Three-component reaction of cycloheptanone, 6-amino-1,3-dimethyluracil and aromatic aldehydes; x-ray structure, and anti-inflammatory evaluation of the products

Article abstract of DOI:10.1515/znb-2008-0917

1,3-Dimethyl-5-aryl-1,6,7,8,9,10-hexahydrocyclohepta[5,6]pyrido[2,3-d] pyrimidine-2,4-diones 4a, b (the linear regioisomers) and the Schiff bases, 6-N-benzylidenamino-1,3-dimethyluracil derivatives 5a, b, were isolated from a three-component reaction of c

Full text of DOI:10.1515/znb-2008-0917

Three-component Reaction of Cycloheptanone, 6-Amino-1,3-Dimethyl-
uracil and Aromatic Aldehydes; X-Ray Structure, and Anti-inflammatory
Evaluation of the Products
Mohamed I. Hegab, Nasser A. Hassan, and Farouk M. E. Abdel-Megeid
Photochemistry Dept., National Research Centre, Dokki, 12622 Cairo, Egypt
Reprint requests to M. I. Hegab. E-mail: apmihegab65@yahoo.com
Z. Naturforsch. 2008, 63b, 1117 – 1126; received April 22, 2008
1,3-Dimethyl-5-aryl-1,6,7,8,9,10-hexahydrocyclohepta[5,6]pyrido[2,3-d]pyrimidine-2,4-diones
4a, b (the linear regioisomers) and the Schiff bases, 6-N-benzylidenamino-1,3-dimethyluracil
derivatives 5a, b, were isolated from a three-component reaction of cycloheptanone, 6-amino-1,3-
dimethyluracil, and 4-chloro- or 4-bromobenzaldehyde. Surprisingly, 1,3-dimethyl-10-aryl-1,5,6,7,
8,9-hexahydrocyclohepta[4,5]pyrido-[2,3-d]pyrimidine-2,4-diones 6f, g (the angular regioisomers
which are described for the first time in the literature under the given reaction conditions) and
the Schiff bases, 6-N-benzylidenamino-1,3-dimethyluracil derivatives 5f, g, were isolated and
characterized from the reaction with 4-methoxybenzaldehyde and 4-cyanobenzaldehyde. However,
the three-component reaction of 6-amino-1,3-dimethyluracil, cycloheptanone, and 2-methoxybenz-
aldehyde afforded 1,3-dimethylbenzo[4,5]pyrido[3,2-d]pyrimidine-3,4-dione (7). Single crystal
X-ray diffraction and 13C NMR studies of 4a and 6f provided support for the established structures.
Some of the new products were tested for antiinflammatory activity comparable to indomethacin.
Key words: Hexahydrocyclohepta[5,6]pyrido[2,3-d]pyrimidines, Hexahydrocyclo-hepta[4,5]pyr-
ido[2,3-d]pyrimidines, Benzo[4,5]pyrido[3,2-d]pyrimidines, X-Ray Structure Determi-
nation, Antiinflammatory Action
Among the methods for the synthesis of 1,3-dimeth-
The interest in the synthesis of pyrido[2,3-d]pyr-
ylpyrido[2,3-d]pyrimidine(1H,3H)-2,4-diones [1, 2], imidines is due to their versatile biological activ-
the three component condensation reaction of 6- ities. They were reported as adenosine kinase in-
amino-1,3-dimethyluracil with cyclic ketones and ap- hibitors [12, 13], calcium antagonists [3], herbicide
propriate aromatic aldehydes is a facile variant. The- antidotes [14], antimicrobial [15] and antibacterial
oretically, this reaction can afford products with a agents [16 – 20], antihistaminic [21], analgesic [22],
linear structure and/or an angular structure [2, 3]. antitumor [23, 24], diuretic, antiaggressive [25], anti-
However, under the conditions of our experiments, folate [26, 27] anticonvulsant [28, 29], antileishman-
only one regioselective product that has the lin- ial [30], antiinflammatory [31], antiviral [32, 33], anti-
ear structure was isolated and characterized as pub- hypertensive [34, 35], and CNS depressing agents [36]
lished in previous reports, and to our knowledge and as mulluscidal agents against Biomphalaria alex-
in no case the angular product was characterized andrina snails [37]. In our previous studies [2] we iso-
or isolated [4 – 6]. This three-component reaction lated only the linear pyrido[2,3-d]pyrimidine products
was reported also for amino-substituted heterocyclic from the one-pot reaction of 6-amino-1,3-dimethylur-
compounds (2-aminobenzimidazole, 3-amino-5-meth- acil with equimolar amounts of cyclic ketones or cyclic
ylthio-1,2,4-triazole, 3,5-diamino-1,2,4-triazole) with 1,3-diketones and aromatic aldehydes. In the present
cyclic ketones and aromatic aldehydes, and un- work we report further on the reaction of 6-amino-1,3-
der reaction conditions similar to ours, the linear dimethyluracil with equimolar amounts of cyclohept-
structure of the products was found [7 – 9]. Also, anone and appropriate aromatic aldehydes, and on the
the microwave-assisted synthesis in a one-pot re- effort to determine the structure of the products. Also,
action was reported to give the linear products we aim at the evaluation of the antiinflammatory activ-
[10, 11].
ity of some of the newly prepared products.
c
0932–0776 / 08 / 0900–1117 $ 06.00 ꢀ 2008 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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1118
M. I. Hegab et al. · Cycloheptanone, 6-Amino-1,3-Dimethyluracil and Aromatic Aldehydes
a, Ar = 4-ClC6H4; b, Ar = 4-BrC6H4; c, Ar = 2-BrC6H4; d, Ar = C6H5; e, Ar = 1-C10H7; f, Ar = 4-CH3OC6H4; g, Ar = 4-CNC6H4; h, Ar =
2-CH3OC6H4.
Scheme 1.
Results and Discussion
The reaction of 6-amino-1,3-dimethyluracil (2)
with equimolar amounts of cycloheptanone (1) and
4-chlorobenzaldehyde afforded two products, hexahy-
drocyclohepta[5,6]pyrido[2,3-d]pyrimidine-2,4-dione
4a and the Schiff base 5a, which were separated by
column chromatography (Scheme 1). The structure
of 4a was verified by elemental analysis, spectral
data and single crystal X-ray diffraction (Fig. 1). The
1H NMR spectrum of 4a showed cycloheptane protons
and two types of methyl protons. In the 13C NMR
spectrum of 4a, signals at δ = 148.55, 149.50, 151.52,
160.85, and 168.95 ppm are in accordance with
previously reported data [38]. The mass spectrum
of 4a showed prominent molecular ion peaks at m/z
(%) = 371 (6) [M,Cl37]+ and 369 (16) [M,Cl35]+. The
identity of 5a is also established based on the NMR
data.
Similarly, two products were isolated from the re-
action of cycloheptanone (1) with equimolar amounts
of 6-amino-1,3-dimethyluracil (2) and 4-bromobenz- Fig. 1. Molecular structure of 4a in the solid state (displace-
ment ellipsoids at the 50 % probability level).
aldehyde (3b), namely 4b and 5b. In the case of 2-
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M. I. Hegab et al. · Cycloheptanone, 6-Amino-1,3-Dimethyluracil and Aromatic Aldehydes
1119
hepta[4,5]-pyrido[2,3-d]pyrimidine-2,4-dione 6g and
the Schiff base 5g (Scheme 1). The 1H and 13C NMR
spectra of compound 6g are compatible with the pro-
posed constitution of 6f; characteristic 13C signals are
found at δ = 107.86 (C-5), 112.38 (C-6), 118.45 (CN),
160.09, and 162.06 ppm (2 CO).
There are several possibilities for the mechanism
of this reaction [2], one of them is based on the as-
sumption that it proceeds initially via the formation of
the α,β-unsaturated ketone intermediate, with a sub-
sequent nucleophilic attack by the amino group of the
uracil derivative on the carbonyl carbon of the α,β-
unsaturated ketone intermediate, followed by cycliza-
tion to give the linear structure (route A) (Scheme 2).
A second possibility is the nucleophilic attack by the
amino group of the uracil derivative on the methylenic
carbon of the α,β-unsaturated ketone intermediate,
followed by cyclization to give the angular structure
(route B) (Scheme 2). An alternative nucleophilic at-
tack of the amino group of the uracil derivative on the
aldehyde group to give the Schiff base, followed by
the reaction with the cyclic ketone in a stepwise mech-
anism to give finally the angular structure (Scheme 2),
can also be postulated.
Fig. 2. Molecular structure of 6f in the solid state (displace-
ment ellipsoids at the 50 % probability level).
bromobenzaldehyde (3c), benzaldehyde (3d), and 1-
naphthalene carbaldehyde (3e), only the corresponding
Schiff bases 5c – e were obtained, respectively, with
no participation of the cyclic ketone in the reaction
(Scheme 1). The structure of compounds 5c, d was
verified by elemental analyses, 1H and 13C NMR and
mass spectra.
Surprisingly, the three component one-pot reaction
of cycloheptanone (1) with equimolar amounts of 6-
amino-1,3-dimethyluracil (2) and 2-methoxybenzalde-
hyde (3h) gave only one product, 1,3-dimethylbenzo-
[4,5]pyrido[3,2-d]pyrimidine-3,4-dione (7). The for-
mation of compound 7 can be accounted for by the for-
mation of the intermediate Schiff base which is present
in the Z-form across the imino double bond and a sub-
sequent electrocyclic ring closure and elimination of
methanol (without participation of the cyclic ketone
in the reaction), as shown in Scheme 3. It is note-
worthy to mention that similar Schiff bases having Z-
configuration and an appropriate ortho-group on the
aryl ring were suggested to undergo such ring clo-
sure reactions [27]. The structure of 7 was verified
by spectral data and elemental analysis. The 1H NMR
spectrum of 7 revealed the absence of methoxy, 5-CH,
and cycloheptane protons. The 13C NMR spectrum of
7 showed signals at δ = 39.16 (CH3), 39.32 (CH3),
111.05 (C-5), 124.25, 125.36, 127.15, 129.48, 133.03,
139.32, 148.50 (Ar-C + C-4a + C-10a), 148.65 (C-9),
151.25 (C-4), and 160.88 (C-2), and the mass spectrum
showed the prominent molecular ion peak at m/z (%) =
241 (74) [M]+.
On the other hand, the reaction of cycloheptan-
one (1) with equimolar amounts of 6-amino-1,3-di-
methyluracil (2) and 4-methoxybenzaldehyde (3f) af-
forded two products, the angular product hexahydro-
cyclohepta[4,5]-pyrido[2,3-d]pyrimidine-2,4-dione 6f
and the Schiff base 5f (Scheme 1). Compound 6f,
which has the angular structure, is reported for the first
time from such a one-pot reaction under the given reac-
tion conditions. Compounds that have such an angular
structure were prepared, however, by using other reac-
tants such as the cyclic vinyl aldehydes and 6-amino-
pyrimidines [39, 40]. The structure of 6f was verified
by spectral data and elemental analysis. The 1H NMR
spectrum of 6f showed ten cycloheptane and two types
of methyl group protons. The 13C NMR spectrum of
6f showed signals at δ = 106.58 (C-5), 113.41 (C-6),
159.52 (C-7), 159.81 (C-8aꢀ), 159.87 (C-4), and 162.25
(C-2) ppm. These data are different from those of 4a
and 4b. Besides, the single crystal X-ray diffraction
analysis of 6f (Fig. 2) confirmed the proposed angular
structure.
Two products were also isolated from the reac-
tion of cycloheptanone (1) with equimolar amounts
of 6-amino-1,3-dimethyluracil (2) and 4-cyanobenzal-
All attempts to obtain the corresponding pyridopyr-
dehyde (3g) and were identified as hexahydrocyclo- imidines through the reaction of the Schiff bases 5a – g
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1120
M. I. Hegab et al. · Cycloheptanone, 6-Amino-1,3-Dimethyluracil and Aromatic Aldehydes
Scheme 2.
with cycloheptanone did not succeed, probably due to b and 6f, g, but derivatives 8c – e, h did not undergo any
the presence of the aryl group of the Schiff base in the reaction when treated with compound 2 which proba-
Z-form across the imino double bond which does not bly suggests the presence of compounds 8c – e, h in the
allow further reaction with cycloheptanone and subse- Z-form (Scheme 4).
quent ring closure as in the case of the formation of
product 7, and this result is in accordance with pre-
vious reports [27]. The reactions of 2-(arylmethylene)
cycloheptanones 8a, b, f, g with 6-amino-1,3-dimeth-
yluracil gave the corresponding pyridopyrimidines 4a,
The molecular graphics of compounds 4a and 6f are
shown in Figs. 1 and 2. Crystal data and details of the
structure determination of compounds 4a and 6f are
shown in Table 1. Some selected bond lengths, bond
angles, and torsion angles are given in Tables 2 and 3.
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M. I. Hegab et al. · Cycloheptanone, 6-Amino-1,3-Dimethyluracil and Aromatic Aldehydes
1121
O
O
DMF
reflux
10 h
H3C
O
H3C
O
N
N
Ar
ArCHO
+
N
N
N
NH2
−
3a g
CH3
CH3
H
−
5a g
2
O
DMF
reflux
10 h
ArCHO
DMF
reflux
48 h
3 h
H3CO
H
O
1
H3C
N
no reaction
O
N
N
CH3
H
−
CH3OH
O
H3C
N
O
N
N
CH3
7
Scheme 3.
Table 1. Crystal data and details of the structure determina-
tion of 4a and 6f.
Crystal data
Compound 4a
Compound 6f
Empirical formula
Formula weight
Shape/color
C20H21ClN3O2
370.860
cube/
colorless
triclinic
¯
P1
C21H23N3O2
349.434
prismatic/
colorless
triclinic
Crystal system
Space group
¯
P1
Temperature, K
298
0.71073
298
0.71073
8.1147 (4)
9.8840 (5)
11.4804 (7)
88.449 (2)
80.566 (2)
87.620 (2)
˚
Wavelength, A
˚
a, A
9.1022 (3)
9.9807 (4)
11.4985 (5)
108.922 (2)
109.622 (2)
94.388 (2)
910.39 (6)
2
˚
b, A
˚
c, A
α, deg
β, deg
γ, deg
3
˚
Volume, A
907.36 (8)
2
1.279
Z
Density (calculated), mg m−3 1.353
θ range for data coll., deg
2.91 – 30.03
2.91 – 25.03
Index ranges hkl
+12, 14, −16→13 +9, 11, 13
Scheme 4.
Antiinflammatory activity
Reflections, measured
Reflexions, independent
Reflexions, observed
Data/parameters
6034
5672
2277
4598
3558
1565
1564/244
1.325
0.048
0.118/0.121
0.32/−0.36
2276/235
1.280
0.051
The antiinflammatory activities of the tested com-
pounds 4a, b, 5a, c,d, e, 6f, g were evaluated accord-
ing to the method of Winter et al. [41]. The tested
compounds were compared with indomethacine as ref-
Goodness-of-fit
R index [I ≥ 3σ(I)]
R1/ wR2 indices (all data), R 0.128/0.105
−3
˚
∆ρfin (max/min), e A
0.52/−0.48
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1122
M. I. Hegab et al. · Cycloheptanone, 6-Amino-1,3-Dimethyluracil and Aromatic Aldehydes
˚
˚
Table 2. Selected bond lengths (A), bond angles (deg), and Table 3. Selected bond lengths A, bond angles (deg), and tor-
torsion angles (deg) for 4a. sion angles (deg) for 6f.
N4–C11
N4–C13
N4–C20
N5–C13
N5–C14
N5–C24
N8–C11
N8–C12
C11–N4–C13
C11–N4–C20
C13–N4–C20
C13–N5–C14
C13–N5–C24
C14–N5–C24
C11–N8–C12
1.382 (3)
1.371 (4)
1.471 (3)
1.395 (3)
1.386 (3)
1.467 (4)
1.341 (3)
1.340 (3)
122.6 (2)
119.9 (2)
117.5 (2)
125.4 (2)
116.9 (2)
117.6 (2)
118.2 (2)
N4–C11–N8
C7–C11–N8
N8–C12–C9
N8–C12–C23
C9–C12–C23
O3–C13–N4
C12–N8–C11–N4
C12–N8–C11–C7
C6–C9–C12–N8
C15–C9–C12–N8
N4–C11–N8–C12
C13–N4–C11–N8
C20–N4–C11–N8
N8–C11–N4–C13
N8–C12–C9–C15
115.7 (2)
123.6 (2)
123.2 (2)
115.4 (2)
121.4 (2)
122.6 (2)
179.7 (4)
−1.0 (3)
2.6 (3)
−178.4 (4)
179.7 (4)
−176.0 (4)
3.3 (2)
N12–C10
N12–C14
N12–C23
N9–C8
N9–C10
N13–C14
N13–C15
N13–C16
C10–N12–C14
C10–N12–C23
C14–N12–C23
C14–N13–C15
C14–N13–C16
C15–N13–C16
1.396 (3)
1.372 (3)
1.460 (3)
1.343 (3)
1.321 (3)
1.387 (3)
1.380 (4)
1.470 (3)
122.9 (2)
119.5 (2)
117.3 (2)
126.2 (2)
116.3 (2)
117.5 (2)
C14–N12–C10–N9
C10–N12–C14–O25
C14–N12–C10–C11
C10–N12–C14–N13
C23–N12–C10–N9
C6–C11–C10–N9
C15–C11–C10–N12
C15–C11–C10–N9
C10–C11–C15–N13
C6–C11–C15–N13
C17–C8–N9–C10
N9–C10–N12–C23
C11–C10–N9–C8
N9–C10–C11–C6
172.9 (4)
−179.3 (5)
−5.1 (3)
0.3 (3)
−0.4 (3)
5.3 (3)
4.1 (3)
−173.7 (5)
1.3 (3)
−177.7 (5)
174.3 (4)
−0.4 (3)
−1.5 (3)
5.3 (3)
−176.0 (4)
−178.4 (4)
Table 4. Antiinflammatory activity for the tested compounds 4a, b, 5a, c, d, e, 6f, ga.
1 h 2 h 3 h
Inhibition rate Edema rate Inhibition rate Edema rate Inhibition rate Edema rate
4 h
Edema rate
Compd. (%)
Inhibition rate
(%)
–
(%)
–
(%)
93.78 5.54
(%)
–
(%)
95.58 6.91
(%)
–
(%)
98.67 6.03
Cont.
84.82 5.09
4a
69.66 4.21 −17.87
71.07 2.57 −16.21
66.57 4.83 −21.51
85.55 5.41 0.86
76.54 5.56 −9.76
71.08 4.75 −16.19
68.19 5.53 −19.61
79.27 5.02 −6.54
68.68 5.97 −19.03
36.35 2.30b −57.15
89.19 2.64 −4.89
87.81 4.52 −6.37
86.93 5.55 −7.30
94.75 2.28 −0.87
87.85 4.34 −8.09
91.93 3.25 −3.82
97.36 5.13 −1.33
92/67 4.50 −6.08
94.13 6.24 −4.60
4b
5a
5c
102.50 8.67
9.30
103.68 3.73
8.48
100.80 5.38
2.16
5d
87.59 4.93 −6.59
88.68 1.34 −5.43
89.44 4.86 −4.63
86.49 4.29 −7.77
76.03 6.92 −18.93
41.38 3.92b −55.88
88.45 6.32 −7.46
93.49 3.96 −1.71
95.13 4.67 −0.47
83.47 7.95 −12.66
76.88 3.70 −19.56
54.11 4.44b −43.39
92.95 6.77 −5.80
96.54 3.94 −2.15
79.92 3.50 −0.76
91.07 7.05 −7.70
76.86 6.74 −22.10
61.28 4.75b −37.89
5e
6f
6g
7
Indo..
a Cont. = control; Indo. = indomethacin; b P < 0.05: statistically significant from control (Dunnett’s test).
erence drug. The results are listed in Table 4. Re- Corporation, Bremen, Germany), (Central Services Labora-
tory, National Research Centre, Cairo, Egypt). IR spectra
were obtained on a Bruker-Vector 22 instrument using KBr
wafers (Micro-analytical Center of Cairo University). Com-
pounds 8a, d [42], 8b, c [43], 8f, h [44] were prepared ac-
cording to literature procedures. Yields of the products refer
to samples after purification.
sults showed that the tested compounds have weak
activities.
Experimental Section
Melting points were determined in open glass capillaries
using an IA 9000 SERIES digital melting point apparatus
(Electrothermal, Essex, U. K.) and are uncorrected. Micro-
analyses were performed for all products on an Elementar-
Vario EL, Microanalytical Unit, Central Services Laboratory,
National Research Centre, Cairo, Egypt. The NMR spectra
were recorded on a Varian Mercury VX-300 NMR spectrom-
eter (Faculty of Science, Cairo University, Cairo, Egypt) and
on a Jeol EX-500 NMR spectrometer (Central Services Lab-
General procedure for the one-pot reaction of 6-amino-1,3-
dimethyluracil, cycloheptanone and an aromatic aldehyde
A mixture of cycloheptanone (1) (1.4 g, 10 mmol), 6-
amino-1,3-dimethyluracil (2) (1.5 g, 10 mmol) and the ap-
propriate aromatic aldehyde (3) (10 mmol) was refluxed in
20 mL of N,N-dimethylformamide (DMF) for 10 h. The sol-
vent was evaporated, and the residue was purified by crystal-
lization or by column chromatography.
1
oratory, National Research Centre, Cairo, Egypt). H NMR
spectra were run at 300 and 500 MHz, and 13C NMR spectra
were run at 75.46 and 125.76 MHz in CDCl3 (δ = 7.26 ppm)
or DMSO (δ = 2.50 ppm) as solvent. Chemical shifts are
quoted in δ and are related to that of the solvents. Mass spec-
tra, EI (70 eV), were recorded on a Thermo Finnigan TRACE
Reaction of 1, 2 and 4-chlorobenzaldehyde (3a)
The products 4a and 5a were isolated by column chro-
GC 2000 GC/MS ISO 9001 instrument (Thermo Electron matography (silica gel 60, particle size 0.06 – 0.20 mm) us-
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M. I. Hegab et al. · Cycloheptanone, 6-Amino-1,3-Dimethyluracil and Aromatic Aldehydes
1123
◦
ing ethyl acetate : petroleum ether 40 – 60 C (1 : 10 v/v) as (3), 167 (3). – C20H20BrN3O2 (414.28): calcd. C 57.98,
eluent.
H 4.86, Br 19.28, N 10.14; found C 57.80, H 4.75, Br 19.00,
N 9.89.
1,3-Dimethyl-5-(4-chlorophenyl)-1,6,7,8,9,10-hexahydro-
cyclohepta[5,6]pyrido[2,3-d]pyrimidine-2,4-dione (4a)
6-[N-(4-Bromobenzylidene)amino]-1,3-dimethyluracil (5b)
Colorless crystals, yield 1.4 g (40 %). – M. p. 187 –
C◦olorless crystals, yield 0.5 g (15 %). – M. p. 284 –
287 C. – IR: v = 1701, 1667 (C=O), 1630 (C=N) cm−1. –
1H NMR (CDCl3): δ = 3.50 (s, 3H, CH3), 3.71 (s, 3H,
CH3), 7.05 (s, 1 H, 5-CH), 7.45 (d, J = 10 Hz, 2 H, Ar-H),
7.84 (d, J = 10 Hz, 2H, Ar-H), 7.98 (s, 1 H, CH=N). –
13C NMR: δ = 28.56 (CH3), 29.68 (CH3), 110.95 (C-5),
123.01, 126.98, 127.21, 130.30, 139.43, 139.79 (Ar-C),
149.21 (C-6), 150.19 (C=N), 151.48 (C-4), 161.11 (C-2). –
C13H12BrN3O2 (322.15): calcd. C 48.46, H 3.75, N 13.04;
found C 48.14, H 3.58, N 12.88.
◦
190 C. – IR: v = 1700, 1660 (C=O) cm−1. – 1H NMR
(CDCl3): δ = 1.72 – 2.02 (m, 6 H, 3 CH2), 2.41 (t, J = 5 Hz,
2 H, CH2), 3.11 (t, J = 5 Hz, 2 H, CH2), 3.29 (s, 3H, CH3),
3.73 (s, 3H, CH3), 6.97 (d, J = 10 Hz, 2 H, Ar-H), 7.40 (d,
J = 10 Hz, 2H, Ar-H). – 13C NMR: δ = 26.18, 27.50, 28.35
(3 CH2), 28.91 (1-CH3), 29.71 (3-CH3), 31.85 (CH2), 39.77
(CH2), 105.95 (C-6, C-4a), 128.05 (C-1ꢀ), 132.04 (C-3ꢀ,
C-5ꢀ), 133.15 (C-2ꢀ, C-6ꢀ), 137.25 (C-4ꢀ), 148.55 (C-5),
149.50 (C-8a), 151.52 (C-7ꢀ), 160.85 (C-4), 168.95 (C-2). –
MS: m/z (%) = 371 (6) [M,Cl37]+, 369 (16) [M,Cl35]+,
340 (4), 277 (34), 275 (100), 249 (14), 247 (45), 217 (5),
190 (11), 177 (6), 165 (30), 163 (90), 128 (14), 114 (14). –
C20H20ClN3O2 (369.83): calcd. C 64.94, H 5.45, Cl 9.58,
N 11.36; found C 64.83, H 5.38, Cl 9.93, N 11.30.
Reaction of 1, 2 and 2-bromobenzaldehyde (3c)
6-[N-(2-Bromobenzylidene)amino]-1,3-dimethyluracil (5c)
Colorless crystals (from dioxane), yield 0.9 g (22 %). –
M. p. 205 – 207 ◦C. – IR: v = 1700, 1658 (C=O), 1625
(C=N) cm−1. – 1H NMR ([D6]DMSO): δ = 3.29 (s,
3H, CH3), 3.59 (s, 3H, CH3), 7.55 (s, 1 H, 5-CH),
7.85 – 7.87 (m, 3 H, Ar-H), 8.14 (d, J = 10 Hz, 1H,
Ar-H), 9.03 (s, 1 H, CH=N). – 13C NMR: δ = 28.01
(CH3), 28.12 (CH3), 110.0 (C-5), 124.19, 125.42, 127.17,
129.27, 133.09, 139.33 (Ar-C), 148.27 (C-6), 148.70 (C=N),
150.98 (C-4), 160.61 (C-2). – MS: m/z ( %) = 321 (100)
[M]+, 293 (14), 290 (17), 241 (16), 209 (29), 207 (37),
129 (12), 114 (15). – C13H12BrN3O2 (322.15): calcd.
C 48.46, H 3.75, N 13.04; found C 48.24, H 3.65,
N 12.89.
6-[N-(4-Chlorobenzylidene)amino]-1,3-dimethyluracil (5a)
Colorless crystals, yield 0.7 g (30 %). – M. p. 234 –
235 ◦C. – IR: v = 1699, 1668 (C=O), 1630 (C=N) cm−1. –
1H NMR (CDCl3): δ = 3.51 (s, 3H, CH3), 3.71 (s, 3H,
CH3), 7.03 (s, 1 H, 5-CH), 7.45 (d, J = 10 Hz, 2 H, Ar-H),
7.85 (d, J = 10 Hz, 2H, Ar-H), 7.98 (s, 1 H, CH=N). –
13C NMR: δ = 28.57 (CH3), 29.68 (CH3), 110.95 (C-5),
123.00, 126.99, 127.21, 130.30, 139.45, 139.80 (Ar-C),
149.20 (C-6), 150.18 (C=N), 151.48 (C-4), 161.10 (C-2). –
C13H12ClN3O2 (277.70): calcd. C 56.22, H 4.35, N 15.13;
found C 56.10, H 4.29, N 15.00.
Reaction of 1, 2 and benzaldehyde (3d)
Reaction of 1, 2 and 4-bromobenzaldehyde (3b)
6-[N-(Benzylidene)amino]-1,3-dimethyluracil (5d)
The products 4b and 5b were isolated by column chro-
matography (silica gel 60, particle size 0.0◦6 – 0.20 mm) us-
ing ethyl acetate : petroleum ether 40 – 60 C (1 : 10 v/v) as
an eluent.
Colorless crystals (from ethyl acetate), yield 0.8 g
◦
(33 %). – M. p. 327 – 330 C. – IR: v = 1699, 1668 (C=O),
1
1630 (C=N) cm−1. – H NMR ([D6]DMSO): δ = 3.29 (s,
3H, CH3), 3.34 (s, 3H, CH3), 5.74 (s, 1 H, 5-CH), 7.07 – 7.89
(m, 5 H, Ar-H), 7.94 (s, 1 H, CH=N). – 13C NMR: δ = 29.83
(CH3), 39.16 (CH3), 86.07 (C-5), 124.69, 126.45, 127.52,
139.56 (Ar-C + C-6), 150.41 (C=N), 154.17 (C-4), 162.66
(C-2). – MS: m/z (%) = 242 (100) [M–H]+, 228 (2), 185 (17),
143 (5), 127 (5), 102 (7). – C13H13N3O2 (243.25): calcd.
C 64.18, H 5.38, N 17.29; found C 63.96, H 5.23, N 17.07.
1,3-Dimethyl-5-(4-bromophenyl)-1,6,7,8,9,10-hexahydro-
cyclohepta[5,6]pyrido[2,3-d]pyrimidine-2,4-dione (4b)
Colorless crystals, yield 0.8 g (20 %). – M. p. 192 –
◦
195 C. – IR: v = 1703, 1658 (C=O) cm−1. – 1H NMR
(CDCl3): δ = 1.73 – 2.05 (m, 6 H, 3 CH2), 2.40 (t, J = 5 Hz,
2 H, CH2), 3.12 (t, J = 5 Hz, 2 H, CH2), 3.29 (s, 3H, CH3),
3.73 (s, 3H, CH3), 6.96 (d, J = 10 Hz, 2 H, Ar-H), 7.38
(d, J = 10 Hz, 2H, Ar-H). – 13C NMR: δ = 26.18, 27.49,
28.33, 28.90, 29.71 (5 CH2), 31.85 (CH3), 39.77 (CH3),
105.94, 128.05, 132.05, 133.14, 137.24, 148.55, 149.49,
151.52 (Ar-C), 160.84 (C-4), 168.95 (C-2). – MS: m/z (%) =
Reaction of 1, 2 and 1-naphthaldehyde (3e)
6-[N-(1-Naphthylmethylidene)amino]-1,3-dimethyluracil
(5e)
Colorless crystals (from dioxane), yield 1.0 g (33 %). –
414 (100) [M]+, 398 (16), 384 (19), 305 (3), 207 (5), 193 M. p. 266 – 269 ◦C. – IR: v = 1689, 1656 (C=O), 1618
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M. I. Hegab et al. · Cycloheptanone, 6-Amino-1,3-Dimethyluracil and Aromatic Aldehydes
(C=N) cm−1. – MS: m/z (%) = 291 (100) [M]+, 263 (22), 1,3-Dimethyl-10-(4-cyanophenyl)-1,5,6,7,8,9-hexahydro-
205 (3), 191 (4), 179 (25), 164 (6), 150 (7). – C17H13N3O2 cyclohepta[4,5]pyrido[2,3-d]pyrimidine-2,4-dione (6g)
(291.29): calcd. C 70.09, H 4.49, N 14.42; found C 69.87,
H 4.35, N 14.15.
Colorless crystals, yield 1.2 g (35 %). – M. p. 258 –
◦
261 C. – IR: v = 2220 (C≡N), 1700, 1660 (C=O), 1628
(C=N) cm−1. – 1H NMR (CDCl3): δ = 1.59 – 1.87 (m,
Reaction of 1, 2 and 4-methoxybenzaldehyde (3f)
6 H, 3 CH2), 2.87 (t, J = 4.8 Hz, 2 H, CH2), 3.48 (s, 3H,
CH3), 3.68 (s, 3H, CH3), 3.80 (t, J = 4.8 Hz, 2 H, CH2),
7.60 (d, J = 8.1 Hz, 2 H, Ar-H), 7.77 (d, J = 8.1 Hz,
2H, Ar-H). – 13C NMR: δ = 25.36, 27.41, 28.57, 29.01,
29.31 (5 CH2), 29.87, 31.07 (2 CH3), 107.86 (C-5), 112.38
(C-6), 118.45 (CN), 125.95, 129.73, 132.08, 133.19, 144.60,
149.13, 151.15, 157.98 (Ar-C), 160.09, and 162.06 (2 CO). –
C21H20N4O2 (360.41): calcd. C 69.97, H 5.59, N 15.54;
found C 69.77, H 5.48, N 15.30.
The products 6f and 5f were isolated by using column
chromatography (silica gel 60, particle size 0.06 – 0.20 mm)
using ethyl acetate : petroleum ether 40 – 60 ◦C (1 : 10 v/v) as
an eluent.
1,3-Dimethyl-10-(4-methoxyphenyl)-1,5,6,7,8,9-hexahydro-
cyclohepta[4,5]pyrido[2,3-d]pyrimidine-2,4-dione (6f)
Colorless crystals, yield 1.0 g (30 %). – M. p. 194 –
6-[N-(4-Cyanobenzylidene)amino]-1,3-dimethyluracil (5g)
◦
196 C. – IR: v = 1700, 1658 (C=O) cm−1. – 1H NMR
Colorless crystals, yield 0.8 g (35 %). – M. p. 287 –
(CDCl3): δ = 1.57 – 2.18 (m, 8 H, 4 CH2), 2.85 (t, J = 5 Hz,
2 H, CH2), 3.36 (s, 3H, NCH3), 3.59 (s, 3H, NCH3), 3.77
(s, 3H, OCH3), 6.90 (d, J = 10 Hz, 2 H, Ar-H), 7.39 (d, J =
10 Hz, 2H, Ar-H). – 13C NMR: δ = 25.70, 27.44, 28.38,
28.87, 29.36 (5 CH2), 29.85 (CH3), 31.85 (CH3), 55.23
(OCH3), 106.58 (C-5), 113.41 (C-6), 130.58, 132.45, 132.98,
148.73, 151.22 (Ar-C), 159.52 (C-7), 159.81 (C-8a), 159.87
(C-4), 162.25 (C-2). – MS: m/z (%) = 365 (100) [M]+, 350
(75), 336 (80), 322 (65), 293 (15), 279 (30), 252 (20), 222
(23), 208 (20), 192 (15), 167 (15). – C21H23N3O3 (365.41):
calcd. C 69.02, H 6.34, N 11.49; found C 68.82, H 6.19,
N 11.34.
◦
290 C. – IR: v = 2225 (C≡N), 1703, 1665 (C=O), 1625
1
(C=N) cm−1. – H NMR (CDCl3): δ = 3.71 (s, 3H, CH3),
4.10 (s, 3H, CH3), 7.63 (s, 1 H, 5-CH), 8.05 (d, J = 8.0 Hz,
2 H, Ar-H), 8.22 (d, J = 8.0 Hz, 2H, Ar-H), 8.48 (s, 1 H,
CH=N). – MS: m/z (%) = 267 (100) [M–H]+, 252 (4), 247
(14), 210 (79), 195 (22), 126 (14), 112 (10). – C14H12N4O2
(268.27): calcd. C 62.67, H 4.51, N 20.88; found C 62.47,
H 4.45, N 22.65.
Reaction of 1, 2 and 2-methoxybenzaldehyde (3h)
1,3-Dimethylbenzo[4,5]pyrido[3,2-d]pyrimidine-3,4-dione
Colorless crystals (from dioxane), yield 0.8 g (35 %). –
6-[N-(4-Methoxybenzylidene)amino]-1,3-dimethyluracil
(5f)
◦
M. p. 225 – 227 C. – IR: v = 1710, 1669 (C=O) cm−1. –
1H NMR ([D6]DMSO): δ = 3.31 (s, 3H, CH3), 3.63 (s, 3H,
CH3), 7.55 – 8.16 (m, 4 H, Ar-H), 9.04 (s, 1 H, CH=N). –
13C NMR: δ = 39.16 (CH3), 39.32 (CH3), 111.05 (C-5),
124.25, 125.36, 127.15, 129.48, 133.03, 139.32, 148.50
(Ar-C + C-4a + C-10a), 148.65 (C-9), 151.25 (C-4), 160.88
(C-2). – MS: m/z (%) = 241 (74) [M]+, 212 (26), 185
(33), 156 (17), 129 (100), 102 (38), 76 (13). – C13H11N3O2
(241.24): calcd. C 64.71, H 4.59, N 17.41; found C 64.35,
H 4.48, N 17.41.
Colorless crystals, yield 0.7 g (25 %). – M. p. 261 –
263 ◦C. – IR: v = 1698, 1659 (C=O), 1624 (C=N) cm−1. –
1H NMR (CDCl3): δ = 3.46 (s, 3H, NCH3), 3.77 (s, 3H,
NCH3), 3.92 (s, 3H, OCH3), 7.07 (d, J = 10 Hz, 2 H, Ar-H),
7.22 (s, 1 H, 5-CH), 7.71 (d, J = 10 Hz, 2H, Ar-H), 7.78
(s, 1 H, CH=N). – 13C NMR: δ = 28.43 (CH3), 29.60
(CH3), 55.76 (OCH3), 106.00 (C-5), 108.48, 119.41, 119.96,
130.37, 139.25, 148.98 (Ar-C), 151.68 (C-6), 152.09 (C=N),
161.49 (C-4), 163.95 (C-2). – MS: m/z (%) = 273 (51) [M]+,
272 (69), 271 (66), 243 (98), 228 (26), 213 (32), 199 (46),
186 (55), 171 (62), 159 (100), 144 (70), 129 (60), 116 (79),
102 (60), 89 (6), 77 (52). – C14H15N3O3 (273.28): calcd.
C 61.52, H 5.32, N 15.37; found C 61.21, H 5.18, N 15.20.
Antiinflammatory activity
The antiinflammatory testing was performed according to
the method of Winter et al. [41]. For this purpose 55 rats (fe-
male) weighing 150 – 180 g were used. Edema was induced
in the left hind paw of all rats by subcutaneous (s. c.) injec-
tion of 0.1 mL of 1 % (w/v) carrageenin in distilled water into
their footpads.
Reaction of 1, 2 and 4-cyanobenzaldehyde (3g)
The products 6g and 5g were isolated by column chro-
Rats were divided into 11 groups of 5 rats each. The first
matography (silica gel 60, particle size 0.0◦6 – 0.20 mm) us- group was kept as control, and was given the respective vol-
ing ethyl acetate : petroleum ether 40 – 60 C (1 : 10 v/v) as ume of the solvent (few drops of DMSO). Animals of the
an eluent.
second to tenth groups were orally administered the tested
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M. I. Hegab et al. · Cycloheptanone, 6-Amino-1,3-Dimethyluracil and Aromatic Aldehydes
1125
compounds 4a, b, 5a, c, d, e, 6f, g, 7 in doses of 50 mg kg−1
,
group. Et represents the edema rate of the treated group, and
1 h before carrageenin injection. The last group was admin- data are expressed as mean S. E. M.
R
istered indomethacin (Indocidꢀ) in a dose of 10 mg kg−1 b.
CCDC 686153 (4a) and 686154 (6f) contain the supple-
wt., orally as a standard reference. The paw volume of each mentary crystallographic data for this paper. The data can
rat was measured using a plethysmometer before carrageenin be obtained free of charge from The Cambridge Crystallo-
injection and then hourly for 4 h post administration of the graphic Data Centre via www.ccdc.cam.ac.uk/data request
plant extracts.
/cif.
The edema rate and inhibition rate of each group were cal-
culated as follows:
Acknowledgements
The authors would like to express their gratitude to Prof.
Dr. I. S. Ahmed-Farag (Solid State Dept., National Research
Centre, Dokki, 12622 Cairo, Egypt) for performing sin-
gle crystal X-ray diffraction measurements and to Prof. Dr.
Wafaa Eleraky (Pharmacology Department, National Re-
search Centre, Dokki, 12622 Cairo, Egypt) for performing
the antiinflammatory evaluation.
Edema rate E (%) = (Vt −Vo/Vo)×100,
Inhibition rate I (%) = (Ec −Et/Ec)×100,
where Vo represents the volume before carrageenin injection
(mL). Vt represents the volume at t hours after carrageenin
injection (mL). Ec represents the edema rate of the control
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