First syntheses of two quinoline alkaloids from the medicinal herb Ruta chalepensis via cyclization of an o-iodoaniline with an acetylenic sulfone

Article abstract of DOI:10.1039/b205408f

The first syntheses of two quinoline alkaloids found in the medicinal herb Ruta chalepensis are reported via the conjugate addition of an o-iodoaniline to an acetylenic sulfone, followed by Pd-catalyzed carbonylation, intra-molecular acylation of the core

Full text of DOI:10.1039/b205408f

First syntheses of two quinoline alkaloids from the medicinal herb Ruta
Chalepensis via cyclization of an o-iodoaniline with an acetylenic sulfone†
Thomas G. Back* and Jeremy E. Wulff
Department of Chemistry, University of Calgary, Calgary, Alberta, Canada T2N 1N4.
E-mail: tgback@ucalgary.ca; Fax: (403) 289-9488; Tel: (403) 220-6256
Received (in Corvallis, OR, USA) 4th June 2002, Accepted 19th June 2002
First published as an Advance Article on the web 8th July 2002
The first syntheses of two quinoline alkaloids found in the
medicinal herb Ruta chalepensis are reported via the
conjugate addition of an o-iodoaniline to an acetylenic
sulfone, followed by Pd-catalyzed carbonylation, intra-
molecular acylation of the coresponding sulfone-stabilized
carbanion, and reductive desulfonylation.
isolated from the roots of Ruta chalepensis, a perennial herb
collected from the northern Saudi desert, which is used in folk
medicine as, inter alia, an antirheumatic and antispasmodic
agent. To our knowledge, there have been no previously
reported syntheses of 1 and 2.
Acetylenic sulfones are useful synthetic intermediates1 that
undergo facile conjugate additions with primary or secondary
amines.1,2 When the amine contains a chloro3 or ester4,5
substituent, subsequent intramolecular alkylations or acylations
provide a short and versatile route to the corresponding nitrogen
heterocycles (e.g. Scheme 1). These cyclizations can be
followed by further functional group manipulations and ulti-
mately desulfonylation,6 and have thus provided new routes to
(2)-pumiliotoxin C,4 other dendrobatid alkaloids containing
indolizidine structures3b and the quinolizidine alkaloid (2)-la-
subine II.5 However, very few cases of conjugate additions of
anilines to acetylenic sulfones have been reported2a,f and we
wished to determine whether these much less nucleophilic
amines could be employed in a similar cyclization protocol.
We now report a procedure for achieving the conjugate
addition and intramolecular acylation of an appropriately o-
functionalized aniline with an acetylenic sulfone, and illustrate
the utility of the procedure in the first syntheses of the recently
discovered quinoline alkaloids 1 and 2.7 Alkaloids 1 and 2 were
Our initial approach to quinolines 1 and 2 was based on the
conjugate addition of methyl anthranilate 4 to acetylenic sulfone
5, followed by intramolecular acylation to the expected product
3, and desulfonylation (Scheme 2). The acetylenic sulfone was
easily prepared by selenosulfonation8 and selenoxide syn-
elimination of the known acetylene 8,9 which was in turn
obtained by a new route from commercially available 6, as
shown in Scheme 3.
However, neither methyl anthranilate nor its N-benzyl
derivative was sufficiently nucleophilic to add to 5, even under
forcing conditions. When various amide and carbamate deriva-
tives of 4 were employed in the presence of a base catalyst, only
the N-formyl derivative 9 afforded the corresponding conjugate
addition product, isolated as the allyl sulfone isomer 11, but in
low yield (Scheme 4). However, the cyclization of 11 proceeded
quantitatively to afford 15 via acylation of the carbanion
generated from the allyl sulfone moiety of 11 with lithium
hexamethyldisilazide (LiHMDS), with concomitant deformyla-
tion (Scheme 4). In an effort to improve the yield of the
conjugate addition step, we attempted to modify the ester
substituent to make it less electron-withdrawing. Thus, for
Scheme 1
† Electronic supplementary information (ESI) available: experimental data
and NMR spectra. See http://www.rsc.org/suppdata/cc/b2/b205408f/
Scheme 2
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CHEM. COMMUN., 2002, 1710–1711
This journal is © The Royal Society of Chemistry 2002

much improved yield compared to the route starting from ester
9. After cyclization of 11 to the quinoline derivative 15,
desulfonylation with aluminium amalgam11 was accompanied
by alkene isomerization to produce alkaloid 1.‡ O-Methylation
of the latter compound completed the synthesis of its congener
2.
In conclusion, we have found a convenient procedure to
overcome the poor reactivity of methyl anthranilate derivatives
in conjugate additions to acetylenic sulfone 5. This was
achieved by employing the conjugate base of the corresponding
N-formyl derivative, and by using the more strongly nucleo-
philic o-iodoaniline 13, with subsequent introduction of the
ester group by palladium-catalyzed carbonylation. This proce-
dure was followed by intramolecular acylation of the corre-
sponding sulfone-stabilized allyl carbanion and reductive
desulfonylation, thereby achieving the first syntheses of the
Ruta Chalepensis alkaloids 1 and 2 in overall yields of 40 and
30%, respectively, from 13 and 5.
Scheme 3
example, the corresponding diethylamide 10 afforded an
improved yield of 66% of the corresponding adduct 12 (Scheme
4). Unfortunately, all attempts to cyclize the latter product to 15
failed.
The most successful overall results were obtained by starting
with the o-iodoaniline 13, which afforded adduct 14 in 77%
yield (Scheme 4). Presumably, absence of the electron-
withdrawing ester group facilitated the conjugate addition. The
required ester moiety was then appended by palladium-
catalyzed carbonylation10 in methanol, thus affording 11, in a
We thank the Natural Sciences and Engineering Research
Council of Canada (NSERC) for financial support. We also
thank NSERC and the Alberta Heritage Foundation for Medical
Research for Postgraduate Studentships to J. E. W.
Notes and references
‡ The 1H and 13C NMR spectra of 1 and 2 were in generally close agreement
with the reported spectra (ref. 7). However, in the 1H NMR spectrum of 1,
we noted a significant concentration dependence, particularly of the
chemical shifts of the signals at d 7.73, 7.58 and 5.87, attributed to H-8, H-7
and H-3, respectively (for complete NMR assignments, see ref. 7). These
chemical shifts were also sensitive to the presence or absence of trace acids.
The concentration and pH dependence may be the result of changes in the
equilibrium between enaminone 1 and its corresponding pyridinol tautomer,
or to changes in intermolecular hydrogen bonding.
1 (a) N. S. Simpkins, Sulphones in Organic Synthesis, Pergamon Press,
Oxford, 1993; (b) T. G. Back, Tetrahedron, 2001, 57, 5263.
2 (a) J. Strating and H. J. Backer, Recl. Trav. Chim. Pays-Bas, 1954, 73,
709; (b) C. J. M. Stirling, J. Chem. Soc., 1964, 5863; (c) C. J. M. Stirling,
J. Chem. Soc., 1964, 5875; (d) C. H. McMullen and C. J. M. Stirling, J.
Chem. Soc. B, 1966, 1217; (e) S. T. McDowell and C. J. M. Stirling, J.
Chem. Soc. B, 1967, 351; (f) W. E. Truce and D. G. Brady, J. Org.
Chem., 1966, 31, 3543; (g) W. E. Truce and L. D. Markley, J. Org.
Chem., 1970, 35, 3275; (h) W. E. Truce and D. W. Onken, J. Org.
Chem., 1975, 40, 3200.
3 (a) T. G. Back and K. Nakajima, Org. Lett., 1999, 1, 261; (b) T. G. Back
and K. Nakajima, J. Org. Chem., 2000, 65, 4543.
4 T. G. Back and K. Nakajima, J. Org. Chem., 1998, 63, 6566.
5 T. G. Back and M. D. Hamilton, Org. Lett., 2002, 4, 1779.
6 C. Nájera and M. Yus, Tetrahedron, 1999, 55, 10547.
7 K. El Sayed, M. S. Al-Said, F. S. El-Feraly and S. A. Ross, J. Nat. Prod.,
2000, 63, 995.
8 (a) T. G. Back, S. Collins and R. G. Kerr, J. Org. Chem., 1983, 48, 3077;
(b) for a review of selenosulfonation, see: T. G. Back, in Organoselen-
ium Chemistry—A Practical Approach, ed. T. G. Back, Oxford
University Press, Oxford, 1999, ch. 9, pp. 176–178.
9 D. L. J. Clive and E.-S. Ardelean, J. Org. Chem., 2001, 66, 4841.
10 J. Tsuji, Palladium Reagents and Catalysts, Wiley, Chichester, 1995,
pp. 188–209.
Scheme 4
11 E. J. Corey and M. Chaykovsky, J. Am. Chem. Soc., 1964, 86, 1639.
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