Zinc chloride catalyzed ring opening of N-arylsulfonyl aziridines by thioamides: A new approach to the synthesis of amidines

Article abstract of DOI:10.1055/s-0034-1378376

The first zinc chloride catalyzed ring opening of N-arylsulfonyl aziridines by thioamides is described. Various thioamides were reacted with N-arylsulfonyl aziridines in the presence of a catalytic amount of dry zinc chloride to provide the corresponding

Full text of DOI:10.1055/s-0034-1378376

2044▌
LETTER
letter
Zinc Chloride Catalyzed Ring Opening of N-Arylsulfonyl Aziridines by
Thioamides: A New Approach to the Synthesis of Amidines
Ring Opening of Aziridines with Thioamides
Khadijeh Hajibabaei, Hassan Zali-Boeini*
Department of Chemistry, University of Isfahan, 81746-73441 Isfahan, Iran
Fax +98(311)6689732; E-mail: h.zali@chem.ui.ac.ir
Received: 05.05.2014; Accepted after revision: 30.05.2014
ous nucleophiles such as thiols, amines, alcohols, and si-
lylated nucleophiles have been developed,11 there are few
reactions involving other sources of nucleophilic sulfur in
ring-opening reactions of aziridines. Aziridines have been
shown to react with dithiocarbamates to give the corre-
sponding β-sulfonamido dithiocarbamates12 and they also
react with carbon disulfide to give the corresponding thi-
azolidin-2-thiones in the presence of several Lewis ac-
ids.13 Recently, a ring-opening reaction between aziridine
derivatives and thioaroylates generated in situ from the re-
action of acyloxyphosphonium and tetrathiomolybdate
salts has been reported.14 In light of these developments,
we were led to study the reaction of thioamides as other
sources of nucleophilic sulfur with aziridines.
Abstract: The first zinc chloride catalyzed ring opening of N-aryl-
sulfonyl aziridines by thioamides is described. Various thioamides
were reacted with N-arylsulfonyl aziridines in the presence of a cat-
alytic amount of dry zinc chloride to provide the corresponding N-
arylsulfonyl amidine derivatives with good to excellent yields.
Key words: amides, Lewis acids, nitrogen, homogeneous catalysis,
sulfur
Amidine derivatives are the key structural framework of
many natural products and pharmaceuticals1 and have
substantial biological activities.2 Various methods have
been developed for the preparation of amidines. Recently,
a new route for the synthesis of amidines via NaI-cata-
lyzed direct condensation of sulfonamide and formamide
derivatives has been reported.3 Numerous three-compo-
nent copper-catalyzed reactions have also been reported
for the construction of N-sulfonyl formamidines.4–6 More-
over, tandem dehydrogenation of aliphatic tertiary amines
and reaction with sulfonyl azides present other innovative
alternatives for the preparation of N-sulfonylamidine de-
rivatives.7 Another method to synthesize N-sulfonylami-
dines benefits from the reaction of enamines with p-
toluenesulfonyl azide.8 However, although, these proto-
cols have synthetic application and diverse substrate
scope, they suffer from the use of harsh conditions, intrin-
sically explosive and/or expensive starting materials, and
corrosive and/or specialized reagents.
The sulfur atom of a tertiary thioamide has a high order of
nucleophilicity and readily reacts with electrophiles.15
Earlier, we reported on the synthesis of thioesters starting
from thioamides as a source of nucleophilic sulfur and re-
acting with protonated alcohols16 and α-haloketones17 as
different electrophiles. In continuation of our studies on
the reaction of thioamides with diverse electrophiles, we
herein describe a simple and fundamentally different ap-
proach to N-arylsulfonyl formamidine derivatives based
on the direct reaction of N-arylsulfonyl aziridines and
morpholino(aryl) methanethiones catalyzed by zinc chlo-
ride.
At the outset of our study, we examined the reaction of
morpholino(phenyl)methanethione (1a) as a test substrate
with 2-phenyl-1-tosylaziridine (2a) in the presence of dry
Zn(OTf)2 as a Lewis acid catalyst. Although, we expected
that thioester 4 would be the product of the reaction, we
were very surprised by the fact that, the reaction product
was not thioester 4 but instead, amidine compound 3a was
obtained as the sole product and in excellent yield (90%,
Scheme 1). Intrigued by this finding and in order to ex-
plore the scope of the reaction, we decided to examine
other nitrogen sources bearing a sulfonyl functionality.
Aziridines exhibit high order of reactivity towards nucle-
ophilic attack due to their ring strain. Therefore they have
been received much attention in organic synthesis as a
good nitrogen source for the preparation of amino-func-
tionalized compounds in recent years.9 Concerning the re-
activity, the most general transformations of these three-
membered ring systems are the ring-opening reactions ini-
tiated by either electrophilic or nucleophilic reagents.10
Although ring-opening reactions of aziridines with vari-
S
NTs
Ts
O
Ph
N
Zn(OTf)2
Ph
N
Ph
N
+
+
Ph
S
Ph
CH2Cl2, 40 °C
O
O
NHTs
1a
2a
3a 90%
4
not formed
Scheme 1
SYNLETT 2014, 25, 2044–2048
Advanced online publication: 28.07.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0034-1378376; Art ID: st-2014-d0378-l
© Georg Thieme Verlag Stuttgart · New York

LETTER
Ring Opening of Aziridines with Thioamides
2045
Table 2 Optimization of the Reaction Conditions for Compound 3aa
First, TsN3 as a source of nitrene having a sulfonyl moiety
was chosen and reacted with thioamide 1a. As expected,
the reaction progressed smoothly but the corresponding
amidine 3a was produced in a lower yield (62%, Table 1).
Other nitrene sources were also tested in the reaction with
thioamide 1a under similar conditions. While TsN·NaCl
(chloramine-T) furnished the amidine 3a in a rather mod-
erate yiled (45%), PhI=NTs produced the desired com-
pound in very low yield (10%). However, no product
yield was observed in the case of using TsN=PPh3 as an
unusual nitrene source.
Entry Catalyst
Solvent
Temp (°C) Time (h) 3a (%)b
1
2
–
CH2Cl2
–
40
130
40
24
2
0
14
56
0
–
3
FeCl3
InCl3
BF3·OEt2
Zn(OTf)2
ZnCl2
CH2Cl2
CH2Cl2
THF
2
4
40
24
24
2
c
5
70
11
90
91
83
6
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
40
Table 1 Comparison of the Synthesis of Compound 3a through the
Reaction of Thioamide 1a with Different Nitrogen Sourcesa
7
40
2
d
8
ZnCl2
40
2
Entry Nitrogen source
Catalyst
Temp Time Yield
(°C) (h) (%)b
e
9
ZnCl2
40
2 (72) 41 (61)
1
2
3
4
5
TsN3
–
–
–
40
40
40
24
48
78
2
62
0
10
11
12
13
14
ZnCl2
ZnCl2
ZnCl2
TsOH
TsOHf
r.t.
40
2
2
67
78
80
<5
29
TsN=PPh3
PhI=NTs
10
90
45
MeCN
CH2Cl2
–
40
2
N-tosyl-2-phenylaziridine Zn(OTf)2 40
TsN·NaCl 40
40
24
2
–
2
130
a Reaction conditions: 1a (1.0 mmol), nitrogen source precursor (1.2
mmol), and catalyst (2 mol%) in CH2Cl2 (3 mL).
b Isolated yield.
a Reaction conditions: 1a (1.0 mmol), 2a (1.2 mmol), and catalyst (2
mol%) in solvent (3 mL) for 2 h.
b Isolated yield.
c The reaction was carried out under a nitrogen atmosphere.
d Conditions: 1 mol% catalyst was used.
e Conditions: 0.5 mol% catalyst were used.
f Considerable amounts of tarry materials were observed.
As indicated in Table 1, only 2-phenyl-1-tosylaziridine
(2a) operated as a successful nitrogen transfer agent to the
thioamide substrate 1a leading to the corresponding N-
sulfonyl amidine 3a. It is worth noting that all of the
above-mentioned sources of nitrene result in dark-colored
complex mixtures which are hard to separate. This could
be the reason for their notably lower product yields. It
should be mentioned that some degree of conversion of
the thioamide 1a into its analogous amide was also ob-
served. These results imply that the reaction of thioamide
substrate 1a with 2-phenyl-1-tosylaziridine (2a) most
likely proceeds by a quite different mechanism.
without the formation of any colored or tarry materials in
moderate to excellent yields (67–91%).
It was found that, in addition to ZnCl2, dry FeCl3 worked
in this reaction and afforded the desired amidine 3a in
moderate yield (Table 2, entry 3). However, using this cat-
alyst, great difficulty was observed in the separation of the
product. No product was observed when using PTSA as a
Brønsted acid at 40 °C even after prolonged reaction time,
but small amount of the product alongside of the large
amounts of tarry material were obtained at higher tem-
perature (Table 2, entries 13 and 14). As we expected the
reaction did not proceed in the absence of catalyst at low
temperature (40 °C) but very small amounts of the ami-
dine product 3a were obtained under solvent-free condi-
tions at elevated temperature (Table 2, entry 2). The
reaction was also tested in a variety of solvents using Zn-
Cl2 as catalyst at 40 °C. Our investigation revealed that the
best solvent for the reaction was CH2Cl2. The effect of dif-
ferent catalyst loadings was also examined, and it was
found that 2 mol% of ZnCl2 (relative to the aziridine 2a)
was the best quantity to complete the reaction. At a lower
catalyst loading the reaction took longer time and was not
complete even after stirring for several days (Table 2, en-
try 9).
In further trials, the role of the catalyst in the reaction was
also probed. Our preliminary findings indicated that vari-
ous types of Lewis acids can be applied in the course of
reaction, but only those which are based on the zinc salts
gave the better results (Table 2).
In this manner, the reaction of the test thioamide 1a with
2-phenyl-1-tosylaziridine (2a) in the presence of dry
Zn(OTf)2 in CH2Cl2 under reflux conditions was investi-
gated. This was very successful and produced the desired
amidine product 3a in 90% yield (Table 2, entry 6). To
avoid the use of moderately expensive Zn(OTf)2 we next
decided to utilize dry ZnCl2 as a cheap and readily avail-
able catalyst and obtained a similar yield (Table 2, entry
7). Fortunately, the reaction of all of the thioamide sub-
strates 1a–m with the arylsulfonyl aziridines 2a,b oc-
curred smoothly in the presence of dry ZnCl2 at 40 °C
After optimizing the conditions, we next examined the
generality of the method by using the reaction of a variety
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2044–2048

2046
K. Hajibabaei, H. Zali-Boeini
LETTER
of thioamides 1a–m and two different arylsulfonyl aziri- elimination of an unstable 2-phenylthiirane molecule. It is
dines 2a,b, and the results are summarized in Table 3.21 It proposed that the thiirane molecule spontaneously de-
was found that the electronic nature of the aryl substituent composes to the corresponding styrene and elemental sul-
on the arylsulfonyl aziridines 2 and the thiomide sub- fur under the reaction conditions.
strates 1 can impact on the efficiency of the reaction. A
notable decrease in yields (Table 3, entries 3j–o) was ob-
served when an electron-withdrawing group was attached
S
Ph
Ph
N
to the aryl substituent of the arylsulfonyl aziridine or thio-
amide. On the other hand, the efficiency of the reaction
was also affected by steric factors and bulky substituents
on the aryl groups caused the product yield to decline
slightly (Table 3, entries 3d–g).
TsN
–
O
+
ZnCl2
Ph
1a
N
Ts
2a
O
N+
Ph
Table 3 ZnCl2-Catalyzed Conversion of Thioamides to Amidine
Derivativesa
S
ZnCl2
Ph
TsN
R
R
S
O
O
ZnCl2
–
Ar
N
S
S
N
ZnCl2
N
N
O
O
CH2Cl2, 40 °C
Ar
O
A
O
Ph
1a–m
2a,b
NTs
O
N
S
Ph
3a–o
Ph
N
NTs
Product 3 Yield (%)b
O
Entry
R
Ar
Ph
3a
B
1
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
3a
3b
3c
3d
3e
3f
91
90
84
79
85
81
78
88
87
76
72
70
69
73
67
Ph
2
4-MeC6H4
4-Me2NC6H4
4-i-PrC6H4
2-naphthyl
2-quinolyl
4-biphenyl
4-HOC6H4
3,4-(MeO)2C6H3
4-ClC6H4
Ph
S
+ S
3
Scheme 2
4
The immediacy and the simplicity of this methodology are
demonstrated in Scheme 3 by comparison with two of the
previous methods. In one of the typical previous proce-
dures, N-sulfonylimidate, formed by three-component re-
5
6
7
3g
3h
3i
8
9
O
Ts
N
+
N
10
11
12
13
14
15
3j
n
R
this work
Ph
S
4-BrC6H4
3-BrC6H4
4-O2NC6H4
4-i-PrC6H4
2-naphthyl
3k
3l
ZnCl2
CH2Cl2
n = 0, 1
3m
3n
3o
O
NO2
NO2
N
n
R
previous method
NaCN (20%)
previous method
TsN3
NTs
a Reaction conditions: 1a–m (1.0 mmol), 2a,b (1.2 mmol), and cata-
lyst (2 mol%) in CH2Cl2 (3 mL) for 2 h.
b Isolated yields.
n = 1
CH2Cl2
MeOH, 50 °C
n = 0
OMe
A probable mechanism for the formation of amidine 3a is
depicted in Scheme 2. 2-Phenyl-1-tosylaziridine (2a) is
first activated by the ZnCl2 catalyst. Then thioamide 1a
undergoes an S-alkylation through nucleophilic attack on
the activated aziridine to form intermediate A. This inter-
mediate then cyclizes to form thiazolidine intermediate B
and transforms to the final amidine product 3a with the
R
+
O
NH
R
N
NTs
O
CuI, Et3N
MeCl
TsN3
+
+
MeOH
R
Scheme 3
Synlett 2014, 25, 2044–2048
© Georg Thieme Verlag Stuttgart · New York

LETTER
Ring Opening of Aziridines with Thioamides
2047
NTs
S
Ts
N
ZnCl2
CH2Cl2, 40 °C
N
O
+
N
O
Ph
2a
3p, 70%
1n
Scheme 4
(3) Chen, S.; Xu, Y.; Wan, X. Org. Lett. 2011, 13, 6152.
action of a terminal alkyne, an arylsulfonyl azide, and an
alcohol is treated with different amines in the presence of
catalytic amounts of NaCN to produce the corresponding
N-arylsulfonyl amidines in two steps.4b Another approach
profits from the reaction of enamines and sulfonyl azides
to attain the desired product.18 Both of these methods are
very effective and useful, but use potentially explosive ar-
ylsulfony azide or toxic NaCN catalyst and require multi-
ple steps; these are drawbacks compared to our protocol.
(4) (a) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127,
2038. (b) Yoo, E. J.; Bae, I.; Cho, S. H.; Han, H.; Chang, S.
Org. Lett. 2006, 8, 1347. (c) Chang, S.; Lee, M. J.; Jung, D.
Y.; Yoo, E. J.; Cho, S. H.; Han, S. K. J. Am. Soc. Chem.
2006, 128, 12366. (d) Kim, J. Y.; Kim, S. H.; Chang, S.
Tetrahedron Lett. 2008, 49, 1745. (e) Yoo, E. J.; Chang, S.
Org. Lett. 2008, 10, 1163.
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45, 3157. (b) Yoo, E. J.; Ahlquist, M.; Bae, I.; Sharpless, K.
B.; Fokin, V. V.; Chang, S. J. Org. Chem. 2008, 73, 5520.
(6) (a) Shang, Y.; He, X.; Hu, J.; Wu, J.; Zhang, M.; Yu, S.;
Zhang, Q. Adv. Synth. Catal. 2009, 351, 2709. (b) Mandal,
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To demonstrate the versatility of the presented method,
the reaction was further extended to a different thioamide
having a methylene moiety (Scheme 4). Hence, thioamide
1n as an example was chosen and reacted with 2-phenyl-
1-tosylaziridine (2a) at the same reaction conditions. As
expected the bulky thioamide reacted efficiently and pro-
vided 3p in a good yield of 70% (Scheme 4).
Fortunately, all of starting thioamides used in the present-
ed method could be readily accessible by the Willgeroadt–
Kindler reaction of their corresponding aldehyde or ace-
tophenone derivatives.19 The aziridine derivatives were
also simply prepared by the known methods.20
(8) Gao, T.; Zhao, M.; Meng, X.; Li, C.; Chen, B. Synlett 2011,
1281.
In conclusion, we have developed a simple procedure for
the imidation of thioamides catalyzed by simple zinc salts
leading to the corresponding N-arylsulfonyl amidines by
utilizing N-arylsulfonyl aziridines as the nitrogen source.
The method is applicable to a broad range of thioamides
and is performed under mild conditions, without need for
an expensive catalyst and gives good yields of product.
Furthermore the thioamides and nitrogen precursors are
readily prepared.
(9) (a) Jacobsen, C. B.; Jørgensen, K. A. Org. Biomol. Chem.
2008, 6, 3467. (b) Nenajdenko, V. G.; Karpov, A. S.;
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M.; Van Speybroeck, V.; Waroquier, M.; De Kimpe, N.
Chem. Commun. 2006, 1554. (c) Lu, P. Tetrahedron 2010,
66, 2549.
(11) (a) Wu, J.; Sun, X.; Sum, W. Org. Biomol. Chem. 2006, 4,
4231. (b) Ghorai, M. G.; Das, K.; Shukla, D. J. Org. Chem.
2007, 72, 5859. (c) Stanković, S.; D’hooghe, M.; Catak, S.;
Eum, H.; Waroquier, M.; Speybroeck, V. V.; Kimpe, N. D.;
Ha, H. Chem. Soc. Rev. 2012, 41, 643. (d) Chandrasekhar,
S.; Narsihmulu, C.; Shameem Sultana, S. Tetrahedron Lett.
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Acknowledgment
We are grateful to the University of Isfahan Research Council for
financial support of this work.
(12) Alagiri, K.; Prabhu, K. R. Chem. Eur. J. 2011, 17, 6922.
(13) Wu, J. Y.; Luo, Z. B.; Dai, L. X.; Hou, X. L. J. Org. Chem.
2008, 73, 9137.
Supporting Information for this article is available online
(14) Gopinath, P.; Debasree, C.; Vidyarini, R. S.;
Chandrasekaran, S. Tetrahedron 2010, 66, 7001.
(15) Jagodzinski, T. S. Chem. Rev. 2003, 103, 197.
(16) Zali-Boeini, H.; Mobin, M. Synlett 2010, 2861.
(17) (a) Zali-Boeini, H.; Eshghi Kashan, M. Green Chem. 2009,
11, 1987. (b) Zali-Boeini, H.; Zali, A. Synth. Commun. 2011,
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 2044–2048

2048
K. Hajibabaei, H. Zali-Boeini
LETTER
(21) Complete experimental procedures and relevant 1H NMR
and 13C NMR spectra and elemental microanalysis for new
compounds are available in the Supporting Information.
Typical Procedure for the Synthesis of N-Arylsulfonyl
Amidine 3a
Morpholino(phenyl) methanethione (1a, 207 mg, 1 mmol)
was then added, and the mixture was stirred at the same
temperature for 2 h. The reaction mixture was then triturated
with H2O (5 mL) to remove ZnCl2 and extracted with
CH2Cl2 (3 × 5 mL). The combined organic layers were dried
over MgSO4, filtered, and concentrated under vacuum.
Finally, the residue was subjected to column chromatog-
raphy on silica gel eluting with PE–EtOAc (1:1) to furnish
amidine 3a as a white solid (314 mg, 91%).
A suspension of anhydrous ZnCl2 (3.2 mg, 2 mol%) in
anhydrous CH2Cl2 (2.0 mL) was refluxed for 5 min, a
solution of 2-phenyl-1-tosylaziridine (2a, 328 mg, 1.2
mmol) in anhydrous CH2Cl2 (1.0 mL) was added slowly, and
the mixture was stirred at 40 °C for a further 5 min.
Synlett 2014, 25, 2044–2048
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