Acetyltrimethylsilane mediated synthesis of dihydrophenanthrenes

Article abstract of DOI:10.1016/j.tetlet.2007.07.014

An easy and efficient synthesis of phenanthrene derivatives through base catalyzed ring transformation of 4-sec-amino-2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles with acetyltrimethylsilane is described in good yields. The advantage of this react

Full text of DOI:10.1016/j.tetlet.2007.07.014

Tetrahedron Letters 48 (2007) 6318–6320
I
Acetyltrimethylsilane mediated synthesis of dihydrophenanthrenes
Ramendra Pratap and Vishnu Ji Ram*
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
Received 7 May 2007; revised 25 June 2007; accepted 5 July 2007
Abstract—An easy and efficient synthesis of phenanthrene derivatives through base catalyzed ring transformation of 4-sec-amino-2-
oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles with acetyltrimethylsilane is described in good yields. The advantage of this
reaction is the direct transformation of 2-oxobenzo[h]chromene into phenanthrene via C–C insertion from acetyltrimethylsilane.
Ó 2007 Elsevier Ltd. All rights reserved.
The synthetic potential of organosilicon reagents for the
regio- and stereocontrolled synthesis of natural prod-
these, 9,10-dihydrophenanthrenes with a pendant ester
1
12
group are reported to behave as liquid crystals and
1
3
ucts and their use as mild reagents in the preparation
of various compounds has been explored extensively.
Organosilicons such as aryl, alkenyl-, allyl- and alkylsil-
anes have been developed as coupling reagents and
the corresponding acids act as 5a-reductase inhibitors.
Numerous approaches have been reported for the syn-
1
4
15
thesis of phenanthrenes and dihydrophenanthrenes
2
16
17
alternatives to magnesium, boron, zinc and tin alkyls.
through ring annulation and intermolecular and
1
8
In addition, aryltrialkoxysilanes have also been devel-
oped as coupling reagents for the synthesis of biaryls
intramolecular cyclization. The majority of the proce-
dures suffer from limitations such as accessibility of the
precursors, multisteps, harsh reaction conditions, func-
tional group tolerance, relatively low overall yields,
and lack of well defined regiocontrol.
3
on reaction with aryl halides. Among the various
organosilanes, alkanoyl- and aroylalkylsilanes are very
prominent and useful in organic synthesis. These
reagents behave like ketones and can be very reactive
4
0
depending upon the group attached to the silicon. Acyl
2,2 -Disubstituted biphenyls have been used as precur-
silanes are considered as poor substrates for functional-
ization due to their high sensitivity to air and light and
are used as aldehyde equivalents especially in the case
of lower aldehydes, which are gases at room tempera-
ture. They can also be used as a source of carbanions
sors for the preparation of phenanthrene by intramole-
1
8
19
cular condensation. Palladium catalyzed reaction of
o-substituted aryl iodides and biphenyl or alkylphenyl-
acetylenes is an alternative route to the synthesis of
2
0
phenanthrenes. They are also prepared through base
catalyzed ring transformation of methyl 6-aryl-4-meth-
ylsulfanyl-2H-pyran-2-one-3-carboxylate with 1-tetr-
alone in moderate yield. The pharmacological
importance and lack of convenient and efficient proce-
dures, prompted us to develop a concise, straightfor-
ward, and economical route for the construction of
phenanthrenes possessing electron withdrawing or
donating substituents. The immense synthetic
potential of organosilicon reagents prompted us to use
acetyltrimethylsilane as a source of carbanions for the
base catalyzed ring transformation of 2-oxo-5,6-
dihydrobenzo[h]chromenes 4 to give phenanthrene
derivatives through C–C insertion.
5
and as acetylating agents. To the best of our knowledge
acetyltrimethylsilane has not been used so far as a
reagent for the synthesis of phenanthrene derivatives,
which are considered to be building blocks for polycyclic
aromatics and heteroaromatics.6
The diverse pharmacological activities associated with
7
phenanthrene derivatives include antimicrobial, anti-
8
9
10
11
malarial, anticancer, anti-HIV, and emetic. Besides
Keywords: Acetyltrimethylsilane; Dihydrophenanthrene; 2-Oxobenzo[h]-
chromenes; Ring transformation.
q
CDRI Communication No. 7217.
*
Corresponding author. Tel.: +91 522 2612411; fax: +91 522
623405; e-mail: vjiram@yahoo.com
Herein, we report an efficient, concise and novel
approach for the synthesis of phenanthrene derivatives.
2
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.07.014

R. Pratap, V. J. Ram / Tetrahedron Letters 48 (2007) 6318–6320
6319
SCH3
CN
O
N
O
NC
COOCH3
CN
O
DMSO/KOH
5-6 h
R
CH COSiMe3
3
+
O
O
4
H CS
3
SCH3
5
3
R
R
KOH/Dry DMF
1
2
C H OH
X
2
5
N
H
3
R
H
Yield (%)
N
O
a
b
N
O
9
4
OCH3
82
N
CN
CN
CN
O
O
SiMe3
SiMe3
O
R
7
R
4
R
Scheme 1. Synthesis of 2-oxo-4-sec-amino-5,6-dihydro-2H-benzo-
h]chromene-3-carbonitriles 4.
N
N
O
O
[
CN
CN
N
2
-Oxo-5,6-dihydrobenzo[h]chromenes 4 used in the
CN
OSiMe3
O
H
synthesis were prepared in two steps. The first step
was the synthesis of 4-methylsulfanyl-2-oxo-5,6-di-
hydrobenzo[h]chromenes 3 via the base catalyzed reac-
tion of methyl 2-cyano-3,3-dimethylthioacrylate 1 and
Si
Me3
R
R
R
6
6
N
R
Yields (%)
1
-tetralone 2 in DMSO. The reaction mixture was
poured onto crushed ice with vigorous stirring to yield
. Amination of 3 with a secondary amine in boiling
ethanol afforded 2-oxo-4-sec-amino-5,6-dihydro-2H-
a
b
c
d
e
f
g
h
Piperidin-1-yl
H
H
H
H
H
68
71
66
61
56
71
61
72
3
4-Methylpiperidin-1-yl
4-Benzylpiperidin-1-yl
4-Benzylpiperazin-1-yl
4-Morpholin-1-yl
2
1
benzo[h]chromene-3-carbonitriles
Scheme 1 and Table 1).
4 in good yields
(
Tetrahydroisoquinolin-2-yl
H
Piperidin-1-yl
OCH
OCH
3
The structures of the 4-sec-amino-2-oxo-5,6-dihydro-
benzo[h]chromene-3-carbonitriles 4, have three electro-
philic centers 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 an elec-
tron-withdrawing substituent at position 3 of the chro-
mene ring. The nucleophile used in this reaction is the
carbanion generated in situ from acetyltrimethylsilane
by base. Thus a mixture of 4, acetyltrimethylsilane 5
and powdered KOH in DMF was stirred for 2–2.5 h
under nitrogen in the dark to avoid side reactions and
decomposition. The progress of the reaction was moni-
tored by TLC and on completion the mixture was
poured onto crushed ice with vigorous stirring and then
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 decreased
4-Methylpiperidin-1-yl
3
Scheme 2. Mechanism involved in the synthesis of 9,10-dihydro-1-sec-
aminophenanthrene-2-carbonitriles (6).
to half possibly due to decomposition of acetyltrimethyl-
silane in air. The product isolated was characterized as
9,10-dihydro-1-sec-aminophenanthrene-2-carbonitrile (6)
and not the expected 9,10-dihydro-1-sec-amino-3-tri-
methylsilylphenanthrene-2-carbonitrile 7, as shown in
Scheme 2.
Since hydrolysis of acetyltrimethylsilane in the presence
2
2
of aqueous base is well documented at room tempera-
ture into silanol and acetaldehyde, the reactions were
carried out in dry DMF under an inert atmosphere.
The reaction is possibly initiated by attack of the car-
banion of 5 generated in situ by base, at the highly elec-
trophilic center at C-10b with Michael addition followed
by intramolecular cyclization involving C-3 of the
chromene ring and the carbonyl functionality of acetyl-
trimethylsilane to form an intermediate. The intermedi-
ate diene after elimination of carbon dioxide undergoes
elimination of trimethylsilanol, to produce the phenan-
threne derivatives.
Table 1. Yields of the different 4-sec-amino-2-oxo-5,6-dihydro-
benzo[h]chromenes 4
4
R
Yields (%)
N
a
b
c
d
e
f
Piperidin-1-yl
H
H
H
H
H
H
OCH
OCH
94
93
86
79
89
87
81
77
4-Methylpiperidin-1-yl
4-Benzylpiperidin-1-yl
4-Benzylpiperazin-1-yl
4-Morpholin-1-yl
Tetrahydroisoquinolin-2-yl
Piperidin-1-yl
In summary, the synthesis of phenanthrenes possess-
ing electron-withdrawing and donating substituents is
reported for the first time through base catalyzed ring
transformation of suitably functionalized 2-oxo-4-sec-
amino-5,6-dihydro-2H-benzo[h]chromenes with acetyl-
trimethylsilane under very mild reaction conditions.
g
h
3
3
4-Methylpiperidin-1-yl

6320
R. Pratap, V. J. Ram / Tetrahedron Letters 48 (2007) 6318–6320
The procedure opens a new avenue for the construction
of phenanthrene derivatives in good yields. All the prod-
ucts were characterized by spectroscopic techniques.
16. (a) Bradsher, C. K. Chem. Rev. 1987, 87, 1277–1297; (b)
Catellani, M.; Motti, E.; Baratta, S. Org. Lett. 2001, 3,
3611–3614.
2
3
1
7. (a) Ramana, M. M. V.; Potnis, P. V. Synthesis 1996, 1090–
092; (b) Radhakrishnan, K. V.; Yoshikawa, E.; Yamam-
1
oto, Y. Tetrahedron Lett. 1999, 40, 7533–7535; (c) Paredes,
E.; Biolatto, B.; Kneetmann, M.; Mancini, P. Tetrahedron
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Acknowledgments
1
8. (a) Harrowven, D. C.; Nunn, M. I. T.; Fenwick, D. R.
Tetrahedron Lett. 2002, 43, 3185–3187; (b) Almeida, J. F.;
Castedo, L.; Fernandez, D.; Neo, A. G.; Romero, V.;
Tojo, G. Org. Lett. 2003, 5, 4939–4941.
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.
1
2
9. Catellani, M.; Motti, E.; Baratta, S. Org. Lett. 2001, 3,
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611–3614.
0. Ram, V. J.; Goel, A. J. Chem. Res. (S) 1997, 460–461.
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23. General procedure for the synthesis of 9,10-dihydro-1-sec-
aminophenanthrene-2-carbonitriles (6): A mixture of 4
(0.5 mmol), acetyltrimethylsilane 5 (0.6 mmol) and KOH
(0.8 mmol) in dry DMF was stirred under a nitrogen
atmosphere in the dark. The reaction was monitored by
TLC. After completion of the reaction excess DMF was
removed under reduced pressure. The reaction mixture
was poured onto crushed ice with vigorous stirring
followed by neutralization with 10% aqueous HCl. The
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5
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9
ꢀ1 1
Viscous oil, yield: 68%; IR (KBr): 2208 (CN) cm ; H
NMR (300 MHz, CDCl ): d 1.70–1.75 (m, 6H, CH ),
2.78–2.83 (m, 2H, CH ), 2.87–2.92 (m, 2H, CH ), 3.22 (br
s, 4H, CH ), 7.25–7.37 (m, 3H, ArH), 7.47 (d, J = 8.37 Hz,
1H, ArH), 7.50 (d, J = 8.37 Hz, 1H, ArH), 7.67–7.70 (m,
1
0. (a) Tanabe, A.; Nakashima, H.; Yoshida, O.; Yamamoto,
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2
N.; Tenmyo, O.; Oki, T. J. Antibiot. 1988, 41, 1708–1710;
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4
1
3
1
3
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1
1
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127.35, 131.37, 132.62, 136.58; MS (ESI) m/z 289 (M +1);
+
HRMS: (EI, 70 eV) calcd for C20
H
20
N
2
288.16265 (M )
found m/z 288.16244. Compound (6d): Viscous oil, yield:
ꢀ
1 1
6
1
18–620; (b) Boger, D. L.; Mullican, M. D. J. Org. Chem.
984, 49, 4045–4050.
61%; IR (KBr): 2211 (CN) cm
CDCl ): d 2.64 (m, 4H, CH ), 2.78–2.83 (m, 2H, CH
2.87–2.95 (m, 2H, CH ), 3.32 (br s, 4H, CH ), 3.61 (s, 2H,
CH ), 7.14–7.40 (m, 8H, ArH), 7.49 (d, J = 8.16 Hz, 1H,
ArH), 7.53 (d, J = 8.22 Hz, 1H, ArH), 7.66–7.69 (m, 1H,
;
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),
2
3
2
1
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+
(M +1); HRMS: (EI, 70 eV) calcd for
C H N
26 25 3
+
640.
379.20485 (M ) found m/z 379.20491.