Synthesis of pyrrolo[3,4-c]quinolines by 1,5-electrocyclisation of non-stabilised azomethine ylides

Article abstract of DOI:10.1016/S0040-4039(03)00232-6

A new route to the pyrrolo[3,4-c]quinoline ring system has been developed via the 1,5-dipolar electrocyclisation reactions of azomethine ylides derived from easily available 3-formylquinoline derivatives. The intermediacy of azomethine ylides was shown by the trapping of the proposed dipoles with N-phenylmaleimide.

Full text of DOI:10.1016/S0040-4039(03)00232-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2343–2346
Synthesis of pyrrolo[3,4-c]quinolines by 1,5-electrocyclisation of
non-stabilised azomethine ylides
´
Aron Pinte´r, Miklo´s Nyerges,* Andrea Vira´nyi and La´szlo´ To
3
ke*
Research Group of the Hungarian Academy of Sciences, Department of Organic Chemical Technology, Technical University of
Budapest, H-1521 Budapest POB 91, Hungary
Received 4 December 2002; revised 13 January 2003; accepted 24 January 2003
Abstract—A new route to the pyrrolo[3,4-c]quinoline ring system has been developed via the 1,5-dipolar electrocyclisation
reactions of azomethine ylides derived from easily available 3-formylquinoline derivatives. The intermediacy of azomethine ylides
was shown by the trapping of the proposed dipoles with N-phenylmaleimide. © 2003 Elsevier Science Ltd. All rights reserved.
Quinolines are an important group of heterocyclic com-
pounds. Among the quinolines 2-chloro-3-formyl-
quinolines occupy a prominent position as they are key
intermediates for further [b]-annelation of a wide vari-
ety of rings and for various functional group intercon-
versions.1 The applications of these methodologies have
yielded beside the huge number of new quinoline
derivatives new synthetic approaches for alkaloids such
as camptothecin,2 luotonin A,3 or nothapodytine (Fig.
1).4
decarboxylation method.8 The reaction of 2-chloro-3-
formylquinolines 1a–c with sarcosine in refluxing xylene
gave 2-methyl-2,4,5,9b-tetrahydro-1H-pyrrolo[3,4-c]-
quinolin-4-ones 4a–c in acceptable yields via the
expected 1,5-electrocyclisation reaction accompanied by
hydrolysis of the chlorine function under the applied
reaction conditions in the presence of the water formed
in the first step9 (Scheme 1).
The intermediacy of azomethine ylides 2 was shown by
trapping the proposed dipoles with N-phenylmaleimide
to give the two isomeric cycloadducts 5 and 6 (endo–exo
ratio :1:1) in a quantitative yield (Scheme 1).10
In this paper we report the first [c]-annelation of this
type of quinoline by 1,5-electrocyclisation of azome-
thine ylides.5 This conversion gives a direct route to the
otherwise hardly accessible pyrrolo[3,4-c]quinoline ring
system.6
After the successful 1,5-electrocyclisation of non-sta-
bilised azomethine ylides, we studied the reactivity of
the analogous ester-stabilised system generated from
the corresponding Schiff-base 7 by thermal 1,2-pro-
totropy.11 In contrast, in these cases, no 1,5-electrocy-
clisation was observed, the 7 imine remained unchanged
even after a prolonged reaction time in refluxing xylene
(Scheme 2). This result is in good agreement with our
earlier observations on the reactivity of azomethine
ylides in electrocyclisation reactions.12
The quinolines (1a–c) were prepared by the method
described by Meth-Cohn from the corresponding
acetanilides by treatment with the Vilsmeier reagent in
a single step.7 The non-stabilized azomethine ylides 2
were generated from these aldehydes 1a–c using the
We performed the next series of experiments with 2-
phenyl-3-formylquinolines 8a–c. In these, with azome-
thine ylides 9 derived from the aldehydes there is a
possibility—besides the 1,5-electrocyclisation—of a 1,7-
electrocyclic ring closure onto the phenyl group.13 The
starting material was prepared in three simple steps
from the 2-chloro-3-formylquinolines including a palla-
dium-catalysed Suzuki coupling with phenylboronic
acid (Scheme 2).
Figure 1.
* Corresponding authors. Tel.: +361-463-2213; fax: +361-463-3648;
e-mail: mnyerges@mail.bme.hu
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00232-6

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A. Pinte´r et al. / Tetrahedron Letters 44 (2003) 2343–2346
2344
Scheme 1. Reagents and conditions: (i) sarcosine (2 equiv.), xylene, 140°C; (ii) N-phenylmaleimide (1 equiv.), sarcosine (2 equiv.),
xylene, 140°C.
Scheme 2. Reagents and conditions: (i) EtO2CCH2NH2·HCl, Et3N, CH2Cl2, rt; (ii) HOCH2CH2OH, PTSA, benzene, reflux; (iii)
PhB(OH)2, Pd(OAc)2 (cat.), K2CO3, DME, H2O; (iv) 5% HCl, THF, 80°C.
The reaction of the resultant quinolines 8a–c with sar-
cosine in refluxing xylene gave 2-methyl-4-phenyl-1H-
pyrrolo[3,4-c]quinolines 12a–c as products in moderate
yields (Scheme 3).9 The 1,5-electrocyclisations in these
cases were followed by full aromatisation to the tetra-
hydro-1H-pyrrolo[3,4-c]quinoline 11 ring system. This
slightly different result compared to the transformation
1 [ 4, may be explained by the delocalisation energy
difference between the lactam products 4 and com-
pounds 12 having a more extended conjugation.
:1:5) in good yield.10 The stereochemistry of the major
isomer (14) was proved by NOE experiments (Scheme
4).
Acknowledgements
This work was financially supported by the National
Fund for Science and Research, Hungary (OTKA Pro-
ject No. T 032221). M.N. thanks the Ministry of Edu-
cation for a Gyo¨rgy Be´ke´sy fellowship. A grant from
the Jo´zsef Varga Foundation given to A.V. is gratefully
appreciated.
The intermediacy of azomethine ylides was again
shown by trapping the dipole with N-phenylmaleimide
to give the two isomeric cycloadducts 13 and 14 (ratio

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A. Pinte´r et al. / Tetrahedron Letters 44 (2003) 2343–2346
2345
Scheme 3. Reagents and conditions: (i) sarcosine (2 equiv.), xylene, 140°C.
Scheme 4. Reagents and conditions: (i) N-phenylmaleimide (1 equiv.), sarcosine (2 equiv.), xylene, 140°C.
References
(d) Murata, G.; Satoru, H.; Teramato, K.; Miura, M.;
Nomura, M. Heterocycles 1993, 36, 2147; (e) Swan, G.
A.; Roy, R. B.; Khandelwal, G. D. J. Chem. Soc. 1974,
891; (f) Jones, K.; Wilkinson, J. J. Chem. Soc., Chem.
Commun. 1992, 1767–1769; (g) Veenstra, S. J.; Fortgens,
R.; Vijn, R. J.; Jong, B. S.; Speckamp, W. N. Tetrahedron
1987, 43, 1147–1156; (h) Gu¨ndel, W.-F.; Bohnert, S. Z.
Naturforsch. 1985, 40b, 1409.
1. Meth-Cohn, O. Heterocycles 1993, 35, 539.
2. (a) Rigby, J. H.; Danca, D. M. Tetrahedron Lett. 1997,
38, 4969; (b) Leue, S.; Miao, W.; Kanazawa, A.; Ge´nis-
son, Y.; Garc¸on, S.; Greene, A. E. J. Chem. Soc., Perkin
Trans. 1 2001, 2903; (c) Comins, D. L.; Nolan, J. M. Org.
Lett. 2001, 1611.
3. Toyota, M.; Komori, C.; Ihara, M. Heterocycles 2002,
56, 101.
4. Carles, L.; Narkunan, K.; Penlou, S.; Rousset, L.;
Bouchu, D.; Ciufolini, M. A. J. Org. Chem. 2002, 67,
4304.
5. For excellent reviews on 1,5-dipolar cyclisations, see: (a)
Taylor, E. C.; Turchi, I. J. Chem. Rev. 1979, 79, 181; (b)
Huisgen, R. Angew. Chem., Int. Ed. Engl. 1980, 19, 947.
6. There have been only a few reports on the preparation of
pyrrolo[3,4-c]quinolines and none of them generally
applicable to the synthesis of these heterocycles: (a)
Horner, L. Justus Liebigs Ann. Chem. 1941, 548, 117; (b)
Roy, R. B.; Swan, G. A. J. Chem. Commun. 1968, 1446;
(c) Roy, R. B.; Swan, G. A. J. Chem. Soc. C 1969, 1886;
7. (a) Meth-Cohn, O.; Narine, B. Tetrahedron Lett. 1978,
19, 2045; (b) Meth-Cohn, O.; Narine, B.; Tarnowski, B.
J. Chem. Soc., Perkin Trans. 1 1981, 1520.
8. (a) Tsuge, O.; Kanemasa, S.; Ohe, M.; Takenaka, S. Bull.
Chem. Soc. Jpn. 1987, 60, 4079; (b) Nyerges, M.; Bala´zs,
L.; Bitter, I.; Ka´das, I.; Ko¨vesdi, I.; Toke, L. Tetrahedron
1995, 51, 6783; (c) Arany, A.; Groundwater, P. W.;
Nyerges, M. Tetrahedron Lett. 1998, 39, 3267.
9. General procedure for the preparation of compounds 4a–c
and 12a–c: The aldehyde (3 mmol) was dissolved in
xylene (30 cm3) and sarcosine (0.54 g, 6.0 mmol) was
added. The reaction mixture was refluxed until the start-
ing aldehyde completely disappeared (judged by TLC).
All the solvent was removed in vacuo and the residue

´
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A. Pinte´r et al. / Tetrahedron Letters 44 (2003) 2343–2346
purified by flash chromatography (eluent petroleum
maleimide (0.17 g 1.0 mmol) and sarcosine (0.36 g 4.0
mmol) were added. The reaction mixture was refluxed for
1 h. On cooling the solvent was removed in vacuo and
the residue was purified by flash chromatography (eluent
petroleum ether–acetone, 3:1) to give the crystalline
product in 90–95% yield. Cycloadduct (14): 1H NMR (250
MHz, d6-DMSO): 8.32 (s, 1H), 8.06 (d, 1H, J 9 Hz),
7.52–7.37 (m, 9H), 7.10 (m, 3H), 3.93 (s, 3H), 3.84 (d,
1H, J 7.3 Hz), 3.65–3.50 (m, 4H), 2.07 (s, 3H); 13C NMR
(63 MHz, d6-DMSO): 176.2 (q), 175.5 (q), 158.4 (q),
157.9 (q), 143.4 (q), 139.9 (q), 134.7 (CH), 131.4 (q),
131.0 (q), 130.8 (CH), 129.8 (2×CH), 129.1 (2×CH), 128.6
(CH), 128.1 (2×CH), 127.9 (CH), 127.8 (q), 126.4 (2×
CH), 123.1 (CH), 104.5 (CH), 68.0 (CH), 57.3 (CH2),
55.5 (CH3), 54.8 (CH), 44.2 (CH), 38.6 (CH3).
ether–acetone 3:1) to give the crystalline product in 40–
60% yield. All new compounds afforded correct elemental
analyses and spectroscopic data. 2-Methyl-2,4,5,9b-tetra-
hydro-1H-pyrrolo[3,4-c]quinolin-4-one (4a): 1H NMR
(250 MHz, d6-DMSO): 7.79 (s, 1H), 7.66 (d, 1H, J 8 Hz),
7.54 (d, 1H, J 8 Hz), 7.44 (t, 1H, J 8 Hz), 7.14 (t, 1H, J
8 Hz), 5.77 (br s, 1H, NH), 5.17 (br s, 1H), 3.69 (t, 1H,
J 9.0 Hz), 3.30 (dd, 1H, J 2.2 and 9.0 Hz), 2.99 (s, 3H,
NCH3); 13C NMR (63 MHz, d6-DMSO): 160.4 (q), 148.5
(q), 130.8 (CH), 128.9 (q), 128.8 (CH), 128.0 (CH), 125.4
(CH), 123.6 (q), 121.3 (CH), 66.0 (CH), 59.8 (CH2), 31.2
(CH3);
2-Methyl-4-phenyl-1H-pyrrolo[3,4-c]quinoline
1
(12a): H NMR (250 MHz, CDCl3): 8.10 (dd, 1H, J 1.5
and 8.0 Hz), 7.97 (dd, 2H, J 1.3 and 7.8 Hz), 7.92 (dd,
1H, J 1.5 and 8.0 Hz), 7.53–7.38 (m, 5H), 7.27 (d, 1H, J
1.5 Hz), 7.20 (d, 1H, J 1.5 Hz), 3.77 (s, 3H, NCH3); 13C
NMR (63 MHz, CDCl3): 155.6 (q, C-4), 142.8 (q, C-5a),
140.3 (q), 129.7 (CH), 129.0 (CH), 128.5 (2×CH), 128.4
(2×CH), 126.0 (CH), 125.8 (CH), 122.9 (q), 122.2 (CH),
121.9 (q), 117.6 (CH), 117.5 (q), 112.8 (CH), 37.4 (CH3).
11. Tsuge, O.; Kanemasa, S. Adv. Heterocycl. Chem. 1989,
45, 232–349.
12. Nyerges, M.; Arany, A.; Fejes, I.; Groundwater, P. W.;
Zhang, W.; Bendell, D.; Anderson, R. J.; Toke, L. Tetra-
hedron 2002, 58, 989.
13. (a) Groundwater, P. W.; Nyerges, M. Adv. Heterocycl.
Chem. 1999, 73, 97–129; (b) Arany, A.; Bendell, D.;
Groundwater, P. W.; Garnett, I.; Nyerges, M. J. Chem.
Soc., Perkin Trans. 1 1999, 2605.
10. General procedure for 1,3-dipolar cycloadditions of azome-
thine ylides 2 and 9 to N-phenyl-maleimide: The aldehyde
(1 mmol) was dissolved in xylene (50 cm3) and N-phenyl-