Simple protocol for the synthesis of 3,4-dihydropyrimidin-2(1H)-ones using SnCl2·2H2O-LiCl as an inexpensive catalyst system

Article abstract of DOI:10.1081/SCC-120030743

A one-pot synthesis of the 3,4-dihydropyrimidin-2(1H)-ones catalyzed by tin chloride-lithium chloride combination catalyst system involving three component heteroannular cyclization is reported.

Full text of DOI:10.1081/SCC-120030743

This article was downloaded by: [University of Arizona]
On: 03 May 2013, At: 09:05
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer
House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Simple Protocol for the Synthesis of
3,4‐Dihydropyrimidin‐2(1H)‐ones Using
SnCl2 · 2H2O–LiCl as an Inexpensive Catalyst System
M. Shailaja a , A. Manjula a , B. Vittal Rao a & Neelakantan Parvathi a
a Organic Chemistry Division—II, Indian Institute of Chemical Technology, Hyderabad,
500007, India
Published online: 16 Aug 2006.
To cite this article: M. Shailaja , A. Manjula , B. Vittal Rao & Neelakantan Parvathi (2004): Simple Protocol for the
Synthesis of 3,4‐Dihydropyrimidin‐2(1H)‐ones Using SnCl2 · 2H2O–LiCl as an Inexpensive Catalyst System, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 34:9, 1559-1564
To link to this article: http://dx.doi.org/10.1081/SCC-120030743
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to
anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the contents
will be complete or accurate or up to date. The accuracy of any instructions, formulae, and drug doses
should be independently verified with primary sources. The publisher shall not be liable for any loss, actions,
claims, proceedings, demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 9, pp. 1559–1564, 2004
Simple Protocol for the Synthesis of
3,4-Dihydropyrimidin-2(1H)-ones
.
Using SnCl2 2H2O–LiCl as an
Inexpensive Catalyst System#
*
M. Shailaja, A. Manjula, B. Vittal Rao,
and Neelakantan Parvathi
Organic Chemistry Division—II, Indian Institute of Chemical
Technology, Hyderabad, India
ABSTRACT
A one-pot synthesis of the 3,4-dihydropyrimidin-2(1H)-ones catalyzed by
tin chloride–lithium chloride combination catalyst system involving
three component heteroannular cyclization is reported.
Key Words: 3,4-Dihydropyrimidin-2(1H)-one; Organic transformation;
Catalyst system.
#IICT communication number 020713.
*
Correspondence: B. Vittal Rao, Organic Chemistry Division—II, Indian Institute of
Chemical Technology, Hyderabad 500007, India; E-mail: vittalrao@iict.ap.nic.in.
1559
DOI: 10.1081/SCC-120030743
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

ORDER
REPRINTS
1560
Shailaja et al.
INTRODUCTION
Compounds possessing 3,4-dihydropyrimidin-2(1H)-one framework
have shown promising biological activity such as calcium channel blocking,
anti-hypertensive, a-1a-adrenergic antagonistic, etc.[1] The core structure is
commonly built up by the reaction between an aldehyde, urea, and b-keto
ester under acidic conditions as proposed by Biginelli in 1893.[2] This reaction
was reinvestigated by Hinkle and Hey in 1929 by replacing the urea with
thiourea, to give the corresponding 3,4-dihydropyrimidin-2(1H)-thione
derivative under the same Biginelli conditions.[3] Of late this reaction has
attracted the attention of many organic chemists. As a result several reports
have appeared for the construction of the core structure by acid catalysts
.
such as BF3 OEt2, PPE, KSF, InCl3, FeCl3, LiClO4, BiCl3, Mn(OAc)2,
lanthanide triflate, ZrCl4, p-toluenesulphonic acid, etc., improving the yields
on one side and retaining the simplicity of the Biginelli’s approach on the
other side in many cases.[4] Encouraged by the surge of catalytic processes
and driven by economic factors, we focussed our attention on the development
of other alternative reagents that are inexpensive, work under mild and cata-
lytic conditions together resulting in higher yields. Guided by these points and
our experience with tin(II) chloride as an excellent Lewis acid[5] for various
organic transformations prompted us to explore its suitability for the three
component condensation leading to dihydropyrimidin-2-one system.
Tin(II) chloride dihydrate is a well-known reducing agent for nitro and azido
groups, a Lewis acid catalyst for C–C bond formation, for deoxygenation of 1,4-
endo peroxides, protection of dicarboxylic acids, and as a selective agent for the
cleavage of p-methoxy benzyl ether.[6] The efficacy of tin chloride for effective
heteroannulation in a ruthenium catalyzed alkyl group transfer reaction in amines
leading to indoles and quinoline is well known.[7] This property was aptly utilized
very recently for the heteroannulation of 2-aminophenols to benzoxazoles.[7]
Intriguedby theroleplayed by tin chloridein somany important organictrans-
formations, its usefulness for the three component heteroannular cyclization was
explored. The encouraging results are exhibited in Table 1. Further the co-catalyst
lithium chloride could improve the yield. The yield of the condensation increased
.
by two folds when equimolar proportion of LiCl was supplemented with SnCl2
2H2O in ethyl alcohol medium. The absence of tin chloride proved to be ineffective
where as combination catalyst system happened to be the catalyst of choice.

ORDER
REPRINTS
Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones
1561
Table 1. The efficacy of tin chloride for heteroannulation with lithium chloride as
co-catalyst.
Melting point (8C)
Yield
(%)
Entry
R1
R2
X
O
Observed
200–202
Reported
4a
4-(OCH3)–
C6H4
CH3
85a
201–202[4l]
4b
4c
4d
4e
4f
4-(CH3)–C6H4
2,6-(Cl)2–C6H3
4-(NO2)–C6H4
4-(F)–C6H4
4-(F)–C6H4
4-(OH)–C6H3
Ph–CH55CH–
3-(OPh)C6H3
3,4-
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CF3
CH3
O
O
O
O
S
80
60
70
70
81
82
60
88
86
171–172
234–236
206–208
174–176
192–193
226–228
230–232
163
170–172[4l]
—
208–209[4b]
175[4l]
—
4g
4h
4i
O
O
O
O
227–229[4b]
232[4l]
—
4j
175–176
177[4k]
(OCH3)2C6H2
4-(OCH3)–
C6H4
4k
CH3
S
80
150–152
150[9]
—
4l
4-(CH3)C6H3
CH3
S
78
220
aWithout the use of co-catalyst (lithium chloride) the yield was 45%.
An array of aldehydes, urea or thiourea with ethylacetoacetate, and ethyl
trifluoroacetoacetate as b-keto esters were employed in order to investigate
the scope of the reaction. The three-component reaction proceeds very
smoothly in about 6–8 hr time in refluxing ethyl alcohol with 10 mol%
each of tin chloride and lithium chloride providing very good yields of the
products.
Reducing prowess of tin chloride in alcoholic medium has no effect on
the nitro group as is evidenced by the neat product formation and no trace
of corresponding amino substituted pyrimidine derivative was observed.
The reagent system is found to be equally effective with thiourea, a feature
unique to the catalyst system, where as many other reagents failed to give
the title compounds under the same conditions. However, the acidity of the
reagent system does not provide the dihyrdopyrimidin-2-one when ethyl
trifluoromethylacetoacetate was used as the b-keto ester. It rather ended
up in hexahydropyrimidine system as pointed out by earlier reports.[8]
It is the unique electronic properties of the –CF3 group coupled with
the not so acidic nature of the reagent system, prevents the removal of

ORDER
REPRINTS
1562
Shailaja et al.
water from the hexahydropyrimidine (4i) to yield the dihydropyrimidin-
2-one.
In conclusion, we have demonstrated experimentally a simple and
straightforward protocol (combination system of SnCl2–LiCl) which pro-
vides dihydropyrimidin-2-one system in high yield and high purity while
retaining the simplicity of the Biginelli concept. The mildness of the
method together with ease of operation should largely extend the scope
of this, as an alternate reagent system, which is safe and inexpensive for
the three-component Biginelli reaction.
EXPERIMENTAL
General Procedure
A mixture of aldehyde (5 mmol), b-ketoester (5 mmol), urea (5 mmol),
and tin(II) chloride–lithium chloride (10 mol% each) were taken in ethanol
(15 mL) and refluxed for the requisite time (reaction monitored by tlc).
After the completion of the reaction, ethanol was removed under reduced
pressure to obtain the product in most of the cases as a solid. This solid was
washed with water, filtered and purified further by recrystallisation (hot
ethanol/methanol). All the yields mentioned in Table 1 are based on isolated
products. Melting points are uncorrected. All the compounds were character-
ized thoroughly by their spectral (IR, NMR, mass) and physical data.
Wherever literature examples were available the data were compared and
were found to be identical with authentic samples. Analytical data for a typical
example is given below.
1
4f: Mp192–1938C; H NMR (200 MHz, CDCl3 þ DMSO-d6): d 1.18
(t, J ¼ 7 Hz, 3H, CH3), 2.38 (s, 3H, CH3), 4.15 (q, J ¼ 7 Hz, 2H, OCH2),

ORDER
REPRINTS
Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones
1563
5.31 (s, 1H, CH), 7.05 (m, 2H, Ar), 7.45 (m, 2H, Ar), 9.22 and 9.95 (2s, 2H,
NH). LRMS: 294 (Mþ). Anal. Calcd. For C14H15 FN2O2S: C, 57.14; H, 5.1; N,
9.52; S, 10.88 found. C, 57.10; H, 4.91; N, 9.42; S, 10.71.
REFERENCES
1. (a) Rovnyak, G.C.; Kimball, S.D.; Beyer, B.; Cucinotta, G.;
DiMarco, J.D.; Gougoutas, J.Z.; Hedberg, A.; Malley, M.F.;
Mcarthy, J.P.; Zhang, R.; Moreland, S. Calcium entry blockers and acti-
vators; conformational and structural determinants of dihydropyrimidine
calcium channel modulators. J. Med. Chem. 1995, 38, 119;
(b) Atwal, K.S.; Swanson, B.N.; Unger, S.E.; Floyd, D.M.;
Moreland, S.; Hedberg, A.; O’Reilly, B.C. Dihydropyrimidine calcium
channel blockers. 30, 3-carbomoyl-4-aryl-1,2,3,4-tetrahydro-6-methyl-5-
pyrimidine carboxylic acid esters as orally effective antihypertensive
agents. J. Med. Chem. 1991, 34, 806; (c) Rovnyak, G.C.; Atwal, K.S.;
Hedberg, A.; Kimball, S.D.; Moreland, S.; Gougoutas, J.Z.;
O’Reilly, B.C.; Schwartz, J.; Malley, M.F. Dihydropyrimidine calcium
channel blockers. 4. Basic-3-substituted-4-aryl-1,4-dihydropyrimidine-
5-carboxylic acid esters—potent antihypertensive agents. J. Med.
Chem. 1992, 35, 3254; (d) Kappe, C.O.; Fabian, W.M.F. Conformational
analysis of 4-aryl-dihydropyrimidine calcium channel modulators. A
comparison of ab intio semi empirical and x-ray crystallographic studies.
Tetrahedron 1997, 53, 2803.
2. Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.
3. Hinkle, L.E.; Hey, D.H. Recl. Trav. Chim. Pays-Bas. 1929, 48, 1280.
4. (a) Gupta, R.; Gupta, A.K.; Paul, S.; Kachroo, P.L. Indian J. Chem. 1995,
34B, 61; (b) Gupta, R.; Gupta, A.K.; Paul, S.; Kachroo, P.L. Improved
synthesis of some ethyl,4-aryl-6-methyl-1,2,3,4-tetrahydropyrimidin-2-
one/thione-5-carboxylates by microwave irradiation. Indian J. Chem.
1995, 34B, 151; (c) Wipf, P.; Cunningham, A. A solid phase protocol
of the Biginelli dihydropyrimidine synthesis suitable for combinatorial
chemistry. Tetrahedron Lett. 1995, 36, 7819; (d) Studer, A.; Jeger, P.;
Wipf, P.; Curran, D.P. Fluorous synthesis: fluorous protocols for the
Ugi and Biginelli multicomponent condensations. J. Org. Chem. 1997,
62, 2917; (e) Hu, E.H.; Sidler, D.R.; Dolling, U.-H. Unprecedented
catalytic three component one-pot condensation reaction: an efficient syn-
thesis of 5-alkoxycarbonyl-4-aryl-3,4-dihydropyrimidin-2(H)-ones.
J. Org. Chem. 1998, 63, 3454; (f) Kappe, C.O.; Falsone, S.F. Polyphos-
phate ester-mediated synthesis of dihydropyrimidines. Improved

ORDER
REPRINTS
1564
Shailaja et al.
conditions for the Biginelli reaction. Synlett. 1998, 718; (g) Bigi, F.;
Carloni, S.; Frullanti, B.; Maggi, R.; Sartori, G. A revision of the Bignelli
reaction under solid acid catalysis. A solvent free synthesis of dihydropyr-
imidines over montmorillonite KSF. Tetrahedron Lett. 1999, 40, 3465;
(h) Lu, J.; Ma, H.R. Iron (III)-catalysed synthesis of dihydropyrimidi-
nones. Improved conditions for Bignelli reaction. Synlett. 2000, 63;
(i) Yadav, J.S.; Subba Reddy, B.V.; Srinivas, R.; Venugopal, C.;
Ramalingam, T. LiClO4-catalysed one pot synthesis of dihydropyrimidi-
nones: an improved protocol for Bignelli reaction. Synthesis 2001, 1341;
(j) Ramalinga, K.; Vijayalakshmi, P.; Kaimal, T.N.B. Bismuth(III)-
catalysed synthesis of dihydropyrimidinones; improved protocol con-
ditions for the Biginelli reaction. Synlett. 2001, 863; (k) Ananda
Kumar, K.; Kasthuraiah, M.; Suresh Reddy, C.; Devendranath Reddy, C.
.
Mn(OAc)3 2H2O-mediated three component, one-pot condensation
reaction: an efficient synthesis of 4-aryl-substituted-3,4-dihydropyrimi-
din-2(1H)-ones. Tetrahedron Lett. 2001, 42, 7873; (l) Venkateshwar
Reddy, Ch.; Mahesh, M.; Raju, P.V.K.; Ramesh Babu, T.; Narayan
Reddy, V.V. Zirconium (IV) chlorides catalysed one pot synthesis of
3,4-dihydropyrimidin-2(1H)-ones. Tetrahedron Lett. 2002, 43, 2657;
(m) Jin, T.; Zhang, S.; Li, T. P-Toluenesulfonic acid-catalysed efficient
synthesis of dihydropyrimidines: improved high yielding protocol for
the Biginelli reaction. Synth. Commun. 2002, 32, 1847.
5. (a) Joju Davis, K.; Bhalerao, U.T.; Vittal Rao, B. Stannous chloride
catalysed deprotection of tetrahydropyranyl ethers. Indian J. Chem.
1997, 36B, 211; (b) Joju Davis, K.; Bhalerao, U.T.; Vittal Rao, B. Stan-
nous chloride dihydrate: a new catalyst for the tetrahydropyranylation
of alcohols. Synth. Commun. 1999, 29 (10), 1679.
6. Paquette, I.A. Encyclopaedia of Reagents for Organic Synthesis; John
Wiley and Sons Inc.: New York, 1995; Vol. 7, 4892–4896 (and refer-
ences cited therein).
7. Cho, C.S.; Kim, D.T.; Zhang, J.Q.; Ho, S-L.; Kim, T-J.; Shim, S.C. Tin (II)
chloride mediated synthesis of 2-substituted benzoxazoles. J. Heterocyclic
Chem. 2002, 39, 421 (and references cited therein).
8. Kappe, C.O.; Falsone, S.F. Polyphosphate ester mediated synthesis of
dihydropyrimidines. Improved conditions for the Biginelli reaction.
Synlett. 1998, 718.
9. Sherif, S.M.; Yousef, M.M.; Mobarak, K.M.; Abdel-Fattah, A-S.M. A
convenient synthesis of thiazolopyrimidines, thiazolodipyrimidines and
heterocyclo-thiazolopyrimidines. Tetrahedron 1993, 49, 9561.
Received in the UK October 25, 2002

Request Permission or Order Reprints Instantly!
Interested in copying and sharing this article? In most cases, U.S. Copyright
Law requires that you get permission from the article’s rightsholder before
using copyrighted content.
All information and materials found in this article, including but not limited
to text, trademarks, patents, logos, graphics and images (the "Materials"), are
the copyrighted works and other forms of intellectual property of Marcel
Dekker, Inc., or its licensors. All rights not expressly granted are reserved.
Get permission to lawfully reproduce and distribute the Materials or order
reprints quickly and painlessly. Simply click on the "Request Permission/
Order Reprints" link below and follow the instructions. Visit the
U.S. Copyright Office for information on Fair Use limitations of U.S.
copyright law. Please refer to The Association of American Publishers’
Fair Use in the Classroom.
(AAP) website for guidelines on
The Materials are for your personal use only and cannot be reformatted,
reposted, resold or distributed by electronic means or otherwise without
permission from Marcel Dekker, Inc. Marcel Dekker, Inc. grants you the
limited right to display the Materials only on your personal computer or
personal wireless device, and to copy and download single copies of such
Materials provided that any copyright, trademark or other notice appearing
on such Materials is also retained by, displayed, copied or downloaded as
part of the Materials and is not removed or obscured, and provided you do
not edit, modify, alter or enhance the Materials. Please refer to our
Website
User Agreement for more details.
Request Permission/Order Reprints
Reprints of this article can also be ordered at
http://www.dekker.com/servlet/product/DOI/101081SCC120030743