N-Chlorosuccinimide is a convenient oxidant for the synthesis of 2,4-disubstituted 1,2,4-thiadiazolidine-3,5-diones

Article abstract of DOI:10.1016/j.tetlet.2008.10.136

N-Chlorosuccinimide has been identified as a convenient and safe alternative oxidant for the oxidative condensation of isothiocyanates and isocyanates to afford 1,2,4-thiadiazolidine-3,5-diones.

Full text of DOI:10.1016/j.tetlet.2008.10.136

Tetrahedron Letters 50 (2009) 257–259
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Tetrahedron Letters
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N-Chlorosuccinimide is a convenient oxidant for the synthesis
of 2,4-disubstituted 1,2,4-thiadiazolidine-3,5-diones
*
Shama Nasim, Peter A. Crooks
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 501A 725 Rose Street, Lexington, KY 40536, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
N-Chlorosuccinimide has been identified as a convenient and safe alternative oxidant for the oxidative
condensation of isothiocyanates and isocyanates to afford 1,2,4-thiadiazolidine-3,5-diones.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 7 October 2008
Revised 25 October 2008
Accepted 28 October 2008
Available online 5 November 2008
The thiadiazolidinone (TDZD) ring system 1 (Fig. 1) possesses
several interesting pharmacological properties.1–5 In particular,
2,4-disubstituted TDZD derivatives inhibit the enzyme glycogen
synthase kinase 3b (GSK3b).2,3 GSK-3b has been shown to be
involved in several important cellular functions, and inhibitors of
this enzyme are believed to have therapeutic potential in the
treatment of disorders such as type-II diabetes and manic depres-
sion.1–4 Recently, it has also been reported that such derivatives
possess potent antileukemic properties.5 However, in spite of the
therapeutic potential of TDZD analogs, the chemistry of this
heterocycle remains relatively underexplored.
In the past, TDZD analogs have been prepared through two
distinct synthetic approaches, that is, the acyl-sulfenation of ureas
with chlorocarbonyl sulfenyl chloride,6 and the oxidative conden-
sation of isothiocyanates with isocyanates.2,3 The latter method
has been widely adopted since the nature of the 2- and 4-substit-
uents can be controlled, which is seldom possible utilizing the for-
mer method.7 Gaseous molecular chlorine2 and sulfuryl chloride6
are the only two oxidants used in the literature for the chlorination
of isothiocyanates to afford S-chloroisothiocarbamoyl chlorides,8
which can then undergo a cyclization cascade with isocyanates
to give the appropriate iminium precursors for the preparation of
TDZDs.1
reflux in either diethyl ether, hexanes, or CH2Cl2, as determined
by visual inspection (i.e., no discoloration of bromine and iodine)
as well as by GC–MS analysis. N-Bromosuccinimide, on the other
hand, afforded
a-bromo benzyl isothiocyanate, as previously re-
ported by Jochims et al.,9 suggesting that iodine, bromine, and their
equivalents are incapable of mediating S-oxidation of isothiocya-
nates that in turn initiate the cyclization sequence leading to the
TDZD ring system. It is possible that the oxidative potentials of bro-
mine and iodine are not appreciably lower than that of the sulfur
atom in the TDZD ring. In fact, this ring system has been demon-
strated to be a strong biological oxidant.5 We indeed found this
to be true during our experiments with Mitsunobu and transi-
tion-state mediated coupling reactions with this heterocycle,
wherein Ph3P, as well as Pd0 [as Pd2(dba)3], rapidly reduced TDZD
2. In both cases, p-iodobenzyl isocyanate (4) was also observed as a
byproduct. The presence of Ph3P@S in the GC–MS spectrum of the
reaction product led us to postulate a mechanism for the reaction
of Ph3P with 2, which is shown in Scheme 1. In the reaction of 2
with Pd2(dba)3, we observed the precipitation of a brown-black
solid that was insoluble in water and organic solvents. This solid
is most likely palladium monosulfide, since Pd0 is known to be
capable of functioning as a reductant, and its formation likely
involves a single-electron transfer (SET) mechanism.10,11
During our ongoing effort at exploring the antileukemic
potential of TDZDs through the preparation of large libraries of
2,4-disubstituted derivatives, a safer, stable, and more convenient
oxidant was required. The use of a number of alternative reagents
to chlorine gas was consequently attempted, employing benzyl
isothiocyanate and ethyl isocyanate as test reactants. Pyridinium
bromide perbromide, molecular bromine, and molecular iodine
were found to be incapable of halogenating the isothiocyanate
intermediate at various temperatures, ranging from ambient to
Chlorine equivalents being the next obvious choice, N-chloro-
succinmide (NCS) and chloramine-T were employed as suspen-
sions in diethylether, toluene, hexanes, and CH2Cl2 in separate
reactions. While chloramine-T was ineffective, NCS (1.0 equiv)
R1
O
N
O
S
N
1
R2
* Corresponding author. Tel.: +1 859 257 1718; fax: +1 859 257 7585.
E-mail address: pcrooks@email.uky.edu (P. A. Crooks).
Figure 1. The thiadiazolidinone (TDZD) ring system.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.136

258
S. Nasim, P. A. Crooks / Tetrahedron Letters 50 (2009) 257–259
the addition of the free radical inhibitor, m-dinitrobenzene, to
O
O
the reaction mixture did not cause a decrease in reaction rate.
These experiments suggested that NCS oxidizes the isothiocyanate
functional group in a classical ionic manner, involving an initial
oxidative reaction of NCS with isothiocyanate, as shown in Scheme
2, which illustrates a postulated mechanism for the reaction of NCS
with benzyl isothiocyanate (5) and ethyl isocyanate. The initial
electrophilic attack of the sulfur of 5 on the chlorine of NCS affords
6, which is immediately converted into 7. Sulfenyl chloride 7
would then be capable of undergoing an electrophilic attack by
the nitrogen of ethyl isocyanate, forming the highly electrophilic
species 8, followed by cyclization to 9. Iminium chloride 9 would
then undergo hydrolysis when exposed to air, yielding 10 and suc-
cinimide. The mechanism proposed for the condensation of 7 with
ethyl isocyanate is conceptually similar to that suggested by Mar-
tinez et al. for the oxidative condensation of isothiocyanates with
isocyanates,2 The initial reaction of NCS with isothiocyanates could
also proceed via an alternative reaction mechanism (Scheme 3)
involving a 6-membered concerted process to yield 11 as the sul-
fenyl chloride intermediate which then undergoes condensation
with ethyl isocyanate in a manner similar to the mechanism shown
in Scheme 2.
N
N
N
I
I
N
S
S
O
O
2
3
P
Ph
Ph
PPh3
Ph
N
Ph3P=S
I
O
4
Scheme 1. Proposed mechanism for the reduction of TDZD with Ph3P.
afforded ca. 10% mass conversion of benzyl isothiocyanate to TDZD
10 (Scheme 2) after workup. A slew of optimizations in reaction
conditions were then attempted in order to improve the efficiency
of this reaction. As a result, it was observed that the use of CHCl3
afforded a more homogenous reaction mixture and a higher con-
version rate than all other solvents that were employed. Refluxing
of the reaction mixture, however, led to the appearance of numer-
ous decomposition products that could not be characterized.
Increasing the number of equivalents of NCS led to an increase in
reaction yield after a period of 16 h, with the yield tapering off at
ca. 60% at 4 equiv or more, indicating that more than 5–6 equiv
of NCS are ineffectual in improving the reaction yield.12 Quantita-
tive recovery of the excess amounts of NCS from the above reac-
tions suggests that the requirement for excessive equivalents of
NCS seems to arise simply from a lower rate of reaction. In order
to increase the reaction rate, we attempted chemical initiation by
the addition of azobisisobutyronitrile (AIBN). However, this
resulted in the appearance of numerous decomposition products
with no appreciable increase in the reaction yield. Photochemical
acceleration by irradiating the reaction with a 400 W Hg-lamp also
did not lead to an increase in the reaction rate.
We next examined the scope and limitations of this reaction
(Table 1). The yields obtained in cases where the isothiocyanates
and isocyanates are alkyl or benzylic (entries 1–4, and 6) are com-
parable to those obtained utilizing the classical chlorine gas
method.2
Phenyl isothiocyanate (entry 5) also afforded the expected
product in good yields when the reactant was an alkyl isocyanate,
however, the use of a phenyl isocyanate (entry 11) resulted in a
very sluggish reaction. Increasing the equivalents of NCS to 10
did not improve the reaction yield, indicating that this method in
its current form is limited in use to the synthesis of non-aryl
substituted TDZDs. Entries 7–9 indicate that olefin, ester, and
acrylyl functionalities remain intact under the reaction conditions.
Interestingly, it was noted that m-anisyl isothiocyanate afforded
the required TDZD analog without concomitant chlorination of
the aromatic ring, which is not the case when the classical chlori-
nation methodology is employed, since we have noted extensive
aromatic chlorination during our experiments with anisyl isothio-
cyanates using molecular chlorine.
Attempts were then made to gain insights into the nature of the
reaction intermediates involved. The lack of an accelerating effect
of radical initiators on the reaction rate suggested that SET mech-
anisms were not significant kinetic components of the reaction
pathway. This was corroborated in another experiment, where
In conclusion, out of a variety of halogen equivalents examined,
NCS was found to be the only halogenating agent that initiates the
reaction pathway for the oxidative condensation of isothiocyanates
with isocyanates to yield 1,2,4-thiadiazolidine-3,5-dione. Com-
pared to the classically used reagents for this transformation (i.e.,
chlorine gas or SO2Cl2), NCS is a safer and a more convenient alter-
native reagent for the preparation of 1,2,4-thiadiazolidine-3,5-
diones.
O
O
N
O
O
N
Cl
N
N
Cl
S
S
6
5
O
N
O
O
O
N
Cl
Cl
S
N
S
N
7
O
O
N
O
N
O
O
N
O
N
8
Cl
N
Cl
S
N
O
S
5
11
S
N
O
Cl
N
O
N
10
O
N
Air
(H2O)
O
+
S
N
O
N
O
S
N
9
+
O
O
O
N
H
O
N
N
H
O
10
Succinimide
Succinimide
Scheme 2. Postulated mechanism for NCS-mediated TDZD formation.
Scheme 3. Alternative mechanism for NCS-mediated TDZD formation.

S. Nasim, P. A. Crooks / Tetrahedron Letters 50 (2009) 257–259
259
Table 1
2. Martinez, A.; Alonso, M.; Castro, A.; Perez, C.; Moreno, F. J. J. Med. Chem. 2002,
45, 1292–1299.
Scope of NCS-induced TDZDs formation
3. Martinez, A.; Alonso, M.; Castro, A.; Dorronsoro, I.; Gelpi, J. L.; Luque, F. J.; Perez,
C.; Moreno, F. J. J. Med. Chem. 2005, 48, 7103–7112.
4. Martinez, A.; Castro, A.; Dorronsoro, I.; Mercedes, A. Med. Res. Rev. 2002, 22,
373–384.
5. Guzman, M. L.; Xiaojie, L.; Corbett, C. A.; Rossi, R. M.; Bushnell, T.; Liesveld, J. L.;
Hebert, J.; Young, F.; Jordan, C. T. Blood 2007, 110, 4436–4444.
6. Slomczynska, U.; Barany, G. J. Heterocycl. Chem. 1984, 21, 241–246.
7. Pilgram, K. H.; Gale, L. H. J. Heterocycl. Chem. 1988, 25, 607–613.
8. Ottmann, G. F.; Hooks, H. Angew. Chem. 1965, 77, 427.
O
O
O
N
S
N
R1 NCS
Cl
N R1
CHCl3, rt, 12 h
R2
R2 NCO
O
1
No
R1
R2
Equiv. of NCS
Yield (%)
9. Hussein, A. Q.; Jochims, J. C. Chem. Ber. 1979, 112, 1948–1955.
10. Patnaik, P. Handbook of Inorganic Chemicals; McGraw-Hill: New York, 2003. p
687.
11. Ishizaki, M.; Yamada, M.; Watanabe, S.; Hoshino, O.; Nishitani, K.; Hayashida,
M.; Tanaka, A.; Hara, H. Tetrahedron 2004, 60, 7973–7981.
1
2
Bn
Bn
Hexyl
Bn
Et
Bn
Bn
2-Cl–Et
Et
4
4
4
4
4
4
4
4
45
50
52
39
45
40
34
52
313
414
5
Ph
12. General experimental procedure: The appropriate isothiocyanate (1 mmol)
and isocyanate (1 mmol) were each dissolved in anhydrous CHCl3
(10 mL/mmol) and NCS (4 mmol) was added in one portion. After stirring at
rt for 12 h under argon and subsequently for 10 min in air, the reaction mixture
was diluted with diethylether and filtered through a sintered glass funnel to
remove unreacted NCS and the precipitated succinimide. The filtrate was
concentrated under reduced pressure and subjected to column
chromatography over silica gel, eluted with 15–20% diethylether–hexanes to
isolate the pure product.
6
7
8
Cyclohexyl
Bn
Bn
Et
Allyl
2-(Carboxyethyl)-ethyl
O
O
9
Bn
4
50
13. 2-Benzyl-4-hexyl-1,2,4-thiadiazolidine-3,5-dione: yellow oil; yield: 52%. 1H NMR
(300 MHz, CDCl3) d 7.34–7.26 (m, 5H), 4.75 (s, 2H), 3.67 (t, J = 7.5 Hz, 2H), 1.66
(m, 2H), 1.30 (m, 6H), 0.87 (t, J = 5.7 Hz, 3H). 13C NMR (300 MHz, CDCl3) d
166.0, 153.4, 134.8, 129.1, 128.9, 128.6, 48.8, 43.1, 31.6, 28.1, 26.6, 22.8, 14.3.
GC–MS m/z 292. Anal. (C15H20N2O2S) C, H, N.
10
1115
m-Anisyl
Bn
Allyl
Ph
4
3–10
21
10
Acknowledgment
14. 2-Chloroethyl-benzyl-1,2,4-thiadiazolidine-3,5-dione: clear viscous oil; yield:
39%. 1H NMR (300 MHz, CDCl3) d 7.44–7.32 (m, 5H), 4.83 (s, 2H), 3.92 (t,
J = 5.7 Hz, 2H), 3.69 (t, J = 5.7 Hz, 2H); 13C NMR (300 MHz, CDCl3) d 165.8,
153.2, 135.0, 128.9, 128.8, 128.4, 46.9, 46.2, 42.1. GC–MS m/z 270. Anal.
(C11H11ClN2O2S) C, H, N.
Financial support from the Leukemia-Lymphoma Society, Grant
#6077-08, is gratefully acknowledged.
15. 2-Phenyl-4-benzyl-1,2,4-thiadiazolidine-3,5-dione: white solid; mp 90 °C; yield:
10%. 1H NMR (300 MHz, CDCl3) d 7.53–7.25 (m, 10H), 4.91 (s, 2H). 13C NMR
(300 MHz, CDCl3) d 165.1, 151.1, 135.9, 135.1, 129.6, 129.3, 128.9, 128.6, 127.1,
123.5, 46.4. GC–MS m/z 284. Anal. (C15H12N2O2S) C, H, N.
References and notes
1. Martinez, A.; Fernandez, E.; Castro, A.; Conde, S.; Rodriguez-Franco, I.; Banos,
J-E.; Badia, A. Eur. J. Med. Chem. 2000, 35, 913–922.