A new [5+1]-annulation route to some quinazoline and fused pyrimidine derivatives

Article abstract of DOI:10.1055/s-2005-861872

β-Dicarbonyl compounds, such as diethyl malonate, ethyl acetoacetate and acetyl acetone have been found to add selectively to the iminoether functionality of the 2-ethoxymethyleneaminonitriles leading to a one-pot synthesis of some quinazoline and fused p

Full text of DOI:10.1055/s-2005-861872

PAPER
1083
A New [5+1]-Annulation Route to Some Quinazoline and Fused Pyrimidine
Derivatives
Synthesis of
Q
h
uinazoline
a
i
t
d
Pyrim
a
idine Deri
l
vatives K. Chattopadhyay,* Rajat Dey, Suman Biswas
Department of Chemistry, University of Kalyani, Kalyani 741235, India
Fax +91(33)25828282; E-mail: skchatto@yahoo.com
Received 23 September 2004; revised 3 January 2005
This paper is respectfully dedicated to Professor Alexander McKillop, University of East Anglia, Norwich, UK
NH2
Nu
Abstract: b-Dicarbonyl compounds, such as diethyl malonate,
CN
N
CN
ethyl acetoacetate and acetyl acetone have been found to add selec-
tively to the iminoether functionality of the 2-ethoxymethyleneam-
inonitriles leading to a one-pot synthesis of some quinazoline and
fused pyrimidine derivatives.
Nu
Nu
X
N
N
3
1 X = OR, NHR etc
2
Key words: annulations, heterocycles, nitriles, Lewis acids, tin
CN
N
CN
N
CN
Bifunctional iminoethers or amidines represented by the
general structure 1 (Scheme 1) have been widely used1,2
for the synthesis of various nitrogen heterocyclic com-
pounds involving stepwise inter- and intramolecular addi-
tion of suitable nucleophilic species. Nucleophiles such as
amines, hydrazines, hydrosulfides and hydroxylamines
add selectively to the azomethine functionality in 1 to give
intermediates which cyclize in an intramolecular fashion
to give heterocycles3–5 (Scheme 1). Carbon nucleophiles
such as Grignard reagents or alkyllithiums predominantly
act as base towards iminoethers forming isonitriles,6 but
phenylmagnesium bromide has been found to add to 2-
amidinonitriles leading to the formation of some quinazo-
line derivatives.7 The behavior of other softer carbon nu-
cleophiles towards iminonitriles has largely remained
unexplored. Various metal catalysts are known8,9 to acti-
vate carbon–carbon bond formation between the cyano
group in nitriles and the inter-carbonylic methylene group
of b-dicarbonyl compounds. For the non-electrophilically
activated nitriles, stannic chloride has been found10 to be
particularly effective. We were interested to examine
whether any selectivity could be observed in the stannic
chloride promoted addition of b-dicarbonyl compounds to
2-ethoxymethyleneaminonitriles of the type 4–6 with an
aim to develop new routes to some nitrogen heterocyclic
systems of interest. Herein, we wish to describe our ef-
forts in this direction.
OEt
OEt
N
OEt
4
5
6
Scheme 1
terization. When a solution of 2-ethoxymethyleneami-
nobenzonitrile (4), diethyl malonate and stannic chloride
in the molar ratio of 1:1:2 was refluxed in toluene for five
hours, an orange colored solid separated. This presumable
tin complex on treatment with saturated sodium carbonate
solution liberated two products after chromatography
which were characterized to be the quinazoline derivative
9a (48%) and the quinoline derivative 10a (19%)
(Scheme 2). The formation of these products could be ex-
plained if it is assumed that a selective addition of diethyl
malonate to the nitrile group in 4 has taken place to form
an intermediate of the type 8 (not isolated) which then cy-
clizes through two different possible modes involving the
ambident nucleophilic centers within the enamine moiety.
R1
O
NH2
OEt
O
CN
R1
R2
SnCl4
+
toluene,
reflux, 5 h
N
OEt
N
O
4
7a R1 = R2 = OEt
7b R1 = OEt, R2 = CH3
7c R1 = R2 = CH3
8
The starting materials 4–6 were easily prepared by acid
catalyzed condensation of the corresponding aminoni-
triles with triethyl orthoformate as described in the litera-
ture.11Although these have been occasionally used
without isolation, their spectroscopic properties are not re-
ported. A simple procedure for their preparation has thus
been developed which allowed their isolation and charac-
R1
NH2
O
O
H
R1
9a, 10a R1 = OEt
9b, 10b R1 = CH3
N
+
N
N
9a 48%
9b 39%
10a 19%
10b 27%
SYNTHESIS 2005, No. 7, pp 1083–1086
Advanced online publication: 17.03.2005
x
x
.
x
x
.2
0
0
5
DOI: 10.1055/s-2005-861872; Art ID: T10804SS
Scheme 2
© Georg Thieme Verlag Stuttgart · New York

1084
S. K. Chattopadhyay et al.
PAPER
mental analyzer. Petroleum ether refers to the fraction boiling in the
range of 60–80 °C. Silica gel used was purchased from Spectro-
chem, India Limited. 1-Amino-2-cyanocyclohexene15 and 1-amino-
2-cyanocyclopentene16 were prepared following literature proce-
dure.
It is interesting to note that when the reaction was con-
ducted under identical conditions but using ethyl aceto-
acetate as the dicarbonyl compound, the same mixture of
products 9a (42%) and 10a (21%) was formed. Reaction
of 4 with acetylacetone analogously led to the formation
of 9b (39%) and 10b (27%). Apparently, one of the carbo-
nyl groups was lost during all of these reactions. Although
it is difficult to predict exactly at which stage the acyl
group is lost, this kind of deacylation12 has been previous-
ly noted in related reactions. Moreover, the products 9a,b
were obtained in geometrically pure form. We have tenta-
tively assigned Z-configuration to these as an intramolec-
ular hydrogen bond between the NH proton and the
carbonyl group is expected to contribute to their stability.
Formation of the dihydroquinazolines 9a,b and the ami-
noquinoline derivatives 10a,b was a pleasing outcome
since various quinazoline and quinoline derivatives are
known to have interesting biological properties.13
2-Ethoxymethyleneaminonitriles 4-6; General Procedure
A solution of the appropriate 2-aminonitrile (0.1 mol) in triethyl
orthoformate (103.7 g, 0.7 mol) was heated under reflux in a flask
fitted with a 15 cm long Vigreux column until the distillation of
EtOH ceased (ca. 1–2 h). The mixture was cooled, and a few crys-
tals of p-TsOH acid were added. The mixture was refluxed again
until no more EtOH was collected (ca. 1 h). Excess solvent was then
distilled off under reduced pressure and the remaining material was
purified by distillation under high vacuum.
Ethyl N-2-Cyanophenylformimidate (4)
Yield: 82%; bp 112 °C/0.5 mm.
IR (neat): 2225, 1640, 1590, 1215 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.80–7.85 (m, 5 H), 4.42 (q, 2 H,
J = 7.5 Hz), 1.42 (t, 3 H, J = 7.5 Hz).
The iminonitrile 5, prepared from 1-amino-2-cyanocyclo-
hexene, was then reacted with diethyl malonate under the
conditions developed previously. The only isolable prod-
13C NMR (100 MHz, CDCl3): d = 156.4, 151.1, 133.6, 133.0, 124.3,
120.8, 117.3, 107.2, 62.2, 14.0.
uct from this reaction was characterized from spectro- Anal. Calcd for C10H10N2O: C, 68.95; H, 5.79; N, 16.08. Found: C,
68.82; H, 5.68; N, 16.13.
scopic and analytical data to be the tetrahydroquinazoline
derivative 11 (Scheme 3). The same product also formed
Ethyl N-2-Cyanocyclohex-1-enylformimidate (5)
from the reaction of 5 with ethyl acetoacetate but a slight
Yield: 86%; bp 110 °C/0.2 mm.
IR (neat): 2230, 1650, 1635, 1595 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.80 (s, 1 H), 4.43 (q, 2 H, J = 7.5
Hz), 2.32 (br s, 4 H), 1.67–1.61 (m, 4 H), 1.32 (t, 3 H, J = 7.5 Hz).
drop in the yield (40%) was noticed. The iminonitrile 6,
prepared from 1-amino-2-cyanocyclopentene, also be-
haved similarly. Thus, the reaction of the latter with dieth-
yl malonate under identical conditions led to the
formation of the pyrimidine derivative 12 as the only isol- 13C NMR (100 MHz, CDCl3): d = 158.4, 154.6, 119.2, 95.9, 62.8,
29.0, 26.5, 21.7, 21.6, 14.0.
able product (41%).
Anal. Calcd for C10H14N2O: C, 67.39; H, 7.92; N, 15.72. Found: C,
67.28; H, 7.99; N, 15.65.
CH2CO2Et
CN
N
CO2Et
CO2Et
N
N
SnCl4
Ethyl N-2-Cyanocyclopent-1-enylformimidate (6)
Yield: 86%; mp 44 °C (toluene).
IR (KBr): 2210, 1630, 1615, 1230 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.80 (s, 1 H), 4.36 (q, 2 H, J = 7.5
Hz), 2.40–2.20 (m, 4 H), 2.10–1.95 (m, 2 H), 1.36 (t, 3 H, J = 7.5
Hz).
+
toluene,
reflux, 5 h
OEt
5 n = 2
6 n = 1
11 n = 2, 48%
12 n = 1, 41%
7a
Scheme 3
13C NMR (100 MHz, CDCl3): d = 163.6, 157.5, 117.0, 98.3, 63.3,
In short, we have demonstrated that the stannic chloride
promoted reaction of b-dicarbonyl compounds with 2-
ethoxymethyleneaminonitriles 4–6 led to the formation of
some important heterocyclic compounds like quinazo-
32.7, 31.8, 21.8, 14.1.
Anal. Calcd for C9H12N2O: C, 65.83; H, 7.37; N, 17.06. Found: C,
65.95; H, 7.22; N, 17.14.
line,14 pyrimidine and quinoline derivatives. Although the Reaction of 2-Ethoxymethyleneaminonitriles 4–6 with b-Dicar-
bonyl Compounds; General Procedure
yields are moderate, the developed [5+1]-annulation pro-
cedure provides direct access to some of these important
heterocyclic ring systems in one step, which may prove to
be of utility.
SnCl2 (1.2 mL, 10 mmol) was added dropwise to a stirred solution
of the appropriate 2-ethoxymethyleneaminonitrile 4–6 (5 mmol)
and the b-dicarbonyl compound (5 mmol) in anhyd toluene (15 mL)
at r.t. under N2. The mixture was refluxed for 5 h by which time an
orange mass separated. It was then allowed to come to r.t., and ex-
cess toluene was distilled off in vacuo. The residual mass was
stirred with aq sat. Na2CO3 solution (40 mL) and then extracted with
EtOAc (2 × 40 mL). The combined organic extracts were washed
successively with H2O (2 × 40 mL), brine (20 mL), and then dried
(Na2SO4). It was filtered and the filtrate was concentrated to leave a
crude product, which was chromatographed on silica gel using an
appropriate eluent.
Melting points were determined in open capillaries and are uncor-
rected. IR spectra were obtained on a Perkin-Elmer 1600 FTIR
1
spectrometer. H NMR and 13C NMR spectra were recorded on a
Bruker DRX-300 spectrometer in CDCl3 or DMSO-d6 and refer-
enced to the solvent signal. Low-resolution mass spectra were re-
corded on a Jeol-JMS 600 instrument at an ionizing potential of 70
eV. Microanalyses were performed on a Perkin-Elmer 204B ele-
Synthesis 2005, No. 7, 1083–1086 © Thieme Stuttgart · New York

PAPER
Synthesis of Quinazoline and Fused Pyrimidine Derivatives
1085
Ethyl (Z)-2-[Quinazolin-4(3H)-ylidene]acetate (9a)
Eluent for chromatography: 30% EtOAc in petroleum ether. Re-
moval of the solvent afforded the product as a colorless solid; yield:
48%; mp 104 °C (EtOAc–petroleum ether) (Lit.17 mp 103 °C); Rf
0.55.
1H NMR (300 MHz, CDCl3): d = 8.86 (s, 1 H), 4.20 (q, 2 H, J = 7.2
Hz), 3.78 (s, 2 H), 2.90–2.78 (m, 2 H), 2.72–2.61 (m, 2 H), 1.87 (br
s, 4 H), 1.27 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 169.3 (s), 166.0 (s), 161.1 (s),
155.4 (d), 129.1 (s), 61.3 (t), 40.9 (t), 32.3 (t), 24.7 (t), 22.3 (t), 22.0
(t), 14.1 (q).
IR (KBr): 3200, 2800, 1650, 1620 cm–1.
1H NMR (400 MHz, CDCl3): d = 12.34 (br s, 1 H), 7.80 (d, 1 H,
J = 3 Hz), 7.72 (d, 1 H, J = 8.9 Hz), 7.61–7.52 (m, 2 H), 7.37–7.28
(m, 1 H), 5.49 (s, 1 H), 4.21 (q, 2 H, J = 6.9 Hz), 1.33 (t, 3 H, J = 6.9
Hz).
MS (EI): m/z (%) = 220 (M+, 48).
Anal. Calcd for C12H16N2O2 (220.27): C, 65.43; H, 7.32; N, 12.72.
Found: C, 65.32; H, 7.53; N, 12.71.
MS (EI): m/z (%) = 216 (M+, 59), 170 (79), 144 (100).
Ethyl 2-(6,7-Dihydro-5H-cyclopenta[d]pyrimidin-4-yl)acetate
(12)
Anal. Calcd for C12H12N2O2 (216.24): C, 66.65; H, 5.59; N, 12.95.
Found: C, 66.83; H, 5.91; N, 12.68.
Eluent for chromatography: 30% EtOAc in petroleum ether. Re-
moval of the solvent afforded the product as a viscous liquid; yield:
41%.
IR (neat): 2979, 1738, 1585, 1561, 1386 cm–1.
Further elution with the same solvent provided the known18 ethyl 4-
aminoquinoline-3-carboxylate (10a) as a colorless solid.
10a
1H NMR (300 MHz, CDCl3): d = 8.92 (s, 1 H), 4.20 (q, 2 H, J = 7.2
Hz), 3.77 (s, 2 H), 3.07–2.94 (m, 4 H), 2.16 (m, 2 H), 1.27 (t, 3 H,
J = 7.1 Hz)
13C NMR (75 MHz, CDCl3): d = 170.1 (s), 168.0 (s), 164.2 (s),
155.6 (d), 134.5 (s), 61.6 (t), 39.6 (t), 34.2 (t), 25.7 (t), 24.2 (t), 14.2
(q).
MS (EI): m/z (%) = 206 (M+, 86), 161 (26), 132 (100).
Yield: 19%; mp 200 °C (EtOH); Rf 0.21.
IR (KBr): 3350, 2980, 1680, 1640, 1590 cm–1.
1H NMR (300 MHz, DMSO-d6): d = 8.91 (s, 1 H), 8.37 (d, 1 H,
J = 8.4 Hz), 8.30 (br s, 2 H), 7.80 (t, 1 H, J = 8.5 Hz), 7.74 (dt, 1 H,
J = 6.9, 1.2 Hz), 7.52 (dt, 1 H, J = 7.2, 1.2 Hz), 4.34 (q, 2 H, J = 6.9
Hz), 1.36 (t, 3 H, J = 6.9 Hz).
MS (EI): m/z (%) = 217 (M+ + 1, 100), 188 (12), 171 (55).
Anal. Calcd for C11H14N2O2 (206.24): C, 64.06; H, 6.84; N, 13.58.
Found: C, 64.23; H, 7.11; N, 13.66.
Anal. Calcd for C12H12N2O2 (216.24): C, 66.65; H, 5.59; N, 12.95.
Found: C, 66.72; H, 5.32; N, 12.94.
Acknowledgment
(Z)-1-[Quinazolin-4(3H)-ylidene]propan-2-one (9b)
Eluent for chromatogarphy: 30% EtOAc in petroleum ether. Re-
moval of the solvent afforded the product as a colorless solid; yield:
39%; mp 111 °C (EtOAc–petroleum ether) (Lit.17 mp 109 °C); Rf
0.61.
Financial assistance from CSIR, New Delhi (Grant No. 01/1676/00/
EMR-II) is gratefully acknowledged.
References
IR (KBr): 3100, 1630, 1614, 1590, 1550, 1480 cm–1.
1H NMR (300 MHz, CDCl3): d = 14.52 (br s, 1 H), 7.98 (d, 1 H,
J = 2.4 Hz), 7.84 (d, 1 H, J = 8.1 Hz), 7.77–7.62 (m, 2 H), 7.45–7.40
(m, 1 H), 6.02 (s, 1 H), 2.26 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 196.9 (s), 149.7 (s), 145.5 (s),
142.5 (d), 133.4 (d), 128.2 (d), 127.3 (d), 123.2 (d), 119.5 (s), 89.3
(d), 29.7 (q).
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Found: C, 71.23; H, 5.46; N, 15.29.
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10b
IR (KBr): 3440, 3340, 3230, 1640, 1585, 1550 cm–1.
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Ethyl 2-(5,6,7, 8-Tetrahydroquinazolin-4-yl)acetate (11)
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S. K. Chattopadhyay et al.
PAPER
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Synthesis 2005, No. 7, 1083–1086 © Thieme Stuttgart · New York