Molecular iodine-catalyzed synthesis of 1,2,3,6-tetrahydropyrimidines

Article abstract of DOI:10.1080/00397911.2011.554061

A short and simple synthesis of tetrahydropyrimidine derivatives were accomplished in good to excellect yields at room temperature by the reaction of dimethylacetalynedicarboxylate, aniline, and formaldehyde in the presence of 5mol% of molecular iodine at room temperature in ethanol for 5min.

Full text of DOI:10.1080/00397911.2011.554061

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Molecular Iodine–Catalyzed Synthesis of
1,2,3,6-Tetrahydropyrimidines
Lingaiah Nagarapu a , Hanmanth Reddy Vulupala a , Ch.
Venkatanarsimhaji a , Rajashaker Bantu a & A. Ramakrishna Reddy a
a Organic Chemistry Division II, Indian Institute of Chemical
Technology, Hyderabad, India
Available online: 07 Dec 2011
To cite this article: Lingaiah Nagarapu, Hanmanth Reddy Vulupala, Ch. Venkatanarsimhaji,
Rajashaker Bantu & A. Ramakrishna Reddy (2012): Molecular Iodine–Catalyzed Synthesis of 1,2,3,6-
Tetrahydropyrimidines, Synthetic Communications: An International Journal for Rapid Communication
of Synthetic Organic Chemistry, 42:14, 2131-2138
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Synthetic Communications1, 42: 2131–2138, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.554061
MOLECULAR IODINE–CATALYZED SYNTHESIS OF
1,2,3,6-TETRAHYDROPYRIMIDINES
Lingaiah Nagarapu, Hanmanth Reddy Vulupala,
Ch. Venkatanarsimhaji, Rajashaker Bantu, and
A. Ramakrishna Reddy
Organic Chemistry Division II, Indian Institute of Chemical Technology,
Hyderabad, India
GRAPHICAL ABSTRACT
Abstract
A short and simple synthesis of tetrahydropyrimidine derivatives were
accomplished in good to excellect yields at room temperature by the reaction of dimethyla-
cetalynedicarboxylate, aniline, and formaldehyde in the presence of 5 mol% of molecular
iodine at room temperature in ethanol for 5 min.
Keywords Anilines; dimethylacetalynedicarboxylate; molecular iodine; room tempera-
ture; tetrahydropyrimidines
INTRODUCTION
The synthesis of tetrahydropyrimidines has gained great importance in organic
and medicinal chemistry as the tetrahydropyrimidine scaffold has displayed a fasci-
nating array of pharmacological properties, and these derivatives are the core unit in
several biologically active[1] HIV protease inhibitors[2] and mycobacterium tubercu-
losis inhibitors. These compounds exhibit antihistaminic[3] and antibacterial activity,
have served as muscarinic receptor agonists for treatment of Alzheimer’s disease,[2]
and are used as building blocks in synthetic organic chemistry.
So far, very few methods have been reported[4,5] for the synthesis of
polysubstituted-1,2,3,6-tetrahydropyrimidines. However, some of the methods
employed for tetrahydropyrimidine synthesis have some limitations. To avoid these
limitations, we have searched for a new iodine catalyst with high catalytic activity,
Received September 23, 2010.
Address correspondence to Lingaiah Nagarapu, Organic Chemistry Division II, Indian Institute of
Chemical Technology, Uppal Road, Hyderabad 500 607, India. E-mail: lnagarapuiict@yahoo.com;
lnagarapu@iict.res.in
2131

2132
L. NAGARAPU ET AL.
easy availability, short reaction time, and simple workup. Iodine attracted our atten-
tion because it has been used in many organic transformations.
In recent years, molecular iodine has gained importance as an inexpensive,
nontoxic, and readily available catalyst for various organic transformations, afford-
ing the corresponding products with high selectivity in excellent yields.[6] The mild
Lewis acidity associated with iodine enhanced its usage in organic synthesis for sev-
eral organic transformations, using stoichiometric levels to catalytic amounts. Owing
to advantages associated with this ecofriendly catalyst, molecular iodine has been
explored as a powerful reagent in organic synthesis.[7]
RESULTS AND DISCUSSION
In continuation of our previous work on the synthesis of heterocyclic com-
pounds,[8] we report a facile, efficient, molecular iodine–catalyzed, one-pot,
three-component method for the preparation of 1,2,3,6-tetrahydropyrimidine deriva-
tives in ethanol at room temperature (Scheme 1).
First, we chose 4-fluoroaniline, dimethylacetalynedicarboxylate, and formalin
solution as substrates and examined the reaction with several catalysts at room tem-
perature (Table 1). The best results were obtained when molecular iodine (5 mol%) in
ethanol at room temperature for 5 min was used (Table 1, Entry 10).
After preliminary experimentation, it was found that a mixture of 2 equivalents
of 4-fluoro aniline, dimethylacetalynedicarboxylate, and 2 equivalents of formalin
solution in the presence of a catalytic amount of molecular iodine (5 mol%) in
Scheme 1. Synthesis of 1,2,3,6-tetrahydropyrimidines.
Table 1. Catalyst effect on the reaction of 4-fluoroaniline, dimethylacetlynedicarboxylate, and formalin
solution
Entry
Catalyst
Solvent
DMSO
Temp. (ꢀC)
Time (min)
Yield (%)
1
CH3COONa
CH3COONa
KFꢁalumina
TBAB
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
Rt
300
720
90
36
18
2
Solvent free
DMSO
3
No reaction
28
36
4
Solvent free
EtOH
90
90
5
TBAB
6
SnCl2ꢁ2H2O
Without catalyst
Without catalyst
NaOH
Solvent free
Solvent free
EtOH
90
10
No reaction
20
7
720
180
300
05
8
9
H2O
Ethanol
Solvent free
No reaction
84.6
20
10
11
Iodine
Iodine
05

1,2,3,6-TETRAHYDROPYRIMIDINES
2133
Table 2. Multicomponent reaction of dimethyacetalynedicarboxylate 1, substituted aniline
2, and formalin solution for the synthesis of 4a–4l
Entry
R
Product
Time (min)
Yield (%)
1
C6H5
2-FC6H4
4a
4b
4c
4d
4e
4f
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
84.6
82.2
84.4
69.1
72.4
76.1
62.3
73.9
71.8
88.5
75.6
68.1
2
3
2,4-diF-C6H3
4-CH3C6H4
2-CH3C6H4
C6H5-CH2
4
5
6
7
2,4-diMe-C6H3
4-OCH3C6H4
4-OCF3C6H4
4-FC6H4
4g
4h
4i
8
9
10
11
12
4j
C6H5-CH(CH3)
3-CH3C6H4
4k
4l
ethanol at room temperature for 5 min afforded dimethyl-1,2,3,6-tetrahydro-1,3-
bis(4-fluorophenyl) pyrimidine-4,5-dicarboxylate 4j (Table 2, Entry 10) in 88.5%
yield. The formation of compound 4j was evident from the appearance of [M þ H]þ
ꢂ1
=
peak at m=z 388 in mass spectrum (ESI), -C O stretching at 1740 cm in IR, and
the appearance of –NCH2N- and –NCH2N-COOEt as individual singlets at d 4.77
and 4.16 (the characteristic cyclized protons).
Encouraged by this success, we attempted the reaction of dimethylacetalynedi-
carboxylate with a range of other aromatic anilines and formalin solution under
similar conditions (using 5 mol% molecular iodine), furnishing the respective
1,2,3,6-tetrahydropyramidine derivatives 4a–4 l (Scheme 1) in excellent yields. The
optimized results are listed in Table 2. Many of the pharmacologically relevant sub-
stitution patterns on the aromatic ring could be introduced with high efficiency. A
variety of substituted aromatic anilines carrying electron-donating or
electron-withdrawing substituents afforded good yields of products with high purity.
Based on the literature reports,[4,5] we propose a plausible mechanism for the
formation of 1,2,3,6-tetrahydropyrimidine (4) in the presence of iodine (Scheme 2).
The hydroamination of dimethylacetalynedicarboxylate (1) with aniline (2) could
rapidly form the active intermediate 5, which would then undergo nucleophilic
addition reaction with formaldehyde and subsequent dehydration to afford
1,2,3,6-tetrahydropyrimidines 4.
In summary, we have developed an economically viable and ecofriendly pro-
cedure for the synthesis of 1,2,3,6-tetrahydropyramidine derivatives with excellent
yields and short reaction times that involves the use of inexpensive molecular iodine
as a catalyst in ethanol at room temperature. Furthermore, the present procedure is
readily amenable to parallel synthesis and generation of combinatorial tetrahydro-
pyrimidone libraries.
EXPERIMENTAL
All the commercial reagents and solvents were used without further purifi-
cation unless otherwise stated. Melting points were recorded on a Buchi 535

2134
L. NAGARAPU ET AL.
Scheme 2. Plausible mechanism for the synthesis of 1,2,3,6-tetrahydropyrimidines.
melting-point apparatus and are uncorrected. All the reactions were monitored by
thin-layer chromatography (TLC) performed on precoated silica-gel 60 F254 plates
(Merck). Compounds were visualized with ultraviolet light at 254 nm and 365 nm,
I2, and heating plates after dipping in 2% phosphomolybdic acid in 15% aqueous
H2SO4 soln. Infrared (IR) spectra were recorded on Perkin-Elmer 683 or 1310
Fourier (FT)–IR spectrometers with KBr pellets. NMR spectra were recorded on Var-
ian Unity 400-MHz and Bruker AMX 300 spectrometers using tetramethylsilane
(TMS) as an internal standard. 13C NMR was recorded on a Varian Unity 100-MHz
instrument using CDCl3 as internal standard. Mass spectra were recorded on a VG
Micromass 7070H and a Finnigan Mat 1020B mass spectrometers operating at 70 eV.
Typical Experimental Procedure for the Preparation
of Compounds 4a–l
Molecular iodine (0.05 g, 0.2 mmol) was added to a stirred mixture of
dimethyacetalynedicarboxylate (1, 0.26 mL, 2.0 mmol), aniline (2, 0.39 mL,
4.0 mmol), and formalin solution (0.63 mL, 40% solution) in ethanol (2 mL) at room
temperature. The reaction was completed within 5 min as indicated by TLC. The sol-
vent was removed under reduced pressure, and then ethyl acetate was added, which
was washed with an aqueous sodium thiosulfate solution. The organic phase was
separated, dried over Na2SO4, and concentrated to give an oily product, which
was purified by flash column chromatography using silica gel (60–120 mesh) and
eluted with EtOAc–hexane (1:9) to afford dimethyl-1,2,3,6 tetrahydro-1,3-
bis(4-fluorophenyl)pyramidine-4,5-dicarboxylate 4a as a syrup.

1,2,3,6-TETRAHYDROPYRIMIDINES
2135
Dimethyl-1,2,3,6-tetrahydro-1,3-diphenylpyrimidine-4,
5-dicarboxylate 4a
IR (KBr): nmax 2949, 2853, 1742, 1697, 1584, 1496, 1436, 1262, 1220, 1113, 758,
1
695 cmꢂ1; H NMR (300 MHz, CDCl3): d 7.24–6.85 (m, 10H, Ar-H), 4.89 (s, 2H,
CH2), 4.22 (s, 2H, CH2), 3.74 (s, 3H, OCH3), 3.55 (s, 3H, OCH3); 13C NMR
(75 MHz, CDCl3): d 165.9, 164.4, 148.0, 146.4, 143.4, 129.1, 126.3, 124.8, 121.0,
117.6, 100.3, 68.6, 52.3, 51.4, 47.3. ESI-MS: m=z ¼ 352 [MþH]þ. Anal. calcd.
for C20H20N2O4: C, 68.17; H, 5.72; N, 7.95; O, 18.16. Found: C, 68.09, H, 5.71;
N, 7.90.
Dimethyl-1,2,3,6-tetrahydro-1,3-bis(2-fluorophenyl)pyrimidine-
4,5-dicarboxylate 4b
IR (KBr): nmax 2952, 1740, 1701, 1595, 1502, 1440, 1267, 1233, 1119, 757 cmꢂ1
;
1H NMR (300 MHz, CDCl3): d 7.16–6.69 (m, 8H, Ar-H), 4.80 (s, 2H, CH2), 4.20 (s,
2H, CH2), 3.75 (s, 3H, OCH3), 3.53 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3): d
165.9, 159.3, 146.5, 136.4, 128.5, 128.2, 124.5, 124.2, 123.8, 120.9, 116.4, 116.1, 100.2,
68.9, 52.5, 51.6, 47.7. ESI-MS: m=z ¼ 388 [M þ H]þ. Anal. calcd. for C20H18F2N2O4:
C, 61.85; H, 4.67; F, 9.78; N, 7.21; O, 16.48. Found: C, 61.80; H, 4.61; N, 7.01.
Dimethyl-1,2,3,6-tetrahydro-1,3-(bis(2,4-bis(fluorophenyl))-
pyrimidine-4,5-dicarboxylate 4c
1
IR (KBr): nmax 3081, 2954, 1736, 1599, 1510, 1436, 1263, 1142, 963 cmꢂ1; H
NMR (CDCl3, 300 MHz): d 7.14–6.67 (m, 6H, Ar-H), 4.68 (s, 2H, CH2), 4.14 (s,
2H, CH2), 3.74 (s, 3H, OCH3), 3.56 (s, 3H, OCH3); 13C NMR (75 MHz, CDCl3):
d 167.7, 165.7, 146.6, 129.4, 129.3, 122.8, 121.6, 115.3, 115.1, 111.5, 111.1, 105.0,
104.8, 99.8, 70.4, 52.6, 51.6, 47.7. ESI-MS: m=z ¼ 424 [M þ H]þ. Anal. calcd. for
C20H16F4N2O4: C, 56.61; H, 3.80; F, 17.91; N, 6.60; O, 15.08, Found: C, 56.59;
H, 3.79; N, 6.61.
Dimethyl-1,2,3,6-tetrahydro-1,3-bis(p-tolyl)pyrimidine-
4,5-dicarboxylate 4d
IR (KBr): nmax 2952, 1739, 1702, 1587, 1509, 1438, 1225, 1112, 836, 759 cmꢂ1
;
1H NMR (CDCl3, 300 MHz): d 7.02–6.78 (m, 8H, Ar-H), 4.81 (s, 2H, CH2), 4.17 (s,
2H, CH2), 3.72 (s, 3H, OCH3), 3.55 (s, 3H, OCH3), 2.38 (s, 3H, CH3), 2.34 (s, 3H,
CH3). ESI-MS: m=z ¼ 380 [M þ H]þ. Anal. calcd. for C22H24N2O4: C, 69.46; H, 6.36;
N, 7.36; O, 16.82. Found: C, 69.38; H, 6.31; N, 7.36.
Dimethyl-1,2,3,6-tetrahydro-1,3-bis(o-tolyl)pyrimidine-
4,5-dicarboxylate 4e
IR (KBr): nmax 2950, 2854, 1742 1695, 1595, 1493, 1436, 1261, 1229, 1116,
1
759 cmꢂ1; H NMR (CDCl3, 300 MHz): d 7.24–6.93 (m, 8H, Ar-H), 4.79 (s, 2H,
CH2), 4.07 (s, 2H, CH2), 3.72 (s, 3H, OCH3), 3.47 (s, 3H, OCH3), 2.22 (s, 3H,

2136
L. NAGARAPU ET AL.
CH3), 2.15 (s, 3H, CH3). ESI-MS: m=z ¼ 380 [M þ H]þ. Anal. calcd. for
C22H24N2O4: C, 69.46; H, 6.36; N, 7.36; O, 16.82. Found: C, 69.43, H, 6.34; N, 7.36.
Dimethyl-1,2,3,6-tetrahydro-1,3-dibenzyl-pyrimidine-
4,5-Dicarboxylate 4f
IR(KBr): nmax 3028, 2949, 2853, 1739, 1687, 1582, 1436, 1286, 1110, 744, 699;
1H NMR (CDCl3, 300 MHz): d 7.25–7.12 (m, 10H, Ar-H), 4.12 (s, 2H, CH2), 3.79 (s,
2H, CH2), 3.89 (s, 3H, OCH3), 3.64 (s, 3H, OCH3), 3.59 (s, 2H, Ar-CH2), 3.52 (s, 2H,
Ar-CH2);13C NMR (75 MHz, CDCl3): d 165.6, 148.1, 137.9, 128.7, 128.3, 128.0,
127.2, 92.0, 65.9, 52.9, 51.1, 48.2. ESI-MS: m=z ¼ 380 [M þ H]þ. Anal. calcd. for
C22H24N2O4: C, 69.46; H, 6.36; N, 7.36; O, 16.82. Found: C, 69.41, H, 6.36; N, 7.31.
Dimethyl-1,2,3,6-tetrahydro-1,3-bis(2,6-methylphenyl))pyrimidine-
4,5-dicarboxylate 4g
1
IR (KBr): nmax 2951, 1742, 1695, 1584, 1436, 1261, 1195, 1122, 771; H NMR
(CDCl3, 300 MHz): d 7.12–6.90 (m, 6H, Ar-H), 4.53 (s, 2H, CH2), 3.99 (s, 2H, CH2),
3.66 (s, 3H, OCH3), 3.48 (s, 3H, OCH3), 2.35 (s, 12H, CH3). ESI-MS: m=z ¼ 408
[M þ H]þ. Anal. calcd. for C22H28N2O4: C, 70.57; H, 6.91; N, 6.86; O, 15.67. Found:
C, 70.57, H, 6.90; N, 6.84.
Dimethyl-1,2,3,6-tetrahydro-1,3-bis(p-anisidyl)pyrimidine-
4,5-dicarboxylate 4h
IR (KBr): nmax 2994, 2924, 1740, 1689, 1576, 1510, 1437, 1244, 1109, 1036, 840,
554;1H NMR (CDCl3, 300 MHz): d 6.93–6.68 (m, 8H, Ar-H), 4.73 (s, 2H, CH2), 4.12
(s, 2 H, CH2), 3.71 (s, 3H, OCH3), 3.54 (s, 3H, OCH3), 3.75 (s, 6H, Ar-OCH3); 13C
NMR (75 MHz, CDCl3): d 166.2, 164.5, 147.5, 142.2. 136.0, 127.3, 120.3, 114.2, 97.3,
70.6, 55.5, 52.4, 51.3, 47.7; ESI-MS: m=z ¼ 412 [M þ H]þ. Anal. calcd. for
C22H24N2O6: C, 64.07; H, 5.87; N, 6.79; O, 23.28. Found: C, 64.06, H, 5.87; N, 6.77.
Dimethyl-1,2,3,6-tetrahydro-1,3-bis(p-trifluoromethoxyphenyl)pyrimidine-
4,5-dicarboxylate 4i
IR (KBr): nmax 2953, 1740, 1704, 1592, 1510, 1260, 1164, 1114, 921, 842, 762;
1H NMR (CDCl3, 300 MHz): d 7.13–6.83 (m, 8H, Ar-H), 4.84 (s, 2H, CH2), 4.20 (s,
2H, CH2), 3.75 (s, 3H, OCH3), 3.59 (s, 3H, OCH3). ESI-MS : m=z ¼ 520 [M þ H]þ.
Anal. calcd. for C22H18F6N2O6: C, 50.78; H, 3.49; F, 21.91; N, 5.38; O, 18.45.
Found: C, 50.78, H, 3.49; N, 5.31.
Dimethyl-1,2,3,6-tetrahydro-1,3-bis(p-fluorophenyl)pyrimidine-
4,5-dicarboxylate 4j
IR (KBr): nmax 2950, 2857, 1740, 1697, 1582, 1514, 1436,1260, 1113, 816,
1
759 cmꢂ1; H NMR (CDCl3, 300 MHz): d 7.00–6.83 (m, 8H, Ar-H), 4.77 (s, 2H,
CH2), 4.16 (s, 2H, CH2), 3.74 (s, 3H, OCH3), 3.56 (s, 3H, OCH3). ESI-MS:

1,2,3,6-TETRAHYDROPYRIMIDINES
2137
m=z ¼ 388[M þ H]þ. Anal. calcd. for C20H18F2N2O4: C, 61.85; H, 4.67; F, 9.78; N,
7.21; O, 16.48. Found: C, 61.84, H, 4.66; N, 7.20.
Dimethyl-1,2,3,6-tetrahydro-1,3-bis(methyl
benzyl)pyrimidine-4,5dicarboxylate 4k
IR (KBr): nmax 2953, 1738, 1683, 1582, 1442, 1373, 1286, 1239, 1191, 1130, 757,
1
700; H NMR (CDCl3, 300 MHz) d: 7.32–7.10 (m, 10H, Ar-H), 4.54–4.47 (q, 1H,
CH, J ¼ 6.79 Hz), 3.55–3.48 (q, 1H, CH, J ¼ 6.79 Hz), 3.93 (s, 3H, OCH3),
3.62–3.58 (m, 5H, -OCH3 & CH2), 3.41 (s, 2H, CH2), 1.44–1.41 (d, 3H, CH3,
J ¼ 6.798), 1.06–1.04(d, CH3, 3H, J ¼ 6.043); 13C NMR (75 MHz, CDCl3): d 166.8,
166.0, 143.8, 138.9, 128.5, 128.3, 128.0, 127.2, 91.7, 60.1, 57.3, 52.9, 51.0, 46.5.
ESI-MS: m=z ¼ 408[M þ H]þ. Anal. calcd. for C24H28N2O4: C, 70.57; H, 6.91; N,
6.86; O, 15.67. Found: C, 70.56; H, 6.91; N, 6.85.
Dimethyl-1,2,3,6-tetrahydro-1,3-bis(m-tolyl)pyrimidine-
4,5-dicarboxylate 4l
1
IR(KBr): nmax 2952, 2859, 1741, 1700, 1583, 1440, 1266, 1189, 1115, 1052; H
NMR (CDCl3, 300 MHz): d 7.18–6.62 (m, 8H, Ar-H), 4.85 (s, 2H, CH2), 4.19 (s, 2H,
CH2), 3.73 (s, 3H, OCH3), 3.58 (s, 3H, OCH3), 2.31 (s, 3H, CH3), 2.25 (s, 3H, CH3).
ESI-MS: m=z ¼ 380[M þ H]þ. Anal. calcd. for C22H24N2O4: C, 69.46; H, 6.36; N,
7.36; O, 16.82. Found: C, 69.46; H, 6.36; N, 7.35.
ACKNOWLEDGMENTS
The authors are thankful to the director of IICT–Hyderabad and the head of
Organic Chemistry Division II, IICT, for their constant encouragement and support.
H. R. V. thanks the Council of Scientific and Industrial Research, New Delhi, for the
award of a fellowship.
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