Heterocyclic analogs of pleiadene. 73. Intramolecular cyclization of cinnamoyl- and o-chlorobenzoylperimidines

Article abstract of DOI:10.1023/A:1021209416136

We have carried out the intramolecular cyclization of the anions of 4(9)- and 6(7)-cinnamoylperimidines and also of 4(9)-o-chorobenzoylperimidine. These partially hydrogenated pyrido- and quino[1,2,3-cd]perimidines were obtained for the first time. Their

Full text of DOI:10.1023/A:1021209416136

Chemistry of Heterocyclic Compounds, Vol. 38, No. 9, 2002
HETEROCYCLIC ANALOGS OF PLEIADENE.
73.* INTRAMOLECULAR CYCLIZATION OF
o
CINNAMOYL- AND -CHLOROBENZOYLPERIMIDINES
I. V. Borovlev1, O. P. Demidov1, and A. F. Pozharskii2
We have carried out the intramolecular cyclization of the anions of 4(9)- and
6(7)-cinnamoylperimidines and also of 4(9)-o-chlorobenzoylperimidine. These partially hydrogenated
1
pyrido- and quino[1,2,3-cd]perimidines were obtained for the first time. Their H NMR spectroscopic
features are discussed.
Keywords: acylperimidines, perimidine, intramolecular cyclization.
We have previously developed two methods for the synthesis of perimidine chalcones and also shown
that the cyclization of 6(7)-cinnamoylperimidines under the action of AlBr3 is accompanied by dearylation to
give 6-hydroxy-1,3-diazapyrene [1]. Under these conditions, 4(9)-cinnamoylperimidine does not react.
The aim of this work was to study the possible cyclization of the anions of 4(9)- and 6(7)-cinnamoyl-
and also o-chlorobenzoylperimidines which could build onto the perimidine six-membered rings at the peri-6,7
and 1,9 positions.
It was found that heating the 4(9)-cinnamoylperimidines 1 in aqueous alcoholic base gave the 7-aryl-
7,8-dihydro-9H-pyrido[1,2,3-cd]perimidin-9-ones cyclization products 4. This conversion evidently occurs via
an intramolecular Michael reaction via the anions 2 and 3.
Ar
7
Ar
Ar
5
.
6
N
.
H
_
.
O
4
_
8
H+
N
N
N
N
N
N
N
OH
3
2
9
O
O
O
10
Ar
1
11
3
2
1
4
a Ar = Ph; b Ar = p-BrC6H4
Previously, similar compounds not containing a substituent at position 7 have been obtained by the
intramolecular acylation of β-(perimidin-1-yl)propionic acids in PPA [2, 3]. Attempts to dearylate compound 4
with AlBr3 were not successful.
_______
* For Communication 72 see [1].
__________________________________________________________________________________________
2
Stavropol State University, Stavropol 355009, Russia; e-mail: nauka@stavsu.ru.
Rostov State
University, Rostov-on-Don 344090, Russia; e-mail: pozharsk@pozhar.rnd.runnet.ru. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 9, pp. 1247-1251, September, 2002. Original article submitted
November 12, 2001.
0009-3122/02/3809-1091$27.00©2002 Plenum Publishing Corporation
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The perimidine N-anion is ambidentate and, when reacting with allyl- and benzylhalides, it behaves as a
C4 [4] and with chalcone as a C6-nucleophile [5]. In this connection we propose a possible cyclization of the
6(7)-cinnamoylperimidines under conditions of base catalysis. Actually, the reaction occurs but under more
rigid conditions when compared with the 4(9)-isomer (refluxing with KOH in ethylene glycol). It was
interesting that the reaction can occur both as a nucleophilic addition of the C6-anion at the double bond
(structure 6'' route a) and also via a synchronous mechanism as an electrocyclic reaction (structure 6''' route b).
N
NH
_
OH
O
Ar
5
–
N
N
N
N
–
N
N
H
6''
_
O
Ar
O
Ar
a
O
Ar
6'
6'''
b
N
NH
N
N
+
+
H
+
–
H
H
Ar
–
O
Ar
O
8
7
a Ar = Ph; b Ar = p-BrC6H4
In both cases the aromaticity of the quinazoline fragment of the molecule is preserved. After protonation
and rearrangement of the intermediates 7 the 8(6)-aryl-6(8)-oxo-1,6,7,8-tetrahydro-1,3-diazapyrenes 8 are
formed and these have been obtained previously by us via another route [1].
In connection with the synthesis of compounds 4 and 8 it was also of interest to prepare their benzo
analogs from the corresponding o-chlorobenzoylperimidines. These were obtained by the acylation of
perimidine 9 with o-chlorobenzoic acid in PPA. As in other, similar examples [6] conditions of kinetic control
(80-85°C) give a mixture of 4(9)- 10 and 6(7)-isomers 11 with the latter predominating and under
thermodynamically controlled conditions (130-135°C) the single reaction product is the
4(9)-o-chlorobenzoylperimidine. Attempts to cyclize the isomer 10 by refluxing in aqueous alcoholic base gave
only the starting material. We propose that the reaction takes place by an SN2 aromatic mechanism and, since the
starting compound is activated only by the carbonyl group, needs more forcing conditions for it to occur. In fact,
refluxing 4(9)-o-chlorobenzoylperimidine (10) with base in ethylene glycol converts it over one hour to the
6H-quino[1,2,3,-cd]perimidin-6-one (12).
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.
.
H
.
N
NH
N
N
O
Cl
N
NH
o-ClC6H4COOH
+
PPA
10
9
_
9
OH
O
8
7
10
11
N
12
Cl
13
11
N
6
_
1
O
OH
5
2
3
4
12
However, the 6(7)- isomer 11 does not participate in a similar reaction, even under prolonged refluxing
with base in ethylene glycol.
The 1H NMR spectrum of compound 10 in DMSO-d6 shows a number of features. Firstly, the signal for
the proton at position 2 appears as a doublet (J = 3.0 Hz) due to interaction with the NH group proton (upon
heating to 60°C the signal is broadened but the doublet structure is retained). Together with the sharp signals for
the aromatic protons of the perimidine ring this points not only to a slow chemical exchange of the NH, but also
to the absence of annular NH-prototropy, even in such a polar solvent. In other words, compound 10 exists
exclusively as the 9- tautomer and the NH proton is found in a split interaction with the carbonyl group and the
solvent. Secondly, when compared with compound 4 and with 9-acetylperimidine (see the Experimental
section), the signal for the 8-H proton is shifted to higher field by 0.6 ppm. In our opinion this is due to the
impossibility on the grounds of steric hindrance of a coplanar positioning of the chlorophenyl group relative the
perimidine ring, as a result of which the given proton is partially shielded by it. The close value of the chemical
shifts of the 8-H protons in 9-acetylperimidine and compounds 4, differing in the spatial position of the carbonyl
group, points to the absence of an anisotropic effect in both cases. But if, in the first compound this is explained
by conformational immobility of the carbonyl due to intramolecular hydrogen bonding, then in compound 4 it is
the result of a non-planar structure for the carbonyl group contained in the ring. In any case, the flattening of the
molecule upon changing to compound 12 leads to a low field shift of the 8-H signal (δ 8.23 ppm against 7.44 in
9-acetylperimidine and 7.47 ppm in compound 4b). The diastereotopic protons of the methylene group in
compound 4 appear as a double doublet with a characteristic spin-spin coupling.
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker WP-200 (200 MHz) instrument with TMS internal standard.
Signal assignments were made using a double resonance method. IR Spectra were recorded on a UR-20
instrument. Monitoring of the course of the reaction and the purity of the synthesized materials was made using
Silufol UV-254 plates and column chromatography was carried out on Chemapol L 40/100 silica gel.
cd
7-Phenyl-7,8-dihydro-9H-pyrido[1,2,3- ]perimidin-9-one (4a).
A mixture of 4(9)-cinnamoyl-
perimidine (0.6 g, 2 mmol), isopropanol (10 ml), water (3 ml), and KOH (0.7 g) was refluxed for 40 min, diluted
with water, and filtered. The precipitate was dissolved in a minimum amount of benzene and chromatographed
through a small layer of silica gel with benzene eluent. The yield of compound 4a after evaporation of solvent
1
was 0.14 g (23%) as yellow crystals; mp 157-159 (benzene–petroleum ether). H NMR spectrum (DMSO-d6),
δ, ppm, J (Hz): 2.99 (1H, dd, J8H H (gem) = 16.2, J8H 7H(cis) = 2.8, 8-Ha); 3.46 (1H, dd, J8H H (gem) = 16.2,
a
b
a
b a
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b
a
b
J
8H 7H(trans) = 6.4, 8-Hb); 5.73 (1H, dd, J78 (cis) = 2.8, J78 (trans) = 6.4, 7-H); 7.02 (1H, dd, J32 = 7.6, J31 = 0.6, 3-H);
7.09 (1H, d, J1110 = 8.9, 11-H); 7.32 (1H, dd, J12 = 7.9, J13 = 0.6, 1-H); 7.35 (5H, m, C6H5); 7.38 (1H, d,
1011 = 8.9, 10-H); 7.55 (1H, dd, J23 = 7.6, J21 =7.9, 2-H); 7.94 (1H, s, 5-H). Found, %: C 80.30; H 4.46; N 9.19.
C20H14N2O. Calculated, %: C 80.52; H 4.73; N 9.39.
J
p
cd
A
mixture
of
7- -Bromophenyl-7,8-dihydro-9H-pyrido[1,2,3- ]perimidin-9-one
(4b).
4(9)-p-bromocinnamoylperimidine (0.67 g, 2 mmol), ethanol (5 ml), water (2.5 ml), and KOH (0.7 g) was
refluxed for 40 min and diluted with water. The dry precipitate was dissolved in a minimum amount of benzene,
refluxed with silica gel, filtered, and the benzene was evaporated. Yield 0.16 g (28%) as yellow crystals;
1
a
b
mp 94-96°C (octane). H NMR spectrum (acetone-d6), δ, ppm, J (Hz): 3.03 (1H, dd, J8H H (gem) = 16.2,
a
b
a
b
a
J
J
8H 7H(cis) = 3.4, 8-Ha); 3.44 (1H, dd, J8H H (gem) = 16.2, J8H 7H(trans) = 6.4, 8-Hb); 5.75 (1H, dd, J78 (cis) = 3.4,
b
78 (trans) = 6.4, 7-H); 7.03 (1H, dd, J32 = 7.7, J31 = 0.9, 3-H); 7.10 (1H, d, J1110 = 8.5, 11-H); 7.36 (1H, dd,
J12 = 8.1, J13 = 0.9, 1-H); 7.39 (2H, d, J = 8.5, 2'- and 6'-H C6H4); 7.47 (1H, d, J1011 = 8.5, 10-H); 7.54 (1H, dd,
J23 = 7.7, J21 = 8.1, 2-H); 7.57 (2H, d, J = 8.5, 3'- and 5'-H, C6H4); 7.77 (1H, s, 5-H). Found, %: C 63.92; H 3.65;
N 7.22. C20H13BrN2O. Calculated, %: C 63.68; H 3.47; N 7.43.
8(6)-Aryl-6(8)-oxo-1,6,7,8-tetrahydro-1,3-diazapyrene (8a and 8b). A mixture of 6(7)-cinnamoyl-
perimidine or 6(7)-p-bromocinnamoylperimidine (1 mmol) and KOH (5 mmol) in ethylene glycol (5 ml) was
refluxed for 3 h, cooled, poured into water (~30 ml), extracted with ethyl acetate (4 × 5 ml), and solvent
evaporated at reflux until turbidity was seen. The precipitated solid formed on cooling was filtered off and dried
to give 8(6)-phenyl-6(8)-oxo-1,6,7,8-tetrahydro-1,3-diazapyrene (8a) (83%) as orange crystals; mp 156-157°C
(ethyl acetate). The yield of 8(6)-p-bromophenyl-6(8)-oxo-1,6,7,8-tetrahydro-1,3-diazapyrene (8b) was 82%,
yellow orange crystals; mp 168-170°C (ethyl acetate). Both samples did not give a depression of melting point
when mixed with samples prepared by us from the alternative route [1].
o
A. A mixture of perimidine (0.68 g, 4 mmol),
Acylation of Perimidine Using -Chlorobenzoic Acid.
o-chlrorbenzoic acid (0.94 g, 6 mmol) and PPA (10 g) was heated to 130-135°C and held with stirring at the
same temperature for 2 h. The reaction mass was cooled to 80°C and poured into cold water (50 ml) with
vigorous stirring. After basification with ammonia to pH ~ 8 the precipitate was filtered off, washed with water,
and dried. The dried precipitate was treated with ethyl acetate (20 ml) and, together with the precipitate, was
transferred to a chromatography column with silica gel (50 g). It was eluted with ethyl acetate, collecting the
first yellow colored fraction. Evaporation of solvent gave 4(9)-o-chlorobenzoylperimidine (10) (0.6 g, 49%) as
yellow crystals; mp 225-227°C (benzene–petroleum ether). 1H NMR spectrum (DMSO-d6), δ, ppm, J (Hz): 6.86
(1H, d, J87 = 9.0, 8-H); 7.01 (1H, d, J78 = 9.0, 7-H); 7.12 (1H, br. d, J65 = 7.7, J64 << 1, 6-H); 7.35 (1H, br. d,
J45 = 8.1, J46 << 1, 4-H); 7.50-7.60 (4H, m, C6H4); 7.64 (1H, br. t, J56 + J54 = 15.8, 5-H); 8.01 (1H, d, J2-NH = 3.0,
2-H); 12.57 (1H, br. s, NH). Found, %: C 70.66; H 3.64; N 9.02. C18H11ClN2O. Calculated, %: C 70.48; H 3.61;
N 9.13.
B. A mixture of perimidine (0.34 g, 2 mmol), o-chlorobenzoic acid (0.47 g, 3 mmol), and PPA (7 g) was
stirred at 80-85°C for 3 h, poured with vigorous stirring into cold water (~ 30 ml), basified with ammonia to
pH ~ 8, and the precipitate was filtered off, washed with water, and dried. It was then treated with ethyl acetate
(5 ml) and, together with the precipitate, transferred to a chromatography column with silica gel. Initial elution
with ethyl acetate gave a first fraction and with a mixture of ethyl acetate and ethanol (10:1) gave a second (both
fractions were yellow in color).
Evaporation of solvent from the first fraction gave compound 10 (0.025 g, 4%) which did not depress
the melting point of a sample prepared as described in method A.
The second fraction gave 6(7)-o-chlorobenzoylperimidine (0.41 g, 67%) as yellow orange crystals;
1
mp 220-221°C (benzene–ethanol). H NMR spectrum (DMSO-d6; reported as the 6-tautomer), δ, ppm, J (Hz):
6.43 (1H, br. d, J45 = 8.1, 4-H); 6.92 (1H, br. d, J98 = 7.3, 9-H); 7.31 (1H, J54 = 8.1, 5-H); 7.4-7.5 (4H, m, C6H4);
7.57 (1H, br. t, J87 + J89 = 16.3, 8-H); 7.73 (1H, s, 2-H), 8.72 (1H, br. d, J78 = 9.0, 6-H). Found, %: C 70.29;
H 3.41; N 9.22. C18H11ClN2O. Calculated, %: C 70.48; H 3.61; N 9.13.
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4(9)-Acetylperimidine was prepared by method [6]. 1H NMR spectrum (CDCl3)*, δ, ppm, J (Hz): 2.56
(3H, s, CH3CO); 6.99 (1H, d, J78 = 9.1, 7-H); 7.11 (1H, dd, J45 = 7.6, J46 = 1.1, 4-H); 7.26 (1H, dd, J65 = 8.1,
J64 = 1.1, 6-H); 7.44 (1H, d, J87 = 9.1, 8-H); 7.51 (1H, dd, J54 = 7.6, J56 = 8.1, 5-H); 7.68 (1H, d, J2-NH = 3.1,
2-H); 12.60 (1H, br. s, NH···O=).
cd
6H-Quino[1,2,3- ]perimidin-6-one (12).
A mixture of 4(9)-o-chlorobenzoylperimidine (0.5 g,
16 mmol), calcined potassium hydroxide (0.4 g, 7 mmol), and ethylene glycol (4 ml) was heated to reflux (when
a red colored solution was formed) and refluxed for 1 h. The reaction mixture was cooled and poured into cold
water (30 ml) and the precipitate was filtered off, washed with water, and dried. Yield 0.26 g (60%) as yellow
brown crystals; mp 282-283°C (benzene–ethanol). 1H NMR spectrum (CD3CN), δ, ppm, J (Hz): 7.24 (1H, br. d,
J12 = 7.3 , 1-H); 7.33 (1H, dd, J87 = 8.1, J89 = 6.8, 8-H); 7.37 (1H, s, 12-H); 7.52 (1H, d, J45 = 9.0, 4-H); 7.53
(1H, dd, J21 = 7.3, J23 = 8.1, 2-H); 7.60 (2H, m, 3-H and 10-H); 7.72 (1H, dd, J98 = 6.8, J910 = 7.7, 9-H); 8.23
(1H, d, J54 = 9.0, 5-H); 8.34 (1H, dd, J78 = 8.1, J79 = 0.9, 7-H). Found, %: C 79.69; H 3.44; N 10.62. C18H10N2O.
Calculated, %: C 79.99; H 3.73; N 10.36.
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2.
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6.
L. A. Kurasov, A. F. Pozharskii, and V. V. Kuz'menko, Zh. Org. Khim., 19, 859 (1983).
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I. V. Borovlev, O. P. Demidov, and A. F. Pozharskii, Khim. Geterotsikl. Soedin., 278 (2002).
A. F. Pozharskii, I. V. Borovlev, and I. S. Kashparov, Khim. Geterotsikl. Soedin., 543 (1975).
_______
* 1H NMR spectrum of this compound is published for the first time.
1095