Synthesis of spirocyclic derivatives of azaphenanthrene containing a hydroxy-m-terphenyl fragment

Article abstract of DOI:10.1134/S1070428010090101

The reaction of 5′-[(2-naphthylamino)methyl]-2′-hydroxy[1, 1′:3′,1″]terphenyl with paraformaldehyde and 1,3-cyclohexanedione, methyl 2,2-dimethyl-4,6-dioxocyclohexanecarboxylate, dimedone, furan-2,4(3H,5H)-dione, indan-1,3-dione led to the formation of spiro derivatives of azaphenanthrene.

Full text of DOI:10.1134/S1070428010090101

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 9, pp. 1323−1326. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © A.L. Kurlovich, V.A. Tarasevich, N.G. Kozlov, 2010, published in Zhurnal Organicheskoi Khimii, 2010, Vol. 46, No. 9, pp. 1324−1327.
Synthesis of Spirocyclic Derivatives of Azaphenanthrene
Containing a Hydroxy-m-Terphenyl Fragment
A. L. Kurlovich a, V. A. Tarasevich a, and N. G. Kozlovb
aInstitute of New Materials Chemistry, National Academy of Sciences of Belarus, Minsk, 220141 Belarus
e-mail: kurlovich_andrey@mail.ru
bInstitute of Physical Organic Chemistry, National Academy of Sciences of Belarus, Minsk, Belarus
Received October 28, 2009
Abstract—The reaction of 5'-[(2-naphthylamino)methyl]-2'-hydroxy[1,1':3',1'']terphenyl with paraformaldehyde
and 1,3-cyclohexanedione, methyl 2,2-dimethyl-4,6-dioxocyclohexanecarboxylate, dimedone, furan-2,4(3H,5H)-
dione, indan-1,3-dione led to the formation of spiro derivatives of azaphenanthrene.
DOI: 10.1134/S1070428010090101
The derivatives of phenanthrene and azaphenanthrene
possess a wide range of biological activity and are used as
pharmaceuticals. Some publications [1–3] mention the anti-
oxidant properties of phenanthrene derivatives. Besides the
phenanthridine ring underlies the structure of certain natural
alkaloids and steroids [4].
ylmethyl)-1,2,3,4-tetrahydro-1-azaphenanthrene}-
3,1'-(4',4'-dimethyl-2',6'-dioxocyclohexane)] (Vb),
spiro-[{1-(2'-hydroxy[1,1':3',1'']terphenyl-5'-ylmethyl)-
1,2,3,4-tetrahydro-1-azaphenanthrene}-3,1'-(4',4'-
dimethyl-3'-methoxycarbonyl-2',6'-dioxocyclohexane)]
(Vc) and spiro[{1-(2'-hydroxy[1,1':3',1'']terphenyl-5'-
ylmethyl)-1,2,3,4-tetrahydro-1-azaphenanthrene}-3,3'-
{2',4'(1'H,5'H)-dioxofuran}] (Vd) (Scheme 2).
The synthesis of spiro derivatives of quinoline was
formerly performed by a three-component condensation
of aromatic amines with dimedone and formaldehyde [5].
Here we report on the first event of a three-component
condensation involving a secondary amine containing
a hydroxy-m-terphenyl fragment. The m-terphenyl derti-
vatives are widely used as polymer stabilizers, dyes, and
also drugs and insecticides [6–8]. 2'-Hydroxy[1,1':3',1'']
terphenyl-5'-carbaldehyde (I) we obtained by procedure
[9] in 95% yield. The reductive amination of carbaldehyde
I with 2-naphthylamine (II) gave 5'-[(2-naphthylamino)
methyl]-2'-hydroxy[1,1':3',1'']terphenyl (III) (Scheme 1).
This reaction may proceed hypothetically via two
mechanisms.According to the first pathway the formation
of the spiro derivatives of the azaphenanthroline proceeds
through the initial reaction of diketones IVa–IVd with
formaldehyde giving the α,β-unsaturated diketone A
where the double bond is activated owing to the conju-
gation with two contiguous carbonyl groups. Diketone
Scheme 1.
Compound III was brought into reaction with
formaldehyde and a series of 1,3-diketones: 1,3-cy-
clohexanedione (IVa), 5,5-dimethyl-1,3-cyclohexane-
dione (dimedone) (IVb), methyl 2,2-dimethyl-4,6-
dioxocyclohexanecarboxylate (IVc), furan-2,4(3H,5H)-
dione (IVd). The reaction of amine III with diones
IVa–IVd was carried out by boiling in ethanol. As
a result we obtained in 85–96% yield spiro[{1-(2'-hy-
droxy-[1,1':3',1'']terphenyl-5'-ylmethyl)-1,2,3,4-tetrahy-
dro-1-azaphenanthrene}-3,1'-(2',6'-dioxocyclohexane)]
(Va), spiro[{1-(2'-hydroxy[1,1':3',1'']terphenyl-5'-
1323

KURLOVICH et al.
1324
Scheme 2.
R1 = R2 = H (a); R1 = Me, R2 = H (b), COOCH3 (c).
A further reacts with the molecule of amine III forming
aminodiketone B.
regiospecifically and with a high degree of stereoselec-
tivity: an exclusive formation is observed of spiro[{1-
(2'-hydroxy[1,1':3',1"]terphenyl-5'-yl-methyl)-1,2,3,4-
tetrahydro-1-azaphenanthrene}-3,1'-(4',4'-dimethyl-3'-
methoxycarbonyl-2',6'-dioxo-cyclohexane)] (Vc).
In keeping with the second mechanism the formation
of aminodiketone B occurs by the reaction of 1,3-dik-
etone with the previously formed hydroxylamine C.
Aminodiketone B rearranges further into intermediate D
analogously to the transformations during the Hofmann–
Martius rearrangement [10]. The subsequent intramo-
lecular Mannich reaction results in compounds Va–Vd.
The reaction of formaldehyde and amine III with
indandione VI (Scheme 3) was performed by boil-
ing in 1-butanol. As a result we obtained in 91% yield
spiro[{1-(2'-hydroxy[1,1':3',1"]terphenyl-5'-yl-methyl)-
1,2,3,4-tetrahydro-1-azaphenanthrene}-3,2'-(1H-indan-
1',3'-dione)] (VII).
The involvement into the cascade cyclization of the
unsymmetrical 1,3-diketone, 4-methoxycarbonyldimedone
(IVc) (methyl 2,2-dimethyl-4,6-dioxocyclohexanecarbox-
ylate), leads to the formation of compound Vc as a mixture
of stereoisomers. Under the relatively mild conditions (at
boiling the components in ethanol) the reaction proceeds
The composition and structure of obtained compounds
III, Va–Vd, and VII were confirmed by elemental analy-
1
sis, IR and H NMR spectra. In the spectrum of amine
III the characteristic absorption band of the stretching
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010

SYNTHESIS OF SPIROCYCLIC DERIVATIVES OF AZAPHENANTHRENE
1325
vibrations of the secondary amino group appeared as
Scheme 3.
a narrow strong band at 3365 cm–1. The characteristic
absorption bands for compounds Va–Vd and VII are
those of the stretching vibrations of the C=O groups at
1695 and 1725 cm–1.
O
O
H
H
III
O
In the 1H NMR spectra of azaphenanthrenes Va–Vd,
and VII a singlet and a doublet were observed at δ 3.40
and 3.82 ppm corresponding to the protons attached to
atoms C4 and C2 of the azaphenanthrene fragment. The
protons of the group NCH2Ar gave rise to a doublet at
δ 4.64 ppm. In the spectrum of spiro derivative Va the
protons of the methylene groups at the carbon atoms
C3' and C5' included into the 1,3-cyclohexane fragment
are observed as two multiplets at δ 2.40 and 2.75 ppm
respectively. The proton of the methylene group of the
1,3-cyclohexane ring linked to the C4' atom appears as
a multiplet at δ 1.85–1.95 ppm. The signal of protons
H3' and H5' is located upfield with respect to that of the
H4' proton due to the influence of the adjacent carbonyl
groups. In the spectrum of azaphenanthrene spiro deriva-
tive Vb the peaks of the methyl groups of the dimedone
fragment are observed at δ 1.05 and 1.20 ppm. In the
1H NMR spectrum of compound Vc the methoxy group
protons resonate at δ 3.30 ppm. The aromatic protons of
the azaphenanthrene fragment give rise to a multiplet
at δ 7.2 ppm and doublets at δ 7.65 and 7.90 ppm. The
proton signals of the aromatic rings of the hydroxy-m-
terphenyl fragment give triplets at δ 7.35, 7.40–7.45 ppm
and a doublet at δ 7.60 ppm.
VI
Ph
AlkOH
O
O
OH
Ph
N
VII
less crystals, mp 168–169°C. IR spectrum, ν, cm–1: 3480
1
(O–H), 2850 (C–H), 1695 (C=O). H NMR spectrum
(CDCl3), δ, ppm: 7.46 d (4Harom, J 7.5 Hz), 7.50–7.55 t
(6Harom, J 7.5 Hz), 7.60 d (4Harom, J 7.5 Hz), 7.84 s
(2Harom), 9.94 s (1H, CH). Found, %: C 83.17; H 5.17.
C19H14O2. Calculated, %: C 83.19; H 5.14.
5 ' - [ ( 2 - N a p h t h y l a m i n o ) m e t h y l ] - 2 ' - h y -
droxy-[1,1':3',1"]terphenyl (III). To a solution of 1.43 g
(0.01 mol) of amine II in 20 ml of ethanol was added
a solution of 2.74 g (0.01 mol) of aldehyde I in 10 ml
of ethanol. The reaction mixture was boiled for 1 h. On
cooling 1.52 g (0.04 mol) of NaBH4 was added, and the
mixture was left overnight. The mixture obtained was
treated with water. The separated precipitate was filtered
off and recrystallized from ethanol. Yield 3.3 g (82%),
colorless crystals, mp 128°C. IR spectrum, ν, cm–1:
3480 (O–H), 3365 (N–H). H NMR spectrum (DMSO-
d6), δ, ppm: 4.50 C (2H, CH2), 6.50–6.60 m (2Harom),
7.25–7.55 m (10Harom; 1H, NH), 7.39–7.80 m (7Harom
1H, OH). Found, %: C 86.80; H 5.71; N 3.50. C29H23NO.
Calculated, %: C 86.75; H 5.77; N 3.49.
EXPERIMENTAL
1
IR spectra were recorded on a spectrophotometer Spe-
cord 75IR from pellets with KBr. 1H NMR spectra were
registered on spectrometers Tesla BS-567A (operating
frequency 100 MHz) and Bruker Avance-500 (operating
frequency 500 MHz), internal reference TMS. The melt-
ing points were measured on a Koeffler heating block.
;
Spiro[{1-(2'-hydroxy[1,1':3',1"]terphenyl-5'-
ylmethyl)-1,2,3,4-tetrahydro-1-azaphenanthrene}-
3,1'-(2',6'-dioxocyclohexane)] (Va). To a solution of
2.68 g (0.005 mol) of amine III in 30 ml of ethanol was
added 0.6 g (0.02 mol) of paraformaldehyde. The mixture
was boiled to complete dissolution of the precipitate, then
0.56 g (0.005 mol) of 1,3-cyclohexanedione was added,
and the boiling was continued for 6–8 h. On cooling
the reaction mixture the separated crystalline precipitate
was filtered off, washed with ethanol, and recrystallized
from benzene. Yield 5.15 g (96%), colorless crystals, mp
2'-Hydroxy[1,1':3',1"]terphenyl-5'-carbaldehyde
(I) was obtained from 2,6-diphenylbenzaldehyde and
hexamethylenetetramine in the presence of CF3CO2H
by procedure [9]. A mixture of 12.5 g (0.051 mol) of
2'-hydroxy[1,1':3',1"]terphenyl, 14.2 g (0.101 mol) of
urotropin, and 50 ml of CF3CO2H was boiled at stirring
for 12 h. On distilling off the solvent 150 ml of 3 N HCl
was added, and the stirring at 80°C was continued for 3 h.
The precipitate was filtered off, washed with water, and
recrystallized from ethanol. Yield 13.2 g (95%), color-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 9 2010

KURLOVICH et al.
1326
227°C. IR spectrum, ν, cm–1: 3445 (O–H), 1725 (C=O),
1695 (C=O). H NMR spectrum (CD3COCD3), δ, ppm:
1.85–1.95 m (2H, CH2), 2.40 m (2H, CH2), 2.75 m (2H,
CH2), 3.40 C (2H, CH2), 3.82 d (2H, NCH2, J 13 Hz),
δ, ppm: 3.40 s (2H, CH2), 3.82 d (2H, NCH2, J 13 Hz),
4.64 d (2H, NCH2Ar, J 11 Hz), 5.20 m (2H, CH2),
7.20–7.25 m (4Harom; 1H, OH), 7.35 t (3Harom, J 7.5 Hz),
7.40–7.45 t (5Harom, J 7.6 Hz), 7.60 d (4Harom, J 7.5 Hz),
7.65 d (1Harom, J 7.5 Hz), 7.90 d (1Harom, J 7.6 Hz). Found,
%: C 79.96; H 5.14; N 2.62. C35H27NO4. Calculated, %:
C 79.98; H 5.18; N 2.66.
1
4.64 d (2H, NCH2Ar, J 11 Hz), 7.20–7.25 m (4Harom
;
1H, OH), 7.35 t (3Harom, J 7.5 Hz), 7.40–7.45 t (5Harom
J 7.6 Hz), 7.60 d (4Harom, J 7.5 Hz), 7.65 d (1Harom
,
,
J 7.5 Hz), 7.90 d (1Harom, J 7.6 Hz). Found, %: C 82.59;
H 5.84; N 2.62. C37H31NO3. Calculated, %: C 82.66;
H 5.81; N 2.61.
Spiro[{1-(2'-hydroxy[1,1':3',1'']terphenyl-5'-
ylmethyl)-1,2,3,4-tetrahydro-1-azaphenanthrene}-
3,2'-(H-indan-1',3'-dione)] (VII). To a solution of 1.37 g
(0.005 mol) of paraformaldehyde in 20 ml of 1-butanol
was added a solution of 2.68 g (0.005 mol) of amine III
in 10 ml of 1-butanol and a solution of 0.73 g (0.005 mol)
of indandione VI in 10 ml of 1-butanol. The reaction
mixture was boiled for 4 h. On cooling the reaction
mixture the separated crystalline precipitate was filtered
off and three times washed with hot acetone. Yield 5.2 g
(91%), colorless crystals, mp 227°C. IR spectrum, ν,
cm–1: 3450 (O–H), 1724 (C=O), 1695 (C=O). 1H NMR
spectrum (DMSO-d6), δ, ppm: 3.40 s (2H, CH2), 3.80 d
(2H, NCH2, J 13 Hz), 4.60 d (2H, NCH2CHAr, J 11 Hz),
7.20–7.25 m (6Harom; 1H, OH), 7.35 t (3Harom, J 7.5 Hz),
7.40–7.45 t (5Harom, J 7.6 Hz), 7.60 d (4Harom, J 7.5 Hz),
7.65 d (1Harom, J 7.5 Hz), 7.90 d (1Harom, J 7.6 Hz). Found,
%: C 84.06; H 5.18; N 2.42. C40H29NO3. Calculated, %:
C 84.04; H 5.11; N 2.45.
Compounds Vb–Vd were similarly prepared.
Spiro[{1-(2'-hydroxy[1,1':3',1"]terphenyl-5'-
ylmethyl)-1,2,3,4-tetrahydro-1-azaphenanthrene}-
3,1'-(4',4'-dimethyl-2',6'-dioxocyclohexane)] (Vb) was
obtained from amine III and dimedone (IVb). Yield 5.2 g
(92%), colorless crystals, mp 229°C. IR spectrum, ν,
cm–1: 3445 (O–H), 1724 (C=O), 1695 (C=O). 1H NMR
spectrum (CD3COCD3), δ, ppm: 1.05 s (3H, CH3), 1.20 s
(3H, CH3), 2.50 m (2H, CH2), 3.25 m (2H, CH2), 3.40 s
(2H, CH2), 3.80 d (2H, NCH2, J 13 Hz), 4.60 d (2H,
NCH2Ar, J 11 Hz), 7.20–7.25 m (4Harom, 1H, OH), 7.35 t
(3Harom, J 7.5 Hz), 7.40–7.45 t (5Harom, J 7.6 Hz), 7.60
d (4Harom, J 7.5 Hz), 7.65 d (1Harom, J 7.5 Hz), 7.90 d
(1Harom, J 7.6 Hz). Found, %: C 82.75; H 6.26; N 2.46.
C39H35NO3. Calculated, %: C 82.80; H 6.24; N 2.48.
Spiro[{1-(2'-hydroxy[1,1':3',1'']terphenyl-5'-
ylmethyl)-1,2,3,4-tetrahydro-1-azaphenanthrene}-
3,1'-(4',4'-dimethyl-3'-methoxycarbonyl-2',6'-dioxo-
cyclohexane)] (Vc) was obtained from amine III and
methyl 2,2-dimethyl-4,6-dioxocyclohexanecarboxylate
(IVc). Yield 5.3 g (85%), Grey crystals, mp 219°C.
IR spectrum, ν, cm–1: 3450 (O–H), 1724 (C=O), 1705
(C=O), 1695 (C=O), 1233 (C–O–C). 1H NMR spectrum
(CDCl3), δ, ppm: 0.90 s (3H, CH3), 0.98 s (3H, CH3),
1.05 s (3H, CH3), 1.20 s (3H, CH3), 2.40 s (1H, CH2),
2.45 s (1H, CH2), 3.20 m (4H, CH2), 3/30 s (3H, CH3),
3,35 s (3H, CH3), 3.45 m (4H, CH2), 3.85 m (4H, NCH2),
4.64 m (4H, NCH2Ar), 7.20–7.25 m (8Harom; 1H, OH),
7.35 m (6Harom), 7.40–7.45 m (10Harom), 7.60 m (8Harom),
7.65 m (2Harom), 7.90 m (2Harom). Found, %: C 78.91;
H 5.94; N 2.22. C41H37NO5. Calculated, %: C 78.95;
H 5.98; N 2.25.
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