A Novel Approach to Pyrrolo[2,1-b]thiazoles

Article abstract of DOI:10.1055/s-2003-42451

5-Aroyl-2-(dimethylamino)methylidene-2,3-dihydro-3-oxopyrrolo[2,1-b] thiazole-7-carboxylic acid esters, -7-carbonitriles and corresponding 7-hetaryl substituted derivatives were prepared. Thus, the substituted acetonitriles (XCH₂CN, where X = CO₂R, CN, hetaryl) were treated with mercaptoacetic acid yielding 2-(X-methylidene)thiazolidin-4-ones, which were N-alkylated with phenacyl bromides. Further formylation of the obtained compounds with excess of DMF·POCl₃ complex led to the above mentioned pyrrolo[2,1-b]thiazoles.

Full text of DOI:10.1055/s-2003-42451

2632
PAPER
A Novel Approach to Pyrrolo[2,1-b]thiazoles
S
ynthesisof Pyrro
n
lo[2,1-
b
]thiaz
t
oles on V. Tverdokhlebov,*a Elizaveta V. Resnyanska,a Andrey A. Tolmachev,b Alexander P. Andrushkoa
a
Enamine Ltd. Co., I. Kudry str. 31, apt.17, 02042, Kiev, Ukraine
b
Kiev National Taras Shevchenko University, Volodimirska str., 62, 01033, Kiev, Ukraine
E-mail: atver@mail.univ.kiev.ua
Received 19 May 2003; revised 12 September 2003
azoleacetonitriles chemistry we have obtained certain
pyrrolo[2,1-b]thiazole-7-carbonitriles6a and related benzo
derivatives.6b Furthermore, several examples of pyrro-
lo[2,1-b]thiazoles formation from 2-thiazole- or 2-thiazo-
Abstract: 5-Aroyl-2-(dimethylamino)methylidene-2,3-dihydro-3-
oxopyrrolo[2,1-b]thiazole-7-carboxylic acid esters, -7-carbonitriles
and corresponding 7-hetaryl substituted derivatives were prepared.
Thus, the substituted acetonitriles (XCH2CN, where X = CO2R,
CN, hetaryl) were treated with mercaptoacetic acid yielding 2-(X- lidineacetic acid derivatives were also reported by other
researchers.7 However, all these findings6,7 are of episodic
methylidene)thiazolidin-4-ones, which were N-alkylated with
phenacyl bromides. Further formylation of the obtained compounds
character and can not be considered as general synthetic
with excess of DMF·POCl3 complex led to the above mentioned
methods. So it is of interest to elaborate general approach
pyrrolo[2,1-b]thiazoles.
to pyrrolo[2,1-b]thiazoles on the basis of 2-thiazoleacetic
acid and related derivatives. It should complete the above
mentioned methods extending the scope of available 7-
Key words: alkylations, heterocycles, pyrrolo[2,1-b]thiazoles, ring
closure, 4-thiazolidinones
carboxylic acid derivatives of the target system. The re-
sults of our investigations in this field are reported herein.
An increasing interest in pyrrolo[2,1-b]thiazoles is caused
by high level of biological activities exhibited by certain
carboxylic acid derivatives of this system. Thus, pyrro-
lo[2,1-b]thiazole-3-carboxylic acid amides are able to
2-(4-Oxothiazolidin-2-ylidene)acetic acid esters 1a,b, the
nitrile 1c and their heterocyclic analogues 1d,e were se-
lected as starting materials because they are readily avail-
able from the corresponding nitriles XCH2CN and
modulate dopaminergic neurotransmission in CNS in
mercaptoacetic acid8 (Scheme 1). The alkylation of the
vivo1 while the corresponding 7-carboxylic acid esters
compounds 1 with 2-bromoacetophenones in the presence
were found to be useful for prevention and treatment of
of K2CO3 was found to proceed smoothly at the nitrogen
atom resulting in 3-(2-aryl-2-oxoethyl)-2-methylidenethi-
azolidin-4-ones 2a–e, 3a,c,d, 4c–e, 5b, 6a. Similarly, the
alkylation with chloroacetic acid anilides yielded N-aryl-
various liver diseases.2 There are two general approaches
to pyrrolo[2,1-b]thiazole-7-carboxylic acid derivatives.
The first one is a thiazole ring annulation to the 2-thioxo-
3-pyrrolidinecarboxylic acid esters by the action of 1,2-
2-methylidene-4-oxo-3-thiazolidineacetamides 7a,c,d,
bielectrophilic reagents.2 The second one is based on the
8a, 9c, 10b. Satzinger reported8b,c the N-alkylation of
cycloaddition reactions of thiazolium ylides,3 imida-
compounds 1a,c and their 5-phenyl substituted deriva-
tives 16 (Figure 1) with simple haloalkanes and dimethyl
zo[2,1-b]thiazoles4 or mesoionic thiazolo[3,2-c]oxazoles5
with dimethyl acetylenedicarboxylate and related unsatur-
sulfate under similar conditions. Also it was shown, that
ated acids derivatives. During our investigations on 2-thi-
Scheme 1 Ar = 2: 4-ClC6H4, 3: 4-BrC6H4, 4: 4-O2NC6H4, 5: Ph, 6: 4-PhC6H4; R = 7: 4-EtOC6H4, 8: 3,4-(MeO)2C6H3, 9: 4-MeC6H4,
10: 4-i-PrC6H4
SYNTHESIS 2003, No. 17, pp 2632–2638
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x.
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Advanced online publication: 23.10.2003
DOI: 10.1055/s-2003-42451; Art ID: Z06403SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Pyrrolo[2,1-b]thiazoles
2633
the N-methyl derivatives 17 could be alkylated for the sec- b]thiazole-7-carboxylic acid esters 11a,b, 12b, 14b, 15a,
ond time at C-5 under more drastic circumstances.8b -carbonitriles 11c, 12c, 13c and their hetaryl substituted
Moreover, with benzyl chloride only bis-benzyl deriv- analogues 11d,e, 12d, 13d,e. Unfortunately, attempts to
atives of 16 were obtained anyway.8b On the other hand, prepare the corresponding pyrrolo[2,1-b]thiazole-5-car-
the alkylation at the exocyclic enamine carbon was de- boxamides via formylation of the 3-thiazolidineacet-
scribed for benzylidene derivatives 18 and deoxo ana- amides 7–10 failed. A mixture of products was formed
logues 19.7b–d Nevertheless, in the present case, in spite of and only impure pyrrolothiazoles could be isolated from
a high activity of the alkylating agents decreasing the se- it. Probably, POCl3 coordination at the carboxamide moi-
lectivity, neither exocyclic carbon nor oxomethylene moi- ety of the starting materials caused side processes produc-
ety underwent alkylation. Compounds 2–6 were the sole ing impurities. So the scope of the method is limited to the
products isolated in good yields.
preparation of the 5-aroyl derivatives 11–15.
Figure 1 Structures of compounds 16–19; X = 16–18: CN, CO2Et;
19: COMe, COPh; R = 16: H; 17: Me
Scheme 2 Ar = 11: 4-ClC6H4, 12: 4-BrC6H4, 13: 4-O2NC6H4, 14:
Ph, 15: 4-PhC6H4; for the substituent X, see: Scheme 1
In contrary to compounds 1a–c, their heterocyclic ana-
logues 1d,e in principle could be alkylated at the other ni-
trogen yielding the products of isomeric structure 20
(Figure 2). The regioisomers 2d,e, 3d, 4d,e, 7d and 20
could not be distinguished on the basis of simple spectral
data (1H and 13C NMR). To resolve this problem and to
confirm the assigned structures 2d,e, 3d, 4d,e, 7d for pre-
pared compounds, the long-range C-H correlation (HM-
BC experiment) was carried out for the derivative 7d. It
revealed the two correlations of the singlet of endocyclic
methylene protons at 4.05 ppm with the signals of 2-C and
4-C of the thiazolone moiety at 148.8 and 172.1 ppm, re-
spectively. Simultaneously, the singlet of the NCH2 group
at 4.57 ppm established the correlations with the same car-
bons signals. These data confirm finally the structure of
7d and exclude the isomeric one 20 where there are no
carbons capable to exhibit correlations with both methyl-
ene signals.
Noteworthy is the incorporation of a one-atom unit into
the acyclic precursor, which is a widely used strategy in
heterocyclic synthesis. However, literature search re-
vealed only the sole application of such an approach to
pyrrolo[2,1-b]thiazole synthesis via incorporation of a C1-
unit into position 5 of the system.9 Hence, the sequence
described herein represents a novel approach to pyrro-
lo[2,1-b]thiazole skeleton construction.
The structures of pyrrolothiazoles 11–15 were confirmed
1
13
by H, C and 2D NMR spectroscopical data. Thus, the
signals of both methylene groups observed in the 1H NMR
spectra of the starting compounds 2–6 at 3.9–4.3 and 5.2–
5.5 ppm disappeared from the spectra of derivatives 11–
15. Instead, the six-proton singlet of the dimethylamino
group at 3.2–3.3 ppm and two one-proton singlets at 7.9–
8.0 and 7.1–7.6 ppm assigned to the methylidene proton
and 6-H, respectively, were present therein. For the latter
one the long-range C-H-correlation (HMBC) experiment
performed for the compound 11d revealed five correla-
tions with the following carbon signals: 7-C at 110.2 ppm,
5-C at 128.2 ppm, 2-C of the benzothiazole moiety at
153.3 ppm, 7a-C at 160.0 ppm and the carbonyl of the
aroyl substituent at C-5 at 181.4 ppm. This correlations set
is a weighty evidence for the assigned structure. The sin-
glet of the methylidene proton also exhibited correlations
with the signals of 2-C at 87.2 ppm and 3-C at 160.2 ppm.
Finally, the mass spectrum of the derivative 11d estab-
lished an expected M·+ value 465.
Figure 2 Structure of compound 20; R1 + R2 = benzo; R1 = 4-
MeC6H4, R2 = H
The formylation of the thiazolones 2–6 with excess of
DMF·POCl3 complex accomplished the preparation of
target system by incorporation of a C1-unit into position 6
(Scheme 2). The pyrrole ring closure is accompanied with
the methylene group transformation into its (dimethyl-
amino)methylidene derivative yielding 5-aroyl-2-(dime-
thylamino)methylidene-2,3-dihydro-3-oxopyrrolo[2,1-
To resume, as a result of present investigation the con-
venient method for preparation of 5-aroyl-2-(dimethyl-
amino)methylidene-2,3-dihydro-3-oxopyrrolo[2,1-b]thia-
zole-7-carboxylic acid derivatives 11a–c, 12a,c, 13c, 14b,
15a and related 7-hetaryl substituted compounds 11d,e,
Synthesis 2003, No. 17, 2632–2638 © Thieme Stuttgart · New York

2634
A. V. Tverdokhlebov et al.
PAPER
Anal. Calcd for C15H14ClNO4S: C, 53.02; H, 4.15; N, 4.12; S, 9.44;
Cl, 10.43. Found: C, 52.94; H, 4.19; N, 4.03; S, 9.38; Cl, 10.50.
12d, 13d,e has been worked out. It utilizes readily avail-
able starting materials and simple experimental proce-
dures thus completing the well known methods.2–5
Moreover, the prepared compounds 11–15 are the rare ex-
amples of 3-oxo derivatives of the target system. To date
only three representatives of pyrrolo[2,1-b]thiazol-3-ones
are described.7d,10 Finally, the present method offers a
novel approach to the formation of pyrrolo[2,1-b]thiazole
skeleton.
2-{3-[2-(4-Bromophenyl)-2-oxoethyl]-4-oxo-2-thiazolidinyli-
dene}acetic Acid Ethyl Ester (3a)
Mp 145 °C (DMF); yield: 1.8 g (80%).
1H NMR: = 1.15 (t, 3 H, J = 7.5 Hz, CH3), 3.99 (s, 2 H, SCH2),
4.05 (q, 2 H, J = 7.5 Hz, OCH2), 5.35 (s, 2 H, NCH2), 5.63 (s, 1 H,
CH), 7.80 (d, 2 H, J = 9.0 Hz, Ar), 7.98 (d, 2 H, J = 9.0 Hz, Ar).
13C NMR: = 14.3 (CH3), 33.4 (5-C), 51.9 (NCH2), 60.9 (OCH2),
91.3 (CHX), 127.3 (4-CAr), 131.5 (3,5-CAr), 132.9 (2,6-CAr), 134.3
(1-CAr), 151.2 (2-C), 166.3 (COO), 173.9 (4-C), 191.6 (COAr).
Thiazolidinones 1a–d were prepared as reported.8 2-Bromoace-
tophenones are commercially available or obtained from commer-
cially available acetophenones via standard procedures.
Chloroacetic acid anilides were obtained according to the described
method.11 All mps were determined in capillary tubes in a Thiele ap-
Anal. Calcd for C15H14BrNO4S: C, 46.89; H, 3.67; N, 3.65; S, 8.34;
Br, 20.79. Found: C, 46.95; H, 3.78; N, 3.57; S, 8.29; Br, 20.59.
2-{3-[2-(Biphenyl-4-yl)-2-oxoethyl]-4-oxo-2-thiazolidi-
nylidene}acetic Acid Ethyl Ester (6a)
1
paratus and are uncorrected. H NMR spectra were recorded on a
Varian VXR-300 (300 MHz) spectrometer in DMSO-d6 solutions.
Chemical shifts ( ) are given in ppm downfield from internal
SiMe4. J values are in Hz. 13C and 2D NMR experiments were per-
formed on a Bruker Avance 500 (500 MHz for 1H and 125 MHz for
13C) spectrometer. For the assignments of hydrogen atoms referred
as Ar, R, and X in the experimental part, please see Schemes 1
and 2. Mass spectra were determined on a Varian 212 instrument at
Mp 185 °C (DMF); yield: 2.0 g (88%).
1H NMR: = 1.15 (t, 3 H, J = 7.5 Hz, CH3), 4.01 (s, 2 H, SCH2),
4.05 (q, 2 H, J = 7.5 Hz, OCH2), 5.39 (s, 2 H, NCH2), 5.63 (s, 1 H,
CH), 7.45–7.55 (m, 3 H, Ar), 7.78 (d, 2 H, J = 8.0 Hz, Ar), 7.89 (d,
2 H, J = 9.0 Hz, Ar), 8.14 (d, 2 H, J = 9.0 Hz, Ar).
13C NMR: = 14.7 (CH3), 32.6 (5-C), 52.5 (NCH2), 60.0 (OCH2),
91.5 (CHX), 125.5 (2 ,6 -CAr), 127.8 (4 -CAr), 128.5 (3 ,5 -CAr),
130.8 (3,5-CAr), 131.4 (2,6-CAr), 134.0 (1-CAr), 141.8 (4-CAr), 143.1
(1 -CAr), 154.1 (2-C), 165.1 (COO), 172.6 (4-C), 191.3 (COAr).
1
70 eV. The purity of all compounds prepared was checked by H
NMR spectroscopy.
2-[4-(4-Methylphenyl)-2-thiazolyl]methylidenethiazolidin-4-
one (1e)
Anal. Calcd for C21H19NO4S: C, 66.12; H, 5.02; N, 3.67; S, 8.41.
Found: C, 66.06; H, 4.95; N, 3.82; S, 8.58.
A solution of 4-(4-methylphenyl)-2-thiazoleacetonitrile (5;12 2.1 g,
10 mmol) and mercaptoacetic acid (1.1 g, 12 mmol) in anhyd pyri-
dine (5 mL) was refluxed for 6 h. After cooling, the precipitated sol-
id was filtered, washed with H2O and dried to yield compound 1e as
yellow crystals; mp 214 °C.
2-{3-[2-[(4-Ethoxyphenyl)amino]-2-oxoethyl]-4-oxo-2-thiazoli-
dinylidene}acetic Acid Ethyl Ester (7a)
Mp 183 °C (EtOH); yield: 1.6 g (73%).
1H NMR: = 1.21 (t, 3 H, J = 7.2 Hz, CH3), 1.33 (t, 3 H, J = 6.9
Hz, CH3), 3.89 (s, 2 H, SCH2), 3.95 (q, 2 H, J = 7.2 Hz, OCH2),
4.08 (q, 2 H, J = 7.2 Hz, OCH2), 4.45 (s, 2 H, NCH2), 5.47 (s, 1 H,
CH), 6.81 (d, 2 H, J = 8.7 Hz, R), 7.43 (d, 2 H, J = 9.0 Hz, R),
10.11 (s, 1 H, NH).
13C NMR: = 14.5 (CH3), 14.7 (CH3), 32.4 (5-C) 46.0 (NCH2),
60.9 (OCH2), 63.2 (OCH2), 92.3 (CHX), 114.0 (3,5-CR), 120.7 (2,6-
CR), 135.4 (1-CR), 154.8 (4-CR), 146.9 (2-C), 166.1 (COO), 167.7
(CONH), 173.7 (4-C).
1H NMR: = 2.33 (s, 3 H, CH3), 3.87 (s, 2 H, CH2), 6.34 (s, 1 H,
CH), 7.24 (d, 2 H, J = 9.0 Hz, C6H4), 7.76 (s, 1 H, 5-HX), 7.89 (d,
2 H, J = 9.0 Hz, C6H4), 12.16 (s, 1 H, NH).
13C NMR: = 21.8 (CH3), 31.4 (5-C), 92.6 (CHX), 125.7 (2,6-Ctol),
130.1 (3,5-Ctol), 131.9 (4-Ctol), 133.1 (1-Ctol), 142.4 (5-CX), 152.3
(2-C), 165.7 (4-CX), 166.6 (2-CX), 172.7 (4-C).
Anal. Calcd for C14H12N2OS2: C, 58.31; H, 4.19; N, 9.71; S, 22.24.
Found: C, 58.16; H, 4.26; N, 9.62; S, 22.29.
Anal. Calcd for C17H20N2O5S: C, 56.03; H, 5.53; N, 7.69; S, 8.80.
Found: C, 55.98; H, 5.69; N, 7.61; S, 8.73.
2-Thiazolidinylideneacetic Acid Ethyl Esters 2a, 3a, 6a, 7a, 8a;
General Procedure
Powdered K2CO3 (1.0 g, 7.2 mmol) was added to a solution of ester
1a (1.1 g, 6 mmol) and the corresponding 2-bromoacetophenone or
chloroacetic acid anilide (6 mmol) in EtOH (5 mL) and the resulting
mixture was refluxed for 1.5–2 h. After cooling, the precipitated
solid was filtered, thoroughly washed with H2O to remove inorgan-
ic materials, dried, and recrystallized (if necessary) from an appro-
priate solvent to give 2a, 3a, 6a, 7a, 8a. An additional portion of
products could be obtained after pouring the ethanolic filtrate into
H2O, filtration of the formed solid and recrystallization.
2-{3-[2-[(3,4-dimethoxyphenyl)amino]-2-oxoethyl]-4-oxo-2-thi-
azolidinylidene}acetic Acid Ethyl Ester (8a)
Mp 193 °C (EtOH); yield: 1.9 g (83%).
1H NMR: = 1.17 (t, 3 H, J = 7.2 Hz, CH3), 3.70 (s, 6 H, 2 OCH3),
3.95 (s, 2 H, SCH2), 4.06 (q, 2 H, J = 7.2 Hz, OCH2), 4.50 (s, 2 H,
NCH2), 5.55 (s, 1 H, CH), 6.89 (d, 1 H, J = 8.8 Hz, R), 7.01 (dd, 1
H, J3 = 8.8 Hz, J4 = 2.0 Hz, R), 7.31 (d, 1 H, J = 2.0 Hz, R), 10.21
(s, 1 H, NH).
13C NMR: = 14.4 (CH3), 33.6 (5-C) 48.3 (NCH2), 55.2 (OCH3),
56.4 (OCH3), 61.4 (OCH2), 92.7 (CHX), 108.6 (2-CR), 113.7 (5-
CR), 120.5 (6-CR), 135.4 (1-CR), 147.6 (4-CR), 149.9 (3-CR), 158.0
(2-C), 165.2 (COO), 168.8 (CONH), 172.1 (4-C).
2-{3-[2-(4-Chlorophenyl)-2-oxoethyl]-4-oxo-2-thiazolidinyli-
dene}acetic Acid Ethyl Ester (2a)
Mp 102 °C (DMF–H2O); yield: 1.5 g (73%).
1H NMR: = 1.16 (t, 3 H, J = 7.5 Hz, CH3), 3.99 (s, 2 H, SCH2),
4.05 (q, 2 H, J = 7.5 Hz, OCH2), 5.35 (s, 2 H, NCH2), 5.63 (s, 1 H,
CH), 7.65 (d, 2 H, J = 9.0 Hz, Ar), 8.06 (d, 2 H, J = 9.0, Ar).
13C NMR: = 14.3 (CH3), 30.7 (5-C), 52.5 (NCH2), 60.1 (OCH2),
91.3 (CHX), 129.0 (3,5-CAr), 133.6 (2,6-CAr), 134.0 (1-CAr), 138.4
(4-CAr), 152.0 (2-C), 165.4 (COO), 174.7 (4-C), 191.7 (COAr).
Anal. Calcd for C17H20N2O6S: C, 53.67; H, 5.30; N, 7.36; S, 8.43.
Found: C, 53.79; H, 5.18; N, 7.45; S, 8.29.
2-Thiazolidinylideneacetic Acid Methyl Esters 2b, 5b, 10b
The methyl esters were obtained from the ester 1b according to
above procedure using MeOH instead of EtOH to avoid a re-esteri-
fication.
Synthesis 2003, No. 17, 2632–2638 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrrolo[2,1-b]thiazoles
2635
2-{3-[2-(4-Chlorophenyl)-2-oxoethyl]-4-oxo-2-thiazolidinyli-
dene}acetic Acid Methyl Ester (2b)
2-(2-Benzothiazolylmethylidene)-3-[2-(4-chlorophenyl)-2-oxo-
ethyl]thiazolidin-4-one (2d)
Mp 163 °C (DMF–H2O); yield: 1.5 g (77%).
Mp 256 °C (DMF); yield: 2.0 g (83%).
1H NMR: = 3.58 (s, 3 H, CH3), 4.01 (s, 2 H, SCH2), 5.36 (s, 2 H,
NCH2), 5.66 (s, 1 H, CH), 7.67 (d, 2 H, J = 8.0 Hz, Ar), 8.07 (d, 2
H, J = 8.0 Hz, Ar).
13C NMR: = 33.5 (5-C), 51.4 (CH3), 53.3 (NCH2), 90.8 (CHX),
129.1 (3,5-CAr), 133.6 (2,6-CAr), 134.2 (1-CAr), 138.3 (4-CAr), 152.2
(2-C), 166.1 (COO), 174.7 (4-C), 192.9 (COAr).
1H NMR: = 4.03 (s, 2 H, SCH2), 5.39 (s, 2 H, NCH2), 6.62 (s, 1 H,
CH), 7.28 (t, 1 H, J = 7.8 Hz, X), 7.42 (t, 1 H, J = 7.8 Hz, X), 7.63
(d, 2 H, J = 9.0 Hz, Ar), 7.83 (d, 1 H, J = 7.8 Hz, X), 7.89 (d, 1 H,
J = 7.8 Hz, X), 8.12 (d, 2 H, J = 9.0 Hz, Ar).
13C NMR: = 33.0 (5-C), 52.1 (NCH2), 92.5 (CHX), 121.2 (7-CX),
121.9 (4-CX), 123.9 (6-CX), 126.3 (5-CX), 128.8 (3,5-CAr), 131.7
(7a-CX), 133.6 (2,6-CAr), 135.5 (1-CAr), 138.2 (4-CAr), 152.9 (2-C),
153.5 (3a-CX), 163.8 (2-CX), 173.2 (4-C), 191.9 (COAr).
Anal. Calcd for C14H12ClNO4S: C, 51.62; H, 3.71; N, 4.30; S, 9.84;
Cl, 10.88. Found: C, 51.55; H, 3.89; N, 4.36; S, 9.77; Cl, 10.94.
Anal. Calcd for C19H13ClN2O2S2: C, 56.92; H, 3.27; N, 6.99; S,
16.00; Cl, 8.84. Found: C, 56.88; H, 3.32; N, 7.06; S, 15.87; Cl,
8.79.
2-[4-Oxo-3-(2-oxo-2-phenylethyl)-2-thiazolidinylidene]acetic
Acid Methyl Ester (5b)
Mp 149 °C (dioxane); yield: 1.3 g (75%).
3-[2-(4-Chlorophenyl)-2-oxoethyl]-2-[4-(4-methylphenyl)-2-
thiazolyl]methylidenethiazolidin-4-one (2e)
Mp 279 °C (DMF); yield: 2.1 g (81%).
1H NMR: = 2.34 (s, 3 H, CH3), 4.06 (s, 2 H, SCH2), 5.39 (s, 2 H,
NCH2), 6.67 (s, 1 H, CH), 7.26 (d, 2 H, J = 9.0 Hz, X), 7.68 (d, 2
H, J = 9.0 Hz, Ar), 7.79 (s, 1 H, 5-HX), 7.91 (d, 2 H, J = 9.0 Hz,
Ar), 8.11 (d, 2 H, J = 9.0 Hz, X).
13C NMR: = 21.1 (CH3), 32.5 (5-C), 52.1 (NCH2), 91.8 (CHX),
125.2 (2,6-Ctol), 129.1 (3,5-CAr), 130.2 (3,5-Ctol), 131.0 (4-Ctol),
133.5 (1-Ctol), 133.6 (2,6-CAr), 135.3 (1-CAr), 137.9 (4-CAr), 140.8
(5-CX), 153.5 (2-C), 166.4 (4-CX), 166.8 (2-CX), 173.4 (4-C), 191.2
(COAr).
1H NMR: = 3.58 (s, 3 H, CH3), 4.00 (s, 2 H, SCH2), 5.36 (s, 2 H,
NCH2), 5.63 (s, 1 H, CH), 7.59 (t, 2 H, J = 10.0 Hz, Ar), 7.72 (t, 1
H, J = 10.0 Hz, Ar), 8.06 (d, 2 H, J = 10.0 Hz, Ar).
13C NMR: = 32.6 (5-C), 51.4 (CH3), 52.5 (NCH2), 92.7 (CHX),
128.2 (3,5-CAr), 133.4 (2,6-CAr), 134.5 (4-CAr), 136.6 (1-CAr), 158.6
(2-C), 170.8 (COO), 173.7 (4-C), 193.2 (COAr).
Anal. Calcd for C14H13NO4S: C, 57.72:, H, 4.50; N, 4.81; S, 11.01.
Found: C, 57.65:, H, 4.39; N, 4.88; S, 11.12.
2-{3-[2-[4-(Isopropyl)phenyl]amino-2-oxoethyl]-4-oxo-2-thia-
zolidinylidene}acetic Acid Methyl Ester (10b)
Mp 125 °C (MeOH); yield: 1.9 g (91%).
Anal. Calcd for C22H17ClN2O2S2: C, 59.92; H, 3.89; N, 6.35; S,
14.54; Cl, 8.04. Found: C, 60.02; H, 3.84; N, 6.21; S, 14.67; Cl,
8.12.
1H NMR: = 1.17 [d, 6 H, J = 6.0 Hz, CH(CH3)2], 2.83 [1 H, m,
CH(CH3)2], 3.60 (s, 3 H, OCH3), 3.95 (s, 2 H, SCH2), 4.50 (s, 2 H,
NCH2), 5.55 (s, 1 H, CH), 7.17 (d, 2 H, J = 9.0 Hz, R), 7.45 (d, 2
H, J = 9.0 Hz, R), 10.19 (s, 1 H, NH).
13C NMR: = 23.4 [CH(CH3)2], 31.0 (5-C), 33.8 [CH(CH3)2], 50.8
(CH3), 54.3 (NCH2), 91.3 (CHX), 119.7 (2,6-CR), 129.7 (3,5-CR),
138.5 (4-CR), 139.9 (1-CR), 162.0 (2-C), 169.1 (COO), 171.4 (4-C),
176.7 (COR).
2-{3-[2-(4-Bromophenyl)-2-oxoethyl]-4-oxo-2-thiazolidinyli-
dene}acetonitrile (3c)
Mp 185 °C (DMF–H2O); yield: 1.8 g (89%).
1H NMR: = 4.26 (s, 2 H, SCH2), 5.28 (s, 2 H, NCH2), 5.38 (s, 1 H,
CH), 7.80 (d, 2 H, J = 8.4 Hz, Ar), 7.97 (d, 2 H, J = 8.4 Hz, Ar).
13C NMR: = 31.6 (5-C), 51.8 (NCH2), 65.6 (CHX), 119.6 (CN),
130.3 (4-CAr), 130.5 (3,5-CAr), 132.3 (2,6-CAr), 140.1 (1-CAr), 162.6
(2-C), 169.6 (4-C), 192.9 (COAr).
Anal. Calcd for C17H20N2O4S: C, 58.60; H, 5.79; N, 8.04; S, 9.20.
Found: C, 58.74; H, 5.71; N, 7.95; S, 9.11.
2-Thiazolidinylideneacetonitriles 2c, 3c, 4c, 7c, 9c and 2-Het-
arylmethylidene-4-thiazolidinones 2d,e, 3d, 4d,e, 7d; General
Procedure
Anal. Calcd for C13H9BrN2O2S: C, 46.31; H, 2.69; N, 8.31; S, 9.51;
Br, 23.70. Found: C, 46.32; H, 2.74; N, 8.23; S, 9.58; Br, 23.79.
Powdered K2CO3 (1.0 g, 7.2 mmol) was added to a solution of 1c–
e (6 mmol) and the corresponding alkylating agent (6 mmol) in
DMF (5 mL) and the resulting mixture was heated at 120–130 °C
for 1.5–2 h. When the derivative 1c was used as starting material,
the cooled mixture was poured into H2O, the precipitated solid was
filtered, dried and recrystallized from aq DMF yielding nitriles 2c,
3c, 4c, 7c, 9c. When the alkylation was carried out for compounds
1d,e, the mixture was cooled, the precipitate formed was filtered,
thoroughly washed with H2O to remove inorganic materials and re-
crystallized (if necessary) from DMF or aq DMF to give 2d,e, 3d,
4d,e, 7d.
2-(2-Benzothiazolylmethylidene)-3-[2-(4-bromophenyl)-2-oxo-
ethyl]thiazolidin-4-one (3d)
Mp 289 °C (DMF); yield: 2.3 g (86%).
1H NMR: = 4.08 (s, 2 H, SCH2), 5.41 (s, 2 H, NCH2), 6.70 (s, 1 H,
CH), 7.31 (t, 1 H, J = 7.8 Hz, X), 7.45 (t, 1 H, J = 7.8 Hz, X), 7.85
(m, 3 H, X, Ar), 7.97 (d, 1 H, J = 7.8 Hz, X), 8.03 (d, 2 H, J = 8.4
Hz, Ar).
13C NMR: = 33.6 (5-C), 52.1 (NCH2), 92.7 (CHX), 122.7 (7-CX),
122.9 (4-CX), 124.9 (6-CX), 125.8 (5-CX), 127.3 (4-CAr), 130.1 (3,5-
CAr), 131.8 (7a-CX), 135.9 (2,6-CAr), 136.8 (1-CAr), 151.8 (3a-CX),
156.1 (2-C), 161.8 (2-CX), 171.9 (4-C), 193.1 (COAr).
2-{3-[2-(4-Chlorophenyl)-2-oxoethyl]-4-oxo-2-thiazolidinyli-
dene}acetonitrile (2c)
Mp 137 °C (DMF–H2O); yield: 1.2 g (68%).
1H NMR: = 4.26 (s, 2H, SCH2), 5.28 (s, 2 H, NCH2), 5.38 (s, 1 H,
Anal. Calcd for C19H13BrN2O2S2: C, 51.24; H, 2.94; N, 6.29; S,
14.40; Br, 17.94. Found: C, 51.19; H, 2.99; N, 6.32; S, 14.28; Br,
18.01.
CH), 7.66 (d, 2 H, J = 9.0 Hz, Ar), 8.05 (d, 2 H, J = 9.0 Hz, Ar).
2-{3-[2-(4-Nitrophenyl)-2-oxoethyl]-4-oxo-2-thiazolidinyli-
dene}acetonitrile (4c)
Mp 196 °C (DMF–H2O); yield: 1.4 g (77%).
1H NMR: = 4.28 (s, 2 H, SCH2), 5.38 (s, 2 H, NCH2), 5.44 (s, 1 H,
CH), 8.28 (d, 2 H, J = 9.0 Hz, Ar), 8.39 (d, 2 H, J = 9.0 Hz, Ar).
13C NMR: = 32.7 (5-C), 51.8 (NCH2), 65.7 (CHX), 116.5 (CN),
129.0 (3,5-CAr), 133.5 (2,6-CAr), 135.9 (1-CAr), 138.4 (4-CAr), 156.5
(2-C), 172.8 (4-C), 192.5 (COAr).
Anal. Calcd for C13H9ClN2O2S: C, 53.34; H, 3.10; N, 9.57; S, 10.95;
Cl, 12.11. Found: C, 53.29; H, 3.21; N, 9.41; S, 11.03; Cl, 12.02.
Synthesis 2003, No. 17, 2632–2638 © Thieme Stuttgart · New York

2636
A. V. Tverdokhlebov et al.
PAPER
13C NMR: = 32.8 (5-C), 52.1 (NCH2), 65.6 (CHX), 116.5 (CN),
123.5 (3,5-CAr), 133.4 (2,6-CAr), 142.9 (1-CAr), 149.4 (4-CAr), 156.6
(2-C), 173.0 (4-C), 193.1 (COAr).
Anal. Calcd for C21H19N3O3S2: C, 59.28; H, 4.50; N, 9.87; S, 15.07.
Found: C, 59.35; H, 4.42; N, 9.84; S, 15.11.
2-Cyanomethylidene-N-(4-methylphenyl)-4-oxo-3-thiazo-
lidineacetamide (9c)
Mp 207 °C (DMF–H2O); yield: 1.5 g (87%).
Anal. Calcd for C13H9N3O4S: C, 51.48; H, 2.99; N, 13.85; S, 10.57.
Found: C, 51.33; H, 3.08; N, 13.80; S, 10.63.
2-(2-Benzothiazolylmethylidene)-3-[2-(4-nitrophenyl)-2-oxo-
ethyl]thiazolidin-4-one (4d)
Mp 219 °C (DMF); yield: 1.9 g (77%).
1H NMR: = 2.24 (s, 3 H, CH3), 4.20 (s, 2 H, SCH2), 4.45 (s, 2 H,
NCH2), 5.36 (s, 1 H, CH), 7.11 (d, 2 H, J = 8.4 Hz, R), 7.42 (d, 2
H, J = 8.4 Hz, R), 10.21 (s, 1 H, NH).
1H NMR: = 4.10 (s, 2 H, SCH2), 5.51 (s, 2 H, NCH2), 6.76 (s, 1 H,
CH), 7.31 (t, 1 H, J = 9.0 Hz, X), 7.45 (t, 1 H, J = 9.0 Hz, X), 7.85
(d, 1 H, J = 9.0 Hz, X), 7.97 (d, 1 H, J = 9.0 Hz, X), 8.35 (d, 2 H,
J = 9.0 Hz, Ar), 8.42 (d, 2 H, J = 9.0 Hz, Ar).
13C NMR: = 32.4 (5-C), 52.1 (NCH2), 92.6 (CHX), 123.0 (4-CX),
123.2 (7-CX), 125.6 (6-CX), 125.4 (5-CX), 128.5 (3,5-CAr), 132.4
(7a-CX), 133.8 (2,6-CAr), 141.2 (1-CAr), 149.1 (4-CAr), 149.8 (3a-
CX), 157.7 (2-C), 167.5 (2-CX), 169.9 (4-C), 193.9 (COAr).
13C NMR: = 20.6 (CH3), 30.9 (5-C), 44.6 (NCH2), 66.8 (CHX),
118.2 (CN), 120.4 (2,6-CR), 127.1 (3,5-CR), 133.1 (4-CR), 137.4 (1-
CR), 153.7 (2-C), 165.0 (CONH), 169.5 (4-C).
Anal. Calcd for C14H13N3O2S: C, 58.52; H, 4.56; N, 14.62; S, 11.16.
Found: C, 58.44; H, 4.59; N, 14.77; S, 11.09.
5-Aroyl-2-(dimethylamino)methylidene-2,3-dihydro-3-oxopyr-
rolo[2,1-b]thiazoles 11–15; General Procedure
Appropriate 2–6 (3 mmol) was added to a cold solution of POCl3
(1.4 g, 9 mmol) in anhyd DMF (5 mL) and the mixture was gently
heated to dissolve the starting material. The resulting solution was
kept at 50–55 °C for 2 h. After cooling, the precipitated solid was
filtered and washed consecutively with H2O, aq sat. NaHCO3 solu-
tion and again with H2O to afford pure 11–15. Further quantities of
derivatives 11–15 were obtained when the filtrate was poured onto
crushed ice, the precipitate formed was filtered, washed as above
and recrystallized from DMF or aq DMF.
Anal. Calcd for C19H13N3O4S2: C, 55.46; H, 3.18; N, 10.21; S,
15.59. Found: C, 55.41; H, 3.07; N, 10.28; S, 15.67.
2-[4-(4-Methylphenyl)-2-thiazolyl]methylidene-3-[2-(4-nitro-
phenyl)-2-oxoethyl]thiazolidin-4-one (4e)
Mp 256 °C (DMF); yield: 2.2 g (81%).
1H NMR: = 2.34 (s, 3 H, CH3), 4.08 (s, 2 H, SCH2), 5.47 (s, 2 H,
NCH2), 6.71 (s, 1 H, CH), 7.26 (d, 2 H, J = 9.0 Hz, X), 7.79 (s, 1 H,
5-HX), 7.91 (d, 2 H, J = 9.0 Hz, X), 8.33 (d, 2 H, J = 9.0 Hz, Ar),
8.41 (d, 2 H, J = 9.0 Hz, Ar).
13C NMR: = 21.2 (CH3), 31.6 (5-C), 52.6 (NCH2), 91.6 (CHX),
125.7 (2,6-Ctol), 128.6 (3,5-CAr), 130.0 (3,5-Ctol), 132.9 (4-Ctol),
133.3 (1-Ctol), 133.4 (2,6-CAr), 140.4 (5-CX), 142.7 (1-CAr), 149.6
(4-CAr), 158.4 (2-C), 167.8 (4-CX), 166.1 (2-CX), 171.4 (4-C), 192.8
(COAr).
5-(4-Chlorobenzoyl)-2-(dimethylamino)methylidene-2,3-dihy-
dro-3-oxopyrrolo[2,1-b]thiazole-7-carboxylic Acid Ethyl Ester
(11a)
Mp 175 °C (DMF–H2O); yield: 0.8 g (66%).
1H NMR: = 1.28 (t, 3 H, J = 7.4 Hz, CH3), 3.26 [s, 6 H, N(CH3)2],
4.24 (q, 2 H, J = 7.4, CH2), 7.17 (s, 1 H, 6-H), 7.56 (d, 2 H, J = 8.4,
Ar), 7.78 (d, 2 H, J = 8.4, Ar), 7.90 (s, 1 H, =CHN).
13C NMR: = 14.5 (CH3), 40.0 [N(CH3)2], 59.0 (OCH2), 87.2 (2-
C), 107.9 (7-C), 124.4 (6-C), 126.1 (3,5-CAr), 127.7 (1-CAr), 129.9
(2,6-CAr), 137.6 (5-C), 140.3 (4-CAr), 141.1 (7a-C), 150.4 (=CHN),
159.5 (3-C), 162.9 (7-CO), 182.1 (5-CO).
Anal. Calcd for C22H17N3O4S2: C, 58.52; H, 3.80; N, 9.31; S, 14.20.
Found: C, 58.66; H, 3.77; N, 9.48; S, 14.09.
2-Cyanomethylidene-N-(4-ethoxyphenyl)-4-oxo-3-thiazoli-
dineacetamide (7c)
Mp 230 °C (DMF–H2O); yield: 1.8 g (92%).
Anal. Calcd for C19H17ClN2O4S: C, 56.37; H, 4.23; N, 6.92; S, 7.92;
Cl, 8.76. Found: C, 56.36; H, 4.19; N, 6.84; S, 8.03; Cl, 8.61.
1H NMR: = 1.34 (t, 3 H, J = 7.2 Hz, CH3), 3.97 (q, 2 H, J = 7.2
Hz, OCH2), 4.15 (s, 2 H, SCH2), 4.42 (s, 2 H, NCH2), 5.21 (s, 1 H,
CH), 6.80 (d, 2 H, J = 9.0 Hz, R), 7.42 (d, 2 H, J = 9.0 Hz, R),
10.04 (s, 1 H, NH).
13C NMR: = 14.7 (CH3), 31.6 (5-C), 45.5 (NCH2), 63.0 (OCH2),
66.5 (CHX), 114.3 (3,5-CR), 116.6 (CN), 120.9 (2,6-CR), 135.0 (1-
CR), 152.4 (2-C), 154.8 (4-CR), 167.6 (CONH), 171.8 (4-C).
5-(4-Chlorobenzoyl)-2-(dimethylamino)methylidene-2,3-dihy-
dro-3-oxopyrrolo[2,1-b]thiazole-7-carboxylic Acid Methyl Es-
ter (11b)
Mp 198 °C (DMF–H2O); yield: 0.9 g (77%).
1H NMR: = 3.26 [s, 6 H, N(CH3)2], 3.78 (s, 3 H, OCH3), 7.18 (s,
1 H, 6-H), 7.56 (d, 2 H, J = 9.0 Hz, Ar), 7.78 (d, 2 H, J = 9.0 Hz,
Ar), 7.91 (s, 1 H, =CHN).
Anal. Calcd for C15H15N3O3S: C, 56.77; H, 4.76; N, 13.24; S, 10.10.
Found: C, 56.81; H, 4.59; N, 13.19; S, 10.13.
13C NMR: = 40.9 [N(CH3)2], 51.6 (OCH3), 87.9 (2-C), 106.9 (7-
C), 124.4 (6-C), 127.1 (1-CAr), 128.5 (3,5-CAr), 129.7 (2,6-CAr),
137.6 (5-C), 140.1 (4-CAr), 141.2 (7a-C), 151.3 (=CHN), 160.0 (3-
C), 163.1 (7-CO), 183.5 (5-CO).
2-(2-Benzothiazolylmethylidene)-N-(4-ethoxyphenyl)-4-oxo-3-
thiazolidineacetamide (7d)
Mp 254 °C (DMF–H2O); yield: 2.3 g (90%).
1H NMR: = 1.33 (t, 3 H, J = 6.9, CH3), 3.98 (q, 4 H, J = 6.9 Hz,
OCH2), 4.05 (s, 2 H, SCH2), 4.57 (s, 2 H, NCH2), 6.53 (s, 1 H, CH),
6.82 (d, 2 H, J = 8.7 Hz, R), 7.29 (t, 1 H, J = 8.1 Hz, X), 7.45 (m,
3 H, R, X), 7.83 (d, 1 H, J = 8.1 Hz, X), 7.91 (d, 1 H, J = 8.1 Hz,
X), 10.09 (s, 1 H, NH).
13C NMR: = 14.6 (CH3), 31.9 (5-C), 45.5 (NCH2), 63.0 (OCH2),
93.7 (CHX), 114.4 (3,5-CR), 120.6 (2,6-CR), 121.2 (7-CX), 121.7 (4-
CX), 123.9 (6-CX), 126.2 (5-CX), 131.5 (1-CR), 133.3 (7a-CX), 148.8
(2-C), 153.2 (3a-CX), 154.6 (4-CR), 163.5 (2-CX), 163.9 (CONH),
172.1 (4-C).
Anal. Calcd for C18H15ClN2O4S: C, 55.32; H, 3.87; N, 7.17; S, 8.20;
Cl, 9.07. Found: C, 55.28; H, 3.98; N, 7.19; S, 8.11; Cl, 9.16.
5-(4-Chlorobenzoyl)-2-(dimethylamino)methylidene-2,3-dihy-
dro-3-oxopyrrolo[2,1-b]thiazole-7-carbonitrile (11c)
Mp 130 °C (DMF–H2O); yield: 0.7 g (65%).
1H NMR: = 3.27 [s, 6 H, N(CH3)2], 7.45 (s, 1 H, 6-H), 7.56 (d, 2
H, J = 9.0 Hz, Ar), 7.79 (d, 2 H, J = 9.0 Hz, Ar), 7.97 (s, 1
H, =CHN).
13C NMR: = 41.1 [N(CH3)2], 77.6 (7-C), 92.8 (2-C), 108.0 (CN),
123.4 (6-C), 126.1 (3,5-CAr), 131.7 (2,6-CAr), 135.5 (5-C), 136.2 (1-
Synthesis 2003, No. 17, 2632–2638 © Thieme Stuttgart · New York

PAPER
Synthesis of Pyrrolo[2,1-b]thiazoles
2637
CAr), 140.3 (4-CAr), 144.0 (7a-C), 150.6 (=CHN), 157.5 (3-C),
180.6 (5-CO).
Anal. Calcd for C17H12BrN3O2S: C, 50.76; H, 3.01; N, 10.45; S,
7.97; Br, 19.86. Found: C, 50.69; H, 3.06; N, 10.49; S, 8.09; Br,
19.71.
Anal. Calcd for C17H12ClN3O2S: C, 57.06; H, 3.38; N, 11.74; S,
8.96; Cl, 9.91. Found: C, 57.13; H, 3.27; N, 11.71; S, 9.01; Cl, 9.95.
7-(2-Benzothiazolyl)-5-(4-bromobenzoyl)-2-(dimethylamino)me-
thylidenepyrrolo[2,1-b]thiazol-3(2H)-one (12d)
Mp 209 °C (DMF); yield: 1.3 g (87%).
1H NMR: = 3.30 [s, 6 H, N(CH3)2], 7.38 (t, 1 H, J = 6.0 Hz, X),
7.50 (m, 2 H, 6-H, X), 7.74 (m, 4 H, Ar), 7.93 (s, 1 H, =CHN), 7.96
(d, 1 H, J = 6.0 Hz, X), 8.06 (d, 1 H, J = 6.0 Hz, X).
13C NMR: = 41.3 [N(CH3)2], 87.5 (2-C), 106.0 (7-C), 120.5 (6-C),
123.3 (7-CX) 124.0 (6-CX), 124.2 (5-CX), 125.0 (4-CX), 128.5 (4-
CAr), 128.9 (5-C), 129.0 (3,5-CAr), 130.7 (2,6-CAr), 132.6 (7a-CX),
136.5 (3a-CX), 137.5 (1-CAr), 149.2 (=CHN), 156.4 (2-CX), 159.2
(7a-C), 160.6 (3-C), 182.6 (5-CO).
7-(2-Benzothiazolyl)-5-(4-chlorobenzoyl)-2-(dimethylamino)me-
thylidenepyrrolo[2,1-b]thiazol-3(2H)-one (11d)
Mp 165 °C (DMF); yield: 1.2 g (86%).
1H NMR: = 3.27 [s, 6 H, N(CH3)2], 7.43 (t, 1 H, J = 8.0 Hz, X),
7.54 (t, 1 H, J = 8.0 Hz, X), 7.59 (s, 1 H, 6-H), 7.63 (d, 2 H, J = 8.4
Hz, Ar), 7.88 (d, 2 H, J = 8.4 Hz, Ar), 7.99 (s, 1 H, =CHN), 8.01 (d,
1 H, J = 8.0 Hz, X), 8.13 (d, 1 H, J = 8.0 Hz, X).
13C NMR: = 40.2 [N(CH3)2], 87.2 (2-C), 110.2 (7-C), 121.8 (7-
CX) 122.2 (4-CX), 123.7 (6-C), 124.6 (6-CX), 126.5 (5-CX), 128.2
(5-C), 128.5 (3,5-CAr), 130.8 (2,6-CAr), 133.4 (7a-CX), 134.8 (3a-
CX), 136.8 (4-CAr), 137.4 (1-CAr), 150.5 (=CHN), 153.3 (2-CX),
160.0 (7a-C), 160.2 (3-C), 181.4 (5-CO).
Anal. Calcd for C23H16BrN3O2S2: C, 54.12; H, 3.16; N, 8.23; S,
12.56; Br, 15.65. Found: C, 54.08; H, 3.13; N, 8.19; S, 12.64; Br,
15.44.
Anal. Calcd for C23H16ClN3O2S2: C, 59.28; H, 3.46; N, 9.02; S,
13.76; Cl, 7.61. Found: C, 59.34; H, 3.44; N, 8.94; S, 13.84; Cl,
7.58.
2-(Dimethylamino)methylidene-2,3-dihydro-5-(4-nitrobenz-
oyl)-3-oxopyrrolo[2,1-b]thiazole-7-carbonitrile (13c)
Mp 237 °C (DMF–H2O); yield: 0.65 g (59%).
1H NMR: = 3.26 [s, 6 H, N(CH3)2], 7.55 (s, 1 H, 6-H), 7.97 (s, 1
H, =CHN), 7.99 (d, 2 H, J = 8.7 Hz, Ar), 8.30 (d, 2 H, J = 8.7 Hz,
Ar).
5-(4-Chlorobenzoyl)-2-(dimethylamino)methylidene-7-[4-(4-
methylphenyl)-2-thiazolyl]pyrrolo[2,1-b]thiazol-3(2H)-one
(11e)
Mp >300 °C (DMF); yield: 1.3 g (87%).
1H NMR: = 2.41 (s, 3 H, CH3), 3.29 [s, 6 H, N(CH3)2], 7.37 (d, 2
H, J = 7.6 Hz, X), 7.61 (m, 3 H, 6-H, Ar), 7.82 (m, 4 H, Ar, X), 7.95
(s, 1 H, =CHN), 8.25 (s, 1 H, 5-HX).
13C NMR: = 21.1 (CH3), 40.2 [N(CH3)2], 87.6 (2-C), 102.3 (7-C),
118.3 (6-C), 124.2 (2,6-Ctol), 124.9 (5-CX), 126.2 (4-CX), 126.5
(3,5-CAr), 128.1 (5-C), 128.6 (3,5-Ctol), 129.1 (4-CAr), 132.0 (2,6-
CAr), 135.5 (1-Ctol), 137.4 (1-CAr), 139.0 (4-Ctol), 150.6 (=CHN),
156.7 (2-CX), 159.4 (7a-C), 160.5 (3-C), 183.0 (5-CO).
13C NMR: = 42.1 [N(CH3)2], 74.3 (7-C), 95.7 (2-C), 108.3 (CN),
119.0 (6-C), 129.0 (3,5-CAr), 132.9 (2,6-CAr), 139.3 (5-C), 141.6 (1-
CAr), 147.0 (7a-C), 149.6 (4-CAr), 151.6 (=CHN), 154.3 (3-C),
182.6 (5-CO).
Anal. Calcd for C17H12N4O4S: C, 55.43; H, 3.28; N, 15.21; S, 8.70.
Found: C, 55.49; H, 3.22; N, 15.13; S, 8.76.
7-(2-Benzothiazolyl)-2-(dimethylamino)methylidene-5-(4-ni-
trobenzoyl)pyrrolo[2,1-b]thiazol-3(2H)-one (13d)
Mp 220 °C (dec.) (DMF); yield: 1.1 g (77%).
1H NMR: = 3.28 [s, 6 H, N(CH3)2], 7.38 (t, 1 H, J = 7.5 Hz, X),
7.49 (t, 1 H, J = 7.5 Hz, X), 7.58 (s, 1 H, 6-H), 7.91 (s, 1 H, =CHN),
7.95 (d, 1 H, J = 7.5 Hz, X), 8.02 (d, 2 H, J = 9.0 Hz, Ar), 8.07 (d,
1 H, J = 7.5 Hz, X), 8.31 (d, 2 H, J = 9.0 Hz, Ar).
13C NMR: = 41.3 [N(CH3)2], 88.6 (2-C), 104.9 (7-C), 119.7 (6-C),
123.1 (7-CX) 124.4 (5-CX), 124.9 (6-CX), 125.6 (4-CX), 126.8 (5-C),
129.5 (3,5-CAr), 131.7 (2,6-CAr), 132.5 (7a-CX), 138.1 (3a-CX),
140.2 (1-CAr), 148.5 (=CHN), 148.6 (4-CAr), 153.9 (2-CX), 163.1
(7a-C), 164.4 (3-C), 182.9 (5-CO).
Anal. Calcd for C26H20ClN3O2S2: C, 61.71; H, 3.98; N, 8.30; S,
12.67; Cl, 7.01. Found: C, 61.66; H, 4.06; N, 8.27; S, 12.62; Cl,
7.15.
5-(4-Bromobenzoyl)-2-(dimethylamino)methylidene-2,3-dihy-
dro-3-oxopyrrolo[2,1-b]thiazole-7-carboxylic Acid Ethyl Ester
(12a)
Mp 185 °C (DMF); yield: 1.0 g (74%).
1H NMR: = 1.27 (t, 3 H, J = 7.5 Hz, CH3), 3.26 [s, 6 H, N(CH3)2],
4.24 (q, 2 H, J = 7.5 Hz, CH2), 7.17 (s, 1 H, 6-H), 7.71 (m, 4 H, Ar),
7.90 (s, 1 H, =CHN).
13C NMR: = 14.4 (CH3), 41.3 [N(CH3)2], 59.2 (OCH2), 89.9 (2-
C), 105.6 (7-C), 122.8 (6-C), 127.4 (3,5-CAr), 127.5 (4-CAr), 128.0
(1-CAr), 130.1 (2,6-CAr), 140.8 (5-C), 141.5 (7a-C), 149.2 (=CHN),
157.0 (3-C), 162.3 (7-CO), 184.8 (5-CO).
Anal. Calcd for C23H16N4O4S2: C, 57.97; H, 3.38; N, 11.76; S,
13.46. Found: C, 57.94; H, 3.47; N, 11.71; S, 13.49.
2-(Dimethylamino)methylidene-7-[4-(4-methylphenyl)-2-thia-
zolyl]-5-(4-nitrobenzoyl)pyrrolo[2,1-b]thiazol-3(2H)-one (13e)
Mp 160 °C (dec.) (DMF); yield: 1.1 g (71%).
1H NMR: = 2.35 (s, 3 H, CH3), 3.27 [s, 6 H, N(CH3)2], 7.28 (d, 2
H, J = 9.0 Hz, X), 7.57 (s, 1 H, 6-H), 7.92 (m, 4 H, X, =CHN, 5-
HX), 8.02 (d, 2 H, J = 6.0 Hz, Ar), 8.33 (d, 2 H, J = 6.0 Hz, Ar).
13C NMR: = 21.8 (CH3), 40.9 [N(CH3)2], 85.6 (2-C), 102.2 (7-C),
118.6 (6-C), 124.2 (2,6-Ctol), 126.0 (3,5-CAr), 126.9 (5-CX), 128.1
(3,5-Ctol), 128.5 (4-CX), 129.8 (5-C), 131.7 (2,6-CAr), 135.7 (1-Ctol),
139.0 (4-Ctol), 141.1 (1-CAr), 148.6 (4-CAr), 153.4 (=CHN), 156.4
(7a-C), 159.6 (2-CX), 162.6 (3-C), 183.0 (5-CO).
Anal. Calcd for C19H17BrN2O4S: C, 50.79; H, 3.81; N, 6.23; S, 7.14;
Br, 17.78. Found: C, 50.62; H, 3.88; N, 6.22; S, 7.11; Br, 17.92.
5-(4-Bromobenzoyl)-2-(dimethylamino)methylidene-2,3-dihy-
dro-3-oxopyrrolo[2,1-b]thiazole-7-carbonitrile (12c)
Mp 179 °C (DMF); yield: 1.1 g (91%).
1H NMR: = 3.26 [s, 6 H, N(CH3)2], 7.45 (s, 1 H, 6-H), 7.71 (m, 4
H, Ar), 7.97 (s, 1 H, =CHN).
13C NMR: = 42.9 [N(CH3)29, 75.3 (7-C), 95.3 (2-C), 108.0 (CN),
120.0 (6-C), 127.1 (4-CAr), 129.3 (3,5-CAr), 133.3 (2,6-CAr), 137.1
(1-CAr), 139.1 (5-C), 146.4 (7a-C), 150.2 (=CHN), 154.2 (3-C),
182.2 (5-CO).
Anal. Calcd for C26H20N4O4S2: C, 60.45; H, 3.90; N, 10.85; S,
12.41. Found: C, 60.38; H, 3.92; N, 10.71; S, 12.46.
Synthesis 2003, No. 17, 2632–2638 © Thieme Stuttgart · New York

2638
A. V. Tverdokhlebov et al.
PAPER
5-Benzoyl-2-(dimethylamino)methylidene-2,3-dihydro-3-ox-
opyrrolo[2,1-b]thiazole-7-carboxylic Acid Methyl Ester (14b)
Mp 126 °C (DMF–H2O); yield: 0.9 g (84%).
Hosokami, T.; Kurebayashi, Y.; Ikeda, T.; Shimoto, Y.; Ide,
S.; Honda, Y.; Suzuki, N. Chem. Pharm. Bull. 1995, 43,
1125.
(3) (a) Padwa, A.; Chiacchio, U.; Venkatramanan, M. K. J.
Chem. Soc., Chem. Commun. 1985, 1108. (b) Tsuge, O.;
Kanemasa, S.; Takenaka, S. Bull. Chem. Soc. Jpn. 1985,
3137. (c) Tsuge, O.; Kanemasa, S.; Takenaka, S.
Heterocycles 1983, 20, 1907. (d) Kraus, G. A.; Nagy, J. O.
Tetrahedron 1985, 41, 3537. (e) Kraus, G. A.; Nagy, J. O.
Tetrahedron Lett. 1981, 22, 2727.
(4) (a) Abe, N.; Nishiwaki, T.; Komoto, N. Bull. Chem. Soc.
Jpn. 1980, 53, 3308. (b) Abe, N.; Nishiwaki, T.; Komoto, N.
Chem. Lett. 1980, 223.
1H NMR: = 3.27 [s, 6 H, N(CH3)2], 3.78 (s, 3 H, OCH3), 7.12 (s,
1 H, 6-H), 7.52 (t, 2 H, J = 7.5 Hz, Ar), 7.64 (t, 1 H, J = 7.5 Hz,
Ar), 7.79 (d, 2 H, J = 7.5 Hz, Ar), 7.91 (s, 1 H, =CHN).
13C NMR: = 40.0 [N(CH3)2], 51.7 (OCH3), 87.0 (2-C), 106.6 (7-
C), 124.7 (6-C), 128.3 (1-CAr), 128.7 (2,6-CAr), 129.3 (3,5-CAr),
133.0 (4-CAr), 137.8 (5-C), 140.4 (7a-C), 150.6 (=CHN), 160.2 (3-
C), 162.8 (7-CO), 182.5 (5-CO).
Anal. Calcd for C18H16N2O4S: C, 60.66; H, 4.53; N, 7.86; S, 9.00.
Found: C, 60.59; H, 4.59; N, 7.70; S, 8.92.
(5) (a) Farbe, J. L.; Farge, D.; James, C.; Lave, D. Spanish
Patent 147317, 1985; Chem. Abstr. 1985, 103, 160500.
(b) Lalezari, I.; Schwartz, E. L. J. Med. Chem. 1988, 31,
1427. (c) Bacque, E.; Bashiardes, G.; Dereu, N.; Nemecek,
C. PCT Int. Appl. WO 9700073, 1997; Chem. Abstr. 1997,
126, 157394.
(6) (a) Volovenko, Yu. M.; Volovnenko, T. A.; Tverdokhlebov,
A. V. Chem. Heterocycl. Compd. (Engl. Transl.) 2001, 37,
1011. (b) Volovenko, Yu. M.; Tverdokhlebov, A. V.;
Gorulya, A. P.; Shishkina, S. V.; Zubatyuk, R. I.; Shishkin,
O. V. Eur. J. Org. Chem. 2002, 4, 663.
(7) (a) Meyer, H. Liebigs Ann. Chem. 1981, 1534. (b) Gupta,
A. K.; Ila, H.; Junjappa, H. Synthesis 1988, 284. (c) Gupta,
A. K.; Chakrasali, R. T.; Ila, H.; Junjappa, H. Synthesis
1989, 141. (d) El-Shafei, A. K.; El-Sayed, A. M.; Abdel-
Ghany, H. Gazz. Chim. Ital. 1990, 120, 193. (e) Schafer,
H.; Gewald, K. J. Prakt. Chem. 1974, 316, 684.
5-(Biphenyl-4-ylcarbonyl)-2-(dimethylamino)methylidene-2,3-
dihydro-3-oxopyrrolo[2,1-b]thiazole-7-carboxylic Acid Ethyl
Ester (15a)
Mp 192 °C (DMF); yield: 1.2 g (89%).
1H NMR: = 1.28 (t, 3 H, J = 7.0 Hz, CH3), 3.26 [s, 6 H, N(CH3)2],
4.25 (q, 2 H, J = 7.0 Hz, CH2), 7.16 (s, 1 H, 6-H), 7.43 (t, 1 H,
J = 7.5 Hz, Ar), 7.51 (t, 2 H, J = 7.5 Hz, Ar), 7.75 (d, 2 H, J = 7.5
Hz, Ar), 7.82 (2 H, d, J = 8.4 Hz, Ar), 7.90 (m, 3 H, Ar, =CHN).
13C NMR: = 14.9 (CH3), 41.3 [N(CH3)2], 59.0 (OCH2), 89.9 (2-
C), 104.6 (7-C), 121.4 (6-C), 125.3 (3,5-CAr), 125.5 (2 ,6 -CAr),
127.8 (4 -CAr), 128.5 (3 ,5 -CAr), 128.6 (1-CAr), 129.6 (2,6-CAr),
131.7 (4-CAr), 141.2 (5-C), 143.2 (7a-C), 143.3 (1 -CAr), 146.3
(=CHN), 156.3 (3-C), 162.4 (7-CO), 183.5 (5-CO).
Anal. Calcd for C25H22N2O4S: C, 67.25; H, 4.97; N, 6.27; S, 7.18.
Found: C, 67.32; H, 5.06; N, 6.23; S, 7.16.
(8) (a) Elnagdi, M. H.; Elmoghayar, R. M. H.; Hammam, A. E.
F. G.; Khallaf, S. A. J. Heterocycl. Chem. 1979, 16, 1541.
(b) Satzinger, G. Liebigs Ann. Chem. 1978, 473.
(c) Satzinger, G. Liebigs Ann. Chem. 1963, 151. (d) Isidor,
J. L.; McKee, R. L. J. Org. Chem. 1973, 38, 3615.
(e) Elnagdi, M. H.; Khalifa, M. A. E.; Ibraheim, M. K. A.;
Elmoghayar, R. M. H. J. Heterocycl. Chem. 1981, 18, 877.
(f) El-Shafei, A. K.; El-Sayed, A. M.; Soliman, A. M. Gazz.
Chim. Ital. 1987, 117, 385.
(9) (a) Knoll, A.; Paetzel, M.; Liebscher, J. German Patent
(East) 262863, 1988; Chem. Abstr. 1989, 111, 153789.
(b) Knoll, A.; Liebscher, J. Z. Chem. 1988, 28, 214.
(10) (a) Coulton, S.; Southgate, R. J. Chem. Soc., Perkin Trans. 1
1992, 961. (b) Cheeseman, G. W. H.; Hawi, A. A. J.
Heterocycl. Chem. 1983, 20, 591.
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Synthesis 2003, No. 17, 2632–2638 © Thieme Stuttgart · New York