An efficient multicomponent synthesis of polysubstituted pyrrolidines and tetrahydropyrimidines starting directly from nitro compounds in water

Article abstract of DOI:10.1055/s-0030-1258138

A distinct approach for the synthesis of 1,3,3-trisubstituted 4,5-dioxopyrrolidines and 1,3,4,5-tetrasubstituted 1,2,3,6-tetrahydropyrimidines has been discovered, in the form of a three-component reaction of nitroarenes, formaldehyde, and dialkyl acetylenedicarboxylates using indium in dilute aqueous HCl at room temperature. The molar ratios of these substrates are 1:1:4 and 2:1:4 for the preparation of dioxopyrrolidines and tetrahydropyrimidines, respectively. The reactions involve the reduction of nitro compounds to amines, which are simultaneously attacked by dialkyl acetylenedicarboxylates and formaldehyde. The products are formed in good to high yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258138

PAPER
2823
An Efficient Multicomponent Synthesis of Polysubstituted Pyrrolidines and
Tetrahydropyrimidines Starting Directly from Nitro Compounds in Water1
Multicomponent
i
Synthe
s
sis of
P
yrr
w
olidines and
T
etra
a
hydropyrim
n
idines ath Das,* Digambar Balaji Shinde, Boddu Shashi Kanth, Gandham Satyalakshmi
Organic Chemistry Division-1, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27160512; E-mail: biswanathdas@yahoo.com
Received 15 April 2010; revised 21 April 2010
tion is that the 4,5-dioxopyrrolidine derivatives prepared
Abstract: A distinct approach for the synthesis of 1,3,3-trisubstitut-
ed 4,5-dioxopyrrolidines and 1,3,4,5-tetrasubstituted 1,2,3,6-tet-
rahydropyrimidines has been discovered, in the form of a three-
component reaction of nitroarenes, formaldehyde, and dialkyl acet-
by Cao et al. was initially considered6a as 3,6-dihydro-1,3-
oxazines and very recently their structures have been
revised6b through X-ray crystallographic analysis. Here,
ylenedicarboxylates using indium in dilute aqueous HCl at room we report a distinct approach for the synthesis of 4,5-di-
temperature. The molar ratios of these substrates are 1:1:4 and 2:1:4
oxopyrrolidine and tetrahydropyrimidine derivatives
for the preparation of dioxopyrrolidines and tetrahydropyrimidines,
respectively. The reactions involve the reduction of nitro com-
pounds to amines, which are simultaneously attacked by dialkyl
starting directly from the nitro compounds.
In continuation of our work7 on the development of useful
synthetic methodologies using aqueous medium, we have
discovered that 1,3,3-trisubstituted 4,5-dioxopyrrolidines
and 1,3,4,5-tetrasubstituted 1,2,3,6-tetrahydropyrim-
idines can be synthesized efficiently through the three-
component reactions of nitroarenes, dialkyl acetylenedi-
carboxylates, and formaldehyde using indium in dilute
aqueous HCl at room temperature. 4,5-Dioxopyrrolidine
derivatives were formed using a molar ratio of 1:1:4 of
these substrates, while tetrahydropyrimidines were pro-
duced when this ratio was 2:1:4 (Scheme 1).
acetylenedicarboxylates and formaldehyde. The products are
formed in good to high yields.
Key words: pyrrolidines, tetrahydropyrimidines, nitro compounds,
multicomponent synthesis, reactions in water
Pyrrolidines and pyrimidines are considered as important
biologically active heterocycles. The former exhibit anti-
cancer, antibacterial, and antifungal properties2 while the
latter antiviral, anti-inflammatory, and muscarinic agonist
activities.3 Tetrahydropyrimidines are also responsible for
salt and heat sensitivity of protein–DNA interactions.4 Di-
oxopyrrolidines and tetrahydropyrimidines can be pre-
pared by multicomponent reactions5 of anilines,
formaldehyde, and alkynoates, but the methods involving
these reactions are limited.6 Moreover, high temperature,
long reaction time, and the exchange of the functional
groups of the alkynoates with the solvents are the prob-
lems in different earlier methods. Another point to men-
Initially, nitrobenzene (1 mmol) was treated with dimeth-
yl acetylenedicarboxylate (DMAD, 1 mmol) and formal-
dehyde (4 mmol) using different metals such as Sn, Zn, In,
and Fe in aqueous HCl at room temperature (Table 1).
Considering the reaction time and yield, indium8 was
found to be most effective to carry out this conversion.
Subsequently indium/aqueous HCl system was used to
prepare a series of 1,3,3-trisubstituted 4,5-dioxopyrro-
lidines (Table 2) following the above method (Scheme 1).
RO
ROOC
O
molar ratio of
the substituents
1:1:4
O
N
30–40 min
COOR
Ar
In, HCl
H2O, r.t.
ArNO2
4 65–76%
+
HCHO
+
molar ratio of
the substituents
2:1:4
1
3
COOR
2
ROOC
Ar
N
30–40 min
ROOC
N
Ar
5 64–72%
Scheme 1 Synthesis of polysubstituted 4,5-dioxopyrrolidines and tetrahydropyrimidines starting directly from nitro compounds
SYNTHESIS 2010, No. 16, pp 2823–2827
x
x.
x
x
.
2
0
1
0
Advanced online publication: 30.06.2010
DOI: 10.1055/s-0030-1258138; Art ID: Z09510SS
© Georg Thieme Verlag Stuttgart · New York

2824
B. Das et al.
PAPER
preparation of pyrrolidine derivatives (Scheme 1),
Table 1 Synthesis of Polysubstituted 4,5-Dioxopyrrolidine 4a Us-
ing Different Metalsa
1,3,4,5-tetrasubstituted
1,2,3,6-tetrahydropyrimidines
were obtained within 30–40 minutes (Table 3).
Entry
Metal
Sn
Time
10 h
Yield (%)b
Table 3 Synthesis of Tetrasubstituted Tetrahydropyrimidinesa
1
2
3
4
30
32
65
10
Entry Ar
R
Productb
Time (min) Yield (%)c
Zn
7 h
1
2
Ph
Me 5a
Me 5b
Me 5c
Me 5d
Me 5e
40
30
40
30
35
40
40
35
40
35
64
72
67
72
65
67
68
67
67
67
In
30–40 min
14 h
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
Fe
a Reaction conditions: nitrobenzene (1.0 mmol), DMAD (1.0 mmol),
formaldehyde (4.0 mmol), metal (2.0 mmol), and aq 1 M HCl at r.t.
b Isolated yields of pure compounds after column chromatography.
3
4
5
Table 2 Synthesis of 1,3,3-Trisubstituted 4,5-Dioxopyrrolidinesa
6
4-MeOC6H4 Me 5f
7
4-F3CC6H4
Ph
Me 5g
Entry Ar
R
Productb Time (min) Yield (%)c
8
Et
Et
Et
5h
5i
1
2
Ph
Me 4a
Me 4b
35
35
40
30
35
35
40
40
35
40
40
40
40
30
40
65
66
69
75
73
73
76
76
68
70
70
67
70
75
67
9
4-F3CC6H4
4-FC6H4
4-MeC6H4
10
5j
3
4-MeOC6H4 Me 4c
a Reaction conditions: nitroarene (2.0 mmol), alkynoate (1.0 mmol),
formaldehyde (4.0 mmol), In metal (4.0 mmol), and aq 1 M HCl at r.t.
b All products were fully characterized by usual spectroscopic tech-
niques.
4
4-FC6H4
4-ClC6H4
4-BrC6H4
3-ClC6H4
4-HOC6H4
3-MeC6H4
4-F3CC6H4
Ph
Me 4d
Me 4e
Me 4f
Me 4g
Me 4h
Me 4i
Me 4j
5
c Yields of pure isolated products after column chromatography.
6
7
In this case also various nitrobenzenes having different
functionalities and both dimethyl and diethyl acetylene-
carboxylates were used. The yields of the products were
good to high (64–72%). The structures of dioxopyrro-
lidines and tetrahydropyrimidines were settled from their
8
9
10
11
12
13
14
15
1
spectral (IR, H and 13C NMR, ESIMS and HRESIMS)
Et
Et
Et
Et
4k
4l
data.
3-MeC6H4
3-ClC6H4
4-FC6H4
In the present conversions, nitro compounds were initially
reduced to amines,9 which then reacted with dialkyl acet-
ylenedicarboxylates and formaldehyde to form the de-
sired heterocycles (Scheme 2).
4m
4n
4o
4-MeOC6H4 Et
In conclusion, we have developed a novel efficient meth-
od for the synthesis of polysubstituted 4,5- dioxopyrro-
lidines and tetrahydropyrimidine derivatives through a
distinct approach involving the multicomponent reaction
of nitro compounds, dialkyl acetylenedicarboxylates, and
formaldehyde using indium in dilute aqueous HCl at room
temperature. The direct application of nitro compounds,
conversion in water, and mild reaction conditions are the
advantages of the present method.
a Reaction conditions: nitroarene (1.0 mmol), alkynoate (1.0 mmol),
formaldehyde (4.0 mmol), In metal (2.0 mmol), and aq 1 M HCl at r.t.
b All products were fully characterized by usual spectroscopic tech-
niques.
c Yields of pure isolated products after column chromatography.
Various nitroarenes were used to prepare these com-
pounds. Both dimethyl and diethyl acetylenedicarboxy-
lates afforded the desired products smoothly. The 4,5-
dioxopyrrolidine derivatives were formed in good to high
yields (65–76%) within 30–40 minutes. The reaction con-
ditions were mild and various functionalities such as hy-
droxy, ether, and halogen remained intact.
The silica gel F254 plates were used for TLC in which the spots were
examined under UV light and then developed by I2 vapor. Column
chromatography was performed with silica gel (BDH 100–200
mesh). Solvents were purified according to standard procedures.
The spectra were recorded with the following instruments; IR:
Perkin-Elmer RX1 FT-IR spectrophotometer; NMR: Varian Gemini
200 MHz (1H) and 50 MHz (13C) spectrometer; ESIMS: VG-
Autospec micromass and HRMS: QSTAR XL, Hybrid MS system
(Applied Biosystems).
When the reaction of nitroarenes (2 mmol), dialkyl acety-
lenedicarboxylates (1 mmol) and formaldehyde (4 mmol)
was conducted under similar conditions as applied for the
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Multicomponent Synthesis of Pyrrolidines and Tetrahydropyrimidines
2825
In, HCl
ArNH2
ArNO2
InCl3
COOR
COOR
ROOC
H
ROOC
ROOC
InCl3
or H+
OH
NHAr
HCHO
H+
HCHO
H+
ArNH2
+
ROOC
NHAr
OR
COOR
COOR
HO
O
ROOC
ROOC
H
O
H+
– H2O
H2O
H+
OH
N
N
OH
RO
O
N
Ar
4
Ar
Ar
O
HCHO
InCl3 or H+
ArNH2
ArN=CH2
ROOC
ROOC
ROOC
ROOC
Ar
HCHO
InCl3 or H+
NHAr
NAr
N
InCl3 or H+
N
ROOC
ROOC
H
Ar
5
NHAr
Scheme 2 Proposed pathway for the synthesis of polysubstituted pyrrolidines and tetrahydropyrimidines starting directly from nitro com-
pounds
1,3,3-Trisubstituted 4,5-Dioxopyrrolidines 4; General Proce-
dure
Methyl 3-Methoxymethyl-1-(3-methylphenyl)-4,5-dioxopyrro-
lidine-3-carboxylate (4i)
Yield: 68%.
IR (KBr): 1771, 1702, 1512, 1252 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.69 (1 H, d, J = 2.0 Hz), 7.62 (1
H, dd, J = 8.0 Hz), 7.31 (1 H, t, J = 8.0 Hz), 7.09 (1 H, dd, J = 8.0,
2.0 Hz), 4.49 (1 H, d, J = 12.0 Hz), 4.20 (1 H, d, J = 12.0 Hz), 3.93
(1 H, d, J = 10.0 Hz), 3.88 (1 H, d, J = 10.0 Hz), 3.76 (3 H, s), 3.22
(3 H, s), 2.43 (3 H, s).
13C NMR (50 MHz, CDCl3): d = 192.9, 166.2, 156.1, 139.6, 139.0,
129.9, 129.2, 128.1, 120.0, 116.3, 72.8, 59.5, 55.1, 53.8, 49.0, 21.4.
To a mixture of nitro compound 1 (1.0 mmol) and In (325 mesh, 2.0
mmol) were added aq 1 M HCl (1 mL) and H2O (2 mL). The mix-
ture was stirred at r.t. for 10 min followed by addition of alkynoate
2 (1 mmol). After 10 min, formaldehyde (3; 4.0 mmol) was added
and the stirring was continued. The reaction was monitored by TLC.
After completion, the mixture was washed with sat. aq NaHCO3
(3 × 5 mL) and H2O (3 × 5 mL), and extracted with EtOAc (3 × 5
mL). The combined extracts were concentrated and the residue was
subjected to column chromatography (silica gel, hexanes–EtOAc)
to obtain pure 4,5-dioxopyrrolidine derivative (Table 2).
ESIMS: m/z = 292 [M + H]+.
HRMS (ESI): m/z calcd for C15H18NO5 [M + H]+: 292.1179; found:
Tetrasubstituted Tetrahydropyrimidines 5; General Procedure
For the preparation of tetrahydropyrimidines, the similar experi-
mental procedure as above for the 1,3,3-trisubstituted 4,5-dioxo-
pyrrolidines was followed using nitro compound 1 (2.0 mmol),
alkynoate 2 (1.0 mmol), and formaldehyde (3; 4.0 mmol), along
with In (325 mesh, 4.0 mmol), aq 1 M HCl (2 mL), and H2O (3 mL)
(Table 3).
292.1192.
Methyl 1-(4-Trifluoromethylphenyl)-3-methoxymethyl-4,5-di-
oxopyrrolidine-3-carboxylate (4j)
Yield: 70%.
IR (KBr): 1777, 1737, 1613, 1462 cm–1.
The spectral (IR, 1H and 13C NMR, and MS) and analytical data of
the unknown products are given below.
1H NMR (200 MHz, CDCl3): d = 8.02 (2 H, d, J = 8.0 Hz), 7.72 (2
H, d, J = 8.0 Hz), 4.54 (1 H, d, J = 12.0 Hz), 4.22 (1 H, d, J = 12.0
Hz), 3.99 (1 H, d, J = 10.0 Hz), 3.89 (1 H, d, J = 10.0 Hz), 3.80 (3
H, s), 3.34 (3 H, s).
13C NMR (50 MHz, CDCl3): d 193.1, 166.1, 155.9, 141.0, 135.0,
125.8 (br), 124.9, 119.4, 74.2, 60.0, 55.1, 53.8, 49.2.
ESIMS: m/z = 346 [M + H]+.
HRMS (ESI): m/z calcd for C15H14F3NO5 + Na [M + Na]+:
Methyl 1-(4-Hydroxyphenyl)-3-methoxymethyl-4,5-dioxopyr-
rolidine-3-carboxylate (4h)
Yield: 76%.
IR (KBr): 3388, 1772, 1699, 1515, 1458 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.65 (2 H, d, J = 8.0 Hz), 6.93 (2
H, d, J = 8.0 Hz), 4.51 (1 H, d, J = 12.0 Hz), 4.22 (1 H, d, J = 12.0
Hz), 4.00 (1 H, d, J = 10.0 Hz), 3.90 (1 H, d, J = 10.0 Hz), 3.80 (3
H, s), 3.31 (3 H, s).
368.0721; found: 368.0726.
13C NMR (50 MHz, CDCl3): d = 194.2, 166.2, 156.0, 155.6, 130.2,
Ethyl 3-Ethoxymethyl-1-phenyl-4,5-dioxopyrrolidine-3-car-
boxylate (4k)
Yield: 67%.
120.8, 115.7, 72.6, 59.9, 55.1, 53.0, 49.9.
ESIMS: m/z = 294 [M + H]+.
IR (KBr): 1769, 1696, 1513, 1459 cm–1.
HRMS (ESI): m/z calcd for C14H16NO6 [M + H]+: 294.0977; found:
294.0978.
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B. Das et al.
PAPER
Dimethyl 1,3-Bis[4-(trifluoromethyl)phenyl]-1,2,3,6-tetrahy-
dropyrimidine-4,5-dicarboxylate (5g)
Yield: 67%.
1H NMR (200 MHz, CDCl3): d = 7.81 (1 H, d, J = 2.0 Hz), 7.78 (1
H, dd, J = 8.0, 2.0 Hz), 7.42 (1 H, t, J = 8.0 Hz), 7.16 (1 H, dd,
J = 8.0, 2.0 Hz), 4.50 (1 H, d, J = 12.0 Hz), 4.28–4.18 (3 H, m), 3.99
(1 H, d, J = 10.0 Hz), 3.90 (1 H, d, J = 10.0 Hz), 3.48 (2 H, q,
J = 7.0 Hz), 2.43 (3 H, s), 1.27 (3 H, t, J = 7.0 Hz) 1.10 (3 H, t,
J = 7.0 Hz).
13C NMR (50 MHz, CDCl3): d = 193.3, 166.2, 156.1, 139.4, 139.2,
135.0, 130.0, 128.2, 120.4, 116.0, 70.5, 67.5, 61.5, 55.6, 49.8, 23.4,
15.0, 14.3.
IR (KBr): 1742, 1706, 1610, 1437 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.58 (2 H, d, J = 8.0 Hz), 7.41 (2
H, d, J = 8.0 Hz), 7.11 (2 H, d, J = 8.0 Hz), 6.82 (2 H, d, J = 8.0 Hz),
5.00 (2 H, s), 4.31 (2 H, s), 3.75 (3 H, s), 3.62 (3 H, s).
13C NMR (50 MHz, CDCl3): d = 165.8, 164.0, 150.2, 147.0, 145.2,
127.1 (br), 124.0, 119.5, 118.2, 116.0, 105.0, 67.2, 52.6, 52.0, 47.2.
ESIMS: m/z = 489 [M + H]+.
HRMS (ESI): m/z calcd for C22H18F6N2O4 + Na [M + Na]+:
ESIMS: m/z = 320 [M + H]+.
HRMS (ESI): m/z calcd for C17H22NO5 [M + H]+: 320.1497; found:
320.1488.
511.1068; found: 511.1060.
Ethyl 3-Ethoxymethyl-1-(3-methylphenyl)-4,5-dioxopyrroli-
dine-3-carboxylate (4l)
Yield: 70%.
IR (KBr): 1775, 1720, 1593, 1481 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.82 (1 H, dd, J = 8.0, 2.0 Hz),
7.80 (1 H, d, J = 2.0 Hz), 7.36 (1 H, t, J = 8.0 Hz), 7.21 (1 H, dd,
J = 8.0, 2.0 Hz), 4.43 (1 H, d, J = 12.0 Hz), 4.28–4.16 (3 H, m), 3.95
(1 H, d, J = 10.0 Hz), 3.88 (1 H, d, J = 10.0 Hz), 3.45 (2 H, q, J = 7.0
Hz), 1.23 (3 H, t, J = 7.0 Hz) 1.08 (3 H, t, J = 7.0 Hz).
Diethyl 1,3-Bis[4-(trifluoromethyl)phenyl]-1,2,3,6-tetrahydro-
pyrimidine-4,5-dicarboxylate (5i)
Yield: 67%.
IR (KBr): 1738, 1700, 1612, 1327 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.54 (2 H, d, J = 8.0 Hz), 7.41 (2
H, d, J = 8.0 Hz), 7.12 (2 H, d, J = 8.0 Hz), 6.83 (2 H, d, J = 8.0 Hz),
4.99 (2 H, s), 4.31 (2 H, s), 4.21 (2 H, q, J = 7.0 Hz), 4.03 (2 H, q,
J = 7.0 Hz), 1.31 (3 H, q, J = 7.0 Hz), 1.03 (3 H, q, J = 7.0 Hz).
13C NMR (50 MHz, CDCl3): d = 166.0, 163.4, 150.2, 146.7, 144.9,
126.9 (br), 123.7, 119.5, 118.2, 116.7, 114.2, 105.0, 67.0, 62.1,
61.0, 47.3, 14.2, 13.6.
ESIMS: m/z = 517 [M + H]+.
HRMS (ESI): m/z calcd for C24H22F6N2O4 + Na [M + Na]+:
13C NMR (50 MHz, CDCl3): d = 192.3, 165.5, 156.2, 140.0, 135.12,
130.0, 126.6, 124.8, 119.1, 117.3, 70.3, 67.5, 62.7, 55.2, 49.0, 15.1,
14.3.
ESIMS: m/z = 340, 342 [M + H]+.
HRMS (ESI): m/z calcd for C16H19ClNO5 [M + H]+: 340.0951;
539.1376068; found: 539.1395.
found: 340.0963.
Dimethyl 1,3-Di(p-tolyl)-1,2,3,6-tetrahydropyrimidine-4,5-di-
carboxylate (5e)
Acknowledgment
Yield: 65%.
The authors thank CSIR and UGC, New Delhi for financial assis-
tance. They are also thankful to NMR, Mass, and IR Divisions of
IICT for spectral recording.
IR (KBr): 1743, 1698, 1578, 1514, 1436, 1260 cm–1.
1H NMR (CDCl3, 200 MHz): d = 7.04 (2 H, d, J = 8.0 Hz), 6.99 (2
H, d, J = 8.0 Hz), 6.82 (2 H, d, J = 8.0 Hz), 6.79 (2 H, d, J = 8.0 Hz),
4.81 (2 H, s), 4.12 (2 H, s), 3.71 (3 H, s), 3.53 (3 H, s), 2.32 (3 H, s),
2.23 (3 H, s).
13C NMR (CDCl3, 50 MHz): d = 166.2, 164.6, 146.0, 140.8, 136.8,
130.7, 130.6, 129.8, 129.7, 125.2, 118.3, 118.1, 69.2, 52.5, 51.4,
47.6, 21.0, 20.5.
References
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ESI-MS: m/z = 381 [M + H]+
HRMS (ESI): m/z calcd for C22H24N2O4 + Na [M + Na]+: 403.1633;
found: 403.1647.
Dimethyl 1,3-Bis(4-methoxyphenyl)-1,2,3,6-tetrahydropyrimi-
dine-4,5-dicarboxylate (5f)
Yield: 68%.
IR (KBr): 1742, 1695, 1582, 1438, 1249 cm–1.
1H NMR (CDCl3, 200 MHz): d = 6.90 (2 H, d, J = 8.0 Hz), 6.81 (2
H, d, J = 8.0 Hz), 6.74 (2 H, d, J = 8.0 Hz), 6.70 (2 H, d, J = 8.0
Hz), 4.72 (2 H, s), 4.11 (2 H, s), 3.72 (6 H, s), 3.70 (3 H, s), 3.53 (3
H, s).
13C NMR (CDCl3, 50 MHz): d = 166.2, 164.1, 158.0, 154.2, 147.5,
142.1, 135.3, 127.1, 120.0, 114.6, 114.1, 96.9, 70.2, 55.2, 55.0,
51.9, 51.0, 47.4.
ESI-MS: m/z = 435 [M + Na]+.
HRMS (ESI): m/z calcd for C22H24N2O6 + Na [M + Na]+: 435.1532;
found: 435.1516.
Synthesis 2010, No. 16, 2823–2827 © Thieme Stuttgart · New York

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Multicomponent Synthesis of Pyrrolidines and Tetrahydropyrimidines
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Synthesis 2010, No. 16, 2823–2827 © Thieme Stuttgart · New York