Synthesis of benzo[a]phenanthridine derivatives by condensation of N-arylmethylene-2-naphthylamines with 5-phenyl- and 5-(p-methoxyphenyl)-1,3-cyclohexanediones

Article abstract of DOI:10.1023/A:1020827812868

Condensation of N-arylmethylene-2-naphthylamines with 5-phenyl- and 5-(p-methoxyphenyl)-1,3-cyclohexanediones in various solvents gave new hexahydrobenzo[a]phenanthridin-4-one derivatives. Three-component condensation of 2-naphthylamine, appropriate aldeh

Full text of DOI:10.1023/A:1020827812868

Russian Journal of General Chemistry, Vol. 72, No. 8, 2002, pp. 1238 1242. Translated from Zhurnal Obshchei Khimii, Vol. 72, No. 8, 2002,
pp. 1320 1324.
Original Russian Text Copyright
2002 by Kozlov, Basalaeva, Skakovskaya.
Synthesis of Benzo[a]phenanthridine Derivatives
by Condensation of N-Arylmethylene-2-naphthylamines
with 5-Phenyl- and 5-(p-Methoxyphenyl)-1,3-cyclohexanediones
N. G. Kozlov, L. I. Basalaeva, and Yu. E. Skakovskaya
Institute of Physical Organic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus
Received November 3, 2000
Abstract Condensation of N-arylmethylene-2-naphthylamines with 5-phenyl- and 5-(p-methoxyphenyl)-1,3-
cyclohexanediones in various solvents gave new hexahydrobenzo[a]phenanthridin-4-one derivatives. Three-
component condensation of 2-naphthylamine, appropriate aldehyde, and 5-(p-methoxyphenyl)-1,3-cyclo-
hexanedione was also studied.
The properties and reactivity of cyclic -diketones
attract a keen attention of organic chemists. Numerous
their derivatives are biologically active compounds,
some of which have found practical application.
Diketone derivatives are used in the synthesis of
prostaglandins, antibiotics, and alkaloids [1 3]. In
addition, cyclic -diketones are convenient model
compounds for studying the effect of cyclic structure
on the properties of the methylene and carbonyl
groups, tautomeric equilibria, and reactivity.
since the yields of hexahydrobenzo[a]phenanthridi-
nones from compound IIIa are greater when the reac-
tion is carried out in butanol. In ethanol, the yield of
the final products does not exceed 15%. The con-
densation of IIIb with N-arylmethylene-2-naphthyl-
amines in ethanol gives hexahydrobenzo[a]phenanthri-
dinones in up to 70% yield, whereas the yield of the
same products in butanol does not exceed 10%.
O
R
The present article describes the synthesis of
phenanthridine derivatives from 5-phenyl-1,3-cyclo-
hexanedione (IIIa) and 5-(p-methoxyphenyl)-1,3-
cyclohexanedione (IIIb) via condensation with N-aryl-
methylene-2-naphthylamines IIa IIj. Schiff bases
IIa IIj were prepared by reaction of 2-naphthylamine
with benzaldehydes Ia Ij by heating for 10 20 min in
an alcoholic solution. 2-Phenyl- and 2-(p-methoxy-
phenyl)-5-aryl-1,2,3,4,5,6-hexahydrobenzo[a]phen-
anthridin-4-ones IVa IVt (Table 1) were obtained by
heating equimolar amounts of compound IIIa or IIIb
and the corresponding Schiff base II in ethanol or
butanol.
O
O
R
H+
O
O
R
OH
5-Phenyl- and 5-(p-methoxyphenyl)-1,3-cyclo-
In keeping with the results of our studies on reac-
hexanediones possess a specific fragment including tions of Schiff bases with -diketones [4, 5], the first
two carbonyls and an active methylene group. Proton
of the methylene group is capable of migrating to the
carbonyl oxygen atom to give a keto enol conjugated
system or of being abstracted to form an enolate ion.
-Diketones in solution give rise to the keto
stage of the process is nucleophilic addition of the
enolate ion derived from 1,3-diketone to the C N
carbon atom of N-arylmethylene-2-naphthylamine.
Arylaminoketo enol A undergoes heterocyclization
with elimination of water, yielding the final product,
2-phenyl- or 2-(p-methoxyphenyl)-5-aryl-1,2,3,4,5,6-
hexahydrobenzo[a]phenanthridin-4-one.
enol
enolate ion equilibrium which is displaced
toward the latter in a proton-acceptor solvent. We
have found that enolization of 5-phenyl-1,3-cyclo-
hexanedione (IIIa) requires a higher temperature than
for 5-(p-methoxyphenyl)-1,3-cyclohexanedione (IIIb),
Obviously, the stages of isolation and purification
of N-arylmethylene-2-naphthylamines for the sub-
1070-3632/02/7208-1238$27.00 2002 MAIK Nauka/Interperiodica

SYNTHESIS OF BENZO[a]PHENANTHRIDINE DERIVATIVES
1239
1
Their structure follows from the H NMR, IR, and
mass spectra. The IR spectra of IV contain bands
belonging to stretching vibrations of the secondary
O
R C H
Ia Ij
1
amino group (3550 3300 cm ) and the carbonyl group
1
(1700 1680 cm ). The strong absorption band in the
1
region 1130 1120 cm arises from vibrations of the
NH2
N=CH R
+
CH3O group present in all 5-aryl-2-(p-methoxyphenyl)-
1,2,3,4,5,6-hexahydrobenzo[a]phenanthridin-4-ones
IVk IVt and also in compounds IVi and IVj. Phen-
anthridinones IVb and IVl give rise to a strong band
IIa IIj
R
1
at 580 560 cm due to stretching vibrations of the
C Br bond; compounds IVg, IVh, IVq, and IVr
show a band at 860 840 cm 1 due to C Cl vibrations,
and the bands at 1380 and 1540 cm in the spectra of
IIIa IIIb
1
IVd and IVn correspond, respectively, to symmetric
and antisymmetric vibrations of the nitro group.
O
O
R
R
3
2
O
O
4
The molecular ion peaks in the mass spectra of
hexahydrobenzo[a]phenanthridinones IV have an in-
tensity of 5 to 20%, and the most abundant (100%) is
an [M C6H4R]+ ion peak; the latter is stable, and
almost no other fragment ion peaks are observed.
These data indicate a low stability of compounds IV
to electron impact.
1
5
R
R
6
12
OH
NH
NH
11
10
7
9
8
IVa IVt
A
1
IIIa, IVa IVj, R = H; I, II, IV, R = C6H5 (a); m-BrC6H4
(b), o-CH3C6H4 (c), p-NO2C6H4 (d), C5H4N(e), C4H3S(f),
o,p-Cl2C6H3 (g), o-F-o -ClC6H3 (h), m,p-(CH3O)2C6H3 (i),
m,m -(CH3O)2-p-HOC6H2 (j); IIIb, IVk IVt, R = CH3O;
IV, R = C6H5 (k), m-BrC6H4 (l), o-CH3C6H4 (m),
p-NO2C6H4 (n), C5H4N (o), C4H3S (p), o,p-Cl2C6H3 (q),
o-F-o -ClC6H3 (r), m,p-(CH3O)2C6H3 (s), m,m -(CH3O)2-
p-HOC6H2 (t).
The H NMR spectra of IVa IVt are given in
Table 2. Signals from protons of the naphthalene core
overlap those from protons of two aromatic rings,
giving rise to two, three, or four groups of multiplets,
depending on the substitution pattern. The relative
intensity of these multiplets (with respect to the
intensity of cycloaliphatic protons) is consistent with
the proposed structure. A downfield shift of the 5-H
signal should be noted. Presumably, this is the result
of anisotropic affect of the neighboring nitrogen atom
and aromatic ring. Unlike 1,2,3,4-tetrahydrobenzo[a]-
phenanthridinones which give a singlet from the
amino group proton [6], the corresponding signal in
sequent synthesis of hexahydrobenzo[a]phenanthri-
dinones inevitably reduce the yield of the final prod-
uct. Taking into account that the synthesis of Schiff
bases II and the condensation of the latter with IIIb
occur in the same solvent, we made an attempt to
effect three-component condensation of 2-naphthyl-
amine, appropriate aldehyde, and 5-(p-methoxy-
1
the H NMR spectra of IVa IVt is a doublet ( 9.80
10.10 ppm). Probably, the molecular geometry is
distorted because of the presence of phenyl or
methoxyphenyl substituent. The distance between the
hydrogen atoms of the dihydropyridine ring and the
NH hydrogen atom shortens, so that coupling of these
protons becomes stronger, and the NH signal appears
as a doublet with J = 4.5 7.8 Hz. In the spectra of
o-substituted compounds IVc, IVg, IVh, IVm, IVq,
and IVr, the NH signal is not split, presumably due to
phenyl)-1,3-cyclohexanedione
(IIIb).
Equimolar
amounts of 2-naphthylamine and aldehyde were
heated in an alcoholic solution, the required amount
of compound IIIb was added, and the mixture was
refluxed for 30 60 min. We thus succeeded in raising
the yield of the final phenanthridinones by 5 10%. In
the case of -diketone IIIa, analogous three-com-
3
ponent condensation turned out to be less effective, steric effect of the ortho-substituent [7].
for the synthesis of Schiff bases II and their sub-
sequent condensation with IIIa require different
solvents.
Compounds IVa IVt absorb in the UV region,
and their electronic spectra are characterized by clearly
defined vibrational structure (Table 3). 2-(p-Methoxy-
phenyl)-5-aryl-1,2,3,4,5,6-hexahydrobenzo[a]phen-
anthridin-4-ones IVk IVt show in the electronic
Tables 1 3 contain the yields, melting points, and
analytical and spectral data of compounds IVa IVt.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 72 No. 8 2002

1240
KOZLOV et al.
Table 1. Yields, melting points, and elemental analyses of 5-aryl-2-phenyl-1,2,3,4,5,6-hexahydrobenzo[a]phenanthridin-
4-ones IVa IVj and 5-aryl-2-(p-methoxyphenyl)-1,2,3,4,5,6-hexahydrobenzo[a]phenanthridin-4-ones IVk IVt
Found, %
H
Calculated, %
H
Comp.
no.
Yield,
%
mp,
C
Formula
C
N
C
N
IVa
IVb
IVc
IVd
IVe
IVf
IVg
IVh
IVi
80
50
40
55
60
50
70
35
65
52
70
45
40
50
55
42
64
30
58
44
302
320
268
86.80
72.46
86.75
77.96
85.37
81.88
74.01
5.74
4.61
6.02
4.95
5.48
5.16
4.49
3.48
2.92
3.41
6.29
5.82
2.90
2.96
3.04
3.06
2.94
3.27
2.74
3.13
5.90
5.53
2.71
2.82
2.91
2.87
2.78
C29H23NO
C29H22BrNO
C30H25NO
86.78
72.5
5.74
4.58
6.00
4.93
5.44
5.18
4.47
4.63
5.86
6.25
5.80
4.71
6.07
5.04
5.51
5.26
4.60
4.76
5.90
5.90
3.49
2.90
3.37
6.28
5.86
2.90
2.98
3.08
3.04
2.93
3.25
2.75
3.15
5.88
5.51
2.73
2.80
2.89
2.85
2.76
86.75
78.00
85.40
81.90
74.00
76.74
80.69
77.50
83.50
70.59
83.60
75.63
82.68
79.53
72.00
74.46
78.20
75.59
291
C29H22N2O3
C34H26N2O
C33H25NOS
C29H21Cl2NO
C29H21ClFNO
C31H27NO3
C31H30NO4
C30H25NO2
C30H24BrNO2
C31H27NO2
C30H24N2O4
C35H28N2O2
C34H27NO2S
C30H23Cl2NO2
C30H23ClFNO2
C32H29NO4
C32H30NO5
317 318
306
267
233 234
325
80.65
77.47
83.52
70.56
83.57
75.62
82.71
79.55
72.02
74.47
78.23
75.62
5.84
6.23
5.76
4.73
6.05
5.06
5.50
5.27
4.57
4.78
5.88
5.92
IVj
IVk
IVl
250
309
310
235
248
253
IVm
IVn
IVo
IVp
IVq
IVr
IVs
IVt
299 (decomp.)
270
254
293
243
Table 2. 1H NMR spectra of 5-aryl-2-phenyl-1,2,3,4,5,6-hexahydrobenzo[a]phenanthridin-4-ones IVa IVj and 5-aryl-2-
(p-methoxyphenyl)-1,2,3,4,5,6-hexahydrobenzo[a]phenanthridin-4-ones IVk IVt, , ppm (J, Hz) (2 5% solutions in
DMSO-d6)
Comp.
no.
1-H, 2-H
3-H
5-H (3J)
Aromatic protons
NH (3J)
IVa
3.30 3.51 m 3.68 4.00 m 5.87 d (5.2) 7.01 7.43 m, 7.72 8.05 m
2.42 2.60 m 2.80 3.00 m 5.90 d (5.0) 7.10 7.50 m, 7.70 8.00 m
9.85 d (7.2)
9.90 d (7.8)
9.80 s
IVb
IVc
IVd
IVe
IVf
IVg
IVh
IVi
2.80 2.95 m 3.20 3.45 m 5.85 s
6.80 6.92 m, 7.00 7.50 m, 7.60 7.90 m
2.40 2.60 m 2.75 3.00 m 6.00 d (5.7) 7.10 7.60 m, 7.80 8.12 m
2.43 2.58 m 2.80 3.00 m 5.84 d (5.2) 7.00 7.50 m, 7.70 8.00 m, 8.12 8.29 m, 8.48 8.59 m 9.85 d (5.9)
2.40 2.68 m 2.75 2.93 m 6.20 d (4.0) 6.50 6.80 m, 7.00 7.55 m, 7.70 8.10 m
10.00 d (4.5)
9.90 d (6.5)
9.90 s
9.86 s
2.48 2.58 m 2.80 3.00 m 6.00 s
2.44 2.60 m 2.78 3.10 m 5.87 s
7.10 7.50 m, 7.70 7.90 m, 8.00 8.15 m
7.00 7.50 m, 7.70 7.90 m, 8.00 8.20 m
2.49 2.58 m 2.72 3.00 m 5.82 d (4.9) 6.50 6.62 m, 6.93 7.10 m, 7.12 7.50 m, 7.70 8.09 m 10.25 d (4.5)
2.46 2.62 m 2.77 2.91 m 5.96 d (5.0) 6.60 6.70 m, 6.80 7.00 m, 7.20 7.55 m, 7.75 8.10 m 10.10 d (5.0)
3.27 3.48 m 3.50 3.84 m 5.80 d (5.8) 7.06 7.52 m, 7.80 8.10 m
2.31 2.44 m 2.97 3.12 m 6.02 d (5.0) 7.15 7.60 m, 7.90 8.20 m
IVj
IVk
IVl
10.00 d (6.0)
9.85 d (7.4)
IVm
IVn
IVo
IVp
IVq
IVr
IVs
IVt
2.70 2.90 m 3.40 3.50 m 5.90 s
2.34 2.59 m 2.80 3.08 m 5.86 d (5.8) 6.80 7.10 m, 7.20 7.70 m
2.40 2.52 m 3.00 3.22 m 5.94 d (5.0) 6.90 7.20 m, 7.40 7.80 m, 8.00 8.15 m, 8.30 8.50 m 9.80 d (6.0)
2.35 2.51 m 2.92 3.03 m 6.00 d (4.6) 6.10 6.56 m, 6.80 7.20 m, 7.40 7.90 m
2.42 2.54 m 2.90 3.15 m 5.85 s
2.38 2.51 m 2.84 3.12 m 6.05 s
2.45 2.53 m 2.85 3.16 m 5.80 d (5.0) 6.40 6.70 m, 6.90 7.15 m, 7.20 7.50 m, 7.75 8.10 m 10.10 d (4.6)
2.34 2.49 m 2.80 3.00 m 6.00 d (5.3) 6.50 6.70 m, 6.80 7.10 m, 7.30 7.60 m, 7.80 8.20 m 10.00 d (5.4)
6.43 6.60 m, 6.70 7.00 m, 7.18 7.50 m, 7.70 7.93 m 9.90 s
10.00 d (4.8)
9.95 d (6.3)
9.90 s
9.90 s
6.20 6.60 m, 6.90 7.30 m, 7.50 8.00 m
7.00 7.40 m, 7.60 7.90 m, 8.00 8.30 m
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 72 No. 8 2002

SYNTHESIS OF BENZO[a]PHENANTHRIDINE DERIVATIVES
1241
spectra an additional absorption maximum at 209
216 nm.
Table 3. UV spectra of 5-aryl-2-phenyl-1,2,3,4,5,6-hexa-
hydrobenzo[a]phenanthridin-4-ones IVa IVj and 5-aryl-
2-(p-methoxyphenyl)-1,2,3,4,5,6-hexahydrobenzo[a]-
phenanthridin-4-ones IVk IVt
EXPERIMENTAL
Comp.
no.
The IR spectra were recorded in KBr on a UR-20
spectrophotometer. The H NMR spectra were ob-
max, nm (log )
1
tained on a Tesla BS-567 spectrometer (100 MHz)
from 2 5% solutions in DMSO-d6; the chemical shifts
were measured relative to TMS as internal reference.
The mass spectra were run on an MKh-1320 instru-
ment. The UV spectra were measured on a Specord
UV-Vis spectrophotometer from solutions in ethanol
IVa
IVb
IVc
IVd
IVe
IVf
IVg
IVh
IVi
220 (4.48), 250 (4.00), 267 (4.18), 282 (4.15), 318
(3.70), 332 (3.79)
232 (4.60), 268 (4.12), 281 (4.22), 292 (4.29), 325
(3.73), 340 (3.90)
217 (4.30), 253 (4.03), 260 (4.15), 280 (4.00), 315
(3.65), 330 (3.70)
217 (4.27), 255 (4.10), 258 (4.10), 279 (4.11), 314
(3.57), 333 (3.64)
216 (4.29), 249 (4.08), 252 (4.11), 283 (4.20), 314
(3.50), 336 (3.59)
230 (4.65), 242 (4.08), 254 (4.13), 270 (4.16), 310
(3.79)
222 (4.33), 247 (4.25), 263 (4.23), 269 (4.18), 320
(3.62), 328 (3.61)
220 (4.46), 251 (4.29), 269 (4.27), 270 (4.17), 317
(3.60), 331 (3.68)
4
(c = 1 10 M).
5-Phenyl-1,3-cyclohexanedione (IIIa) was pre-
pared from diethyl malonate and benzylideneacetone
with intermediate isolation of 6-phenyl-2,4-dioxo-
cyclohexanecarboxylic acid [8]. mp 184 185 C.
5-(p-Methoxyphenyl)-1,3-cyclohexanedione
(IIIb) was synthesized from diethyl malonate and
p-methoxybenzylideneacetone [9]. mp 185 C.
N-Arylmethylene-2-naphthylamines IIa IIj were
obtained by heating equimolar amounts of 2-naphthyl-
amine and appropriate aldehyde in alcohol under
reflux, following the procedure described in [10].
The properties of N-arylmethylene-2-naphthylamines
IIa IId and IIi coincided with those reported in [11].
Below are given compound no., yield (%), and mp
( C): IIe, 50, 100 101; IIf, 65, 75; IIg, 76, 84; IIh,
60, 81; IIj, 62, 159 160.
221 (4.49), 258 (4.15), 274 (4.18), 276 (4.22), 309
(3.54), 325 (3.57)
223 (4.51), 260 (4.09), 270 (4.22), 288 (4.18), 313
(3.49), 330 (3.65)
IVj
IVk
IVl
210 (4.70), 232 (4.20), 260 (4.10), 280 (4.38), 320
(3.75)
216 (4.86), 233 (4.92), 270 (4.26), 280 (4.40), 292
(4.43), 340 (3.96)
IVm
IVn
IVo
IVp
IVq
IVr
IVs
IVt
209 (4.70), 240 (4.18), 254 (4.20), 285 (4.40), 325
(3.84)
5-Aryl-2-phenyl-1,2,3,4,5,6-hexahydrobenzo[a]-
phenanthridin-4-ones IVa IVj. Schiff base IIa IIj,
0.01 mol, was dissolved in 30 ml of butanol, 0.01 mol
of 5-phenyl-1,3-cyclohexanedione (IIIa) was added,
and the mixture was refluxed for 20 60 min. The
precipitate was filtered off, washed with ether, and
recrystallized from benzene alcohol (2:1).
210 (4.65), 236 (4.23), 257 (4.18), 287 (4.35), 328
(3.74)
208 (4.30), 228 (4.18), 248 (4.25), 280 (4.30), 318
(3.76)
211 (3.98), 242 (4.05), 262 (4.14), 276 (4.31), 324
(3.82)
5-Aryl-2-(p-methoxyphenyl)-1,2,3,4,5,6-hexa-
hydrobenzo[a]phenanthridin-4-ones IVk IVt.
A mixture of 0.01 mol of 2-naphthylamine and
0.01 mol of appropriate aldehyde in 50 ml of ethanol
was heated for 10 20 min on a water bath (90 C).
The mixture was cooled, and an equimolar amount of
210 (4.60), 239 (4.13), 259 (4.25), 269 (4.49), 330
(3.70)
208 (4.35), 253 (4.28), 264 (4.00), 281 (4.39), 332
(3.69)
209 (4.59), 258 (4.17), 270 (4.05), 289 (4.37), 335
(3.71)
5-(p-methoxyphenyl)-1,3-cyclohexanedione
(IIIb)
(calculated on the Schiff base formed) was added. The
mixture was heated for 1 2 h, and the precipitate
was filtered off, washed with ether, and recrystallized
from benzene alcohol (3:1).
212 (4.68), 260 (4.20), 269 (4.11), 280 (4.36), 325
(3.60)
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1242
KOZLOV et al.
6. Kozlov, N.G. and Gusak, K.N., Zh. Obshch. Khim.,
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