An efficient one-pot three-component synthesis of 4-phenyl hexahydro-1H-pyrano[2,3-d]pyrimidin-2(8aH)-one derivatives

Article abstract of DOI:10.1002/jhet.379

(Chemical Equation Presented) An efficient method for the synthesis of a series of 4-phenylhexahydro-1H-pyrano[2,3-d]pyrimidin-2(8aH)-one derivatives via the one-pot three-component reaction of aromatic aldehydes, urea or thiourea and 3,4-dihydro-2H-pyran

Full text of DOI:10.1002/jhet.379

May 2010
An Efficient One-Pot Three-Component Synthesis of 4-Phenyl
hexahydro-1H-pyrano[2,3-d]pyrimidin-2(8aH)-one Derivatives
687
Srinivasu V. N. Vuppalapati, Rajashekar Bantu Lingaiah,
and Srinivas Kantevari*
Organic Chemistry Division-II, Indian Institute of Chemical Technology, Hyderabad 500007, India
*E-mail: kantevari@yahoo.com
Received November 5, 2009
DOI 10.1002/jhet.379
Published online 11 May 2010 in Wiley InterScience (www.interscience.wiley.com).
An efficient method for the synthesis of a series of 4-phenylhexahydro-1H-pyrano[2,3-d]pyrimidin-
2(8aH)-one derivatives via the one-pot three-component reaction of aromatic aldehydes, urea or thiourea
and 3,4-dihydro-2H-pyran in DMF/CH3CN using p-TSA catalyst is described. Although three chiral
centers are created, only one diastereomer is formed in a highly selective way. This method has several
advantages such as higher yield, lower cost, and shorter reaction times.
J. Heterocyclic Chem., 47, 687 (2010).
INTRODUCTION
tives using p-TSA as catalyst in DMF/CH3CN under
reflux conditions. This method not only preserved the
simplicity of Biginelli type one-pot condensation but also
remarkably improved the yields of the pyrimidin-2-one
derivatives in shorter reaction times (5–6 h) as against
the longer reaction times required for the other catalysts
(e.g., TMSCl).
Multicomponent reactions (MCRs) are of increasing
importance in organic and medicinal chemistry [1]. In
times, where a premium is put on speed, diversity, and ef-
ficiency in the drug discovery process, MCR strategies
offer significant advantages over conventional linear-type
syntheses [2]. The synthesis of dihydropyrimidinones
using variants of the well-established Biginelli reaction is
one of the most recognized and often used MCRs for the
generation of novel pyrimidine scaffolds [3]. Most nota-
bly are the batzelladine alkaloids, which were found to be
potent HIV gp-120-CD4 inhibitors [4]. There is a wide-
spread interest in the synthesis of pyranopyrimidinones
and related fused ring pyrimidinones with diverse range
of biological properties [5], such as antitumor, antibacte-
rial, antihypertensive, vasodilator, bronchiodilator, hepa-
toprotective, cardiotonic, and antiallergic activities. Some
of them also exhibit antimalarial, antifungal, analgesics,
and herbicidal properties [6]. Recently, modified Biginelli
reaction has been used in accessing fused pyrimidinones
or spiro-fused pyrimidinones [3e,3f]. Recently, Wu and
coworkers [7] reported a TMSCl catalyzed three-compo-
nent diastereoselective reaction of 3,4-dihydro-(2H)-py-
ran with urea/thiourea and aromatic aldehydes to give
respective 4-phenyl hexahydro-1H-pyrano[2,3-d] pyrimi-
din-2(8aH)-ones (thiones). In continuation of our previ-
ous work on the synthesis of heterocyclic compounds [8],
we wish to report an efficient one-pot three-component
method for the preparation of substituted 4-phenyl hexa-
hydro-1H-pyrano[2,3-d] pyrimidin-2(8aH)-one deriva-
RESULTS AND DISCUSSION
Initially, we subjected the condensation of 4-fluoro
benzaldehyde with urea and 3,4-dihydro-2H-pyran in the
presence of various acid catalysts in different solvent
systems at room temperature as well as under reflux
conditions (Table 1). The best yield (95%) of product
4-(4-flurophenyl)hexahydro-1H-pyrano[2,3-d]pyrimidin-
2(8 aH)-one 4g was obtained when p-TSA was used as
catalyst in DMF/CH3CN (1:1) under reflux conditions
(entry 4, Table 1). The formation of product 4g was
1
confirmed by IR, H, 13C, and mass spectral analysis.
Although theoretically three chiral centers are created,
only one diastereomer was formed in a highly selective
way. To access the stereochemistry of the product, we
chose 4-methylbenzaldehyde as substrate and reacted
with urea and 3,4-dihydro-2H-pyran in DMF/CH3CN
(1:1) using p-TSA under identical reaction conditions.
NMR spectral data determined the product as 4-(4-
methylphenyl)hexa hydro-1H-pyrano [2,3-d]pyrimidin-
2(8aH)-one 4a. The spectral data obtained was closely
identical to the literature reported [7], X-ray analyzed,
diasteroselective product 4a.
C
V
2010 HeteroCorporation

688
S. V. N. Vuppalapati, R. Bantu Lingaiah, and S. Kantevari
Vol 47
Table 1
Catalyst effect on the reaction of 4-fluorobenzaldehyde, urea, and 3,4-dihydro-2H-pyran.
Entry
Catalyst
Solvent
Temperature (ꢀC)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
Montmorillonite K10
PPA-SiO2
PPA-SiO2
DMF/CH3CN
DMF/CH3CN
Solvent free
DMF/CH3CN
CH3CN
Reflux
Reflux
120
Reflux
Reflux
Reflux
Reflux
r.t.
10
10
10
5.2
10
10
10
24
24
45
No reaction
No reaction
95
p-TSA
TMSCl/NaI
62
35
Silica sulfuric acid
HCLO4-SIO2
p-TSA
DMF/CH3CN
DMF/CH3CN
DMF/CH3CN
DMF/CH3CN
35
15–20
No reaction
Montmorillonite K10
r.t.
General procedure. Aromatic aldehyde (5 mmol), 3,4-dihy-
dro-2H-pyran (5 mmol) and urea or thiourea (6 mmol) in an-
hydrous DMF/CH3CN (1.5 mL/3 mL) were mixed in a flask
and p-TSA (0.3 mmol) was added at room temperature. The
resulting reaction mixture was stirred at reflux for 5–6 h and
then poured into crushed ice with stirring. The precipitation
was isolated by filtered through a Buechner funnel and washed
with water followed by pet–ether, and then dried to give the
desired product. All products obtained were fully characterized
by spectroscopic methods such as IR, 1H NMR, 13C NMR,
and mass spectroscopy and have been identified by the com-
parison of the spectral data with those reported.
Because of its great facility and easy availability of
catalyst, we further proceeded to examine the scope of
this catalytic transformation. The reaction of 3,4-dihydro-
2H-pyran with a range of other aromatic, and heterocy-
clic aldehydes and urea/thiourea under similar conditions
using p-TSA, furnishing the respective pyrimidin-2-one
derivatives 4a–4l (Scheme 1) in excellent yields. The
optimized results are listed in Table 2. All the products
were fully characterized by IR, NMR, and Mass spectro-
scopic analysis. Many of the pharmacologically relevant
substitution patterns on the aromatic ring could be intro-
duced with high efficiency. A variety of substituted
aromatic heterocyclic aldehydes carrying either electron
donating or withdrawing substituents afforded high yields
of products in high purity. Thiourea has also been used
with similar success to provide corresponding pyrimidin-
2-thione derivatives, which are also of much interest with
regard to the biological activity [9].
4-Phenylhexahydro-1H-pyrano[2,3-d]pyrimidin-2(8aH)-
one 4a. mp 252–254ꢀC; IR (KBr, mmax): 3290, 1685, 1512,
1479, 1181, 1125 cmꢁ1 1H NMR (200 MHz, DMSO-d6): d
.
1.25–1.28 (m, 1H, CH2), 1.46–1.89(m, 4H, CH2 and H-10),
2.30 (s, 3H, CH3), 3.47 (t, J ¼ 10.11 Hz, 1H, H-7), 3.97 (d, J ¼
9.76 Hz, 1H, H-7), 4.48(q, J ¼ 1.92 Hz, 1H, H-9), 4.60 (d, J ¼
11.15 Hz, 1H, H-4), 6.68(s, 1H, NH), 7.08–7.16 (m, 5H, ArH
and NH) Mass LCMS þMS 247. Anal. Calcd. for C14H18N2O2:
C, 68.27; H, 7.37; N, 11.37. Found: C, 68.65; H, 7.86; N, 11.13.
4-(3,4,5-Trimethoxyphenyl)hexahydro-1H-pyrano[2,3-d]
pyrimidin-2(8aH)-one 4b. mp 238–240ꢀC; IR (KBr, mmax):
In summary, we have developed an economically and
environmentally friendly procedure for the synthesis of
substituted 4-phenylhexahydro-1H-pyrano[2,3-d] pyrimi-
din-2(8aH)-ones (thiones) derivatives with excellent
yields and short reaction times, which involves the use
of inexpensive catalyst p-TSA under DMF/CH3CN
reflux conditions. Furthermore, the present procedure is
readily amenable to parallel synthesis and generation of
combinatorial DHPMs libraries.
3371, 3215, 1683, 1597, 1460, 1127, 1033 cmꢁ1 1H NMR
.
(200 MHz, DMSO-d6): d 1.21–1.93 (m, 5H, CH2 and H-10),
3.47–3.55 (m, 1H, H-7), 3.69 (s, 3H, OCH3), 3.82 (s, 6H,
OCH3), 3.95–4.00 (m, 1H, H-7), 4.47–4.50 (m, 1H, H-9), 4.98
(d, J ¼ 10.64 Hz, 1H, H-4), 6.53 (s, 1H, NH), 6.69 (s, 2H,
ArH), 7.30 (brs, 1H, NH); 13C NMR (75 MHz, DMSO-d6): d
20.3 (CH2), 23.0 (CH2), 37.5 (CH), 52.9 (CH), 55.9, 60.0
(OCH3), 65.8 (CH2), 80.2 (CH), 104.7 (ArCH), 125.5, 128.1,
136.9, 152.8 (ArC), 154.8 (C¼¼O); Mass LCMS þMS 323.
Anal. Calcd. for C16H22N2O5: C, 59.61; H, 6.88; N, 8.69.
Found: C, 59.71; H, 6.91; N, 8.71.
EXPERIMENTAL
All reagents were obtained from commercial sources and
used without further purification.1H and 13C NMR spectra were
recorded on Varian FT-200/50 MHz (Gemini) and Bruker UX
NMR FT-300/75 MHz (Avance) instruments, in deuterated
dimethylsulfoxide [D6]-DMSO. Chemical shifts are reported in
parts per million relative to TMS as internal standard. LC-mass
spectra were recorded on a LC-MSD-Trap-SL mass spectrome-
ter. Elemental analyses were performed by Elementar analyzer
Vario EL. Melting points has been recorded on an Electrother-
mal melting point apparatus. The IR spectra were obtained with
Perkin Elmer 240-C instrument using potassium bromide pel-
lets/neat. Analytical TLC of all reactions was performed on
Merck precoated plates (silica gel 60F-254 on glass).
4-(4,5-Dimethoxy-2-nitrophenyl)hexahydro-1H-pyrano[2,3-d]
pyrimidin-2(8aH)-one 4c. mp 231–233ꢀC; IR (KBr, mmax):
3223, 2931, 1687, 1523, 1274, 1175, 1098 cmꢁ1 1H NMR
;
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2010
An Efficient One-Pot Three-Component Synthesis of 4-Phenyl
hexahydro-1H-pyrano[2,3-d]pyrimidin-2(8aH)-one Derivatives
689
Table 2
Multicomponent reaction of 3,4-dihydro-2H-pyran, urea or thiourea, and aromatic aldehydes for the synthesis of 4a–4l.
Entry
R
X
Product
Time (h)
Yield (%)
Ref.
1
2
3
4
5
6
7
8
4-CH3C6H4
O
O
O
O
S
4a
4b
4c
4d
4e
4f
5.5
6.0
5.5
6.0
6.0
5.0
5.2
6.0
98
96
89
91
88
97
95
88
7
–
–
7
7
–
–
–
3,4,5-(OCH3)3C6H2
4,5-(OCH3)2-2-NO2-C6H2
4-OCH3C6H4
4-OCH3C6H4
4-BrC6H4
4-FC6H4
O
O
S
4g
4h
9
10
11
12
2,4-Cl2-C6H3
3-OHC6H4
2,4-Cl2-C6H3
4-FC6H4
S
O
O
S
4i
4j
4k
4l
5.0
5.5
5.0
5.5
84
90
97
86
–
–
–
7
(200 MHz, DMSO-d6): d 1.22 (d, J ¼ 10.92 Hz, 2H, CH2), 1.42–
1.65 (m, 2H, CH2), 2.17 (d, J ¼ 10.92 Hz, 1H, H-10), 3.40–3.52
(m, 2H, H-7), 3.87 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 4.47 (s,
1H, H-9), 5.16 (d, J ¼ 10.19 Hz, 1H, H-4), 6.73 (s, 1H, NH),
7.11 (s, 1H, ArH), 7.36 (brs, 1H, NH), 7.52 (s, 1H, ArH); 13C
NMR (75 MHz, DMSO-d6): d 21.0 (CH2), 23.1 (CH2), 36.9
(CH), 47.4 (CH), 56.3 (OCH3), 65.2 (CH2), 79.9 (CH), 107.4,
110.6 (ArCH), 129.5, 142.5, 148.0, 152.8 (ArC), 154.9 (C¼¼O);
Mass LCMS þMS 338. Anal. Calcd. for C15H19N3O6: C, 53.41;
H, 5.68; N, 12.46. Found: C, 53.49; H, 5.59; N, 12.42.
(CH), 120.5, 129.6 (ArCH), 131.1, 140.8 (Arc), 154.5 (C¼¼O);
mass LCMS þMS 311. Anal. Calcd. for C13H15BrN2O2: C,
50.18; H, 4.86; N, 9.00. Found: C, 50.20; H, 4.98; N, 8.96.
4-(4-Fluorophenyl)hexahydro-1H-pyrano[2,3-d]pyrimidin-
2(8aH)-one 4g. mp 218–220ꢀC; IR (KBr, mmax): 3301, 3245,
1692, 1508, 1220, 1183, 1027 cmꢁ1 1H NMR (200 MHz,
;
DMSO-d6): d 1.28–1.93 (m, 5H, CH2 and H-10), 3.53 (t, J ¼
11.58 Hz, 1H, H-7), 3.97–4.00 (m, 1H, H-7), 4.49 (m, 1H, H-
9), 4.63 (d, J ¼ 10.76 Hz, 1H, H-4), 6.92 (s, 1H, NH), 7.00–
7.09 (m, 2H, ArH), 7.29–7.36 (m, 2H, ArH); 13C NMR (75
MHz, DMSO-d6): d 20.2 (CH2), 22.8 (CH2), 37.7 (CH), 51.9
(CH), 65.8 (CH2), 80.2 (CH), 114.9, 115.2, 129.4 (ArCH),
129.5, 137.5 (ArC), 154.7 (C¼¼O); Mass LCMS þMS 251.
Anal. Calcd. for C13H15FN2O2: C, 62.39; H, 6.04; N, 11.19.
Found: C, 62.32; H, 5.98; N, 11.25.
4-(4-Methoxyphenyl)hexahydro-1H-pyrano[2,3-d]pyrimi-
din-2(8aH)-one 4d. mp 220–222ꢀC; IR (KBr, mmax): 3265,
1682, 1611, 1512, 1274, 1253, 1172, 1030 cmꢁ1 1H NMR
;
(200 MHz, DMSO-d6): d 1.26–1.94 (m, 5H, CH2 and H-10),
3.45 (t, J ¼ 11.65 Hz, 1H, H-7), 3.79 (s, 3H, OCH3), 4.03 (d,
J ¼ 8.73 Hz, 1H, H-7), 4.51 (s, 1H, H-9), 4.65 (d, J ¼ 10.92
Hz, 1H, H-4), 6.79 (s, 1H, NH), 6.86 (d, J ¼ 8.01 Hz, 2H,
ArH),7.24 (d, J ¼ 8.73 Hz, 2H, ArH); 13C NMR (75 MHz,
DMSO-d6): d 21.0, 23.3, 38.0, 53.2, 56.3, 65.9, 80.9, 115.1,
129.5, 129.9, 135.0, 155.2, 158.9; Mass LCMS þMS 263.
Anal. Calcd. for C14H18N2O3: C, 64.10; H, 6.92; N, 10.68.
Found: C, 64.02; H, 6.98; N, 10.68.
4-Furan-2-yl-hexahydro-1H-pyrano[2,3-d]pyrimidin-2(8aH)-
thione 4h. mp >300ꢀC; IR (KBr, mmax): 3196, 2929, 2858,
1619, 1525, 1177, 1029 cmꢁ1 1H NMR (200 MHz, DMSO-
;
d6): d 1.25–1.83 (m, 5H, CH2 and H-10), 3.58–3.62 (m, 1H,
H-7), 3.96 (d, J ¼ 10.97 Hz, 1H, H-7), 4.54 (m, 1H, H-9),
4.68 (d, J ¼ 9.50 Hz, 1H, H-4), 6.34 (s, 1H, NH), 7.14 (d, J
¼ 7.31 Hz, 1H, ArH), 7.40–7.42 (m, 1H, ArH), 7.63 (d, J ¼
7.31 Hz, 1H, ArH), 8.48 (s, 1H, NH); Mass LCMS þMS 239.
Anal. Calcd. for C11H14N2O2S: C, 53.44; H, 5.92; N, 11.76.
Found: C, 53.32; H, 5.82; N, 11.75.
4-(4-Methoxyphenyl)hexahydro-1H-pyrano[2,3-d]pyrimi-
din-2(8aH)-thione 4e. mp 243–245ꢀC; IR (KBr, mmax): 3267,
2935, 2857, 1683, 1611, 1512, 1463, 1254, 1031 cmꢁ1 1H
;
NMR (200 MHz, DMSO-d6): d 1.31–1.95 (m, 5H, CH2 and H-
10), 3.58 (t, J ¼ 11.33 Hz, 1H, H-7), 3.79 (s, 3H, OCH3), 3.99
(d, J ¼ 10.98 Hz, 1H, H-7), 4.50 (m, 1H, H-9), 4.57 (d, J ¼
10.57 Hz, 1H, H-4), 6.88 (d, J ¼ 9.06 Hz, 2H, ArH), 7.22 (d,
J ¼ 8.30 Hz, 2H, ArH) 7.36(brs 1H, NH) 8.47(brs, 1H, NH);
Mass LCMS þMS 279. Anal. Calcd. for C14H18N2O2S: C,
60.40; H, 6.52; N, 10.06. Found: C, 60.38; H, 6.51; N, 10.08.
4-(4-Bromophenyl)hexahydro-1H-pyrano[2,3-d]pyrimidin-
2(8aH)-one 4f. mp 253–256ꢀC; IR (KBr, mmax): 3303, 3208,
4-(2,4-Dichlorophenyl)hexahydro-1H-pyrano[2,3-d]pyri-
midin-2(8aH)-thione 4i. mp 232–234ꢀC; IR (KBr, mmax):
3208, 2924, 1614, 1452, 1258, 1011 cmꢁ1 1H NMR (300
;
MHz, DMSO-d6): d 1.38–2.06 (m, 5H, CH2 and H-10), 3.50
(m, 1H, H-7), 3.82 (d, J ¼ 10.93 Hz, 1H, H-7), 4.50 (m, 1H,
H-9), 4.93 (d, J ¼ 8.59 Hz, 1H, H-4), 7.37–7.46 (m, 3H,
ArH), 8.39 (s, 1H, NH), 8.80 (brs, 1H, NH); Mass LCMS
þMS 317. Anal. Calcd. for C13H14Cl2N2OS: C, 49.22; H, 4.45;
N, 8.83. Found: C, 49.24; H, 4.46; N, 8.81.
1700, 1489, 1297, 1179, 1028 cmꢁ1
;
1H NMR (300 MHz,
4-(3-Hydroxyphenyl)hexahydro-1H-pyrano[2,3-d]pyrimi-
din-2(8aH)-one 4j. mp 244–248ꢀC; IR (KBr, mmax): 3305,
DMSO-d6): d 1.19–1.84 (m, 5H, CH2 and H-10), 3.47 (t, J ¼
11.14 Hz, 1H, H-7), 3.90 (d, J ¼ 11.14 Hz, 1H, H-7), 4.43 (m,
1H, H-9), 4.53 (d, J ¼ 10.76 Hz, 1H, H-4), 6.52 (s, 1H, NH),
7.20 (s, 1H, NH), 7.30 (d, J ¼ 7.93 Hz, 2H, ArH), 7.52 (d, J
¼ 7.93 Hz, 2H, ArH); 13C NMR (75 MHz, DMSO-d6): d 20.2
(CH2), 22.7 (CH2), 37.5 (CH), 52.0 (CH), 65.6 (CH2), 80.1
3228, 1685, 1604, 1508, 1279, 1033 cmꢁ1 1H NMR (200
;
MHz, DMSO-d6): d 1.18–1.76 (m, 5H, CH2 and H-10), 3.40–
3.42 (m, 1H, H-7), 3.90 (d, J ¼ 11.89 Hz, 1H, H-7), 4.40–4.45
(m, 2H, H-9 and H-4), 6.49 (s, 1H, NH), 6.66–6.75 (m, 3H,
ArH), 7.16 (t, J ¼ 8.30 Hz, 1H, ArH) 7.22 (s, 1H, NH); 13C
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

690
S. V. N. Vuppalapati, R. Bantu Lingaiah, and S. Kantevari
Vol 47
Bienayme, H. C.; Oddon, G.; Schmitt, P. Chem Eur J 2000, 6, 3321;
(c) Domling, A.; Ugi, I. Angew Chem Int Ed Engl 2000, 39, 3168.
[2] Dax, S. L.; McNally, J. J.; Youngman, M. A. Curr Med
Chem 1999, 6, 255.
NMR (75 MHz, DMSO-d6): d 20.3 (CH2), 22.8 (CH2), 37.7
(CH), 52.6 (CH), 65.6 (CH2), 80.1 (CH), 113.9, 114.5, 118.1,
129.2 (ArCH), 142.9, 154.6 (ArC), 157.3 (C¼¼O); Mass LCMS
þMS 249. Anal. Calcd. for C13H16N2O3: C, 62.89; H, 6.50; N,
11.28. Found: C, 62.95; H, 6.52; N, 11.23.
[3] (a) Kappe, C. O. Tetrahedron 1993, 49, 6937; (b) Kappe, C.
O. Molecules 1998, 3, 1; (c) Kappe, C. O. Acc Chem Res 2000, 33,
879; (d) Barrow, J. C.; Nantermet, P. G.; Selnick, H. G.; Glass, K. L.;
Rittle, K. E.; Steele, T. G.; Homnick, C. F.; Freidinger, R. M.; Ran-
som, R. W.; Kling, P.; Reiss, D.; Broten, T. P.; Schorn, T. W.; Chang,
R. S. L.; O’Malley, S. S.; Olah, T. V.; Ellis, J. D.; Barrish, A.; Kassa-
hun, K.; Leppert, P.; Nagarathnam, D.; Forray, C. J Med Chem 2000,
43, 2703; (e) Zhu, Y.; Huang, S.; Pan, Y. Eur J Org Chem 2005,
2354; (f) Zhang, H.; Zhou, Z.; Yao, Z.; Xu, F.; Shen, Q. Tetrahedron
Lett 2009, 50, 1622.
4-(2,4-Dichlorophenyl)hexahydro-1H-pyrano[2,3-d]pyri-
midin-2(8aH)-one 4k. mp 258–260ꢀC; IR (KBr, mmax): 3306,
2924, 1698, 1452, 1268, 1028 cmꢁ1 1H NMR (300 MHz,
;
DMSO-d6): d 1.13–1.92 (m, 5H, CH2 and H-10), 3.45–3.49
(m, 1H, H-7), 3.80 (d, J ¼ 9.89 Hz, 1H, H-7), 4.40–4.52 (m,
1H, H-9), 4.92 (d, J ¼ 8.92 Hz, 1H,H-4), 6.62 (s, 1H, NH),
7.34–7.65 (m, 4H, ArH and NH); 13C NMR (75 MHz, DMSO-
d6): d 21.0 (CH2), 22.6 (CH2), 37.0 (CH), 53.0 (CH), 65.2
(CH2), 79.9 (CH), 127.9, 131.0 (ArCH), 136.8, 147.2, 150.3
(ArC), 154.3 (C¼¼O); Mass LCMS þMS 301. Anal. Calcd. for
C13H14Cl2N2O2: C, 51.84; H, 4.69; N, 9.30. Found: C, 51.86;
H, 4.72; N, 9.42.
[4] Bose, D. S.; Sudharshan, M.; Chadhan, S. W. ARKIVOC
2005, 228.
[5] (a) Fosseheim, R.; Svarteng, K.; Mostad, A.; Romming, C.;
Shefter, E.; Triggle, D. J. J Med Chem 1982, 25, 126; (b) Love, B.;
Goodman, M. M.; Snader, K. M.; Tedeschi, R.; Macko, E. J Med
Chem 1974, 17, 956; (c) Hull, R.; Swain, G. Brit. Pat. 868,030 (1961);
(d) Hurst, E. W.; Hull, R. J. J Med Chem 1961, 3, 215; (e) Khania, E.
L.; Sillinietse, G. O.; Ozol, Y. Y.; Dabur, G. Y.; Kimenis, A. A. Khim
Pharm Zh 1978, 78, 1321.
4-(4-Fluoro-phenyl)-hexahydro-1H-pyrano[2,3-d]pyrim-
idine-2(8aH)-thione 4l. mp 256–258ꢀC; IR (KBr, mmax):
3185, 2972, 2875, 1608, 1555, 1512, 1490, 1012 cmꢁ1 1H
;
NMR (200 MHz, DMSO-d6): d 1.24–1.88 (m, 5H, CH2 and H-
10), 3.52 (t, J ¼ 10.98 Hz, 1H, H-7), 3.92 (d, J ¼ 11.10 Hz,
1H, H-7), 4.42 (m, 1H, H-9), 4.48 (d, J ¼ 10.11 Hz, 1H, H-4),
7.20–7.42 (m, 4H, ArH), 8.40 (s, 1H, NH); Mass LCMS þMS
267. Anal. Calcd. for C13H15FN2OS: C, 58.62; H, 5.68; N,
10.52. Found: C, 58.54; H, 5.67; N, 10.54.
[6] (a) Furuya, S.; Ohtaki, T. Eur. Pat. 608,565 (1994); (b)
Coates, W. J. Eur. Pat. 351,058 (1990); (c) Fenn, D., Ed. The Pyrimi-
dines; Wiley: New York, NY, 1994; (d) Heber, D.; Heers, C.; Ravens,
U. Pharmazie 1993, 48, 537; (e) Davoll, J.; Clarke, J.; Elslager, E. F. J
Med Chem 1972, 15, 837.
[7] Zhu, Y.; Huang, S.; Wan, J.; Yan, L.; Pan, Y.; Wu, A. Org
Lett 2006, 8, 2599.
Acknowledgments. The authors thank Dr. J. S. Yadav, Director,
IICT, and Dr. V. V. Narayan Reddy Head, Organic Chemistry Di-
vision-II, IICT, Hyderabad for their constant encouragement and
support.
[8] (a) Srinivas, K.; Srinivasu, V. N. V.; Lingaiah, N. Catal
Commun 2007, 8, 1857; (b) Srinivas, K.; Srinivasu, V. N. V.; Dhanraj
O. B.; Lingaiah N. J Mol Catal A 2007, 266, 109; (c) Srinivas, K.;
Rajashaker, B.; Lingaiah N. J Mol Catal A 2007, 269, 53; (d) Srinivas,
K.; Rajashaker, B.; Lingaiah N. ARKIVOC 2006, xvi, 136; (e) Srini-
vas, K.; Srinivasu, V. N. V.; Rajashaker, B.; Lingaiah, N. J Heterocycl
Chem 2008, 45, 1.
REFERENCES AND NOTES
[1] (a) Biginelli, Passerini three-component and Ugi four-com-
ponent condensations are the most popular among many other reac-
tions for their wide scope and synthetic utility. For reviews, see: (b)
[9] Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.;
Schreiber, S. L.; Mitchison, T. J. Science 1999, 286, 971.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet