An efficient non-catalytic, regioselective approach to the synthesis of angularly fused polycyclic systems

Article abstract of DOI:10.1016/j.tetlet.2009.04.122

A novel approach to the synthesis of partially reduced different ring sizes of PAH analogs with sec.amino and nitrile functionalities is delineated through base-induced ring transformation of 4-sec.amino-2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitril

Full text of DOI:10.1016/j.tetlet.2009.04.122

Tetrahedron Letters 50 (2009) 4239–4242
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient non-catalytic, regioselective approach to the synthesis
of angularly fused polycyclic systems
b,
Ramendra Pratap a, , Vishnu Ji Ram
*
*
a Department of Chemistry, The City College and The City University of New York, 160 Convent Avenue, New York, NY 10031, USA
b Department of Applied Chemistry, Institute of Engineering & Technology, Sitapur Road, Lucknow 226 021, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel approach to the synthesis of partially reduced different ring sizes of PAH analogs with sec.amino
and nitrile functionalities is delineated through base-induced ring transformation of 4-sec.amino-2-oxo-
5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles by a carbanion, generated in situ from cyclopenta-
none, cyclohexanone, cycloheptanone, and cyclooctanone separately in good yields. An increase in the
size of cycloalkanone ring beyond cyclooctanone restricts the ring transformation under analogous
reaction conditions possibly due to bulky conformation of higher homologs. The synthetic method
provides an efficient general route for the construction of angularly fused partially reduced polycyclic
aromatic hydrocarbons: 5-sec.amino-2,3,6,7-tetrahydro-1H-cyclopenta[c]phenanthrene-4-carbonitriles,
Received 6 April 2009
Revised 26 April 2009
Accepted 28 April 2009
Available online 3 May 2009
Keywords:
2-Oxo-4-(piperidin-1-yl)-5,6-dihydro-2H-
benzo[h]-chromene-3-carbonitriles
Ring transformation
6-sec.amino-2,3,4,7,8-pentahydro-1H-benzo[c]phenanthrene-5-carbonitriles,
7-sec.amino-2,3,4,5,8,9-
hexahydro-1H-cyclohepta[c]phenanthrene-6-carbonitriles, and 8-sec.amino-2,3,4,5,6,9,10-heptahydro-
1H-cycloocta[c]phenanthrene-7-carbonitriles.
Cycloalkanone
Ó 2009 Elsevier Ltd. All rights reserved.
Polycyclic aromatic hydrocarbons (PAHs) are ubiquitously pres-
ent as environmental pollutants and most of them are carcinogenic
in animal models. Human populations exposed1,2 to these contam-
inants, produced by incomplete combustion of fossil fuels, coal,
wood burning, and tobacco smoke are real threat and instrumental
in causing cancer. It has been observed that PAHs are activated by
cytochrome P450 to diol epoxides that covalently bind cellular
DNA through C–N linkage and induce tumorigenesis. The steric
constraints in the bay region of PAHs significantly enhance the car-
cinogenicity3,4 and attenuate5–8 further with the formation of fjord
region diol epoxides. It has been observed that the bay region diol
epoxides preferentially bind with amino function of deoxyguano-
sine residue while fjord region diol epoxides preferably react with
amino group of deoxyadenosine of cellular DNA9,10 to form carcin-
ogen-deoxyadenosine adducts, instrumental in tumor initia-
tion.11,12 Recent studies have shown that tumorigenic effect of
PAHs is influenced by the preferred conformation of the adduct
in DNA template. Partial reduction of PAHs brings conformational
change in the adduct and thereby reduces the carcinogenicity of
the molecule.
epoxide II are highly carcinogenic15,16 (Fig. 1). Similar finding has
also been reported with benzochrysenes,17 and dibenzo[a,f]anthra-
cenes18 (Fig. 1).
The extensive literature survey revealed that there are limited
regioselective routes for the synthesis of different ring sizes of
PAH analogs.16–19 This observation led to the synthesis of partially
reduced cycloalkyl[c]phenanthrenes III with distorted conforma-
tion to assess the impact of partial reduction and size of fused ali-
cyclic ring on the degree of distortion and carcinogenicity of the
molecule. Our strategy to synthesize planarity distorted PAHs is
OH
OH
BcP
I
O
Among various carcinogens, benzo[c]phenanthrene (BcP) I is
relatively weak carcinogen13 present in the environment.14 The
two metabolites of BcP 3,4-dihydrodiol I and corresponding diol
(CH2)n
OH
OH
* Corresponding authors: Tel.: +1 646 748 4979; fax: +1 212 650 6107 (R.P.);
tel.: +91 522 2612411; fax: +91 522 2623405 (V.J.R.).
E-mail addresses: ramendrapratap@gmail.com (R. Pratap), vjiram@yahoo.com
(V.J. Ram).
III
II
Figure 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.122

4240
R. Pratap, V. J. Ram / Tetrahedron Letters 50 (2009) 4239–4242
either through (i) partial reduction or (ii) increasing the size of the
fused alicyclic ring or (iii) through substitution in the overcrowd-
ing region of the molecule, or (iv) combination of all.
This manuscript describes the synthesis of diverse partially re-
duced different ring sizes of PAH analogs such as 5-sec.amino-
2,3,6,7-tetrahydro-1H-cyclopenta[c]phenanthrene-4-carbonitriles
N
O
CN
O
O
+
4
5
R
7,
6-sec.amino-1,2,3,4,7,8-hexahydrobenzo[c]phenanthrene-5-
carbonitriles 9, 7-sec.amino-2,3,4,5,8,9-hexahydro-1H-cyclohep-
ta[c]-phenanthrene-6-carbonitriles 11, and 8-sec.amino-2,3,4,5,6,9,
10-heptahydro-1H-cycloocta[c]phenanthrene-7-carbonitriles 13
through base-induced ring transformation of 4-sec.amino-2-oxo-
5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles by a carbanion,
generated in situ from cycloalkanones.
X
O
CN
O
N
CN
O
O
An alternative route to the synthesis of partially reduced cyclo-
alkyl[c]phenanthrenes, pendant with secondary amine and nitrile
functionalities, necessitated the construction of 2-oxo-4-meth-
ylsulfanyl-5,6-dihydro-2H-benzo[h]-chromene-3-carbonitrile 3 as
a key step and was obtained from the reaction of methyl 2-cya-
no-3,3-dimethylthioacrylate 1 with 1-tetralone 2 in the presence
of powdered KOH using DMSO as a solvent at room temperature.
Amination of 3 with secondary amine in refluxing ethanol gave 4-se-
c.amino-2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles 4
in good yields20 (Scheme 1) and was used directly as a precursor for
the ring transformation study.
R
6
R
CN
O
OH
O
N
N
N
CN
OH
CN
-H2O
-CO2
H
R
7
R
R
As is evident from the topography of 4-sec.amino-2-oxo-5,6-
dihydrobenzo[h]chromene-3-carbonitriles 4, that they possess
three electrophilic centers C-2, C-4, and C-10b in which the latter
is highly susceptible to nucleophilic attack due to extended conju-
gation and the presence of an electron-withdrawing CN substitu-
ent at position 3 of the chromene ring. The nucleophiles used for
the ring transformation reactions were carbanions, generated
in situ from cycloalkanones in the presence of base in DMF. The
initial step in the formation of 5-sec.amino-2,3,6,7-tetrahydro-
1H-cyclopenta[c]phenanthrene-4-carbonitriles 7 is attack of the
carbanion at C-10b of the chromene 4 with formation of Michael
adduct followed by ring closure involving carbonyl group of cyclo-
pentanone and C-3 of the chromene with loss of carbon dioxide
and water as depicted in Scheme 2.
N
R
Yields (%)
7
piperidin-1-yl
H
H
H
H
86
78
89
91
a
b
c
4-methylpiperidin-1-yl
tetrahydroisoquinolin-2-yl
4-benzylpiperazin-1-yl
4-[bis(4-fluorophenyl)
methyl]piperazin-1-yl
piperidin-1-yl
d
H
73
78
e
f
OCH3
Scheme 2. Synthesis of 5-sec.amino-2,3,6,7-tetrahydro-1H-cyclopenta-[c]phenan-
threne-4-carbonitriles 7.
Under analogous reaction conditions a mixture of 4 with cyclo-
hexanone 8 in the presence of powdered KOH gave a crude product
9 which was purified through neutral alumina column as 6-sec.a-
mino-1,2,3,4,7,8-hexahydro benzo[c]phenanthrene-5-carbonitriles
in very good yields (Scheme 3). In this reaction also carbanion from
cyclohexanone initiated the ring transformation following similar
course of reaction.
Analogously, a reaction of 2-oxobenzo[h]chromene 4 with
cycloheptanone 10 produced 7-sec.amino-2,3,4,5,8,9-hexahydro-
1H-cyclohepta[c]phenanthrene-6-carbonitriles 11 (Scheme 4).
Under similar reaction conditions the ring transformation of 4
with cyclooctanone in the presence of powdered KOH in DMF pro-
duced 8-sec.amino-2,3,4,5,6,9,10-heptahydro-1H-cycloocta[c]phen-
anthrene-7-carbonitriles 13 in moderate yields (Scheme 5).
The ring transformation of 4 by higher homologs of cycloalka-
nones beyond eight membered did notoccur and lactonewas always
N
O
N
CN
CN
O
+
O
8
4
9
N
Yields (%)
9
4-morpholin-1-yl
4-(pyridine-2-yl)-piperazin-1-yl
88
73
a
b
Scheme 3. Synthesis of 6-sec.amino-1,2,3,4,7,8-hexahydrobenzo[c]-phenanthrene-
5-carbonitriles 9.
SCH3
N
CN
O
N
H
O
CN
O
NC
COOCH3
DMSO/KOH
5-6 h
R
O
+
C2H5OH
O
H3CS
SCH3
3
R
4
R
2
1
Scheme 1. Two-step synthesis of 2-oxobenzo[h]chromene 4.

R. Pratap, V. J. Ram / Tetrahedron Letters 50 (2009) 4239–4242
4241
N
N
O
R
N
CN
O
CN
+
CN
+
O
O
X
NC
O
4
O
10
4
R
R
N
2
11
15
11
N
R
Yields (%)
N
O
O
piperidin-1-yl
H
H
H
H
H
80
81
75
71
73
70
a
b
c
d
e
f
N
C
N
N
C
N
4-methylpiperidin-1-yl
4-benzylpiperidin-1-yl
4-morpholin-1-yl
tetrahydroisoquinolin-2-yl
piperidin-1-yl
CN
H
O
OH
O
OCH3
Scheme 4. Synthesis of 7-sec.amino-2,3,4,5,8,9-hexahydro-1H-cyclohepta[c]phen-
anthrene-6-carbonitriles 11.
CN
O
CN
[O]
O
N
N
O
O
CN
CN
+
14
O
Scheme 6. Synthesis of oxachrysene 14 in lieu of usual product benzochrysene 15.
4
12
13
Acknowledgments
N
Yields (%)
13
The authors are thankful to CSIR, New Delhi for financial sup-
port and the Sophisticated Analytical Instrument Facility, CDRI,
Lucknow for providing spectroscopic data.
piperidin-1-yl
70
68
71
73
75
a
b
c
d
e
4-methylpiperidin-1-yl
4-benzylpiperidin-1-yl
4-morpholin-1-yl
References and notes
tetrahydroisoquinolin-2-yl
1. Harvey, R. G. Polycyclic Aromatic Hydrocarbons. Chemistry and Carcinigenesis;
Cambridge University Press: Cambridge, England, 1991. Chapter 3.
2. Harvey, R. G. In The Handbook of environmental Chemistry: Volume PAHs and
related compounds; Hutzinger, O., Nelson, A., Eds.; Springer: Berlin, Heidelberg,
1977; pp 1–54. Chapter 1.
Scheme
5. Synthesis of 8-sec.amino-2,3,4,5,6,9,10-heptahydro-1H-cyclooc-
ta[c]phenanthrene-7-carbonitriles 13.
3. Hetch, S. S.; El-Bayoumy, K.; Rivenson, A.; Amin, S. Cancer Res. 1994, 54, 21.
4. Hecht, S. S.; Amin, S.; Hulk, K.; Melikian, A. A.; Harvey, R. G. Cancer Res. 1987,
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D. M.; Conney, A. H. Cancer Res. 1980, 40, 3910.
6. Amin, S.; Krzeminski, J.; Rivenson, A.; Kurtzke, C.; Hecht, S. S.; El-Bayoumy, K.
Carcinogenesis 1995, 16, 1971.
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8. Kumar, S. J. Org. Chem. 1997, 62, 8535.
9. Dipple, D. M. Nature 1987, 327, 535.
10. Agarwal, S. K.; Sayer, J. M.; Yeh, H. J.; Pannel, L. K.; Hilton, B. D.; Yagi, H.; erina,
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12. Bigger, C. A. H.; Sawicki, J. T.; Blake, D. M.; Raymond, L. G.; Dipple, A. Cancer Res.
1983, 43, 5647.
13. Stevenson, J. L.; von Haam, E. Am. Ind. Hyg. Assoc. J. 1965, 26, 475.
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15. (a) Wood, A. W.; Chang, R. L.; Levin, W.; Ryan, D. E.; Thomas, P. E.; Croisy-
Delcey, Y.; Yagi, H.; Jerina, D. M.; Conney, A. H. Cancer Res. 1980, 40, 2876; (b)
Harvey, R. G. Acc. Chem. Res. 1981, 14, 218.
recovered. TheattackatC-10bby biggersizeof thecarbanionformed
from higher homologs of cycloalkanone is hindered.
It is quite interesting that the use of fused cyclic ketones such as
1-tetralone, for the ring transformation of 4 did not follow the
same course of reaction under analogous reaction conditions and
the product isolated was characterized as (7,8-dihydro-5-oxa-
benzo[c]chrysene-6-ylidene)acetonitrile 14. In this reaction also
carbanion generated in situ from 1-tetralone attacks at C-10b fol-
lowed by enolate addition to enamine with loss of secondary
amine and subsequent oxidation, yields 1421 in lieu of usual ring
transformed product 15 as depicted in Scheme 6. From this reac-
tion it was concluded that the presence of fused benzene ring in
1-tetralone facilitates the enolization that ultimately participates
in the ring closure to yield 14.
All the synthesized compounds were characterized by spectro-
scopic analysis.22
16. (a) Dipple, A.; Agarwal, S. K.; Yagi, H.; Sayer, J. M.; Jerina, D. M. Nature 1987,
327, 535; (b) Ittah, Y.; Thakker, D. R.; Levin, W.; Croisy-Delcey, M.; Ryan, D. E.;
Thomas, P. E.; Conney, A. H.; Jerina, D. M. Chem. Biol. Interact. 1983, 45, 15; (c)
Agarwal, S. K.; Sayer, J. M.; Yeh, H. J. C.; Pannell, L. K.; Hilton, B. D.; Pigott, M. A.;
Dipple, A.; Yagi, H.; Jerina, D. M. J. Am. Chem. Soc. 1987, 109, 2497; (d) Pataki, J.;
Harvey, R. G. J. Org. Chem. 1982, 47, 20; (e) Bigger, C. A.; St. John, J.; Yagi, H.;
Jerina, D. M.; Dipple, A. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 368; (f) Lakshman,
M. K.; Kole, P. I.; Chaturnedi, S.; Saugier, J. H.; Yeh, H. J. C.; Glusker, J. P.; Carrell,
H. L.; Katz, A. K.; Carol, E. A.; Dashwood, W.-M.; Kenniston, G.; Baird, W. M. J.
Am. Chem. Soc. 2000, 122, 12629.
This is the first non-catalytic approach for the concise synthesis
of partially reduced angularly fused polycyclic aromatic hydro-
carbons through base-induced ring transformation of 4-sec.ami-
no-2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles by a
carbanion generated in situ from cycloalkanone in DMF at room
temperature. This methodology is very efficient, economical, and
provides an easy access for the construction of different ring sizes
of PAHs.

4242
R. Pratap, V. J. Ram / Tetrahedron Letters 50 (2009) 4239–4242
17. (a) Zhang, F.-J.; Cortez, C.; Harvey, R. G. J. Org. Chem. 2000, 65, 3952; (b)
Sharma, A. K.; Kumar, S.; Amin, S. J. Org. Chem. 2004, 69, 3979; (c) Butch, E. R.;
Yagi, H.; Jerina, D. M. Polycyclic Aromat. Compd. 1994, 6, 63.
18. (a) Chowdhary, S.; Zhao, B.; Snieckus, V. Polycyclic Aromat. Compd. 1994, 5, 27;
(b) Harvey, R. G.; Dai, W.; Zhang, J.-T.; Cortez, C. J. Org. Chem. 1998, 63, 8118; (c)
Agarwal, S. K.; Boyd, D. R.; McGuckin, M. R.; Jennings, W. B.; Howarth, O. W. J.
Chem. Soc., Perkin Trans. 1 1990, 1972.
(M+) found for m/z 342.20942. (9a). White powder; yield: 88%; mp: 186–
188 °C; IR (KBr): 2364, 2207, 1626, 1567, 1460, 1220, 1028 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d 1.64–1.70 (m, 2H, CH2), 1.86–1.94 (m, 2H, CH2), 2.65–2.69
(m, 2H, CH2), 2.74–2.78 (m, 2H, CH2), 2.95 (t, J = 5.98 Hz, 2H, CH2), 3.02 (t,
J = 6.81 Hz, 2H, CH2), 3.27 (br s, 4H, CH2), 3.85 (t, J = 4.38 Hz, 4H, CH2), 7.23–
7.32 (m, 3H, ArH), 7.54–7.60 (m, 1H, ArH); 13C NMR (75 MHz, CDCl3): d 21.04,
21.91, 24.05, 27.35, 28.23, 29.49, 49.79, 66.51, 107.56, 116.72, 124.40, 126.04,
126.04, 126.64, 127.49, 131.12, 132.39, 134.06, 139.02, 139.33, 139.52, 148.18;
MS m/z 345 (M++1); HRMS: (EI, 70 eV) calcd for C23H24N2O 344.18886 (M+)
found for m/z 344.18862. (11d). White powder; yield: 71%; mp: 186–188 °C; IR
19. Cheung, J.; Field, L. D.; Regalia, F.; Stemhell, S. Aust. J. Chem. 1995, 48, 1707.
20. Pratap, R.; Ram, V. J. Tetrahedron Lett. 2007, 48, 2755.
21. Pratap, R.; Kumar, R.; Maulik, P. R.; Ram, V. J. Tetrahedron Lett. 2007, 48, 3311.
22. General procedure for the synthesis of cycloalkyl[c]phenanthrene (6): An
equimolar mixture of 2-oxo-4-sec.amino-5,6-dihydro-2H-benzo[h]chromene-
3-carbonitrile (0.5 mmol), cycloalkanone (0.6 mmol), and KOH (0.7 mmol) in
DMF (4 mL) was stirred for 2–3 h. Completion of reaction was monitored by
TLC. Thereafter, reaction mixture was poured onto crushed ice with vigorous
stirring followed by neutralization with 10% HCl. The precipitate obtained was
filtered, washed with water, dried, and purified by neutral alumina column
using 3% ethyl acetate in hexane as eluent. (7b) White powder; yield: 78%; mp:
(KBr): 2935, 2213, 1490, 1404, 1200, 998 cmÀ1 1H NMR (300 MHz, CDCl3): d
;
1.79–1.81 (m, 4H, CH2), 1.90–1.92 (m, 2H, CH2), 2.68–2.73 (m, 4H, CH2), 3.0–
3.04 (m, 2H, CH2), 3.13–3.17 (m, 4H, CH2), 3.21–3.24 (m, 2H, CH2), 3.86 (br s,
4H, CH2), 7.27–7.32 (m, 3H, ArH), 7.36–7.39 (m, 1H, ArH); 13C NMR (75 MHz,
CDCl3): d 24.4, 26.0, 26.8, 28.3, 30.4, 30.5, 32.4, 49.7, 66.6, 107.8, 117.8, 124.7,
126.1, 126.5, 127.5, 133.1, 134.5, 136.4, 138.8, 139.2, 146.4, 147.3; MS m/z 359
(M++1); HRMS: (EI, 70 eV) calcd for C24H26N2O 358.20451 (M+) found for m/z
358.20403. (13a). White powder; yield: 70%; mp: 110–112 °C; IR (KBr): 2903,
140–142 °C; IR (KBr): 2926, 2856, 2372, 2221, 1453, 1272, 1123 cmÀ1
;
1H NMR
2211, 1570, 1400, 1229, 1008 cmÀ1 1H NMR (300 MHz, CDCl3): d 1.47 (br m,
;
(300 MHz, CDCl3): d 1.01 (d, J = 6.67 Hz, 3H, CH3), 1.33–1.44 (m, 2H, CH2), 1.49–
1.59 (m, 1H, CH), 1.69–1.73 (m, 2H, CH2), 2.05–2.14 (m, 2H, CH2), 2.69–2.73 (m,
2H, CH2), 2.80–2.83 (m, 2H, CH2), 3.07 (t, J = 7.35 Hz, 2H, CH2), 3.19 (t,
J = 7.14 Hz, 2H, CH2), 3.30–3.33 (m, 2H, CH2), 7.25–7.32 (m, 3H, ArH), 7.61–7.64
(m, 1H, ArH); 13C NMR (75 MHz, CDCl3): d 20.9, 24.7, 28.2, 29.4, 31.8, 34.1, 50.5,
117.3, 124.9, 125.7, 126.3, 126.7, 133.2, 133.4, 135.2, 135.5, 138.2, 148.1,
150.1; MS m/z 345 (M++1); HRMS: (EI, 70 eV) calcd for C24H26N2 342.20960
4H, CH2), 1.62–1.65 (m, 2H, CH2), 1.70–1.74 (m, 6H, CH2), 1.90–1.93 (m, 2H,
CH2), 2.59–2.63 (m, 2H, CH2), 2.70–2.71 (m, 2H, CH2), 3.01–3.08 (m, 4H, CH2),
3.22 (br s, 4H, CH2), 7.22–7.30 (m, 3H, ArH), 7.57–7.59 (m, 1H, ArH); 13C NMR
(75 MHz, CDCl3): d 22.99, 24.51, 24.65, 25.20, 25.62, 27.75, 28.58, 28.74, 29.10,
31.92, 51.09, 106.86, 117.65, 124.47, 125.92, 126.28, 127.23, 133.37, 133.51,
134.98, 139.27, 139.46, 143.75, 150.15; MS m/z 371 (M++1); HRMS: (EI, 70 eV)
calcd for C26H30N2 370.24090 (M+) found for m/z 370.24111.