Catalyst free, regioselective one-pot three-component synthesis of thiazol-2-imine derivatives in ionic liquid

Article abstract of DOI:10.1016/j.tetlet.2013.08.056

A one-pot three-component approach for the synthesis of thiazol-2-imines has been described by the reaction of amine, phenyl isothiocyanate and β-nitroacrylate in [Hbim]BF₄ ionic liquid. The method is applicable for aromatic, benzylic, aliphatic and cyclic amines. Reusable reaction media, regioselectivity, mild reaction condition, catalyst free and high yield of products are the salient features of this protocol.

Full text of DOI:10.1016/j.tetlet.2013.08.056

Tetrahedron Letters 54 (2013) 5974–5978
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Catalyst free, regioselective one-pot three-component synthesis
of thiazol-2-imine derivatives in ionic liquid
⇑
G. Santosh Kumar, S. Pushpa Ragini, H. M. Meshram
Medicinal Chemistry and Pharmacology Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot three-component approach for the synthesis of thiazol-2-imines has been described by the
reaction of amine, phenyl isothiocyanate and b-nitroacrylate in [Hbim]BF4 ionic liquid. The method is
applicable for aromatic, benzylic, aliphatic and cyclic amines. Reusable reaction media, regioselectivity,
mild reaction condition, catalyst free and high yield of products are the salient features of this protocol.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 17 June 2013
Revised 12 August 2013
Accepted 17 August 2013
Available online 27 August 2013
Keywords:
Amine
Phenyl isothiocyanate
b-Nitroacrylate
Thiazol-2-imines
Regioselectivity and ionic liquid
Thiazole moiety is found as a core unit in various pharmaceuti-
cals as well in agrochemicals such as acrecides, insecticides and
plant growth regulators.1 Particularly, 2-iminothiazoline has been
shown to possess different biological activities2 such as anti-
inflammatory, analgesic and kinase (CDK1, CDK5 and GSK3) inhibi-
tion,3 antifungal,4 melanin-reducing activity (skin whitening
agent)5 and as platelet GPIIb/IIIa receptor antagonists.6 Recently,
of N,N0-dialkylthiourea and in situ generated
a-bromoketones in
one-pot protocol, which is limited to symmetrical thioureas and
a few selected ketones.13 Recently, the three component reaction
of phenacyl bromide or 2-chloro-1,3-dicarbonyl compound, amine
and phenyl isothiocynate has been reported to give thiazol-2-
imines.14 Murru et al.15 reported the one-pot reaction of enolisable
ketones and disubstituted thioureas in presence of 1,10-(ethane-
1,2-diyl) dipyridinium bistribromide (EDPBT) as a brominating
agent to give thiazol-2-imines. Though the reported methods are
satisfactory for the synthesis of thiazol-2-imines, some drawbacks
like harsh reaction condition, low yield, prolonged reaction time
and use of polar, volatile and hazardous organic solvents have been
encountered. In addition to this some of the methods are limited to
Pifithrin (Pft-a) having 2-iminothiazoline skeleton has been pro-
jected as a possible lead for the treatment of major neurodegener-
ative disorders such as Alzheimer’s disease, Parkinson’s disease,
Stroke and cancer therapy (Fig. 1).7
There are various methods for the synthesis of iminothiazolines.
Hantzsch condensation reaction was the first method reported for
the synthesis of 2-aminothiazole moiety using
a-haloketone and
thiourea as starting materials.8 Subsequently other alternative
methods have been reported including copper-catalysed N-pheny-
lation of 2-aminobenzothiazole derivatives,9 condensation of thia-
zol-2(3H)-imines with 4-chloro and 4-isothiocyanato acridines,3
cycloaddition of 5-imino-1,2,4-thiazolidin-3-ones with both elec-
trophilic and nucleophilic unsaturated compounds such as enam-
ines and ester enolates.10 Another method is based on the ring
expansion of 1-aryl methyl-2-(thiocyanatomethyl) aziridine with
F
NH
O
S
O
N
S
NH
N
F
N
O
Figure 1. Representative examples of biologically active thiazol-2-imine
derivatives.
11
an acyl chloride in the presence of TiCl4. In addition to this the
synthesis of thiazol-2-imines was also accomplished by the reac-
tion of substituted amines with isothiocyanates.12 Some of the
methods for the synthesis of thiazol-2-imines comprise the use
H
N
N
BF4
⇑
Corresponding author. Tel.: +91 40 27191640; fax: +91 40 27193275.
E-mail address: hmmeshram@yahoo.com (H.M. Meshram).
Figure 2. Chemical structure of 1-n-butylimidazolium tetrafluoroborate [Hbim]BF4
ionic liquid.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.056

G. Santosh Kumar et al. / Tetrahedron Letters 54 (2013) 5974–5978
5975
Ph
symmetrical thio urea and selected ketones and lack regioselectiv-
ity. In this regard it is desirable to develop efficient one pot method
for the regioselective formation of thiazol-2-imines under mild
reaction conditions.
N
R
S
O
O
[Hbim]BF4
r.t.
25 - 60 min
NO2O
NH2
PhNCS
2
+
+
R2
N
R
R1
O
1
R1 R2
3
4
Multicomponent reactions (MCRs) have recently emerged as
valuable tools in pharmaceutical chemistry because of their wide
range of applications such as atom economy, simplicity and
time-saving features. MCRs are convergent reactions, producing
an extremely high increase of molecular complexity in just one
step.16,17 Due to these significant useful attributes of MCRs, they
have attracted more and more attention from the medicinal chem-
istry community.
R = phenyl, cyclopropyl, cyclohexyl,
benzyl, phenylethyl
82 - 90%
R = Ph, Me1
R = Me, Et2
Scheme 1. Three component synthesis of substituted thiazol-2-imines under
catalyst-free condition by using [Hbim]BF4 as a reaction medium.
Table 1
Screening of reaction mediaa
The use of ionic liquids as a recyclable and environmentally be-
nign medium has been attracting considerable attention for chem-
ical transformations including non-catalytic reactions. The main
advantage of ionic liquids is to reduce or eliminate the use of haz-
ardous and toxic solvents.18 In this context, ionic liquids have
emerged as environmentally friendly substitutes for volatile organ-
ic compounds.19
Entry
Reaction media
Time (min)
Yieldb (%)
1
2
3
4
5
[Hbim]BF4
[Hbim]BF4
[bmim]BF4
[bmim]PF6
[emim]BF4
55
120
120
120
120
90
90
75
72
65
a
Reaction condition: aniline 1a (1 mmol), phenyl isothiocyanate 2 (1 mmol) and
b-nitroacrylates ((Z)-ethyl 3-nitrobut-2-enoate) 3a (1 mmol) in 5 mL ionic liquid.
Due to prominent biological activity of thiazol-2-imines and as
a part of our ongoing interest in the application of ionic liquids20
b
Isolated yield.
Table 2
Synthesis of substituted thiazol-2-iminesa in [Hbim]BF4
Entry
1
R
R1
R2
Et
Product
Time (min)
55
Yieldb (%)
90
Ph N
N
S
S
S
O
4a
4b
CH3
OEt
Ph N
N
O
2
3
CH3
ph
Me
Et
55
25
89
89
OMe
Ph N
N
O
4c
OEt
Ph
S
N
Ph
O
4
5
CH3
CH3
Et
55
55
87
86
4d
4e
N
OEt
Ph N
S
O
Me
N
OMe
Ph N
S
O
6
7
8
9
ph
Et
N
25
60
60
30
86
84
84
82
4f
OEt
Ph
S
Ph N
O
CH3
CH3
ph
Et
N
4g
OEt
Ph N
S
O
Me
Et
N
4h
4i
OMe
Ph N
S
O
N
OEt
Ph
S
Ph N
O
4j
10
11
CH3
CH3
Et
57
57
84
84
N
Ph
OEt
Ph N
S
S
O
4k
Me
N
Ph
OMe
Ph N
O
4l
12
13
ph
Et
Et
N
27
55
82
Ph
OEt
Ph
S
N
Ph N
O
4m
CH3
88
Ph
OEt
(continued on next page)

5976
G. Santosh Kumar et al. / Tetrahedron Letters 54 (2013) 5974–5978
Table 2 (continued)
Entry
R
R1
R2
Product
Time (min)
55
Yieldb (%)
88
Ph N
S
O
14
CH3
Me
N
4n
4o
Ph
Ph N
OMe
S
O
15
ph
Et
N
25
86
Ph
OEt
Ph
a
All products exhibited physical and spectral (NMR, mass and IR) properties in accordance with the assigned structure.
Isolated yield.
b
for the synthesis of biologically active molecules, we herein report
within a shorter reaction time at rt. The results evaluating the merits
of various ionic liquids are presented in Table 1.
a catalyst free one-pot three component protocol of amine, phenyl
isothiocyanate and b-nitroacrylates to give thiazol-2-imines by
using ionic liquid 1-n-butylimidazolium tetrafluoroborate
[Hbim]BF4 (Fig. 2) as a reusable reaction medium. (Scheme 1). To
the best of our knowledge there is no report of a catalyst-free three
component synthesis of thiazol-2-imines by using b-nitroacrylates
as one of the starting materials.
Various amines like aryl, benzylic, cyclic and aliphatic under-
went smooth reaction under standard conditions to furnish thia-
zol-2-imines in high yields. The reaction of anilines was very
rapid and led to high yields of the expected products (Table 2, en-
tries 1, 2 and 3). However other substituted amines reacted com-
paratively slowly to give the corresponding products. For
example the reaction of benzylamine and phenylethylamine pro-
ceeded smoothly under standard reaction conditions to produce
the expected products in good to excellent yields (Table 2, entries
10–15). It is worthy to mention that cyclopropylamine and cyclo-
hexylamine underwent condensation under same reaction condi-
tions to furnish corresponding products in good yields (Table 2,
entries 4–9).
The plausible mechanism of thiazol-2-imines is proposed based
on one of the literature reports.26 Initially amine reacts with phe-
nyl isothiocyanate to form N,N0-disubsituted thiourea which on
Michael addition to b-nitroacrylate forms Michael adduct A, then
A tautomerizes into the reactive species B (aci-nitro tautomer),
which is promptly attacked by the nitrogen atom, with the forma-
tion of the five membered ring C. Finally, elimination of water and
nitroxyl molecules, lead to the formation of the target thiazole-2-
imines 4.
Further we investigate the reusability aspect of [Hbim]BF4 in
detail for the product 4a (Table 2, entry 1). After completion of
the reaction, the product was isolated from [Hbim]BF4 by simply
extracting with ether. Then the residual ionic liquid was dried un-
der vacuum and reused for three cycles. It was noticed that the
yield of the product gradually decreased from first to third cycle
(90%, 87% and 84%), respectively. Hence, our protocol can avoid
the use of organic solvents and metallic reagents significantly
(Scheme 2).
In summary, we have demonstrated a catalyst free one-pot
three component synthesis of thiazole-2-imines in an environmen-
tally benign manner. Moreover this protocol is operationally sim-
ple and can afford the products in high yield. This procedure is
b-Nitroacrylates are an emerging class of electron-poor alkenes,
having two electron-withdrawing groups in
a- and b-positions,
since they can be employed as Michael acceptors with indoles,21
b-dicarbonyl derivatives,22 and amines.23 b-Nitroacrylates are less
readily available compared to 2-chloro-1,3-dicarbonyl compounds.
However, b-nitroacrylates and their derivatives display a signifi-
cantly higher reactivity and efficiency towards N,N0-disubsituted
thiourea compared to the 2-chloro-1,3-dicarbonyl compounds.
The functionalized b-nitroacrylates are easily prepared by nitroal-
dol reaction followed by dehydration of nitroalkane and ethyl gly-
oxalate.24 Therefore, b-nitroacrylates are one of the versatile
intermediates which have replaced highly toxic and lachrymatory
2-chloro-1,3-dicarbonyl compounds to prepare
a variety of
heterocycles.25
Accordingly, we first attempted the reaction of aniline 1a (1
mmol), phenyl isothiocyanate 2 (1 mmol) and b-nitroacrylate,
((Z)-ethyl 3-nitrobut-2-enoate) 3a (1 mmol) in 5 mL ionic liquid
[Hbim]BF4 (Scheme 1).27 After completion of reaction (55 min),
the desired product 4a was obtained in 90% yield, which was con-
firmed by analysing spectral data (Table 2, entry 1). We have not
observed the formation of any isomeric thiazol-2-imine.
Encouraged by this result, we turned our focus on various imid-
azole based ionic liquids such as 1-n-butylimidazolium tetrafluoro-
borate [Hbim]BF4, 1-butyl-3-methylimidazolium tetrafluoroborate
[bmim]BF4, 1-butyl-3-methyl imidazolium hexafluoro phosphate
[bmim]PF6 and 1-ethyl-3-methylimidazolium tetrafluoroborate
[emim]BF4 to study the model reaction in a specific aspect. We no-
ticed that the reaction proceeded smoothly in ionic liquid [Hbim]BF4
without using additional catalyst and gave high yields of products
Ph
N
H
N
H
N
[Hbim]BF
R
N
S
R
Ph
4
NH2
PhNCS
+
R
S
R1
O
1
2
R2
R1
O
4
3R
2
O
NO2
O
H2N2O2
N
-HNO
-H2O
[Hbim]BF
4
Ph
H
N
N
H
N
N
R
R
Ph
R
Ph
N
S
S
S
R1
O
R2
R1
O
R1
O
N
R2
R2
HO
OH
O
N
O
NO2
O
O
OH
A
B
C
Scheme 2. Plausible mechanistic pathway for the formation of substituted thiazole-2-imines in the presence of [Hbim]BF4.

G. Santosh Kumar et al. / Tetrahedron Letters 54 (2013) 5974–5978
5977
23. Ballini, R.; Bazán, N. A.; Bosica, G.; Palmieri, A. Tetrahedron Lett. 2008, 49, 3865.
24. For the preparation of b-nitroacrylates, see: (a) Shin, C.; Yonezawa, Y.;
Narukawa, H.; Nanjo, K.; Yoshimura, J. Bull. Chem. Soc. Jpn. 1972, 45, 3595;
(b) Ballini, R.; Fiorini, D.; Palmieri, A. Tetrahedron Lett. 2004, 45, 7027.
25. (a) Palmieri, A.; Gabrielli, S.; Cimarelli, C.; Ballini, R. Green Chem. 2011, 13,
3333; (b) Ballini, R.; Gabrielli, S.; Palmieri, A. Synlett 2010, 16, 2468.
26. Revial, G.; Lim, S.; Viossat, B.; Lemoine, P.; Tomas, A.; Duprat, A. F.; Pfau, M. J.
Org. Chem. 2000, 65, 4593.
suitable for a variety of amines as well as b-nitroacrylates. Our
method describes the use of b-nitroacrylates for the first time in
a one-pot three component reaction for the synthesis of thiazole-
2-imine derivatives as single isomeric products. Usage of ionic
liquid [Hbim]BF4 makes this procedure very mild, rapid and effi-
cient. The present protocol is also amenable for the synthesis of
new novel compounds which were not prepared earlier (Table 2,
entries 3–15). We believe that the present protocol may be an
attractive alternative over the earlier methods.
27. General procedure:
A mixture of amine (1 mmol), phenyl isothiocyanate
(1 mmol) in 5 mL ionic liquid [Hbim]BF4 was stirred for 5 min at room
temperature then the b-nitroacrylate (1 mmol) was added and the mixture
was stirred at rt for a stipulated time (see Table 2). The progress of the reaction
was monitored by TLC. After the completion of the reaction, the reaction
mixture was extracted with ether (3 ꢀ 15 mL). The combined organic layers
were washed with brine solution, and dried over Na2SO4. Na2SO4 was filtered
off and the solvent was removed under vacuum. The residue obtained was then
purified by silica gel column chromatography (100–200 mesh) using ethyl
acetate/hexane as eluent to get corresponding products. All the obtained
products were characterized by 1H NMR, 13C NMR, Mass and IR spectral data.29
28. Spectral data of compounds:
Acknowledgements
The author G.S.K. thanks CSIR for the award of a fellowship and
S.P.R. thanks Dr. A. Kamal, Outstanding scientist and Head of the
MCP Division, for his support and encouragement.
The authors thank CSIR, New Delhi for financial support as part
of XII Five Year plan programme under title ORIGIN (CSC-0108).
Compound 4a: White solid; Mp 149–151 °C; 1H NMR (300 MHz, CDCl3): d 1.29
(t, J = 7.19 Hz, 3H), 2.23 (s, 3H), 4.23 (q, J = 7.19 Hz, 2H), 6.92 (d, J = 7.19 Hz,
2H), 7.02 (t, J = 7.19 Hz, 1H), 7.28 (t, J = 7.19 Hz, 2H) 7.35 (d, J = 7.19 Hz, 2H),
7.48 (d, J = 7.19 Hz, 1H), 7.55 (t, J = 7.19 Hz, 2H) ppm; 13C NMR (75 MHz,
CDCl3): d 11.5, 14.1, 60.7, 100.5, 121.1, 123.5, 128.8, 129.1, 129.3, 129.7, 136.5,
References and notes
146.8, 151.0, 158.3, 162.0 ppm; IR (KBr):
m = 697, 1092, 1225, 1256, 1296, 1380,
1488, 1581, 1693 cmꢁ1; MS-ESI: m/z = 339 [M+1]+.
1. Albrecht, B. K.; Williams, R. M. Org. Lett. 2003, 5, 197.
Compound 4b: White solid; Mp 96–98 °C; 1H NMR (300 MHz, CDCl3): d 2.26
(3H, s), 3.76 (3H, s), 6.92 (d, J = 7.29 Hz, 2H), 7.02 (t, J = 7.29 Hz, 1H), 7.27 (t,
J = 7.29 Hz, 2H), 7.36 (d, J = 7.29 Hz, 2H), 7.49 (t, J = 7.29 Hz, 1H), 7.55 (t,
J = 7.29 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3): d 11.6, 60.7, 100.4, 121.1,
123.5, 128.6, 129.1, 129.2, 129.7, 136.4, 146.8, 151.1, 158.3, 162.2 ppm; IR
2. (a) Ivanov, Y. Y.; Tkachenko, S. E.; Proshin, A. N.; Bachurin, S. O. Biomed. Chem.
2003, 49, 92; (b) Baumann, R. J.; Mayer, G. D.; Fite, L. D.; Gill, L. M.; Harrison, B.
L. Chemotherapy 1991, 37, 157; (c) Webel, L. M.; Degman, M. B.; Harger, G. F.;
Capps, D. B.; Islip, P. J.; Closier, M. D. J. Med. Chem. 1972, 15, 955; (d) Beyer, H.;
Ruhlig, G. Chem. Ber. 1956, 89, 107.
3. Sondhi, S. M.; Singh, N.; Lahoti, A. M.; Bajaj, K.; Kumar, A.; Lazach, O.; Meijer, L.
Bioorg. Med. Chem. 2005, 13, 4291.
4. Bae, S.; Hahn, H. G.; Dai Nam, K. J. Comb. Chem. 2005, 7, 7.
(KBr)
m
= 698, 766, 1089, 1222, 1257, 1303, 1579, 1614, 1705 cmꢁ1; MS-ESI: m/
z = 325 [M+1]+.
Compound 4c: Yellow solid; 1H NMR (300 MHz, CDCl3): d 1.07 (t, J = 7.19 Hz,
3H), 4.05 (q, J = 7.19 Hz, 2H), 6.98 (d, J = 8.22 Hz, 2H), 7.05 (t, J = 7.19 Hz, 1H),
7.14–7.35 (m, 12H) ppm; 13C NMR (75 MHz, CDCl3): d 13.3, 60.1, 102.4, 120.4,
123.0, 127.0, 127.6, 128.2, 128.4, 128.6, 128.8, 129.2, 129.3, 136.0, 147.1, 150.3,
5. Kim, D. S.; Jeong, Y. M.; Park, I. K.; Hahn, H. G.; Lee, H. K.; Kwon, S. B.; Jeong, J.
H.; Yang, S. J.; Sohn, U. D.; Park, K. C. Biol. Pharm. Bull. 2007, 30, 180.
6. Manaka, A.; Sato, M.; Aoki, M.; Tanaka, M.; Ikeda, T.; Toda, Y.; Yamang, Y.;
Nakaike, S. Bioorg. Med. Chem. Lett. 2011, 11, 1031.
7. (a) Zhu, X. X.; Yu, Q. S.; Culter, R. G.; Culmsee, C. W.; Holloway, H. W.; Lahiri, D.
K.; Mattson, M. P.; Greig, N. H. J. Med. Chem. 2002, 45, 5090; (b) Komarov, P. G.;
Komarova, E. A.; Kondratov, R. V.; Chritov-Tselkov, K.; Coon, J. S.; Chernov, M.
V.; Gudkov, A. V. Science 1999, 285, 1733; (c) Barchechath, S. D.; Tawatao, R. I.;
Corr, M.; Carson, D. A.; Cottam, H. B. J. Med. Chem. 2005, 48, 6409; (d)
Pietrancosta, N.; Moumen, A.; Dono, R.; Lingor, P.; Planchamp, V.; Lamballe, F.;
Bahr, M.; Kraus, J. L.; Maina, F. J. Med. Chem. 2006, 49, 3645.
157.1, 160.2 ppm; IR (KBr):
m = 698, 708, 761, 1075, 1143, 1319, 1489, 1581,
1615, 1673 cmꢁ1; MS-ESI: m/z = 401 [M+1]+.
Compound 4d: Orange viscous liquid; 1H NMR (300 MHz, CDCl3): 0.99 (s, 2H),
1.17 (d, J = 7.17 Hz, 2H), 1.21 (t, J = 7.17 Hz, 3H), 2.61 (s, 3H), 2.76–2.82 (m, 1H),
4.15 (q, J = 7.17 Hz, 2H), 6.97 (d, J = 7.17 Hz, 2H), 7.03 (t, J = 7.17 Hz, 1H), 7.30 (t,
J = 7.17, 2H) ppm; 13C NMR (75 MHz, CDCl3): d 9.7, 13.9, 15.2, 28.6, 60.6, 101.8,
121.2, 123.6, 127.9, 149.2, 151.3, 158.4, 160.8 ppm; IR (KBr)
m = 698, 771, 1085,
1301, 1579, 1617, 1698 cmꢁ1; MS-ESI: m/z = 303 [M+1]+.
Compound 4e: Yellow solid; Mp 80–82 °C; 1H NMR (300 MHz, CDCl3): d 1.04 (s,
2H), 1.23 (d, J = 6.05 Hz, 2H), 2.66 (s, 3H), 2.81–2.87 (m, 1H), 3.72 (s, 3H), 6.99
(d, J = 7.78 Hz, 2H), 7.07 (t, J = 7.78 Hz, 1H), 7.33 (t, J = 7.78 Hz, 2H) ppm; 13C
NMR (75 MHz, CDCl3): d 9.2, 14.1, 26.8, 51.5, 99.3, 121.2, 123.5, 129.5, 149.0,
8. (a) Hantzsch, A.; Weber, J. H. Chem. Ber. 1887, 20, 3118; (b) Traumann, V. Liebigs
Ann. Chem. 1888, 31.
9. Miloudi, A.; El-Abed, D.; Boyer, G.; Finet, J.; Galy, J.; Siri, D. Eur. J. Org. Chem.
2004, 1509.
151.3, 158.3, 162.2 ppm; IR (KBr):
m = 697, 773, 1087, 1304, 1583, 1615,
10. Tittelbach, F.; Vieth, S.; Schneider, M. Eur. J. Org. Chem. 1998, 515.
11. Dhooghe, M.; Waterinckx, A.; De Kimpe, N. J. Org. Chem. 2005, 70, 227.
12. (a) Sanemitsu, Y.; Kawamura, S.; Satoh, J.; Katayama, T.; Hashimoto, S. J. Pestic.
Sci. 2006, 31, 305; (b) De Kimpe, N.; Boelens, M.; Declereq, J.-P. Tetrahedron
1993, 49, 3411; Ingle, S. T.; Kapley, S. M.; Chande, M. S. Proc. Indian Acad. Sci.,
Chem. Sci. 1980, 89, 295.
1700 cmꢁ1; MS-ESI: m/z = 289 [M+1]+.
Compound 4f: Yellow solid; Mp 122–124 °C; 1H NMR (300 MHz, CDCl3): d 0.66
(s, 2H), 0.77 (d, J = 6.86 Hz, 2H), 2.76–2.81 (m, 1H), 4.04 (q, J = 6.86 Hz, 2H),
7.05–7.13 (m, 3H), 7.34–7.49 (m, 7H) ppm; 13C NMR (75 MHz, CDCl3): d 9.6,
15.1, 28.4, 60.4, 101.5, 120.5, 123.1, 128.0, 129.8, 131.3, 149.4, 151.1, 156.2,
156.5, 156.8, 161.0 ppm; IR (KBr):
m = 699, 767, 1073, 1151, 1313, 1369, 1581,
13. Dash, B. C.; Nandi, B. B. J. Indian Chem. Soc. 1979, 56, 70.
1608, 1670 cmꢁ1; MS-ESI: m/z = 365 [M+1]+.
14. (a) Heravi, M. M.; Moghimi, S. Tetrahedron Lett. 2012, 53, 392; (b) Yavari, I.;
Sanaeishoar, T.; Ghazvini, M.; Iravani, N. J. Sulfur Chem. 2010, 31, 169.
15. Murru, S.; Singh, C. B.; Kavala, V.; Patel, B. K. Tetrahedron 2008, 64, 1931.
16. (a) Zhu, J.; Bienayme´, H.; Multi-Component Reactions; Wiley: Weinheim,
2005; (b) Muravyova, E. A.; Shishkina, S. V.; Musatov, V. I.; Knyazeva, I. V.;
Shishkin, O. V.; Desenko, S. M.; Chebanov, V. A. Synthesis 2009, 1375; (c) Maggi,
R.; Ballini, R.; Sartori, G.; Sartorio, R. Tetrahedron Lett. 2004, 45, 2297.
17. (a) Doemling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3169; (b) Khodaei, M.
M.; Khosropour, A. R.; Moghanian, H. Synlett 2006, 916; (c) Huang, S.; Pan, Y.;
Zhu, Y.; Wu, A. Org. Lett. 2005, 7, 3797; (d) Kumar, R.; Raghuvanshi, K.; Verma,
R. K.; Singh, M. S. Tetrahedron Lett. 2010, 51, 5933; (e) Prajapati, D.; Gohain, D.;
Beilstein J. Org. Chem. 2006, 2, 11; (f) Gu, Y. Green Chem. 2012, 14, 2091.
18. Trost, B. M. Science 1991, 254, 1471.
19. (a) Orikoshi, S.; Hamamura, T.; Kajitani, M.; Yoshizawa-Fujita, M.; Serpone, N.
Org. Process Res. Dev. 2008, 12, 1089; (b) He, Y.; Shen, X. J. Photochem. Photobiol.,
A 2008, 197, 253; (c) Chowdhury, S.; Mohan, R. S.; Scott, J. L. Tetrahedron 2007,
63, 2363; (d) Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.; Narsaiah, A. V. Tetrahedron
Lett. 2003, 44, 1047; (e) Yadav, J. S.; Reddy, B. V. S.; Premalatha, K. Adv. Synth.
Catal. 2003, 345, 948; (f) Sheldon, R. J. Chem. Soc., Chem. Commun. 2001, 2399;
(g) Peng, J.; Deng, Y. Tetrahedron Lett. 2001, 42, 5917; (h) Welton, T. Chem. Rev.
1999, 99, 2071.
Compound 4g: Pale yellow solid; mp 120–122 °C; 1HNMR (300 MHz, CDCl3): d
1.25 (t, J = 7.65 Hz, 3H), 1.30–1.94 (m, 10H), 2.61 (s, 3H), 2.8 (m, 1H), 4.18 (q,
J = 7.65 Hz, 2H), 6.99 (d, J = 7.65 Hz, 2H), 7.05 (t, J = 7.65 Hz, 1H), 7.33 (t,
J = 7.65 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3): d 13.8, 14.2, 24.9, 26.4, 28.8,
67.8, 60.4, 97.3, 121.1, 123.2, 129.5, 134.9, 147.4, 151.3, 162.2 ppm; IR (KBr):
m
= 699, 775, 1101, 1207, 1293, 1587, 1620, 1701 cmꢁ1; MS-ESI: m/z = 345
[M+1]+.
Compound 4h: Yellow solid; mp 119–121 °C; 1H NMR (300 MHz, CDCl3): d
1.11–1.97 (m, 10H), 2.62 (s, 3H), 2.8 (m, 1H), 3.71 (s, 3H), 6.99 (d, J = 8.30 Hz,
2H), 7.05 (t, J = 7.55 Hz, 1H), 7.33 (t, J = 8.30 Hz, 2H) ppm; 13C NMR (75 MHz,
CDCl3): d 13.6, 24.9, 26.3, 28.7, 51.4, 58.1, 98.9, 120.9, 123.1, 151.1, 156.5,
162.3 ppm; IR (KBr):
m ;
= 698, 771, 1090, 1205, 1291, 1585, 1612, 1695 cmꢁ1
MS-ESI: m/z = 331 [M+1]+.
Compound 4i: Yellow solid; mp 140–142 °C; 1H NMR (300 MHz, CDCl3): d 1.02
(t, J = 7.55 Hz, 3H), 1.41–1.80 (m, 10H), 2.8 (m, 1H), 3.98 (q, J = 7.55 Hz, 2H),
7.06 (t, J = 7.55 Hz, 3H), 7.27–7.32 (m, 2H), 7.37 (t, J = 7.55 Hz, 2H), 7.47–7.53
(m, 3H) ppm; 13C NMR (75 MHz, CDCl3): d 14.0, 24.8, 26.0, 28.6, 59.6, 60.4,
101.5, 121.0, 123.3, 128.4, 128.8, 129.6, 131.4, 149.1, 151.4, 156.0, 156.3,
160.9 ppm; IR (KBr):
m ;
= 696, 762, 1068, 1199, 1290, 1579, 1612, 1713 cmꢁ1
MS-ESI: m/z = 407 [M+1]+.
Compound 4j: Orange viscous liquid; 1H NMR (300 MHz, CDCl3): d 1.26 (t,
J = 7.08 Hz, 3H), 2.49 (s, 3H), 4.20 (q, J = 7.08, 2H), 5.25 (s, 2H), 7.01–7.10 (m,
3H), 7.24–7.38 (m, 7H) ppm; 13C NMR (75 MHz, CDCl3): 13.3, 14.4, 47.2, 60.6,
99.7, 121.4, 123.6, 126.7, 127.7, 128.8, 129.5, 136.3, 147.0, 150.6, 157.5,
20. (a) Meshram, H. M.; Ramesh, P.; Santosh Kumar, G.; Reddy, B. C. Tetrahedron
Lett. 2010, 51, 4313; (b) Meshram, H. M.; Prasad, B. R. V.; Kumar, D. A.
Tetrahedron Lett. 2010, 51, 3477; (c) Meshram, H. M.; Reddy, P. N.; Sadashiv, K.;
Yadav, J. S. Tetrahedron Lett. 2006, 47, 991; (d) Meshram, H. M.; Madhu Babu,
B.; Santosh Kumar, G.; Pramod, B. T.; Vikas, M. B. Tetrahedron Lett. 2013, 54,
2296.
162.1 ppm; IR (KBr):
m = 697, 750, 1092, 1206, 1262, 1401, 1581, 1617,
1696 cmꢁ1; MS-ESI: m/z = 353 [M+1]+.
Compound 4k: Yellow solid; Mp 82-84 °C; 1H NMR (300 MHz, CDCl3): d 2.49 (s,
3H), 3.74 (s, 3H), 6.26 (s, 2H), 7.02–7.11 (m, 3H), 7.25–7.38 (m, 7H) ppm; 13C
21. Ballini, R.; Gabrielli, S.; Palmieri, A.; Petrini, M. Tetrahedron 2008, 64, 5435.
22. Ballini, R.; Fiorini, D.; Palmieri, A. Tetrahedron Lett. 2005, 46, 1245.

5978
G. Santosh Kumar et al. / Tetrahedron Letters 54 (2013) 5974–5978
Compound 4n: Yellow solid; mp 103–105 °C; 1H NMR (300 MHz, CDCl3): d 2.25
NMR (75 MHz, CDCl3): d 13.2, 47.2, 51.7, 99.4, 121.1, 123.5, 126.5, 127.6, 128.8,
129.4, 136.0, 147.1, 150.4, 157.4, 162.3 ppm; IR (KBr):
m
= 701, 752, 1099, 1202,
(s, 3H), 3.10 (t, J = 6.79 Hz, 2H), 3.71 (s, 3H), 4.15 (t, J = 6.79 Hz, 2H), 7.06 (d,
J = 8.30, 3H), 7.18–7.40 (m, 7H) ppm; 13C NMR (75 MHz, CDCl3): d 12.6, 33.8,
46.2, 51.6, 88.8, 121.3, 123.6, 126.9, 128.7, 128.9, 129.5, 138.2, 147.2, 150.8,
1267, 1402, 1589, 1621, 1701 cmꢁ1; MS-ESI: m/z = 339 [M+1]+.
Compound 4l: Yellow solid; mp 104–106 °C; 1H NMR (300 MHz, CDCl3): d 1.04
(t, J = 6.92 Hz, 3H), 4.03 (q, J = 6.92 Hz, 2H), 4.99 (s, 2H), 7.01–7.05 (m, 2H),
7.10(d, J = 8.65 Hz, 3H), 7.15(d, J = 7.78 Hz, 2H), 7.21–7.25(m, 3H), 7.38(t,
J = 7.78 Hz, 4H), 7.44(d, J = 7.78 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3): d 13.8,
48.2, 60.6, 102.2, 121.2, 123.5, 127.1, 127.2, 128.1, 129.3, 129.5, 129.6, 129.9,
156.7, 162.4 ppm; IR (KBr):
m = 698, 774, 1102, 1215, 1272, 1401, 1587, 1619,
1704 cmꢁ1; MS-ESI: m/z = 353 [M+1]+.
Compound 4o: Light green solid; mp 86–88 °C; 1H NMR (300 MHz, CDCl3): d
1.03 (t, J = 6.79 Hz, 3H), 2.98 (t, J = 6.79 Hz, 2H), 3.88 (t, J = 6.79 Hz, 2H), 4.00 (q,
J = 6.79 Hz, 2H), 6.95 (d, J = 7.55 Hz, 2H), 7.05 (d, J = 7.55 Hz, 2H), 7.13 (d,
J = 6.79 Hz, 3H), 7.23 (t, J = 6.79 Hz, 3H), 7.35–7.55 (m, 5H) ppm; 13C NMR
(75 MHz, CDCl3): d 13.9, 33.6, 46.8, 60.3, 101.8, 121.23, 123.6, 126.5, 127.3,
128.3, 128.5, 128.9, 129.1, 129.5, 130.2, 138.0, 150.7, 156.5, 160.9 ppm; IR
136.5, 148.1, 150.5, 157.1, 160.8 ppm; IR (KBr):
m = 696, 756, 1078, 1124, 1206,
1278, 1390, 1486, 1582, 1611, 1708 cmꢁ1; MS-ESI: m/z = 415 [M+1]+.
Compound 4m: Yellow solid; mp 83–85 °C; 1H NMR (300 MHz, CDCl3): d 1.26 (t,
J = 7.16 Hz, 3H), 2.28 (s, 3H), 3.10 (t, J = 6.79 Hz, 2H), 4.12–4.22 (m, 4H), 7.07 (d,
J = 7.16 Hz, 3H), 7.21 (d, J = 7.16 Hz, 2H), 7.26(s, 1H), 7.31 (t, J = 7.16 Hz, 2H),
7.37 (t, J = 7.16 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3): d 12.7, 14.3, 33.9, 46.1,
60.6, 99.3, 121.3, 123.5, 126.9, 128.7, 129.0, 129.5, 138.2, 148.9, 150.9, 156.8,
(KBr):
m
= 700, 772, 1122, 1214, 1289, 1389, 1589, 1608, 1708 cmꢁ1; MS-ESI:
m/z = 429 [M+1]+.
162.1 ppm; IR (KBr):
m = 697, 750, 1095, 1179, 1216, 1279, 1403, 1566,
1698 cm-1; MS-ESI: m/z = 367 [M+1]+.