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Tetrahedron 64 (2008) 1931e1942

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A convenient one-pot synthesis of thiazol-2-imines: application

in the construction of pifithrin analogues
Siva Murru, C.B. Singh, Veerababurao Kavala, Bhisma K. Patel*
Indian Institute of Technology Guwahati, Guwahati 781 039, Assam, India
Received 10 August 2007; received in revised form 6 November 2007; accepted 22 November 2007
Available online 24 November 2007

Abstract

For the first time a reaction intermediate has been isolated giving further insight into the mechanism of thiazol-2-imine formation. The first
step of the reaction requires a basic medium, while the second step is an acid mediated E1 elimination reaction. An efficient one-pot synthesis of
substituted thiazol-2-imines have been achieved by the condensation of carbonyl compounds with thioureas and 1,3-disubstituted thioureas using
1,10 -(ethane-1,2-diyl)dipyridinium bistribromide (EDPBT). Unsymmetrical 1,3-disubstituted thioureas give regioselective products with
symmetrical ketones, which are mainly governed by the pKas of NH protons of thiourea, whereas symmetrical 1,3-disubstituted thioureas
give regioselective products with symmetrical carbonyl compounds owing to the regioselective bromination of ketones. The methodology is
extended to access novel neurodegenerative drug candidate pifithrin-a analogues in good yields in shorter reaction time. This method is simple,
versatile and is applicable for different 1,3-disubstituted thioureas as well as a range of carbonyl compounds.
Ó 2007 Elsevier Ltd. All rights reserved.

1. Introduction ammonium ditribromide reagent 1,10 -(ethane-1,2-diyl)dipyri-

dinium bistribromide (EDPBT) has been developed in our
The mechanism of thiazol-2-imine formation has not been laboratory, which is far superior than the other reagents in
well understood leading to the proposal of incorrect structures terms of its stability, selectivity and higher bromine content.7
for the products by two independent research groups.1,2 Re- The thiazolidene-2-imine3 or thiazol-2-imine4 or 2-imino-
cently, we have unequivocally demonstrated that the reaction thiazoline15,18,23d,25a ring system as it has been named by dif-
of benzoyl-3-phenylthioureas with bromine/1,10 -(ethane-1,2- ferent groups is present in several drug candidates possessing
diyl)dipyridinium bistribromide (EDPBT) and either acetone interesting biological activities such as muscarinomimetic,
or enolizable ketones in the presence of triethylamine gives antimycotic, hypolipemic, antidiabetic, thrombopoietin
thiazol-2-imine derivatives and not imidazol-2-thione as re- agonism, cell adhesion antagonists, platelet GPIIb/IIIa recep-
ported earlier.3,4 Further, we have established that even in tor antagonists, anti-inflammatory, analgesic and kinase
aqueous media the course of the reaction remains unaltered (CDK1,CDK5 and GSK3) inhibition, schistosomicides, cadio-
giving thiazol-2-imine derivatives instead of imidazol-2- tonics and trichomonides.8 Thiazoline derivatives have found
thiones as reported.2,4 interesting applications in agriculture as acricides, insecticides
Over the last decade attempts have been made to replace and plant growth regulators.9 Recently, 2-imino-thiazolines
the corrosive and toxic bromine with various ammonium tri- were found to have antifungal activity10 and skin whitening
bromides viz. tetrabutylammonium tribromide for various properties.11
synthetically useful organic transformations.5,6 A better The basic 2-aminothiazole moiety was first synthesized by
a Hantzsch condensation reaction involving thiourea and a-
haloketone.12 This approach was subsequently adopted for the
* Corresponding author. Tel.: þ91 361 2582307; fax: þ91 361 2690762. synthesis of N-alkylated imino-thiazolines by replacing thio-
E-mail address: [email protected] (B.K. Patel). ureas with mono-N-substituted thioureas.13 Several alternative

0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.11.076
1932 S. Murru et al. / Tetrahedron 64 (2008) 1931e1942

F benzoylthioureas and a-haloketones, which ultimately led to

NH
S O O the wrong interpretation of the structures of the products in-
N
S volved.1,2 In order to further delineate our objective we rein-
NH
N F vestigated both the reactions1,2 using our newly developed
N
O
bromine equivalent reagent, 1,10 -(ethane-1,2-diyl)dipyridi-
(a) Pft-α (b) KHG22394 nium bistribromide (EDPBT).6i,7 The reagent EDPBT is capa-
ble of brominating enolizable ketones7 as well as generating
Figure 1. Structures of pharmacologically important molecules: (a) p53 inac- 2 equiv of HBr, 1 equiv during bromination of ketone and
tivator; (b) skin whitening agent.
the second equivalent by the nucleophilic displacement of bro-
mide by sulfur thereby making the medium acidic even in the
strategies have been devised, which include N-alkylation presence of 1 equiv of triethylamine (Scheme 1). An acidic
of aminothiazoles,8c,14 potassium thiocyanate treatment of medium facilitates the dehydration of the intermediate tertiary
a-bromoketimines,15 reaction of N-monoalkylated thioureas alcohol. This prompted us to develop a one-pot procedure for
with 3-bromomethyl-2-cyanocinnamonitrile,16 cycloadditions the synthesis of thiazol-2-imine derivative from benzoylphe-
followed by elimination of 5-imino-1,2,4-thiazolidin-3-ones nylthioureas and enolizable ketones.
with enamines and ester enolate,17 ring transformation of 1- The in situ generated a-bromoacetone obtained by the
arylmethyl-2-(thiocyanomethyl)aziridines in the presence of reaction of acetone with 1,10 -(ethane-1,2-diyl)dipyridinium
TiCl4 and acylchloride,18 reaction of N-propargylaniline with bistribromide (EDPBT) reacts with a solution of 1-benzoyl-
acylisothiocyanates,19 and phenylamino acetonitrile with alkyl 3-phenyl-thiourea 1 giving product 1a in 78% isolated yield.
isothiocyanates.20 Less general approaches towards the synthe- The product 1a obtained was found to be identical (melting
sis of these heterocycles involve the reaction of ketone either point, IR, 1H and 13C NMR) to that of the product obtained
with N-alkyl rhodanamine or bisbenzyl formamidine disulfide21 earlier by Zou and by us using molecular bromine.1,3,4 The
or the reaction of a-chloroketones with thiosemicarbazide in an structure of 1a has already been confirmed as having the thi-
acidic medium,22 condensation of a-haloketones with N- azol-2-imine skeleton by X-ray crystallographic analysis.3
benzoyl-N0 -arylthioureas or N,N0 -disubstituted thioureas.23,24 The requirement of an inert atmosphere using bromine by Zou
Pifithrin (Pft-a) (Fig. 1), isolated by screening of chemical et al. is really not necessary when bromine is replaced with
libraries having 2-imino-thiazoline skeleton, is the lead com- EDPBT and the reaction works even under a moist condition.
pound of p53 inactivators and have received increasing attention As speculated earlier, this reagent brominates enolizable
due to its possible applications in several major neurodegenera- ketones to a-bromoketones. The carbon of the bromomethyl
tive disorders such as Alzheimer’s disease, Parkinson’s disease, group is attacked by sulfur of thiourea, which is facilitated
stroke, cancer therapy and other pathologies related to various due to the abstraction of the NH proton flanked by a carbonyl
signalling pathways.25 and a thiocarbonyl moiety leading to the intermediate tertiary
Although some of the methods of preparation of thiazol-2- alcohol.3 However, the Kaupp group has proposed an ionic
imines are effective, the drawbacks associated with most of intermediate with thiocarbenium and alkyl ammonium
the procedures reported in the literature require arduous prepa-
ration of precursor substrates, difficulties in workup and isola- KBr / Oxone
tion, the need for harsh reaction conditions, low yields and long
reaction times. The use of lachrymatory a-haloketones is un- + Br -
3 + Br -
avoidable for methods using thioureas as starting materials. N N
Br3 - N N
There are only two reports on the one-pot procedure for the syn- + Br - +
thesis of 2-iminothiazoline involving N,N0 -dialkylthiourea and EDPBT EDPDB
in situ generated a-bromoketones, which is limited to only +
O O
symmetrical thioureas and few selected ketones.26 Methods us- Br + HBr
ing thioureas are limited to symmetrical thioureas and few R R

selected ketones only thus lacking regioselectivity in 2-imino- Et3N

Ph
thiazoline formation. The important drugs, pifithrin (Pft-a) an- H Ph
H HN N
alogues, have been prepared under a harsh reaction condition N N R R R N N
R Ph R
and at longer reaction times giving lesser yields. In this manu- S
S
S HO
script we have revisited the reaction mechanism and developed R O + Et3N.HBr (Y)
Br
a one-pot synthesis of thiazol-2-imine derivatives, and the syn- O H+
R= COAr, Ar
thetic methodology was applied towards the synthesis of novel
drug candidate pifithrin-a and its analogues. Ph
Ph
Ph
-H2O R N N
E1 elimination N N R
2. Results and discussion N N R
R R H2O S
R + S +
S
H
The genesis of the work started with the two earlier reports
proposing wrong reaction mechanism for the reaction of Scheme 1. Proposed reaction mechanism of thiazol-2-imine formation.
 S. Murru et al. / Tetrahedron 64 (2008) 1931e1942 1933

Figure 2. An ORTEP view with the atomic numbering scheme of (Y).

Figure 3. An ORTEP view with the atomic numbering scheme of 7a.

intermediate (thiazolium) species. We differ with the mecha-

nism proposed by Manaka23f and by Kaupp23i in the sense The NH proton flanked by a carbonyl and a thiocarbonyl
that due to the higher acidity of the NH proton, it would prefer is sufficiently acidic and its deprotonation by triethylamine is
to exist as isothiourea rather than as thiocarbenium ion and feasible and is essential as it enhances the nucleophilicity of
that the thiazolium salt should exist as thiazol-2-imine. Fur- sulfur towards the attack on bromomethyl ketone forming an
ther, the elimination of the intermediate tertiary alcohol is imine derivative. The distance between C(3)eN(3) is 1.308 Å,
not by a base catalyzed E2 mechanism, rather it should be which is typical of an imine CeN double bond. Surprisingly,
by an E1 mechanism. This assumption of ours is confirmed many earlier reports have proposed a base catalyzed E2 type
by isolation of the intermediate 1-benzoyl(4-hydroxy-3,4-di- elimination. This isolated intermediate (Y) is stable under
phenylthiazolylidene)2-imine, obtained by the reaction of ben- basic and neutral conditions. Treatment of the intermediate
zoylthiourea 1 (1 equiv) and acetophenone (1 equiv) in the (Y) with dilute (HCl) led to the formation of thiazol-2-imine
presence of EDPBT (0.5 equiv) and triethylamine (4 equiv).3 with elimination of water, hence a base catalyzed elimination
The intermediate 1-benzoyl(4-hydroxy-3,4-diphenylthiazolyl- is completely ruled out. The hydroxyl group being tertiary
idene)-2-imine obtained was identical to the product obtained in nature is only susceptible to acid catalyzed E1 elimination.
earlier.3 When 1,3-dichloroacetone (1 equiv) was reacted with It may be mentioned here that the use of 1 equiv of
benzoylthiourea 1 (1 equiv) in the presence of triethylamine triethylamine does not make the medium basic for an E2 elimi-
(2 equiv) a solid product (Y) (Scheme 1) was obtained after nation rather the medium remains acidic by just neutralizing
usual workup. Crystallisation of the compound from ethyl one of the two equivalents of HBr generated in the medium
acetate/hexane (4:1) gave a colourless crystal. X-ray crystallo- (Scheme 1).
graphic analysis of the compound revealed the presence of Having successfully established the mechanism of the reac-
thiazol-2-imine skeleton as shown in Figure 2. tion, our next objective was to apply this methodology to var-
ious other benzoylthioureas. When benzoylthiourea 2 was
Table 1
Reactiona of benzoylthioureas with acetone and EDPBT
Substrate Product Yieldb (%)

O S
O N
N N
X H H Y S N Y

X¼H, Y¼H (1) X¼H, Y¼H (1a) 78

X¼H, Y¼p(Cl) (2) X¼H, Y¼p(Cl) (2a) 72
X¼H, Y¼p(Me) (3) X¼H, Y¼p(Me) (3a) 82
X¼H, Y¼o(Cl) (4) X¼H, Y¼o(Cl) (4a) 68
X¼H, Y¼p(Br) (5) X¼H, Y¼p(Br) (5a) 68
X¼m(Br), Y¼H (6) X¼m(Br), Y¼H (6a) 85
a
Reactions were monitored by TLC.
b
Isolated yields. Figure 4. An ORTEP view with the atomic numbering scheme of 10a.
1934 S. Murru et al. / Tetrahedron 64 (2008) 1931e1942

reacted under identical conditions as described above, the X-ray crystal structures of 1a, 2a and 6a all revealed having
product 2a obtained was again found to be identical (melting syn-stereochemistry. The syn selectivity is likely due to the
point, IR, 1H and 13C NMR) to that of the product obtained steric hindrance of the acyl group and the N-phenyl group.
earlier by Wang group2 and also by us in an aqueous medium.4 This observation is consistent with the observations made by
The structure of 1b was already confirmed as having the thi- others.8d,23f
azol-2-imine or thiazolimine skeleton by X-ray crystallo- The acidity of the NH proton of 1,3-disubstituted thiourea is
graphic analysis.4 Thus the course of the reaction and the expected to be less than the NH proton of benzoylthiourea.
reaction mechanism remain unchanged both in the organic Having effectively applied to different benzoylthioureas we
and in the aqueous media. Benzoylthioureas 3, 4 and 5 gave wished to test if this methodology can be applied to 1,3-diaryl
their corresponding thiazol-2-imine products 3a, 4a and 5a, re- thiourea as well. When 1,3-diphenyl thiourea 7 was reacted
spectively (Table 1). Thiazol-2-imine ring formation is general under an identical condition to that described above for
and not specific to a particular benzoylthiourea. When 3-bro- benzoylthioureas a solid product was obtained. The ORTEP di-
mobenzoyl-3-phenylthiourea 6 was reacted under the above agram with atom numbering scheme of 7a is shown in Figure 3.
conditions it gave the corresponding thiazol-2-imine derivative X-ray crystallographic analysis of the product 7a again revealed
6a. The product obtained was again found to be identical the presence of thiazol-2-imine skeleton. The proposed reaction
(melting point, IR, 1H and 13C NMR) to that of the product mechanism for 1,3-disubstituted thiourea is expected to be
obtained earlier by Zou group and independently by us.1,3 The similar to the one proposed for benzoylthiourea.3
presence of thiazol-2-imine skeleton has been confirmed by This methodology was successfully applied to another 1,3-
X-ray crystallographic analysis.3 It may be noted here that disubstituted symmetrical thiourea 8 giving corresponding
product 8a in good yield. In order to study the regioselectivity,
Table 2 unsymmetrical thiourea 1-phenyl-3-p-tolyl-thiourea 9 was re-
Reactiona of 1,3-disubstituted thiourea with acetone and EDPBT
acted under identical condition. The product obtained was
Substrate Product Yieldb an equimolar mixture of 9a and 9a0 indicating the equal ease
(%)
of thiazol-2-imine formation from either side of the thiourea
since the acidity of both NH protons is similar. However,
S
N when naphthyl ring is attached to one of the sides in thiourea
N N 75 it results in exclusive regioselective product 10a obtained via
H H S N
(7)
deprotonation of the NH proton from the naphthyl side of the
(7a) urea 10. The structure of the product 10a was confirmed by
S
X-ray crystallographic analysis. The ORTEP diagram with
N atom numbering scheme of product 10a is shown in Figure 4.
N N 78 Formation of regioselective product 10a is because of the
H H
S N
(8) higher acidic character of the naphthyl NH proton. The mea-
(8a)
sured pKas of 1-naphthylamine and aniline are 3.94 and
S 4.61, respectively (Table 2).
N N
N N 82
H H
S N S N
(9) (9a) (9a')

S N

N N S N 72
H H

(10) (10a)

S
N
N N 69
H H S N
(11)
(11a)

S
N
N N O
66
H H S N O
(12)
(12a)
a
Reactions were monitored by TLC and stopped after 1.5 h.
b
Isolated yields. Figure 5. An ORTEP view with the atomic numbering scheme of 11a.
 S. Murru et al. / Tetrahedron 64 (2008) 1931e1942 1935

Table 3
Reactiona of 1,3-disubstituted thiourea with ketone and EDPBT
Substrate Ketone Product Yieldb (%)
S O
Ph N Ph (1b) 77
N
O
Ph
Ph
S O
(1c) 68
O N N Ph
Ph
Ph
S O
O (1d) 71
N N Ph
O S Ph
Ph
N N
H H O
(1) S O (1e)
65
N N Ph
OH Ph

O
S
N Ph
O 48c
N (1f)
Ph
S
Ph
Ph N (7b) 82
O N
Ph
Ph
S
Ph (7c)
O N 69
N
Ph

Ph
S
O Ph
S (7d) 66
N
Ph N
N N Ph
H H O
(7)
S (7e)
Ph
OH N 70
N
Ph

S Ph
O
N
45c
N (7f)
Ph
a
Reactions were monitored by TLC and stopped after 1.5 h.
b
Isolated yields.
c
Reaction was continued up to 6 h.

However, for substrates possessing phenylic and benzylic The ease of deprotonation from the phenyl side of the NH
systems as in the case of 1-benzyl-3-phenyl-thiourea 11, the proton compared to the benzylic side leading to the formation
NH proton flanked by a phenyl and a thiocarbonyl moiety is of thiazol-2-imine skeleton is demonstrated for substrate 12
more acidic compared to the other NH protons flanked by containing a furyl ring attached to one side.
a benzyl and a thiocarbonyl group giving product 11a obtained So far the formation of thiazol-2-imine is applied to various
by the deprotonation from the phenyl side of the thiourea. This benzoylthioureas and 1,3-disubstituted thioureas with acetone
is because of the higher basicity of the benzyl amine (pKa only. This approach can be applied to various other ketones
9.41) compared to aniline (pKa 4.61). The structure of product as shown in Table 3. Substrate 1-benzoyl-3-phenyl-thiourea
11a is confirmed by single crystal X-ray analysis. The ORTEP 1 was reacted with acetophenone under an identical reaction
diagram with atomic numbering scheme of 11a is shown in condition and the product obtained 1b was found to be identi-
Figure 5. cal (melting point, IR, 1H and 13C NMR) to that of the product
1936 S. Murru et al. / Tetrahedron 64 (2008) 1931e1942

Table 4
Reactiona of 1-benzoyl-3-p-tolyl-thiourea 3 with various ketones
Substrate Ketone Product Time Yieldb (%)

O
(3g)
N 1.5 73
N
Ph S
O

O 1.5 75
N (3h)
MeO Ph N
S
O
Ph
O
O S
O
S N
N
N N (3i) 2.0 55c
H H N
N S
O
(3)
O Ph

O
N (3j) 1.5 78
O O N
O
Ph S
O O

O
1.0 68
H Ph N N (3k)
O S

a
Reactions were monitored by TLC.
b
Isolated yields.
c
0.5 equiv of 2,4-hexan-dione was used.

obtained earlier by Zou and by us using molecular bromine.1,3 Treatment of hexan-2,5-dione with 1 equiv of EDPBT possibly
The structure of product 1b has already been confirmed as gave dibromo product 3,4-dibromo-hexan-2,5-dione in the reac-
having the thiazol-2-imine skeleton by X-ray crystallographic tion medium, which reacts with thiourea 3 giving bis-thiazol-2-
analysis.3 Unsymmetrical ketones such as butan-2-one and imine product 3i in 55% isolated yield. Finally, ethylacetoacetate
1-phenyl-propan-2-one gave products corresponding to the under the present experimental condition gave regioselective
a-bromination at the highly substituted side of the ketones product 3j, which is in accordance with the reported one.23f
with EDPBT finally leading to the formation of regioselective The synthetic utility of this reagent EDPBT and the method-
heterocycles thiazol-2-imine 1c and 1d, respectively. Cyclo- ology was finally demonstrated for the syntheses of neurode-
hexanone with 1-benzoyl-3-phenyl-thiourea 1 gave the prod- generative drug pifithrin-a and its analogues. Even though
uct 1e. Interestingly, anabolic thiazoloandrostane 1f27 was there are some reports for the syntheses of pifithrin analogues,
prepared from 17a-methyl-5a-androstan-17b-ol-3-one in almost all the reported methods use a two-step strategy. The first
moderate yield. The reactivity of 1,3-diphenyl thiourea 7 is stage involves the iodine mediated formation of aminothiazole
similar to 1-benzoyl-3-phenyl-thiourea 1 as shown in Table 3. by the reaction of cyclic ketones and thiourea at 110  C for
The successful applications of the methodology to various 12 h. The product after isolation is then reacted with alkyl
ketones prompted us to test the usefulness of this synthetic halide to give pifithrin-a analogues with an overall yield in
strategy on other ketones and diketones. The in situ generated the range of 30e35%.25a,25d This method suffers due to high
a-brominated products of cyclic ketones such as 1-tetralone reaction temperatures, longer reaction times and less yields
and 6-methoxy-1-tetralone with EDPBT react with 1-benzoyl-3- (Table 4).
(p-tolyl)-thiourea 3 giving thiazol-2-imine products 3g and 3h in As pifithrin-a analogues are very important scaffolds in me-
good yields. The synthetic utility of this method is demonstrated dicinal chemistry, we have applied this methodology to access
in the synthesis of bis-thiazoline product using a 1,4-diketone. these biologically important compounds. The in situ generated
 S. Murru et al. / Tetrahedron 64 (2008) 1931e1942 1937

Table 5
Reactiona of in situ generated aminothiazole with various a-haloketones and alkyl bromides
EDPBT O
S O
O O EDPDB
R
R
EDPBT Br H2N NH2 N N
NH2 NH.HBr
0.5eq Et3N 2 eq S O
S
(13) Br
R

Substrate a-Haloketone/alkyl halide Product Time (h) Yieldb (%)

S
O NH.HBr (13a)
N 4.5 62
Br
O
S
NH.HBr (13b)
O
N
O2N 4.0 54
Br NO2
O
S
S NH. HBr (13c)
O
NH2.HBr N
Me 4.5 57
N Br Me
(13) O
S
NH (13d)
Br N 6.0 66c

S
NH (13e)
Br
N 6.0 60c

a
Reactions were monitored by TLC.
b
Isolated yields.
c
Propargyl and allyl bromides used were from commercial source and not generated in situ.

a-bromocyclohexanone obtained by the reaction of cyclohex- condensation of carbonyl compounds with thioureas and 1,3-
anone and EDPBT in acetonitrile reacts with thiourea to give disubstituted thioureas using EDPBT. The pKas of the NH pro-
aminothiazole. a-Bromoacetophenone prepared from aceto- tons of thioureas dictate the regioselectivity in the case of
phenone using EDPBT in acetonitrile7 was added to the above symmetrical ketones. The regioselective bromination at the
reaction medium containing aminothiazole and triethylamine. more substituted side in the case of unsymmetrical ketones
The pifithrin analogue 13a was obtained in 62% overall iso- produces regioselective product with symmetrically 1,3-disub-
lated yield. The pifithrin 13c and its analogues 13b were pre- stituted thioureas. Bis-thiazoline derivative can be prepared
pared using p-methylacetophenone and p-nitroacetophenone, from dicarbonyl compound. Neurodegenerative drugs pifi-
respectively. Similarly, other analogues 13d and 13e were thrin-a and its analogues have been successfully prepared
also prepared using propargyl and allyl bromide showing the employing this methodology. The pifithrin analogues obtained
versatility of this method. Thus, the present method is superior by this one-pot method is by far the best in terms of shorter
to any of the reported procedure in terms of simplicity and reaction time and better yield. This method is simple, versatile
better yield (Table 5). and can be applied successfully for different 1,3-disubstituted
thioureas as well as a range of carbonyl compounds.
3. Conclusion
4. Experimental
In conclusion, we have isolated the reaction intermediate
and characterized it by X-ray crystallography. Formation of 4.1. General information
thiazol-2-imine is a two-step process, the first step of the reac-
tion requires the medium to be basic for favorable nucleophilic All the reagents were of commercial grade and purified
attack and the intermediate tertiary alcohol is stable under both according to the established procedures. Organic extracts
neutral and basic conditions. The second step of the reaction is were dried over anhydrous sodium sulfate. Solvents were re-
an acid mediated E1 elimination. We have achieved an effi- moved in a rotary evaporator under reduced pressure. Silica
cient one-pot synthesis of substituted thiazol-2-imines by the gel (60e120 mesh size) was used for the column
1938 S. Murru et al. / Tetrahedron 64 (2008) 1931e1942

chromatography. Reactions were monitored by TLC on silica Crystallographic description of Y: crystal dimension (mm):
gel 60 F254 (0.25 mm). NMR spectra were recorded in CDCl3 0.480.270.19; C17H14ClN2O2S, Mr¼345.83; triclinic, space
or DMSO-d6 with tetramethylsilane as the internal standard group P1; a¼11.3616(3) Å, b¼12.2735(2) Å, c¼14.1624(2) Å;
for 1H NMR (400 MHz) and CDCl3 or DMSO-d6 solvent as a¼114.3440(10), b¼104.7900(10), g¼99.1230(10), V¼1659.86(6)
the internal standard for 13C NMR (100 MHz). HRMS spectra (Å3); Z¼4; rcal¼1.320 mg/m3; m (mm1)¼0.358; F (000)¼684;
were recorded using WATERS MS system, Q-Tof premier reflections collected/unique¼15,148/3901; refinement method-
and data analyzed using Mass Lynx4.1. Melting points were ¼full-matrix least-squares on F2; final R indices [I>2sl]
recorded on Buchi B-545 melting point apparatus and are un- R1¼0.0419, wR2¼0.0940, R indices (all data) R1¼0.0671,
corrected. IR spectra were recorded in KBr or neat on a Nicolet wR2¼0.1067; goodness-of-fit¼1.024.
Impact 410 spectrophotometer.
4.4. General experimental procedure I: preparation of
4.2. Crystallographic description 2-benzoylimino-4-methyl-3-phenyl-3H-thiazole (1a) using
EDPBT
Crystal data were collected with Bruker Smart Apex-II CCD
diffractometer using graphite monochromated Mo Ka radiation To a solution of 1,10 -(ethane-1,2-diyl)dipyridinium bistri-
(l¼0.71073 Å) at 298 K. Cell parameters were retrieved using bromide (EDPBT) (0.333 g, 0.5 mmol) in acetonitrile (2 mL)
SMART28 software and refined with SAINT28 on all observed was added acetone (0.116 g, 2 mmol) and stirring continued
reflections. Data reduction was performed with the SAINT for 10 min. During this period, the bromination of acetone
software and corrected for Lorentz and polarization effects. was complete as judged from the disappearance of the orange
The structure was solved by direct methods implemented in colour of EDPBT. The supernatant containing the bromoketone
SHELX-9729 program and refined by full-matrix least-squares was then directly filtered into a solution of 1-benzoyl-3-phenyl-
methods on F2. All non-hydrogen atomic positions were located thiourea 1 (0.256 g, 1 mmol) in acetonitrile (2 mL) containing
in difference Fourier maps and refined anisotropically. The hy- triethylamine (0.101 g, 1 mmol) and kept at 60  C. The reaction
drogen atoms were placed in their geometrically generated po- was completed within 1 h as can be judged from TLC. After
sitions. All the colourless crystals were isolated in rectangular completion of the reaction, solvent was evaporated and ad-
shape from absolute ethanol at room temperature. CCDC num- mixed with ethyl acetate (20 mL). The ethyl acetate layer was
bers for compounds Y, 7a, 10a, and 11a are CCDC 652469, washed with a saturated solution of NaHCO3 (5 mL), dried
CCDC 652470, CCDC 652472 and CCDC 652473, over anhydrous Na2SO4, concentrated under reduced pressure
respectively. These data can be obtained from The Cambridge and purified over a silica gel column (25% EtOAc/hexane) to
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_ give 78% of the product 1a.
request/cif.
4.5. General procedure II: preparation of pifithrin-a
4.3. Preparation of N-benzoyl(4-(chloromethyl)-4- analogues
hydroxy-3-phenylthiazolidine)-2-imine (Y)
To a solution of cyclohexanone (2 mmol) in acetonitrile
To a solution of 1-benzoyl-3-phenyl-thiourea 1 (0.256 g, (2 mL) was added 1,10 -(ethane-1,2-diyl)dipyridinium bistri-
1 mmol) in acetonitrile (2 mL) containing triethylamine (0.202 g, bromide (EDPBT) (0.666 g, 1 mmol) and the reaction stirred
2 mmol) was added a solution of 1,3-dichloroacetone for 10 min. This reaction mixture was then filtered into a solu-
(0.128 g, 1 mmol) in acetonitrile (2 mL). The reaction was tion of thiourea (0.152 g, 2 mmol), triethylamine (0.202 g,
completed within 1 h as can be judged from TLC. After comple- 2 mmol) in acetonitrile (5 mL) and was heated at 80  C for
tion of the reaction, solvent was evaporated and admixed with 5 h to give aminothiazole hydrobromide. The free aminothia-
ethyl acetate (20 mL). The ethyl acetate layer was washed zole was obtained by treating it with triethylamine (0.202 g,
with a saturated solution of NaHCO3 (5 mL), dried over anhy- 2 mmol). Separately, acetophenone (0.240 g, 2 mmol) was
drous Na2SO4, concentrated under reduced pressure and puri- brominated with EDPBT (0.666 g, 1 equiv) using our solvent
fied over a silica gel column (25% EtOAc/hexane) to give free method to give bromoacetophenone.8 The bromoaceto-
85% of the product Y. Compound Y was recrystallized from a phenone was added to crude aminothiazole and the reaction
mixture of EtOAc/hexane (8:2) to give colourless needle like mixture was stirred for 4.5 h. The desired product precipitated
crystals. Mp 137e138  C. Rf (25% EtOAc/hexane) 0.31. dH out from the reaction mixture was filtered and washed with
(400 MHz, CDCl3): 3.04 (d, 1H, J¼12.8 Hz), 3.55 (d, 2H, J¼ acetonitrile to obtain the pure product. Products 13d and 13e
12.8 Hz), 3.78 (d, 1H, J¼12.8 Hz), 6.01 (br s, 1H), 7.10e7.65 were isolated as their free base by sodium carbonate workup.
(m, 7H), 7.85 (d, 1H, J¼7.2 Hz), 7.93 (d, 2H, J¼7.2 Hz). dC
(100 MHz, CDCl3): 37.9, 46.9, 92.7, 120.6, 127.3, 128.3, 129.0, 4.6. Spectral data for selected compounds
129.3, 130.1, 132.6, 137.2, 174.0, 177.5. nmax (KBr): 3334, 3191,
3165, 3063, 2945, 2848, 1655, 1609, 1486, 1025, 702 cm1. 4.6.1. 2-Benzoylimino-3-phenyl-4-methyl-3H-thiazole (1a)
C17H15ClN2O2S (346.84): calcd C 58.87, H 4.36, N 8.08, S White needles, Rf (25% EtOAc/hexane) 0.38, mp 156e
9.24; found C 58.93, H 4.41, N 8.01, S 9.18; HRMS (ESI): 157  C. dH (400 MHz, CDCl3): 2.05 (s, 3H), 6.39 (s, 1H), 7.31
MHþ, found 346.8364, C17H15 Cl N2O2S requires 346.8369. (m, 5H), 7.54 (m, 3H), 8.01 (m, 2H). dC (100 MHz, CDCl3):
 S. Murru et al. / Tetrahedron 64 (2008) 1931e1942 1939

15.2, 104.7, 128.0, 128.2, 128.5, 129.4, 129.6, 131.5, 134.5, 4.6.6. 4-Methyl-3-phenyl-2-(p-tolylimino)-3H-thiazole and
137.0, 137.6, 170.2, 174.5. nmax (KBr): 3050, 2948, 1598, 4-methyl-2-phenylimino-3-(p-tolyl)-3H-thiazole (9aþ9a0 )
1564, 1491, 1458, 1364, 1342, 1275, 1171, 1066, 1017, Reddish oil, Rf (25% EtOAc/hexane) 0.73. dH (400 MHz,
903 cm1. C17H14N2OS (294.38): calcd C 69.36, H 4.79, N CDCl3): 1.82 (br s, 6H), 2.28 (s, 3H), 2.39 (s, 3H), 5.59 (m,
9.52, S 10.89; found C 69.47, H 4.81, N 9.47, S 10.78. HRMS 2H), 6.98 (m, 8H), 7.36 (m, 9H). dC (100 MHz, CDCl3): 15.5,
(ESI): MHþ, found 295.0883, C17H14N2OS requires 295.0905. 20.9, 21.2, 92.9, 93.3, 121.4, 121.6, 121.7, 122.8, 122.9,
128.4, 128.6, 128.9, 129.1, 129.2, 129.5, 129.7, 129.8, 130.2,
4.6.2. 2-Benzoylimino-3-(4-chloro-phenyl)- 132.1, 132.2, 134.9, 135.1, 137.6, 138.3, 149.5, 152.1, 160.9,
4-methyl-3H-thiazole (2a) 161.0. nmax (KBr): 3027, 2920, 1621, 1574, 1506, 1356, 1296,
White needles, Rf (25% EtOAc/hexane) 0.27, mp 199e 1244, 1167, 1112, 1037, 879, 696, 533 cm1. C17H16 N2S
201  C. dH (400 MHz, CDCl3): 2.04 (s, 3H), 6.37 (s 1H), (280.39): calcd C 72.82, H 5.75, N 9.99, S 11.44; found C
7.40 (m, 5H), 7.55 (d, 2H, J¼7.6 Hz), 8.03 (d, 2H, 72.73, H 5.81, N 10.08, S 10.91.
J¼7.6 Hz). dC (100 MHz, CDCl3): 15.1, 104.9, 128.1, 129.3,
129.6, 129.8, 131.6, 134.0, 135.2, 135.9, 136.7, 170.1, 174.4. 4.6.7. 4-Methyl-2-(10 -naphthylimino)-3-phenyl-3H-thiazole
nmax (KBr): 3054, 2912, 1599, 1561, 1489, 1459, 1344, 1270, (10a)
902, 705 cm1. C17H13ClN2OS (328.82): calcd C 62.10, H White cubes, Rf (25% EtOAc/hexane) 0.64, mp 128e129  C.
3.99, N 8.52, S 9.75; found C 62.17, H 4.04, N 8.47, S 9.71. dH (400 MHz, CDCl3): 1.89 (s, 3H), 5.65 (s, 1H), 7.19 (d, 1H,
HRMS (ESI): Mþ, found 328.8215, C17H13ClN2OS requires J¼7.6 Hz), 7.47 (m, 9H), 7.78 (d, 1H, J¼8 Hz), 7.98 (d, 1H,
328.8207. J¼8 Hz). dC (100 MHz, CDCl3): 15.8, 93.9, 115.0, 123.1,
124.0, 125.2, 126.2, 126.5, 128.0, 128.8, 128.9, 129.3, 130.0,
4.6.3. 2-Benzoylimino-3-(2-chlorophenyl)- 135.0, 135.1, 138.1, 148.5, 160.9. nmax (KBr): 3043, 2916,
4-methyl-3H-thiazole (4a) 1620, 1600, 1567, 1492, 1359, 1264, 777, 695, 545 cm1.
White solid, Rf (25% EtOAc/hexane) 0.51, mp 132e133  C. C20H16N2S (316.43): calcd C 75.92, H 5.10, N 8.85, S 10.13;
dH (400 MHz, CDCl3): 1.99 (s, 3H), 6.37 (s, 1H), 7.42 (m, 7H), found C 75.49, H 4.96, N 8.69, S 10.16.
7.98 (d, 2H, J¼8.4 Hz). dC (100 MHz, CDCl3): 14.3, 104.4,
127.9, 128.0, 129.3, 130.1, 130.5, 130.9, 131.4, 132.6, 133.8, 4.6.8. 3-Benzyl-4-methyl-2-phenylimino-3H-thiazole (11a)
135.1, 136.8, 169.7, 174.4. nmax (KBr): 3065, 2917, 1602, White needles, Rf (25% EtOAc/hexane) 0.62, mp 111e
1566, 1481, 1344, 1281, 908, 716, 705 cm1. C17H13ClN2OS 113  C. dH (400 MHz, CDCl3): 2.02 (s, 3H), 5.16 (s, 2H), 5.52
(328.82): calcd C 62.10, H 3.99, N 8.52, S 9.75; found C (s, 1H), 7.03 (m, 3H), 7.30 (m, 7H). dC (100 MHz, CDCl3):
62.38, H 4.08, N 8.31, S 9.78. HRMS (ESI): MHþ, found 14.9, 47.2, 92.6, 121.7, 122.8, 126.8, 127.5, 128.8, 129.5,
328.9611, C17H13ClN2OS requires 328.9605. 135.1, 137.5, 151.6, 160.2. nmax (KBr): 3060, 3021, 2923,
1610, 1577, 1358, 1220, 913, 768, 696 cm1. C17H16 N2S
4.6.4. 2-(3-Bromobenzoylimino)-4-methyl- (280.39): calcd C 72.82, H 5.75, N 9.99, S 11.44; found C
3-phenyl-3H-thiazole (6a) 72.87, H 5.82, N 9.91, S 11.52.
White needles, Rf (25% EtOAc/hexane) 0.41, mp 140e
142  C. dH (400 MHz, CDCl3): 2.06 (s, 3H), 6.40 (s, 1H), 4.6.9. 3-(Furfuryl)-4-methyl-2-phenylimino-3H-thiazole
7.17 (t, 1H, J¼8.0 Hz), 7.32 (d, 2H, J¼7.6 Hz), 7.54 (m, (12a)
4H), 7.93 (d, 1H, J¼6.8 Hz), 8.15 (s, 1H). dC (100 MHz, Reddish oil, Rf (25% EtOAc/hexane) 0.65. dH (400 MHz,
CDCl3): 15.2, 104.9, 122.2, 127.9, 128.1, 128.5, 129.6, CDCl3): 2.23 (s, 3H), 5.08 (s, 2H), 5.51 (s, 1H), 6.36 (t, 1H,
129.7, 132.5, 134.2, 134.7, 137.3, 139.1, 170.3, 172.9. nmax J¼2.8 Hz), 6.42 (d, 1H, J¼3.6 Hz), 7.08 (m, 3H), 7.36 (m,
(KBr): 3086, 2923, 1596, 1557, 1496, 1459, 1450, 1337, 3H). dC (100 MHz, CDCl3): 14.9, 40.6, 92.7, 108.8, 110.9,
1255, 1127, 1033, 907, 739 cm1. C17H13BrN2OS (373.27): 121.8, 123.1, 129.6, 134.9, 142.2, 150.6, 151.7, 159.5. nmax
calcd C 54.70, H 3.51, N 7.50, S 8.59; found C 54.80, H (KBr): 3056, 3027, 2924, 2954, 1614, 1580, 1488, 1396,
3.47, N 7.48, S 8.55. HRMS (ESI): MHþ, found 374.2857, 1317, 1221, 1189, 1146, 1067, 1011, 931, 801, 767, 747,
C17H13BrN2OS requires 374.2809. 696 cm1. C15H14N2OS (270.36): calcd C 66.64, H 5.22, N
10.36, S 11.86; found C 66.73, H 5.34, N 10.21, S 12.41.
4.6.5. 3-(20 ,40 -Dimethylphenyl)-2-(20 ,40 -dimethyl-
phenylimino)-4-methyl-3H-thiazole (8a) 4.6.10. 2-Benzoylimino-3,4-diphenyl-3H-thiazole (1b)
White needles, Rf (25% EtOAc/hexane) 0.76, mp 134e White needles, Rf (25% EtOAc/hexane) 0.62, mp 181e
135  C. dH (400 MHz, CDCl3): 1.76 (s, 3H), 2.07 (s, 3H), 2.24 183  C. dH (400 MHz, CDCl3): 6.70 (s, 1H), 7.12 (d, 2H,
(s, 3H), 2.26 (s, 3H), 2.36 (s, 3H), 5.57 (s, 1H), 6.93 (m, 6H). J¼8.4 Hz), 7.23 (m, 6H), 7.33 (t, 2H, J¼7.6 Hz), 7.39 (d, 3H,
dC (100 MHz, CDCl3): 15.3, 17.7, 17.9, 21.1, 21.4, 93.2, J¼7.0 Hz), 8.10 (d, 2H, J¼8.4 Hz). dC (100 MHz, CDCl3):
120.7, 127.4, 128.1, 129.2, 130.1, 131.4, 132.1, 132.4, 134.2, 107.6, 128.1, 128.5, 128.6, 128.9, 129.0, 129.4, 130.7, 131.6,
135.0, 136.9, 139.1, 148.7, 159.8. nmax (KBr): 3056, 2912, 136.8, 137.7, 139.2, 170.0, 174.7. nmax (KBr): 3064, 2927,
1615, 1585, 1497, 1358, 861, 749 cm1. C20H22N2S (322.48): 1598, 1566, 1492, 1466, 1450, 1435, 1337, 1279, 1200, 1166,
calcd C 74.49, H 6.88, N 8.69, S 9.94; found C 74.26, H 6.93, 1024, 899, 713 cm1. C22H16N2OS (356.45): calcd C 74.13, H
N 8.75, S 9.89. 4.52, N 7.86, S 9.00; found C 74.21, H 4.58, N 7.79, S 8.94.
1940 S. Murru et al. / Tetrahedron 64 (2008) 1931e1942

HRMS (ESI): MHþ, found 357.4563, C22H16N2OS requires 128.7, 128.8, 129.2, 129.4, 129.7, 130.3, 132.8, 138.0, 152.2,
357.4557. 159.4. nmax (KBr): 3021, 2854, 1618, 1577, 1489, 1352, 1141,
760, 688 cm1. C22H18N2S (342.47): calcd C 77.16, H 5.30, N
4.6.11. 2-Benzoylimino-4,5-dimethyl-3-phenyl-3H-thiazole 8.18, S 9.36; found C 77.23, H 5.26, N 8.31, S 9.24.
(1c)
White solid, Rf (25% EtOAc/hexane) 0.46, mp 128e130  C. 4.6.16. 10a,12a-Dimethyl-8-phenylimino-7-phenyl-
dH (400 MHz, CDCl3): 1.95 (s, 3H), 2.28 (s, 3H), 7.31 (m, 5H), l,2,3,3a,3b,4,5,5a,6,7,8,10,10a,10b,11,12,12a-
7.54 (m, 3H), 8.01 (d, 2H, J¼7.2 Hz). dC (100 MHz, CDCl3): hexadecahydro-1H-9-thia-7-aza-dicyclopenta[a,h]-
12.1, 12.4, 115.0, 128.0, 128.2, 128.3, 129.0, 129.4, 129.6, phenanthren-1-ol (7f)
131.4, 137.1, 138.2, 168.4, 174.1. nmax (KBr): 3054, 2923, White amorphous solid, Rf (25% EtOAc/hexane) 0.25, mp
1596, 1558, 1481, 1349, 905, 713 cm1. C18H16N2OS 95e98  C. dH (400 MHz, CDCl3): 0.73 (s, 3H), 0.86 (s, 3H),
(308.41): calcd C 70.10, H 5.23, N 9.08, S 10.40; found C 0.82e2.30 (m, 20H), 3.60 (t, 1H, J¼8.8 Hz), 4.18 (m, 1H),
70.37, H 5.31, N 9.23, S 10.26. 7.03 (m, 2H), 7.37 (m, 8H). dC (100 MHz, CDCl3): 11.2,
12.0, 20.9, 23.5, 28.5, 28.9, 30.5, 31.2, 35.7, 36.7, 37.0,
4.6.12. 2-Benzoylimino-3,5-diphenyl-4-methyl-3H-thiazole 38.2, 41.8, 42.9, 50.9, 53.8, 81.9, 106.3, 121.9, 123.2, 125.2,
(1d) 126.8, 128.3, 128.8, 129.4, 129.5, 137.5, 152.2, 160.8. nmax
White crystalline solid, Rf (25% EtOAc/hexane) 0.70, mp (KBr): 3133, 2928, 2886, 1609, 1577, 1378, 1149, 764,
168e170  C. dH (400 MHz, CDCl3): 2.11 (s, 3H), 7.41 (m, 695 cm1. m/z: 499 (Mþ1). C32H38 N2OS (498.74): calcd
13H), 8.03 (d, 2H, J¼6.8 Hz). dC (100 MHz, CDCl3): 13.7, C 77.07, H 7.68, N 5.62, S 6.43; found C 76.84, H 7.71, N
120.5, 128.0, 128.2, 128.3, 129.1, 129.2, 129.3, 129.4, 129.6, 5.57, S 6.50.
131.5, 132.0, 136.9, 137.9, 168.7, 174.5. nmax (KBr): 3054,
2857, 1596, 1462, 1338, 1174, 902, 718, 691 cm1. C23H18 4.6.17. 2-Benzoylimino-4,5-dihydro-1H-naphtho[1,2-d]-3-
N2OS (370.48): calcd C 74.57, H 4.90, N 7.56, S 8.65; found (p-tolyl)-thiazole (3g)
C 74.73, H 5.08, N 7.38, S 8.83. White cubes, Rf (25% EtOAc/hexane) 0.62, mp 196e197  C.
dH (400 MHz, CDCl3): 2.49 (s, 3H), 2.81 (t, 2H, J¼7.2 Hz), 3.03
4.6.13. N-(1-Hydroxy-10a,12a-dimethyl-7-phenyl- (t, 2H, J¼7.2 Hz), 6.35 (d, 1H, J¼8 Hz), 6.88 (t, 1H, J¼7.2 Hz),
1,2,3,3a,3b,4,5,5a,6,7,10,10a,10b,11,12,12a- 7.09 (t, 1H, J¼7.2 Hz), 7.23 (t, 2H, J¼6.8 Hz), 7.36 (m, 6H),
hexadecahydro-9-thia-7-aza-dicyclopenta[a,h]- 8.11 (d, 2H, J¼7.2 Hz). dC (100 MHz, CDCl3): 21.6, 23.0,
phenanthren-8-ylidene)-benzamide (1f) 30.0, 122.3, 123.2, 126.5, 126.6, 127.5, 128.0, 128.1, 128.5,
Dark red gummy liquid, Rf (25% EtOAc/hexane) 0.21. dH 129.5, 130.0, 131.3, 131.5, 136.3, 136.4, 137.1, 139.0, 169.0,
(400 MHz, CDCl3): 0.76 (s, 3H), 0.86 (s, 3H), 0.80e2.00 (m, 174.5. nmax (KBr): 3025, 3002, 2927, 2837, 1651, 1597, 1563,
19H), 2.31 (d, 1H, J¼8 Hz), 2.60 (d, 1H, J¼16 Hz), 3.65 (t, 1470, 1340, 1316, 1163, 905, 758, 714 cm1. C25H20N2OS
1H, J¼8.4 Hz), 4.15 (m, 1H), 7.42 (m, 7H), 7.81 (d, 1H, (396.51): calcd C 75.73, H 5.08, N 7.06, S 8.09; found C
J¼7.2 Hz), 8.03 (d, 2H, J¼7.2 Hz). dC (100 MHz, CDCl3): 75.79, H 5.18, N 7.18, S 8.23.
11.2, 12.0, 21.0, 23.5, 28.5, 30.5, 31.2, 34.1, 35.7, 36.5, 36.7,
37.0, 37.8, 42.0, 43.0, 51.0, 53.8, 81.9, 117.2, 127.6, 128.0, 4.6.18. 2-Benzoylimino-4,5-dihydro-7-methoxy-1H-
128.7, 129.1, 129.3, 129.4, 130.1, 131.3, 132.1, 137.2, 137.3, naphtho[1,2-d]-3-(p-tolyl)-thiazole (3h)
168.6, 169.7, 174.2. nmax (KBr): 3131, 2923, 2878, 1654, White crystalline solid, Rf (25% EtOAc/hexane) 0.53, mp
1608, 1580, 1376, 1243, 1149, 764, 695 cm1. C33H38 N2O2S 197e199  C. dH (400 MHz, CDCl3): 2.50 (s, 3H), 2.80 (t, 2H,
(526.75): calcd C 75.25, H 7.27, N 5.32, S 6.09; found C J¼6.8 Hz), 3.02 (t, 2H, J¼6.8 Hz), 3.74 (s, 3H), 6.25 (d, 1H,
75.41, H 7.36, N 5.26, S 6.18. J¼8.8 Hz), 6.41 (d, 1H, J¼8.8 Hz), 6.79 (s, 1H), 7.34 (m, 7H),
8.09 (d, 2H, J¼8.8 Hz). dC (100 MHz, CDCl3): 21.6, 22.9,
4.6.14. 3,4-Diphenyl-2-phenylimino-3H-thiazole (7b) 30.2, 55.4, 111, 114.9, 124.6, 127.8, 128.1, 129.4, 129.7,
White needles, Rf (25% EtOAc/hexane) 0.69, mp 189e 130.0, 131.5, 136.4, 137.1, 138.6, 139.0, 159.9, 168.9, 174.4.
192  C. dH (400 MHz, CDCl3): 5.94 (s, 1H), 6.95e7.40 (m, nmax (KBr): 3021, 2924, 2841, 1649, 1602, 1563, 1468, 1339,
15H). dC (100 MHz, CDCl3): 97.4, 121.8, 123.4, 127.7, 128.3, 1318, 1268, 1165, 905, 756, 694 cm1. C26H22 N2O2S
128.4, 128.5, 129.0, 129.1, 129.6, 131.8, 138.1, 140.1, 152.1, (426.54): calcd C 73.21, H 5.20, N 6.57, S 7.52; found C
160.4. nmax (KBr): 3049, 2923, 1618, 1577, 1486, 1360, 1138, 73.14, H 5.09, N 7.58, S 7.67.
710, 694 cm1. C21H16 N2S (328.44): calcd C 76.80, H 4.91,
N 8.53, S 9.76; found C 76.68, H 5.04, N 8.62, S 9.58. 4.6.19. 5,50 -Bis-[2-benzoylimino-4-methyl-3-(p-tolyl)-3H-
thiazole] (3i)
4.6.15. 4-Methyl-3,5-diphenyl-2-phenylimino-3H-thiazole White amorphous solid, Rf (25% EtOAc/hexane) 0.65, mp
(7d) 335e338  C. dH (400 MHz, CDCl3): 2.13 (s, 6H), 2.51 (s,
White crystalline solid, Rf (25% EtOAc/hexane) 0.74, mp 6H), 7.30 (m, 8H), 7.41 (m, 6H), 8.05 (d, 4H, J¼8 Hz). dC
177e179  C. dH (400 MHz, CDCl3): 1.93 (s, 3H), 7.01 (m, (100 MHz, CDCl3): 14.1, 21.6, 109.5, 127.9, 128.1, 129.6,
2H), 7.26 (m, 3H), 7.33 (m, 3H), 7.43 (m, 2H), 7.54 (m, 2H). 130.5, 131.8, 134.6, 135.1, 136.7, 139.7, 169.1, 174.9. nmax
dC (100 MHz, CDCl3): 14.2, 109.6, 121.8, 123.2, 127.3, (KBr): 3063, 2909, 1602, 1572, 1475, 1242, 818 cm1. m/z:
 S. Murru et al. / Tetrahedron 64 (2008) 1931e1942 1941

615 (Mþ1). C36H30N4O2S2 (614.79): calcd C 70.33, H 4.92, N for NMR spectra, CDRI Lucknow for mass spectra and DST
9.11, S 10.43; found C 70.42, H 5.08, N 9.03, S 10.52. FIST for XRD facilities.

4.6.20. 2-Benzoylimino-4-methyl-3-(p-tolyl)-5-ethoxy
carbonylcarboxylic acid ethyl ester-3H-thiazole (3j) References and notes
White crystalline, Rf (25% EtOAc/hexane) 0.35, mp 165e
167  C. dH (400 MHz, CDCl3): 1.36 (t, 3H, J¼7.2 Hz), 2.40 1. Zeng, R.-S.; Zou, J.-P.; Zhi, S.-J.; Chen, J.; Shen, Q. Org. Lett. 2003, 5,
1657.
(s, 3H), 2.48 (s, 3H), 4.32 (q, 2H, J¼7.2 Hz), 7.28 (m, 7H),
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