Simple, three-component, highly efficient green synthesis of thiazolo[3,2-a]pyridine derivatives under neat conditions

Article abstract of DOI:10.1080/00397911.2010.505700

Green, highly efficient, three-component syntheses of thiazolo-[3,2-a] pyridine derivatives via reaction of malononitrile, aromatic aldehydes, and 2-mercaptoacetic acid with a catalytic amount of piperidine without solvent with molar ratios of 2:2:1.2 and 2:2.2:1, respectively, has been reported. Taylor & Francis Group, LLC.

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Simple, Three-Component, Highly
Efficient Green Synthesis of
Thiazolo[3,2-a]pyridine Derivatives
Under Neat Conditions
Ramadan Ahmed Mekheimer a , Noha Mohamed Hilmy b , Afaf Abdel
Hameed a , Sawsan Dacrory a & Kamal Usef Sadek a
a Chemistry Department, Faculty of Science, Minia University, El-
Minia, Egypt
b Women Students–Medical Studies & Sciences Sections, Chemistry
Department, College of Science, King Saud University, Riyadh, Saudi
Arabia
Published online: 29 Jun 2011.
To cite this article: Ramadan Ahmed Mekheimer , Noha Mohamed Hilmy , Afaf Abdel Hameed ,
Sawsan Dacrory & Kamal Usef Sadek (2011): Simple, Three-Component, Highly Efficient Green
Synthesis of Thiazolo[3,2-a]pyridine Derivatives Under Neat Conditions, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 41:17, 2511-2516
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Synthetic Communications1, 41: 2511–2516, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.505700
SIMPLE, THREE-COMPONENT, HIGHLY EFFICIENT
GREEN SYNTHESIS OF THIAZOLO[3,2-a]PYRIDINE
DERIVATIVES UNDER NEAT CONDITIONS
Ramadan Ahmed Mekheimer,1 Noha Mohamed Hilmy,2 Afaf
Abdel Hameed,1 Sawsan Dacrory,1 and Kamal Usef Sadek1
1Chemistry Department, Faculty of Science, Minia University,
El-Minia, Egypt
2Women Students–Medical Studies & Sciences Sections, Chemistry
Department, College of Science, King Saud University, Riyadh,
Saudi Arabia
GRAPHICAL ABSTRACT
Abstract Green, highly efficient, three-component syntheses of thiazolo-[3,2-a]pyridine
derivatives via reaction of malononitrile, aromatic aldehydes, and 2-mercaptoacetic acid
with a catalytic amount of piperidine without solvent with molar ratios of 2:2:1.2 and
2:2.2:1, respectively, has been reported.
Keywords Neat conditions; thiazolo[3,2-a]pyridines; three component
Received December 15, 2009.
Address correspondence to Kamal Usef Sadek, Chemistry Department, Faculty of Science,
Minia University, El-Minia 61519, Egypt. E-mail: kusadek@yahoo.com
2511

2512
R. A. MEKHEIMER ET AL.
INTRODUCTION
Thiazolo[3,2-a]pyridines have received considerable interest because of their
biological activity.[1] They possess many significant bioactivities such as a-glucoside
inhibitors,[2] antibacterial and antifungal activities,[3] b-amyloid production inhibi-
tors,[4] and many other biological activities.[5,6] In spite of their biological activity,
synthesis of 5-amino-7-aryl-6,8-dicyano-3-oxo-2,3-dihydro-7H-thiazolo[3,2-a]pyri-
dine derivatives have received little attention. The conventional methods for their
synthesis are a multistep reaction or use complicated starting materials.[7–9]
A
three-component synthesis was achieved from the reaction of benzylidenemalononi-
trile, N-substituted thiocarbamoylacetamides, and methyl-2-chloroacetate in meth-
anol catalyzed by piperidine.[10] Previously, Elnagdi et al. have also reported an
efficient synthesis of these molecules from the reaction of 2-(a-functionally substi-
tuted alkyl)-4-hydroxythiazoloes with a-functionally substituted cinnamonitrile deri-
vatives or alternatively from the reaction of the later with 2-mercaptoacetic acid,
both in ethanol in the presence of piperidine or triethylamine as catalyst and
reflux.[11,12] Very recently,[13] a microwave-assisted three-component synthesis of
thiazolo[3,2-a]pyridines in water with moderate to good yields has been reported.
It is worth mentioning that multicomponent reactions (MCRs) have attracted the
attention of synthetic organic chemists for building highly functionalized organic
molecules for their atom economy, selectivity, simplicity, energy savings, as well as
environmental friendliness. Also, application of environmentally benign solvent-free
organic reactions represents a powerful green procedure.[14,15]
RESULTS AND DISCUSSION
In continuation our interest in applying environmentally friendly techni-
ques,[16–18] we found that there is no need for prolonged conventional heating, micro-
wave irradiation, or solvent (even it is a benign one) for the synthesis of thiazolo
[3,2-a]pyridines. In the current study, we reported a facile, highly efficient, solvent-
less, three-component protocol for the synthesis of 5-amino-3-oxo-7-aryl-2,
3-dihydro-7H-pyrido[2,1-b][1,3]thiazole-6,8-dicarbonitrile 1 and 5-amino-7-aryl-3-
oxo-2-(1-arylmethylidene)-2,3-dihydro-7H-pyrido[2,1-b][1,3]thiazole-6,8-dicarboni-
trile 5 employing malononitrile (2), aromatic aldehydes (3), and 2-mercaptoacetic
acid (4) with different molar ratios. Thus, in a typical procedure, when a mixture
of neat malononitrite (2), benzaldehyde (3a), mercaptoacetic acid (4), and piperidine
(two drops) in a molar ratio 2:1:1 was fused for 30 s, the reaction mixture was sol-
idified instantaneously, and a mixture of compounds 1a and 5a were obtained in
1
which their structures were established via H NMR spectra, which reflects the
effect of the reactants’ molar ratio on the nature of the end product. After conduct-
ing numerous experiments we have concluded that a molar ratio of 2:2:1.2 of 2, 3,
and 4 yields mainly product 1. However, changing the molar ratio of the same reac-
tants to 2:2.2:1 yields 5 as the sole isolable product (cf. Scheme 1).
The structure of thiazolo[3,2-a]pyridines 1 and 5 were characterized by infrared
1
(IR), H NMR, 13C NMR, heteronuclear multiple-bond correlation (HMBC), and
heteronuclear multiple-quantum correlation (HMQC). It was noticed in HMBC of
5a that the carbonyl carbon atom at 161.5 ppm is coupled to an arylmethylene

THIAZOLO[3,2-a]PYRIDINES IN NEAT CONDITIONS
2513
Table 1. List of thiazolo[3,2-a]pyridines 1a–d and 5a–e
Product
Ar
Time (s)
Yield
Mp (1it.) (ꢀC)
1a
1b
1c
1d
1e
5a
5b
5c
5d
5e
5f
C6H5
30
40
40
60
35
30
60
45
45
40
45
85
82
80
88
82
90
92
87
87
88
80
239–241 (268–240)[13]
293–294 (292–294)[13]
234–238 (234–236)[13]
236–238 (236–238)[13]
232–233
4-Br-C6H4
2-Cl-C6H4
4-OCH3-C6H4
3-NO2-C6H4
C6H5
264–266 (265)[11]
4-OCH3-C6H4
4-NO2-C6H4
3-NO2-C6H5
4-Cl-C6H4
4-Br-C6H4
259–261 (>230)[12]
288–290 (278–279)[13]
197–199 (198)[12]
273–274 (272–273)[13]
proton at 8.41 ppm. The coupling constant value of d ¼ 6.6 Hz suggested that the
molecule is thiazolo[3,2-a]pyridines with an arylmethylene moiety that adopts the
Z configuration. These results were in agreement with our previous results and in
contrast to the reported formation of pyranothiazoles in a similar reaction.[19]
Thiazolo[3,2-a]pyridine derivatives 1 and 5 were chemoselectively synthesized
under their particular optimal reaction conditions, and the results are summarized
in Table 1. To examine the effect of substituted aryl aldehyde (3) on the reaction
rate and the overall yield, various functionalized aryl aldehydes were used. It has
been found that the reaction proceeds smoothly to give thiazolo[3,2-a]pyridines
Scheme 1. Structures of compounds 1 and 5.

2514
R. A. MEKHEIMER ET AL.
Scheme 2. Mechanism to account for formation of 1 and 5.
derivatives in good yields. However, when the aryl substituent was an
electron-donating group, the yields are better. This reflects the effect of the nature
of substituent on the reactivity of the arylidene derivative supposed to be formed as
an intermediate.
On the other hand, conducting the reaction under these conditions without
catalyst resulted in the formation of the corresponding arylidenemalononitrite
derivative as the sole isolable product. Accordingly, the presence of a basic catalyst
is essential. A mechanism to account for the formation of 1 and 5 was demonstrated
in Scheme 2.
CONCLUSION
In conclusion, in green chemistry, it is generally recognized that the best reac-
tion requires no solvent. This study does provide a simple, three-component, green
chemoselective synthesis of thiazolo[3,2-a]pyridines with good yields and almost
no reaction time.

THIAZOLO[3,2-a]PYRIDINES IN NEAT CONDITIONS
2515
EXPERIMENTAL
Melting points are uncorrected and were determined on a Shimadzu
Gallenkamp apparatus. Infrared (IR) spectra were recorded on a Perkin-Elmer
2000 Fourier transform (FT)–IR system in KBr disk. 1H NMR and 13C NMR spec-
1
tra were recorded on a Bruker DPX spectrometer operating at 400 MHz for H
NMR and 100 MHz for 13C NMR in dimethylsulfoxide (DMSO-d6) as a solvent
and tetramethylsilane (TMS) as internal standard; chemical shifts are reported in
d (ppm). Mass spectra were measured on VG Autospec QMS, MS, and MS 9
(AEI) spectrometers with electron impact (EI) of 70 ev.
General Procedure
A mixture of malononitrite, aryl aldehydes, and mercaptoacetic acid with pip-
eridine (two drops) in molar ratios of 2:1:1.2 or 2:2.2:1 was fused for 30–60 s, in
which a precipitate was instantly formed, which was directly crystallized from the
proper solvent to afford either compounds 1a–d or 5a–e. Compounds 1a–d and
5a, c–e have been described previously, and our spectral data (IR, 1H and13C-NMR)
are substantially identical to those reported in literature.
Compound 5b
Mp: 242–243 ꢀC 1H NMR (400 MHz, DMSO-d6): d ¼ 3.33 (s, 3H), 3.57 (S, br,
2H), 3.77 (S, 3H), 4.43 (s, 1H), 6.87 (d, J ¼ 8.8 Hz, 1H), 6.94 (d, J ¼ 8.8 Hz, 1H), 7.12
(d, J ¼ 8.8 Hz, 1H), 7.62 (d, J ¼ 8.8 Hz, 1H), 8.41 (s, 1H). 13C NMR (100 MHz, 1)
(DMSO-d6): d ¼ 38.6, 55.8, 60.2, 70.4, 114.2, 117.3, 118.5, 127.0, 127.3, 130.2,
130.4, 133.1, 134.5, 152.3, 157.6, 158.2, 159.8, 161.5. Found: C, 65.32; H, 3.86; N,
12.66; S, 7.33; Calcd. for C24H17O3N4S: C, 65.29; H, 3.88; N, 12.69; S, 7.26.
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