It is "thiazolidene-2-imine" and not imidazole-2-thione as the reaction product of 1-benzoyl-3-phenylthiourea with Br2/enolizable ketone

Article abstract of DOI:10.1021/ol062371b

The products obtained by the reaction of benzoyl-3-phenylthioureas with bromine and enolizable ketones in the presence of triethylamine are not imidazole-2-thione derivatives as reported (Org. Lett. 2003, 5, 1657-1659) rather they are thiazolidene-2-imine

Full text of DOI:10.1021/ol062371b

ORGANIC
LETTERS
2
006
Vol. 8, No. 23
397-5399
It Is “Thiazolidene-2-imine” and Not
Imidazole-2-thione as the Reaction
5
Product of 1-Benzoyl-3-phenylthiourea
†
with Br /Enolizable Ketone
2
C. B. Singh, Siva Murru, Veerababurao Kavala, and Bhisma K. Patel*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039,
Assam, India
patel@iitg.ernet.in
Received September 27, 2006
ABSTRACT
The products obtained by the reaction of benzoyl-3-phenylthioureas with bromine and enolizable ketones in the presence of triethylamine are
not imidazole-2-thione derivatives as reported (Org. Lett. 2003, 5, 1657−1659) rather they are thiazolidene-2-imine derivatives.
3
We have been utilizing tetrabutylammonium tribromide for
quantitative recovery of the spent reagent. This reagent is
1
2
bromination and for various other organic transformations.
Recently we have synthesized a ditribromide reagent, 1,1′-
ethane-1,2-diyl)dipyridinium bistribromide (EDPBT), which
an excellent source of bromine capable of brominating
varieties of organic substrates and is found to be an excellent
catalyst for the acylation of alcohols with various anhy-
drides. Being a source of bromine we thought to utilize this
for the synthesis of imidazole-2-thione derivative following
(
4
is superior to all known tribromides because of its stability,
higher bromine content per molecule, higher bromination
efficiency, selectivity, reduced phase transfer property, and
5
the reported procedure of Zou et al. When 1-benzoyl-3-
phenylthiourea (1) (1 equiv) was reacted with 1,1′-(ethane-
1,2-diyl)dipyridinium bistribromide (EDPBT) (0.5 equiv) in
acetone (10 mL) in the presence of triethylamine (1 equiv)
the product obtained was identical in all respects (m.p, IR,
†
Dedicated with best wishes to Professor Mihir K. Chaudhuri on the
occasion of his 60th birthday.
1) (a) Chaudhuri, M. K.; Khan, A. T.; Patel, B. K.; Dey, D.;
(
Kharmawophlang, W.; Lakshmiprabha, T. R.; Mandal, G. C. Tetrahedron
Lett. 1998, 39, 8163. (b) Bora, U.; Bose, G.; Chaudhuri, M. K.; Dhar, S.
S.; Gopinath, R.; Khan, A. T.; Patel, B. K. Org. Lett. 2000, 2, 247.
1
13
HNMR and CNMR) with that reported by Zou et al.
8-11
However, X-ray crystallographic analysis
of the product
(2) (a) Roy, R. K.; Bagaria, P.; Naik, S.; Kavala, V.; Patel, B. K. J.
Phys. Chem. A. 2006, 110, 2181. (b) Roy, R. K.; Usha, V.; Patel, B. K.;
Hairo, K. J. Comp. Chem. 2006, 773. (c) Kavala, V.; Patel, B. K. Eur. J.
Org. Chem. 2005, 441. (d) Naik, S.; Kavala, V.; Gopinath, R.; Patel, B. K.
ARKIVOC 2006, 119. (e) Naik, S.; Gopinath, R.; Goswami, M.; Patel, B.
K. Org. Biomol. Chem. 2004, 1670. (f) Gopinath, R.; Haque, Sk. J.; Patel,
B. K. J. Org. Chem. 2002, 67, 5842. (g) Naik, S.; Gopinath, R.; Patel, B.
K. Tetrahedron Lett. 2001, 42, 7679. (h) Gopinath, R.; Patel, B. K. Org.
Lett. 2000, 2, 4177.
revealed an isomeric structure with a completely different
skeleton. The product obtained was not an imidazole
(3) (a) Kavala, V.; Naik, S.; Patel, B. K. J. Org. Chem. 2005, 70, 4267.
(b) Kavala, V.; Naik, S.; Patel, B. K. J. Org. Chem. 2005, 70, 6556.
(4) Naik, S.; Kavala, V.; Gopinath, R.; Patel, B. K. ARKIVOC 2006, 21.
(5) Zeng, R.-S.; Zou, J.-P.; Zhi, S.-J.; Chen, J.; Shen, Q. Org. Lett. 2003,
5, 1657.
1
0.1021/ol062371b CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/20/2006

5
derivative (1c) as reported rather it is 1-benzoyl-3-phenyl-
-methylthiazolidene-2-imine (1a) as shown in Figure 1.
so much different. This prompted us to repeat the reaction
of Zou et al. exactly under their reported conditions using
5
4
molecular bromine. Comparison of melting point, IR, and
1
13
H and CNMR of the sample prepared by us using bromine
following the procedure of Zou et al. and using EDPBT was
identical. Furthermore, all the spectral, analytical and melting
point data obtained were in perfect agreement with those
5
reported by Zou et al.
The structure 1-benzoyl-3-phenyl-4-methylimidazole-2-
thione (1c) as proposed by Zou et al. and the structure
1
-benzoyl-3-phenyl-4-methylthiazolidene-2-imine (1a) ob-
tained by us are two isomeric compounds with the same
molecular formula (C17 OS) which cannot be differenti-
14 2
H N
ated by their elemental composition and HRMS analyses. It
is also difficult to differentiate the two compounds based
1
Figure 1. An ORTEP view with the atomic numbering scheme of
a.
on their HNMR, as both have identical ethylenic, methyl,
1
and aromatic protons. The only difference in the structure is
the presence of a -C*dS group in 1c and a -C*dN- group
in 1a. The DEPT spectrum is not of much help in arriving
at the correct structure as both structures have identical
In our experience of working with organic ammonium
tribromides we have never encountered such a drastic change
in reactivity/selectivity, after all, tribromides are just an
efficient bromine carrier with similar or better reactivity.
Thus, there is no reason why the product obtained by Zou
et al. using molecular bromine instead of EDPBT should be
3
numbers of CH , CH, and C carbon.
Single-crystal X-ray crystallography unequivocally estab-
lished the structure to be 1-benzoyl-3-phenyl-4-methylthi-
azolidene-2-imine (1a). On the basis of the structure we
proposed the following mechanism for the reaction (Scheme
1
). Either the ditribromide reagent EDPBT or bromine
(6) (a) Murav’eva, K. M.; Shckukina, M. N. Zh. Obshch. Khim. 1960,
3
3
0, 2327. (b) Ruettinger, H. H.; Dehne, H.; Schroth, W. Pharmazie 1976,
1, 218. (c) 1-Benzoyl(4-hydroxy-3,4-diphenyl-thiazolidine)-2-imine
(
1
1d): mp 156-157 °C; IR (KBr) V 3222, 3064, 2927, 1595, 1562, 1474,
392, 1324, 1210, 1017, 999, 790, 697 cm-1; 1H NMR (400 MHz, CDCl3)
δ 3.53 (d, 1H, J ) 12.4 Hz), 3.72 (d, 1H, J ) 12.4 Hz),7.20 (m, 10H),
.40 (m, 1H), 7.49 (d, 2H, J ) 7.6 Hz), 7.61 (s,1H), 7.85 (d, 2H, J ) 7.0
Scheme 1. Proposed Mechanism of Formation of 1a
7
13
Hz); C NMR (100 MHz, CDCl3) δ 43.8, 93.4, 126.3, 126.7, 127.7, 127.8,
28.3, 128.9, 131.7, 136.1, 138.5, 141.1, 171.8, 175.2.
7) (a) Rajappa, S.; Nair, M. D.; Advani, B. G.; Sreenivasan, R.; Desai,
1
(
J. A. J. Chem. Soc., Perkin Trans. 1 1979, 1762. (b) Beer, R. J. S.;
Mcmonagle, D.; Siddiqui, M. S. S. Tetrahedron 1979, 35, 1199.
(
8) Crystallographic description of 1a: crystal dimension (mm) 0.28
×
0.20 × 0.17; C17H14N2OS, Mr ) 294.36; triclinic, space group P1; a )
9
.6420(2) Å, b ) 9.9530(2) Å, c ) 16.2792(3) Å; R ) 97.0930(10)°, â )
3
9
2.5310(10)°, γ ) 97.6890(10)°, V ) 1533.44(5) Å; Z ) 4; Fcal ) 1.275
3
-1
mg/m ; µ (mm ) ) 0.211; F(000) ) 616; reflection collected/unique )
2
1
7050/6625; refinement method ) full-matrix least-squares on F ; final R
indices [I > 2σl ] R1 ) 0.0499, wR2 ) 0.1175, R indices (all data) R1 )
.1087, wR2 ) 0.1496; goodness of fit ) 1.015. 1b: crystal dimension
0
(
mm), 0.28 × 0.20 × 0.15; C22H16N2OS, Mr ) 356.43; monoclinic, space
group P2(1)/n; a ) 10.4679(13) Å, b ) 15.2299(18) Å, c ) 11.7243(14)
3
Å; R ) γ ) 90°, â ) 101.491(9)°, V ) 1831.7(4) Å; Z ) 4; Fcal ) 1.293
3
-1
mg/m ; µ (mm ) ) 0.189; F(000) ) 744; reflection collected/unique )
2
1
7704/4573; refinement method ) full-matrix least-squares on F ; final R
indices [I > 2σl ] R1 ) 0.0739, wR2 ) 0.1326, R indices (all data) R1 )
.1827, wR2 ) 0.1597; goodness of fit ) 1.176. 2a: crystal dimension
mm), 0.50 × 0.28 × 0.16; C17H13N2OSBr, Mr ) 373.26; monoclinic, space
group P2(1)/c; a ) 16.059(2) Å, b ) 13.4006(18) Å, c ) 7.6695(11) Å; R
0
(
brominates acetone to bromoacetone. The carbon of the
bromomethyl group is attacked by the sulfur of thiourea,
which is facilitated due to an abstraction of the NH proton
3
)
γ ) 90°, â ) 98.6800 (10)°, V ) 1631.6(4) Å; Z ) 4; Fcal ) 1.520
3 -1
mg/m ; µ (mm ) ) 2.650; F(000) ) 752; reflection collected/unique )
2
1
5962/3897; refinement method ) full-matrix least-squares on F ; final R
indices [I > 2σl ] R1 ) 0.0508, wR2 ) 0.1215, R indices (all data) R1 )
6
by triethylamine giving an isothiourea intermediate. The NH
0
.0844, wR2 ) 0.1394; goodness of fit ) 1.031. 2b: yield 80%; IR (KBr)
-1 1
proton flanked by a carbonyl and a thiocarbonyl moiety is
more acidic, hence it is preferentially deprotonated in the
presence of the other NH proton. Intramolecular attack of
the second NH group of the isothiourea intermediate on the
carbonyl group would give 1-benzoyl(4-hydroxy-3,4-diphen-
V 3058, 1599, 1559, 1438, 1337, 1280, 1193, 1066, 930, 746 cm
; H
NMR (400 MHz, CDCl3) δ 6.74 (s, 1H), 7.13 (d, 2H, 7.2 Hz), 7.24 (m,
7
H), 7.42 (d, 2H, J ) 6.8 Hz), 7.53 (d, 1H, J ) 8 Hz), 8.01 (d, 1H, J ) 7.6
13
Hz), 8.23 (1H, s); C NMR (100 MHz, CDCl3) δ 107.8, 122.3, 128.0,
1
1
28.6, 128.8, 129.0, 129.1, 129.7, 130.5, 132.6, 134.4, 137.6, 139.0, 139.4,
70.1, 173.2.
(
9) SMART V 4.043 Software for the CCD Detector System; Siemens
Analytical Instruments Division: Madison, WI, 1995.
10) SAINT V 4.035 Software for the CCD Detector System; Siemens
Analytical Instruments Division: Madison, WI, 1995.
11) Sheldrick, G. M. SHELXL-97, Program for the Refinement of Crystal
Structures; University of G o¨ ttingen: G o¨ ttingen, Germany, 1997.
6
ylthiazolidine)-2-imine (1d) followed by dehydration of the
(
tertiary alcohol leading to the formation of 1-benzoyl-3-
phenyl-4-methylthiazolidene-2-imine (1a). This mechanism
seems resonable since the thiazolidene-2-imine derivative has
(
5398
Org. Lett., Vol. 8, No. 23, 2006

been prepared by the condensation of acyl and arylacyl
Thiazolidene-2-imine ring formation is general and not spe-
cific to a particular benzoyl thiourea. When 3-bromobenzoyl-
3-phenylthiourea (2) was reacted under the above conditions
separately with acetone and acetophenone both gave corre-
sponding thiazolidene-2-imine derivatives 2a and 2b, re-
spectively. The structure of 2a was again confirmed by
crystal X-ray crystallography as shown in Figure 3.
thioureas with R-haloketones.6,7 Under basic condition several
6
hydroxy thiazolidine derivatives have been isolated. When
we reacted benzoyl thiourea (1) (1 equiv) with phenacyl
bromide (1 equiv) in the presence of triethylamine (1.5 equiv)
in acetonitrile, the corresponding 1-benzoyl(4-hydroxy-3,4-
diphenylthiazolidine)-2-imine (1d)6c derivative precipitated
out quantitatively, which could not be converted to its final
thiazolidene-2-imine (1b) even under reflux condition.
However, on addition of 2 equiv of HBr the final thiaz-
olidene-2-imine (1b) was obtained in quantative yield at
room temperature suggesting an acid-catalyzed elimination
of tertiary alcohol. In this reaction the in situ generated HBr
serves as an acid for the dehydration of the intermediate
tertiary alcohol (1d).
We believe that this may not be an isolated example and
all the structures reported by Zou et al. are expected to have
a thiazolidene-2-imine moiety and not imidazole. To further
demonstrate our claim 1-benzoyl-3-phenylthiourea (1) was
reacted under an identical condition with EDPBT but
replacing acetone with acetophenone. The spectral and
analytical data of the product obtained (1b) were again in
perfect agreement with those reported by Zou et al. It may
be mentioned here that replacement of bromine with EDPBT
also gave the same product. Formation of the thiazolylidene
ring was confirmed by single-crystal X-ray diffraction Figure
Figure 3. An ORTEP view with the atomic numbering scheme of
2a.
In conclusion, we have unambiguously proved that the prod-
ucts obtained by the reaction of benzoyl-3-phenylthuioureas
with bromine/EDPBT and acetone/enolizable ketone in the
presence of triethylamine are thiazolidene-2-imine derivatives
5
not imidazole-2-thione as reported earlier. We also believe
that all other structures reported by Zou et al. are expected
to have a thiazolidene-2-imine moiety and not imidazole.
The wrong structure has led to the proposal of an incorrect
2.
5
reaction mechanism. Further scope of the reaction to other
similar substrates is currently under investigation.
Acknowledgment. B.K.P. and C.B.S. acknowledge the
support of this research from DST New Delhi (SR/S1/OC-
1
5/2006) and CSIR 01(1688)/00/EMR-II. Thanks are due
to CIF IIT Guwahati for NMR spectra and DST FIST for
XRD facility.
Supporting Information Available: Experimental details
1
13
and full characterization of compounds: IR, H and C NMR
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 2. An ORTEP view with the atomic numbering scheme of
b.
1
OL062371B
Org. Lett., Vol. 8, No. 23, 2006
5399