A facile synthesis of 2-substituted 2,3-dihydro-4(1h)-azuleno[1,2-d] pyrimidinones

Article abstract of DOI:10.3987/COM-10-12098

A facile, efficient and novel approach to access 2-substituted 2,3-dihydro-4(1H)-azuleno[2,1-d]pyrimidinones was developed by condensation of methyl 2-amino-3-carbamoylazulene-1-carboxylate with ketones or ary1 aldehydes in the 2,2,2-trifluoroethanol cata

Full text of DOI:10.3987/COM-10-12098

HETEROCYCLES, Vol. 83, No. 2, 2011
365
HETEROCYCLES, Vol. 83, No. 2, 2011, pp. 365 - 370. © The Japan Institute of Heterocyclic Chemistry
Received, 5th November, 2010, Accepted, 16th December, 2010, Published online, 27th December, 2010
DOI: 10.3987/COM-10-12098
A
FACILE SYNTHESIS OF 2-SUBSTITUTED 2,3-DIHYDRO-
4(1H)-AZULENO[1,2-d]PYRIMIDINONES
Dao-Lin Wang,a* Yuan-Feng LI,a Jiao Xu,b Wei Li,a Shao-Fei Li,a and
Li-Nan Lina
a Liaoning Key Laboratory of Synthesis and Application of Functional Compound,
College of Chemistry & Chemical Engineering, Bohai University, Jinzhou
121001, P. R. China
b
Department of Cosmetolog, Jiamusi Institute, Heilongjiang University of
Chinese Medicine, Jiamusi 154007, P. R. China
Abstract - A facile, efficient and novel approach to access 2-substituted
2,3-dihydro-4(1H)-azuleno[2,1-d]pyrimidinones was developed by condensation
of methyl 2-amino-3-carbamoylazulene-1-carboxylate with ketones or ary1
aldehydes in the 2,2,2-trifluoroethanol catalyzed by p-toluenesulfonic acid.
A variety of heterocycle-fused azulenes have so far been obtained on the viewpoints of chemical
properties and physiological activities by several synthetic methods.1-4 In a previous paper, we reported
that 1-acetyl-2-(bromomethyl)azulene reacted with anilines or thio-acetamide to give
2-aryl-3-methylazuleno[1,2-c]pyrroles5 or azuleno[1,2-c]thiophenes6 respectively. Of them,
pyrimidine-fused azulenes were prepared by using different types of stating materials as followings.
2-Amino-1-formylazulene reacted with guanidine to convert to 2-aminoazuleno[2,1-d]pyrimidine.7 When
the reaction of 2-acetylimino-2H-cyclohepta[b]furan derivatives with active methylene compounds to
afford the azuleno[2,1-d]pyrimidine derivatives.8 Quite recently, we have reported the synthesis of
4-N-arylaminoazuleno[2,1-d]pyrimidines
by
the
reactions
of
1-cyano-2-N,N-
dimethylformamidinylazulenes with anilines.9
On the other hand, 2,3-dihydro-4(1H)-quinazolinone derivatives are important bicyclic heterocycles due
to their wide range of biological activities such as anticancer,10 inhibitors of cell multiplication,11
antispermatogenic agent,12 diuretic,13 and antibacterial activities.14

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HETEROCYCLES, Vol. 83, No. 2, 2011
In connection with our studies on the synthetic utilities of heterocycle-fused azulenes, this paper describes
with the preparation of 2-substituted 2,3-dihydro-4(1H)-azuleno[2,1-d]pyrimidinones (3) by the
condensation of methyl 2-amino-3-carbamoylazulene-1-carboxylate (1) with ketones or ary1 aldehydes
(2).
CO2Me
NH2
CO2Me
H
O
N
R1
R2
+
p-TsOH
R1
R2
TFE
reflux
NH
NH2
O
O
1
2
3
Scheme 1
Trifluoroethanol(TFE) have been proven to be advantageous to some kinds of organic reaction due to
their distinguished physiochemical properties,15 such as low nucleophilicity，high polarity and strong
hydrogen bond donating ability.16 In the present study, the favorable solvent effect of TFE in the
cyclization reaction of methyl 2-amino-3-carbamoylazulene-1-carboxylate with ketones or ary1 aldehydes
in the TFE catalyzed by p-toluenesulfonic acid was observed.
The typical procedure for the synthesis of 2-substituted 2,3-dihydro-4(1H)-azuleno [2,1-d]pyrimidinones
was described as follows: Treatment of methyl 2-amino-3-carbamoylazulene-1-carboxylate (1) (1.0
equiv.) with ketones or aldehydes (2) (1.2 equiv.) in the presence of TsOH (0.1 equiv.) in refluxing TFE.
As methyl 2-amino-3-carbamoylazulene-1-carboxylate was subjected to benzaldehyde, a yield of 93%
was obtained in TFE within 8 h. In comparison, when me same reaction was carried out in ethanol instead
of TFE, the product was obtained only in 46% yield. As the reaction time was prolonged for 24 h, the
desired product was obtained in 77% yield. Furthermore, the reaction of methyl
2-amino-3-carbamoylazulene-1-carboxylate with benzaldehyde did not proceed at all in the refluxing TFE
in the absence of TsOH, implying TsOH as a catalyst in the reaction.
Therefore, on the basis of the above experimental results, it is suggested that TsOH is a catalyst for the
cyclization reaction, however the high po1arity and hydrogen bonding interaction of TFE with reactants
must have played some important roles in promoting the reaction of methyl
2-amino-3-carbamoylazulene-1-carboxylate (1) with ketone or aldehyde derivatives (2)．
As shown in Table l, the reaction of methyl 2-amino-3-carbamoylazulene-1-carboxylate (1) with ketones
or aromatic aldehydes (2) smoothly proceeded to give the corresponding 2-substituted
2,3-dihydro-4(1H)-azuleno[2,1-d]pyrimidinones (3) in good yields.

HETEROCYCLES, Vol. 83, No. 2, 2011
367
Table 1. Condensation of methyl 2-amino-3-carbamoylazulene-1-carboxylate (1) with ketones or
aromatic aldehydes (2a-j)
2
Entry
Product （3）
Time /h
Yield /%
R1
H
H
H
R2
C6H4
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
8
8
9
10
6
7
10
48
6
93
90
88
92
87
85
81
24
93
90
4-MeC6H4
4-MeOC6H4
4-FC6H4
Me
H
Me
Me
Me
Me
Et
i-Pr
C6H4
-(CH2)4-
-(CH2)5-
10
3j
7
As anticipated, due to the unfavourable electronic and steric effect, the reaction rate of the acetophenone
was much slower than that of aromatic aldehydes, only 24% yield was obtained in 48 h (Table l, entry 8).
The treatment of cyclic and acyclic alkyl ketones with 1 afforded the corresponding
2,3-dihydro-4(1H)-azuleno[2,1-d]pyrimidinones in excellent yields (81-93%) within 6-10 h (Table l,
entries 5-7, 9, 10).
In conclusion, it was found that the reaction of methyl 2-amino-3-carbamoylazulene-1-carboxylate with
ketones or aromatic aldehydes in the 2,2,2-trifluoroethanol catalyzed by p-toluenesulfonic acid, provided
a facile and efficient method for synthesis of 2-substituted 2,3-dihydro-4(1H)-azuleno[2,1-d]-
pyrimidinones in good yields.
EXPERIMENTAL
All melting points were determined with a Yanaco MP JP-3 apparatusand are uncorrected. The infrared
(IR) spectra were measured on a JascoA-102 IR spectrophotometer. 1H NMR spectra were recorded on
Bruker spectrometer (300MHz). Elemental analyzes were performed on EA 2400Ⅱ elemental analyzer
(Perkin-mlmer).
Preparation of 2-substituted 2,3-dihydro-4(1H)-azuleno[2,1-d]pyrimidin ones.
General procedure: To a solution of methyl 2-amino-3-carbamoylazulene-1- carboxylate17 (1, 0.5 mmol)
in trifluoroethanol (TFE) (15 mL) was added ketones or aromatic aldehydes (2, 0.6 mmol) and
p-toluenesulfonic acid monohydrate (0.05 mmol) and the reaction mixture was refluxed for the

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HETEROCYCLES, Vol. 83, No. 2, 2011
appropriate time (see Table 1). The progress of the reaction was monitored by TLC. After completion of
the reaction, was cooled and diluted with water (25 mL). The precipitate was collected, washed with
water, dried, and purified by column chromatography on silica gel (160-200 mesh) using pertroleum
ether-EtOAc (5:1) as eluent to afford the corresponding products. The physical and spectra data of the
compounds 3a-j are as follows:
2-Phenyl-2,3-dihydro-10-methylcarbonyl-4(1H)-azuleno[2,1-d]pyrimidinone (3a): Pale yellow prisms
(from EtOAc). mp 222-224 ºC; IR (KBr, cm-1): ν 3280(NH), 3226(NH), 1644(C=O), 1628 (C=O).
1H-NMR (CDCl3): δ 3.93 (3H, s, COOCH3), 5.55 (1H, s, NH), 6.20 (1H, s, CH), 7.36 (1H, s, NH),
7.44-7.46 (3H, m), 7.52 (1H, dd, J = 9.6, 9.6 Hz), 7.57-7.62 (4H, m), 9.07 (1H, d, J = 10.0 Hz), 9.31 (1H,
d, J = 10.0 Hz). Anal. Calcd for C20H16N2O3: C 72.28, H 4.85, N 8.43. Found C 72.31, H 4.77, N 8.24.
2-(4’-Methylphenyl)-2,3-dihydro-10-methylcarbonyl-4(1H)-azuleno[2,1-d]pyrimidi none (3b): Pale
yellow prisms (from EtOAc). mp 197-199 ºC; IR (KBr, cm-1): ν 3276(NH), 3219(NH), 1648(C=O),
1631(C=O). 1H-NMR(CDCl3): δ 2.38 (3H, s, CH3), 3.92 (3H, s, COOCH3), 5.75 (1H, s, NH), 6.16 (1H, s,
CH), 7.23 (2H, d, J = 7.6 Hz), 7.31 (1H, s, NH), 7.47 (2H, d, J = 7.6 Hz), 7.53 (1H, dd, J = 9.6, 9.6 Hz),
7.58-7.60 (2H, m), 9.06 (1H, d, J = 9.6 Hz), 9.30 (1H, d, J = 10.0 Hz). Anal. Calcd for C21H18N2O3: C
72.82, H 5.24, N 8.09. Found C 72.91, H 5.36, N 8.23.
2-(4’-Methoxyphenyl)-2,3-dihydro-10-methylcarbonyl-4(1H)-azuleno[2,1-d]pyrimi dinone (3c): Pale
yellow prisms (from EtOAc). mp 210-212 ºC; IR (KBr, cm-1): ν 3280(NH), 3225(NH), 1643(C=O),
1628(C=O). 1H-NMR(CDCl3): δ 3.84 (3H, s, OCH3), 3.93 (3H, s, COOCH3), 5.51 (1H, s, NH), 6.16 (1H,
s, CH), 6.95 (2H, d, J = 8.8 Hz), 7.28 (1H, s, NH), 7.52 (2H, d, J = 8.8 Hz), 7.54 (1H, dd, J = 9.6, 9.6 Hz),
7.58-7.62 (2H, m), 9.07 (1H, d, J = 9.6 Hz), 9.31 (1H, d, J = 9.6 Hz). Anal. Calcd for C21H18N2O4: C
69.60, H 5.01, N 7.73. Found C 69.73, H 5.17, N 7.89.
2-(4’-Fluorophenyl)-2,3-dihydro-10-methylcarbonyl-4(1H)-azuleno[2,1-d]pyrimidi none (3d): Pale
yellow prisms (from EtOAc). mp 251-253 ºC; (KBr, cm-1): ν 3278(NH), 3223(NH), 1644(C=O),
1635(C=O). 1H-NMR(CDCl3): δ 3.94 (3H, s, COOCH3), 5.72 (1H, s, NH), 6.21 (1H, s, CH), 7.14 (2H, d,
J = 8.4 Hz), 7.35 (1H, s, NH), 7.52 (1H, dd, J = 9.6, 9.6 Hz), 7.61 (2H, d, J = 8.4 Hz), 7.70-7.72 (2H, m),
9.07 (1H, d, J = 10.0 Hz), 9.31 (1H, d, J = 10.0 Hz). Anal. Calcd for C20H15FN2O3: C 68.57, H 4.32, N
5.42. Found C 68.72, H 4.36, N 5.57.
2,2-Dimethyl-2,3-dihydro-10-methylcarbonyl-4(1H)-azuleno[2,1-d]pyrimidinone
(3e):
Yellow
needles (from benzene). mp 204-205 ºC; (KBr, cm-1): ν 3295(NH), 3153(NH), 1645(C=O), 1629(C=O).
1H-NMR (CDCl3): δ 1.66 (6H, s, 2xCH3), 3.98 (3H, s, COOCH3), 6.02 (s, 1H, NH), 7.29 (s, 1H, NH),
7.46 (1H, dd, J = 9.6, 9.6 Hz), 7.50 (1H, dd, J = 9.6, 9.6 Hz), 7.56 (1H, dd, J = 9.6, 9.6 Hz), 8.98 (1H, d, J
= 10.0 Hz), 9.26 (1H, d, J = 10.0 Hz). Anal. Calcd for C16H16N2O3: C, 67.59; H, 5.67; N, 9.85. Found: C,
67.42; H, 5.63; N, 9.84.

HETEROCYCLES, Vol. 83, No. 2, 2011
369
2-Ethyl-2-methyl-2,3-dihydro-10-methylcarbonyl-4(1H)-azuleno[2,1-d]pyrimidinone (3f): Yellow
needles (from benzene). mp 201-202 ºC; (KBr, cm-1): ν 3286(NH), 3175(NH), 1657(C=O), 1642(C=O).
1H-NMR (CDCl3): δ 1.05 (3H, t, J = 7.2 Hz, CH3), 1.63 (3H, s, CH3), 1.89 (2H, q, J = 7.2 Hz, CH2), 3.98
(3H, s, COOCH3), 5.51 (1H, s, NH), 7.29 (1H, s, NH), 7.46 (1H, dd, J = 9.2, 9.6 Hz), 7.50 (1H, dd, J =
9.6, 10.0 Hz), 7.53 (1H, dd, J = 9.6, 10.0 Hz), 8.96 (1H, d, J = 10.0 Hz), 9.23 (1H, d, J = 10.0 Hz). Anal.
Calcd for C17H18N2O3: C 68.44, H 6.08, N 9.39. Found C 68.33, H 6.13, N 9.24.
2-Isopropyl-2-methyl-2,3-dihydro-10-methylcarbonyl-4(1H)-azuleno[2,1-d]pyrimi dinone (3g):
Yellow needles (from benzene). mp 194-196 ºC; (KBr, cm-1): ν 3296(NH), 3215(NH), 1659(C=O),
1
1632(C=O). H-NMR(CDCl3): δ 0.99 (6H, d, 2xCH3), 1.64 (3H, s, CH3), 1.77 (2H, d, J = 6.0 Hz, CH2),
1.98 (1H, m, CH), 3.98 (3H, s, COOCH3), 5.36 (1H, s, NH), 7.31 (1H, s, NH), 7.45 (1H, dd, J = 9.6, 10.0
Hz), 7.50 (1H, dd, J = 9.2, 10.0 Hz), 7.55 (1H, dd, J = 9.2, 9.6 Hz), 8.96 (1H, d, J = 10.0 Hz), 9.24 (1H, d,
J = 10.0 Hz). Anal. Calcd for C18H20N2O3: C 69.21, H 6.45, N 8.97. Found C 69.34, H 6.32, N 8.86.
2-Methyl-2-phenyl-2,3-dihydro-10-methylcarbonyl-4(1H)-azuleno[2,1-d]pyrimidi none (3h): Pale
yellow prisms (from benzene). mp 206-208 ºC; (KBr, cm-1): ν 3288(NH), 3224(NH), 1657(C=O),
1626(C=O). 1H-NMR (CDCl3): δ 2.01 (3H, s, CH3), 3.98 (3H, s, COOCH3), 6.08 (1H, s, NH), 7.28-7.30
(1H, m), 7.33-7.37 (2H, m), 7.50-7.54 (3H, m), 7.50 (1H,dd, J = 9.6, 9.6 Hz), 7.56-7.58 (2H, m), 7.78
(1H, s, NH), 9.02 (1H, d, J = 10.0 Hz), 9.24 (1H, d, J = 10.0 Hz). Anal. Calcd for C21H18N2O3: C 72.82, H
5.24, N 8.09. Found C 72.76, H 5.37, N 8.13.
2,2-Tetramethylene-2,3-dihydro-10-methylcarbonyl-4(1H)-azuleno[2,1-d]pyrimidi none (3i): Yellow
needles (from benzene). mp 192-193 ºC; (KBr, cm-1): ν 3265(NH), 3231(NH), 1663(C=O), 1631(C=O).
1H-NMR(CDCl3): δ 1.84-1.88 (4H, m), 2.04-2.08 (4H, m), 3.96 (3H, s, COOCH3), 6.02 (1H, s, brs), 7.42
(1H, s, NH), 7.46 (1H, dd, J = 9.2, 9.6 Hz), 7.51 (1H, dd, J = 9.6, 9.6 Hz), 7.53 (1H, dd, J = 9.6, 10.0 Hz),
8.95 (1H, d, J = 9.6Hz), 9.24 (1H, d, J = 10.0 Hz). Anal. Calcd for C18H18N2O3: C 69.66, H 5.85, N 9.03.
Found C 69.75, H 5.73, N 9.14.
2,2-Pentamethylene-2,3-dihydro-10-methylcarbonyl-4(1H)-azuleno[2,1-d]pyrimidi none (3j): Yellow
needles (from benzene). mp 226-227 ºC; (KBr, cm-1): ν 3282(NH), 3231(NH), 1654(C=O), 1631(C=O).
1H-NMR(CDCl3): δ 1.43-1.48 (2H, m), 1.66-1.68 (4H, m), 1.86-1.90 (2H, m), 1.95-1.99 (2H, m), 3.96
(3H, s, COOCH3), 6.15 (1H, s, NH), 7.29 (1H, s, NH), 7.44 (1H, dd, J = 9.6, 9.6 Hz), 7.49 (1H, dd, J =
9.6, 10.0 Hz), 7.51 (1H, dd, J = 9.6, 9.6 Hz), 7.62 (1H, s, NH), 8.96 (1H, d, J = 9.6 Hz), 9.22 (1H, d, J =
10.0 Hz). Anal. Calcd for C19H20N2O3: C 70.35, H 6.21, N 8.64. Found C 70.42, H 6.35, N 8.53.
We thank the Foundation of Innovation Team Project of Liaoning Education Department (No. 2008T001)
for financial support.

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