Synthesis of partially reduced ferrocenylphenanthrenes from 2-oxobenzo[h]chromenes through C-C insertion

Article abstract of DOI:10.1016/j.tetlet.2007.11.014

An efficient and concise de novo synthesis of ferrocenyl tethered partially reduced phenanthrenes is described through base-catalyzed ring transformation of 4-sec-amino-2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles with acetylferrocene.

Full text of DOI:10.1016/j.tetlet.2007.11.014

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 394–396
Synthesis of partially reduced ferrocenylphenanthrenes
from 2-oxobenzo[h]chromenes through C–C insertionI
Ramendra Pratap and Vishnu Ji Ram*
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
Received 31 August 2007; revised 22 October 2007; accepted 2 November 2007
Available online 5 November 2007
Abstract—An efficient and concise de novo synthesis of ferrocenyl tethered partially reduced phenanthrenes is described through
base-catalyzed ring transformation of 4-sec-amino-2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles with acetylferrocene.
Ó 2007 Elsevier Ltd. All rights reserved.
The chemistry of ferrocene is highly significant because
of its use as a building block for the synthesis of org-
anomaterials1 displaying unusual solid state proper-
ties by virtue of their electron donating nature and
fixed intranuclear spacing. The ability of organoferro-
cenes to form charge transfer complexes and radical
ion salts with a wide range of organic and inorganic
acceptors makes them highly suitable as components
of molecular wires,2 anion sensors3 and potential organ-
ic ferromagnets.4 Various ferrocenyl derivatives are
reported to display antimalarial,5 antitumor,6 and
DNA cleaving7 properties. Phenanthrenes also represent
an important class of compounds abundantly distri-
buted in nature, which exhibit a broad spectrum of
biological activities.8–13 The therapeutic importance of
both these ring systems inspired us to develop a syn-
thetic strategy by which compounds possessing both
ring systems in the same molecule could be prepared
efficiently.
Cyclotrimerization of alkynes in the presence of transi-
tion metal catalysts is a general approach for the
construction of arenes,16 either in a stepwise or con-
certed manner. Highly functionalized ferrocenylarenes
are conveniently obtained from the reaction of ferro-
cenyl alkynes and zirconium cyclopentadiene using
CuCl or NiCl2(PPh3)2 as catalyst.17,18 The size of the
substituent linked to the alkyne enhances the rate of
cyclization and yield of the product. The limitations
of accessibility of precursors, multistep processes,
harsh reaction conditions, low tolerance of func-
tional groups, and use of expensive catalysts, prompted
us to develop a novel approach, which could overcome
the shortcomings of the earlier procedures and also pro-
vide an option for varying the substituent on the aryl
ring.
Herein, we report a novel approach for the synthesis of
various 3-ferrocenyl-9,10-dihydrophenanthrenes, teth-
ered with an electron-withdrawing and donating
substituent through base-catalyzed ring transformation
of 4-sec-amino-2-oxo-5,6-dihydro-2H-benzo[h]chromene-
3-carbonitriles 4 with acetylferrocene 5 in the presence
of powdered KOH in DMF.
Aromatic compounds with covalently linked ferrocene
are also of great interest due to their unusual solid state
properties and limited synthetic approaches.14,15 It was
apparent from a comprehensive literature survey that
partially reduced ferrocenylphenanthrenes have not
been reported so far because of the difficulty in introduc-
ing the ferrocenyl moiety onto a phenanthrene ring.
The 4-sec-amino-2-oxo-5,6-dihydro-2H-benzo[h]-chro-
mene-3-carbonitriles 4 were prepared by reaction of
methyl 2-cyano-3,3-dimethylthioacrylate 1 and 1-tetra-
lone 2 in DMSO using KOH as base followed by
amination of the intermediate 4-methylsulfanyl-2-
oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles
3, with a secondary amine in refluxing ethanol as
described earlier19 (Scheme 1).
Keywords: Acetylferrocene; Ferrocenylphenanthrenes; 2-Oxobenzo[h]-
chromene; Ring transformation.
q CDRI Communication No. 7301.
*
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.2007.11.014

R. Pratap, V. J. Ram / Tetrahedron Letters 49 (2008) 394–396
395
Table 1 (continued)
6 Product
SCH3
CN
O
O
Yields (%)
NC
COOCH3
DMSO/KOH
5-6 h
O
+
H3CS
SCH3
3
R
R
1
2
C2H5OH
N
N
H
R
H
Yield (%)
3
a
b
N
94
82
d
15
CN
OCH3
N
CN
O
N
Yield (%)
R
4
piperidin-1-yl
a
b
c
d
e
f
H
H
H
H
H
H
96
91
81
Fe
O
4-methylpiperidin-1-yl
4-benzylpiperidin-1-yl
4
R
4-benzylpiperazin-1-yl 85
morpholin-4-yl
tetrahydroisoquinolin-2-yl 86
85
h OCH3 4-methylpiperidin-1-yl 75
89
O
g OCH3 piperidin-1-yl
N
CN
Scheme 1. Synthesis of 2-oxobenzo[h]chromene.
e
27
As is evident from the structures of 4-sec-amino-2-oxo-
5,6-dihydrobenzo[h]chromene-3-carbonitriles 4, they
posses three electrophilic centers at C-2, C-4, and C-
10b in which the latter is highly electrophilic and prone
to nucleophilic attack due to extended conjugation and
the presence of a electron-withdrawing substituent at
position 3 of the chromene ring. The nucleophile used
in the present study is the carbanion generated in situ
from acetylferrocene in the presence of a base.
Fe
N
CN
f
22
Fe
Table 1. Ferrocenylphenanthrenes 6 synthesizeda
6
Product
Yields (%)
N
N
CN
CN
g
15
a
25
H3CO
Fe
Fe
CH3
CH3
N
N
CN
CN
b
19
h
18
Fe
H3CO
Fe
a All the compounds synthesized were characterized20 by spectroscopic
techniques.
Thus, a mixture of 4 and acetylferrocene 5 in DMF in
the presence of powdered KOH was stirred for 6–7 h
at room temperature and the progress of the reaction
was monitored by TLC. After completion, the reaction
mixture was poured onto crushed ice with vigorous stir-
ring followed by neutralization with 10% HCl. The pre-
cipitate obtained was filtered, washed with water several
N
c
22
CN
Fe

396
R. Pratap, V. J. Ram / Tetrahedron Letters 49 (2008) 394–396
4. Miller, J. S.; Epstein, A. J. Angew. Chem., Int. Ed. Engl.
1994, 33, 385–415.
N
O
O
COCH3
5. (a) Biot, C.; Glorian, G.; Maciejewski, L. A.; Brocard, J.
S. J. Med. Chem. 1997, 40, 3715–3718; (b) Itoh, T.;
Shirakami, S.; Ishida, N.; Yamashita, Y.; Yoshida, T.;
Kim, H.-S.; Wataya, Y. Bioorg. Med. Chem. Lett. 2000,
10, 1657–1659.
6. Ko¨pf-Maier, P.; Ko¨pf, H. Drugs Future 1986, 11, 297–319;
(b) Ko¨pf-Maier, P.; Ko¨pf, H.; Neuse, E. Angew. Chem.,
Int. Ed. Engl. 1984, 23, 456–457.
N
CN
CN
O
O
+
Fe
O
4
Fe
5
7. Fruhauf, H.-H. Chem. Rev. 1997, 97, 523–596; (b)
Lautens, M.; Tam, W. Chem. Rev. 1996, 96, 49; (c)
Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1984, 23,
539–556; (d) Dell, C. P. Curr. Med. Chem. 1998, 5, 179–
194; (e) Saito, S.; Yamamoto, Y. Chem. Rev. 2000, 100,
2901–2915.
8. Huffmann, C. W.; Traxler, J. T.; Krbechek, L.; Riter, R.
R.; Wagner, R. G. J. Med. Chem. 1971, 14, 90.
9. Wilson, S.; Ruenitz, P. C. J. Pharm. Sci. 1992, 82, 571.
10. Fisch, M. H.; Flick, B. H.; Arditti, J. Phytochemistry 1973,
12, 437.
N
O
O
N
CN
OH
CN
Fe
Fe
6
Scheme 2. A plausible mechanism for the formation of 3-ferro-
cenylphenanthrenes 6.
11. Kelly, T. R.; Li, Q.; Bhushan, V. Tetrahedron Lett. 1990,
31, 161.
12. (a) Tanabe, A.; Nakashima, H.; Yoshida, O.; Yamamoto,
N.; Tenmyo, O.; Oki, T. J. Antibiot. 1988, 41, 1708; (b)
Hoshino, H.; Seki, J.-I.; Takeuchi, T. J. Antibiot. 1989, 42,
344.
13. Cannon, J. G.; Khonji, R. R. J. Med. Chem. 1975, 18,
110.
times and dried. The crude product was purified by neu-
tral alumina column chromatography in 15–30% yields
and characterized as a 3-ferrocenyl-1-sec.amino-5,6-
dihydrophenanthrene-2-carbonitrile 6 (Table 1). Possi-
bly the initial step in the formation of 6 is the Michael
addition of acetylferrocene to 2-oxobenzo[h]chromene
4 followed by ring closure with loss of carbon dioxide
and water as shown in Scheme 2.
14. Nishibayashi, Y.; Segawa, K.; Ohe, K.; Uemura, S.
Organometallics 1995, 14, 5486.
15. Egger, H.; Schlogl, K. Monatsh. Chem. 1964, 96, 1750.
16. (a) Negishi, E.; Holmes, S. J.; Tour, J.; Miller, J. A.;
Cedebaum, F. E.; Swanson, D. R.; Takahashi, T. J. Am.
Chem. Soc. 1989, 111, 3336–3346; (b) Buchwald, S. I.;
Nielsen, R. B. J. Am. Chem. Soc. 1989, 111, 2870–2874; (c)
Negishi, E.; Cedebaum, F. E.; Takahashi, T. Tetrahedron
Lett. 1986, 27, 2829–2832.
17. Takahashi, T.; Tsai, F. Y.; Li, Y. Z.; Nakazima, K.;
Kotora, M. J. Am. Chem. Soc. 1999, 121, 11093.
18. Dufkova, L.; Matsumura, H.; Necas, D.; Stepnicka, P.;
Uhlik, F.; Kotora, M. Collect. Czech. Chem. Commun.
2004, 69, 351–364.
In summary, the synthesis of various ferrocenylphe-
nanthrenes possessing electron-withdrawing and donat-
ing substituents has been reported for the first time
through base-catalyzed ring transformation of suitably
functionalized 2-oxo-4-sec-amino-5,6-dihydro-2H-ben-
zo[h]chromene with acetylferrocene under very mild
reaction conditions through C–C insertion. The proce-
dure is efficient and provides a new avenue for the con-
struction of new ferrocenyl pendant partially reduced
phenanthrenes.
19. Pratap, R.; Ram, V. J. Tetrahedron Lett. 2007, 48, 2755.
20. 1-sec-Amino-3-ferrocenyl-9,10-dihydro-phenanthrene-2-car-
bonitriles (6): A mixture of 4-sec-amino-2-oxo-5,6-di-
hydro-2H-benzo[h]chromene-3-carbonitrile
(0.5 mmol),
Acknowledgments
acetylferrocene and KOH in DMF was stirred for 6–7 h.
The reaction was monitored by TLC. Excess DMF was
removed under reduced pressure and the reaction mixture
was poured onto crushed ice with vigorous stirring
followed by neutralization with 10% aqueous HCl. The
crude product thus obtained was filtered, washed with
water, dried, and purified by neutral alumina column
chromatography using 20% chloroform in hexane as
eluent. Compound 6d: Viscous oil; yield: 15%; IR (KBr):
V.J.R. and R.P. are thankful to CSIR, New Delhi, for
financial support. The authors also thank SAIF, CDRI,
Lucknow, for spectroscopic data.
References and notes
2209 (CN) cmÀ1 1H NMR (300 MHz, CDCl3): d 2.65–
;
1. Ferrocenes; Togni, A., Hayashi, T., Eds.; VCH: Weinheim,
1995.
2. Lehn, J. M. Angew. Chem., Int. Ed. Engl. 1990, 29, 1304–
1319.
3. Beer, P. D.; Dickson, C. A. P.; Fletcher, N.; Goulden, A.
J.; Grieve, A.; Hodacora, J.; Wear, T. J. Chem. Soc.,
Chem. Commun. 1993, 828–830.
2.75 (br s, 4H, CH2), 2.87–2.89 (m, 4H, CH2), 3.45–3.55
(m, 4H, CH2), 3.64 (s, 2H, CH2), 4.20 (s, 5H, FcH), 4.43 (t,
J = 1.83 Hz, 2H, ArH), 4.92 (t, J = 1.86 Hz, 2H, FcH),
7.32–7.41 (m, 8H, ArH), 7.74–7.78 (m, 1H, ArH), 7.82 (s,
1H, ArH); MS m/z 564 (M++1); HRMS: (EI, 70 eV) calcd
for C36H33FeN3, 563.20239 (M+), found m/z 563.20353.