Efficient synthesis of benzimidazo[1,2-a]pyrimidinone derivatives via catalyst-free reactions of Baylis-Hillman acetates, alcohols, and amines with 2-aminobenzimidazole

Article abstract of DOI:10.1002/jhet.324

(Chemical Equation Presented) Benzimidazo[1,2-a]pyrimidinone and its derivatives were easily prepared in good to excellent yields via tandem reactions of 2-aminobenzimidazole with Baylis-Hillman acetates, alcohols, and amines without the use of catalyst and additive in one-pot process. The method provided an efficient and facile route to the title fused heterocyclic compounds with different functional groups.

Full text of DOI:10.1002/jhet.324

March 2010
Efficient Synthesis of Benzimidazo[1,2-a]pyrimidinone
Derivatives via Catalyst-Free Reactions of Baylis–Hillman
Acetates, Alcohols, and Amines with 2-Aminobenzimidazole
373
Yan Wang,a Zahid Shafiq,a,b Li Liu,a* Dong Wang,a and Yong-Jun Chena*
aCAS Key Laboratory for Molecular Recognition, Beijing National Laboratory (BNLMS), Institute
of Chemistry, Chinese Academy of Sciences, Beijing 100080, People’s Republic of China
bDepartment of Chemistry, B. Z. University, Multan-60800, Pakistan
*E-mail: lliu@iccas.ac.cn or yjchen@iccas.ac.cn
Received July 16, 2009
DOI 10.1002/jhet.324
Published online 4 March 2010 in Wiley InterScience (www.interscience.wiley.com).
Benzimidazo[1,2-a]pyrimidinone and its derivatives were easily prepared in good to excellent yields
via tandem reactions of 2-aminobenzimidazole with Baylis–Hillman acetates, alcohols, and amines with-
out the use of catalyst and additive in one-pot process. The method provided an efficient and facile
route to the title fused heterocyclic compounds with different functional groups.
J. Heterocyclic Chem., 47, 373 (2010).
INTRODUCTION
Imidazo[1,2-a]pyrimidines are very important inter-
mediates and widely used in pharmaceutical chemistry
[1]. Among them, benzimidazo[1,2-a]pyrimidinone and
its derivatives have attracted considerable attention
[2,3]. For example, the compound A is a kind of in-
hibitor of Lck kinase, which is a member of Src fam-
ily of cytoplasmic tyrosine kinases. The inhibitor
might be a useful immunosuppressive agent for the
treatment of graft rejection and/or T-cell-mediated
autoimmune diseases [4]. There were several
approaches to develop the benzimidazo[1,2-a]pyrimidi-
nones: the intramolecular substitution reaction of halide
with amines [2], the reaction of 2-aminobenzimidazole
with propiolic esters and a,b-unsaturated esters [3],
and so on. To enhance the diversity of benzimi-
dazo[1,2-a]pyrimidinone compounds, a new type of
substrate is still required.
Recently, it was noteworthy that the reactions of 2-
aminobenzimidazole with several electrophiles, includ-
ing nitrile, a,b-unsaturated carbonyl compounds, cya-
noacetate, and acetylene-dicarboxylate, have been
developed to construct heterocyclic structural unit [5].
The Baylis–Hillman adduct offers an excellent platform
for several chemical transformations because of the
presence of three functional groups including hydroxyl
C
V
2010 HeteroCorporation

374
Y. Wang, Z. Shafiq, L. Liu, D. Wang, and Y.-J. Chen
Vol 47
Scheme 1
Table 1
Reaction of B-H acetates (1) with 2.a
Entry
B-H acetate
Time (h)
Product (R)
Yieldb (%)
1
2
3
4
5
6
7
1a, C6H5
1b, 4-ClC6H4
1c, 2-furyl
1d, 2-F3CC6H4
1e, 3-BrC6H4
1f, 3-MeOC6H4
1g, C2H5
0.5
0.5
1.5
0.5
1.0
1.0
1.0
3a, C6H5
3b, 4-ClC6H4
3c, 2-furyl
3d, 2-F3CC6H4
3e, 3-Br C6H4
3f, 3-MeOC6H4
3g, C2H5
85
93
76
90
97
90
71
(or substituted amino), double bond, and electron-with-
drawing group (alkoxycarbonyl or nitrile) in close prox-
imity. The Baylis–Hillman adducts were illustrated as
valuable precursor for the synthesis of heterocycles and
many biologically active molecules [6]. It was envisaged
that the reaction of 2-aminobenzimidazole with Baylis–
Hillman adducts and their derivatives would provide an
efficient route for the synthesis of annulated benzimida-
zole derivatives.
a 1:2 ¼ 1:1.2; in dioxane at 50ꢀC.
b Isolated yield.
ter of the substituents existed on the Baylis–Hillman
acetates to afford the desired fused heterocycle, benzi-
midazo[1,2-a]pyrimidine derivatives in good to excellent
yields (71–97%).
Herein, we wish to report the catalyst-free reactions
of Baylis–Hillman acetates, alcohols, and amine for the
synthesis of benzimidazo-[1,2-a]pyrimidinone and their
derivatives bearing different functional groups with sig-
nificant convenience [7].
THE REACTIONS OF BAYLIS–HILLMAN
ALCOHOLS (4) WITH 2
In contrast, when the Baylis–Hillman alcohols were
used, the hydroxyl group remained in the product. How-
ever, as indicated by Batra and coworkers [8], the
hydroxyl group was very sensitive to the reaction condi-
tion and ease to be removed out during the intramolecu-
lar cyclization by debenzylation. To our delight, under
the same reaction conditions for Baylis–Hillman acetate,
the fused heterocyclic compounds bearing hydroxyl
group could be obtained in one-pot process (Scheme 2).
As shown in Table 2, various Baylis–Hillman alcohols
(4a–i) derived from aryl aldehydes reacted smoothly
RESULTS AND DISCUSSION
The reactions of Baylis–Hillman acetates (1) with
2-aminobenzoimidazole (2). Initially, the reaction of
Baylis–Hillman acetate 1a (R ¼ Ph) and 2-aminobenzi-
midazole 2 was carried out in dioxane at room tempera-
ture without any catalyst, but no reaction was observed
even after long period of time. However, on raising the
temperature to 50ꢀC, light yellow precipitates formed
only after 30 min, affording (E)-6-benzylidene-5,6-dihy-
dro-8H-benzo[4,5]imidazo[1,2-a]-pyrimidin-7-one 3a in
93% yield (Scheme 1, Table 1, entry 1).
with
2
to give 6-[aryl(hydroxyl)methyl]-benzoimi-
dazo[1,2-a]pyrimidines (5a–i) in good to excellent
yields. The presence of substitute in the ortho position
of the phenyl ring (4f–g) resulted in slow reactivity of
the Baylis–Hillman adduct leading to increase in
1
In H-NMR spectrum of 3a, only one signal of NAH
was observed, which showed the formation of cyclic
product. The formation of lactam structure was further
supported by the IR spectrum, in which an amide car-
bonyl vibration band appeared at 1657 cmꢁ1. The ster-
eochemistry of the newly formed double bond in the
products was established as (E)-configuration by X-ray
diffraction analysis of the single crystal of the product
3d (R ¼ 2-F3CC6H4) (Fig. 1). The structure of the sin-
gle crystal was also an evidence for the formation of the
three nitrogen-containing fused heterocycle.
As shown in Table 1, the substrate scope for the ben-
zimidazo[1,2-a]pyrimidine forming process was quite
broad, and the reaction demonstrated that various Bay-
lis–Hillman acetates bearing aryl, heteroaryl, or alkyl
groups can be used for this transformation. The reaction
proceeded smoothly regardless of the electronic charac-
Figure 1. ORTEP drawing of 3d. [Color figure can be viewed in the
online issue, which is available at www.interscience.wiley.com.]
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2010
Efficient Synthesis of Benzimidazo[1,2-a]pyrimidinone Derivatives via Catalyst-Free
Reactions of Baylis–Hillman Acetates, Alcohols, and Amines with 2-Aminobenzimidazole
375
Scheme 2
Table 3
Reaction of B-H amines (6) with 2.a
Entry
B-H amine
6a, C6H5
Time (h)
Product (R)
Yieldb (%)
1
2
3
4
5
6
7
2.5
5.0
1.0
0.5
1.5
2.0
3.0
7a, C6H5
86
91
94
81
97
96
75
6b, 4-FC6H4
7b, 4-FC6H4
7c, 4-ClC6H4
7d, 4-NO2C6H4
7e, 3-NO2C6H4
7f, 2-NO2C6H4
7g, 4-MeC6H4
6c, 4-ClC6H4
6d, 4-NO2C6H4
6e, 3-NO2C6H4
6f, 2-NO2C6H4
6g, 4-MeC6H4
reaction time (entries 6 and 7). Moreover, the substrate
bearing aromatic heterocyclic (4h) and alkyl group (4i)
also exhibited good ability for the reaction with 2,
affording the corresponding products (5h and 5i) in 78
and 93% yields, respectively (entries 8 and 9).
a 6:2 ¼ 1:1.2; in dioxane at 100ꢀC.
b Isolated yield.
went the Michael addition or allylic substitution
reaction, followed by intramolecular cyclization. The
produced compounds possessed different functions,
double bond, hydroxyl and amino groups, which pro-
vided an opportunity to do derivatization further for
enhancing the diversity of benzimidazo[1,2-a]pyrimidine
compounds.
The reactions of Baylis–Hillman amines (6) with
2. Recently, Lamaty and coworkers assimilated all
applications of the aza-Baylis–Hillman adducts for the
synthesis of nitrogen-containing compounds. It was
demonstrated that when the aza-Baylis–Hillman adduct
(Baylis–Hillman amine) was attacked by a nucleophile,
the reaction could afford a Michael addition product or
an allylic substitution product depending on the reaction
conditions, which resulted in the amino group of aza-
Baylis–Hillman adducts remaining either in the product
or eliminating from the product [9]. When various Bay-
lis–Hillman amines (6a–g) were used in the reaction
with 2, under the same condition for Baylis–Hillman ac-
etate the reactions carried out smoothly to afford the
Michael addition products 7 in high yields (Table 3).
When the substituents in the phenyl ring were electron-
withdrawing groups (6b–f), the reactions proceeded bet-
ter than the substrate bearing electron-donating group in
the phenyl ring (6g) (Entry 7) (Scheme 3).
EXPERIMENTAL
IR spectra were recorded with a Perkin–Elmer 782 IR spec-
1
trometer. H-NMR and 13C-NMR spectra were obtained with a
Bruker DMX-300 (300 MHz) spectrometer. Chemical shifts
are given in ppm relative to tetramethylsilane (TMS), and the
center of the multiplet of the DMSO was also defined as 39.53
ppm for 13C-NMR spectra. HRMS (EI) spectra were measured
on a JEOL JMS-DX303. Melting points were measured with a
Beijing-Taike X-4 apparatus and are uncorrected. Unless other-
wise noted, all reagents were obtained from commercial sup-
pliers and were used without further purification.
According to reference’s method [10], starting from a,b-un-
saturated ester, with aryl or alkyl aldehydes the B-H alcohols
(4a–i), and with imines the B-H amines (6a–g) were synthe-
sized, respectively. B-H acetates (1a–h) were derived
from B-H alcohols by acetyl chloride.
In conclusion, we have developed an efficient method
for the synthesis of benzimidazo[1,2-a]pyrimidine deriv-
atives in good to excellent yields. The developed proto-
col was simple, and no additives or catalysts were
required to promote the reaction. The reaction under-
General procedure for the reaction of Baylis–Hillman
acetates (1a–h) with 2-aminobenzimidazole (2). To a solu-
tion of B-H acetate 1a–h (1 mmol) in dioxane was
added 2-aminobenimidazole 2 (1.2 mmol), and the resultant
reaction mixture was heated at 50ꢀC. Upon completion as
judged by TLC or the reaction time given in Table 1, precipi-
tates were formed, which were filtered and washed with ether.
The crude product was recrystallized from dichloromethane/
Table 2
Reaction of B-H alcohols (4) with 2.a
Entry B-H alcohol Time (h)
Product (R)
Yieldb (%)
1
2
3
4
5
6
7
8
9
4a, C6H5
2.0
2.0
2.0
1.5
2.0
3.0
3.0
1.5
3.0
5a, C6H5
89
93
94
97
98
93
93
78
95
4b, 4-FC6H4
4c, 4-ClC6H4
4d, 4-NO2C6H4
4e, 3-NO2C6H4
4f, 2-NO2C6H4
4g, 2-F3CC6H4
4h, 2-furyl
5b, 4-FC6H4
5c, 4-ClC6H4
5d, 4-NO2C6H4
5e, 3-NO2C6H4
5f, 2-NO2C6H4
5g, 2-F3CC6H4
5h, 2-furyl
Scheme 3
4i, H
5i, H
a 4:2 ¼ 1:1.2; in dioxane at 100ꢀC.
b Isolated yield.
Journal of Heterocyclic Chemistry
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376
Y. Wang, Z. Shafiq, L. Liu, D. Wang, and Y.-J. Chen
Vol 47
petroleum ether to give corresponding products, benzimi-
dazo[1,2-a]pyrimidinone derivatives (3a–g).
cmꢁ1 1H-NMR (300 MHz, DMSO-d6): d 3.85 (s, 3H, CH3),
;
5.33 (s, 2H,CH2), 7.06–7.44 (m, 5H, ArH), 7.44–7.47 (m, 3H,
ArH), 7.89 (s, 1H, CH); 11.84 (brs, 1H, NH); 13C-NMR (75
MHz, DMSO-d6): d 42.2, 55.2, 109.2, 115.6, 115.8, 117.1,
120.6, 121.6, 122.1, 122.6, 129.9, 133.1, 135.2, 138.2, 141.5,
146.4, 159.4, 161.8; HRMS(EI): m/z calcd. for C17H13N3O
(Mþ): 305.1164, found 305.1167.
(E)-6-Benzylidene-5,6-dihydro-8H-benzo[4,5]imidazo[1,2-
a]pyrimidin-7-one (3a). A light brown solid, m.p. > 300ꢀC
(decom.); FTIR (KBr): 3271, 2923, 1668, 1589, 1338 cmꢁ1
;
1H-NMR (300 MHz, DMSO-d6): d 5.33 (s, 2H, CH2), 7.13 (s,
2H, ArH), 7.28–7.65 (m, 7H, ArH), 7.90 (s, 1H, CH), 11.80
(brs, 1H, NH); 13C-NMR (75 MHz, DMSO-d6): d ¼ 42.3,
109.2, 117.1, 120.6, 121.6, 121.8, 128.9, 129.7, 130.6, 133.1,
133.8, 138.1, 141.5, 146.4, 161.8; HR MS(EI): m/z calcd. for
C17H13N3O (Mþ): 275.1059, found 275.1057.
(E)-6-Propylidene-5,6-dihydro-8H-benzo[4,5]imidazo[1,2-
a]pyrimidin-7-one (3g). A white solid; m.p. ¼ 267–268ꢀC
(decom.); FTIR (KBr): 3422, 2888, 1685, 1535, 1349 cmꢁ1
;
1H-NMR (300 MHz, DMSO-d6): d 1.06 (t, 3H, J ¼ 7.5 Hz,
CH3CH2), 2.29 (p, 2H, J ¼ 7.6, 7.4 Hz, CH3CH2), 4.99 (s,
2H, CH2), 6.93 (t, 1H, J ¼ 7.4 Hz, CHCH2), 7.11 (dd, 2H, J
¼ 7.3, 0.7 Hz, ArH), 7.38–7.44 (m, 2H, ArH), 11.5 (brs, 1H,
NH); 13C-NMR (75 MHz, DMSO-d6): d 13.1, 21.6, 41.1,
109.6, 117.7, 121.1, 121.9, 122.1, 133.7, 142.2, 144.9, 147.4,
161.9; HRMS(EI): m/z calcd. for C13H13N3O (Mþ): 227.1059,
found 227.1057.
(E)-6-(4-Chlorobenzylidene)-5,6-dihydro-8H-benzo[4,5]
imidazo[1,2-a]pyrimidine-7-one (3b). A light brown solid,
m.p. > 300ꢀC (decom.); FTIR (KBr): 3271, 2923, 1668, 1589,
1338 cmꢁ1 1H-NMR (300 MHz, DMSO-d6): d 5.31 (s, 2H,
;
CH2), 6.88 (s, 2H, ArH), 7.42–7.67 (m, 7H, ArH), 7.88 (s, 1H,
CH), 11.83 (brs, 1H, NH); 13C-NMR (75 MHz, DMSO-d6): d
42.2, 109.2, 117.1, 120.6, 121.6, 122.7, 128.9, 132.4, 132.8,
133.1, 134.3, 136.7, 141.5, 146.4, 161.6; HR MS(EI): m/z
calcd. for C17H13N3O (Mþ): 309.0669, found 309.0672.
According to the same procedure, starting from Baylis–Hill-
man alcohols (4) and amines (6) with 2-aminobenzimidazole
(2), 5a–i and 7a–g were synthesized and the diastereoselectiv-
ities were around 1:1 determined by NMR.
6-(Phenylhydroxymethyl)-5,6-dihydro-8H-benzo[4,5]imi-
dazo[1,2-a]pyrimidin-7-one (5a). A white solid, m.p. ¼ 233–
235ꢀC (decom.); FTIR (KBr): 3390, 3064, 1665, 1515, 1458,
1334 cmꢁ1 1H-NMR (300 MHz, DMSO-d6): d 3.26 (m, 1H,
;
(E)-6-(Furan-2-ylmethylene)-5,6-dihydro-8H-benzo[4,5]
imidazo[1,2-a]pyrimidin-7-one (3c). A light yellow solid,
m.p. > 300ꢀC (decom.); FTIR (KBr): 3430, 3118, 1684, 1532,
1348 cmꢁ1 1H-NMR (300 MHz, DMSO-d6): d 5.30 (s, 2H,
;
CH2), 6.80 (d, 1H, J ¼ 1.4 Hz, ArH), 7.14–7.20 (m, 3H,
ArH), 7.42–7.54 (m, 2H, ArH), 7.69 (s, 1H, ArH), 8.01 (s, 1H,
CH), 11.8 (brs, 1H, NH); 13C-NMR (75 MHz, DMSO-d6): d
42.6, 109.0, 113.2, 117.1, 117.9, 120.6, 121.6, 123.9, 133.1,
141.5, 146.6, 146.7, 150.4, 161.2; HRMS(EI): m/z calcd. for
C15H11N3O2 (Mþ): 265.0851, found 265.0849.
CHCO), 3.97 (m, 1H, CH2), 4.19 (m, 1H, CH2), 5.08 (5.28)
(m, 1H, OH), (the data in parentheses are for diastereomeric
peaks, the same below), 5.80 (m, 1H, CHOH), 7.01–7.16 (m,
2H, ArH), 7.19–7.33 (m, 2H, ArH), 7.33–7.52 (m, 5H, ArH),
11.53 (s, 1H, NH); 13C-NMR (75 MHz, DMSO-d6): d 36.9,
46.6, 69.8, 108.6, 117.1, 120.6, 121.2, 125.9, 127.1, 128.1,
133.0, 141.7, 142.8, 147.6, 168.6; HRMS(EI): m/z calcd. for
C17H16N3O2 (Mþþ1): 294.1234, found 294.1237.
(E)-6-(o-Trifluoromethylbenzylidene)-5,6-dihydro-8H-ben-
zo[4,5]imidazo[1,2-a]pyrimidin-7-one (3d). A white solid,
m.p. > 300ꢀC (decom.); FTIR (KBr): 3157, 1692, 1531, 1457,
1351 cmꢁ1 1H-NMR (300 MHz, DMSO-d6): d 5.14 (s, 2H,
;
CH2), 7.05–7.14 (m, 3H, ArH), 7.36–7.44 (dd, 2H, J ¼ 7.2,
7.6 Hz, ArH), 7.70 (t, 1H, J ¼ 6.7 Hz, ArH), 7.83–7.92 (dd,
2H, J¼ 7.9, 7.5 Hz, ArH), 8.01 (s, 1H, CH), 11.9 (brs, 1H,
NH); 13C-NMR (75 MHz, DMSO-d6): d 41.5, 109.2, 117.1,
120.8, 121.7, 125.6, 126.3, 126.3, 127.5, 129.6, 130.4, 132.1,
132.9, 133.0, 134.0, 141.4, 146.5, 161.4; HRMS(EI): m/z
calcd. for C18H12N3O F3 (Mþ): 343.0932, found 343.0929.
The crystal used for the X-ray study had the dimensions 0.41
mm ꢂ 0.38 mm ꢂ 0.06 mm. Crystal data: C18 H12 F3 N3 O,
6-[(4-Fluorophenyl)hydroxymethyl]-5,6-dihydro-8H-ben-
zo[4,5]imidazo[1,2-a]pyrimidin-7-one (5b). A white solid,
m.p. ¼ 225–227ꢀC (decom.); FTIR (KBr): 3382, 3056, 1678,
1510, 1457, 1223 cmꢁ1 1H-NMR (300 MHz, DMSO-d6): d
;
3.27 (m, 1H, CHCO), 3.96–4.25 (m, 2H, CH2), 5.07 (5.25) (m,
1H, OH), 5.87–5.90 (m, 1H, CHOH), 6.91–6.97 (m, 1H, ArH),
7.06–7.12 (m, 2H, ArH), 7.15–7.24 (m, 1H, ArH), 7.24–7.34
(m, 2H, ArH), 7.38–7.45 (m, 2H, ArH), 11.50 (s, 1H, NH);
13C-NMR (75 MHz, DMSO-d6): d 37.0, 46.7, 69.2, 108.7,
114.7, 115.0, 117.1, 120.6, 121.2, 127.9, 128.0, 133.0, 141.7,
M
¼
343.31, monoclinic, space group P2(1)/c,
a
¼
6.5560(13), b ¼ 33.361(7), c ¼ 7.1651(14) A, b ¼ 99.55(3) ,
147.6, 168.5; HRMS(EI): m/z calcd. for C17H15N3O2F (Mþ
1): 312.1141, found 312.1143.
þ
ꢀ
˚
V ¼ 1545.4(5) A , Z ¼ 4, Dcalcd ¼ 1.476 g/cm3, F0 ¼ 704,
3
˚
˚
reflections collected: 8887, k ¼ 0.71073 A. CCDC: 738372.
6-[(4-Chlorophenyl)hydroxymethyl]-5,6-dihydro-8H-ben-
zo[4,5]imidazo[1,2-a]pyrimidin-7-one (5c). A white solid,
m.p. ¼ 206–208ꢀC (decom.); FTIR (KBr): 3414, 3054, 1689,
(E)-6-(3-Bromobenzylidene)-5,6-dihydro-8H-benzo[4,5]
imidazo[1,2-a]pyrimidine-7-one (3e). A light yellow solid,
m.p. > 300ꢀC (decom.); FTIR (KBr): 3271, 2923, 1668, 1589,
1526, 1458, 1238 cmꢁ1 1H-NMR (300 MHz, DMSO-d6): d
;
1338 cmꢁ1
;
1H-NMR (300 MHz, DMSO-d6): d 5.31 (s, 2H,
3.28 (m, 1H, CHCO), 3.97–4.27 (m, 2H, CH2), 5.09 (2.27) (m,
1H, OH), 5.76–5.93 (m, 1H, CHOH), 6.85–7.50 (m, 8H, ArH),
11.53 (s, 1H, NH); 13C-NMR (75 MHz, DMSO-d6): d 36.9,
46.6, 69.8, 108.6, 117.1, 120.6, 121.2, 125.9, 127.1, 127.9,
128.1, 133.0, 142.8, 147.6, 168.6; HRMS (EI): m/z calcd. for
C17H15N3O2Cl (Mþ þ 1): 328.0845, found 328.0847.
CH2), 7.12 (t, 2H, J ¼ 2.1 Hz, ArH), 7.41 (m, 1H, CH), 7.50
(m, 2H, ArH), 7.67 (t, 2H, J ¼ 8.0 Hz, ArH), 7.84–7.86 (m,
2H, ArH); 11.9 (brs, 1H, NH); 13C-NMR (75 MHz, DMSO-
d6): d 42.1, 109.2, 117.1, 120.7, 121.7, 122.1, 123.5, 129.0,
130.9, 132.2, 132.9, 133.0, 136.2, 136.5, 141.5, 146.5, 161.5;
HRMS(EI): m/z calcd. for C17H13N3O (Mþ): 355.0143, found
355.0148.
(E)-6-(3-Methoxybenzylidene)-5,6-dihydro-8H-benzo[4,5]
imidazo[1,2-a]pyrimidine-7-one (3f). A white solid; m.p. >
300ꢀC (decom.); FTIR (KBr): 3271, 2923, 1668, 1589, 1338
6-[(4-Nitrophenyl)hydroxymethyl]-5,6-dihydro-8H-ben-
zo[4,5]imidazo[1,2-a]-pyrimidin-7-one (5d). A white solid,
m.p. ¼ 231–233ꢀC (decom.); FTIR (KBr): 3373, 3052, 1667,
1521, 1456, 1348 cmꢁ1 1H-NMR (300 MHz, DMSO-d6): d
;
3.40 (m, 1H, CHCO), 3.98–4.34 (m, 2H, CH2), 5.15 (5.05) (m,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Efficient Synthesis of Benzimidazo[1,2-a]pyrimidinone Derivatives via Catalyst-Free
Reactions of Baylis–Hillman Acetates, Alcohols, and Amines with 2-Aminobenzimidazole
377
1H, OH), 6.17–6.18 (m, 1H, CHOH), 7.06–7.09 (m, 2H, ArH),
7.28–7.38 (m, 2H, ArH), 7.52–7.72 (m, 2H, ArH), 7.97–8.26
(m, 2H, ArH), 11.60 (s, 1H, NH); 13C-NMR (75 MHz,
DMSO-d6): d 36.9, 46.3, 69.0, 108.8, 117.1, 120.6, 121.3,
123.3, 127.4, 133.0, 141.6, 146.7, 147.5, 150.8, 168.1;
HRMS(EI): m/z calcd. for C17H13N4O4 (Mþ þ 1): 339.1086,
found 339.1087.
HRMS(EI): m/z calcd. for C15H14N3O2 (Mþþ1): 218.0924,
found 218.0924.
6-[(Phenyl)tosylaminomethyl]-5,6-dihydro-8H-benzo[4,5]
imidazo[1,2-a]pyrimidin-7-one (7a). A white solid, m.p. ¼
239–241ꢀC (decom.); FTIR (KBr): 3343, 3059, 1680, 1457,
1
1328, 1239 cmꢁ1; H-NMR (300 MHz, DMSO-d6): d 2.24 (s,
3H, CH3), 3.17–3.32 (m, 1H, CHCO), 3.70–4.50 (m, 2H,
CH2CH), 4.60–4.80 (m, 1H, CHNH), 6.90–7.50 (m, 13H,
ArH), 8.40 (8.70) (m, 1H, NHSO2) (the data in parentheses are
for diastereomeric peaks, the same below), 11.53 (s, 1H,
NHCO); 13C-NMR (75 MHz, DMSO-d6): d 20.8, 46.2, 56.3,
66.0, 108.8, 120.8, 121.3, 126.3, 127.0, 127.3, 127.8, 129.0,
129.1, 132.6, 133.0, 137.1, 138.6, 142.2, 147.1, 167.6;
HRMS(EI): m/z calcd. for C24H23N4O3S (Mþ þ 1): 447.1480,
found 447.1485.
6-[(3-Nitrophenyl)hydroxymethyl]-5,6-dihydro-8H-ben-
zo[4,5]imidazo[1,2-a]-pyrimidin-7-one (5e). A white solid,
m.p. ¼ 211–213ꢀC (decom.); FTIR (KBr): 3378, 3051, 1671,
1523, 1456, 1351 cmꢁ1 1H-NMR (300 MHz, DMSO-d6): d
;
3.42 (m, 1H, CHCO), 4.01–4.29 (m, 2H, CH2), 5.25 (5.50) (m,
1H, OH), 5.75–6.19 (m, 1H, CHOH), 7.04–7.11 (m, 2H, ArH),
7.26–7.45 (m, 2H, ArH), 7.64–7.69 (m, 1H, ArH), 7.85–7.92
(m, 1H, ArH), 8.11–8.17 (m, 1H, ArH), 8.27 (m, 1H, ArH),
11.60 (s, 1H, NH); 13C-NMR (75 MHz, DMSO-d6): d 36.9,
46.3, 68.7, 108.9, 117.1, 120.6, 120.8, 121.3, 122.1, 129.6,
132.8, 133.0, 141.6, 145.3, 147.5, 147.8, 168.2; HRMS(EI): m/
z calcd. for C17H13N4O4 (Mþ þ 1): 339.1086, found 339.1087.
6-(2-Nitrophenylhydroxymethzyl)-5,6-dihydro-8H-benzo
[4,5]imidazo[1,2-a]-pyrimidin-7-one (5f). A white solid,
m.p. ¼ 204–206ꢀC (decom.); FTIR (KBr) 3360, 3055, 1671,
6-[(4-Fluorophenyl)tosylaminomethyl]-5,6-dihydro-8H-
benzo[4,5]imidazo[1,2-a]pyrimidin-7-one (7b). A white
solid, m.p. > 300ꢀC (decom.); FTIR (KBr): 3415, 3050, 1680,
1510, 1456, 1160 cmꢁ1
;
1H-NMR (300 MHz, DMSO-
d6): d 2.26 (s, 3H, CH3), 3.15–3.31 (m, 1H, CHCO), 3.70–4.50
(m, 2H, CH2CH), 4.55–4.85 (m, 1H, CHNH), 6.81–7.43 (m,
12H, ArH), 8.38 (8.80) (m, 1H, NHSO2), 11.56 (s, 1H,
NHCO); 13C-NMR (75 MHz, DMSO-d6): d 20.8, 46.1, 55.5,
55.7, 108.9, 114.3, 114.6, 117.2, 120.8, 121.4, 126.4, 129.0,
129.1, 132.6, 133.0, 137.8, 137.9, 142.2, 147.1, 167.5;
1523, 1456, 1340 cmꢁ1 1H-NMR (300 MHz, DMSO-d6) d
;
3.34 (m, 1H, CHCO), 4.11 (m, 1H, CH2), 4.28 (m, 1H, CH2),
5.53 (5.86) (m, 1H, OH), 6.14 (m, 1H, CHOH), 7.10 (m, 2H,
ArH), 7.30 (m, 1H, ArH), 7.41 (m, 1H, ArH), 7.59 (m 1H,
ArH), 7.82 (m, 1H, ArH), 7.91 (m, 1H, ArH), 8.03 (m, 1H,
ArH), 11.60 (s, 1H, NH); 13C-NMR (75 MHz, DMSO-d6) d
37.3, 45.4, 65.1, 108.8, 117.1, 120.6, 121.2, 124.3, 128.6,
129.3, 133.0, 133.5, 138.1, 141.7, 147.2, 147.6, 168.0;
HRMS(EI): m/z calcd. for C17H13N4O4 (Mþ þ 1): 339.1086,
found 339.1087.
HRMS(EI): m/z calcd. for C24H22N4O3SF (Mþ
465.1389, found 465.1391.
þ
1):
6-[(4-Chlorophenyl)tosylmethyl]-5,6-dihydro-8H-benzo
[4,5]imidazo[1,2-a]pyrimidin-7-one (7c). A white solid,
m.p. ¼ 260–262ꢀC (decom.); FTIR (KBr) 3263, 3053, 1689,
1456, 1331, 1159 cmꢁ1 1H-NMR (300 MHz, DMSO-d6) d
;
2.27 (s, 3H, CH3), 3.20–3.32 (m, 1H, CHCO), 3.57–4.32 (m,
2H, CH2CH), 4.55–4.71 (m, 1H, CHNH), 7.00–7.42 (m, 12H,
ArH), 8.40 (8.70) (m, 1H, NHSO2), 11.54 (s, 1H, NHCO);
13C-NMR (75 MHz, DMSO-d6) d 20.8, 30.6, 46.0, 55.7,
108.9, 117.3, 120.9, 121.4, 126.4, 127.7, 129.0, 129.1, 131.8,
132.0, 136.1, 137.6, 137.8, 142.4, 147.1, 167.4; HRMS(EI):
m/z calcd. for C24H22N4O3SCl (Mþ þ 1): 481.1092, found
481.1095.
6-[(2-Trifluoromethylphenyl)hydroxymethyl]-5,6-dihydro-
8H-benzo[4,5]imidazo[1,2-a]pyrimidin-7-one (5g). A white
solid, m.p. ¼ 175–177ꢀC (decom.); FTIR (KBr): 3393, 3054,
1674, 1525, 1456, 1312 cmꢁ1 1H-NMR (300 MHz, DMSO-
;
d6): d 3.15 (m, 1H, CHCO), 4.16 (m, 1H, CH2), 4.35 (m, 1H,
CH2), 5.20 (5.62) (m, 1H, OH), 5.93–6.11 (m, 1H, CHOH),
6.75–7.95 (m, 8H, ArH), 11.58 (s, 1H, NH); 13C-NMR (75
MHz, DMSO-d6): d 36.9, 46.2, 65.1, 108.8, 117.1, 120.6,
121.2, 125.4, 125.5, 127.9, 129.2, 132.4, 133.0, 141.6, 141.8,
6-[(4-Nitrophenyl)tosylaminomethyl]-5,6-dihydro-8H-ben-
zo[4,5]imidazo[1,2-a]pyrimidin-2-one (7d). A white solid,
m.p. ¼ 268–270ꢀC (decom.); FTIR (KBr): 3306, 3056, 1684,
147.5, 167.9; HRMS(EI): m/z calcd. for C18H13N3O2F (Mþ
1): 362.1106, found 362.1101.
þ
1519, 1348, 1157 cmꢁ1 1H-NMR (300 MHz, DMSO-
;
6-(Furan-2-ylmethyl)-5,6-dihydro-8H-benzo[4,5]-imidazo
[1,2-a]pyrimidin-7-one (5h). A yellow solid, m.p. ¼ 206–
208ꢀC (decom.); FTIR (KBr) 3434, 3054, 1685, 1522, 1456,
d6): d 2.24 (s, 3H, CH3), 3.34–3.45 (m, 1H, CHCO), 3.70–4.40
(m, 2H, CH2CH), 4.70–4.95 (m, 1H, CHNH), 7.00–8.00 (m,
12H, ArH), 8.50 (8.83) (m, 1H, NHSO2), 11.56 (s, 1H,
NHCO); 13C-NMR (75 MHz, DMSO-d6): d 20.8, 38.7, 45.3,
51.0, 108.8, 117.1, 120.7, 121.3, 124.1, 126.2, 128.7, 129.1,
130.3, 132.8, 133.0, 133.1, 137.2, 141.3, 142.4, 147.2, 148.1,
167.0; HRMS(EI): m/z calcd. for C24H22N5O5S (Mþ þ 1):
492.1339, found 492.1336.
1384 cmꢁ1 1H-NMR (300 MHz, DMSO-d6) d 3.39 (m, 1H,
;
CHCO), 4.04–4.34 (m, 2H, CH2), 5.09 (5.25) (m, 1H, OH),
5.98–5.99 (m, 1H, CHOH), 6.23–7.64 (m, 7H, ArH), 11.55 (s,
1H, NH); 13C-NMR (75 MHz, DMSO-d6) d 37.4, 44.2, 64.6,
106.8, 108.8, 110.3, 117.1, 120.6, 121.3, 133.0, 141.7, 142.2,
147.5, 155.2, 169.1; HRMS(EI): m/z calcd. for C15H14N3O2
(Mþ þ 1): 284.1026, found 284.1029.
6-[(3-Nitrophenyl)tosylaminomethyl]-5,6-dihydro-8H-ben-
zo[4,5]imidazo[1,2-a]pyrimidin-7-one (7e). A white solid,
m.p. ¼ 281–283ꢀC (decom.); FTIR (KBr): 3300, 3065, 1692,
6-(Methylhydroxymethyl)-5.6-dihydro-8H-benzo-[4,5]imi-
dazo[1,2-a]pyrimidin-7-one (5i). Aꢁw1 hite solid, m.p. ¼ 260–
1530, 1329, 1157 cmꢁ1 1H-NMR (300 MHz, DMSO-d6): d
;
262ꢀC (decom.); FTIR (KBr) cm
;
1H-NMR (300 MHz,
2.21 (s, 3H, CH3), 3.32–3.45 (m, 1H, CHCO), 3.80–4.40 (m,
2H, CH2CH), 4.72–4.95 (m, 1H, CHNH), 6.80–8.00 (m, 12H,
ArH), 8.50 (8.85) (m, 1H, NHSO2), 11.56 (s, 1H, NHCO);
13C-NMR (75 MHz, DMSO-d6): d 20.7, 30.6, 45.6, 55.5,
108.9, 117.1, 120.8, 121.4, 121.9, 122.1, 126.4, 129.0, 129.3,
132.9, 134.1, 137.7, 140.8, 141.6, 142.3, 147.2, 147.3, 166.7;
DMSO-d6) d 3.05 (m, 1H, CHCO), 3.76 (m, 2H, CH2OH),
4.13 (m, 1H, CH2CH), 4.42 (m, 1H, CH2CH), 5.00 (5.02) (m,
1H, OH), 7.11 (m, 2H, ArH), 7.41 (m, 2H, ArH), 11.47 (s, 1H,
NH); 13C-NMR (75 MHz, DMSO-d6) d 38.7, 42.0, 59.1,
108.8, 117.1, 120.6, 121.3, 133.0, 141.7, 147.7, 168.9;
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

378
Y. Wang, Z. Shafiq, L. Liu, D. Wang, and Y.-J. Chen
Vol 47
HRMS(EI): m/z calcd. for C24H22N5O5S (Mþ þ 1): 492.1339,
found 492.1336.
G.; Franco, M.; Latrofa, A.; Genchi, G.; Iacobazzi, V.; Ghiani, C. A.;
Maciocco, E.; Liso, G. Eur J Med Chem 1997, 32, 83.
[2] (a) Descours, D.; Festal, D. Synthesis 1983, 1033; (b)
LaMattina, J. L.; Mularski, C. J.; Muse, D. E. Tetrahedron 1988, 44,
3073.
6-[(2-Nitrophenyl)tosylaminomethyl)-5,6-dihydro-8H-ben-
zo[4,5]imidazo[1,2-a]pyrimidin-7-one (7f). A white solid,
m.p. ¼ 178–180ꢀC (decom.); FTIR (KBr): 3381, 3051, 1697,
1525, 1346, 1160 cmꢁ1 1H-NMR (300 MHz, DMSO-d6):
;
[3] (a) Nawrocka, W. Pol J Chem 1995, 69, 1158; (b) Zanatta,
N.; Amaral, S. S.; Esteves-Souza, A.; Echevarria, A.; Brondani, P. B.;
Flores, D. C.; Bonacorso, H. G.; Flores, A. F. C.; Martins, M. P. Syn-
thesis 2006, 2305, and references cited therein.
d 2.25 (s, 3H, CH3), 3.35–3.50 (m, 1H, CHCO), 3.80–4.45 (m,
2H, CH2CH), 5.30–5.48 (m, 1H, CHNH), 7.05–7.85 (m, 12H,
ArH), 8.65 (8.75) (m, 1H, NHSO2), 11.58 (s, 1H, NHCO);
13C-NMR (75 MHz, DMSO-d6): d 20.8, 38.7, 45.3, 51.0,
108.8, 117.1, 120.7, 121.3, 124.1, 126.2, 128.7, 129.1, 130.3,
132.8, 133.0, 133.1, 137.2, 141.3, 142.4, 147.2, 148.1, 167.0;
HRMS(EI): m/z calcd. for C24H22N5O5S (Mþ þ 1): 492.1339,
found 492.1336.
[4] Martin, M. W.; Newcomb, J.; Nunes, J. J.; Boucher, C.;
Chai, L.; Epstein, L. F.; Faust, T.; Flores, S.; Gallant, P.; Gore, A.;
Gu, Y.; Hsieh, F.; Huang, X.; Kim, J. L.; Middleton, S.; Morgenstem,
K.; Oliveire-dos-Santos, A.; Patel, V. F.; Powers, D.; Rose, P.; Tudor,
Y.; Turci, S. M.; Welcher, A. A.; Zack, D.; Zhao, H.; Zhu, L.; Zhu,
X.; Ghiron, C.; Ermann, M.; Johnston, D.; Saluste, C.-G. J Med Chem
2008, 51, 1637.
6-[(4-Methylphenyl)tosylaminomethyl)-5,6-dihydro-8H-
benzo[4,5]imidazo[1,2-a]pyrimidin-7-one (7g). A white
solid, m.p. ¼ 251–253ꢀC (decom.); FTIR (KBr): 3274, 3052,
[5] (a) Asobo, P. F.; Wahe, H.; Mbafor, J. T.; Nkengfack, A.
¨
E.; Fomum, Z. T.; Sopbue, E. F.; Dopp, D. J Chem Soc Perkin Trans
1692, 1456, 1323, 1159 cmꢁ1 1H-NMR (300 MHz, DMSO-
;
1 2001, 457; (b) Da Settimo, A.; Primofiore, G.; Da Settimo, F.; Mar-
ini, A. M.; Taliani, S.; Salermo, S.; Via, L. D. J Heterocycl Chem
2003, 40, 1091; (c) Shaabani, A.; Rahmati, A.; Naderi, S. Bioorg
Med Chem Lett 2005, 15, 5553; (d) Karci, F.; Demircali, A.; Sener,
I.; Tilki, T. Dyes Pigments 2006, 71, 90; (e) Troxler, F.; Weber, H. P.
Helv Chim Acta 1974, 57, 255.
d6): d 2.26 (s, 3H, CH3), 3.14–3.24 (m, 1H, CHCO), 3.57–4.40
(m, 2H, CH2CH), 4.57–4.64 (m, 1H, CHNH), 6.79–7.39 (m,
12H, ArH), 8.30 (8.85) (m, 1H, NHSO2), 11.49 (s, 1H,
NHCO); 13C-NMR (75 MHz, DMSO-d6): d 20.5, 20.8, 46.2,
56.1, 108.8, 117.2, 119.1, 120.8, 121.3, 127.0, 128.4, 129.0,
132.6, 134.0, 135.6, 136.5, 138.0, 141.1, 147.4, 167.6;
HRMS(EI): m/z calcd. for C25H25N4O3S (Mþ þ 1): 461.1637,
found 481.1642.
[6] Selected reviews, see: (a) Basavaiah, D.; Rao, K. V.;
Reddy, R. J Chem Soc Rev 2007, 36, 1581; (b) Singh, V.; Batra, S.
Tetrahedron 2008, 64, 4511; (c) Lee, K. Y.; Gowrisankar, S.; Kim, J.
N. Bull Korean Chem Soc 2005, 26, 1481; (d) Shi, Y.-L.; Shi, M.
Org Biomol Chem 2007, 5, 1499; (c) Basavaiah, D.; Rao, A. J.;
Satyanarayana, T. Chem Rev 2003, 103, 811; (d) Ciganek, E. In Or-
ganic Reactions; Paquette, L. A., Ed.; Wiley: New York, 1997; Vol.
51, pp 201–350.
Acknowledgments. The authors thank National Natural Foun-
dation of China, Ministry of Science and Technology (No.
2009ZX09501-006) and the Chinese Academy of Sciences for
the financial support.
[7] Very recently, the reaction of 2-aminothiazole with Baylis–
Hillman acetates was reported: Zhong, W.; Guo, B.; Lin, F.; Liu, Y.;
Su, W. Synthesis 2009, 10, 1615.
REFERENCES AND NOTES
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet