Three-component one-pot synthesis of 4-Aryl-2,3-dihydropyrimido[1,2-a] benzimidazol-2-ones catalyzed by l -proline

Article abstract of DOI:10.1002/jhet.1030

An efficient chemoselective synthesis of 4-aryl-2,3-dihydropyrimido[1,2-a] benzimidazol-2-one derivatives from three-component reactions of 2-aminobenzimidazole, Meldrum's acid, and aldehydes via [3+3] atom combination is described. The reaction occurs in

Full text of DOI:10.1002/jhet.1030

1386
Three-Component One-Pot Synthesis of
4-Aryl-2,3-dihydropyrimido[1,2-a]benzimidazol-2-ones
Catalyzed by L-Proline
Vol 49
*
Hassan Sheibani, Kazem Saidi, and Molod Lakaei
Department of Chemistry, Shahid Bahonar University of Kerman, Kerman 76169, Iran
*
E-mail: hsheibani@mail.uk.ac.ir
Received March 29, 2011
DOI 10.1002/jhet.1030
View this article online at wileyonlinelibrary.com.
An efficient chemoselective synthesis of 4-aryl-2,3-dihydropyrimido[1,2-a]benzimidazol-2-one deriva-
tives from three-component reactions of 2-aminobenzimidazole, Meldrum’s acid, and aldehydes via [3+3]
atom combination is described. The reaction occurs in different conditions such as in DMF as solvent at
reflux and in the presence of L-proline as base catalyst.
J. Heterocyclic Chem., 49, 1386 (2012).
INTRODUCTION
Lipson et al. have reported the synthesis of substi-
tuted and unsubstituted 1,2,3,4-tetrahydripyrimido[1,2-a]
benzimidazol-2-and-5-ones from the conjugate addition
of 2-aminobenzimidazole 1 with esters of substituted cin-
namic acids or the acetylenic acids [13]. In this article, we de-
scribe the chemoselective reaction of 2-aminobenzimidazole
with arylidene Meldrum’s acid derivatives to prepare 4-aryl-
2,3-dihydropyrimido[1,2-a]benzimidazol-2-one derivatives
in the presence of base catalyst such as L-proline. Aryli-
dene Meldrum’s acid derivatives were satisfactorily
prepared by condensation of commercially available Mel-
drum’s acid 2 with aldehydes in different conditions, and
these compounds generally used for the generation of the
C═C double bonds [14].
2-Aminobenzo-1,3-diazoles are a biologically important
class of molecules and are versatile reagents, which have been
utilized in synthesis of pharmaceutical productions as 1,
3-dinucleophiles [1,2]. 2-Aminobenzimidazole has three
nitrogen atoms as electron-rich sites. Nucleophilic reactions
on this compound can take place on either the exocyclic or
the endocyclic nitrogen center, depending on the reaction
conditions and the nature of the electrophile [3,4]. The
preparation of fused three-hetero-cyclic compounds has
been reported via reactions of 2-aminobenzimidazole or
2-aminobenzothiazole, with several 1,3-dielectrophiles
[5–7]. Recently, we have reported several reactions of
2-aminobenzimidazole or 2-amino-benzothiazole with
1,3-dielectrophiles such as ethyl-a-cyanocinnamoates,
a-cyanocinnamonitrile, 3-benzylidene-2,4-pentanedione, and
(chlorocarbonyl)phenylketene [8,9], which afforded dihy-
dropyrimido[1,2-a]benzimidazole derivatives (I, II, III,
IV, and V). In these reactions, 2-amino-benzo-1,3-diazoles
act as regioselective compounds (Scheme 1).
Dihydropyrimido[1,2-a]benzimidazoles and their oxo
derivatives deserve interest for their biological and
pharmacological activities and have stimulated new
methods and reagents for the preparation of these
heterocyclic compounds [10]. Condensed pyrimidine
and pyrimidinone compounds with five-membered aro-
matic ring such as 2-aminobenzo-1,3-diazoles have been
shown to exhibit interesting pharmacological properties
[11], and several synthetic methods have been reported
for their preparation [12].
RESULTS AND DISCUSSION
In this study, as exhibited in Scheme 2, we studied the
regioselectivity of three-component reaction of 2-amino-
benzimidazole 1, Meldrum’s acid 2, and aldehydes 3 under
thermal conditions and microwave heating. We found that
when equimolar amounts of 2-aminobenzimidazole are
refluxed with both Meldrum’s acid and aldehydes (3a–f)
in DMF, the compounds 4-aryl-2,3-dihydropyrimido[1,2-
a]benzimidazol-2-one derivatives 4a–f are formed. The
same products are obtained when these reactions are car-
ried out in the presence of L-proline as a base catalyst in
ethanol.
So, we have investigated the regioselectivity of the 2-
aminobenzothiazole 1 with Meldrum’s acid 2 and
© 2012 HeteroCorporation

November 2012
Three-Component One-Pot Synthesis
1387
of 4-Aryl-2,3-dihydropyrimido[1,2-a]benzimidazol-2-ones Catalyzed by L-Proline
Scheme 1
aldehydes 3 in ethanol under microwave irradiation, which
afforded same products with thermal conditions.
product. These products are due to chemoselective addition
of the exocyclic nitrogen center on Cb and endocyclic nitrogen
center on carbonyl groups.
As it is shown in Table 1, yield of the reaction is mark-
edly affected by the reaction conditions, and optimum
results were obtained, when reactions were run in ethanol
and in the presence of L-proline as a base catalyst. The
reactions were carried out in alcoholic solution with high
yields, and enhanced reactivity and selectivity were ob-
served because of the solubility of all the reagents in
alcohol solvent.
As the three-component reaction of 2-aminobenzimidazole
1, Meldrum’s acid 2, and aldehydes 3a–f involve, first,
Knoevenagel condensation to produce arylidene Meldrum’s
acid derivatives followed by Michael addition, we have
investigated the regioselectivity of Michael addition of
2-aminobenzimidazole with arylidene Meldrum’s acid
derivatives 5a,b in various conditions which afforded
products 4a,b (Scheme 3).
The structures of compounds 4a–f were established on
the basis of spectral data and shown distinctive, expected
features. The IR spectra of these compounds measured in
potassium bromide pellets show bands at 3400–3100 cmÀ1
and 1728–1689 cmÀ1 related to elongation of the NH and
C═O groups, respectively. In the 1H NMR spectra of
compounds 4a–f, five kinds of proton signals along with one
signal quite down field (d = 11.70 ppm), arising from the NH
group, and the aromatic proton signals at d = 7.82–6.98 ppm
(m, 9H) were observed. The ABX system of protons of
the moiety ─CH─CH2─ of the pyrimidine ring appeared
at chemical shifts d 5.93 (1H, dd, CH), 3.50 (1H, dd,
3
2JBA = 16.2, JBX = 7.2 Hz, HB) and 2.88 (1H, dd,
CH2 (HA). The 13C NMR of these compounds showed 16
distinct resonances in agreement with the proposed structure.
Although the detailed mechanism of the above reactions in
the diferent reaction conditions not to be fully clarified, the
formation of compounds 4a–f in the presence of L-proline
as a base catalyst could be explained by a reaction sequence that
2-Aminobenzimidazole 1a acts as a binucleophile toward
the deficient centers at Cb and carbonyl group of arylidene
Meldrum’s acid derivatives to release 4-aryl-2,3-dihydropy-
rimidopyrimido[1,2-a]benzimidazol-2-ones as the only
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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H. Sheibani, K. Saidi, and M. Lakaei
Vol 49
Table 1
Synthesis of 4a–f under different reaction conditions.
Without catalyst (DMF as solvent)
L-Proline (ethanol as solvent)
Compd No.
Ar
Time (min)
Yield (%)
Time (min)
Yield (%)
4a
4b
4c
4d
4e
4f
C6H5
4-MeC6H4
4-MeOC6H4
3,4,5-(MeO)3C6H2
4-ClC6H4
60
62
70
60
30
30
80
77
74
70
90
85
10
10
12
12
5
90
90
85
75
92
90
2,4-Cl2C6H3
5
125.77 MHz, respectively. Mass spectra were recorded on a
MS-QP2000A Shimadzu mass spectrometer operating at an
ionization potential of 70 eV. Elemental analyses were
performed using a Heracus CHN-O-Rapid analyzer.
presented in Scheme 4. In principle, these reactions can proceed
via a reaction sequence of condensation, addition, cyclization,
and elimination. L-Proline catalyzed the formation of iminium
ion I, and the higher reactivity of iminum ion compared to the
carbonyl group could facilitate Knoevenagel condensation of
aldehydes with Meldrum’s acid, via intermediate II, and after
the elimination of L-proline, arylidine Meldrum’s acid III might
be produced as an intermediate. 2-Aminobenzimidazole will
attack arylidine Meldrum’s acid derivatives via chemoselective
Michael addition to give the intermediate IV, which followed
by the cycloaddition and losing one molecule of acetone and
CO2 to form the final products 4.
General procedure for the preparation of 4-aryl-2,3-
dihydropyrimido[1,2-a][1,3]benzimidazol-2-one derivatives
(4a–f). Method I. A mixture of 2-aminobenzimidazole (2 mmol),
aldehyde (2 mmol), and Meldrum’s acid (2 mmol) was refluxed
in DMF (2 mL) for the time reported in Table 1 (the progress of
the reaction being monitored by TLC and using n-hexane/ethyl
acetate as an eluent). The product was precipitated from the
reaction mixture after cooling, and then 2-propanol (10 mL)
was added. The precipitate was filtered and recrystallized
from ethanol.
In summary, we have described chemoselective synthesis
of 4-aryl-2,3-dihydropyrimido[1,2-a]benzimida-zol-2-one
derivatives from three-component reactions of 2-aminoben-
zimidazole, Meldrum’s acid, and aldehydes via [3+3]
atom combination in different reaction conditions such
as in DMF as solvent at reflux and in the presence of L-proline
as a base catalyst under reflux condition. The advantage of
these procedures reported here are high conversions and
selectivity, high purity of products, and easy workup.
Method II. A mixture of 2-aminobenzimidazole (2 mmol),
aldehyde (2 mmol), Meldrum’s acid (2 mmol), and L-proline
(0.2 mmol) was refluxed in ethanol (2 mL) for the time reported
in Table 1 (monitored by TLC), and then 30 mL of H2O was
added. The precipitate was filtered off and recrystallized from
ethanol.
2-Phenyl-2,3-dihydropyrimido[1,2-a]benzimidazole-2-one
(4a). Pale yellow crystals. mp 281–284ꢀC. IR (KBr, nma1x/cmÀ1):
3125 (NH), 1728 (C═O), 1649 (C═N), 1589 (C═C). H NMR
(500 MHz, DMSO-d6): 11.70 (1H, s, NH), 7.82 (1H, d, 3JHH = 7.7 Hz
Ar), 7.43–6.98 (8H, m, Ar), 5.93 (1H, dd, 3JXB = 7.1, 3JXA = 3.0 Hz,
CH), 3.50 (1H, dd, 2JBA = 16.2, 3JBX = 7.2 Hz, CH2 (HB)), 2.88 (1H,
EXPERIMENTAL
2
3
dd, JAB = 16.2, JAX = 3.1 Hz, CH2 (HA)). 13C NMR (125 MHz,
DMSO-d6): 165.7 (C═O), 153.7, 143.5, 129.0, 128.6, 127.9, 126.3,
125.6, 124.6, 120.5, 115.8, 113.2, 52.8 (C2), 38.5 (C3). EI-MS, m/z
(%): 263 (M+, 94), 220(76), 167(15), 149(54), 133(100), 103(47),
77(59), 57(64), 43(90). Anal. Calcd. For C16H13N3O: C, 72.99; H,
4.98; N, 15.96 %. Found: C, 72.68; H, 4.75; N, 15.59.
General procedures. Melting points were measured on a
Gallenkamp melting point apparatus and are uncorrected. IR
spectra were measured on a Mattson 1000 FTIR spectrometer.
The proton and carbon NMR spectra were recorded with a
BRUKER DRX-500 AVANCE spectrometer at 500 and
Scheme 3
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November 2012
Three-Component One-Pot Synthesis
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of 4-Aryl-2,3-dihydropyrimido[1,2-a]benzimidazol-2-ones Catalyzed by L-Proline
Scheme 4
2-(4-Methylphenyl)-2,3-dihydropyrimido[1,2-a]benzimidazole-2-
one (4b). Orange crystals. mp 281–285ꢀC. IR (KBr, nmax/cmÀ1):
3321 (NH), 1689 (C═O), 1636 (C═N), 1582 (C═C). 1H NMR
(500 MHz, DMSO-d6): 11.72 (1H, s, NH), 7.44–6.94 (8H, m, Ar),
154.7, 153.8, 144.4, 137.9, 136.8, 130.5, 125.5, 121.4, 116.8,
114.1, 104.8, 60.8 (C2), 59.8 (2OCH3), 54.1 (OCH3), 40.9 (C3).
EI-MS, m/z (%): 353 (M+, 6.5), 279(8.5), 221(15), 196(10.5), 167
(20), 149(91.2), 133(45), 105(25), 69(56), 57(81), 43(100). Anal.
Calcd. For C19H19N3O4: C, 64.58; H, 5.42; N, 11.89 %. Found: C,
64.22; H, 5.36; N, 11.51.
3
3
5.88 (1H, dd, JXB = 7.8, JXA = 2.9 Hz, CH), 3.46 (1H, dd,
3
2
2JBA = 16.3, JBX = 7.5 Hz, CH2(HB)), 2.87 (1H, dd, JAB = 16.4,
3JAX = 3.1 Hz, CH2 (HA)), 2.23 (3H, s, CH3). 13C NMR (125
MHz, DMSO-d6): 167.3 (C═O), 147.9, 141.9, 137.5, 136.3, 132.3,
129.5, 129.1, 126.2, 125.6, 121.6, 120.8, 117.4, 109.5, 51.8 (C2),
38.5 (C3), 20.5 (CH3). EI-MS, m/z (%): 277 (M+, 7), 199(48), 175
(79), 170(79), 160(12), 144(5), 133(100), 118(5), 105(39), 90(12),
78(16), 63(10), 57(3), 51(14), 43(27). Anal. Calcd. For C17H15N3O:
C, 73.63; H, 5.45; N, 15.15%. Found: C, 73.38; H. 5.33; N; 14.91.
2-(4-Methoxyphenyl-2,3-dihydropyrimido[1,2-a]benzimidazole-
2-one (4c). Pale yellow crystals. mp 285–288ꢀC. IR (KBr, nmax/cmÀ1):
2-(4-Chlorophenyl)-2,3dihydropyrimido[1,2-a]benzimidazole-2-
one (4e). White crystals. Mp = 280–283ꢀC. IR (KBr, nmax/cmÀ1):
1
3126 (NH), 1728 (C═O), 1646 (C═N), 1590 (C═C). H NMR
(500 MHz, DMSO-d6): 11.92 (1H, s, NH), 7.91–6.86 (8H, m, Ar),
3
3
5.93 (1H, dd, JXB = 7.5, JXA = 2.9 Hz, CH), 3.50 (1H, dd,
2JBA = 16.6, 3JBX = 7.7 Hz, CH2(HB)), 2.84 (1H, dd, 2JAB = 16.6,
3JAX = 3.0 Hz, CH2 (HA)). 13C NMR (125 MHz, DMSO-d6):
165.5 (C═O), 153.60, 143.5, 139.5, 139.0, 138.2, 132.5,
131.5, 129.7, 129.7, 129.0, 129.0, 128.9, 128.8, 128.2,
128.0, 127.6, 124.64, 116.0, 113.2, 52.3 (C2), 38.2 (C3).
EI-MS, m/z (%): 299 (M+2, 13), 297 (M+, 39), 254(17),
220(15), 196(15), 161(96), 133(74), 118(15), 105(23), 97
(22), 90(27), 83(25), 77(49), 57(61), 43(100). Anal. Calcd.
For C16H12ClN3O: C, 64.54; H, 4.06; N, 14.11%. Found: C,
64.38; H, 3.91; N, 13.79.
1
3431 (NH), 1728 (C═O), 1648 (C═N), 1589 (C═C). H NMR
(500 MHz, DMSO-d6): 11.66 (1H, s, NH), 7.83–6.72 (8H, m, Ar),
3
3
5.84 (1H, dd, JXB = 7.5, JXA = 3.2 Hz, CH), CH), 3.68
2
3
(3H, s, CH3), 3.42 (1H, dd, JBA = 16.1, JBX = 7.5 Hz, CH2
2
3
(HA)), 2.88 (1H, dd, JAB = 16.5, JAX = 3.3 Hz, CH2(HB)).
13C NMR (125 MHz, DMSO-d6): 167.4 (C═O), 159.0,
147.9, 147.9, 132.3, 131.0, 127.0, 124.7, 121.5, 120.7,
117.4, 115.6, 114.4, 109.5, 55.1 (CH3), 51.8 (C2), 38.6 (C3).
EI-MS, m/z (%): 293 (M+, 41), 250 (10), 161 (100), 133(16),
91(10), 77(10), 43(6). Anal. Calcd. For C17H15N3O2: C,
69.61; H, 5.15; N, 14.33 %. Found: C, 69.35; H, 5.04; N, 14.49.
2-(3,4,5-Trimethoxyphenyl)-2,3-dihydropyrimido[1,2-a]
benzimidazole-2-one (4d). Pale yellow crystals. mp 290–295ꢀC. IR
(KBr, nmax/cmÀ1): 3409 (NH), 1713 (C═O), 1665 (C═N), 1591
2-(2,4-Dicholorophenyl)-2,3-dihydropyrimido[1,2-a]
benzimidazole-2-one (4f). Yellow crystals. mp 291–293ꢀC. IR
(KBr, nmax/cmÀ1): 3383 (broad peak, NH), 1695 (C═O), 1636
(C═N), 1586 (C═C). 1H NMR (500 MHz, DMSO-d6): 11.86
3
(1H, s, NH), 7.8 5–6.50 (7H, m, Ar), 6.13 (1H, dd, JXB = 7.6,
2
3
3JXA = 2.8 Hz, CH), 3.58 (1H, dd, JBA = 16.6, JBX = 7.7 Hz,
2
3
CH2(HB)), 2.85 (1H, dd, JAB = 16.4, JAX = 2.9 Hz, CH2
(HA)). 13C NMR (125 MHz, DMSO-d6): 179.9 (C═O),
166.34, 153.0, 148.1, 141.9, 135.1, 133.9, 132.3, 131.8,
129.9, 128.3, 127.6, 122.1, 121.2, 117.6, 109.1, 49.4 (C2),
36.2 (C3). EI-MS, m/z (%): 333 (M+2, 59), 331 (M+, 91),
268(17), 254(14), 199(77), 171 (32), 133(100), 105(17), 90
(47), 75(26), 75(26), 57(24), 43(31). Anal. Calcd. For
C16H11Cl2N3O: C, 57.85; H, 3.34; N, 12.65%. Found: C,
57.32; H, 3.21; N, 12.34.
1
(C═C). H NMR (500 MHz, DMSO-d6): 8.51 (1H, s, NH), 7.85
3
3
(1H, d, JHH = 7.8 Hz, Ar), 7.24 (1H, d, JHH = 7.8 Hz, Ar), 7.17
3
3
(1H, t, JHH = 7.6 Hz, Ar), 7.03 (1H, t, JHH = 7.6 Hz, Ar), 6.79
3
3
(2H, s, Ar), 4.95 (1H, dd, JXB = 10.2, JXA = 4.5 Hz, CH), 3.77
2
(6H, s, OCH3), 3.65 (3H, S, OCH3), 3.19 (1H, dd, JBA = 16.6,
3JBX = 10.4 Hz, CH2(HB)), 3.03 (1H, dd, JAB = 16.6, JAX = 4.4
2
3
Hz, CH2 (HA)). 13C NMR (125 MHz, DMSO-d6): 166.7 (C═O),
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H. Sheibani, K. Saidi, and M. Lakaei
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