Efficient synthesis of tetrahydropyrimidines and pyrrolidines by a multicomponent reaction of dialkyl acetylenedicarboxylates (=dialkyl but-2-ynedioates), amines, and formaldehyde in the presence of iodine as a catalyst

Article abstract of DOI:10.1002/hlca.201100185

Iodine was explored as an efficient catalyst for the synthesis of tetrahydropyrimidines 4 and pyrrolidines 5 by a multicomponent reaction of dialkyl acetylenedicarboxylates (=dialkyl but-2-ynedioates) 1, amines 2, and HCHO 3 at room temperature (Scheme).

Full text of DOI:10.1002/hlca.201100185

Helvetica Chimica Acta – Vol. 94 (2011)
2087
Efficient Synthesis of Tetrahydropyrimidines and Pyrrolidines by a
Multicomponent Reaction of Dialkyl Acetylenedicarboxylates (¼ Dialkyl
But-2-ynedioates), Amines, and Formaldehyde in the Presence of Iodine as a
Catalyst1)
by Biswanath Das*a), Boddu Shashi Kantha), Digambar Balaji Shindea), and Vinod T. Kambleb)
a) Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500607, India
(phone: þ 91-40-7193434; fax: þ 91-40-7160512; e-mail: biswanathdas@yahoo.com)
b) Organic Chemistry Research Laboratory, School of Chemical Sciences, Swami Ramanand Teerth
Marathwada University, Nanded-431606, Maharashtra, India
Iodine was explored as an efficient catalyst for the synthesis of tetrahydropyrimidines 4 and
pyrrolidines 5 by a multicomponent reaction of dialkyl acetylenedicarboxylates (¼dialkyl but-2-
ynedioates) 1, amines 2, and HCHO 3 at room temperature (Scheme). When the molar ratios of these
substrates were 1:2 :4 and 1:1:4, tetrahydropyrimidines and pyrrolidines were formed, respectively. The
products were obtained in high yields (73 – 85%) within a short period of time (25 – 35 min).
Introduction. – Tetrahydropyrimidines and pyrrolidines are important biologically
active heterocycles. The compounds of the first group possess interesting muscarinic
agonist activity [1], and anti-inflammatory [2] and antiviral properties [3]. Pyrrolidines,
on the other hand, have been recognized as anticancer [4], antibacterial [5], and
antifungal agents [6]. However, the compounds were prepared earlier only by a few
methods involving the reactions of amines or nitro compounds, dialkyl acetylenedi-
carboxylates (¼dialkyl but-2-ynedioates) and HCHO at high temperature or in the
presence of acid catalysts [7 – 12]. Moreover, the pyrrolidines initially prepared by
Jiang and co-workers [10] were originally characterized as oxazine derivatives whose
structures have recently been revised [11]. Actually, there are only these two reports of
a similar procedure for the preparation of pyrrolidines starting from amines following
the stated method. Thus, the chemistry of tetrahydropyrimidines and pyrrolidines are
interesting. Here, we report an alternative efficient mild method for the preparation of
these heterocycles.
Results and Discussion. – In continuation of our work on the development of useful
synthetic methodologies [13 – 17], we observed that tetrahydropyrimidines and
pyrrolidines can conveniently be prepared by a three-component reaction of a dialkyl
acetylenedicarboxylate, an amine, and HCHO in the presence of iodine at room
temperature (Scheme). When the molar ratios of these substrates were 1:2 :4 and
1:1:4, 1,3,4,5-tetrasubstituted 1,2,3,6-tetrahydropyrimidines and 1,3,3-trisubstituted
4,5-dioxopyrrolidines respectively, were formed (Scheme).
1
)
Part 224 in the series ꢂStudies on Novel Synthetic Methodologiesꢃ.
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 94 (2011)
Scheme
Initially, the reaction of 4-bromoaniline with dimethyl acetylenedicarboxylate and
HCHO (molar ratio 1:2 :4) was carried out in the presence of different catalysts such
as trifluoroborane ether (1:1) (BF3 · Et2O), p-toluenesulfonic acid (TsOH), phospho-
molybdic acid on silica gel (PMA · SiO2), 2,4,6-trichlorotriazine (TCT), Ce(NH4)2-
(NO3)6, iodine (I2), and perchloric acid adsorbed on silica gel (HClO4 · SiO2) (Table 1).
Considering the yield (81%) of the corresponding tetrahydropyrimidine and the time
of the conversion (35 min), I2 was decided to be the best catalyst for the present
conversion and was subsequently utilized to prepare a series of tetrahydropyrimidines
from different amines (Table 2). Both dimethyl and diethyl acetylenedicarboxylate
were used to prepare these compounds. The conversion was complete within 25 –
35 min, and the products were formed in high yields (78 – 85%).
Table 1. Synthesis of Tetrahydropyrimidines 4d in the Presence of Different Catalystsa)
Catalyst
Time
Yield [%]b)
Catalyst
Time
Yield [%]b)
BF3 · Et2O
TsOH
PMA · SiO2
TCT
2 h
1 h
1 h
5 h
10
trace
20
HClO4 · SiO2
Ce(NH4)2(NO3)6
I2
1 h
45 min
35 min
50
66
81
10
a) Reaction conditions: dimethyl acetylenedicarboxylate (1.0 mmol), 4-bromoaniline (2.0 mmol),
HCHO (4.0 mmol), and catalyst (10 mol-%) at r.t. b) Yield of pure compound after CC.
A similar reaction was carried out with a molar ratio 1:1:4 of dialkyl
acetylenedicarboxylate, amine, and HCHO to prepare various 1,3,3-trisubstituted
4,5-dioxopyrrolidine-3-carboxylates (Table 3). The compounds were derived from
different amines and dimethyl as well as diethyl acetylenedicarboxylates. The
pyrrolidine derivatives were formed in high yields (73 – 81%) within 25 – 35 min.
The structures of the tetrahydropyrimidine and pyrrolidine derivatives were
1
established from their spectral (IR, H- and 13C-NMR, and MS) data and by the
comparison with those of the known compounds [7 – 12].

Helvetica Chimica Acta – Vol. 94 (2011)
2089
Table 2. Synthesis of Tetrasubstituted Tetrahydropyrimidines (Scheme)a)
R1
R2
Productb)
Time [min]
Yield [%]c)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
35
25
25
35
30
25
30
25
35
35
35
35
82
79
82
81
84
85
79
80
78
83
79
80
4-FꢀC6H4
4-ClꢀC6H4
4-BrꢀC6H4
4-MeꢀC6H4
4-MeOꢀC6H4
4-CF3ꢀC6H4
Me
Et
Ph
4j
4k
4l
Et
Et
4-CF3ꢀC6H4
4-FꢀC6H4
a) Reaction conditions: alkynoate (1.0 mmol), amine (2.0 mmol), HCHO (4.0 mmol), and I2 (10 mol-
%) at r.t. b) All products were fully characterized by usual spectroscopic techniques. c) Yield of pure
isolated product after CC.
Table 3. Synthesis of 1,3,3-Trisubstituted 4,5-Dioxopyrrolidines (Scheme)a)
R1
R2
Productb)
Time [min]
Yield [%]c)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Ph
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
25
30
25
25
35
35
25
30
35
25
35
30
25
35
25
25
78
80
81
75
76
74
73
75
76
73
75
74
73
76
81
80
4-MeꢀC6H4
4-MeOꢀC6H4
4-FꢀC6H4
4-ClC6H4
4-BrꢀC6H4
3-ClꢀC6H4
4-HOꢀC6H4
3-MeꢀC6H4
4-CF3ꢀC6H4
2,3-Cl2ꢀC6H3
3-MeꢀC6H4
3-ClꢀC6H4
4-FꢀC6H4
4-MeOꢀC6H4
Ph
Et
Et
Et
Et
a) Reaction conditions: alkynoate (1.0 mmol), amine (1.0 mmol), HCHO (4.0 mmol), and I2 (10 mol-
%) at r.t. b) All products were fully characterized by usual spectroscopic techniques. c) Yield of pure
isolated product after CC.
The catalyst I2 is easily available and little expensive. It behaves as a Lewis acid,
activating the C¼O group of HCHO as well as the triple bond of the dialkyl
acetylenedicarboxylate to form the products [8 – 11].
Conclusion. – We have explored I2 as an efficient catalyst for the one-pot synthesis
of tetrahydropyrimidines and pyrrolidines. The simple experimental procedure, mild

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Helvetica Chimica Acta – Vol. 94 (2011)
reaction conditions, rapid conversions, and high yields are the notable advantages in
applying this easily available and little expensive catalyst.
The authors thank UGC and CSIR, New Delhi, for financial assistance.
Experimental Part
General. Column chromatography (CC): silica gel (SiO2; 100 – 200 mesh; BDH). TLC: SiO2 GF 254
precoated plates. IR-Spectra: PerkinꢀElmer-RX1 FT-IR spectrophotometer; ˜n in cmꢀ1. NMR-Spectra:
Varian-Gemini spectrometer; at 200 (1H) and 50 MHz (13C) in CDCl3; d in ppm rel. to Me4Si as internal
standard, J in Hz. ESI-MS: VG-Autospec-Micromass spectrometer; in m/z (rel. %). Elemental analyses:
Elementar Vario Micro Cube.
1,2,3,6-Tetrahydropyrimidine-4,5-dicarboxylates. A mixture of dialkyl acetylenedicarboxylate
(1 mmol) and amine (2 mmol) in MeOH (3 ml) was stirred at r.t. for 10 min. Then HCHO (4 mmol)
and I2 (10 mol-%) were added, and the mixture was stirred. After completion of the reaction (TLC
monitoring), the solvent was evaporated and the resulting mixture washed with Na2S2O3 soln. (3 ꢁ 5 ml)
and extracted with AcOEt (3 ꢁ 5 ml). The extract was concentrated, and the residue subjected to CC
(hexane/AcOEt): pure tetrahydropyrimidinedicarboxylate.
4,5-Dioxo-pyrrolidine-3-carboxylates. A similar experimental procedure was followed, with an amine
(1.0 mmol), dialkyl acetylenedicarboxylate (1.0 mmol), and HCHO (4.0 mmol), in the presence of I2
(10 mol-%) as catalyst.
Dimethyl 1,3-Bis(4-chlorophenyl)-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4c): Viscous. IR:
1740, 1704, 1595, 1494, 1261. 1H-NMR: 7.22 (d, J ¼ 8.0, 2 H); 7.13 (d, J ¼ 8.0, 2 H); 6.88 (d, J ¼ 8.0, 2 H);
6.78 (d, J ¼ 8.0, 2 H); 4.80 (s, 2 H); 4.15 (s, 2 H); 3.72 (s, 3 H); 3.59 (s, 3 H). 13C-NMR: 165.9; 164.2; 146.5;
146.2; 142.5; 142.2; 132.1; 130.0; 129.6; 125.5; 119.0; 101.1; 68.8; 52.2; 51.3; 47.2. ESI-MS: 443, 445, 447
([M þ Na]þ). Anal. calc. for C20H18Cl2N2O4: C 57.14, H 4.29, N 6.67; found: C 57.23, H 4.21, N 6.73.
Dimethyl 1,3-Bis(4-bromophenyl)-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4d): Solid. M.p.
152 – 1538. IR: 1743, 1688, 1571, 1488, 1265. 1H-NMR: 7.38 (d, J ¼ 8.0, 2 H); 7.29 (d, J ¼ 8.0, 2 H); 6.82 (d,
J ¼ 8.0 2 H); 6.72 (d, J ¼ 8.0, 2 H); 4.70 (s, 2 H); 4.15 (s, 2 H); 3.72 (s, 3 H); 3.59 (s, 3 H). 13C-NMR: 165.5;
164.2; 147.4; 146.0; 142.2; 132.7; 132.0; 126.2; 120.0; 119.5; 113.7; 101.6; 68.8; 52.9; 51.8; 47.2. ESI-MS:
509, 511, 513 ([M þ H]þ). Anal. calc. for C20H18Br2N2O4: C 17.06, H 3.53, N 5.49; found: C 17.18, H 3.48,
N 5.56.
Dimethyl 1,2,3,6-Tetrahydro-1,3-dimethylpyrimidine-4,5-dicarboxylate (4h): Viscous. IR: 1742, 1688,
1587, 1439, 1250. 1H-NMR: 3.86 (s, 3 H); 3.82 (s, 2 H); 3.62 (s, 3 H); 3.41 (s, 2 H); 2.81 (s, 3 H); 2.42 (s,
3 H). 13C-NMR: 166.7; 155.2; 147.5; 92.1; 70.0; 52.5; 51.2; 49.3; 40.7; 37.2. ESI-MS: 229 ([M þ H]þ). Anal.
calc. for C10H16N2O4: C 52.63, H 7.02, N 12.28; found: C 52.72, H, 7.08, N 12.31.
Dimethyl 1,3-Diethyl-1,2,3,6-tetrahydropyrimidine-4,5-dicarboxylate (4i): Viscous. IR: 1742, 1686,
1581, 1436, 1240. 1H-NMR: 3.98 (s, 2 H); 3.86 (s, 3 H); 3.62 (s, 3 H); 3.48 (s, 2 H); 3.08 (q, J ¼ 7.0, 2 H);
2.58 (q, J ¼ 7.0, 2 H); 1.19 (t, J ¼ 7.0, 3 H); 1.13 (t, J ¼ 7.0, 3 H). 13C-NMR: 166.8; 165.4; 147.9; 90.7; 66.5;
52.8; 51.0; 47.5; 46.6; 45.6; 14.8; 13.1. ESI-MS: 257 ([M þ H]þ). Anal. calc. for C12H20N2O4: C 56.25, H
7.18, N 10.94; found: C 56.31, H 7.21, N 10.87.
Methyl 1-(2,3-Dichlorophenyl)-3-(methoxymethyl)-4,5-dioxopyrrolidine-3-carboxylate (5k): Vis-
cous. IR: 3398, 1762, 1702, 1575, 1453, 1453, 1267. 1H-NMR: 7.30 (d, J ¼ 8.0, 1 H); 6.99 (t, J ¼ 8.0,
1 H); 6.70 (d, J ¼ 8.0, 1 H); 4.86 (d, J ¼ 12.0, 1 H); 4.68 (d, J ¼ 12.0, 1 H); 4.18 (s, 2 H). 13C-NMR: 192.8;
165.8; 157.0; 139.8;134.9; 131.2; 129.8; 125.7; 120.2; 69.8; 60.8; 52.4; 51.7; 49.5. ESI-MS: 350, 348, 346
([M þ H]þ). Anal calc. for C14H13Cl2NO5: C 18.56, H 3.76, N 4.05; found: C 18.68, H 3.82, N 4.01.
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Received May 2, 2011