O-Iodoxybenzoic acid mediated oxidative desulfurization of 1,3-disubstituted thioureas to carbodiimides

Article abstract of DOI:10.1055/s-0030-1259072

An efficient and mild oxidative desulfurization procedure using o-iodoxybenzoic acid has been developed for the synthesis of carbodiimides starting from easily synthesizable 1,3-disubstituted thioureas.

Full text of DOI:10.1055/s-0030-1259072

LETTER
3065
o-Iodoxybenzoic Acid Mediated Oxidative Desulfurization of
1,3-Disubstituted Thioureas to Carbodiimides
O
xidative De
s
r
ulfurizat
a
ion of 1,3-
D
m
isubstituted
T
hiour
o
eas to Carbo
d
diimides S. Chaudhari, Prasad S. Dangate, Krishnacharya G. Akamanchi*
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Matunga, Mumbai 400 019, India
Fax +91(22)33611020; E-mail: kgap@rediffmail.com
Received 5 July 2010
excessive use of triethylamine8a as base and possibility of
product instability during isolation after aqueous workup.
Abstract: An efficient and mild oxidative desulfurization proce-
dure using o-iodoxybenzoic acid has been developed for the synthe-
sis of carbodiimides starting from easily synthesizable 1,3-
disubstituted thioureas.
(iii) Desulfurization of thioureas.9,10 This represents the
most general method of synthesis. Desulfurization is ef-
Key words: o-iodoxybenzoic acid, oxidation, desulfurization, thio- fected by reagents such as methanesulfonyl chloride,9b
sulfur dioxide and thionyl chloride,9g phosgene,9j mercu-
urea, carbodiimide
ric oxide9k,l and, very recently, molecular iodine.10 Draw-
backs of these methods are use of noxious and toxic
reagents and removal of phosphorous byproducts formed
during Mitsunobu reaction.9g,h The molecular-iodine-
based method is mild and efficient but suffers from the
limitation of not being applicable for the synthesis of bis-
dialkylcarbodiimides.
Dicyclohexylcarbodiimide (DCC) is used in automated
stepwise synthesis of polypeptides to activate the carbox-
yl group, for example, in the Merrifield method for the
synthesis of the polypeptide ribonuclease A, consisting of
124 amino acids.1 Oligonucleotides are also synthesized
using carbodiimides in automated condensation steps.2
Carbodiimides have been extensively used in organic syn-
thesis as auxiliary reagents in reactions such as Moffatt
oxidation of primary alcohols to aldehydes using DCC/
DMSO combination, conversion of alcohols or phenols
into hydrocarbons via hydrogenation of acylisoureas de-
rived from the corresponding carbodiimide adducts, and
dehydration of aldoximes to nitriles and others.3 Carbodi-
imides have also found use as key synthetic intermediates
in agricultural chemicals4 and pharmacologically active
compounds viz. substituted indoles, quinolidines, and iso-
quinolines displaying strong cytostatic antitumor activi-
ty.5 Aromatic carbodiimides have huge industrial
applications such as stabilizers for polyester-based poly-
urethanes.6
The rich chemistry exhibited by hypervalent organoiod-
ine(V) reagents such as o-iodoxybenzoic acid (IBX) and
Dess–Martin periodinane (DMP) is attributed to the cen-
tral iodine atom having strong electrophilic character cou-
pled with the leaving ability of the phenyliodino group.
The soft electrophilic iodine center can be attacked by a
wide range of nucleophiles including oxygen, nitrogen,
and sulfur nucleophiles. Many transformations have been
reported in the literature with sulfur nucleophiles11 includ-
ing ring expansion of dithianes,11d sulfoxidation,11f and
thioacetal cleavage.11g Our group is extensively working
on hypervalent iodine(V) reagents,12 and has recently re-
ported oxidative dimerization of thioamides to 1,2,4-thia-
diazoles with removal of sulfur.12b
Desulfurization of 1,3-disubstituted thiourea with the hy-
pervalent organoiodine(III) reagent, diacetoxyiodoben-
zene (DIB) to form N-acylated ureas via carbodiimide
intermediates has been reported.13 Based on this, we hy-
pothesized that, in the absence of reactive nucleophiles
such as acetate ion under mild reaction conditions, it
should be possible to isolate the carbodiimide intermedi-
ate and we succeeded.
Methods available for synthesis of carbodiimides can be
broadly classified into three categories:
(i) Thermolysis–decarboxylation of isocyanates.7 Gener-
ally, these reactions are carried out at high temperature in
the presence of metal catalyst and silicon-based re-
agents.7b However, this approach suffers from drawbacks
including low yields, use of toxic transition metals such as
palladium and nickel, toxic waste generation and forma-
tion of dimers or polymers.7c
(ii) Dehydration of ureas.8 Dehydration is effected using
phosgene and alkyl/arylsulfonyl reagents in combination
with bases. Although the process generally results in good
yields, the major concern is formation of highly reactive
side products such as N,N-dimethylcarbamoyl chloride,
When 1,3-diphenylthiourea (1a) was added portionwise
to a cooled solution of IBX and triethylamine in CH2Cl2,
thiourea was rapidly converted into carbodiimide 2a in
high yield with precipitation of sulfur (Scheme 1).
S
IBX, Et3N
N
C N
N
N
CH2Cl2, 0 °C
H
H
1a
+
2a
S
SYNLETT 2010, No. 20, pp 3065–3067
x
x
.x
x
.2
0
1
0
Advanced online publication: 25.11.2010
DOI: 10.1055/s-0030-1259072; Art ID: D17910ST
Scheme 1 Reaction of 1,3-diphenylthiourea with IBX
© Georg Thieme Verlag Stuttgart · New York

3066
P. S. Chaudhari et al.
LETTER
The reaction conditions were optimized with respect to try 8). The reaction was equally efficient with unsymmet-
solvent, temperature, and molar ratio. Reaction occurred rical thioureas (entries 9–14). The rate of hydration of
in different aprotic solvents such as DMF, EtOAc, MeCN, carbodiimides is well documented in the literature and has
CHCl3, CH2Cl2, THF, and toluene with yields in the range been shown to be relatively slow14 and so the rapid reac-
of 60–90% while a higher yield was observed in CH2Cl2. tion, mild conditions, and nonaqueous workup during iso-
At room temperature a number of side products was ob- lation of the carbodiimides meant that this was not a
served (by TLC). For complete reaction a molar ratio of problem in the present method.
1:1:2 for substrate/IBX/triethylamine was found to be sat-
isfactory.
A plausible mechanism for the formation of carbodi-
imides is presented in Scheme 2. Precipitation of sulfur
To establish the generality of the reaction, a variety of 1,3- during the reaction supports the postulated mechanism.
disubstituted thioureas was subjected to the optimized Recovery of the generated trivalent iodine reagent A for
conditions, and the results are summarized in Table 1. In recycling after re-oxidation to IBX by Oxone® was also
general, reactions were very fast and yields were compa- possible.
rable irrespective of the nature of substitution on the aro-
In summary, an efficient method based on oxidative des-
matic rings (entries 2–6). Reaction also proceeded
ulfurization of 1,3-disubstituted thioureas using IBX has
smoothly with sterically hindered 1,3-disubstituted thio-
been developed for the synthesis of carbodiimides. The
ureas (entries 2 and 10).
mild reaction conditions, ease of isolation, and suitability
In the case of 1,3-dicyclohexylthiourea reaction was very for a wide range of substrates makes this approach superi-
slow at 0 °C but proceeded smoothly at room temperature or to other syntheses. IBX oxidations are selective and tol-
for two hours to give 2h in 45% yield with recovery of erate a wide range of functional groups; therefore the
starting material and without formation of byproducts (en- present method could be easily extended to carbodiimide-
Table 1 Preparation of Carbodiimides from 1,3-Disubstituted Thioureasa
S
IBX, Et3N
R1
R2
R1
N
C
N
R2
N
N
CH2Cl2
H
H
1
2
Entry
Substrate 1
Time (min)
Product 2
Yield (%)
Symmetrical (R1 = R2)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Ph
10
10
2a15
2b
2c
90
88
90
92
88
88
86
45b
2-OMeC6H4
3-MeC6H4
4-OMeC6H4
4-ClC6H4
4-BrC6H4
Bn
10
10
2d
2e
10
10
2f
1g
1h
10
2g
2h
c-Hex
120
Unsymmetrical (R1 ≠ R2)
R1
Ph
Ph
Ph
Ph
Ph
Ph
R2
9
10
11
12
13
14
1i
4-MeC6H4
2-ClC6H4
Bn
10
10
10
10
10
10
2i
88
86
90
88
88
85
1j
2j
1k
1l
2k
2l
C6H4CH(Me)
n-Bu
1m
1n
2m
2n
c-Hex
a Reaction conditions: Thiourea (1 equiv), IBX (1 equiv), Et3N (2 equiv) in CH2Cl2 at 0 °C.
b Reaction carried out at r.t.
Synlett 2010, No. 20, 3065–3067 © Thieme Stuttgart · New York

LETTER
Oxidative Desulfurization of 1,3-Disubstituted Thioureas to Carbodiimides
3067
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NEt3
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http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
The author (P.S.C.) is grateful to University Grant Commission
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nancial assistance. We are also thankful to M/S Omkar Chemicals
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Preparation of 1,3-Diphenyl Carbodiimide 2a
To a stirred solution of IBX (0.6 g, 2.19 mmol) and Et3N (0.6
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1,3-diphenylthiourea (0.5 g, 2.19 mmol) portionwise over a
period of 5 min. After completion of reaction, as indicated
by TLC, reaction mixture was concentrated under vacuum,
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product was isolated after evaporation of the hexane extract
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known compounds. Characterization data are provided as
Supporting Information.
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