Acid catalyzed alcoholysis of sulfinamides: Unusual stereochemistry, kinetics and a question of mechanism involving sulfurane intermediates and their pseudorotation

Article abstract of DOI:10.3390/molecules20022949

The synthesis of optically active sulfinic acid esters has been accomplished by the acid catalyzed alcoholysis of optically active sulfinamides. Sulfinates are formed in this reaction with a full or predominant inversion of configuration at chiral sulfur or with predominant retention of configuration. The steric course of the reaction depends mainly on the size of the dialkylamido group in the sulfinamides and of the alcohols used as nucleophilic reagents. It has been found that bulky reaction components preferentially form sulfinates with retention of configuration. It has been demonstrated that the stereochemical outcome of the reaction can be changed from inversion to retention and vice versa by adding inorganic salts to the acidic reaction medium. The unusual stereochemistry of this typical bimolecular nucleophilic substitution reaction, as confirmed by kinetic measurements, has been rationalized in terms of the addition-elimination mechanism, A-E, involving sulfuranes as intermediates which undergo pseudorotations.

Full text of DOI:10.3390/molecules20022949

Molecules 2015, 20, 2949-2972; doi:10.3390/molecules20022949
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molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Acid Catalyzed Alcoholysis of Sulfinamides: Unusual
Stereochemistry, Kinetics and a Question of Mechanism
Involving Sulfurane Intermediates and Their Pseudorotation
Bogdan Bujnicki, Józef Drabowicz and Marian Mikołajczyk *
Department of Heteroorganic Chemistry, Centre of Molecular and Macromolecular Studies, Polish
Academy of Sciences, Sienkiewicza 112, 90-363 Łódź, Poland; E-Mails: bogbujni@cbmm.lodz.pl (B.B.);
draj@cbmm.lodz.pl (J.D.)
* Author to whom correspondence should be addressed; E-Mail: marmikol@cbmm.lodz.pl;
Tel.: +48-42-681-5832.
Academic Editor: Derek J. McPhee
Received: 19 December 2014 / Accepted: 3 February 2015 / Published: 11 February 2015
Abstract: The synthesis of optically active sulfinic acid esters has been accomplished by the
acid catalyzed alcoholysis of optically active sulfinamides. Sulfinates are formed in this
reaction with a full or predominant inversion of configuration at chiral sulfur or with
predominant retention of configuration. The steric course of the reaction depends mainly on
the size of the dialkylamido group in the sulfinamides and of the alcohols used as
nucleophilic reagents. It has been found that bulky reaction components preferentially form
sulfinates with retention of configuration. It has been demonstrated that the stereochemical
outcome of the reaction can be changed from inversion to retention and vice versa by adding
inorganic salts to the acidic reaction medium. The unusual stereochemistry of this typical
bimolecular nucleophilic substitution reaction, as confirmed by kinetic measurements, has
been rationalized in terms of the addition-elimination mechanism, A-E, involving sulfuranes
as intermediates which undergo pseudorotations.
Keywords: sulfur chirality; stereoselective synthesis; chiral sulfinamides; chiral sulfinates;
enantiomer interconversion; nucleophilic substitution; addition-elimination mechanism;
sulfuranes; pseudorotation

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1. Introduction
The mechanism and stereochemistry of nucleophilic substitution reactions at sulfur, SN-S, as well as
at other heteroatoms (P, Si, Se, etc.), have been a subject of extensive studies of many research groups
in recent decades [1]. Due to the fact that sulfur may form tetra- or pentacoordinate compounds
(sulfuranes) [2,3], the most important question concerning the mechanism of SN-S reactions is
whether these reactions occur synchronously according to an SN2-S mechanism or stepwise by an
addition-elimination mechanism, A-E, involving sulfuranes as intermediates that are formed by addition
of nucleophiles, N, to the reaction substrates (Scheme 1).
Scheme 1. Possible mechanisms for nucleophilic substitution reactions at sulfur.
The second closely related problem is connected with the relationship between the structure of
transiently formed sulfuranes and the stereochemical outcome of nucleophilic substitution reactions. It
is now generally accepted that diaxial or diequatorial disposal of entering, N, and leaving, L, groups in a
trigonal bipyramidal structure of transient sulfurane intermediates should lead to inversion of configuration
at sulfur while the steric course of axial-equatorial substitution is predicted to be retention. (Scheme 2).
Scheme 2. Relationship between the structure of transient sulfuranes and stereochemistry of
A-E reactions at sulfur.
However, the steric course of the SN-S reactions proceeding according to the A-E mechanism may
also be affected by permutational isomerization of sulfuranes. This process, commonly called
pseudorotation, consists in the internal ligand reorganization changing the relative positions of axial and
equatorial ligands in a trigonal bipyramidal structure. A single pseudorotation process according to the
Berry mechanism is shown below (Scheme 3). Since pseudorotation processes are of very low energy

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(the energy barriers are in the range from ca. 6 to 8 kcal/mol [4,5]), they may have important influence
on the stereochemical outcome of nucleophilic substitution at sulfur which may vary from inversion to
retention and racemization.
Scheme 3. A single Berry pseudorotation process of a sulfurane structure.
The majority of nucleophilic substitution reactions at the stereogenic sulfur atom occur with inversion
of configuration. For example, this steric course has unequivocally been established in the reaction of
optically active methyl p-toluenesulfinate containing 14C in the methoxy group with methanol catalyzed
by trifluoroacetic acid (Scheme 4) [6]. The measurements of the rate of racemization of this sulfinate
and the rate of isotopic methoxy-methoxy exchange revealed that it loses its optical rotation practically
twice as fast as it loses the radiolabelled methoxy group. This finding provided a clear-cut evidence for a full
inversion of configuration in the elementary process of the methoxy-methoxy exchange at the sulfinyl sulfur.
14
Scheme 4. Acid-catalyzed methanolysis of optically active C-methyl p-toluenesulfinate
and structures of transition state A and sulfurane B.
However, the observation of inversion in the above reaction, as well as in a great number of other SN
reactions at sulfur, does not allow to distinguish between the SN2-S and A-E mechanisms since both the
transition state A and sulfurane intermediate B proposed for the methoxy-methoxy exchange at the chiral
sulfinyl centre explain this steric course. The only conclusion, which can be drawn, is that the sulfurane
B, if it is formed, should decompose before pseudorotation because all substituents around sulfur are
properly placed in a trigonal bipyramidal structure from the viewpoint of apicophilicity.
In contrast to stereoinvertive SN-S reactions, those occurring with retention at the sulfinyl sulfur give
more convincing evidence for the operation of the A-E mechanism. In almost all such reactions reported
so far retention at sulfur was convincingly explained by formation of a transient four-membered ring
sulfurane intermediate with apical-equatorial arrangement of entering and leaving groups that undergoes
pseudorotation and then decomposes to final product with retained configuration [7]. In accord with the
microscopic reversibility rule, the pseudorotation of the primarily formed sulfurane intermediate is

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required to form a new sulfurane with the leaving group in apical position, however, without changing
the preferable apical-equatorial disposal of a four-membered ring. The sulfur oxygen exchange between
the 18O-labelled (+)-(R)-methyl p-tolyl sulfoxide and dimethyl sulfoxide proceeding without racemization,
i.e., with retention, is the best example of the A-E mechanism discussed above (Scheme 5) [8].
18
Scheme 5. Steric course and mechanism of O/16O exchange in optically active methyl
p-tolyl sulfoxide.
In the course of our studies on static and dynamic stereochemistry of organic sulfur compounds,
especially those with the sulfur atom as a sole centre of chirality, we became interested in the reactions
of sulfinamides with alcohols catalyzed by acids (Equation (1)). We hoped that based on this reaction,
completely unknown at the beginning of our work, a new and general synthetic approach to sulfinates
can be devised. Moreover, since the starting sulfinamides were accessible in enantiomeric forms, this
reaction should also provide a new access to optically active sulfinates. Apart from synthetic aspects,
the acid catalyzed alcoholysis of sulfinamides has attracted our attention as a model reaction of
nucleophilic substitution at the sulfinyl sulfur atom. Examination of its stereochemistry could gain
further experimental insight into the complex nature of the SN-S reactions and give new evidence for the
addition-elimination mechanism, A-E.
(1)
In this paper we wish to report the complete results of our detailed investigations of this reaction using
a broad spectrum of optically active sulfinamides, alcohols and acidic catalysts and to rationalize the
most interesting and unique discovery that its steric course varies from inversion to predominant
retention and can be influenced by many factors. Preliminary results of our studies have been reported
in two short communications [9,10].
2. Results and Discussion
2.1. Synthesis of Racemic Sulfinates
At the outset of our studies, the synthetic value of the reaction under discussion was checked out
using racemic sulfinamides as substrates. The latter were easily prepared by condensation of sulfinyl
chlorides with amines. It was found that treatment of a series of racemic sulfinamides 1 and 3 with

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alcohols in the presence of trifluoroacetic acid afforded the corresponding sulfinates 5 and 7 in excellent
yields (Scheme 6). In general, the reactions were carried out at 0 °C or at room temperature using an
excess of alcohol and two molar equivalents of trifluoroacetic acid with respect to sulfinamide. Pure
sulfinates were obtained by distillation or column chromatography.
R2
CF3CO2H
R1
S
OR
R1
N
+ ROH
S
R3
O
O
Yield (%)
5a, R1 = p-Tol, R=Me
5b, R1 = p-Tol, R=Et
88
87
88
91
1b, R1 = p-Tol, R2=R3=Et
1c, R1 = p-Tol, R2=R3=Pri
7c, R1 = Me,
7d, R1 = Me,
R=Prn
R=Pri
3, R3 = Me,
R2=R3=Et
Scheme 6. Synthesis of racemic sulfinates from sulfinamides.
Efficient and simple preparation of racemic sulfinates from sulfinamides paved the way for
elaboration of a chiral version of this conversion in which optically active sulfinamides are used.
2.2. Synthesis of Optically Active Sulfinamides
Having in mind the development of a general synthesis of optically active sulfinates and detailed
examination of the stereochemistry of the sulfinamide→sulfinate conversion, a number of optically
active sulfinamides were prepared. Their structures are shown below (Figure 1).
Figure 1. Optically active sulfinamides.
Optically active sulfinamides 1a–d have been prepared essentially according to the method reported
by Montanari et al. from the diastereoisomerically pure (–)-(S)-menthyl p-toluenesulfinate (4) and the
appropriate dialkylaminomagnesium bromides [11]. This reaction was demonstrated to occur with
inversion of configuration at sulfur (Equation 2).
(2)
However, because in our hands this procedure gave results (see Table 1) different from those reported,
it seems desirable to describe briefly our own observations. Firstly, we found that this reaction in

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THF-ethyl ether or ethyl ether solutions is very slow at −45 °C and occurs with a synthetically acceptable
rate only at temperatures above 0 °C. Secondly, the reaction stereoselectivity was found to be dependent
on the reaction temperature, structure of aminomagnesium bromides and sulfinamides formed. For
example, when the reaction of sulfinate (–)-(S)-4 with pyrrolidinemagnesium bromide was carried out
at 0 °C the sulfinamide 1d was isolated with [α]D = +215 (88.8% op). The same reaction carried out at
room temperature gave 1d with much lower optical rotation, [α]D = +135 (50.7% op), but in a
comparable yield.
Table1. Stereoselective synthesis of p-toluenesulfinamides 1 from (−)-(S)-menthyl
p-toluenesulfinate (4).
Sulfinate 4
Reaction Conditions
Sulfinamide 1
[α]D (Me2CO) Temp. (°C) Time (h) No Yield (%) a [α]D (EtOH) (% op) b
−210.0
−210.0
−210.0
−198.0
−202.0
−202.0
25
15
15
25
0
15
7
20
2
15
15
1a
1b
1c
1c
1d
1d
45
41
35
65
75
70
+5.5
3.5
88
54
42
81
51
+105.0
+104.3
+87.0
+215.0
+135.0
25
a Yields after chromatography. b Optical purity values for 1a and 1b were calculated based on reference [11]
and those for 1d determined in this work.
The stereoselectivity of the reaction leading to the sulfinamide 1c, although low, was found to be
independent of the reaction temperature and 1c turned out to be optically stable under the reaction
conditions. However, our additional experiments showed that it undergoes decomposition in the
presence of diisopropylmagnesium bromide. Therefore, the shorter reaction time resulted in a higher
yield of 1c. These observation taken altogether are most probably indicative of an addition-elimination
mechanism responsible for the partial retention of configuration at sulfur during the replacement of the
menthoxy group by the bulky diisopropylamino moiety. The reaction of the sulfinate (−)-(S)-4 with
dimethylaminomagnesium bromide carried out under our experimental conditions afforded the
sulfinamide 1a that was practically racemized. We believe that in this case the racemization of 1a in the
reaction medium is due to a competive symmetrical exchange of the dimethylamino group at the
sulfinyl sulfur.
Optically pure (+)-(S)-benzenesulfinamide (2a) and (+)-(S)-N-methylbenzene sulfinamide (2b) have
been obtained by reduction of the corresponding sulfoximides with aluminum amalgam according to and
in a full agreement with the procedure reported by Johnson [12,13]. Optically active N,N-dimethyl
derivative 2c was prepared by methylation of the lithium salt of (+)-(S)-2b with methyl iodide at low
temperature (Scheme 7), however, with a very low optical purity (15% op).

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Scheme 7. Synthesis of optically active sulfinamides 2.
Interconversion of Sulfinamide Enantiomers
The synthesis of optically active sulfinamides 1 from (–)-(S)-menthyl p-toluenesulfinate (4) described
above afforded only the (+)-(S)-enantiomers of 1. Therefore, in the course of our study and for the sake
of its completeness it was desirable to find a way for the conversion of the sulfinamides (+)-(S)-1 into
their (–)-(R)-enantiomers. This could avoid the tedious preparation of the diastereoisomeric
(+)-(R)-sulfinate 4. Being stimulated by the original work by Johnson [14] on the interconversion of the
sulfoxide enantiomers involving their O-methylation and subsequent alkaline hydrolysis, we decided to
extend this approach to optically active sulfinamides 1. In view of the fact that racemic
N-p-tolylsulfinylpyrrolidine (1d) forms relatively stable O-alkoxysulfonium salts [15,16], the
sulfinamide (+)-(S)-1d, [α]D +215, was reacted with an excess of methyl triflate in nitromethane to give
the corresponding methoxy-N-pyrrolidinyl-p-tolyl-sulfonium salt that was isolated and in a crude state
hydrolysed under mild alkaline conditions affording (–)-(R)-sulfinamide 1d, [α]D −175. It is necessary
to point out in this place that the absolute configuration and optical purity of the starting sulfinamide
(+)-(S)-1d was established by its conversion accompanied by inversion of configuration at sulfur into
the well known (–)-(S)-methyl p-tolyl sulfoxide with optical rotation value, [α]D −120, which
corresponds to 81% of optical purity. Hence, the optical purity of the sulfinamide (–)-(R)-1d, obtained
is equal to 66%. Most probably the loss of stereoselectivity in the alkaline hydrolysis of sulfonium triflate
is due to a competitive attack of the hydroxy anion at the methoxy carbon giving back the starting
(+)-(S)-1d. The reactions discussed above are summarized in Scheme 8.

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Scheme 8. Interconversion of the N-p-tolylsulfinylpyrrolidine (1d) enantiomers.
2.3. Stereoselective Synthesis of Optically Active Sulfinates and Stereochemistry of Their Formation
Having in hand the enantiomerically enriched sulfinamides 1 and 2 we could achieve the main goal
of the present work i.e., the synthesis of optically active sulfinates and determination of the
stereochemistry of their formation in the acid catalyzed alcoholysis of sulfinamides shown in
Equation (3).
(3)
In general, the reaction of the optically active sulfinamides 1 and 2 with various alcohols was caried
out at room temperature using a great excess of alcohols and two molar equivalents of acidic catalyst.
The progress and termination of the alcoholysis was followed polarimetrically. The isolated, analytically
pure sulfinates 5 and 6 were characterized by IR and NMR spectroscopy. Their optical purity and
absolute configuration were estimated from the literature data or via their stereospecific conversion into
optically active methyl p-tolyl sulfoxide [17–19].
In the first series of experiments (+)-(S)-N,N-diethyl p-toluenesulfinamide (1b) was reacted with
primary, secondary and tertiary alcohols in the presence of strong acids to give the corresponding
optically active sulfinates 5, p-TolS(O)OR. In all the investigated cases the obtained 5 exhibited negative
sign of optical rotation which points to their S-configuration at sulfur and formation with inversion of
configuration. An inspection of the results of this set of experiments, which are summarized in Table 2,
revealed that stereoselectivity of the conversion of (+)-(S)-1b into the sulfinates (−)-(S)-5 is markedly
dependent on the structure of alcohols. With primary alcohols, except benzyl alcohol, a full or almost

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full stereoselectivity was observed. The isopropanolysis reaction gave the corresponding sulfinates with
the stereoselectivity from 58% to 84%. Interestingly, it was dependent to some extent on the nature of
acidic catalyst. When t-butanol was used the reaction stereoselectivity was quite low. A similar gradual
decrease in the reaction yields was found on going from primary to tertiary alcohols. Moreover, the
reaction rates were also changed in the same direction. For example, the termination time of
methanolysis estimated polarimetrically is 45 min, isopropanolysis requires 2.5 h to be completed, while
the reaction with t-butanol is finished after 8 h.
Table 2. Stereoselective synthesis of optically active (+)-(S) O-alkyl p-toluenesulfinates (5)
from sulfinamide (+)-(S)-1b.
Stereochemical
Sulfinamide 1b
Sulfinate 5
R
Outcome
Acid
[α]D
(Me2CO)
+107
Op
(%)
88
Yield
(%)
94.0
76.5
90.0
80.0
95.0
84.0
77.0
87.0
53.0
86.0
61.0
55.0
55.5
[α]D
Op
(%)
88
86
66
84
73
77
88
54
50
54
67
23
8.3
Inversion
No
No
Selectivity
(EtOH)
−192.6
−179.2
−137.5
−161.2
−106.5
−85.9
(%)
100.0
100.0
87.7
91.1
92.0
94.7
65.0
84.7
79.0
81.5
88.5
63.7
54.8
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
CF3CO2H
PhSO3H
5a
5b
5b
5c
Me
Et
100
100
75.5
98.2
84.0
89.5
30
+105
86
+107
88
CF3CO2H
PhSO3H
Et
Prn
+105
86
+106
87
PhSO3H
5e CH2=CHCH2
+105
86
CF3CO2H
PhSO3H
5f
5g
5d
5d
5d
5d
5i
HC=CCH2
PhCH2
Pri
+105
86
−22.6
+96
78.5
86
CF3CO2H
PhSO3H
−109.3
−100.7
−107.9
−134.2
−29.85
−10.6
69.5
58
+105
Pri
Pri
Pri
Bui
+104.7
+105
86
CF3CO2H
HSbF6
62.7
77
86
+104.7
+104.7
86
CF3CO2H
CF3SO3+CF3CO2H
27.4
9.7
86
5i
Bui
These features of the alcoholysis of (+)-(S)-1b mentioned above are due to its partial racemization
and decomposition under the acidic reaction conditions. For instance, when the reaction of (+)-(S)-1b,
[α]D +96 (78.5% op), with t-butanol was quenched at the half-conversion, it was recovered with much
lower optical rotation equal to [α]D +45 (39.8% op) whereas the sulfinate 5i was isolated with almost the
same optical rotation, [α]D −32.5 (25% op), as that when the reaction was complete. Moreover, it was
found that the sulfinamide (+)-(S)-1b in the presence of strong acids undergoes very fast racemization
and decomposition in nonpolar solvents (CCl4, CHCl3) which occur slower in alcohols.
From the dynamic stereochemistry viewpoint, much more interesting results were obtained when
(+)-(S)-N,N-diisopropyl p-toluenesulfinamide (1c) was used as a substrate in acid catalyzed alcoholysis
reaction. In contrast to (+)-1b, (+)-1c was found to be optically and chemically stable under the acidic
reaction conditions. In Table 3 the selected results of this series of experiments are summarized. Thus,
with primary alcohols (MeOH, EtOH, nPrOH) the laevorotatory (S)-sulfinates 5a, 5b and 5c were formed
with predominant inversion of configuration. However, the reaction of (+)-(S)-1c with isopropanol, its
hexadeutero and hexafluoro analogues, cyclohexanol and cyclopentanol afforded unexpectedly the
corresponding dextroratory sulfinates 5d, 5d', 5d'', 5j and 5k with predominant retention of
configuration. The percentage of retention was especially high with cyclohexanol (74.5%). These

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findings show clearly that steric factors in the attacking alcohol and departing dialkylamino group exert
important influence on the stereoselectivity and, first of all, on steric course of the investigated reaction.
Therefore, combination of a sterically hindered alcohol as a nucleophile and a bulky leaving
diisopropylamino group is mainly responsible for the reversal of stereochemistry from inversion to retention.
Table 3. Stereoselective synthesis of optically active O-alkyl p-toluenesulfinates (5),
p-TolS(O)OR, from sulfinamide (+)-(S)-1c using trifluoroacetic acid as catalyst.
Sulfinamide 1c
Sulfinate 5
[α]D (EtOH) Op. (%)
Inversion (%) or Retention (%)
[α]D (Me2CO) Op (%) No
R
Me
Et
+94.4
+94.4
+94.4
+94.4
+86.9
+86.9
+95.0
+95.0
+95.0
+95.0
45.3
45.3
45.3
45.3
42.3
42.3
45.3
45.3
45.3
45.3
5a
5b
5c
5d
−35.0
−35.0
−13.9
+15.8
+10.1
+3.4
16.0
3.4
7.3
7.9
4.6
1.7
22.4
1.8
2.3
1.4
68.75, Inv
53.75, Inv
58.0, Inv
58.7, Ret
55.5, Ret
52.0, Ret
74.5, Ret
52.0, Ret
52.5, Inv
51.5, Inv
Prn
Pri
5d' (CD3)2CH
5h (CF3)2CH
5j
5k
5l
Hexc
Penc
+41.0
+3.3
Et2CH
Bui
−4.4
5m
−2.7
In an extention of the present work the reaction of optically active benzenesulfinamides (+)-(S) 2a–c
with methanol and ethanol catalyzed by trifluoroacetic acid was investigated. As the results collected in
Table 4 show, the sulfinates (–)-6 were formed with inversion of configuration and variable degree of
stereoselectivity. A full inversion of configuration was observed with (+)-(S)-N,N-dimethyl
benzenesulfinamide (2c).
Table 4. Stereoselective synthesis of optically active O-alkyl benzenesulfinates (6),
PhS(O)OR, from benzenesulfinamides (+)-(S)-2 using trifluoroacetic acid as catalyst.
Sulfinamide 2
Sulfinate 6
Inversion (%)
No [α]D (Me2CO) Op (%) No
R
[α]D (EtOH) Op. (%)
2a
2a
2b
2b
2c
2c
+85.7
+85.7
+170.0
+170.0
+39.0
+39.0
100
100
100
100
15.6
15.6
6a Me
6b Et
6a Me
6b Et
6a Me
6b Et
−64.0z
−23.0
24.0
10.8
76.5
78.0
15.6
15.6
62.0
55.4
−204.2
−167.0
−45.5
87.2
89.0
100.0
100.0
−33.4
Having in hand both enantiomerically enriched N-p-toluenesulfinylpyrrolidines (+)-(S)-1d and
(–)-(R)-1d prepared as shown in Scheme 8, we were also able to determine the steric course of their
methanolysis. It turned out that in this case the corresponding enantiomeric sulfinates 5a were formed
in a stereospecific way with inversion of configuration. It is worthy to point out that the synthesis of
both enantiomeric methyl sulfinates 5a (Scheme 9) demonstrates how they can be prepared starting from
only one form of the diastereoisomeric menthyl p-toluenesulfinate (–)-(S)-4.

Molecules 2015, 20
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Scheme 9. Synthesis of enantiomeric O-methyl p-toluenesulfinates (1a) from
N-p-tolylsulfinylpyrrolidines (1d).
The stereochemistry of the acid-catalyzed alcoholysis of sulfinamides may also be affected by
addition of silver perchlorate and other inorganic salts. In a preliminary experiment we found that
isopropanolysis of (+)-(S)-N,N-diethyl p-toluenesulfinamide (1b) catalyzed by trifluoroacetic acid and
carried out in the presence of silver perchlorate occurred with a higher stereoselectivity (92% inversion)
than that observed in its absence (84.7% inversion). Being stimulated by this observation, a detailed
study was undertaken on the effect of added inorganic salts on the steric course of the acid catalyzed
alcoholysis of the sulfinamide (+)-(S)-1c (Equation (4)). The results are outlined in Table 5.
(4)
Table 5. The effect of silver perchlorate on steric course of the acid catalyzed alcoholysis of
sulfinamide (+)-(S)-1c.
Sulfinate 5 Inversion/Retention Ratio with AgClO4 Inversion/Retention Ratio without AgClO4
5a, Me
5b, Et
5c, Prn
5d, Pri
5j, Hexc
100/0
91/9
68.7/31.3
53.7/46.3
58.0/42.0
41.3/58.7
25.5/74.5
100/0
82/18
65.5/34.5
As it is seen, silver perchlorate favours the formation of the sulfinates 5 with inversion of
configuration. The most impressive change was observed with isopropanol and cyclohexanol which
reacted with (+)-(S)-1c in the absence of this inorganic salt with prevailing retention of configuration.

Molecules 2015, 20
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The effect of silver perchlorate discussed above prompted us to investigate the stereochemistry of the
acid catalyzed reaction of the sulfinamide (+)-(S)-1c with isopropanol in the presence of other inorganic
salts (Equation (5)). The results of this set of experiments are collected below.
(5)
An inspection of the results collected in Tables 5 and 6 demonstrates that the added inorganic salts
are able to radically change the overall stereochemistry of the investigated reaction and both the cation
(K) and anion (A) play an important role in this regard. In other words, a new tool was found which
allows us to control and design the reaction stereochemistry.
Table 6. The effect of inorganic salts (KA) on the steric course of the acid catalyzed
isopropanolysis of sulfinamide (+)-(S)-1c.
KA
Prevailing Stereochemistry
55% Retention
KA
Prevailing Stereochemistry
73.0% Inversion
CoCl2
Co(NO3)3
Ni(NO3)2
AgClO4
AgNO3
Ce(NO3)3
CrCl3
NiC2O4
Ag2CO3
Ag2Cr2O7
Ag2SO4
HgBr2
71% Retention
66.0% Inversion
65% Retention
82.0% Inversion
67% Retention
53.0% Inversion
63% Retention
71.0% Inversion
69% Retention
50.5% Inversion
Cd(OAc)2
68% Retention
In contrast to significant influence of inorganic salts, the reaction stereochemistry was found to be
slightly solvent dependent (see Equation (6) and Table 7). Although only four solvents were tested, it
seems that polar solvents may favour retention of configuration.
(6)
Table 7. The effect of solvents on steric course of the acid catalyzed isopropanolysis of
sulfinamide (+)-(S)-1c.
Solvent Inv/Ret Ratio
CHCl3
C6H6
C6H14
55/45
56/46
58/42
49/51
n
CH3CN
2.4. Reaction Kinetics
The observation of a unique stereochemistry of the acid catalyzed alcoholysis of optically active
sulfinamides 5, which may vary from inversion to predominant retention of configuration at the
stereogenic sulfur atom, and its sensitivity to internal (the structure of both reactants) and external (the
presence of inorganic salts) factors prompted us to determine the reaction kinetics as integral part of the
present study aimed at elucidation of the reaction mechanism.

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Two model reactions were chosen for kinetic investigations i.e., isopropanolysis of (+)-(S)-N,N-diethyl
p-toluenesulfinamide (1b) and N,N-diisopropyl p-toluenesulfinamide (1c) with the presence of
trifluoroacetic acid. The latter was used in two molar excess (0.11752 mol/L) in respect to sulfinamide
(0.05876 mol/L) and both reactions were carried out in isopropanol as a solvent used in 200 molar excess.
The progress of the isopropanolysis reaction was followed polarimetrically. The calculated pseudo-first
order rate constants at various temperatures (298–318 K) are listed in Table 8. For comparison purposes,
the pseudo-first order rate constant of the reaction of (+)-(S)-N,N-dimethyl p-toluenesulfinamide (1a) at
310 K was determined. Based on the variable temperature measurements the energy and entropy of
activation (at 25 °C) have been calculated and are shown in Table 9:
Table 8. Kinetic data on alcoholysis of arenesulfinamides, ArS(O)NR1R2, catalyzed by
trifluoroacetic acid.
Run
1
Sulfinamide
Alcohol Temp. (K)
k1(10−4s−1)
16.0 ± 0.35
2.32 ± 0.35
3.75 ± 0.09
5.22 ± 0.10
8.64 ± 0.15
19.5 ± 0.30
33.0 ± 1.2
1a, p-TolS(O)NMe2 PriOH
310.0
298.0
307.1
310.1
318.0
328.0
298.0
298.0
303.7
310.0
316.7
310.0
2
1b,
1b,
3
4
1b, p-TolS(O)NEt2
PriOH
5
1b,
1b,
6
7
1b, p-TolS(O)NEt2 MeOH
1b, p-TolS(O)NEt2 CH3OD
8
47.9 ± 1.5
9
1c,
0.521 ± 0.015
0.935 ± 0.04
1.57 ± 0.04
5.60 ± 0.10
PriOH
i
10 1c, p-TolS(O)NPr2
11 1c,
12
2, p-TolS(O)NMe2 PriOH
Table 9. Activation energy and entropy for isopropanolysis of sulfinamide 1b and 1c
catalyzed by trifluoroacetic acid.
Reaction Ea (kJ mol−1/kJ mol−1) ΔS≠ (J mol−1 k−1/e.u.)
1b
1c
58.3/14
68.1/16.3
−145.5/−34.8
−110.4/−26.4
The values of energy and entropy of activation are characteristic for a typical bimolecular substitution
reaction. The gradual decrease in the reaction rate constants measured at 310 K on going from isopropanolysis
of 1a (k = 16 ± 0.35) to 1b (k = 5.22 ± 0.1) and to 1c (k = 0.935 ± 0.04) indicates that an increase of
steric bulk at the amido-nitrogen atom is responsible for these changes. Similary, the rate constant (at
298 K) of isopropanolysis of 1b (k = 2.32 ± 0.08) is much smaller than that for methanolysis of 1b
(k = 33 ± 1.2) determined at the same temperature. In this case, the difference in rate constants is due to
introduction of a steric bulk to reacting alcohol as a nucleophilic reagent. Such a relationship between
reaction rate constatnts and steric hindrance is typical for bimolecular nucleophilic substitution reactions.
In addition to calculation of the rate constant for the reaction of (+)-(S)-1b with methanol, that plays
here dual role of a nucleophile and a solvent, the corresponding rate constant in deuterated methanol,
CH3OD, was estimated. This allowed us to calculate the kinetic isotopic effect of solvent equal to 1.45.

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(7)
This value of kinetic isotopic effect of solvent points also to bimolecular reaction mechanism.
Moreover, it indicates that protonation is the first and fast reaction step and does not determine the
reaction rate. Interestingly, a very similar value of the kinetic isotopic effect of solvent was reported by
Tillet who investigated hydrolysis of N-aryl arenesulfinamides under acidic conditions [20]. Moreover,
the recent investigation of the hydrolysis rates of N-alkyl and N-aryl methanesulfinamides led the
authors [21] to the conclusion that if nitrogen protonation does occur, it is not the rate-limiting step.
In order to rationalize our most interesting observation of predominant retention of configuration at
sulfur in the reaction of the sulfinamide (+)-(S)-1c with isopropanol catalyzed by trifluoroacetic acid we
took into consideration a possible two-step mechanism for this reaction involving the formation of a
mixed anhydride as intermediate product (Equation (8)). Assuming that its formation and subsequent
isopropanolysis could occur with inversion of configuration, the sulfinate (+)-(R)-5d should be formed
with retention of configuration.
(8)
To support or rule out this mechanistic possibility, the rate constant and steric course of the reaction
were determined at various concentrations of the added sodium trifluoroacetate (Equation (9)). It was
anticipated that the presence of trifluoroacetate anion should facilitate the formation of mixed anhydride
and increase the percentage of retention.
(9)
As it is seen in Table 10, the results of the above kinetic measurements are not consistent with the
hypothesis of a two-step mechanism involving mixed anhydride and double inversion. Therefore, the
diverse stereochemistry of the reaction under discussion is most probably due to a competition between
the inversion and retention processes.
Table 10. The effect of concentration of sodium trifluoroacetate on the rate constants and
stereochemistry of the reaction 9.
Concentration of CF3CO2Na
Rate Contant
Prevailing Stereochemistry
58% Ret
0 mol
16 mol
32 mol
k = (2.73 ± 0.26) 10−4 s−1
k = (3.29 ± 0.06) 10−4 s−1
k = (3.56 ± 0.18) 10−4 s−1
58% Inv
59% Inv
2.5. Discussion
Before discussing the mechanism of the acid catalyzed alcoholysis of sulfinamides it is necessary to
emphasize that the stereochemistry of this reaction studied with optically active sulfinamides shows
unique features. Namely, it was found that optically active sulfinates are formed with a full or

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predominant inversion or predominant retention of configuration at stereogenic sulfur. The predominant
retention of configuration was observed with bulky dialkylamido groups in sulfinamides and with
sterically demanding alkyl substituents in alcohols. Moreover, the stereochemical outcome of the
alcoholysis reaction may be changed from inversion to retention and vice versa by adding inorganic salts
to the reaction medium. To a lesser extent the steric course is influenced by the nature of acid catalysts
and solvents.
On the other hand, in contrast to the unusual stereochemistry, kinetic measurements revealed that the
acid catalyzed alcoholysis of sulfinamides is a typical bimolecular substitution reaction at sulfur and
protonation is a fast and not rate-detemining step. Although the sulfinamide molecule may be protonated
on the nitrogen and oxygen atoms, it is evident that the nitrogen atom is protonated because in this way
a leaving dialkylammonium group is created. Our comparative studies on the spectral properties of
neutral and protonated sulfinamides led us to the same conclusion [22].
Figure 2. Hexaasterane graph showing all possible sulfuranes 1 to 20 internconnected
by pseudorotations (for the sake of clarity hydrogens on the nitrogen and oxygen atoms
are omitted).
All the stereochemical observations on our reaction summarized above may be best rationalized in
terms of the addition-elimination mechanism, A-E, involving sulfurane intermediates that are able to
undergo pseudorotation. Theoretically, addition of an alcohol to the protonated sulfinamide may results
in the formation of twenty chiral sulfuranes interconnected by thirty pseudorotations. Four sulfuranes
are formed by nucleophilic attack of an alcohol on four different walls of the protonated (S)-sulfinamide
tetrahedron. Another six sulfurane structures result from the attact of an alcohol on six edges of the

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tetrahedron. The remaining ten sulfuranes are enantiomeric structures which may be derived from the
(R)-sulfinamide. All these twenty sulfuranes are in equilibrium due to a very low energy for
pseudorotation. They are displayed in the form of a hexaasterane graph, originally proposed by Mislow [23]
for pentacoordinate phosphoranes, which was applied by us to discuss the stereochemical outcome
(retention or inversion) of the alcoholysis of sulfinamides (Figure 2).
As it is now generally accepted that in nucleophilic substitution reactions apical entry and apical
departure are preferred over the equatorial counterparts [24], only four sulfuranes (1, 6, 8, and 14)
resulting from the attack on four walls remain as candidates for the initial products of addition of an
alcohol to (S)-sulfinamide (Scheme 10).
Scheme 10. Sulfuranes formed by nucleophilic attack (apical entry) on four walls of the
protonated (S)-sulfinamide 1 tetrahedron.
In further considerations we assumed that, after addition, the negatively charged sulfinyl oxygen atom
is protonated. Among these four structures the highest probability of formation should have the sulfurane
structure 14 because arrangement of substituents in a trigonal bipyramid is optimal from the viewpoint
of apicophilicity of ligands. Due to the diapical disposal of the entering alkoxy group and leaving
protonated dialkylamido group its direct decomposition should afford sulfinic acid ester 5 as a
substitution product with inverted configuration at sulfur. In fact, this steric course has been observed
for the reaction of alcohols with (+)-(S)-N,N-diethyl p-toluenesulfinamide (1b) and with
(+)-(S)-benzenesulfinamide (2a) (+)-(S)-N-methyl benzenesulfinamide (2b) and (+)-(S)-N,N-dimethyl
benzenesulfinamide (2c). Interestingly, the acid catalyzed methanolysis of both enantiomers of
N-p-tolyslsulfinylpyrrolidine (1d) was occurring with a full inversion of configuration. However, as it
was described earlier, the reactions (+)-(S)-N,N-diisopropyl p-toluenesulfinamide (1c) with secondary
alcohols gave the corresponding sulfinates 5 with predominant retention of configuration. In this case,
in the initially formed sulfurane 14 apical positions are occupied by two bulky groups, namely, the
protonated diisopropylamino group having a tetrahedral structure and bulky alkoxy group. It is
reasonable to expect that steric repulsive interactions between the latter groups and equatorial
substituents (a-e angle ~ 90°) force the sulfurane 14 to pseudorotate to a new trigonal bipyramidal
structure where a number of unfavourable interactions will be diminished. Thus, the pseudorotation of
14 using the lone electron pair as a pivot leads to the sulfurane 15 where two bulky dialkylammonium
group and alkoxy substituent are placed in equatorial positions (e-e angle ~110°), and the steric

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interactions of apical and equatorial substituents are smaller. The next pseudorotation of 15 with the
dialkylammonium group as a pivot results in the formation of the sulfurane 3. In this structure the
unfavourable apical position of the lone electron pair is compensated by the right apical placement of a
strongly apicophilic alkoxy group. To complete the retention pathway it is necessary to put the departing
dialkylammonium moiety into apical position via pseudorotation of 3. The resulting sulfurane 9
decomposes to the sulfinate 5 with retention of configuration. The most probable and shortest pathways
for inversion and retention are shown in Scheme 11.
Scheme 11. Two competing inversion and retention pathways in the acid catalyzed
alcoholysis of sulfinamides 1.
The relative stability and concentration of the sulfuranes 14 and 9 will determine the ratio between
the sulfinates (−)-(S)-5 and (+)-(R)-5 formed.
The important effect of the added inorganic salts on the steric course of the acid catalyzed alcoholysis
of sulfinamides is, at present, very difficult to rationalize and requires further studies. Although it is evident
that sulfinamides and their protonated species may form complexes with inorganic salts, their structures
are unknown and sometimes hard to predict. As in the case of protonation of sulfinamides, the salt cations
may be coordinated to three different sulfinamide sites, to sulfur, oxygen or nitrogen (Scheme 12).
Scheme 12. Preferred steric course of the acid catalysed alcoholysis of sulfinamides in the
presence of silver perchlorate.

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Most probably silver perchlorate, that has been found to strongly prefer the inversion pathway, is
coordinated to the protonated sulfinamide 1 in such a way that silver cation, as a soft metal ion, is bound
to sulfur via its electron pair, while perchlorate anion, still being under control of silver cation, forms
hydrogen bond with the ammonium nitrogen atom. Addition of alcohol to this complex affords the
sulfurane 14' with the same mode of silver perchlorate coordination. In this way, the energy for
pseudorotation of 14' is increased as compared with that of uncomplexed 14 and the direct apical
departure of the dialkylammonium moiety is facilitated affording the sulfinates 5 with inverted
configuration. However, the effect of other salts on the stereochemical outcome of our reaction is still
obscure and should be investigated. Finally, it is necessary to point out that formation of
sulfurane intermediates was postulated not only in the nucleophilic substitution reactions at the
stereogenic sulfur atom [25,26] but also in many diverse chemical reactions [27–32] and enzymatic
biotransformations [33] of organic sulfur compounds.
3. Experimental Section
3.1. General
Melting and boiling points are uncorrected. THF was distilled over K/benzophenone and benzene was
distilled over Na wire, both immediately before use. Chloroform was distilled over P2O5 and stored over
anhydrous Na2CO3. Thin layer chromatography (TLC) was conducted on Silica Gel 60 F254 TLC
purchased from Merck (Darmstadt, Germany). Column chromatography was performed with Merck
Silica gel (200–300 mesh). NMR spectra were recorded at 20 °C with Jeol C 60 HL, Tesla BS-487 C
1
and Bruker HX 90 (Karlsruhe, Germany). H-NMR chemical shifts are reported relative to TMS as
internal starndard. IR spectra were recorded with Specord 71 IR Carl Zeiss and Perkin-Elmer
spectrophotometers (Jena, Germany). Optical rotations were measured at 20 °C using a Perkin-Elmer
141 photopolarimeter. All reactions under anhydrous conditions were carried out under a dry argon
atmosphere. Elemental analyses were done in the Microanalytical Laboratory of the institute. The correct
microanalysis data (H, ±0.3%, C, ±0.4%, S, ±0.4%) were obtained for all new compounds prepared in
this work.
3.2. Synthesis of Optically Active p-toluenesulfinamides 1
General Procedure
To a stirred solution of n-propylmagnesium bromide (0.03 mol) in ethyl ether (50 mL) a solution of
the proper amine (0.03 mol) in ethyl ether (20 mL) was added at room temperature. After 20 min, a
solution of (–)-menthyl p-toluenesulfinate (4) (0.01 mol) in ethyl eter (20 mL) was added at given
temperature. The reaction mixture was stirred for the appropriate time (see below). Then, the reaction
solution was washed with a saturated aqueous solution of NH4Cl (2 × 40 mL), 3% aqueous solution of
HCl (1 × 20 mL) and 5% aqueous solution of Na2CO3 (2 × 20 mL). The organic layer was dried with
MgSO4 and the solvent evaporated. The reaction product 1 was purified by column chromatography.
Analytically pure products 1 were characterized by 1H-NMR and IR spectroscopy.

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(+)-(S)-N,N-Dimethyl-p-toluenesulfinamide (1a). The reaction of (−)-4, [α]D = −210, (acetone) with
dimethylaminomagnesium bromide was carried out at room temperature (25 °C) for 15 h. The crude
product isolated as described above was purified by column chromatography (ethyl ether/n-hexane, 1:2)
1
to afford the pure sulfinamide 1a in 45% yield; [α]D = +5.5 (c, 1.65, EtOH) (3.5% op); H-NMR
(60 MHz, CDCl3) δ 7.45 and 7.11 (AB-system, 4H, H-Ar, JAB = 8 Hz); 2.85 (s, 6H, (CH3)2N); 2.35 (s,
3H, CH3-Ar); IR (film, cm −1) ν 1070, 1085 (S=O).
(+)-(S)-N,N-Diethyl-p-toluenesulfinamide (1b). The reaction of (−)-4, [α]D = −210 (acetone) with
N,N-diethylaminomagnesium bromide was carried out at 15 °C for 7 h. The crude product was purified
by column chromatography (silica gel, ethyl eter/n-hexane, 1:2) to give (+)-(S)-1b, as a colourless liquid
1
in 41% yield; [α]D = +105 (c, 1.48, EtOH) (88% op). H-NMR (60 MHz, CDCl3) δ 7.45 and 7.20
(AB-system, 4H, H-Ar, JAB=8.1 Hz); 3.00 (q, 4H, (CH3CH2)2N, J = 7.0 Hz); 2.35 (s, 3H, CH3-Ar); 1.10
(t, 6H, (CH3CH2)N, J = 7Hz); IR (film, cm−1), ν 1060, 1080 (S=O).
(+)-(S)-N,N-Diisopropyl-p-toluenesulfinamide (1c). The raction of (−)-4, [α]D = −210 (acetone), with
diisopropylmagnesium chloride carried out at 15 °C for 20 h produced sulfinamide 1c which after typical
work up was purified by column chromatography (ethyl ether/n-hexane, 1:4). The pure sulfinamide 1c
1
as a liquid was obtained in 35% yield; [α]D = + 104.3 (c, 1.12; EtOH) (50% op); H-NMR (60MHz,
CDCl3) δ 7.35 and 7.15 (AB-system, 4H, H-Ar, JAB = 8.0 Hz); 3.43 (sp, 2H, (CH3)2CHN, J = 8Hz); 2.35
(s, 3H, CH3-Ar); 1.35 (d, 6H, (CH3)2CHN, J = 6.5 Hz); 1.05 (d, 6H, (CH3)2CHN, J = 6.5 Hz); IR
(toluene, cm−1) ν 1115 (S=O).
(+)-(S)-N-p-Tolylsulfinylpyrrolidine (1d). Treatment of (−)-4, [α]D = −202 (acetoe) with
pyrrolidinemagnesium bromide at 0 °C for 15 h gave the desired sulfinamide 1d in 74% yield;
[α]D = +215 (c, 1.5; EtOH) (80.8% op); mp. 43–49 °C; 1H-NMR (60 MHz, CD3NO2) δ 7.53. and 7.10
(AB-system, 4H, H-Ar, JAB = 8 Hz); 3.41–2.57 (m, 4H, (CH2CH2)2N); 2.27 (s, 3H, CH3-Ar); 1.85–1.55
(m, 4H, (CH2CH2)2N);
(−)-(S)-Methyl p-tolyl sulfoxide from (+)-(S)-1d. To a solution of methyllithium (0.015 mol) in ethyl
ether (20 mL) a solution of (+)-(S)-1d, [α]D = 215, (0.005 mol) in ethyl ether (20 mL) was added at room
temperature. After 2 h stirring at room temperature, the reaction mixture was quenched with water. The
separated ether layer was washed with water (2 × 10 mL) and the combined water layers were extracted
with n-hexane (3 × 25 mL) and then with chloroform (3 × 25 mL). The chloroform extracts were dried over
MgSO4. After evaporation of the solvent, the title sulfoxide was obtained by TLC (ethyl ether/n-hexane, 5:1)
in 70% yield; [α]D = −119.6 (c, 1.1, ethanol) (80.8% op), mp 71–73 °C, 1H-NMR (60 MHz, CDCl3) δ
7.50 and 7.30 (AB-system, 4H, H-Ar, JAB = 8 Hz), 2.60 (s, 3H, CH3-SO), 2.35 (s, 3H, CH3-Ar); IR (KBr)
ν 1060, 1080 (S=O).
(+)-(S)-Benzenesulfinamide (2a). According to the procedure described by Johnson, the reduction of
(+)-(S)-S-methyl-S-phenyl-sulfoxyimine [α]D = +36.5 (c, 2.0, acetone) with aluminum amalgam was
carried out in a water-THF solution (1:9) for 2 h. After standard work up, the crude reaction product was
purified by chromatography (silica gel 200–300 mesh, acetone/n-heptane, 2:1) to give (+)-(S)-2a as a

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white solid, mp. 95–101 °C, [α]D = +85.7 (c, 1.82; acetone) [lit. [10], [α]D = 82.9; mp. 102–103 °C after
crystallization from ethyl ether]; 1H-NMR (60MHz, CDCl3) δ 7.90–7.35 (m, 5H, H-Ar); 3.45 (s, 2H, H2N).
(+)-(S)-N-Methyl benzenesulfinamide (2b). Reduction of (+)-(S)-N,S-dimethyl-S-phenyl-sulfoximine,
[α]D = +183 (c, 1.5 acetone), with aluminum amalgam in a H2O-THF (1:9) carried out as described above
gave the desired product 2b which, after stardard work up, was purified by chromatography (silica gel
200–300 mesh), acetone/n-heptane, 3:2) to give the pure (+)-(S)-2b as a solid, mp. 49–52 °C; [α]D = 170
(c, 1.21; acetone); 1H-NMR (60 MHz, CD3OD) δ 7.80–7.45 (m, 5H, H-Ar); 4.80 (s, 1H, NH); 2.40 (s,
3H, CH3-Ar).
(+)-(S)-N,N-Dimethyl benzenesulfinamide (2c). To a solution of (+)-(S)-2b (0.01 mol) in THF a solution
of n-butyllithium (0.01 mol) in n-hexane was added at −70 °C. The reaction mixture was stirred at this
temperature for 1 h. Then, methyl iodide (0.01 mol) was added and stirring was continued for additional
1 h, warming slowly the reaction solution to room temperature (20 °C). The reaction solution was washed
with water (25 mL) and the organic layer dried over dry MgSO4. Removal of the solvent gave the residue,
which was purified by column chromatography (ethyl ether/n-hexane, 1:2) to afford in 55% yield the
pure (+)-(S)-2c, [α]D = +39 (c, 1.28, acetone) (15.6% op); 1H-NMR (60 MHz, CDCl3) δ 7.75–7.30 (m, 5H,
H-Ar); 2.70 (s, 6H, (CH3)2N)
Conversion of (+)-(S)–N-p-tolylsulfinylpyrrolidine (1d) into its enantiomer (−)-(R)-1d. To a solution of
(+)-1d, [α]D =+215 (81% op) (0.002 mol) in nitromethane (30 mL) methyl triflate (0.004 mol) was added
at room temperature. After 30 min, the solvent and an excess of methyl triflate were evaporated to give
the corresponding sulfonium salt [1H-NMR (60 MHz, CD3NO2) δ 730–780 (q, 4H), 4.25 (s, 3H),
3.10–3.90 (m, 4H), 2.39 (s, 3H). The crude sulfonium triflate obtained as above was dissolved
immediately in water (30 mL) and a solution of sodium hydroxide (0.02 N) was added, When pH of the
reaction solution reached the value above 7 (phenolphthalein assay, red colour) the reaction was
terminated. The water solution was washed with n-hexane (3 × 40 mL) and extracted with chloroform
(1 × 20 mL). The combined organic extracts were dried over MgSO4 and evaporated to give the
sulfinamide (−)-(R)-1d as a white solid in 70% yield; [α]D = −175 (c, 1.16 ethanol) (65.8% op), mp.
1
43–45 °C; H-NMR (60 MHz, CD3NO2) δ 7.50. and 7.10 (AB-system, 4H, H-Ar, JAB = 8 Hz); 3.41–
2.57 (m, 4H, (CH2CH2)2N); 2.27 (s, 3H, CH3-Ar); 1.85–1.55 (m, 4H, (CH2CH2)2N).
3.3. Optically Active Alkyl p-Toluenesulfinates 5 and Alkyl Benzenesulfinates 6 from Acid Catalyzed
Alcoholysis of Optically Active Sulfinamides 1 and 2
General Procedure
To a solution of sulfinamide 1 or 2 (0.001 mol) in an appropriate alcohol (5 mL) was added acidic
catalyst (0.002 mol) The reaction progress was followed polarimetrically. When the reaction was
completed, water (25 mL) was added and the resulting solution was extracted with n-hexane (2 × 20 mL)
and chloroform (1 × 20 mL). The combined organic extracts were dried over MgSO4. After evaporation
of the solvents, sulfinate esters 5 and 6 were purified by column chromatography (silica gel 200–300 mesh,

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n-hexane-ethyl ether, 10:1). Their optical rotations, optical purities and absolute configurations are given
in Tables 2–4. In Table 11 the selected spectroscopic data of sulfinates 5 and 6 are collected.
Table 11. Spectroscopic properties of O-alkyl arenesulfinates 5 and 6 ArS(O)OR’.
No
5a
Ar
R
IR(S=O) cm−1
1H-NMR (60 MHz, CDCl3 δ (ppm)
7.45 and 7.25 (AB-system, 4H, H-Ar, JAB = 7.5 Hz); 3.30 (s, 3H,
CH3O); 2.35 (s, 3H, CH3-Ar).
p-Tol
Me
1126
7.45 and 7.25 (AB-system, 4H, H-Ar, JAB = 8 Hz); 3.90 and 3.50
(ABX3-system, 2H, CH3-O, JAB = 10.5 Hz, JAX = JBX = 7 Hz); 2.40 (s,
3H, CH3-Ar); 1.20 (t, 3H, CH3CH2, J = 7 Hz)
5b
5c
p-Tol
p-Tol
p-Tol
Et
Prn
Pri
1120
1125
7.45 and 7.23 (AB-system, 4H, H-Ar, JAB = 8.0 Hz); 3.82 and 3.44
(ABX2-system, 2H, CH2O, JAB = 8.5 Hz, JAX = JBX = 7 Hz); 1.60 (sx,
2H, CH3CH2, J = 7 Hz); 0.9 (t, 3H, CH3CH2, J = 7Hz)
7.50 and 7.30 (AB-syst, 4H, H-Ar, JAB = 8 Hz); 4.50 (sp, 1H,
(CH3)2CHO, J = 6 Hz); 2,35 (s, 3H, CH3-Ar); 1.31 and 1.18 (d,d, 6H,
(CH3)2CH, J = 6 Hz)
5d
1130
1130
–
7.45 and 7.20 (AB-system, 4H, H-Ar, JAB = 8.5 Hz); 4.44 (m, 1H,
CH(CD3)2); 2.35 (s,3H, CH3-Ar)
5d'
p-Tol (CD3)2CH
7.50 and 7.30 (AB-system, 4H, H-Ar. JAB = 8.5 Hz) 4.35 (sp, 1H,
(CF3)2CH, JF-H = 6 Hz); 2.40 (s, 3H, CH3-Ar).19F-NMR (CDCl3); δ =
+95.2, (d, 6F, (CF3)CH, JF-H = 6Hz) (C6F6 as internal standard)
7.40 and 7.25 (AB-system, 4H, H-Ar, JAB = 8 Hz); 4.10–4.35 (m, 1H,
CHO); 2.35 (s, 3H, CH3-Ar); 2.10–1.05 (m, 10H, Cy-H)
7.45 and 7.20 (AB-system, 4H, H-Ar, JAB = 8 Hz); 4.60(m, 1H, CHO);
2.40 (s, 3H, CH3-Ar);1.95–1.30 (m, 8H, Cp-H)
5d'' p-Tol
(CF3)2CH
5j
p-Tol
p-Tol
Hexc
Penc
1130
1125
5k
7.60 and 7.35 (AB-system, 4H, H-Ar, JAB = 8 Hz); 4.00–3.20 (m, 2H,
OCH2CH); 2.40 (s, 3H, CH3-Ar); 1.85 (m, 1H, (CH3)2CH); 0.90 (d, 6H,
(CH3)2CH, J = 6 Hz)
5m
5n
5l
p-Tol
p-Tol
p-Tol
Bui
But
1128
1125
–
7.45 and 7.20 (AB-system, 4H, H-Ar, JAB = 8.5 Hz); 2.35 (s, 3H,
CH3Ar); 1.45 (s, 9H, (CH3)3CO)
7.70 and 7.35 (AB-system, 4H, H-Ar, JAB = 8 Hz); 4.20 (mc, 1H, CHO);
2.35 (s, 3H, CH3-Ar); 1.90–1.20 (m, 4H, CH3CH2-O); 0.95 and 0.90 (t,t,
6H, CH3CH2CHO, J = 6 Hz)
Pentyl-3
6a
6b
Ph
P
Me
Et
1125
–
7.60–7.35 (m, 5H, H-Ar), 3.32 (s, 3H, CH3O)
7.70–7.40 (m, 5H, H-Ar), 4.00 (q, 2H, CH3CH2O, J = 7 Hz), 1.30 (t, 3H,
CH3CH2, J = 7 Hz)
s-singlet, d-doublet, dd-double doublet, d,d-two doublets, t-triplet, t,t-two triplets, q-quartet, sx-sextet,
sp-septet, m-multiplet, Penc-cyclopentyl, Hexc-cyclohexyl.
3.4. Conversion of Selected Sulfinates 5 into Methyl p-tolyl Sulfoxide
General Procedure
To a freshly prepared methylmagnesium iodide (0.015 mol) a solution of the appropriate sulfinate
(0.0005 mol) in ether (50 mL) was added dropwise. After stirring for 2 h, to the reaction mixture
saturated NH4Cl aqueous solution (1 × 30 mL) was added. The separated ethereal layer was washed with

Molecules 2015, 20
2970
3% aqueous solution of HCl (1 × 10 mL) and 3% aqueous solution of NaHCO4 (2 × 20 mL). The organic
phase was dried over MgSO4. Evaporation of the solvent afforded methyl p-tolyl sulfoxide which was
purified by column chromatography (silica gel, 200–300 mesh, methylene chloride); mp. 71–73 °C;
1H-NMR (60 MHz, CDCl3) δ 7.55 and 7.35 (AB-system, 4H, H-Ar, JAB = 8 Hz), 2.60 (s, 3H, CH3-SO),
2.35 (s, 3H, CH3-Ar); IR (KBr, cm−1) ν 1060, 1080 (S=O). Optical rotations of the sulfoxides obtained
from sulfinates 5 and 6 are summarized in Table 12.
Table 12. Determination of optical purity of sulfinates (−)-5 by their conversion into
(+)-(R)-methyl p-tolyl sulfoxide.
p-Tol S(O)OR
MeS(O)-Tol-p
Op (%) Conf.
No
5e
R
[α]D
Conf.
[α]D
+108.0
+111.3
+13.6
+7.5
CH2=CH–CH2 −106.5
CH2=CHCH2 −86.0
S
S
S
S
S
S
S
S
73
77
R
R
R
R
R
R
R
R
5f
5d'
5d''
5j
(CD3)2CH
(CF3)2CH
Hexc
−19.8
−10.3
−23.9
−6.5
9.2
5.1
13.8
3.5
6.2
4.2
+20.6
+5.2
5k
5l
Penc
Et2CH
Bui
−11.7
−8.2
+9.2
5m
+6.2
Acknowledgments
We thank the Polish Academy of Sciences for a financial support of this work.
Author Contributions
B. Bujnicki performed the experiments; J. Drabowicz conceived, designed and performed the
experiments; M. Mikołajczyk conceived, designed the experiments and wrote the paper.
Conflicts of Interest
The authors declare no conflict of interest.
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