Microwave assisted one-pot synthesis of pyrrolo[2,1-b]thiazol-6-ones from α-Aroyl ketene-N,S-acetals

Article abstract of DOI:10.1002/jhet.334

(Chemical Equation Presented) α-Aroyl ketene-N,S-acetals 3 prepared by the reaction of b-oxothioamides 1 with phenacyl bromides 2, underwent sequential cyclizations under microwave irradiation to afford pyrrolo[2,1-b]thiazol-6-ones 6 in good yields. A double cyclization takes place regioselectively in one pot and variety of functionalized pyrrolo[2,1-b]thiazol- 6-ones were prepared by this protocol. The mode of cyclization under microwave condition is different from conventional heating.

Full text of DOI:10.1002/jhet.334

430
Microwave Assisted One-Pot Synthesis of Pyrrolo[2,1-b]thiazol-6-
ones from a-Aroyl Ketene-N,S-acetals
Vol 47
Paulson Mathew,a* M. Prasidha,a and C. V. Asokanb
aDepartment of Chemistry, St. Thomas’ College, Thrissur, Kerala 680001, India
bSchool of Chemical Sciences, Mahatma Gandhi University, Kottayam, Kerala 686560, India
*E-mail: paulson.org@gmail.com
Received August 31, 2009
DOI 10.1002/jhet.334
Published online 4 March 2010 in Wiley InterScience (www.interscience.wiley.com).
This article is dedicated to our research guide Dr. C. V. Asokan who died on February 3, 2007.
a-Aroyl ketene-N,S-acetals 3 prepared by the reaction of b-oxothioamides 1 with phenacyl bromides
2, underwent sequential cyclizations under microwave irradiation to afford pyrrolo[2,1-b]thiazol-6-ones
6 in good yields. A double cyclization takes place regioselectively in one pot and variety of functional-
ized pyrrolo[2,1-b]thiazol-6-ones were prepared by this protocol. The mode of cyclization under micro-
wave condition is different from conventional heating.
J. Heterocyclic Chem., 47, 430 (2010).
INTRODUCTION
Direct alkylation of thioamides using alkyl halide
affords ketene-N,S-acetals which is widely used as a
synthon in heterocyclic synthesis [14]. Recently we
have explored the synthetic potential of a-aroyl ketene-
N,S-acetals prepared by the alkylation of b-oxothioa-
mides 1 for the synthesis of functionalised pyrroles [15].
a-Aroyl ketene-N,S-acetals were previously prepared in
our laboratory as an intermediate for the synthesis of
functionalized thiophenes via alkylation of thioamides
using 1,2-bielectrophiles in presence of base [16].
The structural diversity and biological importance
exhibited by pyrrolothiazoles have made them attractive
targets for synthesis [1]. Pyrrolo[2,1-b]thiazoles are
known to display a wide range of biological activities
such as antileukemic [2], platelet-activating factor antag-
onistic [3] and for prevention and treatment of various
liver diseases [4]. The common strategy for their synthe-
ses involves ring annelation of appropriately functional-
ized pyrroles [5,6] or thiazoles [7,8]. Other approaches
are based on the cycloaddition reactions of thiazolium
ylides [9], imidazo[2,1-b]thiazoles [10] or mesoionic
thiazolo[3,2-c]oxazoles [2] with dimethyl acetylenedi-
carboxylate and related unsaturated acid derivatives.
Recently, thiazadiene, an unsymmetrical polyhetropo-
lyene, on sequential reaction with a-carbonyl bromide
was converted into pyrrolo[2,1-b]thiazoles [11]. Ring
contraction strategy is also used for constructing this
heterobicyclic system [12]. All these reported methods
needed multistep reaction sequences. Recently, micro-
wave-assisted organic synthesis has attracted consider-
able attention due to enhanced reaction rates, high
yields, improved selectivity, and cleaner products [13].
Herein, we report an efficient, microwave assisted, and
environmentally benign one pot method for the prepara-
tion of pyrrolo[2,1-b]thiazol-6-ones 6 from easily acces-
sible a-aroyl ketene-N,S-acetals 3. To the best of our
knowledge, this is the first report on the direct transfor-
mation of an open chain system into pyrrolo[2,1-b]thia-
zole derivative using a one pot strategy.
RESULTS AND DISCUSSION
Initially, alkylation of thioamide 1 with one equiv. of
a 1,2-bielectrophile—phenacyl bromide in the presence
of K2CO3 (2 equiv.) as the base in acetone at room tem-
perature was carried out expecting monoalkylation at
sulphur followed by in situ cyclization to form thiazole
4, which could be further transformed into the pyrrolo-
thiazoles. However, we isolated only the monoalkylated
a-aroyl ketene-N,S-acetals 3 in nearly quantitative yields
(Scheme 1, Table 1). The unexpected complex pattern
1
of peaks observed in the H NMR (360 MHz) spectrum
of 3 is apparently due to the diastereotopic nature of the
methylene protons. For example, in 3a, ethyl moiety
showed a triplet at d 1.27 and two sets of doublets each
at d 3.40 and 3.50 (J ¼ 12). Another doublet of doublet
appeared at 3.79 (1H, J ¼ 12 Hz) and 4.08 (1H, J ¼ 12
Hz) due to SCH2 moiety. The NCH2 moiety showed a
C
V
2010 HeteroCorporation

March 2010
Microwave Assisted One-Pot Synthesis of Pyrrolo[2,1-b]thiazol-6-ones from
a-Aroyl Ketene-N,S-acetals
431
Scheme 1
multiplet at d 4.18–4.26 ppm. By recording the 1H
NMR spectrum at higher frequency (500 MHz), we fur-
ther confirmed these sets of peaks as doublet of doublet
rather than peaks arising from the possible geometrical
isomeric forms.
Since the thiazole 4 containing structural units that
can be easily transformed into pyrrolo[2,1-b]thiazoles,
we attempted their pyrrole ring annulation studies. Simi-
lar cyclization has been previously reported by our
group for the synthesis of pyrroles from ketene-N,S-ace-
tals using Vilsmeier Haack reagent (POCl3/DMF) [15].
Tverdokhlebov et al. used the same reagent for the syn-
thesis of pyrrolo[2,1-b]thiazoles from thiazoles [17].
Attempts using base catalysts or Vilsmeier Haack rea-
gent failed to afford pyrrolothiazoles. However, the thia-
zole 4a or 4b after heating under reflux in acetic acid
for a period of 15 h, we observed the formation of pyr-
rolo[2,1-b]thiazoles 5a and 5b in 48% and 42% yields
respectively (Scheme 1). To our surprise, other thiazoles
(4c–4f) even after refluxing in acetic acid for 24 h, it
was possible to isolate only the unreacted starting mate-
rial. Failure of the above cyclization was apparently due
to the unfavorable orientation of the aroyl moiety in the
thiazole 4.
Next, taking 3a as a model substrate, its cyclization
to thiazole 4a was attempted. Initial experiments using
K2CO3 as the base in acetone under reflux conditions
failed to afford thiazole. Use of a strong base like KOH
in ethanol or NaH in DMF afforded only intractable
mixture of products. Further studies using acid catalysts
showed that the ketene-N,S-acetals 3 can be easily trans-
formed into thiazoles 4. Thus, a solution of the ketene-
N,S-acetal 3a in acetic acid was heated at 70ꢀC for 4 h;
the thiazole 4a was formed quantitatively. Using a simi-
lar protocol the thiazole 4b was prepared (Table 2).
Alternatively, when the alkylation of the thioamide 1a
was attempted in the presence of excess of K2CO3 (8
equiv.) in DMF, thiazole 4a was formed in good yields.
The same strategy was used for the preparation of thia-
zoles 4b–f (Table 2).
The observation that the N,S-acetal 3a underwent fac-
ile cyclization in presence of acetic acid prompted us to
irradiate
a
solution of 3a in acetic acid under
Table 1
Table 2
Ketene-N,S-acetals 3 prepared from thioamide 1.
Thiazoles 4 prepared from thioamide 1 or from ketene-N,S-acetal 3.
Product
R1
R2
Yield (%)
Product
R1
R2
Yield (%)
3a
3b
3c
3d
3e
3f
CH3
OCH3
H
Br
OCH3
Br
H
Cl
Cl
Cl
H
92
88
92
94
85
94
96
4a
4b
4c
4d
4e
4f
H
Br
Cl
Cl
H
H
CH3
H
88
87
85
86
80
82
H
H
OCH3
H
CH3
CH3
3g
H
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

432
P. Mathew, M. Prasidha, and C. V. Asokan
Vol 47
Table 3
Pyrrolo[2,1-b]thiazol-6-ones 6 prepared from ketene-N,S-acetal 3.
and 13C NMR spectra were recorded on a Bruker DRX-300
MHz or AM-360 MHz spectrometer in CDCl3. Chemical shifts
are expressed in parts per million. Coupling constants J are
given in Hertz. Mass spectra-EIMS, FAB, were obtained on a
Finngen-Mat 312, Jeol SX 102/Da-600 instruments respec-
tively. Elemental analyses were recorded on an elementar vario
EL III analyzer.
General procedure for the synthesis of a-aroyl ketene-
N,S-acetals (3). A suspension of the thioamide 1 (10 mmol)
and anhyd K2CO3 (20 mmol) in dry acetone (30 mL) was
refluxed with stirring for 30 min. The mixture was cooled and
phenacyl bromide 2 (10 mmol) was added followed by stirring
at room temperature for 4 h. When the reaction was completed
(TLC), the mixture was poured into ice-cold water and
extracted using CH2Cl2 (2 ꢁ 50 mL). The organic layer was
washed with water (2 ꢁ 100 mL), dried using anhyd Na2SO4
and evaporated. The crude product thus obtained was purified
by column chromatography over silica gel using hexane: ethyl
acetate (7 : 3) as eluent afforded the a-aroyl ketene-N,S-acetals
3a–g (Table 1).
Ethyl[3-(4-methylphenyl)-3-oxo-1-(2-oxo-2-phenyl-ethylsul-
fanyl)-propenylamino]acetate (3a). White solid; mp 143–
145ꢀC. 1H NMR (360 MHz, CDCl3): d 1.27 (t, 3H, J ¼ 7.2
Hz, CH2CH3), 2.39 (s, 3H, ArCH3), 3.40 (1H, J ¼ 12 Hz,
CH2CH3), 3.50 (1H, J ¼ 12 Hz, CH2CH3), 3.79 (1H, J ¼ 12
Hz, SCH2), 4.08 (1H, J ¼ 12 Hz, SCH2), 4.18–4.26 (m, 2H,
NCH2), 6.09 (s, 1H, vinylic), 7.21 (d, 2H, J ¼ 8 Hz, 2H,
ArH), 7. 39 (m, 3H, ArH), 7.59 (m, 2H, ArH), 7.77 (d, 2H, J
¼ 8 Hz, ArH) ppm. 13C NMR (90 MHz, CDCl3): d 14.5, 22.2,
48.1, 52.5, 62.3, 97.4, 126.4, 129.3, 129.7, 130.0, 133.7, 135.0,
141.9, 145.8, 156.5, 168.8, 195.9, 196.1. EIMS: m/z (%)
397.16 (Mþ, 12), 379.16 (100), 306.15 (38), 246.14 (45), and
119.1 (70). Anal. Calcd. for C22H23NO4S (397.13): C, 66.48;
H, 5.83; N, 3.52. Found: C, 66.35; H, 5.87; N, 3.58.
Product
R1
R2
Yield (%)
6a
6b
6c
6d
6d
6f
CH3
OCH3
H
OCH3
Br
H
Cl
Cl
H
81
85
82
80
76
84
H
H
H
microwave. Thus, by dissolving 3a in acetic acid fol-
lowed by microwave irradiation for 15 min at 150ꢀC in
a microwave synthesizer, transformation to the corre-
sponding pyrrolo[2,1-b]thiazole 6a was observed in 81%
yield. Using a similar protocol we have prepared other
pyrrolothiazoles (6b–f) in good yields (Table 3). Elec-
tron withdrawing or donating substituents have little
effect on the mode of cyclization or on the overall yield
of the pyrrolothiazoles 6 formed. When we reduced
only the reaction time to 10 min, the reaction was
incomplete and could be possible to isolate a mixture of
the intermediate thiazole 4a and the pyrrolothiazole 6a
in a ratio 1 : 3. In an independent experiment, transfor-
mation of 4a to 6f was observed under microwave heat-
ing. It is interesting to note that the mode of cyclization
during pyrrole ring annelation step in conventional heat-
ing is different from that in microwave conditions.
Thus, under microwave conditions pyrrolothiazoles 6
were formed which is structurally different form the
pyrrolothiazoles 5, formed during conventional heating.
This is apparently due to the fact that under microwave
conditions, the geometry of the exocyclic double bond
present in the initially formed thiazole 4 was affected to
a lesser extend and the ethyl carboxylate functionality
underwent rapid conformational changes favoring the
regioselective formation of pyrrolothiazoles 6. While in
conventional heating the reverse is true leading to the
formation of pyrrolothiazole 5.
Ethyl{1-[2-(4-chlorophenyl-2-oxo-ethylsulfanyl]-3-(4-methoxy-
phenyl)-3-oxo-propenylamino}acetate (3b). White solid; mp 95–
1
97ꢀC. H NMR (360 MHz, CDCl3): d 1.26 (t, 3H, J ¼ 7.2 Hz,
CH2CH3), 3.36 (d, 1H, J ¼ 12 Hz, CH2CH3), 3.43 (1H, J ¼
12 Hz, CH2CH3), 3.85 (d, 1H, J ¼ 18 Hz, SCH2), 3.84 (s, 3H,
ArOCH3), 4.05 (d, 1H, J ¼ 18 Hz, SCH2), 4.16–4.30 (m, 2H,
NCH2), 5.04 (bs, 1H, NH), 6.06 (s, 1H, vinylic), 6.91 (d, 2H,
J ¼ 8 Hz, 2H, ArH), 7. 38 (d, 3H, J ¼ 8Hz, ArH), 7.55 (d,
2H, J ¼ 8 Hz, ArH), 7.86 (d, 2H, J ¼ 8 Hz, ArH) ppm. MS
(FAB): m/z 448 (Mþ þ H). Anal. Calcd. for C22H22ClNO5S
(447.09): C, 58.99; H, 4.95; N, 3.13. Found: C, 58.76; H,
4.90; N, 3.17.
In summary, we have developed a convenient and ef-
ficient one-pot procedure for the synthesis of a variety
of pyrrolo[2,1-b]thiazoles from less expensive as well as
easily accessible ketene-N,S-acetals under microwave
conditions in a regioselective and efficient manner. The
reaction is very fast and the product can be easily sepa-
rated from the reaction medium by dilution using water
followed by filtration.
Ethyl{1-[2-(4-chloro-phenyl-2-oxo-ethylsulfanyl]-3-oxo-3-phe-
1
nyl propenylamino}acetate (3c). White solid. mp 98–100ꢀC. H
NMR (360 MHz, CDCl3): d 1.28 (t, 3H, J ¼ 7.2 Hz,
CH2CH3), 3.39 (d, 1H, J ¼ 10 Hz, CH2CH3), 3.47 (d, 1H, J ¼
10 Hz, CH2CH3), 3.77 (d, 1H, J ¼ 18 Hz, SCH2), 4.07 (d, 1H,
J ¼ 18 Hz, SCH2), 4.15–4.32 (m, 2 H, NCH2), 4.99 (bs, 1H,
NH), 6.10 (s, 1H, vinylic), 7.39–7.45 (m, 3H, ArH), 7. 56 (d, J
¼ 8Hz, 2H, ArH), 7.89 (d, 2H, J ¼ 7 Hz, ArH) ppm. 13C
NMR (90 MHz, CDCl3): d 14.5, 44.8, 48.0, 63.1, 90.6, 96.2,
127.7, 128.5, 128.7, 129.1, 129.4, 131.8, 135.5, 139.3, 139.7,
166.1, 170.7, 187.7 ppm. MS (FAB): m/z 418 (Mþ þ H).
Anal. Calcd. for C21H20ClNO4S (417.08): C, 60.35; H, 4.82;
N, 3.35. Found: C, 60.49; H, 4.91; N, 3.28.
EXPERIMENTAL
Thioamide 1 was prepared as reported [15(b)]. Microwave-
assisted reactions were done in a multimode microwave reac-
tor (Biotage InitiatorTM). Melting points were obtained on a
Buchi-530 melting point apparatus and are uncorrected. 1H
Ethyl{3-(4-bromophenyl)-1-[2-(4-chloro-phenyl)-2-oxo-ethyl-
sulfanyl]-3-oxo propenylamino}acetate (3d). White solid. mp
147–149ꢀC. 1H NMR (360 MHz, CDCl3): d 1.28 (t, 3H, J ¼
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2010
Microwave Assisted One-Pot Synthesis of Pyrrolo[2,1-b]thiazol-6-ones from
a-Aroyl Ketene-N,S-acetals
433
10 Hz, CH2CH3), 3.43 (q, 2H, J ¼ 10 Hz, CH2CH3), 3.78 (d,
1H, J ¼ 18 Hz, SCH2), 4.08 (d, 1H, J ¼ 18 Hz, SCH2), 4.16–
4.32 (m, 2 H, NCH2), 4.99 (bs, 1H, NH), 6.10 (s, 1H, vinylic),
7.40 (d, J ¼ 10 Hz, 2H, ArH), 7.55–7.57 (m, 4 H, ArH), 7.88
(d, 2H, J ¼ 10 Hz, ArH) ppm. 13C NMR (90 MHz, CDCl3): d
14.2, 49.0, 62.4, 95.9, 106.9, 125.1, 128.5, 129.4, 130.7, 131.5,
136.2, 138.3, 139.8, 164.3, 166.9, 181.8, 185.7 ppm. EIMS: m/
z (%) 497.1 (Mþ þ 2, 14), 479.1 (82), 406.1 (48), 324.2 (22),
240.2 (25), 183.1 (82) and 139.1 (100). Anal. Calcd. for
C21H19BrClNO4S (494.99): C, 50.77; H, 3.85; N, 2.82. Found:
C, 50.65; H, 3.89; N, 2.76.
Ethyl[3-(4-methoxyphenyl)-3-oxo-1-(2-oxo-2-phenyl-ethyl-
sulfanyl)-propenylamino]acetate (3e). Pale yellow glass. 1H
NMR (360 MHz, CDCl3): d 1.26 (t, 3H, J ¼ 7.2 Hz,
CH2CH3), 3.38 (d, 1H, J ¼ 14 Hz, CH2CH3), 3.49 (1H, J ¼
14 Hz, CH2CH3), 3.79 (d,1H, J ¼ 18 Hz, SCH2), 3.84 (s, 3H,
ArOCH3 þ 1H, SCH2), 4.06 (d, 1H, J ¼ 18 Hz, SCH2), 4.15–
4.28 (m, 2H, NCH2), 4.50 (bs, 1H, NH), 6.07 (s, 1H, vinylic),
6.92 (d, 2H, J ¼ 9 Hz, 2H, ArH), 7. 41 (m, 3H, ArH), 7.61 (d,
2H, J ¼ 7 Hz, ArH), 7.87 (d, 2H, J ¼ 9 Hz, ArH). 13C NMR
(90 MHz, CDCl3): d 14.1, 44.3, 47.6, 55.3, 62.4, 89.6, 96.1,
113.4, 126.5, 128.7, 129.2, 132.1, 140.3, 162.1, 165.2, 170.3,
186.1, 187.1 ppm. EIMS (CHCl3/CH3CNþHþ): m/z (%) 414.1,
(Mþ þ H 12), 396.2 (100), 366.2 (18), 248.1 (35). Anal.
Calcd. for C22H23NO5S (413.13): C, 63.90; H, 5.61; N, 3.39.
Found: C, 63.82; H, 5.67; N, 3.43.
Ethyl[3-(4-bromophenyl)-3-oxo-1-(2-oxo-2-phenyl-ethylsul-
fanyl) propenylamino]acetate (3f). White solid. mp 98–99ꢀC.
1H NMR (360 MHz, CDCl3): d 1.27 (t, 3H, J ¼ 7.2 Hz,
CH2CH3), 3.43 (d, 1H, J ¼ 10 Hz, CH2CH3), 3.53 (d, 1H, J ¼
10 Hz, CH2CH3), 3.81 (d, 1H, J ¼ 18 Hz, SCH2), 4.08 (d, 1H,
J ¼ 18 Hz, SCH2), 4.20–4.30 (m, 2 H, NCH2), 4.51 (s, 1H,
NH), 6.03 (s, 1H, vinylic), 7.31 (d, 2H, J ¼ 7 Hz, 2H, ArH),
7. 43 (m, 3H, ArH), 7.60 (m, 2H, ArH), 7.82 (d, 2H, J ¼ 7
Hz, ArH) ppm. 13C NMR (90 MHz, CDCl3): d 14.5, 44.8,
53.8, 62.7, 96.8, 126.9, 129.0, 129.3, 130.5, 131.9, 132.5,
138.6, 140.5, 166.9, 170.6, 182.6, 186.2 ppm. MS (FAB): m/z
462 (Mþ þ H). Anal. Calcd. for C21H20BrNO4S (461.03): C,
54.55; H, 4.36; N, 3.03. Found: C, 54.62; H, 4.29; N, 3.06.
Ethyl[3-oxo-1-(2-oxo-2-phenyl-ethylsulfanyl)-3-phenyl-pro-
penylamino]acetate (3g). White solid. mp 118–120ꢀC. 1H
NMR (360 MHz, CDCl3): d 1.29 (t, 3H, J ¼ 7.2 Hz,
CH2CH3), 3.42 (1H, J ¼ 10 Hz, CH2CH3), 3.53 (1H, J ¼ 10
Hz, CH2CH3), 3.81 (1H, J ¼ 18 Hz, SCH2), 4.11 (1H, J ¼ 18
Hz, SCH2), 4.18–4.32 (m, 2 H, NCH2), 4.82 (s, 1H, NH), 6.11
(s, 1H, vinylic), 7.40–7.48 (m, 6H, ArH), 7.61 (d, 2H, ArH),
7.90 (d, 2H, J ¼ 8 Hz, ArH) ppm. 13C NMR (90 MHz,
CDCl3): d 14.5, 44.8, 48.1, 62.9, 90.4, 97.6, 126.9, 127.7,
128.7, 129.3, 129.4, 131.7, 139.8, 140.6, 166.4, 170.8, 187.6
ppm. MS (FAB): m/z 385 (Mþ þ H). Anal. Calcd. for
C21H21NO4S (383.12): C, 65.78; H, 5.52; N, 3.65. Found: C,
65.86; H, 5.59; N, 3.60.
mmol). The mixture was stirred at room temperature for 4 h
then at 100ꢀC for 2 h. It was then cooled, poured into ice-
cold water and extracted using ethyl acetate (2 ꢁ 50 mL).
The organic layer was washed with water (2 ꢁ 100 mL),
dried using anhyd Na2SO4 and evaporated. The crude product
thus obtained was purified by column chromatography over
silica gel using hexane: ethyl acetate (7 : 3) as eluent to give
4a–f (Table 2).
Ethyl 2-{2-[(Z)-oxo(phenyl)ethylidene]-4-phenyl-1,3-thiazol-
3-yl}acetate (4a). Pale yellow needles; mp. 130–131ꢀC. 1H
NMR (300 MHz, CDCl3) d 1.27 (t, 3H, J ¼ 7 Hz, CH2CH3),
4.26 (q, 2H, J ¼ 7 Hz, CH2CH3), 4.50 (s, 1H, NCH2), 6.32 (s,
1H, vinylic), 6.40 (s, 1H, tzol CH), d 7.42 (m, 6H, ArH), d
7.94 (m, 4H, ArH). 13C NMR (75.5 MHz, CDCl3) d 14.1
(CH2CH3), 48.9 (NCH2), 62.2 (CH2CH3), 86.4 (tzol CH),
106.0 (vinylic), 126.8 (C4, tzol CH), 164.0 (C2, tzol), 128.1,
128.9, 129.3, 129.7, 129.9, 130.4, 139.6, 140.9 (ArC), d 167.1
and 183.1 (carbonyl). EIMS: m/z (%) 365 (Mþ, 82), 336 (41),
292 (51), 275 (15), 214 (33), 186 (36), 147 (54), 134 (58), and
105 (100). Anal. Calcd. for C21H19NO3S (365.45): C, 69.02;
H, 5.24; N, 3.83. Found: C, 68.72; H, 5.36; N, 3.57.
Ethyl 2-{2-[(Z)-(4-bromophenyl)(oxo)ethylidene]-4-phenyl-
1,3-thiazol-3-yl}acetate (4b). Pale yellow crystalline solid; mp
1
118–120ꢀC. H NMR (300 MHz, CDCl3) d 1.19 (t, 3H, J ¼ 7
Hz, CH2CH3), 4.20 (q, 2H, J ¼ 7 Hz, CH2CH3), 4.53 (s, 1H,
NCH2), 6.46 (s, 1H, vinylic), 7.19 (s, 1H, tzol CH), 7.30–7.47
(m, 7H, ArH), 7.75 (d, 2H, J ¼ 8 Hz, ArH). 13C NMR (75.5
MHz, CDCl3) d 14.2 (CH2CH3), 49.1 (NCH2), 62.3 (CH2CH3),
86.2 (tzol CH), 106.4 (vinylic), 125.0 (C4, tzol), 164.5 (C2,
tzol), 128.6, 128.3, 129.1, 129.5, 129.9, 131.4, 138.7, and
141.2 (ArC), 167.09 and d 181.82 (carbonyl) ppm. EIMS: m/z
(%) 443 (Mþ, 50), 445 (Mþ þ 2, 51), 411 (32), 260 (21), 216
(22), 185 (100), 157 (74), 134 (74), and 105 (51). Anal. Calcd.
for C21H18BrNO3S (444.34): C, 56.76; H, 4.08; N, 3.15.
Found: C, 56.52; H, 4.16; N, 3.02.
Ethyl 2-{2-[(Z)-(4-chlorophenyl)(oxo)ethylidene]-4-(4-meth-
ylphenyl)-1,3-thiazol-3-yl}acetate (4c). White crystalline solid;
1
mp 148–149ꢀC. H NMR (300 MHz, CDCl3) d 1.27 (t, 3H, J
¼ 7 Hz, CH2CH3), 2.41 (s, 3H, CH3), 4.28 (q, 2H, J ¼ 7.2
Hz, CH2CH3), 4.51 (s, 1H, NH CH2), 6.25 (s, 1H, vinylic),
6.40 (s, 1H, tzol CH), 7.27 (m, 4H, ArH), 7.37 (d, 2H, J ¼ 8
Hz, ArH), 7.86 (d, 2H, J ¼ 8 Hz, ArH). 13C NMR (75.5 MHz,
CDCl3) 14.2 (CH2CH3), 49.1 (NCH2), 62.2 (CH2CH3), 86.3
(tzol CH), 106.0 (vinylic), 126.4 (C4, tzol), 164.5 (C2 tzol),
127.0, 128.4, 129.4, 129.8, 136.4, 138.3, 140.2, 141.3 (ArC),
167.2, and d 181.6 (carbonyl) ppm. EIMS: m/z (%) 415 (Mþ
þ 2, 23), 413 (Mþ, 72), 396 (41), 340 (38), 263 (15), 200
(26), 188 (34) and 139 (100). Anal. Calcd. for C22H20ClNO3S
(413.92): C, 63.84; H, 4.87; N, 3.38. Found: C, 64.08; H,
4.56; N, 3.24.
Ethyl 2-{2-[(Z)-(4-chlorophenyl)(oxo)ethylidene]-4-phenyl-
1,3-thiazol-3-yl}acetate (4d). White crystalline solid; mp 110–
1
General procedure for the synthesis of thiazoles
(4). Method (a): From ketene-N,S-acetal 3: To a suspension of
the ketene-N,S-acetal 3a or 3b (10 mmol) in glacial acetic acid
(10 mL) was heated at 70ꢀC with stirring for 4 h. The reaction
mixture was cooled, diluted with water (50 mL), and the pre-
cipitated product was filtered, recrystallized from ethanol to
afford the thiazole 4a or 4b in moderate yields.
Method (b): From thioamide 1: To a suspension of the thio-
amide 1 (10 mmol) in anhyd DMF (30 mL) was added
K2CO3 (80 mmol) followed by phenacyl bromide 2 (10
111ꢀC. H NMR (300 MHz, CDCl3) d 1.28 (t, 3H, J ¼ 7 Hz,
CH2CH3), 4.27 (q, 2H, J ¼ 7 Hz, CH2CH3), 4.51 (s, 1H,
NCH2), 6.26 (s, 1H, vinylic), 6.44 (s, 1H, tzol CH), 7.37–7.48
(m, 7H, ArH), 7.87 (d, 2H, J ¼ 8 Hz, ArH). 13C NMR (75.5
MHz, CDCl3), 14.2 (CH2CH3), 48.1 (NCH2), 62.3 (CH2CH3),
86.4 (tzol CH), 106.0 (vinylic), 126.8 (C4 tzol) 164.0 (C2
tzol), 127.7, 128.4, 129.2, 129.9, 136.4, 138.3, 141.2 (ArC ),
167.1, and d 181.6 (carbonyl) ppm. EIMS: m/z (%) 401, (Mþ
þ2, 28), 399 (Mþ, 85), 382 (27), 326 (34), 298 (24), 249 (21),
183 (53), 141 (54), 139 (100), and 111 (100). Anal. Calcd. for
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

434
P. Mathew, M. Prasidha, and C. V. Asokan
Vol 47
C21H18ClNO3S (399.89): C, 63.07; H, 4.54; N, 3.50. Found:
C, 62.74; H, 4.78; N, 3.45.
General procedure for the synthesis of pyrrole[2,1-b]thia-
zol-6-ones (6). To a 10 mL glass vial equipped with a small
magnetic stirring bar, a-aroyl ketene-N,S-acetal 2 (1.0 mmol)
was added followed by glacial acetic acid (3 mL). The mixture
was then irradiated in a microwave synthesizer for 15 min at
150ꢀC. After completion of the reaction, the vial was cooled
to 50ꢀC by air jet cooling before it was opened. It was then
diluted with water (20 mL), and the precipitated product was
collected by filtration, washed with cold water and recrystal-
lized from ethyl acetate to afford 6a–f (Table 3).
7-(4-Methyl-benzoyl)-3-phenyl-pyrrolo[2,1-b]thiazol-6-one
(6a). White solid; mp 206–207ꢀC. 1H NMR (360 MHz,
CDCl3): d 2.40 (s, 3H ArCH3), 4.62 (s, 2H, NCH2), 6.80 (s,
1H tzol), 7.53 (s, 7H, ArH), 8.05 (d, 2H, J ¼ 7 Hz, ArH). 13C
NMR (90 MHz, CDCl3): d 22.1, 59.3, 109.2, 127.7, 128.4,
128.9, 129.6, 129.9, 130.8, 135.5, 141.5, 142.7, 179.8, 185.4,
185.9. HRMS: calcd. for C20H15NO2S 333.0823, found
333.0809.
3-(4-Chloro-phenyl)-7-(4-methoxy-benzoyl)pyrrolo[2,1-b]thiazol-
6-one (6b). White solid; mp 211–213ꢀC. 1H NMR (360 MHz,
CDCl3): d 3.84 (s, 3H, OCH3), 4.93 (s, 2H, NCH2), 6.99–7.01
(d, 2H, J ¼ 7.2 Hz, ArH), 7.47 (s, 1H tzol), 7.61–7.63 (d, 2H,
J ¼ 7.2 Hz, ArH), 7.79–7.81 (d, 2H, J ¼ 7.2 Hz, ArH), 8.12–
8.14 (d, 2H, J ¼ 7.2 Hz, ArH). 13C NMR (90 MHz, CDCl3): d
54.8, 59.9, 108.5, 127.6, 129.8, 131.0, 131.5, 135.1, 139.9,
162.4, 178.5, 183.0, 186.2. EIMS (THF/HCOOH): m/z (%)
384.1, Mþ þ H 100), 316.4 (56), 288.4 (78), 244.3 (12), 166.2
(18). Anal. Calcd. for C20H14ClNO3S (383.04): C, 62.58; H,
3.68; N, 3.65. Found: C, 62.69; H, 3.74; N, 3.58.
7-Benzoyl-3-(4-chloro-phenyl)-pyrrolo[2,1-b]thiazol-6-one
(6c). White solid. mp 200–202ꢀC. 1H NMR (360 MHz,
CDCl3): d 4.93 (s, 2H, NCH2), 7.46–7.48 (m, 7H, ArH), 6.50
(s, 1H tzol), 7.61–7.63 (d, 2H, J ¼ 7.2 Hz, ArH), 7.79–7.81
(d, 2H, J ¼ 7.2 Hz, ArH), 7.97–7.99 (d, 2H, J ¼ 7.2 Hz,
ArH). 13C NMR (90 MHz, CDCl3): d 59.7, 108.2, 127.4,
127.8, 128.2, 129.1, 129.4, 129.7, 130.1, 135.0, 138.5, 139.8,
178.0, 184.1, 186.3. MS (FAB): m/z 354 (Mþ þ H). Anal.
Calcd. for C19H12ClNO2S (353.03): C, 64.50; H, 3.42; N,
3.96. Found: C, 64.41; H, 3.38; N, 3.99.
7-(4-Methoxy-benzoyl)-3-phenyl-pyrrolo[2,1-b]thiazol-6-one
(6d). White solid. mp 216–218 ꢀC. 1H NMR (360 MHz,
CDCl3): d 3.78 (s, 3H, OCH3), 4.88 (s, 2H, NCH2), 6.93–6.95
(d, 2H, J ¼ 7.2 Hz, ArH), 7.36 (s, 1H tzol), 7.47 (s, 3H, ArH),
7.70 (s, 2H, ArH), 8.07–8.09 (d, 2H, J ¼ 7.2 Hz, ArH). 13C
NMR (90 MHz, CDCl3): d 55.7, 59.7, 108.3, 127.9, 128.9,
129.3, 129.6, 130.9, 131.2, 131.4, 140.9, 162.2, 178.3, 182.8,
186.1. MS (FAB): m/z 350 (Mþ þ H). Anal. Calcd. for
C20H15NO3S (349.08): C, 68.75; H, 4.33; N, 4.01. Found: C,
68.62; H, 4.38; N, 4.07.
7-(4-Bromo-benzoyl)-3-phenyl-pyrrolo[2,1-b]thiazol-6-one
(6e). White solid; mp 222–224ꢀC. 1H NMR (360 MHz,
CDCl3): d 4.63 (s, 2H, NCH2), 6.84 (s, 1H tzol), 7.54–7.60
(m, 7H, ArH), 8.04 (d, 2H, J ¼ 7.2 Hz, ArH). 13C NMR (90
MHz, CDCl3): d 59.3, 109.2, 109.4, 126.9, 127.8, 128.3,
129.9, 129.9, 130.9, 131.4, 136.9, 141.6, 179.9, 184.6, 185.4.
MS (FAB): m/z 398 (Mþ þ H), 400 (Mþ þ H þ 2). Anal.
Calcd. for C19H12BrNO2S (396.98): C, 57.30; H, 3.04; N,
3.52. Found: C, 57.18; H, 3.10; N, 3.55.
Ethyl
2-{2-[(Z)-(4-methoxyphenyl)(oxo)ethylidene]-4-(4-
methylphenyl)-1,3-thiazol-3-yl}acetate (4e). Pale yellow glass.
1H NMR (300 MHz, CDCl3) d 1.28 (t, 3H, J ¼ 7 Hz,
CH2CH3), 2.17 (s, 3H, CH3), 4.27 (q, 2H, J ¼ 7 Hz,
CH2CH3), 4.69 (s, 1H, NCH2), 6.46 ppm (s, 1H, vinylic), 6.48
ppm (s, 1H, tzol CH), 6.77 (d, 2H, J ¼ 8 Hz, ArH), 6.90 (d,
2H, J ¼ 8 Hz, ArH), 7.04 (d, 2H, J ¼ 8 Hz, ArH), 7.28 (d,
2H, J ¼ 8 Hz, ArH). 13C NMR (75.5 MHz, CDCl3) 14.2
(CH2CH3), 21.3 (CH3), 49.1 (NCH2), 55.3 (OCH3), 62.2
(CH2CH3), 86.1 (tzol CH), 105.5 (vinylic) 127.3 (C4 tzol),
161.6 (C2 tzol ), 113.5, 128.8, 129.4, 129.7, 132.7, 139.9,
140.9, and 163.8 (ArC), 167.4 and 182.5 (carbonyl) ppm.
EIMS: m/z (%) 409 (Mþ, 78), 336 (32), 306 (15), 228 (25),
200 (16), 172 (11), 135 (100), and 121 (92). Anal. Calcd. for
C23H23NO4S (409.50): C, 67.46; H, 5.66; N, 3.42. Found: C,
67.32; H, 5.73; N, 3.48.
Ethyl 2-{4-(4-methylphenyl)-2-[(Z)-oxo(phenyl)ethylidene]-
1,3-thiazol-3-yl}acetate (4f). Pale yellow crystalline solid; mp
1
128–129ꢀC. H NMR (300 MHz, CDCl3) d 1.28 (t, 3H, J ¼ 7
Hz, CH2CH3), 2.41 (s, 3H, CH3), 4.27 (q, 2H, J ¼ 7 Hz,
CH2CH3), 4.51 (s, 1H, NCH2), 6.26–7.95 (m, 10H, ArH þ
tzol H). 13C NMR (75.5 MHz, CDCl3) d 14.1 (CH2CH3), 21.3
(CH3), 48.9 (NCH2), 62.4 (CH2CH3), 90.0 (tzol CH), 105.8
(vinylic), 126.5 (C4 tzol), 165.9 (C2 tzol), 127.3, 128.3, 129.3,
129.7, 130.4, 131.2, 137.4, and 138.9 (ArC), 170.3 and 187.1
(carbonyl). EIMS: m/z (%) 379 (Mþ, 84), 362 (31), 306 (51),
278 (18), 232 (13), 188 (16), 147 (34), 119 (58) and 105
(100). Anal. Calcd for C22H21NO3S (379.47): C, 69.63; H,
5.58; N, 3.69. Found: C, 69.32; H, 5.67; N, 3.76.
General procedure for the synthesis of pyrrolothiazoles
(5). A suspension of the thiazole 3 (10 mmol) in glacial acetic
acid (10 mL) was refluxed with stirring for 15 h. The mixture
was cooled and poured into ice cold water and extracted using
CHCl3 (2 ꢁ 50 mL). The organic layer was washed with water
(2 ꢁ 50 mL) and dried using anhyd Na2SO4. The solvent was
evaporated and the crude product thus obtained was purified
by column chromatography over silica gel using hexane: ethyl
acetate as eluent (4 : 1) to afford 5a or 5b.
Ethyl 3,6-diphenylpyrrolo[2,1-b]-[1,3]thiazole-5-carboxylate
1
(5a). Pale yellow glass. H NMR (300 MHz, CDCl3) d 0.65 (t,
3H, J ¼ 7 Hz, CH2CH3), 3.45 (q, 2H, J ¼7 Hz, CH2CH3),
6.34 (s, 1H pyrrole CH), 6.52 (s, 1H, tzol CH(7.07–8.07 (m,
10H, ArH) ppm. 13C NMR (75.5 MHz, CDCl3) d 12.6, 59.0,
99.6 (tzol CH), 109.7, 112.3, 125.3, 126.2, 127.4, 127.5,
127.6, 128.8, 129.1, 131.7, 132.7, 135.6, 137.7 (ArH), 159.48.
EIMS: m/z (%) 347 (Mþ, 48), 302 (24), 275(100), 241 (18),
215 (15), 202 (12), 172 (15), 145 (20), and 102 (27). Anal.
Calcd. for C21H17NO2S (347.43): C, 72.60; H, 4.93; N, 4.03.
Found: C, 72.43; H, 4.86; N, 4.14.
Ethyl 3-(4-methylphenyl)-6-phenylpyrrolo[2,1-b][1,3]thia-
zole-5-carboxylate (5b). Pale yellow glass.1H NMR (300 MHz,
CDCl3) d 0.68 (t, 3H, J ¼ 7 Hz, CH2CH3), d 3.50 (q, 2H, J ¼
7 Hz, CH2CH3), d 2.30 (s, 3H, CH3), d 6.33 (s, 1H, pyrrole
CH), d 6.49 (s, 1H, tzol CH), d 7.13–7.53 (m, 9H, ArH) ppm.
13C NMR (75.5 MHz, CDCl3) d 14.0, 21.7, d 60.4, 101.0 (tzol
CH). 110.6, 126.7, 127.6, 128.0, 128.9, 129.6, 130.2, 130.5,
134.0, 135.8, 137.8, 137.2, 139.0, 160.9. EIMS: m/z (%) 361
(Mþ, 47), 316 (22), 289 (100), 273 (14), 210 (8), 145 (15), and
115 (31). Anal. Calcd. for C22H19NO2S (361.46): C, 73.10; H,
5.30; N, 3.88. Found: C, 73.28; H, 5.43; N, 3.74.
7-Benzoyl-3-phenyl-pyrrolo[2,1-b]thiazol-6-one (6f). White
1
solid; mp 216–217ꢀC. H NMR (360 MHz, CDCl3): d 4.62 (s,
2H, NCH2), 6.80 (s, 1H tzol), 7.45–7.53 (m, 8H, ArH), 8.12
(d, 2H, J ¼ 7.2 Hz, ArH). 13C NMR (90 MHz, CDCl3): d
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2010
Microwave Assisted One-Pot Synthesis of Pyrrolo[2,1-b]thiazol-6-ones from
a-Aroyl Ketene-N,S-acetals
435
[8] (a) Tverdokhlebov, A. V.; Andrushko, A. P.; Tolmachev,
A. A. Synthesis 2006, 1433; (b) Tverdokhlebov, A. V.; Andrushko, A.
P.; Resnyanska, E. V.; Tolmachev, A. A. Synthesis 2004, 2317.
[9] Berry, C. R.; Zificsak, C. A.; Gibbs, A. C.; Hlasta, D. J.
Org Lett 2007, 9, 4099.
59.3, 109.2, 109.3, 127.7, 128.2, 128.4, 129.5, 129.9, 130.8,
132.2, 138.2, 141.6, 179.8, 185.4, 186.0. MS (FAB): m/z 320
(Mþ þ H). Anal. Calcd. for C19H13NO2S (319.07): C, 71.45;
H, 4.10; N, 4.39. Found: C, 71.58; H, 4.16; N, 4.32.
[10] Abe, N.; Nishiwaki, T.; Komoto, N. Bull Chem Soc Jpn
1980, 53, 3308.
Acknowledgments. P.M. thank SAIF, CDRI, Lucknow, India
for providing spectral and analytical data and the Kerala State
Council for Science Engineering and Technology (KSCSTE),
Kerala, India for financial support.
[11] Landreau, C.; Janvier, P.; Julienne, K.; Meslin, J. C.;
Deniaud, D. Tetrahedron 2006, 62, 9226.
[12] Geyer, A.; Agoston, K. Tetrahedron Lett 2004, 45, 1895.
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Chemists: Strategies, Instruments and Protocols; Wiley-VCH: Wein-
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet