veera Reddy
Aravaa, and Subha Marata Chenna Subbaraob
b
aResearch and Development Center, Suven Life Sciences Limited, Hyderabad, India; Department of
Chemistry, Sri Krishnadevaraya University, Anantapur, India
ABSTRACT
ARTICLE HISTORY
Received 25 April 2020
An efficient and simple approach for the direct synthesis of aryl and
heteroaryl sulfonic esters was developed using DMS and DES as
alkoxysulfonylation reagents. The reaction is operationally simple
and scalable. This protocol does not require solvent, expensive cata-
lysts, base, ligand additives or other reagents. A wide range of sul-
fonic esters were synthesized in moderate to good chemical yields.
This method has the advantage of low cost, facile and tolerated a
wide range of substrates.
KEYWORDS
Dimethyl sulfate; diethyl
sulfate; sulfonic esters;
solvent-free synthesis;
catalyst-free synthesis
GRAPHICAL ABSTRACT
OMe
O
S
SO3Me
Solvent -free
MeO
OMe
MeO
O
2
1a
3a
Introduction
Aromatic sulfonic esters are valuable intermediates in organic synthesis, and various sul-
fonic esters have important pharmacological properties.[1–5] Sulfonic ester is a common
fragment in many pharmaceuticals, materials, dyes, pesticides and other bioactive com-
pounds.[6–12] Sulfonates are also one of the most important classes in surfactant indus-
try as detergents and surface active agents.[13] In addition, sulfonic esters are also play a
unique role in coupling reactions.[14,15]
Studies indicate that sulfonic esters exhibit a wide range of bioactivities including
antitumor, antimalarial, antiproliferative and MAO inhibitory activities (Fig. 1).[12a,16–21]
Generally, the sulfonic esters are accessible by several steps through tedious proce-
dures.[22] However; these processes suffer from some limitations with respect to func-
tional group tolerance, stability and harsh reaction conditions. Traditionally sulfonic
esters are synthesized by the reaction of the appropriate alcohol or phenol with sulfonyl
chlorides in the presence of bases[21–25] (Scheme 1a), which required the preparation of
highly sensitive and unstable sulfonyl chlorides.
CONTACT Bharath Kumar Goud Bhatthula
goudbk@yahoo.com
Research and Development Center, Suven Life
Sciences Limited, Hyderabad, India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
B. K. G. BHATTHULA ET AL.
S
O
NHMe
O
N
H
O
O
O
N
S
O
O
S
O
O
N
Cl
S
O
O
O
S
HO
O
O
N
O
H
Coumarin Congeners (MAO-A inhibitor)
Sulfonates (Antimicrotubule agents)
Bacterial thymidylate synthase inhibitor
(N,O-didansyl-L-tyrosine (DDT))
O
O
S
O
N
H
N
N
N
OH
N
N
O
S
O
O
O
N
S
O
O
KN62 (P2X7 receptor antagonist)
Carbazoles Furophores (phospho-STAT3 inhibitor)
Figure 1. Bioactive compounds containing sulfonic esters.
To overcome these issues, various synthetic strategies have been developed, which
includes the reaction of aryl diazonium salts with alcohols[26] (Scheme 1b), sulfonic
acids with trimethyl and triethylorthoformates[27] (Scheme 1c), sulfonation using sulfur
trioxide amine complexes,[28] phenols with thiols using H2O2–POCl3 system[29] (Scheme
1d), aromatic compounds with copper sulfate as the sulfonation reagent,[30] sulfonyl flu-
orides with phenols,[31] thiophenols with alcohols using 9-mesityl-10-methyl acridinium
ion (AcrþꢀMes) as a photocatalyst[32] (Scheme 1e), sulfonic acids using polymer-bound
triazenes,[33] sodium sulfinates with phenol[34] (Scheme 1f), phenols with sulfonyl chlor-
ides using cupric oxide as catalyst[35] and other routes have been also reported.[36–38]
However, these protocols have some limitations, such as long reaction times, harsh
reaction conditions, use of ligand additives, bases, expensive catalysts or reagents, num-
ber of side reactions, or multistep synthesis. Therefore, it is still need to develop a
straightforward and general protocol.
Though the dimethyl and diethyl sulfates are mainly used as alkylating agents in
organic synthesis and these are preferred by the industry because of its low cost and
high reactivity, we found that these sulfates are also useful to generate aromatic or het-
erocyclic aromatic sulfonic esters in one step (Tables 2–10).
Fortunately, not much literature has reported describing the utilization of alkylating
reagents such as DMS, DES or other sulfates as alkoxysulfonylation reagents. Despite
the importance of sulfonic esters, there currently exists no procedure for achieving the
transformation of aromatic or heterocyclic aromatic compounds directly to a sulfonic
ester in one synthetic step.
Thus, direct alkoxysulfonylation using the DMS or DES will be remarkably different
from traditional or recently developed methods, which do not involve solvent, catalyst,
base, ligand additives or other expensive reagents. Herein, we report alkoxysulfonylation
process employing DMS and DES as the sulfonation reagents to afford various arene
and heteroarene sulfonic esters in moderate to good yields (Tables 2–10). The signifi-
cance of the given chemistry is the direct one-step transformation of low-cost DMS or
DES to sulfonic esters.

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3
Previous works:
a) Traditional approaches
O
S
O
Traditional
approach
1
OH
O
O
R
O
Cl
2
2
S
1
R
R
R
b) Copper catalyzed synthesis of sulfonic esters from alcohols and DABSO
CuBr
O
O
2
Ar-N BF
DABCO.(SO )
2 2
R-OH
2
4
S
R
rt, under air
c) Esterification of sulfonic acid with trimethyl and triethyl orthoformates
Ar
O
O
O
O
O
2
CH(OR )
S
3
1
S
1
2
R
OH
R
OR
2
R = CH , C H
3
2
5
d) Phenols with thiols using H O - POCl system
2
2
3
O
O
H O -POCl
3
1
2
2
S
Ar
R
SH
Ar OH
1
R
O
e) Thiophenols to sulfonic esters under photopromoted oxidative reaction conditions
O
S
O
2
SH
R
+
-
O
1
2
5 mol% Acr -Mes ClO4
1
R
HO R
R
f) Iodine-induced synthesis of sulfonate esters via cross-coupling reactions of sodium
sulfinates with phenols
OH
1
R
O
O
R S O
O
I
2
1
R S ONa
R
K CO /CH OH
2
3
3
g) Present work:
O
2
O
S
R
O
O
1
2
2
1
R
R O S OR
O
R = alkyl
R
2
Direct one-step synthesis of sulfonic esters from aromatic and heterocyclic aromatic
compounds
Scheme 1. Synthesis of sulfonic esters
Results and discussion
Initial stages of our work, we selected anisole and dimethyl sulfate as model substrates
for the alkoxysulfonylation. After a series of screening studies on the reaction conditions
with DMS as sulfonation reagent (for details, see Table 1), we found that the use of
3 mol of DMS with anisole (1.0 mol) delivered the maximum yield (62%) of correspond-
ing ester 3a (see Table 1, entry 3). The yield was lower when the amount of DMS was
reduced to 1.0 equiv. (Table 1, entry 1). A similar result was obtained when 2.0 equiv.
of DMS was utilized (Table 1, entry 2), increasing the amount of DMS to 4 or 6 equiv.
did not show any obvious improvement on the chemical yield (Table 1, entries 4
and 5).
Generally, temperature is an important factor for various reactions. We then studied
the temperature effect on the reaction and found that, the temperature have significant

4
B. K. G. BHATTHULA ET AL.
Table 1. Optimization of the reaction conditions for the formation of sulfonic ester 3aa.
OMe
O
S
SO3Me
Solvent -free
MeO
OMe
MeO
O
2
1a
3a
DMS
(equiv)
Temp.
(0 ꢁC)
Reaction
time (h)
Yield
(%)b
Entry
1
2
3
4
5
6
7
8
9
1.0
2.0
3.0
4.0
6.0
3.0
3.0
3.0
3.0
95
95
95
95
95
rt
50
150
180
4
4
4
4
4
20
15
4
30
48
62
62
63
0
0
37
7
4
aReaction conditions: anisole (10 mmol), under N2 atmosphere.
bIsolated yield
effect on the reaction (Table 1, entries 6–9). Initially, the reaction of anisole with DMS
was examined at room temperature and 50 ꢁC, no desired product was observed
(Table 1, entries 6 and 7). To our delight, the sulfonic ester was isolated in 62% yield
when the reaction temperature was increased to 95 ꢁC (Table 1, entry 3). We further
explored the reaction at higher temperatures. It was found that no better yields were
obtained at elevated temperatures (Table 1, entries 8 and 9), and 95–100 ꢁC was demon-
strated as the best choice. The results are presented in Table 1.
With the optimized reaction conditions in hand, to demonstrate the generality of this
method, we then started to explore the substrate scope of this reaction and the results
are shown in Tables 2–10. Substrate generality studies showed that this process provided
a facile access toward diversely substituted sulfonic esters with good efficiency.
According to results, a series of functional groups on the aromatic ring, including
alkyl, alkoxy, aryl, aryloxy, amine, ester, halide and hydroxy functional groups all are
well tolerated in this transformation. A variety of sulfonic esters could be produced
under the reaction conditions (Tables 2–10). Halogenated aromatic moieties survived
the reaction conditions well, allowing for subsequent structural elaboration of the sul-
fonic esters.
To evaluate the scope of the sulfonating groups, two reagents DMS and DES were
tested with anisole under the standard conditions. As shown in Table 2 (3a and 3b),
both of the reagents participating in the coupling and gave the corresponding sulfonic
esters in good yields.
It was found that the reaction was efficient with electron-donating groups such as
methyl, ethyl, isopropyl, tert-butyl, phenyl, methoxy, ethoxy, phenoxy, amine and
hydroxy groups are present on the aromatic ring. On the other hand, the presence of
electron withdrawing groups such as halogens and nitro groups on the aromatic ring
drastically influenced the reactivity, low yields or no sulfonic ester formation was
observed (Table 6).

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SYNTHETIC COMMUNICATIONSV
5
Table 2. Substrate scope for alkoxysulfonylation of aryl ethersa,b
.
O
95oC
R2O
S
OR2
R1
R1
O
O
S
R2
O
R2 = Me, Et
O
2
1
3
SO3Et
SO3Me
SO3Me
SO3Me
SO3Et MeO
MeO
MeO
3b, 4h, 54%
MeO
MeO
EtO
EtO
3a, 3h, 62%
3c, 6h, 44%
3d, 8h, 53%
3e, 3h, 55%
OMe
OMe
SO3Me
SO3Me
SO3Me
Me
MeO
SO3Me Me
O
Me
EtO
Me
SO3Me
OMe
3g, 4 h, 53%
3i, 5h, 38%
3j, 5h, 52%
3f, 5 h, 59%
3h, 5h, 42%
O
SO3Me
Me
SO3Me
SO3Me
MeO3S
MeO2C
O
MeO2C
O
Me
3k, 17h, 58%c,d
3l, 6h, 64%
3m, 4h, 55%
aReaction conditions: 1 (10 mmol), DMS or DES (30 mmol) under N2 atm.
bIsolated yield.
cTemp.110 ꢁC.
dDMS (60 mmol).
Table 3. Substrate scope for alkoxysulfonylation of benzene and its alkyl and aryl derivativesa,b
.
O
95oC
R1
MeO
S
O
2
OMe
R1
O
S
O
Me
O
1
3
SO3Me
SO3Me
SO3Me
SO3Me
SO3Me
i-Pr
Me
Et
t-Bu
3o, 10h, 37%
3p, 9h, 40%
3q, 4h, 51%c
3r, 4h, 31%c
SO3Me
3n, 8h, 44%
Me
Me
SO3Me
SO3Me
SO3Me
Me
Me
SO3Me
Me
Me
3u, 4h, 45%d
MeO3S
3w, 5h, 32%c,d
3v, 8h, 47%c
3s, 12h, 42%
3t, 8h, 50%
aReaction conditions: 1 (10 mmol), DMS (30 mmol) under N2 atm.
bIsolated yield.
cTemp. 150 ꢁC.
dDMS (50 mmol).

6
B. K. G. BHATTHULA ET AL.
Table 4. Substrate scope for alkoxysulfonylation of phenol and its derivativesa,b
.
O
95oC
R1
MeO
S
OMe
R1
O
S
O
Me
O
1
O
2
3
F
Cl
SO3Me
SO3Me
SO3Me
HO
3y, 5h, 50%
HO
HO
3z, 2-F, 4-OH, 4h, 36%
3aa, 2-OH, 4-F, 4h, 12%
3x, 3h, 60%
Me
Br
Me
SO3Me
SO3Me
HO
HO
HO
3ab, 6h, 39%
SO3Me
3ac, 2-Me, 4-OH, 3h, 33%
3ad, 2-OH, 4-Me, 3h, 20%
3ae, 10h, 45%
aReaction conditions: 1 (10 mmol), DMS (30 mmol) under N2 atm.
bIsolated yield.
Table 5. Substrate scope for alkoxysulfonylation of aromatic acidsa,b
.
O
95oC
R1
R2O
S
OR2
R1
O
S
O
R2
O
O
R1 = alkyl, COOH, OH R2 = Me, Et
R1 = alkyl, COOR2, OH, OR2
1
2
3
Me
SO3Me
SO3Me
MeO2C
Me
SO3Me
SO3Me
SO3Me
CO2Me
HO
MeO2C
3af, 30h, 0%c
Me
CO2Me
3aj, 8h, 47%
CO2Me
3ag, 5h, 33%c
3ai, 25h, 0%
3ah, 10h, 51%c
OH
MeO2C
SO3Me
OH
SO3Et
SO3MeMeO2C
SO3Me
OMe
HO
MeO2C
CO2Et
3an, 5h, 42%
3am, 8h, 15%c,d
3ak, 7h, 65%
3al, 10h, 43%
aReaction conditions: 1 (10 mmol), DMS or DES (40 mmol) under N2 atm.
bIsolated yield.
cTemp. 140 ꢁC.
dDMS (50 mmol).
First, alkoxysulfonylation of aryl ethers was explored (Table 2, entries 3a–3k) with
DMS/DES. As expected, all the reactions proceeded efficiently to provide the corre-
sponding products in good yields. In addition, alkoxysulfonylation of phenoxyacetic
acid methyl ester and (2,5-dimethylphenoxy)acetic acid methyl ester using DMS was
accomplished, and the corresponding 3l and 3m were obtained in 64% and 55% yields,
respectively (Table 2). The successful application of the alkoxysulfonylation protocol

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7
Table 6. Substrate scope for alkoxysulfonylation of aryl halides and nitro benzenea,b
.
O
170oC
R1
R1
MeO
S
OMe
O
S
O
Me
O
R1 = halide, NO2
O
3
1
2
SO3Me
Cl
SO3Me
SO3Me
I
SO3Me
O2N
SO3Me
F
Br
3ao, 25h, 0%
3aq, 25h, 8% 3ar, 24h, 6%
3as, 25h, 0%
3ap, 25h, 0%
aReaction conditions: 1 (10 mmol), DMS (30 mmol) under N2 atm.
bIsolated yield.
Table 7. Substrate scope for alkoxysulfonylation of polycyclic aromatic compoundsa,b.
R1
O
95oC
R1
R2O
S
OR2
O
S
O
R2
O
R1 = H, OMe
R2 = Me, Et
O
2
5
4
OMe
OMe
SO3Me
SO3Et
SO3Me
5a, 3h, 47%
5c & 5d, 57% (C1 : C2 = 70 : 30)c
5b, 6h, 41%
aReaction conditions: 1 (10 mmol), DMS or DES (30 mmol) under N2 atm.
bIsolated yield.
cIsomers, the ratio of 5c and 5d was determined by 1H NMR spectroscopy analysis.
Table 8. Isomer distribution in the sulfonic ester of naphthalene 5c and 5da.
O
O
MeO
S
OMe
O
S
Me
O
O
2
4
5
Temp.
(0 ꢁC)
Reaction
time (h)
YIeld
(%)b
Ratioc of
5c and 5d
Entry
1
2
3
4
5
6
95
95
95
120
170
170
7
25
40
6
4
20
57
54
53
56
50
23
70:30
55:45
45:55
63:37
42:58
0:100
aReaction conditions: Naphthalene (10 mmol), DMS (30 mmol), under N2 atmosphere.
bIsolated yield.
cThe ratio of 5c and 5d was determined by 1H NMR spectroscopy analysis

8
B. K. G. BHATTHULA ET AL.
Table 9. Substrate scope for alkoxysulfonylation of heterocyclic aromatic compoundsa,b
.
a)
SO3R
O
95oC
RO
S
OR
X
X
O
X = NH, S
R = Me, Et
X = NH, R = Et, 7, 8h, 34%
X = S, R = Me, 8, 6h, 36%
6
2
-------------------------------------------------------------------------------------------------
b)
O
RO3S
95oC
OR
CO2R
COOH
RO
S
O
2
N
H
N
H
R = Me, 10, 10h, 51%c
R = Et, 11, 8h, 49%c
9
R = Me, Et
-------------------------------------------------------------------------------------------------
c)
COOEt
SO3Et
COOH
EtO
MeO
O
S
MeO
95oC
8 h
OEt
S
S
O
2
13, 39%c
12
aReaction conditions: 1 (10 mmol), DMS or DES (30 mmol) under N2 atm.
c
bIsolated yield. DMS or DES (40 mmol)
Table 10. Substrate scope for alkoxysulfonylation of aromatic aminesa,b
.
a)
R
R
N
NH2
H
H
N
N
N
O
S
R
R
R
R
120oC
20h
RO
OR
SO3R
SO3R
O
R = Me, 16, 28%c,d
R = Et, 20, 0%
R = Me, 17, 7% R = Me, 18, 4%
R = Et, 21, 6% R = Et, 22, 4%
R = Me, 15, 9%
R = Et, 19, 17%
14
R = Me, Et
----------------------------------------------------------------------------------------------------------------------------------------------------------
b)
R
N
R
N
H
O
N
95oC
RO
S
OR
RO3S
SO3R
SO3R
O
R = Me, 25, 10h, 39%e
R = Et, 29, 32h, 18%d
R = Me, 24, 10h, 15%d
R = Et, 28, 32h, 18%d
R = Me, Et
23
R
N
H
N
RO3S
SO3R
R = Me, 27, 10h, 12%d
R = Et, 31, 32h, 6%d
R = Me, 26, 10h, not
observedd
R = Et, 30, 32h, 9%d
aReaction conditions: 1 (10 mmol), DMS or DES (30 mmol) under N2 atm.
bIsolated yield.
cTemp.150 ꢁC.
dDMS (50 mmol).
eDMS (70 mmol).

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SYNTHETIC COMMUNICATIONSV
9
with aryl ethers to obtain 3a–3m encouraged our further efforts toward the preparation
of other aromatic/heterocyclic aromatic sulfonic esters (results shown in Tables 3–10).
The reaction of benzene gave the desired product 3n in 44% yield. Next, the effects
of moderate electron donating groups (alkyl) on the aromatic ring such as methyl, ethyl,
isopropyl and tert-butyl were investigated. Alkyl derivatives of benzene such as toluene,
ethyl benzene, cumene and tert-butylbenzene under these conditions proceeded
smoothly to give the desired products (Table 3, 3o–3r) in good yields. In addition, the
dialkyl derivatives of benzene such as o, m and p-xylene’s were also transformed into
the desired products (Table 3, 3s–3u) in 42%, 50% and 45% yields, respectively.
Alkoxysulfonylation of biphenyl afforded 47% of mono (3v) and 8.0% of di-substi-
tuted (3w) sulfonic esters with DMS 3.0 equiv. and increasing the amount of DMS to 5
equiv. gave mono (3v) and diesters (3w) in 24% and 32% yields, respectively (Table 3).
Next, Phenol was examined in this system under the standard reaction conditions and
the desired sulfonic ester was obtained in 60% yield (Table 4, 3x) along with 6%
methoxy-sulfonic ester (Table 2, 3a). Halo and alkyl substituted phenols, such as o-
chloro, m-bromo and p-cresol all proceeded smoothly to afford the corresponding prod-
ucts (Table 4, 3y, 3ab and 3ae) in good yields. Whereas, m-fluorophenol under standard
conditions gave two isomers such as 2-fluoro-4-hydroxy benzenesulfonic acid methyl
ester and 4-fluoro-2-hydroxybenzenesulfonic acid methyl ester in 36% and 12% yields,
respectively (Table 4, 3z and 3aa). m-cresol also gave two isomers 3ac and 3ad in 33%
and 20% yields, respectively (Table 4).
We next studied the reaction with aromatic carboxylic acids such as benzoic acid
and o, p and m-toluic acids. Results show that, non-substituted benzoic acid failed to
produce sulfonic ester under the reaction conditions (Table 5, 3af), only carboxylic
ester was formed, which may be due to the electronic effects, whereas o and p-toluic
acids undergo carboxylic acid esterification and ring alkoxysulfonylation reactions
simultaneously (Table 5, 3ag and 3ah). In the case of m-toluic acid, the reaction
with DMS gave only methyl ester, tried at different temperatures (95 ꢁC, 120 ꢁC, 150ꢁ
and 175 ꢁC), no sulfonic ester formation was observed, (Table 5, 3ai). The reason for
this fact may be arisen from the steric effect and low activity of m-toluic acid. The
position of the substituted groups on the ring also showed an effect on the reaction.
When the two substituent’s on the ring are not the same, results become more com-
plex, in the above compound both are different directing groups (ortho and meta),
methyl is a week electron donor, whereas carboxylic group is strong withdrawing,
reduced electron density at o-and p positions to methyl group in m-toluic acid could
be influenced the reaction.
To examine whether the present protocol can useful to hydroxy-benzoic acids, we
took different phenolic acids (Table 5) and subjected them to the reaction conditions.
Interestingly, along with esterification of carboxylic group, sulfonic ester formation was
noticed for o, p and m-hydroxy benzoic acids (see Table 5). Reaction with p-hydroxy-
benzoic acid was studied at elevated temperatures to check the possibility of O-methyla-
tion of hydroxy group, along with carboxylic acid esterification and sulfonic ester
formation, methylation of the hydroxy group was noticed, however, a lower yield was
obtained (see Table 5, 3am).

10
B. K. G. BHATTHULA ET AL.
The results listed in the Tables 2–5 showed that aromatic compounds with electron-
donating groups attached on the phenyl ring underwent this process smoothly to give
the corresponding products (3a–3an) in good to excellent yields.
Not surprisingly, the sulfonylation procedure was not effective for aryl halides, due to
their deactivating nature toward electrophilic aromatic substitution because of the elec-
tronegative effect. Reaction of aryl halides such as fluoro and chloro under these condi-
tions was unsuccessful and low yields were observed for bromo and iodo compounds.
As expected the presence of strong electron-withdrawing nitro group on the aromatic
ring failed to produce the sulfonic ester derivatives (see Table 6).
It should be noted that polycyclic aromatic compounds naphthalene and its deriva-
tives were also suitable substrates for this transformation. We examined the reactions of
naphthalene and 1-methoxynaphthalene under the optimized conditions. In the case of
1-methoxynaphthalene, the desired products (Table 7, 5a and 5b) were obtained in
good yields with DMS and DES. However, in the case of naphthalene, two sites are
available for substitution, C-1 and C-2, the alkoxysulfonylation of naphthalene with
DMS under standard reaction conditions at 95 ꢁC afforded two products as 7:3 ratio of
1
inseparable regioisomers 5c and 5d (Table 7, 57% yield), identified by H NMR (isola-
tion by column chromatography was difficult). As expected, at 95 ꢁC kinetically con-
trolled product of C-1 isomer is obtained as major (5c). However, at higher
temperatures and with time, the 1-ester rearranges to the thermodynamically more sta-
ble 2-ester (See Table 8, 5d).
It is notable that the substrate scope could be further extended to heterocyclic aro-
matic compounds. Among heterocyclic aromatic compounds, indole, benzothiophene
and their derivatives were chosen and tested. The reaction of indole and their deriva-
tives was successful and the corresponding sulfonic esters were obtained in moderate to
good yields (Table 9, 7, 10 and 11). Next, with benzothiophene and its derivatives, the
corresponding reactions took place smoothly to give 8, or 13 in 36%, or 39% yield,
respectively.
To further extend the practicability of this process, we next explored the transform-
ation of the aromatic amines to sulfonic esters. We found that both primary and sec-
ondary aromatic amines were capable for this alkoxysulfonylation, affording the desired
products in low to moderate yields. Aromatic primary amine such as aniline gave a
lower yield of 9% of 15 and 8% of 16 with DMS 3.0 equiv, and no desired products 15
and 16 were observed as well when 1.0 eq of DMS was added to the standard reaction.
With 1.0 eq. of DMS, N-methyl aniline (17) and N,N-dimethyl aniline (18) could be
isolated 34% and 20% yields, respectively. This result indicated that this alkoxysulfonyla-
tion experienced both N-methyl and N,N-dimethyl products as reaction intermediates.
Because of the competitive reaction between both alkoxysulfonylation and methylation,
increasing the amount of DMS 3–5 mol and temp. to 150 ꢁC improved on the chemical
yield of 16 to 28% (Table 10). However, surprisingly reaction of tert-aromatic amine,
N,N-dimethylaniline with DMS was not given desired product. The reason was,
although N,N-dimethylaniline is extremely reactive toward electrophilic aromatic substi-
tution, possibility of formation of quaternary ammonium salt with DMS (N-alkylation)
decreases the reactivity of N,N-dimethylaniline. The quaternary ammonium group is
strong electron withdrawing, and electrophilic aromatic substitution is disfavored.

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SYNTHETIC COMMUNICATIONSV
11
Finally, secondary aromatic amine, N,N-diphenylamine under standard conditions with
DMS (5 equi.) gave mono and di sulfonic esters such as 24 and 25 in 15% and 33%
yields, respectively, increasing the DMS to 7.0 equi. gave 39% disulfonic ester (25) as
major product and only traces of mono ester was observed. Whereas, surprisingly reac-
tion with DES (5 equi.) gave a mixture of three sulfonic esters along with N-ethyl N,N-
diphenylamine (Table 10, 28, 29 and 30).
Conclusion
In summary, we have developed a simple, convenient and straightforward synthetic
approach for the synthesis of sulfonic esters. Compared with literature procedures, the
synthetic protocol developed herein showed advantages such as commercially available
and inexpensive reagents, broad substrate scope with a wide range of functional group
tolerance, and obviation of tedious step by step operations. Another advantage of this
method over reported methods is that it does not require an expensive catalyst, base,
ligand or other reagents. This methodology provides an easy access to the synthesis of
sulfonic esters from aromatic and heterocyclic aromatic compounds under catalyst and
solvent free conditions.
Experimental section
General description
Solvents and chemicals were purchased from commercial sources and used without fur-
1
ther purification. H and 13C NMR spectra were recorded on Bruker AV 400-MHz
instrument. Chemical shifts are (d) reported in parts per million (ppm), and coupling
constants (J) are reported in Hertz (Hz). Splitting patters are described as follows; br,
broad; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet. Column chromatography
was performed on silica gel (100–200 mesh). IR specta were recorded on a PerkinElmer
Spectrum 100 FTIR spectrophotometer as KBr pellets or with the neat product. Mass
spectra (MS) were recorded on an API 2000 LCMS/MS AB Sciex spectrometer. HRMS
(ESI) were taken on an AB Sciex tripleTOF 5600þ and Bruker Daltonics MicrOTOF
mass analyzers. Analytical thin-layer chromatography was carried out using E-Merck
60F254 aluminum-backed plates of silica gel (0.2 mm). Developed plates were visualized
by using UV light or potassium permanganate solution.
General procedure a for the preparation of sulfonic esters
A mixture of arene/heteroarene (0.01 mol) and alkyl sulfate 2 (0.03 mol) was stirred at
95 ꢁC under nitrogen atmosphere until the consumption of the starting material as
monitored by TLC was complete. After cooling to room temperature, the reaction mix-
ture was diluted with ethyl acetate (20 mL) and washed with water (20 mL), and aq.
ammonia solution (20 mL ꢂ 2). The organic layer was dried over anhydrous sodium
sulfate, solvent was removed under reduced pressure, and then purified through silica
gel column chromatography to give the corresponding sulfonic esters.

12
B. K. G. BHATTHULA ET AL.
General procedure B for the preparation of sulfonic esters
A mixture of phenol (0.01 mol) and alkyl sulfate 2 (0.03 mol) was stirred at 95 ꢁC under
nitrogen atmosphere until TLC showed the disappearance of the starting material. After
cooling to room temperature, the reaction mixture was diluted with ethyl acetate
(20 mL) and washed with water (20 mL). A solution of aqueous sodium hydroxide
(10%, 10 mL) was added to the organic layer, and the resulting solution was stirred for
10 min. The layers were separated and the aqueous layer was acidified using aq.HCl
(3.0 M), then extracted with ethyl acetate (2 ꢂ 10 mL). The combined organic layers
were dried over sodium sulfate, filtered and concentrated under reduced pressure, and
then purified through silica gel column chromatography to afford the corresponding
sulfonic esters.
General procedure C for the preparation of sulfonic esters
A mixture of aromatic amine (0.01 mol) and alkyl sulfate 2 (0.03 mol) was stirred at
95 ꢁC under nitrogen atmosphere until TLC showed the disappearance of the starting
material. After cooling to room temperature, the reaction mixture was diluted with ethyl
acetate (20 mL) and washed with water (20 mL ꢂ 3). The organic layer was dried over
anhydrous sodium sulfate, solvent was removed under reduced pressure, and then puri-
fied through silica gel column chromatography to afford the corresponding sul-
fonic esters.
4-Methoxybenzenesulfonic acid methyl ester (3a)
General procedure A was followed for the reaction of anisole (1.08 g, 10 mmol) and
dimethyl sulfate (3.78 g, 30 mmol). The residue was purified by column chromatography
on silica gel using ethyl acetate:hexane (10:90) as the eluent to afford product
1
3a[26,32,39–43] (1.25 g, 62% yield) as a color less syrup; H NMR (400 MHz, CDCl3) d
7.84 (d, J ¼ 8.8 Hz, 2H), 7.02 (d, J ¼ 8.8 Hz, 2H), 3.88 (s, 3H), 3.72 (s, 3H); 13C NMR
(100 MHz, CDCl3) d 163.87, 130.19, 126.37, 114.50, 56.10, 55.74; IR (Neat, cmꢀ1) ꢀmax
2953.44, 2843.64, 1579.04, 1597.88, 1499.03, 1358.11, 992.07, 564.03; MS: m/z
203.1 (M þ H)þ.
1H and 13C NMR spectra, HRMS can be found via the “Supplementary Content” sec-
tion of this article’s Webpage.
Acknowledgments
The authors are grateful to Suven Life Sciences management for allowing us to publish
these results.
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