Comparison of conventional and microwave-assisted synthesis of some new sulfenamides under free catalyst and ligand

Article abstract of DOI:10.1007/s00706-018-2261-4

Abstract: Sulfenamide and its derivatives (S–N bond) have been synthesized with classical method in the literature. However, microwave-assisted synthesis of a series of N-(substituted phenylthio), N-(benzylthio), N-(cyclothio), and N-(2-mercaptobenzimidazolyl)amines has been not in the literature yet. They have been obtained from treating some amines (4?mmol) with thiophthalimides (PhthSR, 1?mmol) using sulfur transfer reagent in the presence of 2-ethoxyethanol (β-ee, neat) under microwave irradiation at 50?°C. The scope of this reaction was shown by the efficient synthesis of sulfenamides in good to excellent yields of 70–98% under free catalyst and ligand. Nine of the synthesized sulfenamide derivatives are novel. All of the thiols react with morpholine to give corresponding sulfenamides in excellent yields of 78–98%. Thiophenol, 4-methylthiophenol, 4-chlorothiophenol, and 4-fluorothiophenol react with cyclohexylamine to give corresponding sulfenamides in high yields 81–92%. Thiophenol, 4-methylthiophenol, 4-chlorothiophenol react with pyrrolidine to give corresponding sulfenamides in good yields of 70–76%. We observed that the reaction of t-butylamine with N-(phenylthio)phthalimide gave desired sulfenamide under microwave irradiation in the presence of DPPH as radical scavenger reagent in high yield of 93%. Aniline, benzylamine, 1-hexylamine, ethanolamine, diethylamine, N-ethyl-n-butylamine, N-ethylaniline, N-benzylmethylamine, t-butylamine react with thiols to give symmetrical disulfides instead of desired products under microwave irradiation, 2-ethoxyethanol as a solvent (neat), and at 50?°C. In this study, microwave-assisted synthesis method was compared with the classical method. All the products obtained were purified with chromatographic method and the analysis of these products was confirmed with IR, ¹H NMR, ¹³C NMR spectroscopy, MS spectrometry, and elemental methods. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-018-2261-4

Monatshefte für Chemie - Chemical Monthly
https://doi.org/10.1007/s00706-018-2261-4(0123456789(). -, vo Vl
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ORIGINAL PAPER
Comparison of conventional and microwave-assisted synthesis
of some new sulfenamides under free catalyst and ligand
Hasan Yakan1 Halil Ku¨tu¨k2
•
Received: 17 February 2018 / Accepted: 24 June 2018
Ó Springer-Verlag GmbH Austria, part of Springer Nature 2018
Abstract
Sulfenamide and its derivatives (S–N bond) have been synthesized with classical method in the literature. However, microwave-
assisted synthesis of a series of N-(substituted phenylthio), N-(benzylthio), N-(cyclothio), and N-(2-mercaptobenzimida-
zolyl)amines has been not in the literature yet. They have been obtained from treating some amines (4 mmol) with thioph-
thalimides (PhthSR, 1 mmol) using sulfur transfer reagent in the presence of 2-ethoxyethanol (b-ee, neat) under microwave
irradiation at 50 °C. The scope of this reaction was shown by the efficient synthesis of sulfenamides in good to excellent yields of
70–98% under free catalyst and ligand. Nine of the synthesized sulfenamide derivatives are novel. All of the thiols react with
morpholine to give corresponding sulfenamides in excellent yields of 78–98%. Thiophenol, 4-methylthiophenol, 4-chloroth-
iophenol, and 4-fluorothiophenol react with cyclohexylamine to give corresponding sulfenamides in high yields 81–92%.
Thiophenol, 4-methylthiophenol, 4-chlorothiophenol react with pyrrolidine to give corresponding sulfenamides in good yields
of 70–76%. We observed that the reaction of t-butylamine with N-(phenylthio)phthalimide gave desired sulfenamide under
microwave irradiation in the presence of DPPH as radical scavenger reagent in high yield of 93%. Aniline, benzylamine,
1-hexylamine, ethanolamine, diethylamine, N-ethyl-n-butylamine, N-ethylaniline, N-benzylmethylamine, t-butylamine react
with thiols to give symmetrical disulfides instead of desired products under microwave irradiation, 2-ethoxyethanol as a solvent
(neat), and at 50 °C. In this study, microwave-assisted synthesis method was compared with the classical method. All the
products obtained were purified with chromatographic method and the analysis of these products was confirmed with IR, 1H
NMR, 13C NMR spectroscopy, MS spectrometry, and elemental methods.
Graphical abstract
Keywords Sulfenamides Á Thiophthalimides Á Sulfur transfer reagent Á 2-Ethoxyethanol Á Microwave heating
Introduction
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s00706-018-2261-4) contains
supplementary material, which is available to authorized
users.
Sulfenamides are compounds containing divalent sulfur
bonded to trivalent nitrogen (Scheme 1). The S–N bond
contains lone pairs of electrons on both sulfur and nitrogen,
but differences in electronegativity between the two atoms
result in bond polarization, resulting in a reactive S–N
bond, which can be cleaved both to electrophiles and
nucleophiles [1–4]. It is said that the sulfenamides have
two reaction centers; sulfur with variable valence is
& Hasan Yakan
hasany@omu.edu.tr
1
Department of Chemistry, Faculty of Education, Ondokuz
Mayis University, 55139 Atakum, Samsun, Turkey
2
Department of Chemistry, Faculty of Arts and Sciences,
Ondokuz Mayis University, 55139 Atakum, Samsun, Turkey
123

H. Yakan, H. Kütük
sulfenamides have been used as additive. In the vulcan-
ization process of both natural and synthetic rubber, they
serve as both a source of sulfur and as a cross-linking agent
[1, 8, 13]. In the agriculture industry, they have been noted
as insecticides, fungicides, and ovicides [12, 13]. They
have lately been reported as growth regulators in plants,
and some have potential surgical significance [13, 14].
They have been used in materials protection. In peptide and
alkaloid synthesis, the compounds have been used as pro-
tective groups [12, 13].
Scheme 1
susceptible to nucleophilic attack and nitrogen is suscep-
tible to electrophilic attack [4–7]. The reaction with
nucleophiles involves nucleophile attacking more elec-
tropositive sulfur species to displace the nitrogen fraction
[3, 4, 8].
Microwave heating has been developed as an efficient
method to support a diversity of many organic reactions
[15–17]. In recent years, high-fast microwave assisted
chemistry has attracted a remarkable amount of interest
[18, 19]. Microwave-assisted synthesis has been repre-
sented to decrease reaction times, raise product yields and
improve product purities by diminishing undesired side
reactions when compared with classical heating methods
[20–24].
Sulfenamides are used as sulfenyl transfer reagents in
many organic reactions such as synthesis of sulfides,
disulfide, trisulfide, sulfenate ester, alkyl(aryl)dialkylamino
succinimidosulfonium salts, and amine carbotrithioates
[9–11].
Synthesis of sulfenamide moieties were prepared by
various methods (Scheme 2). Huttunen and co-workers
For long years, practical applications of sulfenamides
have been studied [12–14]. In the rubber industry,
Scheme 2
123

Comparison of conventional and microwave-assisted synthesis of some new sulfenamides under…
Scheme 3
were the first researchers to report microwave-assisted
synthesis of sulfenamides [14]. They obtained from met-
formin and disulfides in the presence of AgNO3 and
methanol in 30 min at 80 °C under microwave irradiation.
Harpp and Back reported the synthesis of sulfenamides
from thiophthalimides and amines for 0.5–15.5 h under
classical heating [25].
presence of 2-ethoxyethanol (b-ee, neat) under microwave
irradiation. To achieve this, first sulfenimides (thiophthal-
imides) are prepared from the corresponding thiols by
reaction with phthalimide in hot acetonitrile–pyridine, and
then added to solution of bromine in acetonitrile. However,
microwave-assisted synthesis of N-(4-substituted phe-
nylthio), N-(benzylthio), N-(cyclothio), and N-(2-mercap-
tobenzimidazolyl)amines has not been in the literature yet.
Nine of the synthesized sulfenamide derivatives are novel.
Moreover, in all cases much shorter reaction times and
higher yields were achieved under microwave irradiation
compared with traditional heating except for N-(2-
mercaptobenzimidazolyl)morpholine.
Generally, the amines react with sulfur compounds or
thiols react with amines to give sulfenamides. Since sul-
fenyl chlorides are sulfenylating reagents, chlorine gas has
been used as the chlorinating reagent [26–28]. Also, a
general method for preparation of sulfenamides occurred
by the reaction with aromatic sulfenyl halides and ammo-
nia or primary–secondary amines [26, 27]. Excess amine or
another acid acceptor, such as triethylamine, alkali-metal
hydroxide, sodium hydride, and others were used to neu-
tralize the acid formed in the reaction condition [13, 26]. A
second method for the synthesis of these occurs through the
reaction between thiols and amines in the presence of
oxidizing agents [26, 29]. Hydrogen peroxide, potassium
persulfate, potassium ferricyanide, hypochlorites, and the
halogens have been used as oxidizing reagents [29]. Also,
synthesis of sulfenamides was reported from disulfides and
amines in the presence of silver or mercuric salts in alka-
line medium by Davis and co-workers [10]. The mecha-
nism is first considered to comprise the complexation of
metal ion with one of the disulfide sulfurs, then the
nucleophile amine attack the other sulfur [10]. Taniguchi
reported the preparation of sulfenamides from thiols and
amines with the use of a copper catalyst and ligand
[30, 31]. In addition, he obtained sulfenamides by reaction
of thiosulfonates with amines in the presence of catalyst
and ligand in DMSO. However, these methods require
harsh reaction medium, the use of large amounts of the
catalyst and oxidant, excess amines or use of base, the use
of metal salts, and the use of expensive, air-sensitive, and
poisonous reagents, which potentially prove serious dan-
gerous materials into the ecosystem. Therefore, a more
effective and environmentally friendly method is needed.
Herein, we report a simple, eco-friendly, and efficient
method for the synthesis of sulfenamides by reaction of
substituted thiophthalimide derivatives with amines in the
Results and discussion
In our investigations, we began with the model reactions
for the synthesis of sulfenamides under microwave irradi-
ation (MW).
First model reaction
In our initial attempt, the reaction of t-butylamine with N-
(phenylthio)phthalimide was chosen as a model reaction
under microwave irradiation (Scheme 3). To identify
optimal conditions, we studied the effects of various times
and different temperatures. The reaction mixture was
irradiated for 1–45 min at 30–150 °C. Also, we studied the
effects of various solvents such as CH3CN, DMSO, CHCl3,
and EtOH, but they gave no desired product. In another
process, different amounts of starting reagents (1.0:1.0;
1.0:1.2; 1.0:1.5; 1.0:2.2) gave diphenyl disulfide instead of
desired product.
Second model reaction
In the second attempt, the reaction of t-butylamine with N-
(phenylthio)phthalimide was chosen as a model reaction
under microwave irradiation in the presence of
2-ethoxyethanol (Scheme 4). To identify the optimal con-
ditions, we studied the effects of various times and
123

H. Yakan, H. Kütük
Scheme 4
Scheme 5
O
β
-EE
S
H
N
S
N
+
H2N
+
S
S
H
O
Product
different temperatures. The reaction mixture was irradiated
for 3–90 min at 30–60 °C. In another process, different
amounts of starting reagents (1.0:1.0; 1.0:2.5) gave
diphenyl disulfide instead of desired product. It was
observed that the symmetric disulfides and N,N0-bi(ph-
thalimide) are an intermediate in this transformation.
(1.0 equiv) with 3a (4.0 equiv) in the presence of b-ee in
60 min at 50 °C under microwave irradiation gave 4aa an
excellent yield of 92%. At higher temperature and longer
reaction time 4aa was obtained in lower yields of 10–33%,
whereas diphenyl disulfide occurred in of 57–78% yields
(Table 1, entries 6–8). The temperature of reaction above
60 °C, gave symmetric disulfide 5 instead of the desired
product (Table 1, entries 9, 10; see schemes S47–S50 in
the electronic supplementary material). The time of reac-
tion prolonged or diminished at 50 °C, to give corre-
sponding sulfenamide good yields 55–86% (Table 1,
entries 11–13). We studied the effects of various solvents
such as diglyme, glyme, and ethylene glycol under 50 °C
(Table 1, entries 14–16).These solvents have very high
polarity. They give successful results with 64–75% yields.
However, the best result is obtained b-ee as shown in
Table 1.
Third model reaction
In the third attempt, the reaction of cyclohexylamine with
N-(phenylthio)phthalimide was chosen as a model reaction
under microwave irradiation in the presence of
2-ethoxyethanol to give desired product and diphenyl
disulfide as by-product (Scheme 5). Though the nucle-
ophilicity of t-butylamine is more than cyclohexylamine, t-
butylamine is steric hindrance. Thus, our second model
reaction did not work because of the amine reagents.
However, this reaction began with the nucleophilic attack
on the sulfur atom on the disulfides by the amine and gave
corresponding sulfenamides.
The efficient method for the synthesis of sulfenamides 4
by the reaction of substituted thiophthalimide derivatives
2a–2j with amines 3a–3c in the presence of
2-ethoxyethanol (b-ee, neat) under microwave irradiation
is shown in Table 2. To achieve this, first sulfenimides 2
were prepared from the corresponding thiols 1 by reaction
with phthalimide in hot acetonitrile–pyridine, then, added
solution of bromine in acetonitrile [33–36]. 10 items of
sulfenimides were obtained in good to excellent yields
ranging from 72 to 92%. The scope of this reaction was
shown by the efficient synthesis of sulfenamides in good to
excellent yields of 70–98% at 50 °C. Thiophthalimides
which had electron-donating or electron-withdrawing
groups were used and, as desired, it gave good yield of
products. It can be seen that electron-donating and
To identify the optimized conditions, the reaction mix-
ture was irradiated for 5–90 min. Also, the effects of var-
ious temperature, time, and reaction conditions were
studied (Table 1). We investigated different amounts of
starting reagents (1.0:1.0; 1.0:1.5; 1.0:2.5; 1.0:4.0) to
obtain the desired product 4aa and symmetric disulfide 5a
in 30 min at 50 °C in the presence of b-ee (Table 1, entries
1–4). While the expected sulfenamide (N-(phenylthio)-N-
cyclohexylamine, 4aa) was obtained in 30–83% yields,
diphenyl disulfide was obtained in 8–55% yields. When the
time of reactions prolonged under the same condition, good
results were achieved (Table 1, entry 5). The reaction of 2a
123

Comparison of conventional and microwave-assisted synthesis of some new sulfenamides under…
Table 1 Optimization of the reaction conditions
O
β−ee
S
H
N
N
+
H2N
+
S
S
MW
S
H
O
2a
3a
4aa
5a
Entry
2a:3a
Solvent
T/°C
Yielda/% 4aa:5a
Timeb/min
1
1.0:1.0
1.0:1.5
1.0:2.5
1.0:4.0
1.0:4.0
1.0:4.0
1.0:4.0
1.0:4.0
1.0:4.0
1.0:4.0
1.0:4.0
1.0:4.0
1.0:4.0
1.0:4.0
1.0:4.0
1.0:4.0
1.0:4.0
1.0:4.0
1.0:4.0
1.0:4.0
b-ee
50
50
50
50
50
60
60
60
75
90
50
50
50
50
50
50
50
50
50
50
30:55
35:52
54:34
83:8
30
30
30
30
60
30
60
90
60
60
90
20
10
60
60
60
60
60
60
60
2
b-ee
3
b-ee
4
b-ee
5
b-ee
92:5
6
b-ee
10:78
15:65
33:57
0:95
7
b-ee
8
b-ee
9
b-ee
10
11
12
13
14
15
16
17
18
19
20
b-ee
0:95
b-ee
86:7
b-ee
67:25
55:36
75:14
71:17
64:27
0:41
b-ee
Glyme
Diglyme
Et.gly.c
EtOH
CH3CN
DMSO
CHCl3
0:52
0:63
0:48
aIsolated yields by column chromatography
bReaction time monitored by TLC
cEthylene glycol as solvent
electron-withdrawing groups did not demonstrate any dif-
ference on the yields. The best yield (98% for 4fb) was
obtained from reaction of 4-bromophenylthiophthalimide
(2f) and morpholine (3b). The lower yields (70%) were
obtained when the reaction was conducted 2b with pyrro-
lidine (3c). It was observed that when cyclohexylamine
(3a) reacted with sulfenimides 2a–2j under microwave
irradiation for 2.0 h at 50 °C, only four sulfenimides (2a,
2b, 2c, 2g) succeeded to perform the desired product in
high yields of 81–92% after purification. When morpholine
(3b) was treated with thiophthalimides 2a–2j under
microwave irradiation for 0.5–2.5 h at 50 °C, the corre-
sponding sulfenamides 4 accomplished to obtain high
yields in 78–98% after purification. When pyrrolidine (3c)
reacted with several sulfenimides 2a–2j under microwave
irradiation for 1.0–3.0 h at 50 °C, only three corresponding
sulfenamides (4ac, 4bc, 4 cc) were isolated after purifica-
tion in good yields of 70–76%.
under different time, temperature, and various reaction
conditions (both solvent and free-solvent). 9 items of the
amines (aniline, benzylamine, 1-hexylamine, ethanola-
mine, diethylamine, N-ethyl-n-butylamine, N-ethylaniline,
N-benzylmethylamine, t-butylamine) react with sulfen-
imides 2a–2j to give symmetric disulfides astonishingly.
We observed that aliphatic and aromatic amines (9 items)
did not work in this reaction for the synthesis of
sulfenamides (Scheme 6a). However, the sulfenimides
react with just cyclohexylamine (3a), morpholine (3b), and
pyrrolidine (3c) to correspond to the sulfenamide 4 as
shown in Scheme 6b.
It was observed that the reaction of t-butylamine with N-
(phenylthio)phthalimide gave N-(phenylthio)-N-(t-butyl)a-
mine (4ad) under microwave irradiation for 60 min at
50 °C in the presence of DPPH as radical scavenger
reagent in high yield (93%) after purification (Scheme 7;
see schemes S1–S3 in the electronic supplementary mate-
rial). Taniguchi reported that the same reaction was
obtained for 1080 min yield in 88% with the use of a
We tested the reaction of sulfenimides 2a–2j with those
of amines (12 items of aliphatic and aromatic amines)
123

H. Yakan, H. Kütük
Table 2 Synthesis of sulfenamides
Products
Timea/h
Yieldb/%
Lit. m.p./°C
M.p./°C
4aa
4ab
4ac
4ba
4bb
4bc
4ca
4cb
4cc
4db
4eb
4fb
4ga
4gb
4hb
4ib
1
92
95
74
84
92
70
81
97
76
88
82
98
87
89
78
80
86
–
Oil
1
33–36 [37]
31–34
Oil
2
–
2
–
Oil
1.5
3
–
130–132
Oil
–
2
–
Oil
0.5
3
–
127–129
Oil
–
2
–
48–52
116–118
135–138
Oil
2
–
2
–
2
–
0.5
2
–
132–136
71–73
138–141
122–125
74–76 [38]
2.5
2.5
–
–
4jb
Conditions: sulfenimides (1 mmol), amines (4 mmol)
aThe best result during reaction in 0.5–3 h. Reactions were monitored each 30 min for best yields
bIsolated yields after column chromatography
123

Comparison of conventional and microwave-assisted synthesis of some new sulfenamides under…
Scheme 6
Table 3 The effect of radical scavenger reagents
Scheme 7
2a/mmol
t-Butylamine/mmol
Reagentsa
Yieldb/%
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.5
2.5
2.5
2.5
2.5
2.5
4.0
4.0
4.0
4.0
4.0
4.0
BHA (10%)
BHA (20%)
BHT (20%)
BHT (30%)
BHT (40%)
BHT (50%)
C vit. (10%)
C vit. (25%)
C vit. (40%)
C vit. (50%)
DPPH (5%)
DPPH (10%)
67
67
66
66
67
68
68
68
70
70
85
93
copper catalyst and ligand [30, 31]. However, we found
that the reaction of t-butylamine with 2b, 2c, and 2e did not
give the corresponding sulfenamide under same conditions.
To clarify the mechanism, we studied different reaction
conditions under microwave irradiation. For example, we
investigated the time of the reaction (0.5–2 h), reaction
medium (both solvent and free-solvent) and in the presence
and absence of 2,2-diphenyl-1-picrylhydrazyl (DPPH) as
radical scavenger reagent. Also, the effect of radical
scavenger reagents was tested by butylated hydroxytoluene
(BHT) [39], butylated hydroxyanisole (BHA) [40], ascor-
bic acid (C vit.) [41], and DPPH [42] as shown in Table 3.
A good yield was obtained for 60 min at 50 °C in the
presence of DDPH and b-ee as solvent. We understood that
the procedure was not inhibited by radical scavenger
reagent.
Conditions: 60 min at 50 °C
aRadical scavenger reagents and % molarity of sulfenimides (2a)
bIsolated yields after column chromatography
corresponding sulfenamides. In addition, Rattanangkool
and co-workers reported sulfenamides via disulfides as an
intermediate in the reaction by the reaction thiols with
amines in the presence of oxidant [32]. Second,
sulfenamides can be obtained from direct nucleophilic
attack of amines on the sulfur atom on the sulfenimides
(Scheme 8). Furthermore, Suwa and co-workers suggested
a mechanism of disulfides with heterolytic S–N scission in
sulfenimide [43].
From these results, we suggested a mechanism for the
preparation of sulfenamides which included two possible
pathways. First, symmetric disulfides were astonishingly
obtained from sulfenimides and these amines. We sug-
gested that the symmetric disulfides and N,N0-bi(phthal-
imide) are an intermediate in this transformation. Then, this
reaction began with the nucleophilic attack on the sulfur
atom on the disulfides by the amine and gave
To compare the microwave-assisted synthesis method
with the traditional heating method, the synthesis of some
sulfenamides was also accomplished. In Table 4, related
experimental data are given. It is obvious that in all cases
123

H. Yakan, H. Kütük
Scheme 8
O
δ−
δ+
S
O
O
O
N
S
R
2
R
S
N N
+
R
O
O
O
O
H
R
S
N
R1
excess
N N
+
+
S
R
O
O
O
S
N
R1
2
+
+
2
HN
R
O
O
O
R1
N
H
R1
δ−
δ+
S
R
N
R2
NH
>
S
+
N
R2
O
O
R
O
H
O
N
R
R2
+
R2
N
R1
N
S
+
HN
S
R1
O
O
R
much fewer reaction times and higher yields were suc-
ceeded under microwave irradiation compared with tradi-
with 95% yield in 60 min; our work as classical heating in
62% yield in 600 min.
tional
heating
except
for
N-(2-
mercaptobenzimidazolyl)morpholine (4jb). For example,
with traditional heating, N-(phenylthio)-N-cyclohexylamine
(4aa) was obtained in 80% yield in 1080 min; under MW
conditions, after 60 min the yield of the reaction was 92%;
our work as classical heating in 58% yield in 600 min.
Similarly, under the traditional method, N-(phenylthio)-
morpholine (4ab) was obtained with 82% yield in 1080 min,
whereas under microwave conditions it was synthesized
Conclusion
We observed that all of thiols react with morpholine to give
corresponding sulfenamides in excellent yields of 78–98%.
Thiophenol, 4-methylthiophenol, 4-chlorothiophenol, and
4-fluorothiophenol react with cyclohexylamine to give
corresponding sulfenamides in high yields of 81–92%.
Cyclohexylamine does not work with the other thiols.
123

Comparison of conventional and microwave-assisted synthesis of some new sulfenamides under…
Table 4 Comparison of microwave and classical heating for synthesized compounds
Products
Classical heating (our)a
Our MW heating
Time/min
Time/min
Yield/%
Yield/%
4aa
4ab
4ac
4ba
4bb
4bc
4ca
4cb
4cc
4db
4eb
4fb
4ga
4gb
4hb
4ib
1080 (600)
80 [37] (58)
60
60
92
95
74
84
92
70
81
97
76
88
82
98
87
89
78
80
86
1080 (600)
82 [37] (62)
180 (600)
90 [44] (67)
120
120
90
–
–
– (600)
– (42)
–
–
180
120
30
–
–
–
14 [45]
– (900)
44 [46] (45)
180
120
120
120
120
30
–
–
–
–
– (600)
– (47)
–
–
–
–
1140
76 [38]
92 [47] (69)
92 [48]
120
150
150
1080 (720)
120
4jb
aReflux in ethanol
Thiophenol, 4-methylthiophenol, 4-chlorothiophenol react
with pyrrolidine to give corresponding sulfenamides in
good yields of 70–76%. Pyrrolidine does not work with the
other thiols. We noticed that the reaction of t-butylamine
with N-(phenylthio)phthalimide gave desired sulfenamide
under microwave irradiation in the presence of DPPH as
radical scavenger reagent in high yield of 93%.
Experimental
All starting materials and solvents were purchased from
¨
˜
Fluka, Aldrich, Carlo Erba, Riedel-deHaen, Acros Organ-
ics, and Merck Chemical Company and were used without
further purification. CEM Discover LabMate microwave
reactor (nominal power 300 W; pressure 20 bar) was used
in the microwave reactions under the closed vessel process.
Commercial CEM thick wall Pyrex reaction vessels were
used in the experiments with continuous stirring (800 rpm).
The temperature control was preserved by the built-in
infrared detector/controller. In experiments, a fiber optic
probe was also used to detect the internal temperature of
the reaction. It has features such as improved magnetic
stirring capabilities and cooling technology for enhanced
yields. IR spectra were recorded on a Bruker Vertex 80v
Aniline, benzylamine, 1-hexylamine, ethanolamine,
diethylamine, N-ethyl-n-butylamine, N-ethylaniline, N-
benzylmethylamine, t-butylamine react with thiols to give
symmetrical disulfides instead of desired products (under
microwave irradiation, 2-ethoxyethanol as a solvent, and at
50 °C).
We report a facile, eco-friendly, and novel method for
the synthesis of sulfenamides by the reaction of thioph-
thalimides with amines in the presence of 2-ethoxyethanol
(b-ee, neat) under microwave irradiation at 50 °C. Nine of
the synthesized sulfenamide derivatives are novel. All the
reactions conducted under microwave irradiation achieved
higher yields in shorter times compared with classical
heating, except for one. Eventually, we have presented the
first report of a series of these sulfenamides under micro-
wave irradiation.
spectrophotometer. H NMR and 13C NMR spectra were
1
determined in CDCl3 a Bruker AC 200 MHz, Varian
Mercury 300 MHz, Varian Mercury 400 MHz spectrome-
ters using TMS as the internal standard. The splitting
patterns are indicated as s (singlet), d (doublet), dd (doublet
of doublet), and m (multiplied). Melting points were
measured with a Stuart SMP 30 electrothermal apparatus
and were uncorrected. Reactions were monitored by Thin-
Layer Chromatography (TLC) on DC-Silica Gel Kieselgel
60 F254 Merck plates and the spots were located using a
Camag UV lamp at 254 nm. MS spectra were determined
on a Thermo Finnigan Trace DSQ and Thermo Scientific
123

H. Yakan, H. Kütük
CH3), 2.11–1.12 (m, 10H) ppm; 13C NMR (100 MHz,
CDCl3): d = 141.1, 129.4, 125.7, 142.4, 52.9, 35.2, 25.4,
24.7, 21.3 ppm.
Quantum (TSQ) Access Max spectrometers. Elemental
analyses were performed on a LECO, CHNS-932 ele-
mental analyser with the VTF-900 high-temperature
Pyrolysis Furnace by the R&D Training and Measure
Central of Middle East Technical University (METU) in
Ankara, Turkey.
N-(4-Methylphenylthio)morpholine (4bb, C11H15NOS) Rf =
ꢀ
0.45 (100% n-hexane); FT-IR (KBr): t = 3145, 2988,
1
1125, 1084, 914, 723 cm-1; H NMR (400 MHz, CDCl3):
d = 7.39–7.34 (d, 2H), 7.27–7.22 (d, 2H), 3.55-3.41 (t,
4H), 2.96–2.82 (t, 4H), 1.86 (s, CH3) ppm; 13C NMR
(100 MHz, CDCl3): d = 135.3, 131.3, 129.1, 126.5, 66.7,
48.0, 22.6 ppm.
General procedure for the synthesis
of sulfenimides 2a–2j
Thiols (21 mmol) and 2.94 g phthalimide (20 mmol) were
dissolved in 18 cm3 of hot pyridine–acetonitrile (4:5 mix-
ture), and the resulting solution was cooled to room tem-
perature with continuous stirring. A solution of 3.79 g
bromine (1.22 cm3, 24 mmol) in 10 cm3 acetonitrile was
then added drop by drop over 0.5 h. After a further period
of 2 h, 40 cm3 methanol was added drop by drop over
0.5 h. The products were cooled in an ice-water bath for
0.5 h, and then 2a–2j was isolated by filtration [33–35].
N-(4-Methylphenylthio)pyrrolidine (4bc, C11H15NS) Rf =
ꢀ
0.37 (8% chloroform ? 92% n-hexane); FT-IR (KBr): t
1
= 3127, 2983, 1072, 893, 688 cm-1; H NMR (400 MHz,
CDCl3): d = 7.73–7.70 (d, 2H), 7.34–7.31 (d, 2H),
3.25–3.20 (t, 4H), 1.77–1.71 (t, 4H), 2.43 (s, CH3) ppm;
13C NMR (100 MHz, CDCl3): d = 143.1, 133.5, 129.4,
127.3, 47.7, 24.9, 21.3 ppm.
N-(4-Chlorophenylthio)-N-cyclohexylamine
(4ca, C12H16ClNS) Rf = 0.39 (100% n-hexane); FT-IR
Microwave-assisted synthesis method
-1
ꢀ
(KBr): t = 3412, 3128, 2978, 1104, 924, 828, 673 cm
;
1H NMR (300 MHz, CDCl3): d = 7.61–7.55 (d, 2H),
7.31–7.26 (d, 2H), 3,12–3.14 (p, 1H), 2.43 (s, NH),
1.77–1.06 (m, 10H) ppm; 13C NMR (75 MHz, CDCl3):
d = 142.4, 141.0, 129.4, 125.7, 55.0, 36.4, 28.0, 21.3 ppm.
Substituted thiophthalimide derivatives 2a–2j (1 mmol)
with amines 3a-3c (4 mmol) were ground thoroughly and
then taken into a 10 cm3 pressure tube and subjected to
microwave heating (CEM discover) in the presence of
2-ethoxyethanol (b-ee, neat). The reaction vessel was
sealed and heated in microwave for 30–180 min at 50 °C.
The process of the reaction was displayed by TLC at reg-
ular intervals on silica gel with a mixture of hexane and
ethyl acetate (4:1) as the eluent. Next, the mixture was
extracted with ethyl acetate (2 9 10 cm3) and the com-
bined organic layer was dried over anhydrous sodium
sulfate. After completion of the reaction, the solvent was
evaporated and the residue was purified by column chro-
matography on a silica gel using generally hexane as eluent
to afford the pure products 4.
N-(4-Nitrophenylthio)morpholine (4db, C10H12N2O3S) Rf =
ꢀ
0.45 (5% chloroform ? 95% n-hexane); FT-IR (KBr): t
= 3110, 3030, 1501, 1363, 1186, 1087, 1000, 683 cm-1
1H NMR (300 MHz, CDCl3): d = 8.14–8.12 (d, 2H),
7.37–7.34 (d, 2H), 3.78–3.74 (t, 4H), 3.39–3.35 (t, 4H)
ppm; 13C NMR (75 MHz, CDCl3): d = 145.1, 130.1,
126.6, 121.0, 55.7, 42.7 ppm.
;
N-(4-Methoxyphenylthio)morpholine (4eb, C11H15NO2S) Rf =
0.45 (8% chloroform ? 92% n-hexane); FT-IR (KBr):
-1
;
1H
ꢀ
t = 3109, 2964, 1287, 1174, 1073, 962, 705 cm
NMR (300 MHz, CDCl3): d = 7.48–7.54 (d, 2H),
6.89–6.82 (d, 2H), 3.79–3.77 (t, 4H), 3.19–3.16 (t, 4H),
2.38 (s, CH3) ppm; 13C NMR (75 MHz, CDCl3):
d = 160.6, 132.6, 126.1, 114.6, 55.4, 46.5, 30.9 ppm.
Classical heating method
Substituted thiophthalimide derivatives (5.0 mmol) and the
appropriate amines (20.0 mmol) were ground thoroughly
and transferred to a 100 cm3 flask. The mixture was
refluxed in 30 cm3 2-ethoxyethanol over a hotplate stirrer.
The progress of the reaction was monitored by TLC. The
product was purified as described above, after completion
of the reaction.
N-(4-Bromophenylthio)morpholine (4fb, C10H12BrNOS) Rf =
0.61 (10% chloroform ? 90% ethyl acetate); FT-IR (KBr):
t = 3147, 2977, 1160, 1108, 897, 718, 638 cm-1; 1H NMR
ꢀ
(400 MHz, CDCl3): d = 7.37–7.33 (d, 2H), 7.23–7.19 (d,
2H), 3.65–3.42 (t, 4H), 3.14–2.83 (t, 4H) ppm; 13C NMR
(100 MHz, CDCl3): d = 132.6, 128.7, 126.9, 123.5, 60.9,
50.8 ppm.
N-(4-Methylphenylthio)-N-cyclohexylamine
N-(4-Fluorophenylthio)-N-cyclohexylamine
(4ga, C12H16FNS) Rf = 0.42 (100% n-hexane); FT-IR
(4ba, C13H19NS) Rf = 0.41 (100% n-hexane); FT-IR
1
(KBr): t = 3372, 3084, 2987, 1113, 872, 686 cm-1; H
ꢀ
-1
ꢀ
(KBr): t = 3420, 3055, 2952, 1174, 1058, 965, 644 cm
;
NMR (400 MHz, CDCl3): d = 7.61–7.57 (d, 2H),
7.31–7.27 (d, 2H), 4.14–4.08 (p, 1H), 3.04 (s, NH), 2.41 (s,
1H NMR (400 MHz, CDCl3): d = 7.76–7.68 (d, 2H),
123

Comparison of conventional and microwave-assisted synthesis of some new sulfenamides under…
20. Loupy A, Petit A, Hamelin F, Texier-Boullet F, Jacquault P,
Mathe’ D (1998) Synthesis 1998:1213
7.53–7.43 (d, 2H), 3.98 (s, NH), 3.29 (p, 1H), 2.13–1.28
(m, 10H) ppm; 13C NMR (100 MHz, CDCl3): d = 145.5,
130.6, 128.7, 125.7, 53.0, 35.2, 25.4, 24.6 ppm.
¨
21. Lidstrom P, Tierney J, Wathey B, Westman J (2001) Tetrahedron
57:9225
22. Varma RS (1999) Green Chem 1:43
N-(4-Fluorophenylthio)morpholine (4gb, C10H12FNOS) Rf =
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24. Anastas PT, Warner JC (1998) Green chemistry: theory and
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25. Harpp DN, Back TG (1971) Tetrahedron Lett 52:4953
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ꢀ
0.43 (100% n-hexane); FT-IR (KBr): t = 3169, 3068,
1
1155, 1110, 1012, 930, 743 cm-1; H NMR (400 MHz,
CDCl3): d = 7.54–7.37 (d, 2H), 7.23–7.06 (d, 2H),
3.57–3.32 (t, 4H), 3.09–2.84 (t, 4H) ppm; 13C NMR
(100 MHz, CDCl3): d = 161.3, 135.4, 130.9, 123.4, 66.9,
47.7 ppm.
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Acknowledgements We would like to thank Ondokuz Mayis
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