An efficient de novo synthesis of partially reduced phenanthrenes through C-C insertion

Article abstract of DOI:10.1021/jo0711079

(Chemical Equation Presented) An efficient and novel approach to the synthesis of highly congested 3-alkyl-, 4-alkyl-, 3-aryl-, 3,4-dialkyl-, 4-alkyl-3-aryl-, and 3,4-diaryl-9,10-dihydro-1-sec-aminophenanthrene-2- carbonitriles has been delineated through

Full text of DOI:10.1021/jo0711079

cer,4 antimycotic,5,6 anti-HIV,7 and emetic properties.8 9,10-
Dihydrophenanthrenes with a pendant carboxyl group at position
2 are reported9 as an inhibitor of 5R-reductase and useful in
the treatment of pharmacological disorders associated with
elevated levels of dihydrotestosterone. Numerous methods are
being reported for the synthesis of phenanthrenes2 and
dihydrophenanthrenes10-16 through ring annulation17 and inter-
molecular18 and intramolecular19 cyclization. A majority of the
procedures have certain limitations of accessibility of the
precursors, require multiple steps, have harsh reaction condi-
tions, are incompatible with the presence of a functional group,
have relatively low overall yield, and lack well-defined regio-
control elements. 2,2′-Disubstituted biphenyls have been used
as precursors for the preparation of phenanthrene by intramo-
lecular condensation,18 cycloisomerization,20 metal-catalyzed
rearrangement of alkene-alkynes,21 and photocyclization22
depending upon the functionality present on the biphenyl moiety.
Palladium-catalyzed cyclization of arynes with alkynes is also
an alternative route21 for the synthesis of phenanthrene. Recently,
9,10-disubstituted phenanthrenes have been prepared23 from
palladium-catalyzed reaction of o-substituted aryl iodides and
diphenyl or alkylphenylacetylenes. These are also prepared
through the ring transformation of methyl 6-aryl-4-methylsul-
fanyl-2H-pyran-2-one-3-carboxylates by 1-tetralone in 59-67%
yields.24 The diverse pharmacological activities and limitations
of convenient and efficient procedures prompted us to develop
a concise, straightforward, and economical route to the synthesis
of this class of compounds without use of any catalyst.
An Efficient De Novo Synthesis of Partially
Reduced Phenanthrenes through C-C Insertion†
Ramendra Pratap and Vishnu Ji Ram*
Medicinal and Process Chemistry DiVision, Central Drug
Research Institute, Lucknow 226001, India
Vjiram@yahoo.com
ReceiVed May 25, 2007
An efficient and novel approach to the synthesis of highly
congested 3-alkyl-, 4-alkyl-, 3-aryl-, 3,4-dialkyl-, 4-alkyl-
3-aryl-, and 3,4-diaryl-9,10-dihydro-1-sec-aminophenanthrene-
2-carbonitriles has been delineated through the base-catalyzed
ring transformation of 5,6-dihydro-2-oxo-4-sec-amino-2H-
benzo[h]chromene-3-carbonitrile by carbanion derived in situ
from various ketones in moderate to good yields. 9,10-
Dihydrophenanthrenes with and without substituent in the
bay region are efficiently and regioselectively synthesized
by using propanal and acetyltrimethylsilane as a source of
carbanion. Even the synthesis of bisphenanthrenes has been
achieved by the ring transformation of 5,6-dihydro-2-oxo-
4-sec-amino-2H-benzo[h]chromene-3-carbonitrile by 2-acet-
ylphenanthrene in moderate yield. Highly substituted 3-amino-
1-sec-amino-5,6-dihydrophenanthrene-2,4-dicarbonitriles have
also been prepared from the reaction of 2-oxobenzo[h]-
chromene and malononitrile.
(3) Huffmann, C. W.; Traxler, J. T.; Krbechek, L.; Riter, R. R.; Wagner,
R. G. J. Med. Chem. 1971, 14, 90.
(4) Wilson, S.; Ruenitz, P. C. J. Pharm. Sci. 1992, 82, 571.
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(6) Kelly, T. R.; Li, Q.; Bhushan, V. Tetrahedron Lett. 1990, 31, 161.
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O.; Oki, T. J. Antibiot. 1988, 41, 1708. (b) Hoshino, H.; Seki, J.-I.; Takeuchi,
T. J. Antibiot. 1989, 42, 344.
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S.; Haudin, P. A. J. Am. Chem. Soc. 1977, 99, 618. (b) Boger, D. L.;
Mullican, M. D. J. Org. Chem. 1984, 49, 4045.
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(b) Ram, V. J.; Goel, A. J. Chem. Res., Synop. 1997, 460.
(13) Erdman, H.; Ronlan, A. Acta Chem. Scand. 1969, 23, 249.
(14) Gilchrist, T. L.; Summersell, R. J. J. Chem. Soc., Perkin Trans. 1
1988, 2595.
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Chem. 1975, 28, 65.
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Motti, E.; Baratta, S. Org. Lett. 2001, 3, 3611.
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Radhakrishnan, K. V.; Yoshikawa, E.; Yamamoto, Y. Tetrahedron Lett.
1999, 40, 7533. (c) Paredes, E.; Biolatto, B.; Kneetmann, M.; Mancini, P.
Tetrahedron Lett. 2002, 43, 4601.
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Lett. 2002, 43, 3185. (b) Almeida, J. F.; Castedo, L.; Fernandez, D.; Neo,
A. G.; Romero, V.; Tojo, G. Org. Lett. 2003, 5, 4939.
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(21) Katz, T. J.; Sivavec, T. M. J. Am. Chem. Soc. 1985, 107, 737.
(22) Pena, D.; Pe´rez, D.; Guitian, E.; Castedo, L. J. Am. Chem. Soc.
1999, 121, 5827.
Phenanthrenes represent an important class of compounds
abundantly distributed in nature1 as a substructure that are useful
precursors for natural product synthesis2 and exhibit a broad
spectrum of biological activities such as antimalarial,3 antican-
† CDRI Communication No. 7174.
(1) (a) Dawidar, A. M.; Abou-Elzahab, M. M.; El-Fedawy, M. G.;
Raghib, H. M. J. Saudi Chem. Soc. 2004, 8, 275. (b) Majumder, P. L.; Pal,
S. Phytochemistry 1992, 31, 3225. (c) Della Greca, M.; Fiorentino, A.;
Mangoni, L.; Molinaro, A.; Monaco, P.; Previtera, L. Tetrahedron Lett.
1992, 33, 5257. (d) Aknin, M.; Samb, A.; Mirailles, J.; Costantino, V.;
Fattorusso, E.; Mangoni, A. Tetrahedron Lett. 1992, 33, 555. (e) Biswas,
M.; Som, U. K.; Ghosh, P. K.; Dutta, C. P.; Banerji, A. Tetrahedron 1988,
44, 4871. (f) Matsuo, A.; Nozaki, H.; Suzuki, M.; Nakayama, M. J. Chem.
Res., Synop. 1985, 174. (g) Sargent, M. V.; Stanojevic, E. J. Chem. Soc.,
Perkin Trans. 1 1984, 1972. (h) Bhandari, S. R.; Kapadi, A. H. Phytochem-
istry 1983, 22, 747. (i) Majumder, P. L.; Sarkar, A. K. Indian J. Chem.,
Sect. B 1982, 21, 829. (j) Chapatwala, K. D.; De la Cruz, A. A.; Miles, H.
Life Sci. 1981, 29, 1997.
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(24) (a) Ram, V. J.; Goel, A. J. Chem. Res., Synop. 1997, 460. (b) Ram,
V. J.; Nath, M.; Srivastava, P.; Sharkhel, S.; Maulik, P. R. J. Chem. Soc.,
Perkin Trans. 1 2000, 3719.
(2) Floyd, A. J.; Dyke, S. F.; Ward, S. E. Chem. ReV. 1976, 76, 509.
10.1021/jo0711079 CCC: $37.00 © 2007 American Chemical Society
Published on Web 08/18/2007
7402
J. Org. Chem. 2007, 72, 7402-7405

SCHEME 1. Regioselectivity of Benzo[h]chromene (II) and Synthetic Limitations of 2H-Pyran-2-one-3-carboxylate (IV) for the
Synthesis of Congested Phenanthrenes
SCHEME 2. Synthesis and Yields of 5,6-Dihydro-2-oxo-4-sec-amino-2H-benzo[h]chromene-3-carbonitriles26 (4)
SCHEME 3. Synthesis of 9,10-Dihydro-3-alkyl-,
3,4-Dialkyl-, 3-Aryl-4-alkyl-, 3-Aryl-, and
construction of highly congested 9,10-dihydrophenanthrenes,
3,4-Diarylphenanthrenes (6)
In search of a novel and efficient synthetic route for the
5,6-dihydro-2-oxo-4-sec-amino-2H-benzo[h]chromene-3-carbo-
nitrile (II) has been considered as a most appropriate precursor
to overcome the synthetic limitations of methyl 6-aryl-4-
methylsulfanyl-2H-pyran-2-one-3-carboxylate (IV), which, used
earlier as synthon,24 lacks regioselectivity as it gives a mixture
of two products VI and VII on reaction with 1-tetralone. In
addition, it has no option to introduce a group other than ester
in the bay region as well as amino functionality at the C-1 and
presence of an electron-withdrawing CN substituent at the C-3
C-3 positions of the phenanthrene ring (Scheme 1).
position of the chromene ring.
Various ketones such as acetone, ethyl methyl ketone, aryl
methyl ketone, propiophenone, deoxyanisoin, 3-acetylphenan-
threne, propanal, acetyltrimethylsilane, and malononitrile have
been used as source of carbanions.
The synthetic potential of 5,6-dihydro-2-oxo-4-sec-amino-
2H-benzo[h]chromene-3-carbonitriles (4) is enormous and
obtained by the base-catalyzed condensation-cyclization of
1-tetralone (2) and methyl 2-cyano-3,3-dimethylthioacrylate25
(1) followed by amination with sec-amine in refluxing ethanol
in high yields26 (Scheme 2). There is no limitation in using the
secondary amine for the amination reaction. We have used
piperidine, substituted piperidines, and morpholine as secondary
amines in the present study. These secondary amines did not
influence the course of reaction (Scheme 2).
Thus, an equimolar mixture of 5,6-dihydro-2-oxo-4-sec-
amino-2H-benzo[h]chromene-3-carbonitrile (4) and ketone in
the presence of powdered KOH in dry DMF was stirred for
45-90 min and thereafter poured onto crushed ice with vigorous
stirring and neutralized with 10% HCl. The precipitate obtained
was filtered, dried, and finally purified on silica gel or a neutral
alumina column (Scheme 3). All the alkyl-substituted phenan-
threnes (6a-d) prepared by using dialkyl ketones as a source
of carbanion are listed in Table 1.
The scope of the reaction was further explored using different
kind of ketones such as propiophenone and deoxyanisoin as a
source of carbanions for the ring transformation reaction of
chromene 4. Thus, a reaction of 4 with propiophenone and
As evident from the topography of the 5,6-dihydro-2-oxo-
4-sec-amino-2H-benzo[h]chromene-3-carbonitrile (4), the posi-
tions C-2, C-4, and C-10b are electrophilic in nature. Among
these three centers, the latter is highly electrophilic and prone
to nucleophilic attack because of extended conjugation and the
(25) Gompper, R.; Topfl, W. Chem. Ber. 1962, 95, 2861.
(26) Pratap, R.; Ram, V. J. Tetrahedron Lett. 2007, 48, 2755.
J. Org. Chem, Vol. 72, No. 19, 2007 7403

TABLE 1. Yields of Various 9,10-Dihydro-3-arylphenanthrenes (6)
SCHEME 4. Mechanism Involved in the Synthesis of
1-sec-Amino-9,10-dihydrophenanthrene-2-carbonitriles (8)
and 1-sec-Amino-9,10-dihydrophenanthrene-4-
methyl-2-carbonitriles (9)
yields
6
R
Z
(%)
a
CH3
CH3
CH3
CH3
C6H5
C6H5
4-CH3O-C6H4
4-CH3O-C6H4
C6H5
4-Cl-C6H4
4-Br-C6H4
4-CH3-C6H4
4-CH3O-C6H4
3,4-(Cl)2-C6H3
2-thienyl
1-pyrenyl
C6H5
piperidin-1-yl
4-methylpiperidin-1-yl
piperidin-1-yl
4-methylpiperidin-1-yl CH3
piperidin-1-yl CH3
4-methylpiperidin-1-yl CH3
H
H
CH3
86
78
81
81
88
79
91
89
87
91
89
91
81
88
93
76
84
73
51
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
s
piperidin-1-yl
4-methylpiperidin-1-yl 4-CH3O-C6H4
4-CH3O-C6H4
piperidin-1-yl
piperidin-1-yl
piperidin-1-yl
piperidin-1-yl
piperidin-1-yl
piperidin-1-yl
piperidin-1-yl
piperidin-1-yl
morpholin-4-yl
4-methylpiperidin-1-yl
H
H
H
H
H
H
H
H
H
H
H
C6H5
phenanthren-2-yl 4-methylpiperidin-1-yl
deoxyanisoin separately under analogous reaction conditions
produced 3-aryl-4-methyl-1-sec-amino-5,6-dihydrophenanthrenes
(6e,f) and 3,4-di(4-anisyl)-1-sec-amino-5,6-dihydrophenan-
threnes (6g,h) in very good yields. In these reactions, carbanion
generated at either methyl or methylene carbon attacks at C-10b
of the chromene 4 with ring closure and concomitant elimination
of carbon dioxide and water.
The reaction was further generalized for regioselective
introduction of an aryl/heteroaryl group at position 3 of the 9,-
10-dihydrophenanthrenes (6i-r) and bisphenanthrene (6s) with
2,3′ linkage by stirring an equimolar mixture of 4, aryl methyl
ketone, or 2-acetylphenanthrene and powdered KOH in DMF
for 2 to 3 h. Usual workup and column chromatographic
purification produced 3-aryl/heteroarylphenanthrenes (6i-s).
However, use of 1-tetralone as a nucleophile under analogous
conditions produced (7,8-dihydro-5-oxabenzo[c]chrysene-6-
ylidene)acetonitrile27 following a different course of reaction.
The formation of 6i-s is initiated through attack of carbanion
at C-10b of 4 with ring closure followed by elimination of
carbon dioxide and water.
The synthetic potential of benzo[h]chromene was explored
further for the synthesis with or without alkyl substituent in
the bay region following a different strategy. Thus, for the
synthesis of phenanthrene without any substituent in the bay
region, aqueous acetaldehyde was used as a source of carbanion,
but the strategy failed to produce the target compound under
analogous conditions possibly because of the water content of
acetaldehyde. To overcome this difficulty, acetyltrimethylsilane
was used as an acetaldehyde equivalent for the ring transforma-
tion. This strategy worked very well, and ultimately we
succeeded in isolating 1-sec-aminophenanthrene-2-carbonitrile
in good yield. Thus, a mixture of 4, acetyltrimethylsilane (7b),
and powdered KOH in DMF was stirred for 2 to 2.5 h under
nitrogen atmosphere in the dark to avoid a side reaction and
decomposition. The progress of the reaction was monitored by
TLC, and thereafter the mixture was poured onto crushed ice
with vigorous stirring and neutralized with 10% HCl. The
precipitate obtained was filtered, washed with water several
times, and dried. The crude product was purified by column
chromatography. This reaction was also carried out in aerobic
and dark conditions, but the yield of the final product was
reduced to half possibly because of decomposition of acetyl-
trimethylsilane in the presence of light and air. The product
isolated was characterized as 9,10-dihydro-1-sec-aminophenan-
threne-2-carbonitriles (8) in place of contemplated product 9,-
10-dihydro-1-sec-amino-3-trimethylsilylphenanthrene-2-carbo-
nitriles, as the reaction followed a course different from the
normal one as shown in Scheme 4. The reaction is possibly
initiated by the attack of carbanion generated in situ by base,
and it attacks the highly electrophilic center at C-10b with
Michael addition followed by intramolecular cyclization involv-
ing C-3 of the chromene ring and carbonyl functionality of
acetyltrimethylsilane to form an intermediate. The intermediate
after elimination of carbon dioxide forms a cyclic transition state,
which undergoes Brook rearrangement28 to form an oxygen
silicon bond with elimination of trimethylsilinol, which produces
phenanthrene derivatives.
Further synthesis of 4-alkyl-substituted phenanthrenes was
directly synthesized through base-catalyzed ring transformation
of 4 with propanal 7a under analogous reaction conditions. The
mechanism of these reactions is depicted in Scheme 4.
(27) Pratap, R.; Kumar, R.; Maulik, P. R.; Ram, V. J. Tetrahedron Lett.
2007, 48, 3311.
(28) (a) Brook, A. G. J. Am. Chem. Soc. 1958, 80, 1886. (b) Brook, A.
G. Acc. Chem. Res. 1974, 7, 77.
7404 J. Org. Chem., Vol. 72, No. 19, 2007

SCHEME 5. Mechanism Involved in the Synthesis of
3-Amino-1-sec-amino-9,10-dihydrophenanthrene-2,
4-dicarbonitriles (11)
3-Methyl-1-(piperidin-1-yl)-9,10-dihydrophenanthrene-2-car-
bonitrile (6a): Viscous oil; yield: 86%; IR (neat): 2928, 2851,
1
2365, 2216, 1596, 1382, 1352, 1029 cm-1; H NMR (300 MHz,
CDCl3): δ 1.70-1.72 (m, 6H), 2.50 (s, 3H) 2.72-2.88 (m, 4H),
3.21 (bs, 4H), 7.23-7.34 (m, 3H), 7.39 (s, 1H), 7.69 (dd, J ) 6.54
and 4.59 Hz, 1H); MS m/z 303 (M+ + 1); HRMS (EI, 70 eV)
calcd for C21H22N2, 302.17830 (M+); found for m/z, 302.17856.
3-Phenyl-1-(piperidin-1-yl)-9,10-dihydrophenanthrene-2-car-
bonitrile (6i): White powder; yield: 87%; mp: 128-130 °C; IR
(KBr): 2938, 2815, 2369, 2341, 2219, 1592, 1351, 1211, 1157,
1
1116, 1029, 948, 889, 834, 763, 705 cm-1; H NMR (300 MHz,
CDCl3): δ 1.67-1.75 (m, 6H), 2.82-2.87 (m, 2H), 2.92-2.97 (m,
2H), 3.27 (bs, 4H), 7.27-7.32 (m, 3H), 7.40-7.51 (m, 3H), 7.54-
7.58 (m, 3H), 7.71-7.75 (m, 1H); 13C NMR (75 MHz, CDCl3): δ
22.1, 22.9, 25.6 (2C), 27.3, 50.8 (2C), 105.7, 117.5, 120.1, 123.5,
125.9, 126.7, 127.1, 127.2 (2C), 127.4, 127.7 (2C), 132.6, 133.2,
136.7, 137.7, 138.6, 144.3, 153.5; MS m/z 365 (M+ + 1); HRMS
(EI, 70 eV) calcd for C26H24N2, 364.19395 (M+); found for m/z,
364.19394.
Typical Procedure for the Synthesis of 9,10-Dihydro-1-sec-
aminophenanthrene-2-carbonitriles (8a,b). 8a,b were obtained
by stirring a mixture of 4 (0.5 mmol), acetyltrimethylsilane 7b (0.6
mmol), and KOH (0.8mmol) in dry DMF under nitrogen atmosphere
in dark. The reaction was monitored by TLC. After completion of
reaction, excess DMF was removed under reduced pressure.
Thereafter, the reaction mixture was poured onto crushed ice with
vigorous stirring followed by neutralization with 10% aqueous HCl.
The precipitate obtained was filtered, washed with water, dried,
and purified by neutral alumina column chromatography using 40%
chloroform in hexane as eluent.
The synthetic potential of 2-oxo-5,6-dihydrobenzo[h]chromene
(4) was explored further using malononitrile as a source of
carbanion for the synthesis of highly congested phenanthrenes
(11) through ring transformation reactions. Thus, under analo-
gous conditions, stirring of an equimolar mixture of 4 and
malononitrile (10) in the presence of powdered KOH in DMF
for 2 to 3 h and followed by usual workup and column
chromatographic purification produced highly congested 3-amino-
1-sec-amino-9,10-dihydrophenanthrene-2,4-dicarbonitriles (11)
in moderate yields.
This reaction is also initiated by the attack of carbanion,
formed in situ from activated methylene of malononitrile, at
C-10b with ring closure involving a cyano group and C-3 of
benzo[h]chromene ring followed by elimination of carbon
dioxide to yield 3-amino-1-sec-amino-9,10-dihydrophenan-
threne-2,4-dicarbonitriles (9) in moderate yields. The plausible
mechanism of the reaction is shown in Scheme 5.
In summary, this is the first report of the straightforward
synthesis of congested 9,10-dihydrophenanthrenes from 5,6-
dihydro-2-oxo-4-sec-amino-2H-benzo[h]chromene-3-carboni-
triles through base-catalyzed ring transformation by carbanion
generated from various ketones, acetyltrimethylsilane, malono-
nitrile, and aldehyde in the shortest possible step in moderate
to high yields. This procedure provides an option to introduce
various substituents in the A and C rings of the phenanthrene.
1-Piperidin-1-yl-9,10-dihydrophenanthrene-2-carbonitrile (8a):
1
Viscous oil; yield: 64%; IR (neat): 2208 (CN) cm-1; H NMR
(300 MHz, CDCl3): δ 1.70-1.75 (m, 6H), 2.78-2.83 (m, 2H),
2.87-2.92 (m, 2H), 3.22 (bs, 4H), 7.25-7.37 (m, 3H), 7.47 (d, J
) 8.37 Hz, 1H), 7.50 (d, J ) 8.37 Hz, 1H), 7.67-7.70 (m, 1H);
13C NMR (75 MHz, CDCl3): δ 22.1, 22.9, 25.5, 27.2, 51.0, 105.3,
118.7, 123.4, 125.8, 126.7, 127.3, 131.4, 132.6, 136.6; MS m/z 291
(M+ + 1); HRMS (EI, 70 eV) calcd for C20H20N2, 288.16265 (M+);
found for m/z, 288.16244.
3-Amino-1-(piperidin-1-yl)-9,10-dihydrophenanthrene-2,4-di-
carbonitriles (11). These were prepared by stirring an equimolar
mixture of 4, malononitrile 10, and KOH in DMF. The usual
workup and neutral alumina column chromatographic purification
using 3% ethyl acetate in hexane as eluent gave 11.
3-Amino-1-piperidin-1-yl-9,10-dihydrophenanthrene-2,4-di-
carbonitrile (11a): Light yellow powder; yield: 65%; mp: 182-
184 °C; IR (KBr): 3419, 2862, 2213, 1601, 1555, 1498, 1401, 1330,
1007, 951, 765 cm-1; 1H NMR (300 MHz, CDCl3): δ 1.69-1.73
(m, 6H), 2.58-2.63 (m, 2H), 2.68-2.73 (m, 2H), 3.29 (t, J ) 4.80
Hz, 4H), 5.13 (bs, 2H, NH2), 7.28-7.32 (m, 1H), 7.34-7.39 (m,
2H), 8.06-8.09 (m, 1H); MS m/z 329 (M+ + 1); HRMS (EI, 70
eV) calcd for C21H20N4, 328.16880 (M+); found for m/z, 328.16891.
Experimental Section
Typical Procedure for the Synthesis of 3-Alkyl-, 3,4-Dialkyl-,
3-Aryl-, 3-Aryl-4-alkyl-, 3,4-Diaryl-, 4-Alkyl-1-sec-amino-9,10-
dihydrophenanthrene-2-carbonitriles (6a-s and 9a,b). A mixture
of 2-oxo-4-sec-amino-5,6-dihydro-2H-benzo[h]chromene-3-carbo-
nitrile (0.5 mmol) and acetone/ethyl methyl ketone/propiophenone/
deoxyanisoin/arylmethylketone/propanal (0.6 mmol) in dry DMF
(4 mL) was stirred in the presence KOH (0.8 mmol) for 1-3 h.
After consumption of starting material, excess of DMF was removed
under reduced pressure and the reaction mixture was poured onto
crushed ice with vigorous stirring and acidified with 10% HCl to
neutral pH. The product separated was filtered while in situation
of oily compound it was extracted with chloroform (3 × 20 mL)
and dried over sodium sulfate, and the solvent was removed under
vacuum. The crude product obtained was purified by silica gel/
neutral alumina column chromatography.
Acknowledgment. We are grateful to CSIR, New Delhi,
for their financial support and SAIF, CDRI, Lucknow, for
providing characterization data.
Supporting Information Available: Experimental details and
chemical characterization data. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO0711079
J. Org. Chem, Vol. 72, No. 19, 2007 7405