Efficient Synthesis of Sulfinate Esters and Sulfinamides via Activated Esters of p -Toluenesulfinic Acid

Article abstract of DOI:10.1055/s-0037-1610254

Sulfinate esters were prepared by the process of activating p -toluenesulfinic acid with either cyanuric chloride, methanesulfonyl chloride, or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-HCl). Activation of p -toluenesulfinic acid with cyanuric chloride led to the formation of sulfinate esters that were accompanied by the formation of the corresponding sulfones. The use of methanesulfonyl chloride for activation via methanesulfonic p -toluenesulfinic anhydride afforded mixtures of sulfinate esters and methanesulfonates. The use of the carbodiimide EDC proved to yield the best results with the highly selective formation of the target sulfinate esters. The use of trimethylacetic p -toluenesulfinic anhydride or cyanuric chloride to achieve the synthesis of sulfinamides proved to be ineffective due to poor chemoselectivity of the nucleophilic attack on the activated p -toluenesulfinic acid anhydride. Ultimately, the use of EDC-HCl to form the sulfinamides proved to be the best pathway for synthesis.

Full text of DOI:10.1055/s-0037-1610254

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–L
paper
A
en
S. H. Gafur et al.
Paper
Synthesis
Efficient Synthesis of Sulfinate Esters and Sulfinamides via
Activated Esters of p-Toluenesulfinic Acid
Cl
Sayed Habibul Gafur
Cl
N
N
Stephanie L. Waggoner
Eric Jacobsen
O
S
Cl
N
Cl
ROH
O
S
N
N
p-Tol
OR
Et3N
Christopher G. Hamaker
Shawn R. Hitchcock*
p-Tol
O
N
Cl
4 examples
66–84%
O
S
+ Et3NHCl
p-Tol
OH
Department of Chemistry, Illinois State University, Normal,
IL 61790-4160,
USA
Me2N
HCl
N
O
O
O
S
N
C N
hitchcock@ilstu.edu
S
or
O
NH
S
p-Tol
Me2N
OR
NHR
p-Tol
p-Tol
DMAP, CH2Cl2
ROH or RNH2
9 examples
60–99%
12 examples
28–97%
Received: 09.06.2018
Accepted after revision: 25.07.2018
Published online: 21.08.2018
ters through the use of the putative mixed anhydride p-tol-
uenesulfinic trimethylacetic anhydride derived the reaction
of sodium p-toluenesulfinate with trimethylacetyl chlo-
ride.12 In this regard, there was an interest in developing a
more efficient synthetic pathway that would possess bene-
ficial aspects of low cost, expediency, and purification of
the sulfinate ester products.
DOI: 10.1055/s-0037-1610254; Art ID: ss-2018-m0396-op
Abstract Sulfinate esters were prepared by the process of activating
p-toluenesulfinic acid with either cyanuric chloride, methanesulfonyl
chloride, or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochlo-
ride (EDC-HCl). Activation of p-toluenesulfinic acid with cyanuric chlo-
ride led to the formation of sulfinate esters that were accompanied by
the formation of the corresponding sulfones. The use of methanesulfo-
nyl chloride for activation via methanesulfonic p-toluenesulfinic anhy-
dride afforded mixtures of sulfinate esters and methanesulfonates. The
use of the carbodiimide EDC proved to yield the best results with the
highly selective formation of the target sulfinate esters. The use of
trimethylacetic p-toluenesulfinic anhydride or cyanuric chloride to
achieve the synthesis of sulfinamides proved to be ineffective due to
poor chemoselectivity of the nucleophilic attack on the activated p-tol-
uenesulfinic acid anhydride. Ultimately, the use of EDC-HCl to form the
sulfinamides proved to be the best pathway for synthesis.
Furukawa and co-workers7b,c had demonstrated that 2-
chloro-1-methylpyridiniium iodide (Mukaiyama’s salt)
could be used to effect the synthesis of sulfinate esters in
yields ranging from 23–76% (Scheme 1). This method was
attractive for the ease of activating the sulfinic acid, but was
lacking in terms of the yield, which was most likely involved
the necessary removal of the N-methylpyridone by-product
as mentioned by the authors.7 With this limitation taken
into consideration, an alternate activating agent was
sought. Blotny13 had demonstrated that cyanuric chloride
(13), a versatile chlorinating agent,14 could be employed in
the preparation of sulfonyl chlorides 15. The successful use
of cyanuric chloride by Blotny served as the inspiration for
its application in this work.
Cyanuric chloride (13) was considered as a potential al-
ternate activating agent that might offer a degree of im-
provement over the 2-chloro-1-methylpyridinium iodide as
the by-product of the use of cyanuric chloride hydrolyzes in
water. Thus, the investigation began with the treatment of
p-toluenesulfinic acid (4, R = p-MeC6H4) with cyanuric chlo-
ride to form the putative activated sulfinate ester 17 (R = p-
MeC6H4). It was not determined if the activated ester 17
formed the corresponding sulfinyl chloride 2. Nonetheless,
the reaction mixture was stirred for 30 minutes and an al-
cohol substrate was added. p-Nitrobenzyl alcohol was used
as the initial test substrate. The initial reaction design (Table
1, entry 1) involved the use of 0.55 equivalent of cyanuric
chloride and dichloromethane as the solvent. These condi-
tions resulted in a 61% conversion (as determined by 500 1H
Key words sulfinate ester, sulfinic acid, sulfinamide, cyanuric chloride,
EDC, activated ester
The development of synthetic methods for the prepara-
tion of sulfinate esters has been of interest due to their util-
ity in the synthesis of synthetic intermediates1 and their
application in biochemical studies as chemical probes for
live cell imaging.2,3 This utility has been the stimulus for
much method development with sulfinate esters. Since the
pioneering efforts of Douglass in the preparation of sulfi-
nate esters from sulfinyl chlorides,4 a variety of methods
have been developed. These preparative pathways may
originate from sulfinyl chlorides 2,5 sodium sulfinates 3,6
sulfinic acids 4,7 sulfonyl chlorides 5,8 sulfonyl hydrazides
6,9 and p-toluenesulfonylmethyl isocyanides 710 (Figure 1).
Basak and co-workers have recently published on the syn-
thesis of sulfinate esters through the Wittig ylide-mediated
decomposition of N-sulfonylhydrazones 8.11 Our work in
this field focused on the expedient synthesis of sulfinate es-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

B
S. H. Gafur et al.
Paper
Synthesis
sulfinamides, sulfoxides, asymmetric applications,
biochemical studies
Me
Me
Me
SOCl
Me
Me
Me
SO2Cl
2
3
5
6
O
Me
S
SO2Na
SO2H
SO2NHNH2
SO2CH2NC
OR
1
4
7
Me
SO2NHN=CHArR
8
Figure 1 Methods for the synthesis of sulfinate esters
Furukawa and co-workers, 1980
Me
N
O
Cl
S
I
I
Me
Me
O
O
S
O
N
9
N
+
S
R
OH
R
OR'
R
O
Et3N, acetone
4
10
1
11
Blotny, 2003
Cl
Cl
N
Cl
N
N
13
Cl
Et3N, acetone
O
R
O
O
O
N
N
N
N
Cl
N
O
O
+
S
S
S
OH
R
Cl
R
O
Cl
HO
N
Cl
12
14
15
16
Proposed transformation
Cl
Cl
N
Cl
N
N
13
Cl
Et3N, acetone
O
S
O
S
O
S
N
N
N
N
Cl
N
+
R
OH
R
Cl
R
O
Cl
HO
N
Cl
4
17
2
16
Scheme 1 Proposed cyanuric chloride pathway
NMR spectroscopic analysis) of the starting alcohol to the
target sulfinate ester 1a with concomitant formation of the
corresponding sulfone 18a in a ratio of 90:10. The number
of equivalents of cyanuric chloride was increased by a factor
of two (1.10 equiv) in an attempt to increase the percent
conversion. In this way, a 95% conversion was achieved with
a nearly doubling of the formation of the unwanted sulfone
18a. The sulfone by-product is proposed to originate from
activation of the p-nitrobenzyl alcohol by cyanuric chloride,
and subsequent nucleophilic substitution by the p-toluene-
sulfinic acid (Scheme 2). When the solvent was changed to
THF, the amount of the sulfone 18a formed was significant-
ly decreased. Presumably, the use of THF favored formation
and reaction of the activated ester 17 over the presumed in-
termediate 20 illustrated in Scheme 2. Further experimen-
tation was conducted with p-chloro- and p-bromobenzyl
alcohol leading to comparable results. Interestingly, the use
of L-menthol led to a complete conversion to the corre-
sponding sulfinate ester with no observed formation of the
L-menthyl p-tolyl sulfone. The absence of the correspond-
ing sulfone was attributed to the steric environment of the
secondary alcohol of L-menthol as compared to the more
reactive primary benzylic alcohols.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

C
S. H. Gafur et al.
Paper
Synthesis
Table 1 Cyanuric Chloride as an Activating Agent
Cl
N
Cl
N
N
O
S
O
O
Cl
N
Cl
O
S
N
N
ROH
Et3N
S
+
p-TolSO2H
p-Tol
R
p-Tol
OR
solvent, 30 min
4
p-Tol
O
Cl
17
1a–d
18a–c
Entry
Alcohol, R
Solvent
Sulfinate ester
C3N3Cl3 (equiv)
Sulfonea Yield (%)
Conv. (%)
Yield (%)b
1
2
3
4
5
6
7
8
9
p-O2NC6H4CH2
p-O2NC6H4CH2
p-O2NC6H4CH2
p-O2NC6H4CH2
p-ClC6H4CH2
p-ClC6H4CH2
p-BrC6H4CH2
p-BrC6H4CH2
L-menthol
CH2Cl2
CH2Cl2
THF
1a
1a
1a
1a
1b
1b
1c
1c
1d
0.55
1.10
0.55
1.10
0.55
1.10
0.55
1.10
1.10
18a, 10
18a, 17
18a, 1.0
18a, 7.0
18b, 0.5
18b, 10
18c, 1.5
18c, 5.0
18d, 0
61
95
nd
nd
69
77
70
66
71
79
84
70
THF
88
THF
87
THF
90
THF
94
THF
85
THF
100c
a Percentage of sulfone in the crude reaction mixture as determined by 500 MHz 1H NMR spectroscopy.
b Isolated chemical yield after flash chromatography. nd: Not detected.
While the formation of the sulfinate esters 1a–d
through the cyanuric chloride activation method was suc-
cessful, there was an ongoing concern of the concomitant
formation of the sulfone by-product. The development of a
synthetically useful pathway via an activated ester ap-
proach was still considered an obtainable goal. To this end,
the use of methanesulfonyl chloride as an activating agent
was explored in place of cyanuric acid. p-Toluenesulfinic
acid was reacted with methanesulfonyl chloride for a peri-
od of 30 minutes followed by the addition of the p-nitro-
benzyl alcohol and the scavenger base triethylamine, and
the reaction was stirred for 12 hours (Table 2). Analysis of
the methanesulfonate ester 23 in a ratio of 70:30, respec-
tively.
There was a concern that not enough time had been
given for the formation of the presumed methanesulfonic
p-toluenesulfinic anhydride (22). If this were the case, then
the methanesulfonate 23 was forming due to the presence
of unreacted methanesulfonyl chloride. To address this con-
cern, the reaction time for formation of 22 was extended to
two hours. In addition to the change in the induction time
for the formation of the mixed anhydride, the solvents di-
chloromethane and THF were used in competing reactions.
It was determined that the amount of the methanesulfon-
ate increased when the induction time was increased to
two hours and the solvent employed was dichloromethane.
1
the crude product by 500 MHz H NMR spectroscopy re-
vealed that the sulfinate ester 1a had formed in addition to
Cl
Cl
Cl
N
N
N
N
O2N
N
N
Et3N, CH2Cl2
N
Cl
O
O
N
Cl
Cl
OH
Cl
N
Cl
O2N
O2N
NO2
19
13
Cl
13'
+
Et3NHCl
20
Cl
O
O
O
Et3N
N
N
N
N
S
H
S
O
– Et3NHCl
HO
N
Cl
O
N
Cl
Me
Me
18a
21
O2N
20
4
Scheme 2 Proposed pathway of sulfone formation
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

D
S. H. Gafur et al.
Paper
Synthesis
Table 2 Synthesis and Application of the Methanesulfonic p-Toluenesulfinic Anhydride
O
S
OCH2-p-C6H4NO2
p-Tol
O
1a
O
O
MeSO2Cl
solvent
p-NO2C6H4CH2OH
S
S
p-TolSO2H
O
+
p-Tol
Me
ROH
Et3N
4
O
O
ROH
S
22
Me
OCH2-p-C6H4NO2
23
Entry
Solvent
Induction time
Conversion (%)
1a/23
1
2
3
CH2Cl2
CH2Cl2
THF
30 min
2 h
100
100
96
70:30
60:40
87:13
2 h
When THF was used as the solvent, the formation of the
sulfinate ester 1a over the sulfonate 23 improved signifi-
cantly. However, the ratio was still not considered ideal as
the products 1a and 23 could not be easily separated by
chromatography due to the similarities in polarity. The for-
mation of these two products is proposed to originate from
the formation of the activated ester 22 upon which nucleo-
philic attack is not chemoselective enough to warrant syn-
thetic utility. Consequently, this activation method was
abandoned as there was no straightforward method to sup-
press formation of the methanesulfonate ester to levels that
would be synthetically useful.
The last option that was considered was based on the
work of Kobayashi and co-workers7d who had demonstrat-
ed the utility of N,N′-dicyclohexylcarbodiimide (DCC) as an
activating agent for the formation of sulfinate esters. Furu-
kawa and co-workers7b,c also employed DCC, and more re-
cently, Hajipour and co-workers7a also used DCC in the syn-
thesis of sulfinate esters, but under solvent-free conditions.
The limitation from these combined works were focused on
the chromatographic separation of residual DCC starting
material from the reaction mixture, the chromatographic
removal of the dicyclohexylurea by-product, and to a lesser
degree the formation and removal of the commonly en-
countered by-product of sulfinate ester formation, namely
thiosulfonates originating from coupling reactions between
sulfinic acids and their activated counterparts.12
EDC-HCl was employed in a series of reactions focused on
the synthesis of sulfinate esters through a carbodiimide-
based approach. Freshly prepared p-toluenesulfinic acid
was combined with an alcohol substrate, and 4-(dimethyl-
amino)pyridine (DMAP) in dichloromethane. This reaction
mixture was then treated with EDC-HCl and stirred for 12–
15 hours (Table 3). The reactions were easily extracted and
the water-soluble urea by-product was not observed. The
isolated chemical yields ranged from 67 to 99% after chro-
matographic isolation. Attempts to influence the diastereo-
selectivity of sulfinate ester formation with L-menthol by
altering the temperature (Table 3, entries 4, 5, 6) were not
successful as the diastereomeric ratio only varied from
1
48:52 to 40:60 as determined by 500 MHz H NMR spec-
troscopy.
Interestingly, the alcohol substrate trans-1,3-diphenyl-
2-propen-1-ol afforded the corresponding sulfone rather
than the sulfinate ester. Alcohols that are benzylic and allyl-
ic have been shown to form the corresponding sulfone un-
der conditions designed for sulfinate ester formation.15
Nonetheless, the utility of the activation approach for the
formation of sulfinate esters had been demonstrated with
activating agents such as cyanuric chloride and EDC-HCl.
Based on the success of these approaches in the synthe-
sis of sulfinate esters, there was also an interest in the
preparation of the related sulfinamides16 through a com-
mon pathway. Before exploring usage of the cyanuric chlo-
ride and EDC-HCl activation methodologies, the previously
developed mixed anhydride methodology was investigated.
To this end, the trimethylacetic p-toluenesulfinic anhydride
was prepared and reacted with (S)-(–)-1-phenylethylamine
(27) (Scheme 3). This reaction generated a mixture of prod-
ucts that included the expected sulfinamide 28 (46% isolat-
ed yield) and the corresponding pivalamide 29 in a nearly
1:1 ratio as determined by 500 MHz 1H NMR spectroscopy,
and a thiosulfonate by-product 30.
Despite these limitations, the carbodiimide approach
was still considered to be attractive for its ease of operation.
To exploit the carbodiimide approach in a manner that
would address these limitations fully, or in part, 1-ethyl-3-
(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC-
HCl), was selected. This carbodiimide reagent is known to
generate a water-soluble urea by-product thereby facilitat-
ing isolation of the desired organic product without con-
comitant contamination and necessitated chromatographic
removal of the urea. With this taken into consideration,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

E
S. H. Gafur et al.
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Synthesis
Table 3 Synthesis of Sulfinate Esters by EDC Activation of p-Toluenesulfinic Acid
·HCl
Me2N
N
O
HN
N
C N
O
S
ROH
S
p-TolSO2H
R
O
NH
p-Tol
Me2N
O
+
NH
HCl
O
p-Tol
DMAP, CH2Cl2
ROH
4
(H3C)2N
24
1a–i
25
Entry
Alcohol
Sulfinate ester
Yield (%)a
1
2
p-nitrobenzyl alcohol
1a
1b
1c
1d
1d
1d
1e
1f
69
p-chlorobenzyl alcohol
70
3
p-bromobenzyl alcohol
69
4
L-menthol (reaction ran at 25 °C)
99 (48:52)
97 (40:60)
95 (40:60)
96
5
L-menthol (reaction ran at –15 °C)
L-menthol (reaction ran at –78 °C)
2-phenylethanol
6
7
8
sec-butyl alcohol
85
9
trans-1,3-diphenyl-2-propen-1-ol
(S)-(+)-3-hydroxytetrahydrofuran
(1S,2S,3S,5R)-(+)-isopinocampheol
1g
1h
1i
60b
10
11
67 (48:52)
85 (45:55)
a Isolated chemical yield after flash chromatography. Ratio of the sulfinate diastereomers determined by 500 MHz 1H NMR spectroscopy is given in parentheses.
b The product was isolated as the sulfone.
Me
O
S
H2N
O
S
O
t-BuCOCl
27
Na
O
t-Bu
O
CH2Cl2
Et3N
Me
Me
3
26
Me
O
S
Me
O
Me
O
S
O
+
+
N
t-Bu
N
H
S
H
Me
Me
28
29
30
Scheme 3 Sulfinamide synthesis via the mixed anhydride approach
The failure of the mixed anhydride pathway to yield a
practical methodology for the preparation of sulfinamides
led to the pursuit of the cyanuric chloride methodology. To
this end, freshly prepared p-toluenesulfinic acid (4) was
treated with cyanuric chloride and stirred for 30 minutes
followed by addition of (S)-1-phenylethylamine and tri-
ethylamine (Scheme 4). The sulfinamide product 28 was
obtained in 28% yield after isolation by flash column chro-
matography. The low yield was attributed to the higher nu-
cleophilicity of the amine substrate towards the cyanuric
chloride leading to formation of the putative aminated by-
product 31.17 The low yield of the product suggested that
the neither of these methodologies would be suitable for a
practical synthesis of sulfinamides. The use of EDC as the
activating agent was pursued as it had been successful in its
application in the synthesis of sulfinate esters.
A variety of conditions were explored for the optimized
preparation of sulfinamides through the EDC route. It was
determined that when the order of addition involved the
reaction of the p-toluenesulfinic acid with the carbodiim-
ide over a 30-minute period, the yield of the target sulfin-
amide was compromised (25–62%) and there was signifi-
cant formation of the thiosulfonate by-product (Scheme 5).
When the reagents were combined and the carbodiimide
was added last, the thiosulfonate by-product was mini-
mized and the sulfinamide product could be isolated more
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

F
S. H. Gafur et al.
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Synthesis
Table 4 Synthesis of Sulfinamides by EDC-HCl Activation of p-Toluene-
Cl
N
sulfinic Acida
Cl
N
N
(S)-PhCH(Me)NH2
Cl
Cl
O
S
N
N
Yield (%)b
p-TolSO2H
solvent, 30 min
Et3N
4
p-Tol
O
N
Cl
Entry Amine
Sulfinamide Method a Method b
17
1
sec-butylamine
34
35
36
37
28
36
25
–
68
92
58
90
74
67
44
33
78
61
97
28
Cl
2
benzylamine
O
Me
N
N
Me
Ph
3
phenethylamine
+
S
p-Tol
N
H
Ph
Cl
N
N
H
4
3,4-dimethoxyphenethylamine
(R)-(+)-1-phenylethylamine
–
5
62
–
28 (28%)
31
6
(S)-(–)-1-(1-naphthyl)ethylamine 38
Scheme 4 Sulfinamide synthesis using cyanuric chloride as the activat-
ing agent
7
tert-butylamine
pyrrolidine
39
40
41
42
43
44
–
8
18
–
9
piperidine
readily. The examples included primary amines, sterically
congested primary amines, cyclic secondary amines, a car-
bazate, and a hydrazide (Table 4). The isolated chemical
yields ranged from 28 to 97%. The low yield of 28% for the
synthesis of the benzhydrazide-based sulfinamide was at-
tributed to the low solubility of the benzhydrazide starting
material in the reaction solvent dichloromethane. Nonethe-
less, the isolated yields were mostly good to excellent for
the preparation of the target sulfinamides.
10
11
12
morpholine
–
tert-butyl carbazate
benzhydrazide
–
–
a See Scheme 5 for methods.
b All yields are derived from product isolation through chromatographic puri-
fication.
78% yield. Since the diastereomers (epimeric at the stereo-
genic sulfur) had marginally different retention factors on
silica gel, a careful separation of the diastereomers by col-
umn chromatography was carried out. Although complete
separation was not possible, the early fractions from the
column contained a diastereomer that readily recrystal-
lized. The latter fractions contained a mixture of the diaste-
reomers that proved to be more difficult to recrystallize
due to the viscous, oil like nature of the fractions. The abso-
lute configuration of the pure white crystalline compound
was determined to be (Ss,S) by X-ray crystallography (Figure
2). This corresponded to the diastereomeric configuration
of (SS,S)-46b, which in turn corresponded to the 500 MHz
With the methodology for sulfinamide synthesis in
hand, the preparation of amino ester based sulfinamides
was pursued (Table 5). To this end freshly prepared p-tolue-
nesulfinic acid was reacted with the commercially available
enantiomerically pure amino esters in triethylamine fol-
lowed by the addition of EDC to induce the coupling to af-
ford the sulfinamides in good to excellent yields. The ratio
of the diastereomers formed was determined by the inte-
1
gration of the methyl ester signal in the 500 MHz H NMR
spectra.
In the case of the L-phenylglycine methyl ester 46b, a
diastereomeric mixture of sulfinamides was obtained in
HCl
Me2N
N
O
S
Me
N
C N
O
O
p-TolSO2H
O
NH
p-Tol
4
S
(a)
p-Tol
S
DMAP, CH2Cl2
30 min induction
self-coupling
Me2N
30
24
O
RNH2
S
R
p-Tol
N
R'
28, 32, 33, 40
N
O
S
O
RNH2 or RR'NH
O
NH
p-Tol
S
R
(b)
4
p-Tol
N
DMAP, CH2Cl2
EDC-HCl
R'
RNH2
N
28, 34–44
Scheme 5 EDC-based synthesis of sulfinamides
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

G
S. H. Gafur et al.
Paper
Synthesis
Table 5 Synthesis of Amino Acid-Based Sulfinamides by EDC Activation of Sulfinic Acid
·HCl
Me2N
O
N
C
N
R
R
O
S
O
S
R
p-TolSO2H
+
OMe
Cl
+
N
H
N
H
CO2Me
CO2Me
p-Tol
p-Tol
DMAP, CH2Cl2, TEA
4
NH3
45a–d
(RS,S)-46a–d
(SS,S)-46a–d
Entry
R
Compound
Yield (%)
δ (CO2CH3) (SS,S)
δ (CO2CH3) (RS,S)
Ratio
1
2
3
4
Bn
46a
46b
46c
46d
54
78
64
94
3.64
3.66
3.70
3.68
3.74
3.74
3.79
3.78
56:44
57:43
62:38
60:40
Ph
i-Pr
t-Bu
1H NMR spectral signal for the methyl ester peak at 3.66
ppm. There is a likelihood that the other N-p-tolylsulfinyl-
α-amino esters 45a,c,d adopt a similar conformation in the
solution state of the NMR sample (CDCl3), and consequent-
ly, there is a likelihood that the methyl ester peak resonat-
ing at the lower ppm value (see Table 5) represents the
(SS,S)-diastereomer in those cases as well.
Chemical reagents were used as purchased. CH2Cl2 was purchased as
an anhydrous reagent. All reactions were conducted in flame-dried or
oven dried glassware under a N2 atmosphere. Crude reaction mix-
tures were purified by flash chromatography using an automated
flash chromatograph. The stationary phase was 40 g normal phase
silica gel cartridges. The collected fractions were analyzed by TLC
with TLC plates coated with fluorescent indicator F254, and visualized
1
with UV light. All H and 13C NMR spectra were recorded in CDCl3 or
DMSO-d6 using a Bruker Ultrashield Avance III NMR spectrometer op-
erating at 500 MHz (or 400 MHz) for 1H NMR spectra and operating at
125 MHz (or 100 MHz), respectively. Chemical shifts were reported in
parts per million (δ scale), and coupling constant (J values) are listed
in hertz (Hz). TMS was used as internal standard (δ = 0). IR spectral
values were reported in reciprocal centimeters (cm–1) and were mea-
sured as a neat liquid, Nujol mull, or as a neat liquid film from an
evaporated CDCl3 solution.
For Electrospray Ionization High-Resolution Mass Spectrometry (ESI-
HRMS), samples were prepared in concentrations of 5–25 ppm in
HPLC grade MeOH/H2O/formic acid (1:1:0.01). Analytical data were
collected using a ThermoScientific Q-Exactive ESI mass spectrometer.
Sulfinate Esters 1; 4-Bromobenzyl p-Toluenesulfinate (1c), Typical
Procedure
To a 250 mL flame-dried N2 purged round-bottomed flask was added
p-toluenesulfinic acid (0.525 g, 3.36 mmol), 4-bromobenzyl alcohol
(0.598 g, 3.20 mmol), and DMAP (0.078 g, 0.64 mmol) sequentially
and dissolved in anhyd CH2Cl2 (14 mL). To the solution was added 1-
ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.644
g, 3.36 mmol) in one portion and stirred for 16 h at r.t. The reaction
mixture was diluted with CH2Cl2 (30 mL) and washed with aq 1 M HCl
(30 mL) and brine (30 mL). The organic layer was dried (MgSO4), fil-
tered, and solvents removed under reduced pressure. The crude prod-
uct was purified by flash column chromatography (hexanes/EtOAc,
95:5; Rf = 0.14) to yield 0.719 g (69%) of the title compound as a trans-
parent yellow oil.
Figure 2 ORTEP diagram of (SS,S)-46b
In conclusion, a unified one-pot activation method em-
ploying the carbodiimide EDC has been developed for the
preparation of both sulfinate esters and sulfinamides. The
EDC activation approach proved to be superior to the use of
cyanuric chloride as an activating agent. Cyanuric chloride
formed sulfinate esters, but with concomitant formation of
the corresponding sulfone. The EDC methodology did not
form significant amounts of the sulfone product, but did
cleanly form the target compounds. The method proved to
be successful in the synthesis of a series of N-p-tolyl-
sulfinyl-α-amino esters. While the diastereoselectivities
were not optimal, it was possible to isolate a single diaste-
reomer from the L-phenylglycine series.
IR (neat): 3048, 1912, 1595, 1133, 1014, 804 cm–1
.
1H NMR (400 MHz CDCl3): δ = 2.37 (s, 3 H), 4.42 (d, J = 11.7 Hz, 1 H),
4.88 (d, J = 11.7 Hz, 1 H), 7.05–7.07 (m, 2 H), 7.27–7.28 (m, 2 H), 7.37–
7.39 (m, 2 H), 7.54–7.56 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.6, 64.6, 122.5, 125.3, 129.9, 130.2,
131.7, 134.8, 141.5, 143.0.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

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S. H. Gafur et al.
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ESI-HRMS: m/z calcd for C14H13BrO2SNa (M + Na+): 346.9712; found:
ESI-HRMS: m/z calcd for C15H16O2SNa (M + Na+): 283.0763: found:
346.9714.
283.0764.
4-Nitrobenzyl p-Toluenesulfinate (1a)
s-Butyl p-Toluenesulfinate (1f)
The crude product was purified by flash column chromatography
(hexanes/EtOAc, 95:5; Rf = 0.14) to yield 0.719 g (69%) of the title
compound as a yellow oil.
The crude product was purified by flash column chromatography
(hexanes/EtOAc, 95:5; Rf = 0.17) to yield 1.00 g (85%) of the title com-
pound as a transparent oil.
IR (neat): 3054, 1607, 1347, 1134, 1081, 852, 814 cm–1
.
IR (neat): 1597, 1137, 1026, 993, 964, 890 cm–1
.
1H NMR (400 MHz CDCl3): δ = 2.37 (s, 3 H), 4.53 (d, J = 12.6 Hz, 1 H),
5.01 (d, J = 12.6 Hz, 1 H), 7.29–7.30 (m, 2 H), 7.34–7.38 (m, 2 H), 7.56–
7.58 (m, 2 H), 8.09–8.13 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.5, 63.4, 123.7, 125.3, 128.7, 129.9,
141.1, 143.1, 143.4, 147.5.
1H NMR (400 MHz CDCl3): δ (mixture of diastereomers) = 0.90 (t, J =
7.4 Hz, 3 H), 0.98 (t, J = 7.5 Hz, 3 H), 1.25 (d, J = 6.3 Hz, 3 H), 1.40 (d, J =
6.3 Hz, 3 H), 1.51–1.79 (m, 4 H), 2.44 (s, 6 H), 4.35–4.47 (m, 2 H),
7.33–7.35 (m, 4 H), 7.61–7.65 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ (mixture of diastereomers) = 9.5, 9.6,
21.31, 21.4, 30.1, 30.4, 77.4, 77.6, 124.8, 124.9, 129.5, 124.8, 124.9,
129.5, 142.3, 142.9, 143.0.
ESI-HRMS: m/z calcd for C14H13NO4SNa (M + Na+): 314.0457; found:
314.0460.
ESI-HRMS: m/z calcd for C11H16O2SNa (M + Na+): 235.0763; found:
235.0765.
4-Chlorobenzyl p-Toluenesulfinate (1b)
The crude product was purified by flash column chromatography
(hexanes/EtOAc, 95:5; Rf = 0.14) to yield 0.634 g (70%) of the title
compound as a transparent oil.
trans-1,3-Diphenyl-2-propenyl p-Tolyl Sulfone (1g)
The crude product was purified by flash column chromatography
(hexanes/EtOAc, 90:10; Rf = 0.17) to yield 0.337 g (60%) of the title
compound as a transparent oil.
IR (neat): 1598, 1134, 1017, 954, 922, 808 cm–1
.
1H NMR (400 MHz CDCl3): δ = 2.37 (s, 3 H), 4.44 (d, J = 11.7 Hz, 1 H),
4.90 (d, J = 11.7 Hz, 1 H), 7.12–7.14 (m, 2 H), 7.21–7.24 (m, 2 H), 7.27–
7.28 (m, 2 H), 7.54–7.56 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.5, 64.5, 125.3, 128.7, 129.8, 129.9,
134.3, 141.5, 143.0.
IR (Nujol): 1756, 1377, 1142, 978, 811, 750, 713 cm–1
.
1H NMR (400 MHz CDCl3): δ = 2.42 (s, 3 H), 4.84 (d, J = 7.76 Hz, 2 H),
6.53–6.63 (m, 2 H), 7.22–7.24 (m, 2 H), 7.29–7.39 (m, 10 H), 7.55–7.57
(m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.6, 75.4, 120.3, 126.8, 128.5, 128.65,
128.69, 128.9, 129.3, 129.7, 132.6, 134.5, 136.0, 138.0, 144.6.
ESI-HRMS: m/z calcd for C14H13ClO2SNa (M + Na+): 303.0217; found:
303.0219.
ESI-HRMS: m/z calcd for C22H20O2SNa (M + Na+): 371.1076; found:
371.1082.
(1R,2S,5R)-(–)-Menthyl p-Toluenesulfinate (1d)
The crude product was purified by flash column chromatography
(hexanes/EtOAc, 98:2; Rf = 0.14) to yield 1.02 g (99%) of the title com-
pound as a wax.
(S)-(+)-3-Hydroxytetrahydrofuryl p-Toluenesulfinate (1h)
The crude product was purified by flash column chromatography
(hexanes/EtOAc, 85:15; Rf = 0.17) to yield 0.615 g (67%) of the title
compound as a transparent oil.
IR (neat): 1596, 1133, 1080, 956, 916 cm–1
.
1H NMR (500 MHz CDCl3): δ (mixture of diastereomers) = 0.74 (d, J =
6.9 Hz, 3 H), 0.85–0.91 (m, 8 H), 0.92 (d, J = 1.5 Hz, 3 H), 0.93 (d, J = 2.0
Hz, 3 H), 1.02–1.11 (m, 2 H), 1.21–1.31 (m, 2 H), 1.35–1.44 (m, 2 H),
1.45–1.55 (m, 2 H), 1.66–1.74 (m, 4 H), 2.08–2.19 (m, 3 H), 2.28–2.33 (
m, 1 H), 2.44 (s, 6 H), 4.14 (ddd, J = 10.8, 10.8, 4.5 Hz, 1 H), 4.22 (ddd,
J = 10.8, 10.8, 4.5 Hz, 1 H) 7.33–7.35 (m, 4 H), 7.61–7.64 (m, 4 H).
IR (neat): 1136, 1079, 959, 907, 862, 814 cm–1
.
1H NMR (400 MHz CDCl3): δ (mixture of diastereomers) = 1.96–2.02
(m, 2 H), 2.17–2.23 (m, 2 H), 2.46 (s, 6 H), 3.64–3.71 (m, 2 H), 3.78–
3.88 (m, 4 H), 3.90–3.99 (m, 2 H), 4.93–4.98 (m, 2 H), 7.36–7.38 (m, 4
H), 7.61–7.63 (m, 4 H).
13C NMR (125 MHz, CDCl3): δ (mixture of diastereomers) = 15.5, 15.6,
20.9, 20.9, 21.5, 21.5, 23.1, 23.2, 25.2, 25.5, 31.7, 31.9, 33.9, 34.0, 43.0,
43.6, 47.9, 48.2, 80.0, 81.9, 124.5, 124.9, 129.6, 129.60, 142.3, 142.5,
143.3, 143.3.
13C NMR (100 MHz, CDCl3): δ (mixture of diastereomers) = 21.4, 33.7,
34.2, 66.7, 73.2, 73.7, 76.2, 76.5, 125.0, 125.1, 129.70, 129.7, 142.0,
142.8, 142.9.
ESI-HRMS: m/z calcd for C11H14O3SNa (M + Na+): 249.0556; found:
249.0558.
ESI-HRMS: m/z calcd for C17H26O2SNa (M + Na+): 317.1546; found:
317.1552.
(1S,2S,3S,5R)-(+)-Isopinocampheyl p-Toluenesulfinate (1i)
2-Phenylethyl p-Toluenesulfinate (1e)
The crude product was purified by flash column chromatography
(hexanes/EtOAc, 98:2; Rf = 0.14) to yield 0.867 g (85%) of the title
compound as a clear oil.
The crude product was purified by flash column chromatography
(hexanes/EtOAc, 95:5; Rf = 0.14) to yield 0.803 g (96%) of the title
compound as a transparent yellow oil.
IR (neat): 3030, 1597, 1133, 1081, 967, 865, 814 cm–1
IR (neat): 15.97, 1134, 1081, 970, 911, 15.97, 1134, 1081, 970, 911,
.
836 cm–1
.
1H NMR (500 MHz CDCl3): δ = 2.44 (s, 3 H), 2.95 (m, 2 H) 3.84 (dt, J =
10.1, 6.9 Hz, 1 H), 4.25 (ddd, J = 10.1, 7.4, 6.9 Hz, 1 H), 7.15–7.18 (m, 2
H), 7.23–7.26 (m, 1 H), 7.29–7.32 (m, 4 H), 7.51–7.53 (m, 2 H).
1H NMR (500 MHz CDCl3): δ (mixture of diastereomers) = 0.91 (s, 3
H), 0.92 (s, 3 H), 0.96 (d, J = 7.4 Hz, 3 H), 1.09 (dd, J = 16.3, 9.9 Hz, 2 H),
1.20 (d, J = 7.4 Hz, 3 H), 1.22 (s, 3 H), 1.24 (s, 3 H), 1.81–1.91 (m, 4 H),
1.96–1.99 (m, 1 H), 2.05–2.09 (m, 1 H), 2.13–2.26 (m, 3 H), 2.34–2.40
13C NMR (125 MHz, CDCl3): δ = 21.5, 36.3, 64.7, 125.3, 126.7, 128.5,
129.1, 129.7, 137.4, 141.7, 142.7.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

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S. H. Gafur et al.
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(m, 2 H), 2.45 (s, 6 H), 2.61–2.69 (m, 1 H), 4.59 (ddd, J = 9.6, 5.2, 4.5
Hz, 1 H), 4.68 (ddd, J = 9.8, 5.3, 4.7 Hz, 1 H), 7.34–7.37 (m, 4 H), 7.63–
7.65 (m, 4 H).
ESI-HRMS: m/z calcd for C15H17NOSNa (M + Na+): 282.0923; found:
282.0925.
13C NMR (125 MHz, CDCl3): δ (mixture of diastereomers) = 19.4, 19.7,
21.4, 23.8, 23.8, 27.4, 33.7, 33.8, 37.0, 37.6, 38.2, 41.4, 44.7, 45.2, 47.5,
47.6, 78.0, 79.1, 125.0, 125.1, 129.5, 129.5, 142.3, 143.0.
N-(p-Tolylsulfinyl)-3,4-dimethylphenethylamine (37)
The product was purified by flash chromatography (70:30, hex-
anes/EtOAc) to yield 0.46 g (90%) of the title compound as a clear oil.
ESI-HRMS: m/z calcd for C17H24O2SNa (M + Na+): 315.1389; found:
IR (neat): 3298, 1593, 1516, 1261, 1156, 1088, 1030, 812, 754 cm–1
.
315.1393.
1H NMR (400 MHz CDCl3): δ = 2.41 (s, 3 H), 2.76 (t, J = 6.9 Hz, 2 H),
3.02–3.12 (m, 1 H), 3.31–3.41 (m, 1 H), 3.84 (s, 3 H), 3.86 (s, 3 H),
3.98–4.06 (m, 1 H), 6.64–6.72 (m, 2 H), 6.79 (d, J = 8.1 Hz, 1 H), 7.30
(d, J = 8.1 Hz, 2 H), 7.53 (d, J = 8.1 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.3, 36.5, 42.3, 42.3, 55.8, 56.0, 111.4,
112.1, 120.8, 125.9, 129.5, 131.0, 141.1, 141.2, 147.7, 149.0.
Sulfinamides; General Procedure
To a flame-dried, N2 purged 100 mL round-bottomed flask was added
p-toluenesulfinic acid (0.30 g, 1.9 mmol), DMAP (0.039 g, 0.32 mmol)
and dissolved in CH2Cl2 (8 mL). To the solution was added the desired
amine (1.6 mmol) followed by EDC-HCl (0.36 g, 1.9 mmol) and stirred
for 18 h. Afterwards, the reaction mixture was diluted with CH2Cl2
(30 mL), washed with aq 1 M HCl (20 mL) and brine (20 mL) sequen-
tially. The organic layer was dried (MgSO4), filtered, and solvents re-
moved under reduced pressure to give the crude reaction product,
which was then purified by flash chromatography.
ESI-HRMS: m/z calcd for C17H21NO3S (M + H+): 320.1315; found:
320.1315.
N-Toluenesulfinyl-(R)-(+)-1-phenylethylamine (28)
The crude product was purified via flash chromatography (70:30,
hexanes/EtOAc) to yield 0.307 g (74%) of the product as a white solid;
mp 68–70 °C; [α]D +21.19 (c = 1.00, CHCl3).
rac-N-(p-Tolylsulfinyl)-s-butylamine (34)
IR (Nujol): 3206, 1595, 1084, 1053 cm–1
.
The product was purified by flash chromatography (70:30, hex-
anes/EtOAc) to yield 0.23 g (68%) of the title compound as clear oil.
IR (Nujol): 3205, 1597, 1088, 1063 cm–1
1H NMR (500 MHz, CDCl3): δ (both diastereomers) = 1.49 (d, J = 6.8
Hz, 3 H), 1.65 (d, J = 6.8 Hz, 3 H), 2.40 (s, 3 H), 2.44 (s, 3 H), 4.13 (d, J =
16.8 Hz, 1 H), 4.25 (d, J = 16.8 Hz, 1 H), 4.57–4.62 (m, 1 H), 4.68–4.73
(m, 1 H), 7.2–7.3 (m, 10 H), 7.39–7.46 (m, 4 H), 7.59 (d, J = 8.1 Hz, 2 H),
7.63 (d, J = 8.1 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ (both diastereomers) = 21.3, 24.1, 24.6,
52.1, 53.5, 125.6, 125.9, 126.4, 127.0, 127.3, 127.5, 128.5, 128.6, 129.3,
129.5, 141.0, 141.1, 141.5, 142.6, 143.5, 144.0.
.
1H NMR (500 MHz, CDCl3): δ (both diastereomers) = 0.78 (t, J = 7.4 Hz,
3 H), 0.90 (t, J = 7.4 Hz, 3 H), 1.10 (d, J = 6.5 Hz, 2 H), 1.21 (d, J = 6.5 Hz,
2 H), 1.28–1.60 (m, 6 H), 2.34 (s, 3 H), 3.24–3.369 (m, 4 H), 3.63 (d, J =
6.7 Hz, 1 H), 3.75 (d, J = 5.7 Hz, 1 H), 7.19–7.24 (m, 4 H), 7.52 (d, J = 3.1
Hz, 2 H), 7.53 (d, J = 3.1 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ (both diastereomers) = 10.0, 10.2, 21.2,
22.0, 22.4, 31.0, 31.1, 51.1, 52.2, 125.6, 125.8, 129.3, 129.3, 140.9,
140.9, 142.3, 142.7.
ESI-HRMS: m/z calcd for C15H17NOS (M + H+): 260.1104; found:
260.1107.
ESI-HRMS: m/z calcd for C11H17NOS (M + H+): 212.1104; found:
212.1105.
N-Tolylsulfinyl-(S)-(–)-α-(1-naphthyl)ethylamine (38)
The crude product was purified via flash chromatography (70:30,
hexanes/EtOAc) to yield 0.331 g (67%) of the product as a white solid;
mp 110–113 °C; [α]D +97.3 (c = 1.00, CHCl3).
N-(p-Tolylsulfinyl)benzylamine (35)
The product was purified by flash chromatography (70:30, hex-
anes/EtOAc) to yield 0.23 g (92%) of the title compound as a white sol-
id; mp 69–72 °C.
IR (Nujol): 3215, 1596, 1087, 1055 cm–1
1H NMR (400 MHz CDCl3): δ = 2.42 (s, 3 H), 3.91 (dd, J = 14.7, 8.4 Hz, 1
H), 4.18–4.32 (m, 2 H), 7.26–7.34 (m, 7 H), 7.62–7.70 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.3, 44.6, 126.0, 127.6, 128.3, 128.6,
129.6, 137.9, 141.0, 141.3.
ESI-HRMS: m/z calcd for C14H15NOS (M + H+): 246.0947; found:
246.0947.
IR (Nujol): 3187, 1594, 1054 cm–1
.
1H NMR (500 MHz, CDCl3): δ (both diastereomers) = 1.70 (d, J = 6.7 Hz,
3 H), 1.81 (d, J = 6.7 Hz, 3 H), 2.31 (s, 3 H), 2.40 (s, 3 H), 4.44 (s, 1 H),
4.60 (s, 1 H), 5.39–5.44 (m, 1 H), 5.51–5.56 (m, 1 H), 7.12 (d, J = 8.12
Hz, 2 H), 7.28 (d, J = 7.8 Hz, 2 H), 7.40–7.56 (m, 8 H), 7.59–7.64 (m, 3
H), 7.68 (d, J = 7.2 Hz, 1 H), 7.74 (d, J = 8.1 Hz, 1 H), 7.83 (d, J = 8.6 Hz,
2 H), 7.92 (d, J = 7.9 Hz, 1 H), 8.00 (d, J = 5.3 Hz, 1 H), 8.31 (d, J = 8.6 Hz,
1 H).
13C NMR (125 MHz, CDCl3): δ (both diastereomers) = 21.2, 21.3, 23.4,
24.2, 47.9, 50.6, 123.0, 123.4, 123.7, 123.9, 125.4, 125.5, 125.6, 125.7,
125.8, 126.1, 126.3, 128.0, 128.3, 128.9, 129.1, 129.3, 129.5, 130.2,
130.8, 133.8, 134.1, 139.0, 139.4, 141.1, 141.3, 141.4, 142.7.
.
N-Tolylsulfinylphenethylamine (36)
ESI-HRMS: m/z calcd for C19H19NOS (M + H+): 310.1260; found:
310.1264.
The crude product was purified via flash chromatography (70:30,
hexanes/EtOAc) to yield 0.24 g (58%) of the product as a white solid;
mp 51–54 °C.
IR (Nujol): 3206, 1598, 1089, 1061 cm–1
.
N-Tolylsulfinyl-tert-butylamine (39)
1H NMR (500 MHz, CDCl3): δ = 2.41 (s, 3 H), 2.82 (t, J = 7.1 Hz, 2 H),
3.06–3.14 (m, 1 H), 3.33–3.42 (m, 1 H), 4.36 (brs, 1 H), 7.16 (d, J = 7.4
Hz, 2 H), 7.20–7.31 (m, 5 H), 7.55 (d, J = 8.2 Hz, 2 H).
The crude product was purified via flash chromatography (70:30,
hexanes/EtOAc) to yield 0.149 g (44%) of the product as a white solid;
mp 79–81 °C.
13C NMR (125 MHz, CDCl3): δ = 21.3, 36.9, 42.1, 126.1, 126.4, 128.5,
IR (Nujol): 1596, 1087, 1042, 818 cm–1
.
128.9, 129.5, 138.8, 141.0, 141.2.
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S. H. Gafur et al.
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1H NMR (500 MHz, CDCl3): δ = 1.40 (s, 3 H), 2.40 (s, 3 H), 3.79 (s, 1 H),
7.28 (d, J = 8.3 Hz, 2 H), 7.58 (d, J = 8.3 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 21.2, 31.1, 54.1, 125.6, 129.3, 140.8,
N2-(p-Tolylsulfinyl)benzhydrazide (44)
The product was purified by flash chromatography (70:30, hex-
anes/EtOAc) to yield 0.12 g (28%) of the title compound as a white sol-
id; mp 129–132 °C.
143.6.
IR (neat): 3436, 3187, 1662, 1295, 1216, 1090, 1065, 940 cm–1
.
ESI-HRMS: m/z calcd for C11H17NOS (M + H+): 212.1104; found:
1H NMR (MHz CDCl3): δ = 2.42 (s, 3 H), 6.89 (br d, J = 4.2 Hz, 1 H),
7.35(d, J = 8.2 Hz, 2 H), 7.39–7.45 (m, 2 H), 7.51–7.54 (m, 1 H), 7.69 (d,
J = 7.4 Hz, 2 H), 7.74 (d, J = 8.0 Hz, 2 H), 8.00 (br d, J = 4.6 Hz, 1 H).
212.1103.
N-(p-Tolylsulfinyl)pyrrolidine (40)
13C NMR (MHz, CDCl3): δ = 20.8, 125.5, 127.1, 128.2, 129.3, 131.6,
131.9, 137.8, 142.4, 168.1.
ESI-HRMS: m/z calcd for C14H14N2O2S (M + H+): 275.0849; found:
275.0848.
The product was purified by flash chromatography (70:30, hex-
anes/EtOAc) to yield 0.11 g (33%) of the title compound as a transpar-
ent oil.
IR (neat): 3026, 1597, 1088, 1067 cm–1
.
1H NMR (MHz CDCl3): δ = 1.80–1.89 (m, 4 H), 2.40 (s, 3 H), 2.96–3.05
(m, 2 H), 3.29–3.39 (m, 2 H), 7.27–7.30 (m, 2 H), 7.54–7.58 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.3, 26.0, 46.0, 125.8, 129.5, 140.8,
N-p-Tolylsulfinamido-L-phenylalanine Methyl Ester [(RS,S)- and
(SS,S)-46a]
The product was purified via flash column chromatography (CHCl3/
MeOH, 99:1) and was obtained as a translucent oil (0.29 g, 57%).
141.6.
ESI-HRMS: m/z calcd for C11H15NOS (M + H+): 210.0947; found:
210.0947.
IR (neat): 3291, 1493, 1211, 1172, 1069 cm–1
.
1H NMR (500 MHz, CDCl3): δ (mixture of diastereomers) = 2.41 (s, 3
H), 2.43 (s, 3 H), 2.77–2.85 (m, 2 H), 3.07 (dd, J = 13.8, 6.82 Hz, 1 H),
3.20 (dd, J = 13.8, 6.82 Hz, 1 H), 3.64 (s, 3 H), 3.74 (s, 3 H), 3.93–3.97
(m, 1 H), 4.25–4.29 (m, 1 H), 4.64 (d, J = 8.6 Hz, 1 H), 4.92 (d, J = 9.7 Hz,
1 H), 6.97–6.99 (m, 4 H), 7.19–7.35 (m, 6 H), 7.40 (d, J = 8.3 Hz, 4 H),
7.49 (d, J = 8.3 Hz, 4 H).
13C NMR (125 MHz CDCl3): δ = 21.3, 39.9, 40.6, 52.3, 52.5, 53.7, 56.9,
125.7, 126.0, 126.9, 127.1, 128.4, 128.6, 129.4, 129.5, 129.5, 129.6,
135.8, 136.0, 140.3, 141.2, 141.3, 141.5, 172.5, 173.3.
N-(p-Tolylsulfinyl)piperidine (41)
The product was purified by flash chromatography (70:30, hex-
anes/EtOAc) to yield 0.28 g (78%) of the title compound as a transpar-
ent oil that slowly solidified to a white solid; mp 62–64 °C.
IR (neat): 1651, 1597, 1452, 1212, 1088, 1038, 912, 813 cm–1
1H NMR (400 MHz CDCl3): δ = 1.48–1.68 (m, 6 H), 2.41 (s, 3 H), 2.90–
3.00 (m, 2 H), 3.05–3.15 (m, 2 H), 7.30 (d, J = 7.9 Hz, 2 H), 7.53 (d, J =
8.2 Hz, 2 H).
.
ESI-HRMS: m/z calcd for C17H20NO3S (M + H+): 318.1158; found:
318.1155
13C NMR (100 MHz, CDCl3): δ = 21.4, 24.0, 26.2, 46.9, 126.2, 129.5,
140.4, 141.0.
ESI-HRMS: m/z calcd for C12H17NOS (M + H+): 224.1104; found:
224.1103.
N-p-Tolylsulfinamido-L-phenylglycine Methyl Ester [(RS,S)- and
(SS,S)-46b]
The product was purified via flash column chromatography (CHCl3/
MeOH, 99:1) and was obtained as a clear wax (0.33 g, 69%).
N-Tolylsulfinylmorpholine (42)
The crude product was purified via flash chromatography (70:30,
hexanes/EtOAc) to yield 0.22 g (61%) of the product as a white solid;
mp 120–121 °C.
IR (Nujol): 1594, 1108, 1066, 819 cm–1
1H NMR (500 MHz, CDCl3): δ = 2.42 (s, 3 H), 2.93–3.00 (m, 2 H), 3.12–
3.19 (m, 2 H), 3.66–3.76 (m, 4 H), 7.32 (d, J = 8.3 Hz, 2 H), 7.55 (d, J =
8.3 Hz, 2 H).
IR (neat): 3236, 1738, 1204, 1166, 1092 cm–1
.
1H NMR (500 MHz, CDCl3): δ (mixture of diastereomers) = 2.37 (s, 3
H), 2.45 (s, 3 H), 3.66 (s, 3 H), 3.74 (s, 3 H), 4.88 (d, J = 7.5 Hz, 1 H), 5.07
(d, J = 5.8 Hz, 1 H), 5.17 (d, J = 5.8 Hz, 1 H), 5.56 (d, J = 7.5 Hz, 1 H),
7.00–7.03 (m, 2 H), 7.16–7.22 (m, 2 H), 7.33–7.45 (m, 6 H), 7.50 (d, J =
8.2 Hz, 4 H), 7.64 (d, J = 8.2 Hz, 4 H).
13C NMR (125 MHz CDCl3): δ = 21.3, 21.4, 52.8, 53.0, 55.0, 58.7, 125.6,
126.3, 127.2, 128.0, 128.5, 128.7, 129.0, 129.3, 129.6, 136.9, 137.1,
140.0, 141.4, 141.7, 171.5, 172.3.
.
13C NMR (125 MHz, CDCl3): δ = 21.3, 45.7, 66.9, 126.1, 129.6, 139.2,
141.5.
ESI-HRMS: m/z calcd for
C
11H15NO2S (M+): 225.0824; found:
ESI-HRMS: m/z calcd for C17H19NO3S (M + H+): 304.1002; found:
304.1012.
225.1962.
Chromatographic purification allowed for the partial isolation of the
faster eluting diastereomer (SS,S)-46b.
N2-(p-Tolylsulfinyl)-tert-butyl Carbazate (43)
The product was purified by flash chromatography (60:40, hex-
anes/EtOAc) to yield 0.42 g (97%) of the title compound as a yellow oil.
N-p-Tolylsulfinamido-L-phenylglycine Methyl Ester [(SS,S)-46b]
IR (Nujol): 3154, 1597, 1017 cm–1
.
The product was purified by flash chromatography (70:30, hex-
anes/EtOAc) to yield 2.34 g (78%) of the title compound as a mixture
of diastereomers (only the major isolated diastereomer is reported);
mp 72–75 °C.
1H NMR (400 MHz CDCl3): δ = 1.36 (s, 9 H), 2.41 (s, 3 H), 6.08 (br, 1 H),
6.58 (br, 1 H), 7.32 (d, J = 7.9 Hz, 2 H) 7.67 (d, J = 7.9 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.4, 28.1, 81.3, 126.1, 129.5, 138.2,
1H NMR (500 MHz CDCl3): δ = 2.42 (s, 3 H), 3.63 (s, 3 H), 5.07 (d, J = 5.8
142.2, 155.6.
Hz, 1 H), 5.17 (d, J = 5.8 Hz, 1 H), 7.30–7.44 (m, 7 H), 7.60–7.64 (m, 2
H).
ESI-HRMS: m/z calcd for C14H14N2O2S (M + H+): 271.1111; found:
271.1110.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

K
S. H. Gafur et al.
Paper
Synthesis
13C NMR (125 MHz, CDCl3): δ = 21.5, 52.9, 58.8, 125.7, 127.8, 128.8,
ESI-HRMS: m/z calcd for C14H21NO3S (M + H+): 284.1315; found:
129.1, 129.8, 137.0, 141.5, 141.9, 171.7.
284.1313.
ESI-HRMS: m/z calcd for C16H17NO3S (M + H+): 304.1002; found:
304.1003.
Funding Information
N-p-Tolylsulfinamido-L-valine Methyl Ester [(RS,S)- and (SS,S)-46c]
The authors acknowledge support of this research by the Department
of Chemistry at Illinois State University.
The product was purified via flash column chromatography (CHCl3/
MeOH, 99:1) and was obtained as a clear oil (0.35 g, 81%).
)(
IR (neat): 3243, 1740, 1202, 1179 cm–1
.
Acknowledgment
1H NMR (500 MHz, CDCl3): δ (mixture of diastereomers) = 0.70 (d, J =
6.7 Hz, 3 H), 0.79 (d, J = 6.9 Hz, 3 H), 0.95 (d, J = 6.9 Hz, 3 H), 1.05 (d, J =
6.7 Hz, 3 H), 1.79–1.89 (m, 1 H), 2.07–2.16 (m, 1 H), 2.44 (s, 6 H), 3.43
(dd, J = 10.4, 5.5 Hz, 1 H), 3.70 (s, 3 H), 3.79 (s, 3 H) 3.83 (dd, J = 8.5, 5.5
Hz, 1 H), 7.28–7.34 (m, 4 H), 7.57–7.64 (m, 4 H).
13C NMR (125 MHz CDCl3): δ = 17.7, 18.0, 18.8, 19.2, 21.4, 31.4, 32.2,
52.2, 52.3, 57.5, 61.7, 125.5, 126.2, 129.4, 129.6, 140.6, 141.4, 141.6,
141.9, 173.1, 173.9.
The authors thank the reviewers for useful suggestions.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610254.
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ESI-HRMS: m/z calcd for C13H20NO3S (M + H+): 270.1158; found:
270.1154.
References
Chromatographic purification allowed for the partial isolation of the
faster eluting diastereomer (SS,S)-46c.
(1) (a) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010,
110, 3600. (b) Khiar, N.; Fernandez, I. Chem. Rev. 2003, 103,
3651.
N-p-Tolylsulfinamido-L-valine Methyl Ester [(SS,S)-46c]
(2) Malwal, S. R.; Labade, A.; Andhalkar, A. S.; Sengupta, K.;
Chakrapani, H. Chem. Commun. 2014, 50, 11533.
(3) Hemmi, M.; Shindo, Y.; Nakajima, T.; Nishiyama, S.; Oka, K.;
Sato, M.; Hiruta, Y.; Citterio, D.; Suzuki, K. Chem. Asian J. 2018,
13, 648.
1H NMR (400 MHz, CDCl3): δ = 0.92 (d, J = 6.8 Hz, 3 H), 1.02 (d, J = 6.8
Hz, 3 H), 2.04–2.14 (m, 1 H) 2.41 (s, 3 H), 3.68 (s, 3 H), 3.81 (dd, J = 8.8,
5.2 Hz, 1 H), 4.60 (d, J = 8.8 Hz, 1 H), 7.28–7.34 (m, 2 H), 7.57–7.64 (m,
2 H).
13C NMR (100 MHz, CDCl3): δ = 17.8, 19.3, 21.4, 32.3, 52.3, 61.8, 125.6,
129.6, 141.7, 142.0, 173.2.
(4) (a) Douglass, I. B. J. Org. Chem. 1965, 30, 633. (b) Douglass, I. B.;
Farah, B. S.; Thomas, E. G. J. Org. Chem. 1960, 26, 1996.
(5) (a) Peltier, H. M.; Evans, J. W.; Ellman, J. A. Org. Lett. 2005, 7,
1733. (b) Evans, J. W.; Fierman, M. B.; Miller, S. J.; Ellman, J. A.
J. Am. Chem. Soc. 2004, 126, 8134. (c) Khiar, N.; Alcudia, F.;
Espartero, J.-L.; Rodríguez, L.; Fernández, I. J. Am. Chem. Soc.
2000, 122, 7598. (d) Whitesell, J. K.; Wong, M.-S. J. Org. Chem.
1991, 56, 4552. (e) Harpp, D. N.; Friedlander, B. T.; Larsen, C.;
Steliou, K.; Stockton, A. J. Org. Chem. 1978, 43, 3481.
(6) (a) Tranquilino, A.; Andrade, S. R. C. P.; da Silva, A. P. M.;
Menezes, P. H.; Oliveira, R. A. Tetrahedron Lett. 2017, 58, 1265.
(b) Huang, M.; Hu, L.; Shen, H.; Liu, Q.; Hussain, M. I.; Pan, J.;
Xiong, Y. Green Chem. 2016, 18, 1874.
(7) (a) Hajipour, A. R.; Falahati, A. R.; Ruoho, A. E. Tetrahedron Lett.
2006, 47, 2717. (b) Furukawa, M.; Ohkawara, T.; Noguci, Y.;
Nishikawa, M.; Tomimatsu, M. Chem. Pharm. Bull. 1980, 28, 134.
(c) Furukawa, M.; Okawara, T.; Noguchi, Y.; Nishikawa, M. Syn-
thesis 1978, 441. (d) Miyaji, Y.; Minato, H.; Kobayashi, M. Bull.
Chem. Soc. Jpn. 1971, 44, 862.
ESI-HRMS: m/z calcd for C13H19NO3S (M + H+): 270.1158; found:
270.1157.
N-p-Tolylsulfinamido-L-tert-leucine Methyl Ester [(RS,S)- and
(SS,S)-46d]
The product was purified by flash chromatography (70:30, hex-
anes/EtOAc) to yield 0.42 g (94%) of the title compound as a clear oil.
IR (neat): 3293, 1739, 1217, 1160, 814 cm–1
.
1H NMR (500 MHz, CDCl3): δ (mixture of diastereomers) = 0.78 (s, 9
H), 1.02 (s, 9 H), 2.44 (s, 6 H), 3.21 (d, J = 11.2 Hz, 1 H), 3.68 (s, 3 H),
3.69 (d, J = 9.8 Hz, 1 H), 3.78 (s, 3 H), 4.63 (d, J = 9.8 Hz, 1 H), 5.00 (d,
J = 11.2 Hz, 1 H), 7.33 (d, J = 7.9 Hz, 4 H), 7.58 (d, J = 8.2 Hz, 2 H), 7.62
(d, J = 8.2 Hz, 2 H).
13C NMR (125 MHz CDCl3): δ = 21.3, 26.5, 33.6, 34.8, 51.8, 52.0, 60.0,
64.9, 125.4, 126.2, 129.3, 129.5, 140.0, 141.4, 141.5, 142.0, 172.8,
173.6.
(8) Klunder, J. M.; Sharpless, K. B. J. Org. Chem. 1987, 52, 2598.
(9) (a) Pogaku, N.; Krishna, P. R.; Prapurna, Y. L. Synth. Commun.
2017, 47, 1239. (b) Kadari, L.; Krishna, P. R.; Prapurna, Y. L. Adv.
Synth. Cat. 2016, 358, 3863.
(10) Bu, B.; Li, Z.; Qian, P.; Han, J.; Pan, Y. Chem. Asian J. 2015, 11, 478.
(11) Choudhary, D.; Khatri, V.; Basak, K. Org. Lett. 2018, 20, 1703.
ESI-HRMS: m/z calcd for C14H22NO3S (M + H+): 284.1315; found:
284.1323.
Chromatographic purification allowed for the partial isolation of the
faster eluting diastereomer (SS,S)-46d.
N-p-Tolylsulfinamido-L-tert-leucine Methyl Ester [(SS,S)-46d]
(12) Jacobsen, E.; Chavda, M. K.; Zikpi, K. M.; Waggoner, S. L.; Passini,
D. J.; Wolfe, J. A.; Larson, R.; Beckley, C.; Hamaker, C. G.;
Hitchcock, S. R. Tetrahedron Lett. 2017, 58, 3073.
1H NMR (400 MHz CDCl3): δ = 1.00 (s, 9 H), 2.42 (s, 3 H), 3.66 (s, 3 H),
3.67 (d, J = 9.8 Hz, 1 H), 4.62 (d, J = 9.8 Hz, 1 H), 7.28–7.34 (m, 2 H),
7.56–7.63 (m, 2 H).
(13) Blotny, G. Tetrahedron Lett. 2003, 44, 1499.
(14) (a) Blotny, G. Tetrahedron 2006, 62, 9507. (b) De Luca, L.;
Giacomelli, G.; Porcheddu, A. Org. Lett. 2002, 4, 553. (c) De Luca,
L.; Giacomelli, G.; Porcheddu, A. J. Org. Chem. 2001, 66, 7907.
13C NMR (100 MHz, CDCl3): δ = 21.4, 26.5, 33.7, 52.1, 60.1, 126.3,
129.4, 140.1, 141.5, 173.7.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L

L
S. H. Gafur et al.
Paper
Synthesis
(15) (a) Alcohols derived from the Baylis–Hillman reaction also form
sulfones. See reference 12. (b) Benzylic and allylic sulfinate
esters can be rearranged to sulfones by palladium-catalyzed
1,3-rearrangements, see: Jagusch, T.; Gais, H.-J.; Bondarev, O.
J. Org. Chem. 2004, 69, 2731.
L. J. Org. Chem. 2007, 72, 683. (c) Drabowicz, J.; Pacholczyk, M.
Phosphorus, Sulfur Relat. Elem. 1987, 29, 257. (d) Furukawa, M.;
Okawara, T. Synthesis 1976, 339.
(17) Afonso, C. A. M.; Lourenço, N. M. T.; Rosatella, A. de. A. Molecules
2006, 11, 81.
(16) Alternate sulfinamide syntheses: (a) Dai, Q.; Zhang, J. Adv.
Synth. Catal. 2018, 360, 1123. (b) Harmata, M.; Zheng, P.; Huang,
C.; Gomes, M. G.; Ying, W.; Ranyanil, K.-O.; Balan, G.; Calkins, N.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–L