Oxidative reactions of azines. 12. Dehydrogenation and oxidation of 2-methyl-9-phenyl-2,3-dihydro-1H-2-azafluorene

Article abstract of DOI:10.1007/s10593-006-0139-6

The oxidation of 2-methyl-9-phenyl-2,3-dihydro-1H-2-azafluorene by air, manganese dioxide, and potassium permanganate has been studied. Depending on the nature of the oxidant it was found that this dihydroazafluorene derivative can be dehydrogenated to th

Full text of DOI:10.1007/s10593-006-0139-6

Chemistry of Heterocyclic Compounds, Vol. 42, No. 5, 2006
OXIDATIVE REACTIONS OF AZINES.
12*. DEHYDROGENATION AND OXIDATION OF
2-METHYL-9-PHENYL-2,3-DIHYDRO-1H-2-AZAFLUORENE
S. V. Volkov, A. N. Levov, O. E. Volkova, N. M. Kolyadina, K. B. Polyanskii,
and A. T. Soldatenkov
The oxidation of 2-methyl-9-phenyl-2,3-dihydro-1H-2-azafluorene by air, manganese dioxide, and
potassium permanganate has been studied. Depending on the nature of the oxidant it was found that this
dihydroazafluorene derivative can be dehydrogenated to the indeno[2,1-c]pyridine anhydro base series,
be hydroxylated, oxygenated, or undergo fission to a 2-formamidomethyl-substituted indan-1-one.
Keywords: 2-azafluorene, anhydro base, 2,3-dihydro-1H-2-azafluorene, manganese dioxide, indeno-
[2,1-c]pyridines, potassium permanganate, dehydrogenation, oxidation.
Continuing our study of the reactions of azafluorenes [2] and the oxidative conversions of heterocyclic
compounds containing an allylamine fragment [1, 3] we have turned our attention to the route of oxidation of
2-methyl-9-phenyl-2,3-dihydro-1H-2-azafluorene (1) [4]. This azafluorene derivative is an immediate precursor
of the antihistamine and anticholinergic drug thephorin and has a diarylaminoalkylmethane structural fragment
which is a so called "magic" pharmacophoric group [5].
In this connection, the chemical modification of the molecule 1 is an important undertaking in increasing
the potential biological activity of derivatives based on it.
In this work we report the oxidation and dehydrogenation of the starting compound 1 using air,
manganese dioxide, and permanganate anion. Since the free base 1b is of low stability it is usually prepared and
stored as the hydrobromide 1a, basification of which is carried out immediately before the experiment. However,
we have noted that prolonged stirring of a suspension of the salt 1a in a mixture of aqueous base and benzene
with passage of air causes gradual colorizing of the organic layer to dark-blue and then to formation of a black
precipitate. Analysis of the black-blue crystals obtained showed that, in this case, besides the base 1b there is
formed as side product the high melting anhydro base 2 in 8% yield (Table 1) which has a benzoannelated
pseudoazulene structure.
The 1H NMR spectrum (Table 2) shows the absence of the signals for methylene protons at C-1 and C-3
(in the spectrum of the hydrogenated derivative they absorb as a doublet at 3.68 and singlet at 3.41 ppm
respectively). To low field there are found two doublet signals at 7.15 and 8.55 ppm with a spin-spin coupling of
4.9 Hz and one singlet at 7.39 ppm having integrated intensities of 1H each and assigned to protons H-3,4 and
_______
* For Communication 11 see [1].
__________________________________________________________________________________________
Russian Peoples Friendship University, Moscow 117198; e-mail: swelfen@mail.ru. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 724-730, May, 2006. Original article submitted
September 30, 2004.
636
0009-3122/06/4205-0636©2006 Springer Science+Business Media, Inc.

KOH/H2O
KOH/O2
:
N
Me
N
Me
Ph
Ph
N
Me
2A
. HBr
cat., 540°C
Ph
1a
1. MeI
2. OH–
+
N
Me
N
–
H
Ph
Ph
3
2B
H-1 respectively and this points to a conversion of the heterocyclic fragment to a 1,4-dihydropyridine of quinoid
type (2A form). The mass spectrum of compound 2 (Table 3) shows a maximum intensity peak at m/z 257 for the
molecular ion. The ion peak with m/z 242 corresponds to the [M-Me]+ fragment. A pseudoazulene structure for
this compound is confirmed by the mass spectroscopic peaks for double charged ions (with m/2z 127.5 and 121)
which are typical of cyclopenta- and indenopyridine series anhydro bases [6]. The previous formation of the
anhydro base 2 was registered only qualitatively in [7] by recording the electronic absorption spectrum of a
hexane extract obtained after treatment of the dihydroazafluorene salt 1a with sulphur at 200°C and subsequent
basification of the reaction mixture. For additional structural confirmation of the pseudoazulene 2 we have
carried out a thermocatalytic aromatization of compound 1b in the vapor phase (540°C) with the use of the
industrial catalyst K-16 (a mixture of metal oxides) [8]. The 9-phenyl-2-azafluorene (3) was prepared (12%
yield) and its iodomethylate was converted to the pseudoazulene 2 by the action of base. The spectroscopic data
and melting point (a mixed sample did not show a depression of the melting point) for the anhydro base obtained
by a counter synthesis proved identical for both samples. It should be noted that the anhydro base 2 is fully
stable upon storage as crystals in the absence of air and light. However, it is rapidly decolorized by the action of
acid due to the conversion of the zwitterionic 10π-electronic form 2B to the 8π-pyridinium system [6].
TABLE 1. Characteristics of the Compounds Synthesized
Found, %
——————
Calculated, %
Empirical
formula
Compound
mp, °C*
Yield, %
8
С
Н
N
2
С19Н15N
88.34
88.72
5.92
5.84
5.74
5.45
212-215
(with decomp.)
3
4
C18H13N
88.68
88.89
78.67
78.89
5.42
5.35
5.25
5.19
5.90
5.76
4.98
4.84
122-124
12
41
C19H15NO2
132-135
(with decomp.)
5
6
C19H15NO2
C19H15NO2
78.64
78.89
5.24
5.19
4.97
4.84
143-145
(with decomp.)
20
3
78.65
78.89
5.24
5.19
4.97
4.84
156-159
(with decomp.)
7
8
9
C19H19NO2
C19H13NO2
C18H15NO2
77.68
77.82
79.32
79.44
77.71
77.98
6.52
6.48
4.61
4.53
5.50
5.42
4.83
4.78
4.91
4.88
5.12
5.05
5
8.5
6
158-160
52-54
637

638

TABLE 3. Mass Spectra of Compounds 2-6, 8, 9
Com-
pound
m/z (Irel, %)*
2
3
4
5
6
8
9
257 [M]+ (100), 242 [M–Me]+ (48), 241 (29), 240 (22), 213 (15), 129 (31),
128.5 [M]2+ (50), 121 (10), 116 (9)
243 [M]+ (100), 242 [M–H]+ (18), 241 (12), 240 (6), 215 (10), 213 (8), 189 (3),
166 [M–Ph]+ (6), 139 (4)
289 [M]+ (69), 273 (50), 272 [M–OH]+ (96), 260 (17), 244 (18), 212 [M–Ph]+ (100),
202 (19), 196 (20), 77 (38)
289 [M]+ (42), 273 (28), 272 [M–OH]+ (68), 260 (7), 244 (14), 212 [M–Ph]+ (100),
202 (28), 189 (21), 165 (13), 77 (44)
289 [M]+ (59), 273 (18), 272 [M–OH]+ (65), 260 (5), 244 (4), 212 [M–Ph]+ (100),
202 (10), 105 (12), 77 (21)
287 [M]+ (80), 286 (100), 259 [M–CO]+ (25), 231 [M–2CO]+ (33),
202 [M–NMe(CO)2]+ (37), 105 (85), 101 (50), 95 (45), 77 (63), 43 (55)
277 [M]+ (0), 274 (18), 249 [M–CO]+ (23), 248 [M–CHO]+ (100), 243 (50),
234 (21), 220 (31), 219 (27), 218 (23)
_______
* [M] and the 8 strongest peaks are given.
Hence it has been shown for the first time that prolonged contact of a basic solution of the 2,3-dihydro-
1H-2-azafluorene 1b with air gives a stepwise oxidative dehydrogenation to form the indenopyridine series
anhydro base which has the pseudoazulene fragment and is more stable under these conditions.
In this connection it was important to determine the oxidative route for the low stability anhydro base 1b
in the presence of various oxidizing agents. First the reaction of compound 1b with induced bubbling of air
through its neutral solution in chloroform was studied. The reaction was carried out over one week at room
temperature and gave a 41% yield of the hydroxylated lactam 4, the structure of which was proved by mass
spectrometry and also by 1H NMR.
O
O
MnO2
O2
N
N
Me
1b
Me
CHCl3, 20°C
100 h
MeCN, 20°C
48 h
OH
HO
Ph
Ph
KMnO4,
MeCN,
5
4
0°C, 2 h
HO
OH
HO
+
N
4
5
+
N
+
Me
Me
O
Ph
Ph
6
7
The oxidation of the 3-CH2 group to a carbonyl was indicated first by the low field shift of the N-methyl
group proton signal (∆δ = 0.85 ppm when compared with the starting material) and secondly by the singlet
appearance for the signal of the H-4 proton at 6.72 ppm (in the spectrum of the starting material it appears as a
triplet). Proton H-1 gives a broad singlet at 3.32 ppm and the OH group a broad singlet at 3.44 ppm.
639

Another route for the oxidation of compound 1b was revealed in the action of manganese dioxide in
acetonitrile at 20°C. The use of these conditions led to formation of a complex mixture of products from which
the 9-hydroxy-2-methyl-2,3-dihydro-2-azafluoren-3-one (5) could be separated in 20% yield. A further decrease
in the oxidative selectivity was seen upon changing to the use of potassium permanganate. Thus under Wagner
reaction conditions the complex reaction mixture could be separated chromatographically to give low yields
(2-5%) of the three isomeric lactams 4-6 and the product of cis dihydroxylation 7 (the structure of which was
proved from 1H NMR and mass spectra, see Experimental).
It was also interesting to study the oxidation of the hydroindenopyridine 1 taken as the hydrobromide 1a
using permanganate anion. In this case the reaction mixture yielded the imide 8 (8.5% yield) and also the product
of a more fundamental oxidation which was the substituted indanone 9 (yield 6%). The latter can be formed as
the result of a cascade oxidation of the piperidine fragment initially to the 3-oxo derivative and then with cis-
dihydroxylation of the olefine bond to give a lactamdiol which then underwent oxidation fission of the Cβ–Cγ
bond and loss of one carbon atom [9].
O
Ph
Me
KMnO4, Me2CO
N
+
1a
N
Me
20°C, 5 h
CHO
O
O
Ph
9
8
1
In the H NMR spectrum of the indanone 9 the protons of the methyl, methylene, and formyl groups
give double singlet signals with the same 2:1 ratio of integrated intensities in each pair. This confirms the
presence of an amide group in the molecule, existing in CDCl3 solution as the two cisoid and transoid isomeric
forms.
EXPERIMENTAL
1H NMR spectra were recorded on a Bruker WM-400 (400 MHz) spectrometer using CDCl3 solvent and
with TMS as internal standard. Mass spectra were obtained on MAT-112 and MX-1303 instruments with direct
introduction of the sample into the ionization chamber and ionization intensity of 70 eV. IR spectra were taken
on an IR-75 spectrometer for KBr tablets. Silufol UV-254 TLC plates were used for TLC and revealed using
iodine vapor. Column chromatography used Silicagel L 32/63. Compounds 1a and 1b were prepared as reported
in [4]. The physicochemical and spectroscopic characteristics of the compounds synthesized are given in
Tables 1-3.
2-Methyl-9-phenyl-2H-indeno[2,1-c]pyridine (2). A mixture of the hydrobromide 1a (12 g, 35 mmol),
KOH (50%, 30 ml), and benzene (50 ml) was stirred at room temperature for 14 days. The precipitated black-
blue crystals were filtered off and dried to give compound 2 (0.75 g).
9-Phenyl-9H-2-azafluorene (3). A solution of the indenopyridine 2 (5 g, 19 mmol) in benzene (25 ml)
was passed through a contact tube containing the K-16 industrial catalyst (30 g) at 530-550°C for 3 h. The
solvent was removed in vacuo and the residue (3.8 g) was treated with HCl (1:1, 30 ml) and extracted with
benzene (2 × 30 ml) to remove nonnitrogen compounds. The aqueous layer was basified with NaOH to pH 11
and extracted with benzene. The benzene extract was dried with magnesium sulfate, benzene was distilled off,
and the residue (1.1 g) was purified through a silica gel column (1.5 × 40 cm) using ethyl acetate–hexane (1:10)
as eluent to give compound 3 (0.55 g) as white crystals. A solution of the azafluorene 3 (0.2 g, 0.8 mmol) and
CH3I (1 g, 7 mmol) in absolute benzene (15 ml) was refluxed for 1 h. The precipitate that separated was washed
640

with ether and dried to give the azafluorene iodomethylate 3a (0.15 g, 49%). A suspension of the quaternary salt
3a (0.15 g, 0.4 mmol) in water (20 ml) was treated with 40% KOH solution. The black colored precipitate
formed was separated, washed with water, and dried to give the pseudoazulene 2 (0.06 g, 63%) with melting
point and 1H NMR spectra identical to the sample formed as above (mixed samples did not give a depression of
melting point).
1-Hydroxy-2-methyl-3-oxo-9-phenyl-2,3-dihydro-1H-indeno[2,1-c]pyridine (4).
A
solution of
compound 1b (0.16 g, 0.62 mmol) in chloroform was stirred for 7 days with gentle bubbling of air (1 ml / min).
Distillation of solvent then gave an oily, dark-brownish residue. Addition of ether gave the crystalline brownish
substance 4 (0.07 g) with IR spectrum, ν, cm-1: 1670 (C=O), 3400 (OH).
9-Hydroxy-2-methyl-3-oxo-9-phenyl-2,3-dihydro-9H-indeno[2,1-c]pyridine (5).
A
mixture of
compound 1b (0.8 g, 3.09 mmol) and manganese dioxide (0.54 g, 6.18 mmol) in MeCN (10 ml) was stirred at
room temperature for 48 h. The MnO2 was filtered off and washed with acetonitrile (5 ml). Distillation of solvent
gave an oily dark-brownish residue which was separated on a chromatographic column using ethyl acetate as
eluent to give compound 5 as beige crystals (0.12 g). IR spectrum, ν, cm-1: 1620 (C=O), 3250 and 3400 (OH).
Oxidation of Compound 1b Using Potassium Permanganate. Finely ground potassium permanganate
(3.05 g, 19 mmol) was added over 0.5 h to a solution of compound 1b (5 g, 19 mmol) in acetonitrile (150 ml)
with cooling (-5°C). The mixture was stirred for 2 h at 0°C and MnO2 was filtered off and washed with
acetonitrile (20 ml). Vacuum distillation of solvent gave an oily residue which was separated on a silica gel
column. Elution with chloroform gave 4,4a-dihydroxy-2-methyl-9-phenyl-2,3,4,4a-tetrahydro-1H-
indeno[2,1-c]pyridine (7) (0.3 g) as a viscous oil. IR spectrum, ν, cm-1: 3100, 3400 (br). Elution with acetone
then gave compound 4 (0.12 g), compound 5 (0.18 g), and 3-hydroxy-2-methyl-1-oxo-9-phenyl-2,3-dihydro-
1H-indeno[2,1-c]pyridine (6) (0.15 g) as yellow crystals. IR spectrum, ν, cm-1: 1640 (C=O), 3400 (OH).
Oxidation of Hydrobromide 1a with Potassium Permanganate. Potassium permanganate (0.46 g,
2.9 mmol) was added portionwise over 0.5 h to a solution of compound 1a (1 g, 2.9 mmol) in acetone (40 ml)
with cooling to -5°C. The mixture was stirred at room temperature for 5 h and MnO2 was filtered off and washed
with hot acetone (3 × 10 ml). After distillation of solvent the oily residue was separated on a silica gel column.
Elution with benzene gave 2-methyl-1,3-dioxo-9-phenyl-2,3-dihydro-1H-indeno[2,1-c]pyridine (8) as red-
brownish crystals (0.07 g). IR spectrum, ν, cm-1: 1640, 1665, 1690 (C=O). Elution with ether then gave 2-(N-
formyl-N-methyl)aminomethyl-1-oxo-3-phenylindene (9) as yellow-orange crystals (0.05 g). IR spectrum, ν,
cm-1: 1650 (NCHO), 1700 (C=O).
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