2-Oxobenzo[h]chromene: a novel entry for the concise and efficient synthesis of indeno[1,2-c]phenanthrenes

Article abstract of DOI:10.1016/j.tetlet.2007.04.087

An efficient and concise synthesis of 7-sec-amino-5,13-dihydro-6H-indeno[1,2-c]phenanthrene-8-carbonitriles is described through base catalyzed ring transformation of 4-sec-amino-2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles with 1-indanone in mod

Full text of DOI:10.1016/j.tetlet.2007.04.087

Tetrahedron Letters 48 (2007) 4379–4382
2-Oxobenzo[h]chromene: a novel entry for the concise and
efficient synthesis of indeno[1,2-c]phenanthrenesI
Ramendra Pratap and Vishnu Ji Ram*
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
Received 20 March 2007; revised 11 April 2007; accepted 18 April 2007
Available online 22 April 2007
This Letter is dedicated to Professor R. P. Rastogi, on the occasion of his 81st birthday
Abstract—An efficient and concise synthesis of 7-sec-amino-5,13-dihydro-6H-indeno[1,2-c]phenanthrene-8-carbonitriles is described
through base catalyzed ring transformation of 4-sec-amino-2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles with 1-inda-
none in moderate to good yields.
Ó 2007 Elsevier Ltd. All rights reserved.
R
Polycyclic aromatic hydrocarbons (PAHs) are environ-
mental pollutants and can be introduced into the atmo-
sphere through incomplete combustion of organic
matters,1 fossil fuels,2 and also from tobacco smoke.2
Most PAHs are potent carcinogens and are metabolized
by cytochrome P-450 and epoxide hydrolase to bay
region epoxides responsible for carcinogenicity.3–5 These
metabolites covalently bind to cellular DNA through a
C–N linkage, resulting in mutations, leading to tumor
induction.
N
CN
III
II
I
Figure 1. 9H-Indeno[2,1-c]phenanthrene (I), 13H-indeno[1,2-c]phen-
anthrene (II), 5,13-dihydro-6H-[1,2-c]phenanthrenes (III).
The steric constraints in the bay region are believed to
enhance the carcinogenicity.6,7 More polar metabolites
play a significant role in carcinogenesis, particularly
those which have more than one bay or fjord region.
polycyclic aromatic hydrocarbons, it was found that the
planarity of the ring is one of the factors behind their
mutagenic property. We decided to prepare partially
reduced indeno[1,2-c]phenanthrenes (III) to distort the
planarity and to reduce the binding affinity of their
metabolites with cellular DNA in order to diminish
the mutagenic properties (Fig. 1). Thus, we planned to
prepare 7-sec-amino-5,13-dihydro-6H-indeno[1,2-c]phen-
anthrene-8-carbonitriles (III). Reduction of the olefinic
bond between C5–C6 in II would result in compound
III. Partial catalytic reduction of II is not easy and
may lead to a complex mixture. Thus, we planned our
synthetic strategy to start with a precursor having a
reduced olefinic bond. We contemplated achieving our
objective by using 4-sec-amino-2-oxo-5,6-dihydro-2H-
benzo[h]chromene-3-carbonitriles 4 as precursors for
the ring transformation reactions. The precursors were
prepared in two steps through base induced condensa-
tion–cyclization of 1-tetralone 2 and methyl 2-cyano-
3,3-dimethylthioacrylate 1 followed by amination of
Through an extensive literature survey it is evident that
the chemistry of 9H-indeno[2,1-c]phenanthrene (I) is
little developed8 in comparison to 13H-indeno[1,2-c]-
phenanthrene (II). The derivatives of 9H-indeno[2,1-c]-
phenanthrene (I) are mostly noncarcinogenic but the
mutagenic properties of 13H-indeno[1,2-c]phenanth-
renes has not been explored enough due to the non-
availability of compounds of this ring system. Through
extensive study of the carcinogenic properties of various
Keywords: Indeno[1,2-c]phenanthrenes; 2-Oxobenzo[h]chromenes;
Ring transformation.
q CDRI Communication No. 7182.
*
Corresponding author. Tel.: +91 522 2612411; fax: +91 522
2623405; e-mail: vjiram@yahoo.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.087

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R. Pratap, V. J. Ram / Tetrahedron Letters 48 (2007) 4379–4382
Table 2. Yields of 7-sec-amino-5,13-dihydro-6H-indeno[1,2-c]phenan-
threne-8-carbonitriles 6
the resulting 4-methylsulfanyl-2-oxo-5,6-dihydro-2H-
benzo[h]chromene-3-carbonitriles 3 with a secondary
amine in refluxing ethanol in excellent yields (Scheme
1, Table 1).9
6
Product
Yield (%)
SCH3
N
CN
O
CN
a
68
NC
COOCH3
DMSO/KOH
5-6 h
R
O
O
+
H3CS
SCH3
R
3
1
2
C2H5OH
HN
N
R
Yield (%)
3
a
b
H
OCH3
94
82
N
b
71
CN
O
CN
O
R
4
Scheme 1.
Table 1. Yields of the different 4-sec-amino-2-oxo-5,6-dihydrobenzo[h]-
chromenes 4
c
66
4
R
Yields (%)
N
N
CN
a
b
c
d
e
f
Piperidin-1-yl
H
H
H
H
H
H
OCH3
OCH3
96
91
81
79
88
82
85
71
4-Methylpiperidin-1-yl
4-Benzylpiperidin-1-yl
4-Benzylpiperazin-1-yl
4-Morpholin-1-yl
Tetrahydroisoquinolin-2-yl
Piperidin-1-yl
g
h
4-Methylpiperidin-1-yl
N
d
75
N
N
CN
CN
+
O
O
O
5
4
R
Path B
O
X
Path A
CN
O
N
O
O
N
CN
e
64
CN
O
7
R
R
N
O
O
N
N
CN
OH
CN
CN
OH
N
H
f
60
CN
R
6
R
R
Scheme 2. Mechanism involved in the formation of 6 and alternative
product 7.

R. Pratap, V. J. Ram / Tetrahedron Letters 48 (2007) 4379–4382
4381
Table 2 (continued)
anthrene-8-carbonitrile 6. There was also the possibility
of formation of product 7 from this reaction. The initial
step is possibly an attack of the carbanion generated
in situ from 1-indanone at C-10b of 4 with formation
of a Michael adduct and thereafter the reaction may fol-
low either path A or B. If the reaction follows path A,
the Michael adduct formed in situ undergoes cyclization
involving C-3 and the carbonyl function of 1-indanone
with concomitant loss of carbon dioxide and water to
yield 6 as shown in Scheme 2 (Table 2). In the formation
of product 7 the Michael adduct may undergo enoliza-
tion followed by cyclization involving the enolic OH
and C-4 of the chromeme ring with elimination of the
secondary amine to yield product 7.
6
Product
Yield (%)
N
CN
g
77
H3CO
N
h
74
CN
It is surprising to note that under analogous conditions
the reaction of 4 with 1-tetralone followed path B to
produce only oxachrysene 8. The only difference in the
bicyclic ketones is the presence of the fusion of a benz-
ene ring with cyclopentanone in indanone and with a
cyclohexanone in 1-tetralone. The cyclopentanone ring
in indanone is highly strained, which makes it very reac-
tive. Enolization of the indanone ring in the first inter-
mediate may increase the strain further and hence
disfavors further enolization to attain a stable confor-
mation, Scheme 3.
H3CO
The topography of compound 4 reveals the presence of
three electrophilic centers C-2, C-4, and C-10b, in which
the latter is highly electrophilic due to extended conjuga-
tion and the presence of an electron withdrawing CN
substituent at position 3 of the chromene ring and is
consequently prone to nucleophilic attack. The nucleo-
phile used was a carbanion generated in situ from 1-
indanone.
All the synthesized compounds were characterized by
spectroscopic analysis.10
In summary, this protocol provides an easy and concise
access to partially reduced 7-sec-amino-5,13-dihydro-
6H-indeno[1,2-c]phenanthrene-8-carbonitriles through
the ring transformation of suitably functionalized
2-oxo-5,6-dihydrobenzo[h]chromenes with 1-indanone
in good yields.
Thus, a mixture 4, 1-indanone 5 and NaH in DMF was
stirred at room temperature for 1–2 h. During this peri-
od, all the starting material was consumed with the
appearance of a new product on TLC. The reaction mix-
ture was poured onto crushed ice with vigorous stirring
and thereafter neutralized with 10% aqueous HCl. The
resulting precipitate was filtered washed with water
and dried. The crude product, on purification by column
chromatography, gave a product which was character-
ized as 7-sec-amino-5,13-dihydro-6H-indeno[1,2-c]phen-
Acknowledgments
V.J.R. and R.P. are thankful to the CSIR, New Delhi,
for financial support. The authors also thank SAIF,
CDRI, Lucknow for spectroscopic data.
CN
O
CN
O
References and notes
R
1. Harvey, R. G. Polycyclic Aromatic Hydrocarbons. Chem-
istry and Carcinogenicity; Cambridge University Press:
England, 1991, Chapter 3; (a) Kumar, S. J. Org. Chem.
1997, 62, 8535–8539.
2. Harvey, R. G.; Dia, W.; Zhang, J.-T.; Cortez, C. J. Org.
Chem. 1998, 63, 8118–8124.
3. Lehr, F.; Kumar, S.; Levin, W.; Wood, A. W.; Chang, R.
L.; Conney, A. H.; Yagi, H.; Sayer, J. M.; Jerina, D. M. In
Polycyclic Aromatic Hydrocarbons: Chemistry and Carci-
nogenesis; Harvey, R. G., Ed.; ACS Symposium Series
283; American Chemical Society: Washington, DC, 1985;
pp 63–84.
R
7
8
N
O
X
CN
O
1-tetralone
1-indanone
5
X
4
R
N
N
CN
CN
4. Thakker, D. R.; Yagi, H.; Levin, W.; Wood, A. W.;
Conney, A. H.; Jerina, D. M. Bioact. Foreign Compd.
1985, 7, 117.
R
R
6
Scheme 3. A comparative study of 1-indanone and 1-tetralone on the
ring transformation of 4.
5. Harvey, R. G.; Geaintov, N. E. Acc. Chem. Res. 1988, 21,
66.

4382
R. Pratap, V. J. Ram / Tetrahedron Letters 48 (2007) 4379–4382
6. Hecht, S. S.; El-Bayoumy, K.; Rovinson, A.; Amin, S.
2.72–2.77 (m, 2H, CH2), 2.91 (br s, 2H, CH2), 3.19 (br s,
2H, CH2), 3.47 (br s, 2H, CH2), 4.15 (s, 2H, CH2), 7.29–
7.47 (m, 5H, ArH), 7.56 (d, J = 7.29 Hz, 1H, ArH), 7.94 (d,
J = 7.53 Hz, 1H, ArH), 8.55 (d, J = 7.62 Hz, 1H, ArH);
13C NMR (CDCl3, 75 MHz): 22.15, 30.74, 35.37, 38.01,
51.56, 122.17, 124.34, 126.48, 126.83, 127.14, 127.80,
127.85, 128.28, 134.23, 135.55, 135.91, 137.06, 139.10,
143.37, 144.03, 153.17; Mass (ESI): 391 (M++1); C28H26N2
(390.51) calcd: C, 86.12; H, 6.71; N, 7.17, found: C, 86.43;
H, 6.67; N, 7.31. Compound (6h). White solid; yield: 74%;
Cancer Res. 1994, 54, 21.
7. Hecht, S. S.; Amin, S.; Hule, K.; Melikian, A. A.; Harvey,
R. G. Cancer Res. 1987, 47, 5310.
8. (a) Marrocchi, A.; Minuti, L.; Morozzi, G.; Pampanella,
L.; Taticchi, A. Carcinogenesis 1996, 17, 2009–2012; (b)
Heller, H. G.; Salisbury, K. J. Chem. Soc. (C) 1970, 1997–
2000; (c) Heller, H. G.; Salisbury, K. J. Tetrahedron Lett.
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9. Pratap, R.; Ram, V. J. Tetrahedron Lett. 2007, 48, 1715–
1719.
mp 196–198 °C; IR (KBr): 2210 (CN) cmÀ1 1H NMR
;
10. General procedure for the synthesis of 7-sec-amino-5,13-
dihydro-6H-indeno[1,2-c]phenanthrene-8-carbonitriles (6):
A mixture of 2-oxo-4-sec-amino-5,6-dihydro-2H-benzo[h]-
chromene-3-carbonitrile 4 (0.5 mmol), 1-indanone (0.6 mmol)
in DMF (5.0 mL) and sodium hydride (0.7 mmol) was
stirred for 1–2 h. The reaction mixture was poured onto
crushed ice with vigorous stirring and neutralized with 10%
HCl (4.0 mL). The resulting precipitate was filtered,
washed with water, and purified by neutral alumina
column chromatography using 2% ethyl acetate in hexane
as eluent. Compound (6b). White solid; yield: 71%; mp
200–202 °C; IR (KBr): 2214 (CN) cmÀ1; 1H NMR (CDCl3,
300 MHz): 1.04 (d, J = 5.94 Hz, 3H, CH3), 1.47 (br s, 1H
CH), 1.62 (br s, 2H, CH2), 1.74 (d, J = 11.16 Hz, 2H, CH2),
(CDCl3, 300 MHz): 1.03 (d, J = 5.91 Hz, 3H, CH3), 1.40–
1.44 (m, 1H, CH), 1.59–1.62 (m, 2H CH2), 1.73 (d,
J = 11.07 Hz, 2H, CH2), 2.69–2.73 (m, 2H, CH2), 2.90 (br
s, 2H, CH2), 3.16 (br s, 2H, CH2), 3.49 (br s, 2H, CH2), 3.87
(s, 3H, OCH3), 4.08 (s, 2H, CH2), 6.85–6.92 (m, 2H, ArH),
7.32–7.45 (m, 2H, ArH), 7.54 (d, J = 7.32 Hz, 1H, ArH),
7.86 (d, J = 8.58 Hz, 1H, ArH), 8.54 (d, J = 7.68 Hz, 1H,
ArH); 13C NMR (CDCl3, 75 MHz): 21.0, 28.43, 29.44,
34.05, 36.97, 50.29, 54.05, 110.41, 112.09, 117.60, 120.92,
123.06, 125.66, 125.85, 126.46, 126.99, 133.51, 134.02,
135.77, 137.88, 140.64, 141.96, 142.73, 157.79, 158.16;
Mass (ESI): 421 (M++1); C29H28N2O (420.54) calcd:
C, 82.82; H, 6.71; N, 6.66, found: C, 89.05; H, 6.81; N,
6.51.