Non-expensive, open-flask and selective catalytic systems for the synthesis of sulfinate esters and thiosulfonates

Article abstract of DOI:10.1016/j.tetlet.2017.02.025

Two simple and efficient methods for the synthesis of sulfinate esters and thiosulfonates from sodium salts of sulfinic acids are described. Different alcohols were converted into the corresponding sulfinate esters in good yields and purity in an open flask. By the adjustment of the reaction conditions thiosulfonates could also be obtained in a very short reaction time.

Full text of DOI:10.1016/j.tetlet.2017.02.025

Accepted Manuscript
Non-Expensive, Open-Flask and Selective Catalytic Systems for the Synthesis
of Sulfinate Esters and Thiosulfonates
Arisson Tranquilino, Silvia R.C.P. Andrade, Ana Paula M. da Silva, Paulo H.
Menezes, Roberta A. Oliveira
PII:
S0040-4039(17)30202-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.02.025
TETL 48636
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
11 December 2016
30 January 2017
9 February 2017
Please cite this article as: Tranquilino, A., Andrade, S.R.C., da Silva, A.P.M., Menezes, P.H., Oliveira, R.A., Non-
Expensive, Open-Flask and Selective Catalytic Systems for the Synthesis of Sulfinate Esters and Thiosulfonates,
Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.02.025
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Non-Expensive, Open-Flask and Selective
Catalytic Systems for the Synthesis of
Sulfinate Esters and Thiosulfonates
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Arisson Tranquilino, Silvia R. C. P. Andrade, Ana Paula M. da Silva, Paulo H. Menezes and
Roberta A. Oliveira

1
Tetrahedron Letters
Non-Expensive, Open-Flask and Selective Catalytic Systems for the Synthesis of
Sulfinate Esters and Thiosulfonates
Arisson Tranquilino, Silvia R. C. P. Andrade, Ana Paula M. da Silva, Paulo H. Menezes* and
Roberta A. Oliveira*
Departamento de Química Fundamental, Universidade Federal de Pernambuco, Recife- PE, Brazil
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Two simple and efficient methods for the synthesis of sulfinate esters and thiosulfonates from
sodium salts of sulfinic acids are described. Different alcohols were converted into the
corresponding sulfinate esters in good yields and purity in an open flask. By the adjustment of
the reaction conditions thiosulfonates could also be obtained in a very short reaction time.
Available online
Keywords:
Sulfinate esters
2017 Elsevier Ltd. All rights reserved.
Thiosulfonates
Sulfinic acids sodium salts
Sulfur compounds
Tricoordinate sulfur
Sulfur compounds are widely used in organic synthesis and
the importance of sulphides, sulfoxides and sulfones not only to
increase the structural complexity of organic molecules but also
and alcohols as starting materials would be a more appropriate
choice due to their commercial availability, low cost and high
stability. In addition, sulfinic acids can act as nucleophiles or
1
1c
in asymmetric reactions is unquestionable.
electrophiles, depending on the conditions used.
Tricoordinate sulfur compounds such as sulfinate esters
and sulfoxides can adopt a trigonal pyramidal structure,
however, the presence of an electron lone pair gives to the
sulfur centre a tetrahedral framework and unlike amines,
sulfoxides and sulfinate esters are configurationally stable at
For preliminary optimization of the reaction conditions,
sodium p-toluenesulfinate, 1a (1 mmol) and methanol (1 mL)
were submitted to acidic conditions using CH Cl as solvent at
2 2
room temperature. The results are depicted on Table 1.
When the reaction was performed without the use of H
SO
2 4
2
ambient temperatures.
in CH
1, entry 1). The addition of 0.5 equiv. of H
sulfinate ester 2a in low yield after 24 h (Table 1, entry 2).
By increasing the amount of H SO in the reaction higher
conversions of 1a to 2a were observed (Table 1, entries 2-5).
However, when 4 equiv. of H SO were used, a significant
2 2
Cl , the desired product was not observed after 24 h (Table
The synthesis of sulfinate esters is mainly based on the
2
SO gave the desired
4
seminal work developed by Douglass using sulfinyl
3
chlorides. Some other methods for the synthesis of this
2
4
4
class of compounds such as the use of N-nitroso sultams,
substitution of benzyl alcohols with arylsulfonylmethyl
2
4
5
6
isocyanides, reaction of sulfonyl hydrazides with alcohols,
decrease in the conversion together with the formation of the
corresponding sulfone was observed after 24 h (Table 1, entry 6).
This result is in agreement with the literature where the acid-
7
8
alcoholysis of sulfinamides, the use of disulfides were also
described.
o
More recently, the oxidation of sulphides to the
catalysed reaction of sulfinic acids and benzyl alcohols at 100 C
9
11
corresponding sulfinyl radicals and the use of equimolar
gave the corresponding sulfones. A dramatic effect was
1
0
amounts of BF
3
Et
2
O and sodium sulfinates were also
observed when 4 Å molecular sieves were used in the reaction,
where the reaction time decreased to 8h and the desired product
2a was obtained in a conversion of 80% (Table 1, entry 7).
The optimized reaction conditions namely: 1a (1 mmol) and
described. These methods, however, have some limitations
such as the need of inert atmosphere, the generation of
sulfur dioxide as by product or the use of unpleasant
sulphides.
methanol (1.2 mmol) using H
2 4
SO (2 equiv.) and 4 Å molecular
12
Thus, despite the plethora of methods for the synthesis of
sulfinate esters, the development of a simple and reliable
method, based on the use of easy to handle reagents and mild
reaction conditions would be of the great interest.
sieves in CH Cl were then applied to different alcohols.
2
2
An interesting fact to be observed is that, depending on the
structure of the alcohol, it can be used as the solvent in the
2 2
reaction without the need of CH Cl . The results are described on
The use of Brønsted acids as catalysts in academic
laboratories and chemical manufacturing plants is universal and,
this fact, together with the use of sodium salts of sulfinic acids
Table 2.

2
Tetrahedron Letters
Table 1. Effect of the amount of H
2
SO
4
on the synthesis of
More recently, the use of thiosulfonates gained particular
attention due to the fact that these reagents are more effective in
a
methyl benzenesulfinate, 2a
15
sulfenylation reactions when compared to disulfides. In
addition, these compounds exhibit greater stability and ease of
handling when compared to sulfenyl chlorides. Moreover,
interesting biological activities and industrial applications in fine
1
6
17
18
19
conditions
chemicals, photographic processes and as protecting groups
were described.
b
Entry
5a (%)
H SO
2 4
(equiv.)
Time (h)
1
2
3
4
5
6
7
-
24
24
24
24
24
24
8
-
These facts led to the development of several methods for the
synthesis of thiosulfonates, being the most common approach
0.5
1.0
1.5
2.0
4.0
2.0
36
42
65
88
78
20
based on the oxidation of the corresponding disulfides. Other
2
1
22
approaches based on the use of sulfides, sulfonic acids,
23
24
25
sulfonyl chlorides, and sulfinic acids and esters were also
described.
c
80
The synthesis of methyl and diaryl sulfones using salts of
sulfinic acid and aryl iodides promoted by copper was
a
Reaction conditions: Reactions were performed with 1a (1 mmol) and
MeOH (1.0 mL) using the indicated amount of H SO in CH Cl (4 mL) at
the temperature indicated. Determined by GC analysis; 4 Å molecular
sieves (200 mg) was added to the reaction.
2
6
described by Wang. By analogy, the adjustment of the
reaction conditions developed for the synthesis of sulfinate
esters by using 0.5 equiv. of copper iodide (I) and an excess
2
4
2
2
b
c
2 4
of H SO (7.5 equiv.) gave the corresponding thiosulfonates
From Table 2 it can be seen that the method was efficient for
most of the alcohols used. When primary aliphatic alcohols such
as methanol, ethanol and n-propanol were used, good yields were
observed in all cases (Table 2, entries 1-3).
in good yield, purity and in a very short reaction time
compared to the methods previously described on the
literature (Scheme 1).
A similar yield was observed when a secondary aliphatic
alcohol was used (Table 2, entry 4). The effect of alcohol
bulkiness was more evident when t-butanol was used, where only
traces of 2e were observed together with a complex mixture of
compounds after 16 h (Table 1, entry 5).
Allyl and propargyl alcohols also gave the corresponding
sulfinate esters 2f and 2g in good yields (Table 1, entries 6 and
7). This result is important while 2g is a precursor for the
synthesis of allenic sulfones through a [2,3]-sigmatropic
13
rearrangement. Benzyl alcohol also gave the corresponding
product 2h also in good yield (Table 1, entry 8).
Scheme 1. Synthesis of thiosulfonates
An interesting result was obtained when (-)-menthol was used
as the alcohol source where (1R,2S,5R)-(−)-Menthyl (S)-p-
toluenesulfinate, 2i was obtained in 50% yield in a 53:47
diastereomeric ratio (Table 1, entry 9). The synthesis of 2i is
generally carried out by converting 1a into the corresponding p-
toluenesulfinyl chloride using thionyl chloride in benzene
followed by the addition of (-)-menthol. The less soluble (S)-(−)
diastereomer can be isolated by recrystallization from the mixture
In summary, we have shown an efficient and versatile method
for the synthesis of sulfinate esters and thiosulfonates from
commercially available and low cost sulfinic acids in a very
chemoselective way.
In the case of sulfinate esters, the use of different alcohols
gave the corresponding products in good to moderate yields
without the need of anhydrous solvents or sulfonyl chlorides as
precursors.
The method is simple, fast and general, allowing further
applications in the synthesis of more complex compounds. By
changing the reaction conditions, thiosulfonates can be obtained
in a reaction promoted by cooper iodide in an open flask. The
products were obtained in a very short reaction time when
compared to the previously described methods.
14
using acetone at −20°C.
In order to explore the scope of the reaction other sodium
sulfinates were used. For example, sodium benzenesulfinate 1b
gave similar results for primary (Table 2, entries 12-13) and
secondary alcohols (Table 2, entry 14) indicating that the method
is general for aromatic sulfinic acids.
When sodium 1-methyl 3-sulfinopropanoate, 1c was
submitted to the optimized reaction conditions using methanol,
the corresponding product 2p was obtained in 52% after 12 h
Acknowledgments
(
Table 2, entry 15). However, when n-propanol was used, a
We gratefully acknowledge CNPq (482299/2013-4 and
84778/2011-0), CAPES and FACEPE (APQ-0471-1.06/15) for
financial support. P.H.M is also thankful to CNPq for his
fellowship.
mixture corresponding to the desired product 2q and the product
resulting from the transesterification reaction 2r were obtained in
5
sodium trifluoromethylsulfinate was used, the corresponding
product 2s was not obtained (Table 1, entry 17).
4
6% yield in a 60:40 ratio (Table 2, entry 16). Finally, when
Another factor that must be taken into account in the
development of new synthetic methods is the scale-up of the
reaction. Thus, when the synthesis of chiral sulfinate ester 2i was
performed using 1.0 g (6 mmol) of 1a under the conditions
described on Table 2, the desired product was obtained in 72%
yield, indicating that the developed reaction conditions could be
also applied to carry out reactions on a larger scale.

3
a
Table 2. Synthesis of different sulfinate esters 2 from the corresponding sulfinic acid sodium salts, 1 and alcohols
Yield
2
Time
entry
1
R OH
2
(
h)
b
(
%)
c
c
c
c
1
2
3
4
5
6
7
76
p-TolSO
2
Na, 1a
MeOH
EtOH
8
2
a
70
69
67
1
1
1
1
1
a
a
a
a
a
8
2b
n-PrOH
i-PrOH
t-BuOH
8
2
c
8
2d
d
-
16
5
2
e
e
e
e
63
65
65
2
f
1
1
a
a
8
4
2g
8
9
BnOH
2h
e
50
1a
(-)-menthol
4
2i
f
1
1
0
1
-
1
1
a
a
16
16
2j
f
-
2l
c
c
c
1
1
1
1
1
1
2
3
4
5
6
7
84
73
71
PhSO
2
Na, 1b
MeOH
EtOH
8
8
2
m
1
1
b
b
2
n
i-PrOH
MeOH
n-PrOH
8
2
o
52
2
MeCO (CH
2
)
2 2
SO Na, 1c
12
15
2
p
g
56
1
c
2
q+2r
f
-
3
CF SO
2
Na, 1d
MeOH
16
2
s
a
Reaction conditions: Reactions were performed with 1 (1 mmol), ROH (3 mmol), H
2
SO
4
(106 µL, 2 equiv.) and 4 Å molecular
(4 mL) at room temperature. isolated yields; The reaction was performed using 1.0 mL of the alcohol
b
c
sieves (200 mg) in CH
2
Cl
2
d
e
f
without losses in the yield. Only traces observed after 16h; 1.5 equiv. of H
2
SO
4
was used; The product was not observed after 16 h;
g
Obtained as an inseparable mixture in a 60:40 ratio determined by GC analysis.

4
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2
2
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1
Representative Procedure for the Synthesis of methyl 4-
methylbenzenesulfinate (2a): In a test tube containing sodium p-
toluenesulfinate, 1a (178 mg, 1 mmol) was added methanol (1 mL, 25
mmol) followed by dichloromethane (4 mL). Under stirring, sulfuric
acid (106
powdered 4 Å molecular sieves (200 mg) was added. The mixture
was stirred for additional period and then diluted with
L, 2 equiv.) was added, dropwise. After 30 minutes,
8
h
dichloromethane (10 mL) and transferred to a separation funnel. The
organic phase was washed with water (2 x 20 mL), dried over
anhydrous MgSO
4
and filtered through a pad of silica. The solvents
were removed in vacuo to yield 129 mg (76%) of the tittle compound
1
3
sufficiently pure for characterization. H NMR (300 MHz, CDCl ) 
7
3
2
.57 (d, J = 9 Hz, 2H); 7.33 (d, J = 9 Hz, 2H); 3.45 (s, 3H); 2.41 (s,
1
3
H); C NMR (75 MHz, CDCl
1.5.
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)  142.8, 140.9, 129.7, 125.4, 49.4,
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1
3
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5
Tetrahedron Letters
Non-Expensive, Open-Flask and Selective Catalytic Systems for the
Synthesis of Thiosulfonates and Sulfinates
Arisson Tranquilino, Silvia R. C. P. Andrade, Ana Paula M. da Silva
Paulo H. Menezes* and Roberta A. Oliveira*
Depto de Química Fundamental, Universidade Federal de Pernambuco, Recife- PE, Brazil
Highlights:

A versatile method for the synthesis of sulfinate esters and thiosulfonates is
described;


The methodology is simple and flexible in design;
Sulfinate esters were obtained in good yields without the need of anhydrous
solvents;

Thiosulfonates were obtained in a reaction promoted by cooper iodide in an
open flask.