Synthesis of benzohetero[3, 2-a]pyrimidines using cyclic β-keto lactone as a building block

Article abstract of DOI:10.1007/s00706-008-0062-x

A novel method for the synthesis of 3-(2-substituted ethyl)-2- methylbenzohetero[3,2-a]pyrimidines in high yield (80-85%) was achieved, which involves a dihydrofuranone intermediate, readily obtained from β-ketolactone to 2-aminobenzoheterocycles. The maj

Full text of DOI:10.1007/s00706-008-0062-x

Monatsh Chem (2009) 140:235–241
DOI 10.1007/s00706-008-0062-x
ORIGINAL PAPER
Synthesis of benzohetero[3, 2-a]pyrimidines using cyclic b-keto
lactone as a building block
Raghunath B. Toche Æ Bhausaheb K. Ghotekar Æ
Muddassar A. Kazi Æ Madhukar N. Jachak
Received: 26 May 2008 / Accepted: 26 August 2008 / Published online: 30 September 2008
Ó Springer-Verlag 2008
Abstract A novel method for the synthesis of 3-(2-substi-
tuted ethyl)-2-methylbenzohetero[3,2-a]pyrimidines in high
yield (80–85%) was achieved, which involves a dihydrof-
uranone intermediate, readily obtained from b-ketolactone
to 2-aminobenzoheterocycles. The major advantage of the
methodology is the high yield and product purity.
and other biological activities [11–15]. Fused pyrimidines
with a 3-(2-chloroethyl) side chain are important com-
pounds in medicinal chemistry [16–18].
In a previous report [19] a-formyl-c-butyrolactone was
condensed with 2-aminoheterocycles to introduce the 3-(2-
chloroethyl) side chain in fused heterocycles. Now, we
wish to report about the incorporation of both a methyl
group at the 2-position along with a 3-(2-chloroethyl) side
chain in fused heterocycles, which we attempted by the
condensation of a-acetyl-c-butyrolactone with 2-amino-
heterocycles. Reports [20–22] about the condensation of
a-acetyl-c-butyrolactone with 2-aminobenzothiazoles and
2-aminopyridines led to the synthesis of fused heterocycles
as a mixture of two products [21]. These reports inspired us
to develop a new route towards the synthesis of benzo-
hetero[3,2-a]pyrimidines. As part of our continued interest
[23, 24] in the synthesis of novel heterocyclic compounds,
we have recently reported the synthesis of chromenes,
quinolines and pyrazolo[3,4-b]pyridines via multi-compo-
nent reactions. In this communication, we report about the
condensation of amines with ketones for the synthesis of
new benzohetero[3,2-a]pyrimidines having a 2-methyl-3-
(2-chloroethyl) side chain using cyclic b-ketolactone and
2-aminoheterocycles. Cyclic b-ketolactone reacts similarly
to biselectrophile in ring-switching reactions [25, 26], and
2-aminoheterocycles act as bisnucleophiles.
Keywords Biselectrophilic reactions Á Fused pyrimidine Á
4,5-Dihydro-furan-2(3H)-one Á Ammonium acetate Á
Heterocycles
Introduction
Fused pyrimidines have shown antipsychotic [1], antihy-
pertensive [2] and potent in vivo central nervous activities
[3]. They have also been used as tranquilizers [4], a-2-
antagonists [5, 6] and exhibit high affinity for a-2-adre-
noceptor with high selectivity vs. the a-receptor. Similarly,
benzo[3,2-c]pyrimidines and thiazolo[3,2-c]pyrimidines
have shown central dopamine and serotonin antagonistic
activity [7]. These compounds have been used as neuro-
leptics (especially atypical) antidepressants, sedatives,
hypnotics, cerebral protestants and muscle relaxants [8]
and antiallergic bronchodilators [9]. Benzimidazolo[3,2-c]
pyrimidines have been used as antihistamines [10]. Several
of these compounds exhibit antitumor cytotoxic activity
Results and discussion
R. B. Toche (&) Á B. K. Ghotekar Á M. A. Kazi Á M. N. Jachak
Organic Chemistry Research Centre,
Department of Chemistry,
2-Aminoheterocycles 1a–1d were condensed with a-acetyl-
c-butyrolactone (2) either by refluxing in toluene in the
presence of a catalytic amount of PTSA or by heating in
ammonium acetate to obtain the target compounds. It was
observed that 1a–1c upon reaction with 2 in toluene using
K. T. H. M. College,
Gangapur Road, Nashik 422002, Maharashtra, India
e-mail: raghunath_toche@rediffmail.com
B. K. Ghotekar
e-mail: bhausaheb.ghotekar@rediffmail.com
123

236
R. B. Toche et al.
catalytic amounts of PTSA at reflux temperature furnished
the thermodynamically favored (Z)-2-aminoethylidene
heterodihydrofuranone intermediates 3a–3c in 80–85%
yield. Here, PTSA acts as a selective catalyst, protonating the
oxygen of the keto carbonyl of lactone and initiating the
subsequent attack of the amino moiety to yield the enamine
intermediates 3a–3c. The use of other acids, such as sulfuric,
hydrochloric or acetic acid, or neat reaction conditions lead
to inseparable mixtures of products.
11.10 ppm. This structure was also confirmed by 13C NMR
analysis, which is given in the experimental part, and the
elemental analysis is in agreement with the structure pro-
posed. Upon reaction with sodium ethoxide in ethanol, the
dihydrofuranones 3a and 3b are cyclized to fused pyrimi-
dones 5a and 5b, having a 2-hydroxyethyl side chain in 80–
85% yield. Interestingly, it was observed that under the same
reactions conditions compound 3c produced unexpected
uracil 4 in 73% yield, which results from ring closure fol-
lowed by subsequent ring opening. IR, 1H NMR and
elemental analysis methods were used to deduce the struc-
tures of 4, 5a and 5b (given in the experimental part). For
example, the IR of compound 4 showed bands at 3,340,
3,200 cm-1 for hydroxyethyl and phenolic OH, the amide
CO is observed at 1,660 cm-1. The 1H NMR of 4 in DMSO-
d6 shows triplet-quartet at 1.19 and 4.31 ppm J = 7 Hz for
the ethoxy group; two triplets at 2.63 and 4.62 ppm are
J = 7 Hz observed for the –CH2CH2O– group. The broad
singlet at 3.52 and 9.84 ppm was observed for hydroxyethyl
and phenolic OH. Compounds 3a–3c, 5a–5b and 5d when
refluxed with POCl3 gave the expected benzohetero
[3,2-a]pyrimidones 6a–6d with a 2-chloroethyl side chain in
80–82% yield (Schemes 1, 2, 3).
The structures of 3a–3c were confirmed by spectro-
scopic and analytical methods. Just to give an example, the
IR of dihydrofuranone 3a shows peaks at 2,910 and
1,700 cm-1 for NH and CO. The unexpected decrease of
lactone C=O by 40–45 cm-1 can be explained by inter-
molecular hydrogen bonding [27] between NH and CO,
which stabilizes the (Z)-isomer. In addition the (E)-isomer
would suffer from steric repulsion between the methyl and
the carbonyl group at the allyl system.
1
The H NMR of 3a in DMSO-d6 shows a singlet at
2.52 ppm for methyl protons. The triplet at 2.85 ppm and
3.95 ppm J = 7 Hz is observed for –CH2CH2O group.
Aromatic protons are observed between 7.30 and 7.95 ppm.
The D2O exchangeable NH proton shows a broad singlet at
O
O
Toluene / PTSA
O
C2H5ONa / C2H5OH
OH
Cl
N
N
R
reflux, 10 h
X=O
N
OH
CH3CH2O
X
N
H
3a-3c
4
2 h
C2H5ONa /
C2H5OH
POCl3
1 h
O
reflux
O
OH
O
N
+
NH2
POCl3 / reflux
2 h
N
R
N
R
O
O
R
N
X
N
X
6a-6d
X
1a-1d
2
5a-5b, 5d
C2H5ONa /
C2H5OH
1h
OCOCH3
O
NH4OAc
N
120 °C, 1 h
X = NH
R
N
X
7
1
R
X
3
R
X
5,6
R
X
a
b
c
H
OCH3
H
S
S
O
a
b
c
H
OCH3
H
S
S
O
a
b
c
H
OCH3
H
S
S
O
d
H
NH
d
H
NH
Scheme 1
123

Synthesis of benzohetero[3, 2-a]pyrimidines using cyclic b-keto lactone as a building block
237
Scheme 2
N3
O
NaN3 / DMF
N
4 h
R
N
Cl
X
O
8a, 8b
N
R
N
OCH2CH3
X
O
N
C2H5ONa / C2H5OH
1h X = NH
6a, 6d
R
N
X
9
8
R
X
a
b
H
H
S
NH
Scheme 3
O
O
O
O
Toluene/ PTSA
+
2
reflux, 8 h
80%
H2N
N
NH2
H3C
N
N
N
H
CH3
H
11
10
2
The SN displacement of chlorine in 6a and 6d with
NaN3/DMF at 70–80 °C furnished azido derivatives 8a
and 8b. Ethyl ether 9 was obtained by refluxing 6d with
sodium ethoxide in ethanol. The formation of 8a, 8b and
9 indicated the presence of chloroethyl side chain in 6a,
6d, while formation of 6a–6d confirmed the dihydrof-
uranone structures of 3a–3c. Previously, [16] we have
reported these types of reactions in ammonium acetate.
But the same strategy does not work for the reactions of
1a–1d with cyclic b-ketolactone 2. We observed that 1a–
1c forms salt with ammonium acetate, reducing electron
donating tendency of the amino group. On the other
hand, 2-aminobenzimidazole 1d can react with lactone 2,
furnishing benzimidazolo[3,2-a]pyrimidine 7, which has
an ethyl acetoxy side chain. It was observed that the
2-hydroxyethyl group gets acetylated in ammonium
acetate. This type of phenomenon, though uncommon in
the literature, was observed in some cases [19]. When 7
was refluxed in basic medium, compound 5d with a free
alcohol moiety resulted, which could be converted to
compound 6d bearing a chloroethyl side chain upon
heating under reflux in phosphorous oxychloride.
Conclusion
Reaction of cyclic b-ketolactones and 2-aminoheterocycles
in toluene with PTSA as a catalyst led to thermodynami-
cally stable (Z)-2-aminoethylidene benzo[d]thiazol/benzo[d]
oxazoldihydrofuranoneintermediatesin80–85%yield,which
gives facile ring closure bezohetero[3,2-a]pyrimidin-4(1H)-
ones having a 2-chloroethyl/2-hydroxyethyl side chain in
80–85%. The new route was useful to obtain fused pyrimi-
dines with improved yields as a single product.
Experimental
Melting points were determined on a Gallenkamp melting-
1
point apparatus in open capillary tubes. The H NMR and
13C NMR spectra were recorded on a Varian XL-300
spectrometer (300 MHz). Chemical shifts were reported in
ppm from internal tetramethylsilane standard and are given
1
in d-units. H NMR and 13C NMR spectra are scanned
using CDCl3 or DMSO-d6. Infrared spectra were taken with
a Shimadzu FTIR-408 with potassium bromide pellets.
Elemental analyses are performed on a Hosli CH-Analyzer
and are within 0.3 of theoretical values. All reactions
were monitored by thin layer chromatography, carried out
The reaction of 2 with 2,6-diaminopyridine (10) under
similar conditions gave 2, 6-dihydrofuranone intermediate
11 in 80% yields.
123

238
R. B. Toche et al.
ppm; 13C NMR (300 MHz, DMSO-d6): d = 17.2 (CH3),
24.3 (CH2), 67.2 (OCH2), 103.1, 110.7, 119.2, 123.9,
124.9, 141.5, 150.0, 152.5, 154.2, 166.3 ppm.
on 0.2-mm silica gel 60 F254 (Merck) plates using UV light
(254 and 366 nm) for detection. Starting materials were
obtained from commercial suppliers and used without
further purification. Common reagent-grade chemicals
were either commercially available and were used without
further purification or prepared by standard literature
procedures.
(3Z)-3-{1-[(6-{[(1Z)-1-(2-Oxodihydrofuran-3(2H)-yli-
dene)ethyl]amino}-pyridin-2-yl)amino]ethylidene}
dihydrofuran-2 (3H)-one (11, C17H19N3O4)
Yield 2.63 g (80%), mp 233 °C (DMF); Rf 0.21 (toluene/
acetone 9:1); IR (KBr): vꢀ = 1,700, 1,650, 1,570, 1,500,
General procedure for the synthesis of Z-2-
aminoethylidene Dihydrofuranones 3a–3c and 11
1,450, 1,420 cm-1
;
1H NMR (300 MHz, DMSO-d6):
d = 2.51 (s, 6H, CH3), 2.93 (t, J = 7.1 Hz, 4H, 2CH2),
4.34 (t, J = 7 Hz, 4H, 2CH2O), 6.70 (d, J = 8.1 Hz, 1H,
C4–H), 7.71 (d, J = 8 Hz, 2H, C3–H, C5–H), 10.49 (bs,
2H, 2NH) ppm.
A mixture of 0.01 mol 2-aminoheterocycles 1a–1c/10 and
1.28 g a-acetyl-c-butyrolactone, 2 (0.01 mol, 1.10 cm3)
and a catalytic amount (0.020 g) of p-toluenesulfonic acid
in 20 cm3 toluene was refluxed for 8–10 h. (TLC Check).
After complete conversion the solvent was removed in
vacuo. The residue was stirred in 30 cm3 cold water. The
solid was collected by filtration, washed with water, dried
and recrystallized from a proper solvent.
General procedure for the synthesis
of (2-hydoxyethyl)pyrimidines 4, 5a and 5b
To a solution of 0.01 mmol compound 3a–3b or 3d dis-
solved in 30 cm3 absolute ethanol was added a solution of
sodium ethoxide (0.23 g freshly cut sodium metal dis-
solved in 10 cm3 absolute ethanol) and the reaction
mixture refluxed for 1 h. The solvent was removed under
reduced pressure, the residue was stirred in 100 cm3 cold
water and acidified with 2 N hydrochloric acid. The pre-
cipitated solid product was collected by filtration, washed
with cold water, dried and recrystallized from a proper
solvent.
(Z)-3-(1-(Benzo[d]thiazolo-2-ylamino)ethylidene)
dihydrofuran-2(3H)-one (3a, C13H12N2O2S)
Yield 2.13 g (82%), mp 179 °C (DMF); Rf 0.42 (toluene/
acetone 9:1); IR (KBr): vꢀ = 2,910, 1,700, 1,640, 1,540,
1,490 cm-1; 1H NMR (300 MHz, DMSO-d6): d = 2.52 (s,
3H, CH3), 2.85 (t, J = 7 Hz, 2H, CH2), 4.40 (t, J = 7 Hz,
2H, CH2), 7.30 (dt, J = 7.3 & 2.7 Hz, 1H, C5–H), 7.41
(dt, J = 8.3 & 2.5 Hz, 1H, C6–H), 7.72 (dd, J = 8.3 &
2.8 Hz, 1H, C4–H), 7.95 (dd, J = 8.3 & 2.3 Hz, 1H, C7–
H), 11.10 (bs, 1H, NH) ppm; 13C NMR (300 MHz, DMSO-
d6): d = 19.2 (CH3), 25.2 (CH2), 67.0 (OCH2), 104.1,
112.7, 123.3, 124.8, 125.6, 129.0, 123.9, 133.7, 144.3,
163.3 ppm.
1-(2-Hydropheny)-2-ethoxy-4-methyl-5-
(2-hydroxyethyl)pyrimidin-6(1H)-one (4, C15H18N2O4)
Yield 2.08 g (72%), mp 204 °C (acetonitrile); Rf 0.13
(toluene/acetone 9:1); IR (KBr): vꢀ = 3,340 (OH), 3,200,
2,900, 1,660, 1,600, 1,540, 1,450 cm-1
;
1H NMR
(300 MHz, DMSO-d6): d = 1.19 (t, J = 7 Hz, 3H, CH3),
2.32 (s, 3H, CH3), 2.63 (t, J = 7 Hz, 2H, CH2), 3.52 (s, 1H,
OH), 4.32 (q, J = 7 Hz, 2H, CH2), 4.62 (t, J = 7 Hz, 2H,
CH2O), 6.91 (dt, J = 7.3 & 2.3 Hz, 1H, C4–H), 7.03 (dd,
J = 8.3 & 2.6 Hz, 1H, C6–H), 7.11 (dd, J = 8.3 & 2.8 Hz,
1H, C3–H), 7.32 (dt, J = 8.3 & 2.8 Hz, 1H, C5–H), 9.84
(bs, 1H, OH) ppm.
(Z)-3-(1-(6-Methoxybenzo[d]thiazolo-2-ylamino)
ethylidene)dihydrofuran-2(3H)-one (3b, C14H14N2O3S)
Yield 2.46 g (85%), mp 206 °C (DMF); Rf 0.32 (toluene/
acetone 9:1); IR (KBr): vꢀ = 2,950, 1,690, 1,650, 1,600,
1,550, 1,510, 1,700, 1,430 cm-1 1H NMR (300 MHz,
;
DMSO-d6): d = 2.56 (s, 3H, CH3), 2.94 (t, J = 7 Hz, 2H,
CH2), 3.81 (s, 3H, OCH3), 4.42 (t, J = 7 Hz, 2H, CH2O),
7.03 (dd, J = 8.3 & 2.3 Hz, 1H, C5–H), 7.54 (m, 2H, C4–
H, C7–H), 10.95 (bs, 1H, NH) ppm; 13C NMR (300 MHz,
DMSO-d6): d = 15.5 (CH3), 23.9 (CH2), 69.2 (OCH2),
55.9 (OCH3), 101.1, 105.0, 113.2, 122.8, 125.5, 141.3,
152.2, 156.8, 170.0, 174.5 ppm.
3-(2-Hydroxyethyl)-2-methyl-1,3-benzthiazolo[3,2-a]
pyrimidin-4(1H)-one (5a, C13H12N2O3S)
Yield 2.15 g (78%), mp 189 °C (acetonitrile); Rf 0.15
(toluene/acetone 7:3); IR (KBr): vꢀ = 3,260, 2,911, 1,660,
1
1,590, 1,510, 1,460 cm-1; H NMR (300 MHz, DMSO-
d6): d = 2.32 (s, 3H, CH3), 2.82 (t, J = 7 Hz 2H, CH2),
3.44 (t, J = 7 Hz, 2H, CH2O), 4.65 (bs, 1H, OH), 7.62 (m,
2H, C7–H, C8–H), 8.06 (dd, J = 8.3 & 2.7 Hz, 1H, C6–H),
8.32 (dd, J = 8.3 & 2.8 Hz, 1H, C9H) ppm; 13C NMR
(300 MHz, DMSO-d6): d = 19.9 (CH3), 26.6 (CH2), 65.3
(OCH2), 105.0, 113.2, 126.3, 128.4, 133.6, 135.0, 136.9,
138.7, 163.0, 173.5 ppm.
(Z)-3-(1-(Benzo[d]oxazol-2-ylamino) ethylidene)-
dihydrofuran-2 (3H)-one (3c, C13H12N2O3)
Yield 1.85 g (76%), mp 187 °C (ethanol); Rf 0.40 (toluene/
acetone 8:2); IR (KBr): vꢀ = 1,700, 1,650, 1,580, 1,510,
1,450 cm-1; 1H NMR (300 MHz, DMSO-d6): d = 2.51 (s,
3H, CH3), 2.96 (t, J = 7 Hz, 2H, CH2), 4.40 (t, J = 7 Hz,
2H, CH2O), 7.22–7.83 (m, 4H, Ar–H), 11.06 (bs, 1H, NH)
123

Synthesis of benzohetero[3, 2-a]pyrimidines using cyclic b-keto lactone as a building block
239
3-(2-Hydroxyethyl)-2-methyl-8-methoxy-1,3-benzothiazolo
[3,2-a]pyrimid- in-4(1H)-one (5b, C14H14N2O3S)
3-(2-Chloroethyl)-2-methyl-1,3-benzthiazolo[3,2-a]
pyrimidin-4(1H)-one (6a, C13H11N2OSCl)
Yield 2.37 g (82%), mp 195 °C (ethanol); Rf 0.12 (toluene/
acetone 8:2); IR (KBr): vꢀ = 3,400, 2,910, 1,660, 1,600,
Yield 2.08 g (75%), mp 141 °C (ligroin) [Lit21 mp 144 °C];
Rf 0.50 (toluene/acetone 9:1); IR (KBr): vꢀ = 1,670, 1,590,
1,560, 1,500, 1,470, 1,430 cm-1
;
1H NMR (300 MHz,
1,500, 1,440 cm-1 1H NMR (300 MHz, DMSO-d6):
;
DMSO-d6): d = 2.37 (s, 3H, CH3), 2.70 (t, J = 7 Hz, 2H,
CH2O), 3.35 (t, J = 7 Hz, 2H, CH2O), 3.83 (s, 3H, OCH3),
4.72 (bs, 1H, OH), 7.13 (d, J = 8.2 Hz, 1H, C6–H), 7.75
(d, J = 2.7 Hz, 1H, C9–H), 8.80 (dd, J = 8.3 & 2.8 Hz,
1H, C7–H) ppm; 13C NMR (300 MHz, DMSO-d6):
d = 20.9 (CH3), 28.1 (CH2), 55.9 (OCH3), 59.5 (OCH2),
111.3, 114.4, 116.1, 122.9, 129.5, 131.1, 153.0, 156.6,
160.3, 163.5 ppm.
d = 2.52 (s, 3H, CH3), 3.15 (t, J = 7 Hz 2H, CH2), 3.85
(t, J = 7 Hz, 2H, CH2Cl), 7.52 (dt, J = 8.2 & 2.8 Hz, 1H,
C7–H), 7.76 (dt, J = 8.3 & 2.2 Hz, 1H, C8–H), 8.06 (dd,
J = 8.3 & 2.7 Hz, 1H, C6–H), 8.30 (dd, J = 8.3 & 2.8 Hz,
1H, C9H) ppm; 13C NMR (300 MHz, DMSO-d6): d = 20.9
(CH3), 23.2 (CH2), 41.9 (OCH2), 116.1, 121.6, 124.7, 125.8,
129.6, 130.1, 137.2, 153.0, 155.0, 163.3 ppm.
3-(2-Chloroethyl)-2-methyl-8-methoxy-1,3-benzothiazolo
[3,2-a]pyrimidin-4(1H)-one (6b, C14 H13Cl2N2O2S)
Yield 2.75 g (80%), mp 178 °C (ligroin); Rf 0.16 (toluene/
acetone 9:1); IR (KBr): vꢀ = 2,910, 1,660, 1,600, 1,570,
Procedure for the synthesis of 3-(2-Hydoxyethyl)-2-
methylbenzimidazolo[3,2-a] pyrimidin-4(1H)-one
(5d, C13H13N3O2)
1
1,510, 1,480, 1,440 cm-1; H NMR (300 MHz, DMSO-
d6): d = 2.42 (s, 3H, CH3), 3.15 (t, J = 7 Hz, 2H, CH2),
3.76 (t, J = 7 Hz, 2H, CH2Cl), 3.83 (s, 3H, OCH3), 6.92
(d, J = 8.3 Hz, 1H, C6–H), 7.13 (d, J = 2.3 Hz, 1H, C9–
H), 8.80 (dd, J = 8.3 & 2.2 Hz, 1H, C7–H) ppm; 13C NMR
(300 MHz, DMSO-d6): d = 18.4 (CH3), 25.9 (CH2), 63.2
(OCH3), 45.5 (OCH2), 118.1, 126.6, 122.7, 128.8, 127.6,
133.1, 139.2, 156.0, 159.0, 169.2 ppm.
Benzimidazolo[3,2-a]pyrimidine 7 (0.01 mol) was refluxed
in a solution of sodium ethoxide (0.23 g sodium metal
dissolved in 10 cm3 ethanol) in 20 cm3 ethanol for 1 h. The
solvent was removed under reduced pressure. The residue
obtained was stirred in 30 cm3 cold water. The solid pre-
cipitate was collected by filtration, washed with water,
dried, and recrystallized from a proper solvent.
3-(2-Chloroethyl)-2-methyl-1,3-benzoxazolo
Yield 1.83 g (80%), mp 286 °C (DMF); Rf 0.16
(toluene/methanol 9:1); IR (KBr): vꢀ = 3,100, 1,670,
[3,2-a]pyrimidin-4(1H)-one (6c, C13H11ClN2O2)
Yield 2.06 g (79%), mp 140 °C (ligroin); Rf 0.19 (toluene/
methanol 9:1); IR (KBr): vꢀ = 1,680, 1,640, 1,600,
;
1,530 cm-1 1H NMR (300 MHz, CDCl3): d = 2.50 (s,
3H, CH3), 3.22 (t, J = 7 Hz, 2H, CH2), 3.83 (t, J = 7 Hz,
2H, CH2Cl), 7.21 (dt, J = 8.2 & 2.8 Hz, 1H, C7–H), 7.36
(dt, J = 8.3 & 2.2 Hz, 1H, C8–H), 8.08 (dd, J = 8.3 &
2.7 Hz, 1H, C6–H), 8.26 (dd, J = 8.3 & 2.8 Hz, 1H, C9H)
ppm; 13C NMR (300 MHz, DMSO-d6): d = 19.2 (CH3),
24.3 (CH2), 65.2 (OCH2), 106.1, 118.7, 119.2, 126.9,
133.9, 148.5, 155.0, 156.5, 158.2, 168.0 ppm.
1
1,640, 1,610, 1,580, 1,540, 1,490, 1,460 cm-1; H NMR
(300 MHz, DMSO-d6): d = 2.04 (s, 3H, CH3), 2.72 (t,
J = 7 Hz, 2H, CH2), 3.36 (t, J = 7 Hz, 2H, CH2O), 4.65
(bs, 1H, OH), 7.22 (dt, J = 8.3 & 2.8 Hz, 1H, C8–H),
7.30 (dt, J = 8.3 & 2.7 Hz, 1H, C7–H), 7.50 (dd,
J = 8.3 & 2.8 Hz, 1H, C6–H), 8.41 (dd, J = 7.3 &
2.9 Hz, 1H, C9–H), 12.60 (bs, 1H, NH) ppm; 13C NMR
(300 MHz, DMSO-d6): d = 21.3 (CH3), 29.1 (CH2), 57.5
(OCH2), 116.3, 119.4, 122.1, 122.9, 125.2, 128.1, 138.4,
156.6, 164.0 ppm.
3-(2-Chloroethyl)-2-methyl-1,3-benzoimidazolo
[3,2-a]pyrimidin-4(1H)-one (6d, C13H12ClN3O)
General procedure for the synthesis of 3-
(2-chloroethyl)-2-methylhetero[3,2-a]
pyrimidin-4(1H)-one 6a–6d
Yield 1.95 g (75%), mp 230 °C (DMF ethanol); Rf 0.23
(toluene/methanol 9:1); IR (KBr): vꢀ = 3,100, 1,660, 1,630,
1,610, 1,570, 1,520, 1,500, 1,470, 1,440 cm-1; H NMR
1
Dihydrofuranone 3a–3c, 5a–5b, or 5d (0.01 mol) was
refluxed in 30 cm3 phosphorous oxychloride for 2 h. The
excess of phosphorous oxychloride was removed under
reduced pressure. Ice-cold water (100 cm3) was added to
the reaction mixture, which was followed by neutralization
with 6 g solid sodium carbonate and further stirring for 2 h.
The precipitated product was collected by filtration,
washed with water, dried, and recrystallized.
(300 MHz, DMSO-d6): d = 2.40 (s, 3H, CH3), 3.01 (t,
J = 7 Hz, 2H, CH2), 3.92 (t, J = 7 Hz, 2H, CH2Cl), 7.32
(dt, J = 8.3 & 2.2 Hz, 1H, C7–H), 7.50 (dt, J = 8.3 &
2.2 Hz, 1H, C8–H), 7.62 (dd, J = 8.3 & 2.2 Hz, 1H,
C6–H), 8.43 (dd, J = 8.3 & 2.3 Hz, 1H, C9–H), 12.61 (bs,
1H, NH) ppm; 13C NMR (300 MHz, DMSO-d6): d = 21.7
(CH3), 23.2 (CH2), 41.9 (OCH2), 116.1, 116.4, 119.0,
122.0, 122.9, 125.6, 138.4, 153.0, 157.6, 163.0 ppm.
123

240
R. B. Toche et al.
Procedure for the synthesis of 3-(2-Acetoxyethyl)-2-
methylbenzimidazolo- [3,2-a] pyrimidin-4(1H)-one
(7, C15H15N3O3)
NMR (300 MHz, DMSO-d6): d = 2.04 (s, 3H, CH3),
2.72 (t, J = 7 Hz, 2H, CH2N3), 3.36 (t, J = 7 Hz, 2H,
CH2), 7.22 (dd, J = 8.3 & 2.8 Hz, 1H, C6–H), 7.60 (dd,
J = 8.3 & 2.8 Hz, 1H, C9–H), 8.82 (dt, J = 8.3 &
2.8 Hz, 1H, C7–H), 8. 94 (dt, J = 8.2 & 2.3 Hz, 1H,
C8–H), 12.60 (bs, 1H, NH) ppm; 13C NMR (300 MHz,
DMSO-d6): d = 17.9 (CH3), 28.1 (CH2), 58.0 (OCH2),
110.1, 122.7, 129.4, 136.5, 139.5, 143.2, 145.3, 148.8,
154.2 ppm.
A 100-cm3 round-bottom flask containing a mixture of
1.32 g 2-aminobenzimidazole 1d (0.01 mol), 1.28 g
a-acetyl-c-butyrolactone (2) (0.01 mol, 1.10 cm3), and
2.95 g ammonium acetate (0.05 mol) was heated at 120 °C
for 1 h. Cold water (30 cm3) was added to the viscous
reaction mixture and stirred for 30 min to remove excess of
ammonium acetate. The precipitated solid product was
collected by filtration, washed with water, dried, and re-
crystallized. Yield 2.28 g (80%), mp 232 °C (DMF); Rf
0.52 (toluene/acetone 9:1); IR (KBr): vꢀ = 3,100, 1,730,
Procedure for the synthesis of 3-(2-Ethoxyethyl)-2-
methyl-1,3-benzimidazolo[3,2-a] pyrimidin-4(1H)-
one (9, C15H17N3O2)
1
1,670, 1,610, 1,570, 1,530, 1,490, 1,460 cm-1; H NMR
A suspension of 2.46 g 6d (0.01 mol) in 30 cm3 ethanol
was refluxed in a solution of sodium ethoxide (0.23 g
sodium dissolved in 10 cm3 ethanol) for 1 h. The solvent
was removed under reduced pressure. The residue was
stirred in 100 cm3 water and then acidified with 2 N
hydrochloric acid. The precipitated solid was collected by
filtration, dried, and recrystallized. Yield 2.11 g (78%), mp
225 °C (ethanol); IR (KBr): vꢀ = 3,100 (NH), 1,630 (CO),
(300 MHz, DMSO-d6): d = 2.04 (s, 3H, CH3), 2.41 (s, 3H,
CH3), 2.67 (t, J = 7 Hz, 2H, CH2), 4.22 (t, J = 7 Hz, 2H,
CH2O), 7.22 (dt, J = 8.3 & 2.8 Hz, 1H, C8–H), 7.30 (dt,
J = 8.3 & 2.8 Hz, 1H, C7–H), 7.5(dd, J = 8.3 & 2.8 Hz,
1H, C6–H), 8.41(dd, J = 7.3 & 2.7 Hz, 1H, C9–H), 12.60
(bs, 1H, NH) ppm; 13C NMR (300 MHz, DMSO-d6):
d = 20.7 (CH3), 21.3 (CH3), 24.8 (CH2), 61.5 (OCH2),
115.1, 116.5, 120.0, 123.0, 125.2, 125.5, 138.4, 153.0,
157.6, 161.0, 170.3 ppm.
1,600, 1,520, 1,500, 1,470, 1,450 cm-1
;
1H NMR
(300 MHz, DMSO-d6): d = 1.13 (t, J = 7 Hz, 3H, CH3),
2.41 (s, 3H, CH3), 2.83 (t, J = 7 Hz, 2H, CH2), 3.41
(t, J = 7 Hz, 2H, CH2), 3.50 (q, J = 7 Hz, 2H, CH2), 7.23
(dt, J = 8.3 & 2.7 Hz, 1H, C7–H), 7.31 (dt, J = 8.3 &
2.7 Hz, 1H, C8–H), 7.45 (dd, J = 8.3 & 2.7 Hz, 1H,
C6–H), 8.40 (dd, J = 8.3 & 2.8 Hz, 1 H, C9–H), 12.60
(s, 1H, NH) ppm; 13C NMR (300 MHz, DMSO-d6):
d = 15.5 (CH3), 21.3 (CH3), 25.9 (CH2), 67.7 (OCH2),
68.3 (OCH2), 116.1, 116.5, 119.0, 122.0, 123.3, 125.2,
138.4, 147.2, 148.8, 166.3 ppm.
General procedure for the synthesis of 3-(2-azidoethyl)-
2-methyl-1,3-benzthiazolo[3,2-a] pyrimidin-4 (1H)-
one 8a–8b
Compound 6a–6b (0.01 mol) was stirred with 1.95 g
sodium azide (0.03 mmol) in 30 cm3 DMF and 5 cm3
water at 60–70 °C for 4 h. The product was precipitated by
adding 100 cm3 cold water in the reaction mixture. The
precipitated solid was collected by filtration, washed with
cold water, and recrystallized from a proper solvent.
Acknowledgments The authors are thank UGC New Delhi for
finacial assistance under MRP, and University of Punjab, Chandigarh,
for the instrumental facility. The authors also highly thank the higher
authorities of NDMVP Samaj’s and KTHM College, Nashik.
3-(2-Azidoethyl)-2-methyl-1,3-benzthiazolo[3,2-a]
pyrimidin-4(1H)-one (8a, C13H11N5OS)
Yield 2.28 g (80%), mp 94 °C, (Cyclohexane); Rf 0.45
(toluene/acetone 9:1); IR (KBr): vꢀ = 2,110 (N3), 1,670
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(CO), 1,590, 1,577, 1,550, 1,514 cm-1
;
1H NMR
(300 MHz, DMSO-d6): d = 2.32 (s, 3H, CH3), 2.82
(t, J = 8.3 Hz 2H, CH2N3), 3.44 (t, J = 8.3 Hz, 2H,
CH2), 7.63 (m, 2H, C7–H, C8–H), 8.06 (dd, J = 8.3 &
2.6 Hz, 1H, C6–H), 8.30 (dd, J = 8.3 & 2.6 Hz, 1H, C9H)
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26.2 (CH2), 59.0 (OCH2), 108.1, 121.7, 127.3, 135.8,
138.6, 141.0, 143.9, 147.7, 155.3 ppm.
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