Expeditious solvent-free synthesis of 1,3-thiazolanes via multicomponent reactions

Article abstract of DOI:10.1016/j.cclet.2014.02.002

A series of 1,3-thiazolane derivatives have been synthesized via multicomponent reactions of activated acetylenes, primary amines and isothiocyanates in the presence of a catalytic amount of N-methylimidazole under solvent-free conditions.

Full text of DOI:10.1016/j.cclet.2014.02.002

G Model
CCLET-2879; No. of Pages 3
Chinese Chemical Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Expeditious solvent-free synthesis of 1,3-thiazolanes via
multicomponent reactions
b
c
Zinatossadat Hossaini a, , Faramarz Rostami-Charati , Mahboube Eslami Moghadam ,
*
Fatemeh Moghaddasi-Kochaksaraee a
a Department of Chemistry, Qaemshahr Branch, Islamic Azad University, Qaemshahr, Iran
b Department of Chemistry, Faculty of Science, Gonbad Kavous University, P.O. Box 163, Gonbad, Iran
c Chemistry & Chemical Engineering Research Center of Iran, Tehran, Iran
A R T I C L E I N F O
A B S T R A C T
Article history:
A series of 1,3-thiazolane derivatives have been synthesized via multicomponent reactions of activated
Received 18 November 2013
Received in revised form 6 January 2014
Accepted 9 February 2014
Available online xxx
acetylenes, primary amines and isothiocyanates in the presence of
methylimidazole under solvent-free conditions.
a catalytic amount of N-
ß 2014 Zinatossadat Hossaini. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Keywords:
1,3-Thiazolane
Activated acetylenes
Primary amines
Solvent-free
Arylisothiocyanate
1. Introduction
Heterocycles are key compounds in the development of modern
pharmaceutical chemistry, which is the reason why the design of
Multicomponent reactions (MCRs) are defined by three or more
reactants joining in a one-pot procedure to afford a single product
[1–4]. They are economically and environmentally useful because
multi-step syntheses frequently produce a large amount of waste
because the complex isolation actions often involve uncomfort-
able, toxic, and hazardous solvents after each step [5–8]. MCRs are
absolutely suited for combinatorial library synthesis and are
increasing utilized in discovery of new drugs and agrochemicals
[9]. They represent a useful tool toward the one-pot synthesis of
diverse and complex compounds as well as small and drug-like
heterocycles [10,11]. Green chemistry holds significant potential
not only for the reduction of byproducts, waste, and energy
consumption but also in the expansion of new methodologies
toward new materials, using existing technologies [12]. Medicinal
and pharmaceutical chemistry possibly have the best chance to
capitalize the green chemistry technologies [13]. For the perspec-
tive of the eco-friendly ‘‘green chemistry’’, a reaction should
ideally, be conducted under solvent-free conditions with minimal
or no side-product formation and with utmost atomeconomy [14].
amenable synthetic approaches for new heterocyclic systems is
still significant challenge [15]. The thiazolium ring present in
vitamin B1 serves as an electron sink and its coenzyme form is
important for the decarboxylation of keto-acids [16]. Several
pesticides possessing a heterocycle with an S or an N atom are
known in agriculture. A large numbers of heterocycles have
emerged as active pharmaceutical ingredients in several drugs for
their potential anti-inflammatory [17,18], anti-tumor [19] anti-
hyperlipidemic [20], anti-hypertensive [21], anti-HIV infections
[22], and several other biological properties [23,24].
Hence, we investigated a simple three-component reaction
between activated acetylenic compounds, primary amines and
isothiocyanates in the presence of a catalytic amount of N-
methylimidazole under solvent-free conditions at room tempera-
ture which afforded 1,3-thiazolane derivatives 4 in good isolated
yields. Propargylic esters gave lower yields (Scheme 1).
2. Experimental
All chemicals used in this work were purchased from Fluka
(Buchs, Switzerland) and were used without further purification.
Melting points were measured on an Electrothermal 9100
apparatus. Elemental analyses for C, H, and N were performed
*
Corresponding author.
E-mail address: zshossaini@yahoo.com (Z. Hossaini).
http://dx.doi.org/10.1016/j.cclet.2014.02.002
1001-8417/ß 2014 Zinatossadat Hossaini. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Please cite this article in press as: Z. Hossaini, et al., Expeditious solvent-free synthesis of 1,3-thiazolanes via multicomponent reactions,
Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.02.002

G Model
CCLET-2879; No. of Pages 3
2
Z. Hossaini et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
H
N
NR'
R''
NHR'
1
3
+ 2
Solvent- free
N-Methylimidazole (5 mol%)
R
H
R
_
H
N
S
N
+
S
+
R
N
C
S + R'NH2
NR' X3N
5
R'''
r.t., 6 h
R
+
R''
S
7
R'''
4a-j
+
R''
8
_
N
X3N
R'''
+
R'''
2
1
3
N
R''
R
R'
Me
Et
R''
Products
R'''
Yield (%)
6
Me
NR'
NHR
Ph
4a
4b
4c
4d
CO2Me
CO2Me
CO2Et
CO2Et
CO2Me
CO2Me
CO2Et
75
87
70
75
NR'
_
_
4-MeO-C6H4
4-MeO-C6H4
4-Me-C6H4
S
NR
NR'
R''
S
NX3
R
N
S
_
R''
n-Bu
t-Bu
Me
R'''
R'''
+
+
R''
NX3
10
CO2Et
NX3
R'''
4
4-Br-C6H4
4e
4f
80
9
CO2Me
CO2Me
75
78
Me
4-NO2-C6H4
CO2Me
CO2Me
CO2Et
CO2Me
CO2Me
CO2Et
Scheme 2. Proposed mechanism for the synthesis of compound 4.
4g
4h
4i
Me
Et
t-Bu
Me
Me
75
56
R'
N
S
Me
Me
H
H
CO2Me
CO2Et
4-MeO-C6H4
MeO2C
Me
Me
N-Methylimidazole (5 mol%)
Me
52
4j
+
Me
N
H
11
+
S
NR
R
N
C
Solvent free, r.t., 3 h
R'
H
Scheme 1. Synthesis of compound 4 using primary amines, activated acetylenic
1
CO2Me
12a-b
compounds and isothiocyanates.
3
R
R'
Yield (%)
12a
12b Me
4-MeO-C6H4
45
38
CO2Me
H
NR'
NR'
Scheme 3. Reaction of activated acetylenes, isothiocyanates and secondary amins
in the presence of catalytic amount of N-methyl imidazole.
R
H
R
S
N
S
N
H
R''
H
H
The carbonyl groups resonances in the 13C NMR spectra of 4a
appeared at d 172.5 (C55O), d 173.7 (C55O). Also the mass spectra of
4a displayed the molecular ion peak with the correct m/z values.
A proposed mechanism for the formation of compound 4 is
shown in Scheme 2. Apparently, the zwitterionic intermediate 6
that formed from the reaction of N-methylimidazole (X3N) and the
R''
R'''
R'''
Fig. 1. Anti arrangement of 4.
using a Heraeus CHN–O-Rapid analyzer. Mass spectra were
recorded on a FINNIGAN-MAT 8430 spectrometer operating at
an ionization potential of 70 eV. IR spectra were measured on a
Shimadzu IR-460 spectrometer. 1H NMR and 13C NMR spectra were
measured with a BRUKER DRX-500 AVANCE spectrometer at 500.1
and 125.8 MHz, respectively, using CDCl3 as a solvent and TMS as
an internal standard or 85% H3PO4 as an external standard.
General procedure for preparation of compounds 4 and 12: To a
magnetically stirred mixture of activated acetylenes 3 (2 mmol)
electron deficient acetylenic ester
3 is protonated by the
intermediate 5 that was generated in situ from the reaction of
primary amine 2 and isothiocyanate 1, producing intermediates 7
and 8. Nucleophilic attack of the conjugate base 7 on intermediate
8 leads to adduct 9, which undergoes a proton transfer process to
afford a new zwitterion 10. Finally, intramolecular cyclization of 10
with the elimination of N-methylimidazole produces compound 4.
Under similar conditions, these reactions proceed well with
secondary amines but the yields of reactions are lower (Scheme 3).
The configuration of compound 12b is confirmed by nuclear
Overhauser effect (NOE) measurements. Thus, when the olefin
signal was irradiated, the C55NCH3 protons were enhanced by
about 10%, while the N(CH3)2 protons showed no significant
enhancement. Thus, the configuration was deduced from the NOE
measurements and the same configuration was assumed for the
other derivatives of 12.
and N-methylimidazole (5 mol%) was added
a mixture of
isothiocyanates 1 and primary amines 2 or secondary amine 11
(2 mmol) at room temperature. The reaction mixture was then
stirred. After the completion of the reaction [TLC (AcOEt/hexane
1:7) monitoring], 15 mL of H2O was poured into the reaction
mixture. The solid residue was filtered and washed by cold diethyl
ether to afforded pure compounds 4 and 12.
3. Results and discussion
4. Conclusion
The structures of compounds 4a–j were apparent from the 1H-
NMR, 13C NMR and IR spectra which are in agreement with the
proposed structures. For example, the 1H NMR spectrum of 4a
In conclusion, we found that the reaction of activated acetylenic
compounds with isothiocyanates and primary amines in the
presence of a catalytic amount of N-methylimidazole leads to a
facile formation of some functionalized 1,3-thiazolanes under
solvent-free conditions without using any additional catalyst. Also,
butendioate and acrylate derivatives can be synthesized via the
reaction of activated acetylenic compounds with isothiocyanate
and secondary amines in the presence of a catalytic amount of N-
methylimidazole.
displayed two signals for vicinal methine protons at
4.92, which appeared as two doublets with 3JHH values of 12.4 Hz.
The methoxy groups showed two singlets at 3.78 and 3.85.
Observation of 3JHH = 12.4 Hz for the vicinal methine protons in 4a
indicates the dominance of anti arrangement. Since compound 4
possesses two stereogenic centers, two enantiomers with anti
HCCH arrangements are possible (Fig. 1).
d 4.78 and d
d
d
Please cite this article in press as: Z. Hossaini, et al., Expeditious solvent-free synthesis of 1,3-thiazolanes via multicomponent reactions,
Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.02.002

G Model
CCLET-2879; No. of Pages 3
Z. Hossaini et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
3
References
[14] G. Nagendrappa, Organic synthesis under solvent-free condition: an environmen-
tally benign procedure, Resonance 7 (2002) 59–68.
[15] P.M. Dewick, Medicinal Natural Products: A Biosynthetic Approach, 2nd ed.,
Wiley, Chichester, UK, 2002.
[16] R. Breslow, On the mechanism of thiamine action. IV. Evidence from studies on
model systems, J. Am. Chem. Soc. 80 (1958) 3719–3726.
[1] A. Do¨mling, Isocyanide based multi component reactions in combinatorial chem-
istry, Comb. Chem. High Throughput Screening 1 (1998) 1–22.
[2] A. Do¨mling, I. Ugi, Multicomponent reactions with isocyanides, Angew. Chem. Int.
Ed. 39 (2000) 3169–3210.
[17] S. Miwatashi, Y. Arikawa, E. Kotani, et al., Novel Inhibitor of p38 MAP kinase as an
anti-TNF-drug: discovery of N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-
yl]-2-pyridyl]benzamide (TAK-715) as a potent and orally active anti-rheumatoid
arthritis agent, J. Med. Chem. 48 (2005) 5966–5979.
[18] C. Papadopoulou, A. Geronikaki, D. Hadjipavlou-Litina, Synthesis and biological
evaluation of new thiazolyl/benzothiazolyl-amides derivatives, Il Farmaco 60
(2005) 969–973.
[19] Y. Kumar, R. Green, K.Z. Borysko, et al., Synthesis of 2,4-disubstituted thiazoles
and selenazoles as potential antitumor and antifilarial agents. 1. Methyl 4-
(isothiocyanatomethyl)thiazole-2-carbamates-selenazole-2-carbamates, and re-
lated derivatives, J. Med. Chem. 36 (1993) 3843–3848.
[20] R. Pereira, C. Gaudon, B. Iglesias, et al., Synthesis of the PPAR-selective agonist
GW501516 and C4-thiazole-substituted analogs, Bioorg. Med. Chem. Lett. 16
(2006) 49–54.
[3] L. Weber, Multi-component reactions and evolutionary chemistry, Drug Discov.
Today 7 (2002) 143–147.
[4] A. Shaabani, A. Maleki, A.H. Rezayan, A. Sarvary, Recent progress of isocyanide-
based multicomponent reactions in Iran, Mol. Divers. 15 (2011) 41–68.
[5] J. Zhu, H. Bienayme, Multicomponent Reactions, Wiley-VCH, Weinheim,
Germany, 2005.
[6] P. Wipf, C. Kendall, Novel applications of alkenyl zirconocenes, Chem. Eur. J. 8
(2002) 1779–1784.
[7] G. Balme, E. Bossharth, N. Monteiro, Pd-assisted multicomponent synthesis of
heterocycles, Eur. J. Org. Chem. (2003) 4101–4111.
[8] A. Jacobi von Wangelin, H. Neumann, D. Gordes, et al., Multicomponent coupling
reactions of aldehydes and amides: an efficient tool for organic synthesis, Chem.
Eur. J. 9 (2003) 4286–4294.
[9] (a) A. Domling, I. Ugi, Multicomponent reactions with isocyanides, Angew. Chem.
Int. Ed. 39 (2000) 3168–3210;
[21] Y. Tsurumi, H. Ueda, K. Hayashi, et al., WS75624 A and B, new endothelin
converting enzyme inhibitors isolated from Saccharothrix sp. No. 75624, J. Anti-
biot. 48 (1995) 1066–1072.
(b) I. Ugi, A. Domling, Multicomponent reactions in organic chemistry, Endeavour
18 (1994) 115–122;
[22] F.W. Bell, A.S. Cantrell, M. Hoberg, et al., Phenethylthiazolethiourea (PETT)
compounds, a new class of HIV-1 reverse transcriptase inhibitors 1. Synthesis
and basic structure-activity relationship studies of PETT analogs, J. Med. Chem. 38
(1995) 4929–4936.
(c) S. Heck, A. Domling, A versatile multi-component one-pot thiazole synthesis,
Synlett (2000) 424–426.
[10] L. Weber, The application of multi-component reactions in drug discovery, Curr.
Med. Chem. 9 (2002) 2085–2093.
[23] D.S. Millan, R.H. Prager, C. Brand, P.H. Hart, The synthesis and activity of oxazole
and thiazole analogues of urocanic acid, Tetrahedron 56 (2000) 811–816.
[24] W.L. Wang, D.Y. Yao, M. Gu, et al., Synthesis and biological evaluation of novel
bisheterocycle-containing compounds as potential anti-influenza virus agents,
Bioorg. Med. Chem. Lett. 15 (2005) 5284.
[11] I. Yavari, A.S. Shahvelayati, A. Malekafzali, Efficient synthesis of functionalized 2
4-diaminothiazoles from tetramethylguanidine, isothiocyanates, and a-bromo-
ketones, J. Sulfur Chem. 31 (2010) 499–508.
[12] G.W.V. Cave, C.L. Raston, J.L. Scott, Recent advances in solventless synthesis with
remarkable versatility, Chem. Commun. (2001) 2159–2169.
[13] R.A. Sheldon, Catalysis: the key to waste minimization, Chem. Ind. (1997) 12–15.
Please cite this article in press as: Z. Hossaini, et al., Expeditious solvent-free synthesis of 1,3-thiazolanes via multicomponent reactions,
Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.02.002