An unusual synthesis of tetrahydrobenzo[f]isoquinolines

Article abstract of DOI:10.1016/j.tetlet.2007.09.059

A facile and short synthesis of 2-oxo-4-sec-amino-2,3,5,6-tetrahydrobenzo[f]isoquinoline-1-carbonitriles has been delineated through base catalyzed ring transformation of 5,6-dihydro-2-oxo-4-sec-amino-2H-benzo[h]chromene-3-carbonitrile by cyanoacetamide i

Full text of DOI:10.1016/j.tetlet.2007.09.059

Tetrahedron Letters 48 (2007) 7982–7985
An unusual synthesis of tetrahydrobenzo[f]isoquinolinesI
Ramendra Pratap,a Resmi Raghunandan,b P. R. Maulikb and Vishnu Ji Rama,*
aMedicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India
bMolecular and Structural Biology Division, Central Drug Research Institute, Lucknow 226 001, India
Received 9 July 2007; revised 29 August 2007; accepted 7 September 2007
Available online 14 September 2007
Abstract—A facile and short synthesis of 2-oxo-4-sec-amino-2,3,5,6-tetrahydrobenzo[f]isoquinoline-1-carbonitriles has been
delineated through base catalyzed ring transformation of 5,6-dihydro-2-oxo-4-sec-amino-2H-benzo[h]chromene-3-carbonitrile by
cyanoacetamide in excellent yields.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
ture survey revealed that the chemistry of highly func-
tionalized benzo[f]isoquinoline ring systems is meagerly
explored.
Isoquinoline ring systems have been identified as major
structural motifs, widely present in various natural
products of chemical and therapeutic importance.1
Annoretine2 (Ia) and litabamine3 (Ib) are the two phen-
anthrene alkaloids isolated from Annota Montana and
Litsea cubeba, respectively, in Figure 1, in which the for-
mer exhibits cytotoxic activity4 against different human
cell cultures whilst the latter is active as a platelet anti-
aggregant5 and against acetyl choline esterase.6 These
alkaloids belong to the family of [2,1-f]isoquinolines
and, surprisingly, have received little attention towards
the development of their chemistry. An extensive litera-
These diverse pharmacological activities and limited
synthetic procedures inspired us to develop a novel
and facile synthetic route, which could provide com-
pounds with the benzo[f]isoquinoline motif.
A multistep synthesis of [2,1-f]isoquinolines has been
reported7 from [2-(2-styrylphenyl)ethyl]methylcarbamic
acid ethyl ester through a Bischler–Napieralski cycliza-
tion followed by photocyclization. Pyrolysis of 4-(2-
ethynylphenyl)pyridine at 810 ꢁC and 0.5 mbar pressure
resulted in benzo[f]isoquinolines as the major product.8
This procedure is only of theoretical importance. Cycli-
zation of stilbenes by tributyltin hydride and AIBN in
toluene at 80 ꢁC produced9 benzo[f]isoquinoline as a
major product. Junjappa and co-workers10 have also
reported the synthesis of this class of compounds from
the reaction of the oxoketene dithioacetal derived from
1-tetralone and enol acetals in the presence of phosphoric
acid. A base catalyzed condensation of 1,2-(dibromo-
methylene)naphthalene with ethyl acetamidocyanoace-
tate is also an alternative route11 for the construction
of tetrahydrobenzo[f]isoquinolines. They have also been
prepared12 by electrocyclization of 1-vinyl-3,4-dihydro-
naphthalene-2-carboxaldehyde and N,N-dimethylhyd-
razones with the loss of dimethylamine. Recently,
there is a thermolytic transformation of benzocyclobut-
enes into quinodimethane intermediates as dienes, which
undergo intramolecular Diels–Alder cyclization reaction
to produce13 benzo[f]isoquinolines. A new approach for
O
R1
CN
HN
R2
N
N
R
H3CO
CH3
II
OH
Ia) R1 = R2 = H (Annoretine)
Ib) R1 = OH; R2 = OCH3 (Litebamine)
Figure 1.
Keywords:
2-Oxo-4-(piperidin-1-yl)-5,6-dihydro-2H-benzo[h]-chro-
mene-3-carbonitriles; Ring transformation; Benzo[f]-isoquinoline.
q CDRI Communication No. 7305.
*
Corresponding author. Tel.: +91 522 2612411; fax: +91 522
2623405; e-mail: vjiram@yahoo.com
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.059

R. Pratap et al. / Tetrahedron Letters 48 (2007) 7982–7985
7983
the synthesis of 5,6-dihydrobenzimidazo[1,2-b]benzo[f]-
isoquinolines has been reported14 through condensa-
tion–cyclization of the oxoketene dithioacetal derived
from 1-tetralone with 2-methyl/cyanomethylbenz-
imidazole but this procedure has the limitation of
providing only methylsulfanyl substituted fused
benzo[f]isoquinolines.
N
O
N
O
CN
NH2
CN
NH2
NC
DMF/KOH
+
O
O
4
O
5
CN
O
R
R
Herein, we report an efficient synthesis of 2-oxo-4-sec-
amino-2,3,5,6-tetrahydrobenzo[f]-isoquinoline-1-carbo-
nitriles 6 through base catalyzed ring transformation
of 5,6-dihydro-2-oxo-4-sec-amino-2H-benzo[h]chromene-
3-carbonitriles 4 by cyanoacetamide using powdered
KOH as a base in DMF. However, we failed to effect
the analogous ring transformation of 2-oxo-4-methyl-
sulfanyl-5,6-dihydro-2H-benzo[h]chromene-3-carbonitri-
les 3 by cyanoacetamide, possibly due to the preference
of a substitution reaction at C-4 of the chromene ring
rather than the attack at C-10b for the ring transforma-
tion. To avoid these side reactions, 5,6-dihydro-2-oxo-4-
sec-amino-2H-benzo[h]chromene-3-carbonitriles were
considered more appropriate precursors for the ring
transformation reaction and were synthesized in two
steps. The first step was the synthesis of 2-oxo-4-meth-
N
H
CN
NH
N
N
H
NH
O
O
CN
R
CN
-CH3CN
R
N
NH
O
CN
R
6
6
R
Duration
Yields (%)
N
ylsulfanyl-5,6-dihydro-2H-benzo[h]chromenes
3 from
a
b
c
d
e
f
H
H
H
H
H
H
piperidin-1-yl
2
1.5
2
95
92
97
95
91
90
97
89
the reaction of methyl 2-cyano-3,3-dimethylthioacrylate
1 and 1-tetralone 2 in DMSO using powdered KOH as a
base. Amination15 of 3 was affected by refluxing with a
secondary amine in ethanol (Scheme 1).
4-methyl-piperidin-1-yl
4-benzyl-piperidin-1-yl
tetrahydroisoquinolin-2-yl
4-benzyl-piperazine-1-yl
marpholin-4-yl
2
2.5
1.5
1.5
2
The topography of 5,6-dihydro-2-oxo-4-sec-amino-2H-
benzo[h]chromene-3-carbonitriles 4 revealed the pres-
ence of three electrophilic centre C-2, C-4 and C-10b
in which the latter is highly prone to nucleophilic attack
due to extended conjugation and the presence of an elec-
tron withdrawing CN substituent at C-3 position of the
chromene ring. The nucleophile used as a carbanion was
generated in situ from cyanoacetamide. Thus, a mixture
of 4, cyanoacetamide 5 and powdered KOH in DMF
was stirred at room temperature for 2–3 h. During this
period all the precursors were consumed with the
appearance of a new spot on TLC. The reaction mixture
was poured onto crushed ice with vigorous stirring and
thereafter neutralized with 10% HCl. The resulting
g
h
OCH3 piperidin-1-yl
OCH3 4-methyl-piperidin-1-yl
Scheme 2. A plausible mechanism for the synthesis of 2-oxo-4-sec-
amino-2,3,5,6-tetrahydrobenzo[f]isoquinoline-1-carbonitriles (6).
precipitate was filtered, washed with water and dried.
The crude products were purified by crystallization from
chloroform–methanol and characterized as 2-oxo-4-sec-
amino-2,3,5,6-tetrahydrobenzo[f]-isoquinoline-1-carbo-
nitriles 6.
A plausible reaction mechanism is shown in Scheme 2.
The reaction is initiated by the attack of a carbanion
generated in situ from cyanoacetamide at C-10b through
the Michael addition followed by ring closure involving
the amide nitrogen and C-4 of the chromene ring with
the loss of carbon dioxide and acetonitrile to yield 6
(Scheme 2).
SCH3
CN
O
NC
COOCH3
DMSO/KOH
5-6 h
R
O
O
+
H3CS
SCH3
3
R
1
2
HN
C2H5OH
2. X-ray structural analysis
R
Yield (%)
3
a
b
H
OCH3
X-ray diffraction studies16 of 2-oxo-4-piperidin-1-yl-
2,3,5,6-tetrahydrobenzo[f]isoquinoline-1-carbonitrile 6a
revealed that the compound has a non-planarity induced
chirality due to distortion in the aromatic rings. The
conformation with arbitrary numbering is shown as an
ORTEP diagram in Figure 2.
94
82
N
O
CN
O
4
R
The presence of a cyano group in the bay region forces
the molecule to buckle from the most favourable planar
Scheme 1. Two step synthesis of 4-sec-amino-2-oxobenzo[h]chromene-
3-carbonitriles (4).

7984
R. Pratap et al. / Tetrahedron Letters 48 (2007) 7982–7985
Figure 2. Displacement ellipsoid plot (30% probability) showing the
molecular structure of 6.
Figure 5. Structures of the benzo[f]isoquinoline showing the presence
of both enantiomers and diastereomers.
arrangement through the bending of the aromatic rings
out of the plane. The cyano group and the rings are also
in different planes and in this situation the molecule
acquires a helical conformation. The average mean
plane angle for the twist between the terminal rings is
33.22ꢁ and the distance between the non-bonded carbon
atoms in two molecules present in an asymmetric unit is
The benzo[f]isoquinoline 6a crystalized in a space group
of C2/c. The crystal packing reveals the presence of two
non-equivalent molecules in the asymmetric unit, Figure
4.
There are 16 molecules in the unit cell with two pairs of
P and M enantiomers as shown in Figure 5. Out of the
16 molecules, 8 conformers have same bond distances as
well as torsion angles, while the other 8 have different
bond distances as well as torsion angles. This confirmed
the presence of both enantiomeric as well as diastereo-
meric pairs in the unit cell.
˚
˚
3.060 A and 3.093 A.
The X-ray studies further showed that the terminal rings
are nearly planar while the central ring adopts a half
chair conformation with a torsion angle C1–C10B–
C10A–C10, À34.28ꢁ. It has structural analogy with
the X-ray structure of methyl 1-(4-chlorophenyl)-3-
hydroxy-7-methoxy-9,10-dihydrophenanthrene-4-carb-
oxylate.17 The torsional angle C4–C4A–C4B–C5 in the
phenanthrene-4-carboxylate of the previously reported
compound is 28.24ꢁ and the twist between the terminal
rings is 28ꢁ while the distance between the non-bonded
Semi-empirical calculations were also performed for
both benzo[f]isoquinoline and methyl 1-aryl-3-hydro-
xy-5,6-dihydrophenanthrene-4-carboxylate. Theoretical
calculations were performed in order to study the influ-
ence of carbonyl as well as CN/COOCH3 substituents.
The semi-empirically optimized structures were then
compared with the X-ray crystal structure. The struc-
tural parameters matched excellently with those previ-
ously obtained through X-ray structure analyses. All
the molecules were fully optimized by the AM1 method.
The geometry optimization showed that in the presence
of a CN substituent in the bay region of benzo[f]isoquin-
oline, the torsion angle C1–C10B–C10A–C10 is 33.11ꢁ
whereas the experimental value is À34.28ꢁ. When CN
is replaced by COOCH3 the torsion angle decreases to
28ꢁ both experimentally and theoretically. The theoreti-
cal calculation showed that the torsion angles of
phenanthrene derivatives with CN and COOCH3
substituents in the bay region are 29ꢁ and 28ꢁ, respec-
tively. The theoretical calculation and X-ray structure
analysis revealed that in presence of a CN substituent
in the bay region increases the distortion and non-
planarity of the rings.
˚
carbon atoms is 3.025 A. From these observations, it
is inferred that the presence of an isoquinoline ring with
cyano substituent increases the degree of distortion and
non-planarity induced helicity in the molecule (Fig. 3).
Figure 3. Methyl 1-(4-chlorophenyl)-3-hydroxy-7-methoxy-9,10-di-
hydrophenanthrene-4-carboxylate.
Figure 4. Diastereomers of the benzo[f]isoquinoline present in the
asymmetric unit showing bond distances and torsion angles.
Figure 6. Crystal packing of benzo[f]isoquinoline showing the presence
of intermolecular N–HÁ Á ÁO interactions.

R. Pratap et al. / Tetrahedron Letters 48 (2007) 7982–7985
7985
12. Gilchrist, T. L.; Healy, M. A. M. Tetrahedron 1993, 49,
2543–2556.
13. Verrat, C.; Hoffmann, N.; Pete, J. P. Synlett 2000, 1166–
1168.
14. Panda, K.; Suresh, J. R.; Illa, H.; Junjappa, H. J. Org.
Chem. 2003, 68, 3498–3506.
The crystal structure of benzo[f]isoquinoline demon-
strated supramolecular assembly through intermolecular
˚
˚
N–HÁ Á ÁO interactions [N3–O1:2.785 A; H3–O1:1.94 A
and N3–H3–O1:167ꢁ] with the formation of an eight-
membered ring as indicated in Figure 6.
15. Pratap, R.; Ram, V. J. Tetrahedron Lett. 2007, 48,
2755.
All the compounds synthesized were characterized by
spectroscopic analysis.18
16. The crystal data of 6a: C21.71H21.71N3.43O1.14, M = 349.00,
˚
˚
monoclinic, C2/c, a = 28.997(3) A, b = 13.1900(1) A, c =
3
˚
˚
In summary, this is the first protocol for an efficient and
convenient synthesis of 2-oxo-4-sec-amino-2,3,5,6-tetra-
hydrobenzo[f]isoquinoline-1-carbonitriles 6 through base
catalyzed ring transformation of 5,6-dihydro-2-oxo-
18.057(2) A, b = 116.480(1)ꢁ, V = 6181.7(1) A , Z = 16,
Dc = 1.312 g cmÀ3, l(Mo-Ka) = 0.083 mmÀ1, F(000) =
2592, rectangular block, yellow, size = 0.5 · 0.16 ·
0.345 mm, 6350 reflections measured (Rint = 0.0187),
5445 unique, wR2 = 0.1448 for all data, conventional
R = 0.0501 [(D/r)max = 000)] on F-values of 3615 reflec-
tions with I > 2r(I), S = 0.944 for all data and 415
parameters. Unit cell determination and intensity data
collection (2h = 50ꢁ) were performed on a Bruker P4
diffractometer at 293(2) K. Structure solutions by direct
methods and refinements by full-matrix least-squares
methods on F2. Programs: XSCANS [Siemens Analytical
X-ray Instrument Inc.: Madison, Wisconsin, USA 1996],
SHELXTL-NT [Bruker AXS Inc.: Madison, Wisconsin,
USA 1997]. CCDC (Deposit No: 661402) contains the
supplementary crystallographic data. These data can be
obtained free of charge from www.ccdc.cam.uk/conts/
retrieving.html [or from the Cambridge Crystallographic
Data Center, 12 Union Road, Cambridge, CB2 1EZ, UK;
fax: (internat.) +44 1223/336 033; e-mail: deposit@ccdc.
cam.ac.uk.
4-sec-amino-2H-benzo[h]chromene-3-carbonitrile
by
cyanoacetamide.
Acknowledgement
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
1. Bentley, K. Nat. Prod. Rep. 2000, 17, 247.
2. Wu, Y.-C.; Chang, G.-Y.; Duh, C.-Y.; Wang, S. K.
Phytochemistry 1993, 33, 497.
3. Wu, Y.-C.; Liou, J. Y.; Lee, S.-S.; Lu, S. J. Tetrahedron
Lett. 1991, 32, 4169.
17. Sarkhel, S.; Goel, A.; Ram, V. J.; Chaudhary, S.; Maulik,
P. R. Acta Crystallogr. 1997, C53, 1713.
18. General procedure for the synthesis of 2-oxo-4-sec-amino-
2,3,5,6-tetrahydrobenzo[f]isoquinoline-1-carbonitriles 6: A
mixture of 4 (0.5 mmol), cyanoacetamide 5 (0.6 mmol) and
powdered KOH in DMF was stirred at room temperature
for 2–3 h. During this period all the starting materials were
consumed with the appearance of a new spot on TLC.
Thereafter the reaction mixture was poured on crushed ice
with vigorous stirring followed by neutralization with 10%
HCl. The resulting precipitate was filtered, washed with
water, dried and purified through neutral alumina column
chromatography using chloroform as an eluent. Com-
pound (6a): Yield 95%; mp >250ꢁC; 1H NMR (CDCl3,
300 MHz) d 1.74–1.76 (m, 6H, CH2), 2.48–2.52 (m, 2H,
CH2), 2.71–2.75 (m, 2H, CH2), 3.36–3.38 (m, 4H, CH2),
7.26–7.29 (m, 1H, ArH), 7.37–7.39 (m, 2H, ArH), 8.17–
8.22 (m, 1H, ArH); 13C NMR (CDCl3, 75 MHz): d 22.5,
22.9, 24.6, 28.4, 49.3, 86.6, 104.5, 117.1, 125.6, 126.3,
129.3, 130.1, 138.1, 152.6, 153.1, 162.8; IR (KBr): 2214
(CN) cmÀ1; mass (ESI-MS) m/z 306 [M++1]; HRMS
(70 eV): M+ Calcd for C19H19N3O 305.15281, found:
305.15269.
4. (a) Whaley, W. M.; Meadow, M. J. Org. Chem. 1954, 19,
661; (b) Galiazzo, G.; Bortolus, P.; Masetti, F. J. Chem.
Soc., Perkin Trans. 2 1975, 1712; (c) Masetti, F.; Bartocci,
G.; Mazzucato, U. Gazz. Chim. Ital. 1982, 112, 255; (d)
Tanga, M. J.; Almquist, R. G.; Smith, T. J. J. Heterocycl.
Chem. 1985, 22, 1597.
5. Wu, Y.-C.; Liou, J. Y.; Duh, C.-Y.; Lee, S.-S.; Lu, S. T. J.
Pharmacol. 1997, 49, 706.
6. Chiou, C.-M.; Kang, J.-J.; Lee, S.-S. J. Nat. Prod. 1998,
61, 46.
´
´
7. Martinez, E.; Estevej, J. C.; Estevej, R. J.; Castedo, L.
Tetrahedron 2001, 57, 1973–1979.
8. Dix, I.; Doll, C.; Hopf, H.; Jones, P. G. Eur. J. Org. Chem.
2002, 2547–2556.
9. Michael, J. P. Nat. Prod. Rep. 2002, 19, 742–760.
10. Gupta, A. K.; Illa, H.; Junjappa, H. Tetrahedron 1990, 46,
2561–2572.
11. (a) Wang, C.; Moseberg, H. I. Tetrahedron Lett. 1995, 36,
3623–3626; (b) Kotha, S.; Sreenivasachary, N. J. Indian
Inst. Sci. 2001, 81, 277–286.