Selective endo and exo iodocyclizations in the synthesis of quinolines and indoles

Article abstract of DOI:10.1021/ol052518j

A simple, efficient method for a divergent synthesis of indoles, quinolines, and quinolinones using a highly selective endo/exo iodocyclization procedure is described.

Full text of DOI:10.1021/ol052518j

ORGANIC
LETTERS
2006
Vol. 8, No. 2
243-246
Selective endo and exo Iodocyclizations
in the Synthesis of Quinolines and
Indoles
Karl O. Hessian and Bernard L. Flynn*
Department of Medicinal Chemistry, Victorian College of Pharmacy,
Monash UniVersity, 381 Royal Pde, ParkVille VIC 3052, Australia
bernard.flynn@Vcp.monash.edu.au
Received October 17, 2005
ABSTRACT
A simple, efficient method for a divergent synthesis of indoles, quinolines, and quinolinones using a highly selective endo/exo iodocyclization
procedure is described.
The iodocyclization of heteroatoms such as oxygen, nitrogen,
and sulfur with tethered alkynes has proven to be an effective
method of preparing a large variety of heterocyclic-ring
systems.1-7 Important heterocycles such as furans,1 pyrroles,2
thiophenes,3 indoles,4 benzo[b]furans,5 and benzo[b]thio-
phenes,6 among others,7 have been accessed using this
protocol. We have employed this protocol in structure-
activity relationship studies of some novel tubulin polym-
erization inhibitors in a manner that provides judicious and
convenient modification of both the substituents and the
scaffold, for example, 1 and 2 (Figure 1).8 Herein, we report
(1) (a) Bew, S. P.; Knight, D. W. J. Chem. Soc., Chem. Commun. 1996,
1007. (b) El-Taeb, G. M. M.; Evans, A. B.; Knight, D. W.; Jones, S.
Tetrahedron Lett. 2001, 42, 5945. (c) Sniady, A.; Wheeler, K. A.;
Dembinski, R. Org. Lett. 2005, 7, 1769.
(2) (a) Knight, D. W.; Redfern, A. L.; Gilmore, J. J. Chem. Soc., Perkin
Trans. 1 2001, 2874. (b) Knight, D. W.; Redfern, A. L.; Gilmore, J. J.
Chem. Soc., Perkin Trans. 1 2002, 622.
(3) (a) Flynn, B. L.; Flynn, G. P.; Hamel, E.; Jung, M. K. Bioorg. Med.
Chem. Lett. 2001, 11, 2341. (b) Ren, X.-F.; Turos, E.; Lake, C. H.; Churchill,
M. R. J. Org. Chem. 1995, 60, 6468. (c) Ren, X.-F.; Konaklieva, M. I.;
Shi, H.; Dickey, S.; Lim, D. V.; Gonzalez, J.; Turos, E. J. Org. Chem.
1998, 63, 8898.
(4) (a)Yue, D.; Larock, R. C. Org. Lett. 2004, 6, 1037. (b) Amjad, M.;
Knight, D. W. Tetrahedron Lett. 2004, 45, 539. (c) Barluenga, J.; Trincado,
M.; Rubio, E.; Gonzalez, J. M. Angew. Chem., Int. Ed. 2003, 42, 2406. (d)
ten Hoedt, R. W. M.; Koten, G. V.; Noltes, J. G. Synth. Commun. 1977, 7,
61.
(5) (a) Banwell, M. G.; Flynn, B. L.; Wills, A. C.; Hamel, E. Aust. J.
Chem. 1999, 52, 767. (b) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Marinelli, F.;
Moro, L. Synlett 1999, 1432.
Figure 1. Potent heterocyclic tubulin polymerization inhibitors.3a,6a
(6) Flynn, B. L.; Verdier-Pinard, P.; Hamel, E. Org. Lett. 2001, 3, 651.
(b) Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905. (c) Hessian, K.
O.; Flynn, B. L. Org. Lett. 2003, 5, 4377.
(7) (a) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002, 67,
3437. (b) Yao, T.; Larock, R. C. J. Org. Chem. 2003, 68, 5936. (c) Bellina,
F.; Biagetti, M.; Carpita, A.; Rossi, R. Tetrahedron 2001, 57, 2857. (d)
Peng, A.; Ding, Y. J. Am. Chem. Soc. 2003, 125, 15006. (e) Arcadi, A.;
Cacchi, S.; Giuseppe, S. D.; Fabrizi, G.; Marinelli, F. Org. Lett. 2002, 4,
2409. (f) Djuardi, E.; McNelis, E. Tetrahedron Lett. 1999, 40, 7193. (g)
Yue, D.; Della Ca, N.; Larock, R. C. Org. Lett. 2004, 6, 1581
highly selective 5-exo- and 6-endo-digonal iodocyclization
protocols that give direct access to a variety of indoles and
quinolines and their application to the synthesis of analogues
of 1 and 2.
(8) (a) Flynn, B. L.; Hamel, E.; Jung, M. K. J. Med. Chem. 2002, 45,
2670. (b) Chaplin, J. H.; Flynn, B. L. J. Chem. Soc., Chem. Commun. 2001,
1594. See also refs 3a, 5a, 6a, and 6c.
10.1021/ol052518j CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/23/2005

Studies by both Larock and our group have shown that
5-endo-digonal iodocyclization of readily available alkyl(2-
alkynylphenyl) sulfides 3a is an effective method for
constructing 3-iodobenzo[b]thiophenes 4a, which are acti-
vated toward C-3 substitution by virtue of the functionality
of the iodo group (Scheme 1).6 Larock and Noltes have
was converted into the iodocyclization precursors 10-12 by
reaction with lithium acetylides to give 10, followed by
oxidation to give 11 and 1,2-addition of MeMgCl to the
ketone 11 to give 12 (Scheme 3).6c The tertiary alcohols 12
Scheme 3. Preparation of Iodocyclization Precursors
Scheme 1. 3-Iodobenzo[b]thiophenes and 3-Iodoindoles from
5-endo-Digonal Iodocyclization.
shown that equivalent 2-alkynyldimethylanilines 3b can also
participate in related iodocyclizations to give 3-iodoindoles
4b.4a,d
Recently, we reported the preparation and iodocyclization
of systems where the tether between the sulfide and the
alkyne had been extended by one carbon, in particular, of
1-(2-alkylthiophenyl)alk-2-yn-1-ones 5a and 1-(2-alkylthio-
phenyl)alk-2-yn-1-ols 5b systems (Scheme 2).6c Interestingly,
were not purified but were used as crude reaction mixtures
in the iodocyclization step (see below).
Unlike the ketone-linked sulfides 5a, which underwent
highly selective 5-exo-digonal iodocyclization, the equivalent
dimethylamino systems 11 proved highly selective for the
6-endo-digonal pathway to give quinolinones 13 (Scheme
4).11 The variations in reaction conditions that we have
Scheme 2. 5-exo-Digonal and 6-endo-Digonal Cyclization of
5
Scheme 4. Iodocyclization of 11 in Dichloromethane
the possible 5-exo-digonal and 6-endo-digonal iodocycliza-
tion pathways of such systems are not predicted by Baldwin’s
rules and may provide for either or both products.3a,9
We observed that the different sulfides 5 all exhibited a
strong bias toward the 5-exo-digonal pathway to give 6 rather
than the 6-endo-digonal pathway to give 7 (Scheme 2).6c This
was consistent with the earlier observations of Ren et al. on
equivalent, nonbenzofused systems.3b In this report, we
describe the iodocyclizations of dimethylamino equivalents
of 5, which exhibit somewhat different endo/exo selectivities.
The dimethylamino containing iodocyclization precursors
10-12 were prepared in an almost identical manner to that
previously described for some of the alkylthio systems 5
(Scheme 2).
employed to date (change in solvent and change in the Iδ+
source) have not affected the endo/exo selectivity of these
iodocyclization reactions.12
When the secondary and tertiary alcohols 10 and 12,
respectively, were subjected to iodocyclization, it was
revealed that these systems could be directed down either a
6-endo-digonal or a 5-exo-digonal pathway depending on
the nature of the reaction conditions (Scheme 5). When
iodocyclization of the alcohols 10 and 12 was performed in
Readily available 2-fluorobenzaldehyde (8) was converted
(10) Damhaut, P. Tetrahedron 1997, 53, 5785.
to 9 by nucleophilic aromatic substitution.10 This aldehyde
(11) No 5-exo digonal product could be detected in the 1H NMR spectra
of the crude reaction mixtures. The endo nature of this iodocyclization
reaction was based on the characterization of 13a using HMBC (see
Supporting Information).
(9) (a) Johnson, C. D. Acc. Chem. Res. 1993, 26, 476. (b) Baldwin, J.
E.; Thomas, R. C.; Kruse, L. I.; Silberman, L. J. Org. Chem. 1977, 42,
3846. (c) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734. (d)
Baldwin, J. E.; Cutting, J.; Dupont, W.; Kruse, L.; Silberman, L.; Thomas,
R. C. J. Chem. Soc., Chem. Commun. 2001, 736.
(12) Iodocyclizations were also performed in ethanol and acetonitrile
using iodine. ICl and N-iodosuccinimide were used as alternative iodonium
sources in dichloromethane and acetonitrile.
244
Org. Lett., Vol. 8, No. 2, 2006

solvent (dilute solutions in acetonitrile).15 How the protic
nature of the solvent affects the endo/exo selectivity of the
iodocyclization pathway is uncertain. A proposed mechanism
for the conversion of 14 and 16 to 15 and 17, respectively,
is given in Scheme 6. Loss of iodomethane from 14 to give
Scheme 5. Iodocyclization of 10 and 12 in Different Solvents
Scheme 6. Proposed Mechanism for the Conversion of 14 and
16 to 15 and 17, Respectively
acetonitrile or dichloromethane using iodine, the 6-endo-
product 14 was formed as a white precipitate. The quaternary
ammonium salts 14 were often unstable and were generally
not isolated but converted to the quinolinium salt 15 by direct
heating of the reaction mixture.13
When iodocyclization of the alcohols 10 and 12 was
performed in ethanol or methanol using iodine, the 5-exo-
digonal product 16 was formed as a white precipitate. As
with the quaternary ammonium salts 14, the salts 16 were
generally not isolated but converted to the 2-acylindoles 17
upon direct heating of the reaction mixture.13 It should be
noted that, for iodocyclizations involving tertiary alcohols
of the type 12, the alcohols are not isolated but are
iodocyclized as crude reaction mixtures resulting from the
alkylation of the relevant ketone 11. Accordingly, the yields
of 15c and 15d and 17c and 17d are calculated from the
associated ketones 11a and 11b. It is also noteworthy that
the N-methylquinolinium salts of the type 15 can be
conveniently demethylated to give the parent quinolines (see
below).14
At this stage, we are not able to offer a completely
satisfactory explanation for the alternation of the endo/exo
selectivity observed for the iodocyclizations of systems 10
and 12 in different solvents. The key difference at this stage
appears to be in the protic nature of the solvent rather than
in its polarity because both dichloromethane and acetonitrile
gave 15 as the product and 17 was only formed in ethanol
or methanol.
18 is followed by expulsion of the hydroxyl in 18 to give
19. Because only one equivalent of iodine is used in these
reactions, the hydroxide counterion in 19 presumably dis-
places the iodo group in iodomethane to give the observed
iodide salt 15. Loss of iodomethane from 16 gives 20. As
previously proposed for the equivalent benzo[b]thiophenes
6b,6c these systems can be converted to the 2-acylindoles
17 either by 1,3-allylic migration of the hydroxyl group to
give 21 and elimination of HI or by allylic substitution of
the hydroxyl group in 20 with ethanol to give 22 (for
reactions performed in ethanol), which loses iodoethane from
the oxonium species 23 to give 17.
The 5-exo-digonal iodocyclization reaction can also be
used to access 2-[(Z)-1-iodoalkenyl]indoles 24 (Scheme 7)
on the basis of observations made during our work on benzo-
[b]thiophenes 6b (R′ ) CH2R′′′), which could be directed
to give rise to the equivalent 2-[(Z)-1-iodoalkenyl]benzo[b]-
thiophenes.6c This required the formation of the acetates 10b-
Ac and 12b-Ac, respectively, which were conveniently
formed by addition of acetic anhydride to the alkoxide
resulting from nucleophilic addition to the aldehyde and
ketones of 9 and 11b, respectively (Scheme 7).
Iodocyclization of the acetates 10b-Ac and 12b-Ac in
ethanol gives the intermediate acetates 16-Ac. The reaction
mixture is then evaporated to dryness to remove all traces
It also appears that the formation of 14 and 16 is under
kinetic control because they both form quickly at room
temperature, precipitate from the reaction mixtures, and do
not interconvert when subsequently dissolved in the same
(15) Similar iodocyclizations of sulfur and nitrogen heteroatoms involving
alkenes often proceed in a 5-exo-digonal fashion but then undergo a 1,2-
rearrangement to give a 6-endo-digonal-type product under thermal condi-
tions. See: Gataullin, R. R.; Minnigulov, F. F.; Khakimova, T. V.; Fatykhov,
A. A.; Spirikhin, L. V.; Abdrakhmanov, I. B. Russ. Chem. Bull., Int. Ed.
2002, 51, 1329 and ref 3a.
(13) Samples of 14 and 16 (R ) n-Pr and R′ ) H) were isolated, and an
1H NMR spectrum and an LCMS were obtained on each (see Supporting
Information).
(14) Deady, L. W.; Korytsky, O. L. Tetrahedron Lett. 1979, 20, 451.
Org. Lett., Vol. 8, No. 2, 2006
245

Applying the same Suzuki coupling to 13a gives analogue
26. Finally, 1,2-addition of 3,4,5-trimethoxyphenyllithium
to 11a followed by iodocyclization of the crude tertiary
alcohol in ethanol gives the indole 27 (Scheme 8).
Scheme 7. Formation of 2-(1-Iodoalkenyl)indoles 24a and
24b by Iodocyclization of 10b-Ac and 12b-Ac
Scheme 8. Synthesis of Analogues of 1 and 2
of ethanol, and the crude product 16-Ac is heated in 1,2-
dichloroethane (DCE) to give 2-[(Z)-1-iodoalkenyl]indoles
24a and 24b in good overall yields from 9 and 11b,
respectively (minor amounts of the E-isomer were observed
upon standing). The exchange of ethanol for DCE as the
solvent is required to avoid allylic substitution of the acetate
for an ethoxy group, giving rise to an intermediate of the
type 22, which would lead to the formation of ketone 17
(Scheme 6). Likewise, the presence of the acetate groups in
10b-Ac and 12b-Ac prevents the possibility of any competing
1,3-allylic migration of the hydroxyl substituent in the
equivalent intermediate of 20 (Scheme 6) leading to ketone
17.16
We are currently using these selective iodocyclization
reactions in our ongoing structure-activity relationship
studies of tubulin polymerization inhibitors of the types 1
and 2. In particular, we were interested in displaying the
key pharmacophoric units, para-methoxyphenyl and 3,4,5-
trimethoxyphenyl, over a range of different heterocyclic
cores. For example, demethylation of 15a followed by Suzuki
coupling with 3,4,5-trimethoxyphenylboronic acid gives 25.
Acknowledgment. The authors thank Dr. Martin Scanlon
and Mr. Stuart Thomson for assistance in obtaining the
HMBC spectra and Iliad Chemicals Pty Ltd. for financial
support.
Supporting Information Available: Detailed synthetic
procedures and spectral data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(16) Evaporating the ethanol from the crude mixture of 16 (R ) n-Pr,
R′ ) H) and adding acetonitrile and heating lead to a 1:2 mixture of indoles
17b and 24a.
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