An efficient and versatile route to the synthesis of 9,10-dihydro-3-formylphenanthrenes

Article abstract of DOI:10.1016/j.tetlet.2007.01.049

An innovative and efficient route to the synthesis of 9,10-dihydro-3-formylphenanthrenes 7 has been delineated through the ring transformation of 2-oxo-4-sec-amino-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles 4 with methyl glyoxaldimethylacetal 5 to ma

Full text of DOI:10.1016/j.tetlet.2007.01.049

Tetrahedron Letters 48 (2007) 1715–1719
An efficient and versatile route to the synthesis
of 9,10-dihydro-3-formylphenanthrenesI
Ramendra Pratap and Vishnu Ji Ram*
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
Received 20 November 2006; revised 2 January 2007; accepted 10 January 2007
Available online 14 January 2007
Abstract—An innovative and efficient route to the synthesis of 9,10-dihydro-3-formylphenanthrenes 7 has been delineated through
the ring transformation of 2-oxo-4-sec-amino-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles 4 with methyl glyoxaldimethylac-
etal 5 to masked 3-dimethoxymethyl-1-sec-amino-9,10-dihydrophenanthrene-3-carbonitriles 6 followed by deacetalation with
Amberlyst 15 in excellent yields.
Ó 2007 Elsevier Ltd. All rights reserved.
The presence of a formyl group in a molecule makes it
highly versatile for generating molecular diversity
through C–C and C–heteroatom bond formation.1 For-
myl derivatives are invariably used as ligands for the
synthesis of metal chelates. They are also useful building
blocks for the construction of various synthetic and nat-
ural products of therapeutic importance. There are var-
ious ways to introduce a formyl group onto an aromatic
ring. Among these protocols, Gatterman,2 Gatterman-
Koch3 and Vilsmeier-Haack4 reactions are prominent.
The use of formylating agents such as orthoformate,5
chloride in the presence of 5% Pd–BaSO4 catalyst in
very good yields. This route is also useful for the prepa-
ration of 9-formyl phenanthrene, which has also been
prepared14 by the reaction of phenanthrene and HCN
as well as from the interaction of 9-phenanthrylmagne-
sium bromide and ethyl orthoformate.
The lack of a concise, straightforward protocol for the
construction of 9,10-dihydro-3-formylphenanthrene in-
spired us to develop a novel, short and efficient synthesis
as an alternative to the former procedures.
6
7
formyl fluoride–BF3 and dichloromethyl ether–AlCl3
are alternative routes to the synthesis of formyl arenes.
These are also obtained by oxidation of methyl or hy-
droxy methyl arenes,8 or reduction of nitriles,9 amides10
and acid chlorides.11
2-Oxo-4-sec-amino-5,6-dihydro-2H-benzo[h]chromene-
3-carbonitriles (4), which were used as synthons for the
SCH3
It was a great surprise to us that the chemistry of form-
ylphenanthrenes had not been explored significantly
after 1936. The synthesis of 1-formylphenanthrene has
been reported12 from 1-phenanthranilide by conversion
into imidoyl chloride followed by reduction with SnCl2
and HCl, while 2- and 3-formylphenanthrenes were pre-
pared13 by the hydrogenation of the corresponding acid
CN
O
NC
COOCH3
DMSO/KOH
6 h
R
O
O
+
H3CS
SCH3
R
3
1
2
HNR1R2
NR1R2
C2H5OH
CN
O
O
Keywords: Tetralone; Formylphenanthrene; 2-Oxo-4-sec-amino-5,6-
dihydro-2H-benzo[h]chromene-3-carbonitriles; Masked aldehyde;
Ring transformation.
q CDRI Communication No. 7079.
R
4
*
Scheme 1. Reaction showing the synthesis of 2-oxo-4-sec-amino-5,6-
dihydro-2H-benzo[h]chromene-3-carbonitriles.
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.2007.01.049

1716
R. Pratap, V. J. Ram / Tetrahedron Letters 48 (2007) 1715–1719
Table 1. Duration of reaction and yields of the various 2-oxo-5,6-
dihydrobenzo[h]chromenes
preparation of 9,10-dihydro-3-formylphenanthrenes
were synthesized in two steps. The first step was the
synthesis of 4-methylsulfanyl-2-oxo-5,6-dihydro-2H-
benzo[h]chromene-3-carbonitrile 3, from the reaction
of methyl 2-cyano-3,3-dimethylthioacrylate 1 and 1-tetr-
alone 2 in the presence of powdered KOH in DMSO.
The second step was the amination of 3 with a sec-amine
in refluxing ethanol (Scheme 1 and Table 1).
Compound
Structure
Duration of
reaction (h)
Yields
(%)
SCH3
CN
3a
6
6
94
82
O
O
SCH3
CN
From the topography of 2-oxo-4-sec-amino-5,6-dihy-
dro-2H-benzo[h]chromene-3-carbonitriles 4 it is evident
that the C-2, C-4 and C-10b positions are electrophilic
in nature. Position C-10b is highly susceptible to nucleo-
philic attack due to the extended conjugation and the
presence of an electron-withdrawing substituent at posi-
tion 3 of the chromene ring. The masked 9,10-dihydro-
3-formylphenanthrenes 6 were prepared by stirring an
equimolar mixture of 4, methyl glyoxaldimethylacetal
5 and powdered KOH in dry DMF at room temperature
for 2.5–4 h, followed by pouring the reaction mixture
onto crushed ice with vigorous stirring. Neutralization
of the reaction mixture with 10% aqueous HCl provided
a precipitate, which was filtered, washed with water and
finally purified on a neutral alumina column and charac-
terized as the masked aldehydes 6 in 72–91% yield
(Scheme 2 and Table 2). There was also the possibility
of formation of (3-dimethoxymethyl-9,10-dihydro-2-
oxaphenanthrene-1-ylidene)acetonitrile by cyclization
involving the enolic OH and C-4 of the 2-
oxobenzo[h]chromene through Michael addition fol-
lowed by elimination of the secondary amine. However,
under the applied reaction conditions no such product
was isolated possibly due to the presence of the elec-
tron-releasing acetal group, which did not facilitate
enolization.
3b
4a
O
O
H3CO
N
O
5.5
96
CN
O
CH3
N
O
4b
6.5
91
CN
O
C6H5
4c
N
O
7
81
CN
O
The reaction was possibly initiated by the attack of a
carbanion, generated in situ from methyl glyoxaldime-
thylacetal 5 at C-10b with ring closure followed by
decarboxylation and dehydration to yield 6. The deace-
talation of 6 by Amberlyst 15 led to aldehyde 7 in high
yields (Scheme 3 and Table 3).
N
O
4d
6
82
CN
O
To the best of our knowledge, this is the first report on
the synthesis of functionalized 9,10-dihydro-3-formylph-
enanthrenes using 2-oxo-4-sec-amino-5,6-dihydro-2H-
benzo[h]chromene-3-carbonitriles 4 as substrates for
CH3
N
O
4e
5.5
71
1R2RN
CN
O
O
O
NR1R2
5
CN
4
O
CN
3
6
DMF/KOH
OCH3
OCH3
O
2
H3C
+
10b
7
O
O
10a
1
H3CO
OCH3
OCH3
10
5
8
R
9
4
R
C6H5
1R2RN
1R2RN
O
O
N
H3CO
NC
OCH3
CN
CN
OH
OH
4f
N
O
6
79
H
OCH3
1R2RN
OCH3
CN
O
OCH3
OCH3
R
R
6
R
Scheme 2.

R. Pratap, V. J. Ram / Tetrahedron Letters 48 (2007) 1715–1719
1717
NR1R2
CN
Table 2. Duration of reaction and yields of the various masked 9,10-
dihydro-3-formylphenanthrene aldehydes
NR1R2
CN
Compound Structure
Duration of Yields
reaction (h) (%)
Amberlyst 15
CHCl3
OCH3
OCH3
CHO
R
R
6
7
N
Scheme 3.
CN
6a
3
84
OCH3
OCH3
Table 3. Duration of reaction and yields of the various 9,10-dihydro-3-
formylphenanthrene aldehydes
Compound Structure
Duration of Yields
reaction (h) (%)
CH3
N
6b
2.5
72
N
CN
7a
3
98
CN
OCH3
OCH3
CHO
CH3
N
C6H5
7b
2.5
99
CN
N
6c
3
86
CHO
CN
OCH3
OCH3
C6H5
N
7c
3
97
CN
CHO
N
6d
6e
6f
4
76
91
87
CN
OCH3
OCH3
N
7d
4
99
CN
CH3
CHO
CH3
N
3.5
CN
OCH3
OCH3
N
7e
3.5
99
CN
H3CO
C6H5
CHO
H3CO
C6H5
N
N
N
2.5
N
7f
3.5
98
CN
CN
OCH3
OCH3
CHO

1718
R. Pratap, V. J. Ram / Tetrahedron Letters 48 (2007) 1715–1719
Synthesis
of
4-methylsulfanyl-2-oxo-5,6-dihydro-2H-
ring transformation reactions with methyl glyoxaldime-
thylacetal 5. The synthetic strategy is very simple and
straightforward. The yields were excellent without the
use of any catalyst.
benzo[h]chromene-3-carbonitrile (3a): Compound 3a was
obtained by stirring an equimolar mixture of methyl 2-
cyano-3,3-dimethylthioacrylate (0.05 mol, 10.15 g) and 1-
tetralone (0.05 mol, 7.3 mL) in the presence of powdered
KOH (0.06 mol, 3.4 g) in DMSO (50 mL) for 5–6 h.
Thereafter, the reaction mixture was poured onto crushed
ice with vigorous stirring. The precipitate was filtered,
washed with water then dried and purified by crystalliza-
tion from methanol. Yield: 94%; mp: 204–206 °C; IR
(KBr): 2922, 2370, 2207, 1699, 1612, 1570, 1508,
1446, 1372, 1279, 1257, 1221, 1155, 1132, 1092, 1037,
All the compounds synthesized were characterized by
spectroscopic techniques.15 This methodology provided
a new avenue for the synthesis of congested 9,10-dihy-
dro-3-formylphenanthrenes in excellent yields.
968, 900, 784, 742 cmÀ1; H NMR: (300 MHz, CDCl3): d
1
Acknowledgements
2.77–2.83 (m, 2H, CH2), 2.88–2.96 (m, 2H, CH2), 2.98 (s,
3H, SCH3), 7.23–7.27 (m, 1H, ArH), 7.31–7.44 (m, 2H,
ArH), 7.86–7.88 (m, 1H, ArH); 13C NMR (75 MHz,
CDCl3): d 16.26, 20.37, 25.56, 91.60, 110.89, 113.69,
123.70, 125.19, 126.28, 126.69, 130.88, 137.01, 153.23,
157.07, 167.07; MS m/z 270 (M++1); HRMS: (EI, 70 eV)
calcd for C15H11NO2S 269.05105 (M+) found for m/z
269.05153.
V.J.R. and R.P. are thankful to the CSIR, New Delhi,
for financial support. The authors also thank SAIF,
CDRI, Lucknow, for providing spectroscopic data.
Synthesis of 4-(piperidin-1-yl)-2-oxo-5,6-dihydro-2H-
benzo[h]chromene-3-carbonitrile (4a): Compound 4a was
prepared by refluxing a mixture of 3a (0.01 mol, 2.7 g) and
piperidine (0.012 mmol, 1.3 mL) in ethanol (50 mL) for
5 h. The reaction mixture was cooled to room temperature
and filtered. The resulting precipitate was crystallized from
ethanol, yield: 96%; mp: 238–240 °C; IR (KBr): 2938,
2855, 2208, 1702, 1611, 1513, 1452, 1349, 1302, 1245, 1145,
1095, 1049, 1003, 974, 939, 896, 760, 709 cmÀ1; 1H NMR:
(300 MHz, CDCl3): d 1.76 (br s, 6H, CH2), 2.65–2.70 (m,
2H, CH2), 2.86–2.91 (m, 2H, CH2), 3.51–3.53 (m, 4H,
CH2), 7.21–7.24 (m, 1H, ArH), 7.30–7.41 (m, 2H, ArH),
7.82–7.86 (m, 1H, ArH); MS m/z 307 (M++1); HRMS:
(EI, 70 eV) calcd for C19H18N2O2 306.1360 (M+) found
for m/z 306.1358.
References and notes
1. Mohata, P. K.; Kumar, U. K. S.; Sriram, V.; Illa, H.;
Junjappa, H. Tetrahedron 2003, 59, 2631.
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Delassus, A.; Jacquier, R. Org. Prep. Proced. Int. 1993,
25, 338; (b) Jutz, C. Adv. Org. Chem. 1976, 9, 225; (c)
Meth-Cohn, O.; Goon, S. J. Chem. Soc., Perkin Trans. 1
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(e) Meth-Cohn, O.; Tarnowski, B. In Advances in
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Michalik, M.; Montero, A.; Peseke, K. Synthesis 2001,
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Tillyer, R. D.; Grabowski, E. J. J.; Reider, P. J. Tetra-
hedron Lett. 2001, 42, 6815.
Synthesis of masked formylphenanthrenes (6): An equimo-
lar mixture of 2-oxo-4-sec.amino-5,6-dihydro-2H-
benzo[h]chromene-3-carbonitrile (0.5 mmol), methyl gly-
oxaldimethylacetal (0.5 mmol) and powdered KOH
(0.7 mmol) in dry DMF was stirred at room temperature
for 2–3 h. Thereafter, the reaction mixture was poured
onto crushed ice with vigorous stirring. Neutralization
with 10% aqueous HCl gave a precipitate which was
filtered, washed with water and purified by neutral
alumina column chromatography using hexane:ethyl ace-
tate (99:1) as the eluent. Compound 6d: Yield: 76%; mp:
168–170 °C; IR (KBr): 2928,2838, 2367, 2341, 2219, 1658,
1588, 1552, 1427, 1375, 1255, 1216, 1118, 1065, 971, 893,
762 cmÀ1 1H NMR: (300 MHz, CDCl3): 2.73–2.78 (m,
;
2H, CH2), 2.88 (br s, 2H, CH2), 3.04 (br s, 2H, CH2), 3.49
(s, 6H, OCH3), 3.65 (br s, 2H, CH2), 4.38 (br s, 2H, CH2),
5.65 (s, 1H, CH), 7.02–7.05 (m, 1H, ArH), 7.13–7.35 (m,
6H, ArH), 7.78–7.81 (m, 1H, ArH), 7.87 (s, 1H, ArH);13C
NMR: (75 MHz, CDCl3): 22.10, 27.07, 29.35, 47.40, 51.46,
53.40, 100.98, 106.02, 115.02, 117.59, 123.66, 124.49,
124.88, 124.97, 125.90, 126.71, 127.60, 127.99, 132.41,
133.28, 133.40, 135.47, 136.62, 138.85, 140.10, 151.56; MS
m/z 411 (M++1); HRMS: (EI, 70 eV) calcd for
C27H26N2O2 410.1994 (M+) found for m/z 410.1988.
Synthesis of 3-formylphenanthrenes (7): These were
obtained by stirring a solution of masked formylphe-
nanthrene 6 (0.2 mmol) in chloroform with Amberlyst 15
for 2.5–4 h. The progress of the reaction was monitored by
TLC. After completion, the reaction mixture was filtered
and the solvent was removed under reduced pressure. The
solid obtained was crystallized from chloroform:methanol
(1:1). Compound 7e: Yield: 99%; mp: 164–166 °C; IR
(KBr): 2923, 2848, 2362, 2219, 1698, 1593, 1430, 1384,
9. Zilberman, E. N.; Pyryalova, P. S. J. Gen. Chem. USSR
1963, 33, 3348.
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14. Miller, H. F.; Bachman, G. B. J. Am. Chem. Soc. 1935, 57,
766.
15. Representative procedure for the synthesis of 2-oxo-4-sec-
amino-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles (4):

R. Pratap, V. J. Ram / Tetrahedron Letters 48 (2007) 1715–1719
1719
1353, 1220, 1152, 1101, 1055, 972, 900, 838, 758, 700 cmÀ1
;
2.58 Hz, 1H, ArH), 7.71 (d, J = 8.61 Hz, 1H, ArH), 8.02
(s, 1H, ArH), 10.36 (s, 1H, CHO); 13C NMR: (75 MHz,
CDCl3): 20.87, 27.18, 28.42, 29.27, 33.83, 50.15, 54.11,
111.55, 112.08, 118.25, 124.60, 125.26, 135.08, 138.10,
139.29, 140.10, 153.67, 159.29, 188.30; MS m/z 361
(M++1); HRMS: (EI, 70 eV) calcd for C23H24N2O2
360.1837 (M+) found for m/z 360.1843.
1H NMR: (300 MHz, CDCl3): 1.01 (d, J = 6.3 Hz, 3H,
CH3), 1.41–1.44 (m, 1H, CH), 1.61–1.64 (m, 2H, CH2),
1.73–1.77 (m, 2H, CH2), 2.81 (t, J = 6.69 Hz, 2H, CH2),
2.94 (t, J = 6.48 Hz, 2H, CH2), 3.13–3.16 (m, 2H, CH2),
3.40–3.44 (m, 2H, CH2), 3.86 (s, 3H, OCH3), 6.81 (d,
J = 2.4 Hz, 1H, ArH), 6.87 and 6.89 (dd, J = 2.58 and