Bismuth(III) chloride-catalyzed intramolecular hetero-Diels-Alder reactions: A novel synthesis of hexahydrodibenzo[b,h][1,6]naphthyridines

Article abstract of DOI:10.1016/S0040-4039(02)00018-7

BiCl₃ efficiently catalyzed the intramolecular hetero-Diels-Alder reactions of aldimines generated in situ from aromatic amines and the N-allyl derivative of o-aminobenzaldehyde in refluxing acetonitrile to afford a novel class of hexahydrodibe

Full text of DOI:10.1016/S0040-4039(02)00018-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1573–1575
Bismuth(III) chloride-catalyzed intramolecular hetero-Diels–Alder
reactions: a novel synthesis of
†
hexahydrodibenzo[b,h][1,6]naphthyridines
Gowravaram Sabitha,* E. Venkata Reddy, Ch. Maruthi and J. S. Yadav
Organic Division I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 25 October 2001; revised 11 December 2001; accepted 20 December 2001
Abstract—BiCl efficiently catalyzed the intramolecular hetero-Diels–Alder reactions of aldimines generated in situ from aromatic
3
amines and the N-allyl derivative of o-aminobenzaldehyde in refluxing acetonitrile to afford a novel class of hexahydrodiben-
zo[b,h][1,6]naphthyridine derivatives. The products are isolated as mixtures of trans and cis diastereoisomers in a 1:1 ratio, in good
to excellent yields. © 2002 Elsevier Science Ltd. All rights reserved.
The hetero-Diels–Alder reaction is one of the most
powerful methods for the synthesis of nitrogen2
Treatment of aniline 1a with the N-allyl derivative of
9
o-aminobenzaldehyde 2 in the presence of 10 mol%
1
heterocycles and gives access to many building blocks.
BiCl in refluxing acetonitrile resulted in the formation
3
10
This strategy offers a powerful solution to many prob-
of a mixture of two products 3a and 3a% as trans and
cis diastereoisomers in a 1:1 ratio in 94% yield. The
reaction was completed in 2 h, as indicated by TLC by
in situ generation of the imine, followed by an
intramolecular [4+2] cycloaddition reaction to afford
the products. Although it can be considered as the
product that would result from a Diels–Alder reaction,
the stepwise mechanism might actually be operating.
The ratio of the products was determined by isolating
the two isomers in pure form using silica gel column
chromatography and the stereochemistry of the prod-
3
lems in complex natural product synthesis. Tetra-
hydroquinoline derivatives constitute an important
class of natural products displaying a wide range of
4
interesting biological activities. The synthesis of these
5
derivatives has been studied extensively in solution as
6
well as on solid phase using [4+2] cycloaddition reac-
7
tions. Recently bismuth(III) derivatives have emerged
as efficient catalysts in various organic transformations
of interest because of their friendly ecological behavior.
In continuation of our interest in intramolecular hetero-
8
1
Diels–Alder reactions, we herein report highly efficient
ucts was based on coupling constants in their H NMR
BiCl -catalyzed [4+2] cycloaddition reactions of anilines
spectra and NOE difference experiments. In compound
3a, the H-6a proton appeared as a td at l 1.50, its
coupling with the H-12a and H-6% protons resulting in a
triplet with a large J value (J=10.5 Hz), which again
splits into a doublet with a small J value (J=3.9 Hz) by
coupling to the nearby H-6 proton.
3
with the N-allyl derivative of o-aminobenzaldehyde,
containing an electron rich olefin substituent, for the
synthesis of a novel class of nitrogen heterocyclic
compounds, hexahydrodibenzo[b,h][1,6]naphthyridine
derivatives (Scheme 1).
Scheme 1.
Keywords: hetero-Diels–Alder reactions; bismuth(III) chloride; hexahydrodibenzonaphthyridines.
*
Corresponding author.
IICT communication No. 01X12.
†
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00018-7

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G. Sabitha et al. / Tetrahedron Letters 43 (2002) 1573–1575
imine derived in situ from an o-aminobenzaldehyde
derivative with aromatic amines.
Acknowledgements
This clearly indicated the axial positions of the H-6a
and H-12a protons and hence the trans ring fusion.
Whereas in compound 3a% the H-6a proton appeared as
a dt at l 1.55, its coupling with the H-6% proton
resulting in a doublet with a large J value (J=12.8 Hz)
which is split into a triplet with a small J value (J=2.6
Hz) by coupling with the H-12a and H-6 protons which
are in equatorial positions. This represents a cis fusion
at the ring junction. Moreover, in the trans fused
isomer 3a, the H-12a proton appears as a doublet at l
E.V.R. and Ch.M. thank CSIR, New Delhi for the
award of Fellowships.
References
1
. (a) Kappe, C. O.; Munphree, S. S.; Padwa, A. Tetra-
hedron 1997, 14179; (b) Carruthers, W. Cycloaddition
Reactions in Organic Synthesis; Pergamon: Oxford, 1990;
(
7
c) Pindur, U.; Lutz, G.; Otto, C. Chem. Rev. 1993, 93,
41; (d) Waldmann, H. Synthesis 1994, 535.
3.95 with a large J value due to vicinal coupling with
the axial H-6a proton (J12a,6a=10.5 Hz). The large
vicinal coupling was taken as strong evidence for the
trans ring fusion, which was further confirmed by a
weak NOE peak between H-6a and H-12a in com-
pound 3a. In cis isomer 3a%, the doublet due to the
H-12a proton appeared at l 4.30 with a small J value
resulting from vicinal coupling with an equatorial H-6a
proton (J12a,6a=2.6 Hz). The cis configuration of H-6a
and H-12a in compound 3a% was also confirmed by a
strong NOE peak between them.
2. (a) Helmchen, G.; Karge, R.; Weetman, J. In Modern
Synthetic Methods; Scheffold, R., Ed.; Springer: Berlin,
1986; Vol. 4, p. 216; (b) Shipman, M. Contemp. Org.
Synth. 1994, 1.
3
. Reviews: (a) Boger, D. L.; Weinberg, S. M. Hetero
Diels–Alder Methodology in Organic Synthesis; Academic:
Orlando, 1987; Chapters 2 and 9; (b) Weinberg, S. M. In
Comprehensive Organic Synthesis; Trost, B. M.; Fleming,
I., Eds. Heterodienophile additions to dienes. Pergamon:
Oxford, 1991; Vol. 5, Chapter 4.2, p. 401; (c) Tietze, L.
F.; Keltschan, G. Top. Curr. Chem. 1997, 189, 1; (d)
Motorina, I. A.; Grierson, D. S. Tetrahedron Lett. 1999,
40, 7211; (e) Motorina, I. A.; Grierson, D. S. Tetrahedron
Lett. 1999, 40, 7215.
Under similar conditions, several aromatic amines 1b–i
were treated with the N-allyl derivative 2 to illustrate
the novelty of the present strategy for the synthesis of
the title compounds and the results are summarized in
Table 1. Although Lewis acids such as ZnCl , FeCl ,
4. (a) Katritzky, A. R.; Rachwal, S.; Rachwal, B. Tetra-
hedron 1996, 52, 15031 and references cited therein; (b)
Johnson, J. V.; Ranckman, S.; Baccanari, P. D.; Roth, B.
J. Med. Chem. 1989, 32, 1942.
5. (a) Kiselyov, A. S.; Armstrong, R. W. Tetrahedron Lett.
1997, 38, 6163; (b) Ma, Y.; Qian, C.; Xie, M.; Sun, J. J.
Org. Chem. 1999, 64, 6462; (c) Yadav, J. S.; Reddy, B. V.
S.; Madhuri, C.; Sabitha, G. Synthesis 2001, 7, 1065; (d)
Jones, W.; Kiselyov, A. S. Tetrahedron Lett. 2000, 41,
2
3
ZrCl , AlCl and BF ·OEt have been found to pro-
4
3
3
2
mote the intramolecular hetero-Diels–Alder reaction,
more than stoichiometric amounts of the acids were
required. The reaction times were also too long with
moderate yields, whereas the BiCl -catalyzed reaction is
3
more effective by overcoming the above-mentioned
drawbacks.
2309.
In summary, a novel, mild and highly efficient method
for the synthesis of hexahydrodibenzo[b,h][1,6]-
naphthyridine derivatives has been developed that relies
on an intramolecular [4+2] cycloaddition reaction of an
6. (a) Kiselyov, A. S.; Smith, L.; Armstrong, R. W. Tetra-
hedron 1998, 54, 5089; (b) Kiselyov, A. S.; Smith, L. S.;
Virgilio, A.; Armstrong, R. W. Tetrahedron 1998, 54,
7987; (c) Kiselyov, A. S.; Zhang, D. Synlett 2001, 7, 1173.
a,b
Table 1. BiCl -catalyzed synthesis of hexahydrodibenzo[b,h][1,6]naphthyridines
3
R1
R2
Time (h)
Overall yield 3 and 3% (%)
c
Entry
Substrate (amine)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
CH3
Br
H
H
H
OH
H
H
H
CH3
OCH3
Cl
F
H
CH3
Amine
2
2
94
92
94
90
96
93
90
92
94
1.5
2
1.5
1.5
2
1.5
1.5
1-Naphthyl
a
All reactions were conducted in refluxing acetonitrile using 10 mol% BiCl .
The products were characterized by MS, IR, H and C NMR spectra.
Yield refers to the 1:1 mixture of product diastereoisomers isolated after column chromatography.
3
b
c
1
13

G. Sabitha et al. / Tetrahedron Letters 43 (2002) 1573–1575
1575
7
8
. Review: (a) Suzuki, H.; Ikegami, T.; Matano, Y. Synthe-
sis 1997, 249; (b) Vidal, S. (Synlett Spotlight 31), Synlett
indicated by TLC, the reaction mixture was quenched
with dilute HCl and extracted with ethyl acetate. The
2
001, 1194.
organic layer was washed with a NaHCO solution, brine
3
. (a) Tetrahydrochromano[4,3-b]quinolines: Sabitha, G.;
Venkata Reddy, E.; Yadav, J. S. Synthesis 2001, 10, 1979;
and dried over Na SO . The solvent was evaporated in
2
4
vacuo and the crude product was chromatographed on
silica gel (EtOAc/hexane, 3:97) to afford 3 and 3% in
(b) Octahydroacridines: Sabitha, G.; Venkata Reddy, E.;
Yadav, J. S. communicated to Synthesis 2002, in press.
. The construction of precursor 2 was achieved from
methyl anthranilate by tosylation (82%), followed by
prenylation (74%) of the amine group and a two-step
procedure involving reduction with LAH (83%) followed
9
0–96% yield. Selected analytical data for compound 3a
9
1
(
trans): H NMR (200 MHz, CDCl ): l 1.10 (s, 3H,
3
-
CH ), 1.30 (s, 3H, -CH ), 1.50 (td, 1H, J=10.5, 3.9 Hz,
3
3
H-6a), 2.30 (s, 3H, -CH ), 3.40 (dd, 1H, J=13.2, 10.5 Hz,
H-6%), 3.95 (d, J=10.5 Hz, H-12a), 4.35 (dd, 1H, J=13.2,
3
by oxidation using IBX (90%) of the ester group in an
3
.9 Hz, H-6), 6.50 (d, 1H, J=7.9 Hz, ArH), 6.65 (t, 1H,
J=7.9 Hz, ArH), 6.95 (t, 1H, J=7.9 Hz, ArH), 7.05–7.35
m, 6H, ArH), 7.45 (d, 2H, J=7.9 Hz, ArH), 7.95 (d, 1H,
1
overall yield of 45%. H NMR (400 MHz, CDCl ): l 1.40
3
(
s, 3H, -CH ), 1.60 (s, 3H, -CH ), 2.45 (s, 3H, -CH ),
3 3 3
(
3
5
.80–3.90 (m, 1H, N-CH ), 4.40–4.60 (m, 1H, N-CH ),
2 2
.05–5.10 (m, 1H, -CHꢀC-), 6.75 (d, 1H, J=8.3 Hz,
+
J=7.9 Hz, ArH). MS (m/e): 418 (M ). Selected analytical
data for compound 3%a (cis): H NMR (200 MHz,
CDCl ): l 1.20 (s, 3H, -CH ), 1.40 (s, 3H, -CH ), 1.55 (dt,
1
1
H-6), 4.30 (d, 1H, J=2.6 Hz, H-12a), 6.05 (d, 1H, J=7.7
Hz, ArH), 6.60 (t, 1H, J=7.7 Hz, ArH), 6.90 (t, 1H,
J=7.7 Hz, ArH), 7.05–7.45 (m, 8H, ArH), 7.95 (d, 1H,
1
ArH), 7.25 (d, 2H, J=8.3 Hz, ArH), 7.40–7.50 (m, 2H,
ArH), 7.55 (d, 2H, J=8.3 Hz, ArH), 7.95 (d, 1H, J=8.3
Hz, ArH), 10.25 (s, 1H, -CHO).
3
3
3
H, J=12.8, 2.6 Hz, H-6a), 2.40 (s, 3H, -CH ), 3.10 (t,
3
H, J=12.8 Hz, H-6%), 4.10 (dd, 1H, J=12.8, 3.8 Hz,
1
0. General procedure: BiCl3 (10 mol%) was added to a
mixture of aniline 1 (1 mmol) and the N-allyl derivative
of o-amino benzaldehyde 2 (1.1 mmol) in 5 mL of
acetonitrile. The reaction mixture was stirred at acetoni-
trile reflux temperature for 1.5–2 h. On completion, as
+
J=7.7 Hz, ArH). MS (m/e): 418 (M ).