Antimony trichloride catalyzed three-component reaction of urea, aldehydes and cyclic enol ethers: A novel route to 4-arylhexahydrofuro[2,3-d]pyrimidin- 2(3H)-ones

Article abstract of DOI:10.1016/j.tetlet.2010.10.064

Antimony trichloride efficiently catalyses diastereoselective three-component reaction of urea, aromatic aldehydes and 2,3-dihydrofuran or 3,4-dihydro-2H-pyran leading to 4-arylhexahydrofuro[2,3-d]pyrimidin-2(3H)-ones and 4-arylhexahydro-1H-pyrano[2,3-d]p

Full text of DOI:10.1016/j.tetlet.2010.10.064

Tetrahedron Letters 52 (2011) 26–28
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Antimony trichloride catalyzed three-component reaction of urea,
aldehydes and cyclic enol ethers: a novel route to
4-arylhexahydrofuro[2,3-d]pyrimidin-2(3H)-ones
⇑
R. N. Bhattacharya, Pradip Kundu, Gourhari Maiti
Department of Chemistry, Jadavpur University, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Antimony trichloride efficiently catalyses diastereoselective three-component reaction of urea, aromatic
aldehydes and 2,3-dihydrofuran or 3,4-dihydro-2H-pyran leading to 4-arylhexahydrofuro[2,3-d]pyrimi-
din-2(3H)-ones and 4-arylhexahydro-1H-pyrano[2,3-d]pyrimidin-2(8aH)-ones, respectively in good
yield.
Received 26 August 2010
Revised 4 October 2010
Accepted 7 October 2010
Available online 21 October 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Antimony trichloride
Urea
2,3-Dihydrofuran
Aldehydes
Diastereoselective
4-Arylhexahydrofuro[2,3-d]pyrimidin-
2(3H)-ones
4-Arylhexahydro-1H-pyrano[2,3-
d]pyrimidin-2(8aH)-ones
Multicomponent coupling reactions (MCRs) offer significant
advantages over classical stepwise methods, because they offer ra-
pid and convergent construction of complex molecules without the
need of isolation and purification of any of the intermediates,
resulting in substantial minimization of waste, labour, time and
cost.1 It is a process that triggers the conversion of three or more
starting materials in one-pot to a product displaying large molecu-
lar diversity containing functional group characteristics of all the
precursors. Thus, such reactions are economically and environ-
mentally more attractive and have become an important tool in
modern organic synthesis. They lead to one-pot atom-economic
synthesis of highly functionalised molecules, which in many cases
are of pharmacological importance capable of controlling enzy-
matic and other biological functions. These molecules are accessi-
ble more easily and economically than the biological therapeutics.
With drug-like skeletal structure capable to fit specific receptors,
they usually exhibit enhanced bioactivity, especially orally.2 By
the use of MCR, it is possible to build up a library of molecules use-
ful to establish the nature of a pharmacophore and hence the mol-
ecule of maximum bioactivity.
Fused ring pyrimidinones have shown a broad spectrum of
pharmacological activities and have attracted the interest of syn-
thetic organic chemists over the years.3 They have antibacterial,
antitumor, antihypertensive, cardiotonic, bronchodilator, antialler-
gic, antimalarial, analgesic and even herbicidal properties in some
cases.4–11 However, there had been less exploration of the pharma-
cological properties of hexahydrofuropyrimidinones due to the ab-
sence of a convenient synthetic route. Therefore, these type of
compounds attracted much attention due to their importance for
QSAR study of fused ring pyrimidinones. Recently, Wu and co-
workers disclosed12 a novel three-component, one-pot reaction
involving alkynes, urea or thiourea and aldehydes for the synthesis
of pyrimidinones derivatives mediated by TMS-Cl. Very recently,
Pandey et. al. explored13 a simple and efficient organocatalytic
multicomponent reaction involving 3,4-dihydro-(2H)-pyran, aro-
matic aldehydes and urea/thiourea as substrates and L-proline/
TFA as catalyst to afford hexahydropyrano pyrimidinones (thiones)
in good yields. With this background, in our effort to investigate
the scope of antimony trichloride as a mild Lewis acid catalyst in
organic synthesis,14 we were prompted to find a general synthetic
route towards 4-arylhexahydrofuro[2,3-d]pyrimidin-2(3H)-ones
and homologous 4-arylhexahydro-1H-pyrano[2,3-d]pyrimidin-
2(8aH)-ones by a MCR involving urea, aldehydes and cyclic enol
ethers (Fig. 1).
⇑
Corresponding author. Tel./fax: +91 33 2414 6223.
E-mail address: ghmaiti123@yahoo.co.in (G. Maiti).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.064

R. N. Bhattacharya et al. / Tetrahedron Letters 52 (2011) 26–28
27
R
H
O
SbCl3 (10 mol %)
NH
+
+RCHO
n(H2C)
n(H2C)
H2N NH2
Ethanol,
Reflux (3.5-7 hrs)
O
O
N
O
n = 1,2
H
H
Figure 1. Synthetic route to pyrano and furano pyrimidinones.
We report herein an efficient synthetic route for the preparation
of pyrano and furano[2,3-d]pyrimidinone derivatives in excellent
yield catalysed by SbCl3 and to the best of our knowledge this is
the first report of the use of antimony trichloride as a catalyst for
the synthesis of these type of compounds. Initially, we carried
out the reaction between benzaldehyde, urea and 2,3-dihydrofuran
using different catalysts-solvents combinations in order to find
optimal reaction conditions. The results are summarised in Table 1.
From Table 1, it is evident that antimony trichloride and ethanol
was found to be the most effective catalyst and solvent respec-
tively both in terms of reaction time and yield. The reaction also
proceeds at room temperature but was very slow (Table 1, entry
11). The progress of the reaction was marked by the appearance
of a reddish colour. The optimum quantity of catalyst was screened
and it was found that on increasing the amount of catalyst from
5 mol % to 10 mol %, yield of the reaction increases gradually but
beyond 10 mol % there is no significant improvement of the rate
as well as yield of the reaction. Replacing urea with thiourea did
not produce the corresponding thio-derivative, instead a complex
reaction mixture was obtained which could not be characterised.
The reason for not producing the desired product with thiourea
is probably due to the deactivation of the catalyst which needs to
be studied in detail. To explore the scope of the reaction, we carried
out reactions with various substituted aromatic aldehydes.
Figure 2. X-ray structure of enantiomeric 3b molecule in a unit cell.
contained two molecules, an enantiomeric pair maintaining a cen-
tre of symmetry between them.
Notably, only a single diastereomer was formed from the reac-
tions employing aldehydes 2a–e, in spite of three consecutive chi-
ral centres being present in the molecule. This could be explained
by the proposed mechanism in light of work by Wu and co-
workers12 Initially, a condensation reaction occurs between urea
and aldehyde to form N-acyliminium species which then under-
goes nucleophillic attack by 2,3-dihydrofuran at the imine carbon
to yield an oxonium intermediate with a diastereotopic face.
Now the cyclization occurs by attack of the NH2 group in an exo
fashion, endo attack being disfavoured as the electrophillic cabon
in question is spatially much away from the NH2 group.
However, the aromatic aldehydes having a nitro group led to
diastereomeric mixtures (Table 2, entries 6 and 7). The ratio of iso-
mers was determined from their 1H NMR spectrum. In case of 2,6-
dichlorobenzaldehyde (2c) no diastereomeric mixture was formed
(Table 2, entry 3). So it might be apprehended that the reaction is
very much dependant on the electronic nature of the substituents
on the aromatic ring.
The relative stereochemistry was unequivocally determined by
the nOe and NOESY experiments and by the X-ray crystallographic
analysis (Fig. 2) of compound 3b.17 In nOe difference spectrum of
3e in deaerated DMSO-d6 solvent, significant enhancement was
observed for the hydrogen at C-9 on irradiation of C-10 hydrogen,
which confirmed the cis stereochemistry of ring fusion.
Encouraged by these results, we performed reactions between
urea, aldehydes and 3,4-dihydro-2H-pyran in an effort to build
up similar 4-arylhexahydro-1H-pyrano[2,3-d]pyrimidin-2(8aH)-
one motifs (Table 3). Good to very good yields were obtained with
X-ray structure provided a direct evidence of the cis fused ring
juncture. Crystallization was done in mixed solvent of ethanol
and ethyl acetate by slow evaporation process. In fact each unit cell
Table 1
Optimization of the reaction conditionsa
Table 2
Diastereoselective synthesis of 4-aryl hexahydro furo[2,3-d]pyrimidin-2(3H)-onea,b
Ar
CHO
H
SbCl3
(10 mol %)
Catalyst
(10 mol-%)
H
H
O
O
NH
NH
+
+
ArCHO
2a-g
+
+
H2N
NH2
Solvent
O
Ethanol,
Reflux (3-6 hrs)
H2N NH2
O
O
N
O
O
N
O
H
H
H
3a-g
Entry
Catalyst
Solvent
Temp (°C)
Time (h)
Yieldb (%)
c
1
2
3
4
5
6
7
8
9
ZnCl2
ZnCl2
CH2SO4
CAN
p-TsoH
p-TsoH
SbCl3
SbCl3
SbCl3
SbCl3
SbCl3
C2H5OH
CH3CN
C2H5OH
C2H5OH
CH3CN
C2H5OH
CH3CN
C2H5OH
Toluene
CH3NO2
C2H5OH
78
82
78
78
82
78
82
78
10
10
10
10
10
10
8
Entry
Ar
Time (h)
Product
Yieldc (%)
c
Trace
36
45
26
79
1
2
3
4
5
6
7
Phenyl
4.0
3.5
6.0
4.5
3.5
3.0
3.0
3a
3b
3c
92
91
81
92
86
88
93
2-Bromophenyl
2,6-Dichlorophenyl
4-Fluorophenyl
4-Methoxyphenyl
4-Nitrophenyl
3d
3e
3fd
3ge
4
92
110
100
rt
10
10
72
Trace
2-Nitrophenyl
c
10
11
a
Reaction condition: urea (1.2 mmol), aromatic aldehydes (1.0 mmol),
55
SbCl3(0.1 mmol), 2,3-dihydrofuran (1.5 mmol).15,16
a
All compounds were characterised by 1HNMR, 13CNMR, HRMS, IR.
b
Reaction conditions: urea (1.2 mmol), benzaldehyde (1.0 mmol) in 3 ml solvent,
c
catalyst (0.1 mmol), 2,3-dihydrofuran (1.5 mmol), reflux.
Yield refers to pure and isolated yield.
2:1 Diastereomeric mixture obtained.
10:1 Diastereomeric mixture obtained.
b
d
Pure, isolated yield after column chromatography.
Desired product not formed.
c
e

28
R. N. Bhattacharya et al. / Tetrahedron Letters 52 (2011) 26–28
Table 3
References and notes
Preparation of 4-arylhexahydro-1H-pyrano[2,3-d]pyrimidin-2(8aH)-onesa,b
1. (a) Balme, G.; Bosshart; Monteiro, E. N. Eur. J. Org. Chem. 2003, 4101–4111; (b)
Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51–80; (c) Orru, R. V. A.; Greef, M.
Synthesis 2003, 1471–1499; (d) Zhu, J. Eur. J. Org. Chem. 2003, 1133–1144; (e)
Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321–
3329; (f) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 112, 3168–3210; (g)
Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun. 2003, 551–564; (h)
Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602–1694; (i) Tietze, L. F.
Chem. Rev. 1996, 96, 115–136; (j) Tietze, L. F.; Haunert, F. In Stimulating
Concepts in Chemistry; Vogtle, F., Stoddart, J. F., Shibasaki, M., Eds.; Wiley:
VCH:Weinheim, 2000; pp 39–64.
R
H
SbCl3
(10 mol %)
O
NH
RCHO
+
+
Ethanol,
NH2
H2N
O
O
N
O
Reflux (5 h)
H
H
4a-g
Entry
R
Product
Yieldc (%)
2. (a) Padwa, A. In Progress in Heterocyclic Chemistry; Suschitzky, H., Scriven, E. F.
V., Eds.; Pergamon: Oxford, 1994; Vol. 6, pp 36–55; (b) Butler, M. S. J. Nat. Prod.
2004, 67, 2141–2153.
3. (a) Atwal, K. S.; Rovnyak, G. C.; O’Reilly, B. C.; Schwartz, J. J. Org. Chem. 1989, 54,
5898–5907; (b) Kappe, C. O.; Fabian, W. M. F.; Semones, M. A. Tetrahedron
1997, 53, 2803–2816; (c) Zhu, Y.; Huang, S.; Pan, Y. Eur. J. Org. Chem. 2005,
2354–2367.
4. The Pyrimidines; Fenn, D., Ed.; Wiley: New York, NY, 1994.
5. Ghorab, M. M.; Hassan, A. Y. Phosphorus, Sulfur Silicon Relat. Elem. 1998, 141,
251.
1
2
3
4
5
6
7
Phenyl
4a
4b
4c
4d
4e
4f
88
88
91
94
93
85
82
40-Methylphenyl
40-Chlorophenyl
40-Methoxyphenyl
40-Nitrophenyl
40-Hydroxy-30methoxyphenyl
E-Styryl
4g
a
Reaction conditions: urea (1.2 mmol), aromatic aldehydes (1.0 mmol),
6. Coates, W. J. Eur. Patent 351058, 1990.
SbCl3(0.1 mmol), 3,4-dihydro-2H-pyran (1.5 mmol).
b
All compounds were characterised by 1HNMR, 13CNMR, HRMS, IR.
7. (a) Fosseheim, R.; Svarteng, K.; Mostad, A.; Romming, C.; Shefter, E.; Triggle, D.
J. J. Med. Chem. 1982, 25, 126–131; (b) Levitt, G. U.S. Patent 4,339,267, 1982.; (c)
Love, B.; Goodman, M. M.; Snader, K. M.; Tedeschi, R.; Macko, E. J. Med. Chem.
1974, 17, 965.
8. (a) Broom, A. D.; Shim, J. L.; Anderson, G. L. J. Org. Chem. 1976, 41, 1095–1099;
(b) Grivsky, E. M.; Lee, S.; Sigel, C. W.; Duch, D. S.; Nichol, C. A. J. Med. Chem.
1980, 23, 327–329.
9. Davoll, J.; Clarke, J.; Elslager, E. F. J. Med. Chem. 1972, 15, 837–839.
10. Furuya, S.; Ohtaki, T. Eur. Patent 608565, 1994.
11. Kitamura, N.; Onishi, A. Eur. Patent 163599, 1984.
c
Yield refers to pure and isolated yield.
excellent diastereoselectivity. In all the cases, only a single diaste-
reomer was obtained.
Thus SbCl3 has been proved to be a superior and mild Lewis acid
catalyst in terms of economy, handling, reaction time and yield
compared to the earlier literature.12,13 It also showed tolerance to
free phenolic hydroxyl group as in 4f. The reaction was also
12. Zhu, Y.; Huang, S.; Wan, J.; Yan, L.; Pan, Y.; Wu, A. Org. Lett. 2006, 8, 2599–2602.
and the references cited therein.
13. Pandey, J.; Anand, N.; Tripathi, R. P. Tetrahedron 2009, 65, 9350–9356. and the
references cited therein.
smooth employing an a,b unsaturated aldehyde with no side reac-
tions to yield 4g.
14. (a) Russowsky, D.; Canto, R. F. S.; Sanches, S. A. A.; D’Oca, M. G. M.; Fátima,
Â.; Pilli, R. A.; Kohn, L. K.; Antônio, M. A.; Carvalho, J. E. Bioorg. Chem. 2006,
34, 173–182; (b) Cepanec, I.; Litvic´, M.; Filipan-Litvic´, M.; Grüngold, I.
Tetrahedron 2007, 63, 11822–11827; (c) Maiti, G.; Kundu, P. Tetrahedron Lett.
2006, 47, 5733–5736; (d) Maiti, G.; Kundu, P. Synth. Commun. 2007, 37,
2309–2316; (e) Bhattacharya, R. N.; Kundu, P.; Maiti, G. Synth. Commun.
2010, 40, 476–481.
In summary, we have developed a mild and efficient reaction
between urea, aldehydes and cyclic enol ethers leading to 4-
arylhexahydrofuro[2,3-d]pyrimidin-2(3H)-ones and homologous
4-arylhexahydro-1H-pyrano[2,3-d]pyrimidin-2(8aH)-ones using
catalytic SbCl3 with high atom economy. The notable advantages
of this method are operational simplicity, use of inexpensive SbCl3
catalyst, mild reaction conditions, ease of isolation of products and
non-toxic ethanol as solvent. Due to easy availability of the starting
materials, the reaction might prove to be very useful for building
up pyrimidine scaffolds. Further studies in this area to explore
the synthetic applications of the reaction are being carried out in
our laboratory.
15. Representative
experimental
procedure
for
the
synthesis
of
4-
arylhexahydrofuro[2,3-d]pyrimidin-2(3H)-one (3a): To
a
solution of
benzaldehyde (106 mg, 1 mmol) in 3 ml ethanol, urea (72 mg, 1.2 mmol) was
added and stirred at room temperature for 15 min. To this stirred solution,
SbCl3 (22 mg, 0.1 mmol) was added followed by addition of 2,3-dihydrofuran
(105 mg, 1.5 mmol) and was refluxed for 4 h fitted with a reflux condenser and
a calcium chloride guard tube. The progress of the reaction was followed by
TLC. After completion of the reaction, the volatiles were removed under
reduced pressure and the product was purified by column chromatography
over silica gel (60–120) eluting with 50% ethyl acetate in hexane to afford 3a
(200 mg, 0.92 mmol, 92%) as a white crystalline solid; mp 200 °C. 1H NMR
Acknowledgments
(300 MHz, DMSO-d6):
d 1.62–1.67 (m, 1H), 1.87–1.99 (m, 1H), 2.28 (t,
J = 3.8 Hz, 1H), 3.65 (dd, J = 8.5, 13.9 Hz, 1H), 3.91 (dd, J = 8.0, 15.0 Hz, 1H),
4.10 (d, J = 7.8 Hz, 1H), 4.80 (t, J = 3.9 Hz, 1H), 6.80 (s, 1H), 7.18 (s,1H), 7.25–
7.40 (m, 5H); 13C NMR (75 MHz, DMSO-d6): d 27.5, 41.6, 55.0, 63.9, 83.4, 127.7,
128.0, 128.9, 142.1, 155.8. HRMS: calcd for C12H14N2NaO2 241.0953; found
241.0956.
We express our sincere thanks to Mr. Sudipta Chatterjee, Assis-
tant Professor in Chemistry, Serampore College, Serampore, West
Bengal, India for crystallographic analysis. We also thank the
Department of Chemistry, Jadavpur University for financial and
infrastructural support from UGC-CAS and PURSE-DST programme.
16. This protocol was followed for all reactions listed in Table 2 and Table 3 except
otherwise stated with reaction times listed thereof.
17. Selected X-ray crystallographic data for compound 3b:
rectangular, a = 7.1060(14) Å, b = 13.373(3) Å, c = 25.901(5) Å,
b = 90.00°,
= 90.00°, V = 2461.3(9) Å3. CCDC-778922 contains the
C
12H13BrN2O2,
a
= 90.00°,
Supplementary data
c
Supplementary crystallographic data for the structure reported in this letter.
These data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/datarequest/cif.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.10.064.