Simple synthesis of 6-substituted 4a-methyl-1,2,3,4,4a,10b- hexahydrophenanthridines and -9,10-benzophenanthridines

Article abstract of DOI:10.1023/B:COHC.0000037314.13773.dc

A route has been developed for the synthesis of 6-substituted 4a-methyl-1,2,3,4,4a,10b-hexahydrophenanthridines and -9,10- benzophenanthridines. The effect has been shown of the nature of the substituent at position 10 of the ring on the chemical shift of the proton at position 10b.

Full text of DOI:10.1023/B:COHC.0000037314.13773.dc

Chemistry of Heterocyclic Compounds, Vol. 40, No. 5, 2004
SIMPLE SYNTHESIS OF 6-SUBSTITUTED
4a-METHYL-1,2,3,4,4a,10b-HEXA-
HYDROPHENANTHRIDINES AND
-9,10-BENZOPHENANTHRIDINES
Yu. V. Shklyaev and Yu. V. Nifontov
A
route has been developed for the synthesis of 6-substituted 4a-methyl-1,2,3,4,4a,10b-
hexahydrophenanthridines and -9,10-benzophenanthridines. The effect has been shown of the nature of
the substituent at position 10 of the ring on the chemical shift of the proton at position 10b.
Keywords: 9,10-benzophenanthridines, hexahydrophenanthridines, diastereomers, Ritter reaction.
Aromatic phenanthridines have been studied adequately well [1-4]. However there is only one study on
the chemistry and biological activity of hydrogenated phenanthridines, which is probably linked with the
absence of convenient methods of synthesizing them [3].
The synthesis of 6-R-4a-methyl-1,2,3,4,4a,10b-hexahydrophenanthridines (R = Me, CH2COOEt) from
1-methyl-2-phenylcyclohexanol has been described [5]. In spite of its superficial simplicity it requires the use of
the difficultly available 2-phenylcyclohexanone and in addition a mixture of all the possible diastereomers is
formed.
+
H
HO
+
+
Me
Me
Me
2
3
1
10
7
*
10b
RCN
*
4
*
*
9
8
or
4a
Me
Me
NH
N5
6
COR2
R1
1, 2
3, 4
R = Me, SMe, CH2COOEt, CH2CONH2; 1 R1 = Me, 2 R1 = SMe, 3 R2 = OEt, 4 R2 = NH2
__________________________________________________________________________________________
Institute of Technical Chemistry, Urals Branch of the Russian Academy of Sciences, Perm 614990;
e-mail: cheminst@mpm.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, Vol. 40, No. 5,
pp. 706-710, May, 2004. Original article submitted October 23, 2001.
594
0009-3122/04/4005-0594©2004 Plenum Publishing Corporation

It was discovered by us that identical products are also formed by the Ritter reaction from 2-methyl-
1-phenylcyclohexanol, obtained from phenyl magnesium bromide and 2-methylcyclohexanone. As was shown in
[6], when alkyl substituents are present at the second carbon atom of 1-aryl-2,2-dialkylethanols, transposition of
the reaction center is observed, and the tertiary carbocation formed in this way, which is not stabilized by a
neighboring aryl residue, is the only one which can interact with a nitrile group. 2-Methyl-1-phenylcyclohexanol
reacts with nitriles in a similar manner with the formation of phenanthridines 1-4.
The Ritter reaction proceeds similarly and for 2-methyl-1-(1-naphthyl)cyclohexanol, obtained from
1-naphthylmagnesium bromide and 2-methylcyclo-hexanone, leads to the preparation of the previously unknown
6-substituted 4a-methyl-1,2,3,4,4a,10b-hexahydro-9,10-benzophenanthridines 5-8.
Me
HO
R1CN
COR2
*
*
CN
*
*
Me
Me
N
NH
R1
5, 6
COR2
7, 8
5 R1 = Me, 6 R1 = SMe,
7 R2 = OEt, 8 R2 = NH2
A characteristic feature of compounds 1-8 is the presence of a signal for the 10b proton of the
1
phenanthridine ring in the H NMR spectrum. For the 6-R-1,2,3,4,4a,10b-derivatives 1-4 this signal is found at
2.70-2.73 ppm. For compounds 5-8 the signal is displaced to substantially lower field (for 5 to 3.52, for 6 to
3.38, for 7 to 3.50, and for 8 to 3.39 ppm), which, in our view, may be explained by the significant deshielding
of this proton due to the π-electrons of the naphthalene ring. In addition this signal is a doublet of doublets,
which in combination with the singlet of the methyl group in position 4a of the ring, indicates the presence of
only one pair of enantiomers. Additional confirmation is given by the presence of only one signal for the vinyl
proton and the heterocyclic NH for compounds 3, 4, 7, and 8.
With the aim of clarifying the role of the substituent in position 10 of the phenanthridine ring we studied
the behavior in this reaction of 1-(2,5-dimethylphenyl)-2-methylcyclohexanol, obtained from
2,5-xylylmagnesium bromide and 2-methylcyclohexanone. It turned out that in this case the preparation was
observed of only one pair of enantiomers of derivatives of 4a,7,10-trimethyl-1,2,3,4,4a,10b-hexahydro-
phenanthridines 9-12. However the signal of the proton at position 10b of the ring at 2.52-2.59 ppm was
displaced towards high field in comparison with compounds 1-4, which is explained by the shielding of this
proton by the methyl group at position 10.
Me
Me
Me
COR2
*
R1CN
*
CN
*
*
Me
Me
OH
Me
N
NH
Me
Me
Me
R1
9, 10
COR2
11, 12
9 R1 = Me, 10 R1 = SMe,
2
2
11 R = OEt, 12 R = NH2
595

TABLE 1. Spectral Characteristics of Compounds 1-12
1Н NMR spectrum, δ, ppm (J, Hz)
Н arom.
IR spectrum,
Compound
ν, cm-1
3Н, s,
4a-Me
8H, complex. m,
(CH2)4
1H, dd,
10b-Н*
Other protons
1-HOC6H4COOH*2
—
0.73
0.80
1.35-2.00
1.12-1.96
2.70
2.72
6.80-7.78 (8Н, m)
7.10-7.56 (4Н, m)
2.47 (3Н, s, 6-CH3)
2.54 (3Н, s, 6-SCH3)
2
1620, 1580,
1500, 1320
3
4
5
6
7
8
3280, 1735,
1605, 1580
0.83
0.82
0.75
0.80
0.97
0.95
1.16-2.01
1.21-2.00
1.00-2.00
0.99-2.10
1.43-1.92
1.20-1.80
2.73
2.72
3.52
3.38
3.50
3.39
7.02-7.49 (4Н, m)
7.13-7.71 (4Н, m)
1.20 (3Н, t, CH3 ester); 4.10 (2Н, q, ОСН2);
5.19 (1Н, s, СН); 8.80 (1Н, s, NН)
3440, 3360, 3190,
1650, 1610
5.21 (1Н, s, СН); 6.32 (2Н, br. s, NH2); 8.60 (1Н, s, NH)
1620, 1580, 1500
1622, 1585, 1510
3250, 1725, 1610
7.50-7.93 (5Н, m);
8.20 (1Н, d, 7-Н)
2.40 (3Н, s, 6-CH3)
7.60-7.95 (5Н);
8.25 (1Н, d, 7-Н)
2.47 (3Н, s, SCH3)
7.60-7.99 (5Н, m);
8.23 (1Н, d, 7-Н)
7.50-7.80 (5Н, m);
8.15 (1Н, d, 7-Н)
1.22 (3Н, t, CH3 ester); 4.10 (2Н, q, ОСН2);
5.23 (1Н, s, СН); 8.90 (1Н, s, NH)
5.23 (1Н, s, СН); 6.25 (2Н, br. s, NH2); 9.40 (1Н, s, NH)
3310, 3245,
1645, 1610
9-HOC6H4COOH*2
—
0.73
0.58
1.22-1.99
1.30-2.05
2.52
2.55
6.93-7.66 (6Н, m)
6.88 (1Н, d);
6.93 (1Н, d)
2.43 (3Н, s, 6-CH3); 2.31 (3H, s, 7-CH3); 2.28 (3H, s, 10-CH3)
2.27 (3Н, s, 10-CH3); 2.34 (3Н, s, 7-CH3);
2.60 (3Н, s, 6-SCH3)
10
1620, 1585, 1510
11
12
3280, 1735,
1605, 1580
0.86
0.81
1.30-1.90
1.20-1.80
2.53
2.59
7.05(1Н, d);
7.12 (1Н, d)
1.22 (3Н, t, J = 7.4, CH3 ester); 2.27 (3Н, s, 10-CH3);
2.48 (3Н, s, 7-CH3); 4.08 (2Н, q, J = 7.3, ОСН2);
4.73 (1Н, s, СН); 9.03 (1Н, s, NН)
3440, 3355, 3190,
1650, 1605
7.00 (1Н, d);
7.04 (1Н, d)
2.26 (3Н, s, 10-CH3); 2.47 (3Н, s, 7-CH3);
4.79 (1Н, s, СН); 6.20 (2Н, br. s, NH2); 9.60 (1Н, s, NH)
_______
* J = 8.3 Hz.
*2 Compounds 1 and 9 were identified as salicylates.

TABLE 2. Physicochemical Properties of Compounds 1-12
Found, %
——————
Calculated, %
Empirical
formula
Compound
mp, °С
Yield, %
С
Н
N
1-HOC6H4COOH*
C22H25NO3
С15Н19NS
С18Н23NО2
С16Н20N2О
С19Н21N
75.33
75.21
7.03
7.12
4.11
3.99
123-124
(ethyl acetate)
39
50
61
66
49
62
81
83
39
53
59
62
2
73.60
73.47
7.85
7.76
5.84
5.71
85-86
(hexane)
3
75.50
75.79
8.12
8.07
5.00
4.91
64-65
(hexane)
4
75.31
75.00
8.01
7.81
10.80
10.94
129-130
(benzene)
5
86.83
86.69
8.05
7.98
5.12
5.33
117-118
(hexane)
6
С19Н21NS
С22Н25NО2
С20Н22N2О
C24H29NO3
С17Н23NS
С20Н27NО2
С18Н24N2О
77.00
77.29
7.20
7.12
4.84
4.75
69-70
(hexane)
7
78.61
78.81
7.55
7.46
4.31
4.18
115-116
(hexane)
8
78.21
78.43
7.30
7.19
9.31
9.15
210-211
(ethanol)
9-HOC6H4COOH*
75.85
75.99
7.72
7.65
3.79
3.69
127-128
(ethanol)
10
11
12
74.83
74.67
8.37
8.48
5.20
5.13
102-103
(hexane)
76.80
76.68
8.54
8.63
4.60
4.47
89-90
(hexane)
75.91
76.06
8.53
8.51
10.00
9.86
119-120
(ethyl acetate)
_______
* Compounds 1 and 9 were identified as salicylates.
EXPERIMENTAL
The IR spectra were taken on a UR 20 spectrophotometer in nujol. The 1H NMR spectra were recorded
on a Bruker AM 300 spectrophotometer (300 MHz) in DMSO-d6, internal standard was TMS.
The progress of reactions and the purity of the compounds obtained were checked by TLC on Silufol UV
254 plates (chloroform–acetone, 9:1), visualizer was a 0.5% solution of chloranil in toluene.
2-Methylcyclohexanone (from Lancaster) was used without preliminary purification. Synthesis of the
initial carbinols was effected by a standard procedure from 2-methylcyclohexanone and the appropriate
arylmagnesium bromide in diethyl ether. After distillation in vacuum the obtained mixture of carbinol and the
1
corresponding styrene (~3 : 1, according to data of H NMR and liquid chromatography) was used in the
reaction without further purification allowing for the molar content of the components.
6-Substituted 4a-Methyl-1,2,3,4,4a,10b-hexahydrophenanthridines and Ethyl Esters of
(4a-Methyl-1,2,3,4,4a,5,6,10b-octahydro-6-phenanthridinylidene)acetic Acid (1-3, 5-7, 9-11) (General
Procedure). A mixture of carbinol (0.1 mol) and nitrile (0.1 mol) was added dropwise with stirring and cooling
(0-10°C) to conc. H2SO4 (50 ml). The mixture was stirred for 30 min, diluted with water (300 ml), and extracted
with toluene (50 ml). The organic layer was rejected, and the remainder was made alkaline with aqueous
ammonia to pH 8-9. The separated solid (for compounds 2, 3, 5-7, 10, 11) was removed, washed with water,
dried in the air, and recrystallized from an appropriate solvent.
597

Compounds 1 and 9 were oils and were identified as salicylates. A solution of salicylic acid (1.38 g, 0.01
mol) in dry ether (20 ml) was added in one portion to a solution of substituted 4a-methyl-1,2,3,4,4a,10b-
hexahydrophenanthridine 1 or 9 (0.01 mol) in dry diethyl ether. The mixture was stirred for 1 min and left for 30
min. The separated solid was removed, washed on the filter with ether (20 ml), and recrystallized.
Amides of (4a-Methyl-1,2,3,4,4a,5,6,10b-octahydro-6-phenanthridinylidene)acetic Acids (4, 8, 12)
(General Procedure). Cyanoacetamide (1.68 g, 0.02 mol) was dissolved with stirring in cold conc. H2SO4
(15 ml) and the appropriate carbinol (4.28 g, 0.02 mol) was added rapidly in one portion. The mixture was
stirred for 15 min, diluted with water (100 ml), and extracted with benzene (20 ml). The organic layer was
rejected, and the aqueous layer made alkaline to pH 8-9. The precipitated solid was filtered off, washed with
water, dried in the air, and recrystallized.
The work was carried out with the financial support of RFFI (grant No. 01-03-96479).
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