Oxidative coupling of 4α,9-diaza-1,2,4α,9α-tetrahydro-fluorenes. 5*. Reaction with o-aminophenol and o-aminothiophenol

Article abstract of DOI:10.1023/A:1015351628312

Oxidative coupling of 4α9-diaza-1,2,4α,9α-tetrahydro-9H-fluorenes with o-aminophenol and o-aminothiophenol in the presence of MnO₂ gives o-hydroxyphenyl- and o-mercaptophenylquinonediimines, cyclization of which gives derivatives of phenoxazine

Full text of DOI:10.1023/A:1015351628312

Chemistry of Heterocyclic Compounds, Vol. 38, No. 2, 2002
OXIDATIVE COUPLING OF
4α,9-DIAZA-1,2,4α,9α-TETRAHYDRO-
FLUORENES. 5*. REACTION WITH
o
o
-AMINOPHENOL AND -AMINOTHIOPHENOL
O. Yu. Slabko, N. V. Ageenko, G. A. Verbitski, and V. A. Kaminski
Oxidative coupling of 4α,9-diaza-1,2,4α,9α-tetrahydro-9H-fluorenes with o-aminophenol and
o-aminothiophenol
in
the
presence
of
MnO2
gives
o-hydroxyphenyl-
and
o-mercaptophenylquinonediimines, cyclization of which gives derivatives of phenoxazine and
phenothiazine.
Keywords: phenoxazines, phenothiazines, quinonediimines, oxidative coupling.
The oxidative coupling of 4α,9-diaza-1,2,4α,9α-tetrahydro-9H-fluorenes with primary amines gives
quinonediimines of the 4α,9-diaza-1,2,4α,9α-tetrahydro-6H-fluorene series [2]. It is of interest to study similar
oxidative coupling with primary amines containing additional O-, S-, and N- nucleophilic centers since, in this
case, there is the possibility of an intramolecular cyclization to give phenoxa(thia)zine structures possessing
potential biological activity [3].
We have examined the reaction of the compound 1a,b derivatives with aromatic o-binucleophiles
(o-aminophenol, o-aminothiophenol, and anthranilic acid) in the presence of MnO2 to give the quinonediimines
2a,b, 3a,b, 4a. Along with compounds 3a,b there were formed in small amounts the disulfides 7a,b and 8a,b but
it was not possible to separate them from compounds 3a,b due to their very similar chromatographic properties.
Treatment of compounds 2a,b with acetic acid (and compounds 3a,b with NaOH in ethanol) caused an
intramolecular cyclization to form the phenoxazine 5b and phenothiazine 6a,b products. The cyclization product
from compound 2a could not be isolated although a reaction did occur. Compound 5b had been prepared before
by the reaction of the corresponding quinonemonoimine of the diazatetrahydrofluorene series with
o-aminophenol but in significantly lower yield [4]. Compound 4 did not cyclize in the conditions indicated
above.
The IR spectra of all of the compounds prepared (Table 1) showed absorption bands for enamine
[C(3)–C(4)] bonds and a quinoid structure typical of the quinoid system of diazatetrahydrofluorene. The spectra of
compounds 2a,b showed a band for a hydrogen bonded OH group and the spectrum of compound 4a an
absorption for the carboxylic C=O group. There are also weak absorption bands for an NH2 group in the spectra
of compounds 3a,b due to the admixture of compounds 7a,b.
_______
* For Communication 4 see [1].
__________________________________________________________________________________________
Far Eastern State University, Vladivostok 690600, Russia; e-mail: slabko@chem.dvgu.ru. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 248-252, February, 2002. Original article submitted
January 20, 2000.
226
0009-3122/02/3802-0226$27.00©2002 Plenum Publishing Corporation

6
NH2
R2
4
5
7
8
XH
R1
3
N
2
NH
MnO2
R
9
1
1a, b
N
N
N
XH
R2
R2
X
R1
R1
N
N
MeCOOH (X = O)
NaOH (X = S)
N
R
R
5b, 6a, b
2a, b, 3a, b, 4a
N
S
S
S
N
NH2
R2
R2
R1
R1
N
N
N
N
R
R
2
8a, b
1-8 a R = H, R1+R2 = (CH2)4; b R = R2 = Ph, R1 = H, 2, 5 X = O; 3, 6 X = S; 4 X = COO
7a, b
1
In their H NMR spectra of the prepared compounds the quinoid proton signals are generally similar to
the analogous data for quinoid compounds previously obtained in this series [2, 4]. The spectra of compounds
2a,b, 4a show doubling of the signals for the 5-H protons. A similar doubling of the signals had been observed
before in the spectra of the N-arylquinonediimine series of diazatetrahydrofluorene [2]. We propose that these
compounds are
a
mixture of the Z- and E-forms;
a
similar picture being observed for
N-aryl(aroyl)quinoneimines [5, 6].
With the aim of comparing the relative stability of the quinonediimine stereomers we have carried out
quantum chemical calculation of the overall energy of the Z- and E-forms of 6-phenylimino-4α,9-diaza-
1,2,4α,9α-tetrahydro-6H-fluorene using the AM1 method with complete geometrical optimization. A full
component analysis showed a high stability for the Z-form, which is explained by the greater value for the
interaction of the N(4a) unshared electron pair with the π-antibonding orbital of the C(4b)–C(5) bond. From the
calculated data, the phenyl substituent is turned at an angle of 56° relative to the plane of the quinoid ring both
for the Z- and the E-forms. This agrees with data for the N-aroylbenzoquinonemonoimines in which the
non-planar conformation is energetically more favored with the aroyl fragment perpendicular to the plane of the
quinoid ring [7]. In the study [8] it was shown that 2,6-di-tert-butyl-N-p-nitrophenylbenzoquinoneimines exist at
room temperature as a mixture of stereomers with an experimentally determined inversion barrier of
75.5 kJ/mole. The calculated barrier for Z,E-inversion in our case is 80 kJ/mole and the enthalpy of formation
-3.7 kJ/mole and this is sufficient for the existence of a mixture of stereomers with the Z-form predominating.
227

TABLE 1. IR and NMR Data for the Synthesized Compounds
Com-
IR spectrum, ν, cm-1
1H NMR spectrum, δ, ppm (J, Hz) (Irel. signal)
pound
С(3)=С(4)
С=N
C=C quin.
Other
2-Н
3-Н
5-Н
8-Н
Аr–Н
Other
—
2
1668
1631
1628
1584,
1522
3400 br. (ОН)
*
—
6.04 s (Z) (5)
6.12 s (E) (1)
*
6.80-7.15 m
2a
2b
3a
2
1648
1669
1580,
3380
(OH)
3449,
3370 weak
(NH2)
3.84 dd (10.0; 3.0) 5.44 d (3.0) 5.21 s (Z) (8)
*
6.80-7.50 m
6.60-7.80 m
—
1520
5.00 s (E) (1)
2
1632,
1625
1587,
1572
*
—
6.08 d (2.0) (3)
6.02 d (2.0) (1)
5.58 d (2.0) (0.7)
5.47 br. s (2)
*
4.28 br. s (NH) (2H)
1648
1660
1629
1630
1588,
1573
3436,
3380 weak
(NH2)
3.82 dd (10.0; 3.0) 5.47 d (3.0) 5.13 d (2.0) (1)
5.36 d (3.0) 4.50 br. s (6)
4.48 br. s (1)
7.25 d (10.0) 6.80-7.45 m
6.36 dd (8.0; 2.0)
—
3b
4a
4.42 br. s (0.7)
2
1574,
1565
3435 br.,
*
—
6.30 s (Z) (5)
*
8.35 d (8.5) (1H)
1700 (COOH)
6.12 s (E) (1)
7.50 t (8.5) (1H)
7.07-7.37 m
1649
1668
1642
1606
1616
1618
1578
1586
1566
—
—
—
—
*
—
—
—
6.18 s
5.27 s
—
—
—
—
—
5b
6a
6b
6.90 s
7.05-7.60 m
7.05-7.50 m
2
7.82 dd (10.0; 3.0)
*
_______
* Overlapping with the signals of the CH2 protons.
*2 Overlapping with the signals of the ArH protons.

TABLE 2. Characteristics for the Synthesized Compounds
Found, %
——————
Com-
pound
Empirical
formula
Calculated, %
mp, °C
Yield, %
C
H
N
C25H27N3O
C33H29N3O
C26H27N3O2
C33H27N3O
C25H25N3S
C33H27N3S
78.34
77.92
7.23
7.01
10.87
10.91
145-146
133-134
68
62
88
72
80
62
2a
2b
4a
5b
6a
6b
82.11
6.26
8.83
81.99
6.00
8.70
75.92
75.55
6.31
6.54
9.87
Did not melt
280-282
10.17
82.41
5.95
8.54
82.33
5.61
8.73
75.65
75.19
6.03
6.27
10.67
10.53
156-158
80.10
5.14
8.41
295-297
79.68
5.43
8.45
The spectra of compounds 3a,b containing an admixture of compounds 7 and 8 showed four signals for
the 5-H proton and the spectrum of compound 3b two signals for the 3-H vinyl proton. We propose that the
signals of the 5-H proton with greatest intensity are assigned to the Z- and E-forms of compounds 3a,b and the
low intensity signals to compounds 7 and 8, each of which exists as a single stereomer.
The mass spectroscopic data for the molecular ions correspond to those calculated for the molecular
masses of the compounds. In the mass spectra of 3a,b (see Experimental), along with strong molecular ion peaks
corresponding to the given compounds, there are observed peaks which agree with compounds 7 and 8. Using
HPLC it was shown that a mixture of three compounds exists with very closely similar retention times.
EXPERIMENTAL
IR spectra were obtained on a Spectrum-1000 BX-11 instrument for KBr tablets and CH2Cl2 solutions
and NMR spectra on a Bruker WM-250 (250 MHz) instrument using CDCl3 or DMSO-d6 solvent and TMS
internal standard. Chromatograms and mass spectra were taken using liquid chromatography with an
HP LC-MSD 1100, API-ES-positive ionization-electrospray, and fragmentor voltage varying in the range
5-250 V. Monitoring of the reaction course and the purity of the obtained products was carried out on Silufol
and Sorbfil plates.
Characteristics for the synthesized compounds are given in Table 2.
Oxidative Coupling of 4α,9-Diaza-1,2,4α,9α-tetrahydro-9H-fluorenes 1a,b with Binucleophiles.
MnO2 (10-12 mmol) was added with stirring to a solution of compound 1a or 1b (1 mmol) and the reagent
(o-aminophenol, o-aminothiophenol, anthranilic acid, 1.1 mmol) in acetone (50 ml) and stirring was continued
at room temperature until the TLC spot for starting material had disappeared. The MnO2 was filtered off,
washed with acetone. The filtrate was diluted threefold with water and Na2CO3 (compounds 2a,b, 3b) or NaCl
(compound 3a) was added, and the precipitate was filtered off, dried, and chromatographed on an Al2O3 column.
In the case of compound 3a it was eluted with a mixture of petroleum ether and acetone, for compound 4 a
mixture of chloroform and ethanol, and in the remaining examples a mixture of petroleum ether and ethyl
acetate. Mass spectrum, m/z, for the mixture 3a, 7a, 8a: 402 (3a), 525 (7a), 801 (8a), [M+]; for the mixture 3b,
7b, 8b: 500 (3b), 623 (7b), 997 (8b), [M+].
Cyclization of Compounds 2,3. A. A solution of the quinonediimine 2a (0.3 mmol) in acetic acid
(5 ml) was held at room temperature for 3 days, water (15 ml) was added, and the product was neutralized with
Na2CO3 solution, extracted with ether, the extract evaporated at room temperature, and the residue was
triturated with hexane. Pure compound 5b was obtained and it was identical to that obtained previously [4]
chromatographically and in its IR spectrum.
229

B. A solution of compound 3a,b (3 mmol) (containing an admixture of compounds 7 and 8) in 5 ml of a
5% solution of NaOH in ethanol was held for 1 day at room temperature (in the case of compound 3a) or
refluxed for 2 h (for compound 3b), diluted with water (15 ml), and neutralized with an aqueous solution of
acetic acid (10%). The precipitate formed was filtered off, dried, and chromatographed on Al2O3 using
petroleum ether–ethyl acetate as eluent.
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