Synthesis of substituted quinolines by electrophilic cyclization of N-(2-alkynyl)anilines

Article abstract of DOI:10.1021/ol0476218

(Chemical Equation Presented) Quinolines substituted in the 3-position by an iodo or phenylseleno group are readily prepared in good to excellent yields by the reaction of propargylic anilines with appropriate electrophiles under mild reaction conditions.

Full text of DOI:10.1021/ol0476218

ORGANIC
LETTERS
2005
Vol. 7, No. 5
763-766
Synthesis of Substituted Quinolines by
Electrophilic Cyclization of
N-(2-Alkynyl)anilines
Xiaoxia Zhang, Marino A. Campo, Tuanli Yao, and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
larock@iastate.edu
Received November 18, 2004
ABSTRACT
Quinolines substituted in the 3-position by an iodo or phenylseleno group are readily prepared in good to excellent yields by the reaction of
propargylic anilines with appropriate electrophiles under mild reaction conditions.
Quinolines and their derivatives occur in numerous natural
products, and many of them display interesting biological
Scheme 1
activity.1 In particular, halogen-containing quinolines are of
significant interest because the halogen atom sometimes plays
a pivotal role in the compound’s bioactivity, and such
compounds provide a further avenue for structural elabora-
tion.2 Many methods for the synthesis of quinolines are
known,3 but due to their importance, the development of new
synthetic approaches using mild reaction conditions remains
an active research area.4
been synthesized by a photochemical method,7 a modified
Although simple 3-bromoquinolines can be obtained by
Skraup quinoline synthesis employing halo-substituted ac-
the bromination of quinoline hydrochlorides,5 the site-
roleins and anilines,8 and the Friedla¨nder quinoline synthesis.2c
selective aromatic halogenation of substituted quinolines
Some of these methods suffer relatively low yields, poor
remains a synthetic challenge.6 3-Haloquinolines have also
regioselectivity, and/or rather lengthy synthetic sequences.
(1) (a) Michael, J. P. Nat. Prod. Rep. 1997, 14, 605. (b) Balasubramanian,
M.; Keay, J. G. In ComprehensiVe Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford, 1996;
Vol. 5, p 245.
(2) (a) Newhouse, B. J.; Bordner, J.; Augeri, D. J.; Litts, C. S.; Kleinman,
E. F. J. Org. Chem. 1992, 57, 6991. (b) Torii, S.; Xu, L. H.; Sadakane, M.;
Okumoto, H. Synlett 1992, 513. (c) Nobuhide, M.; Yoshinobu, Y.; Hiroshi,
I.; Yoshio, O.; Tamejiro, H. Tetrahedron Lett. 1993, 24, 8263. (d) Croisey-
Delcey, M.; Croisy, A.; Carrez, D.; Huel, C.; Chiaroni, A.; Ducrot, P.;
Bisagni, E.; Jin, L.; Leclercq, G. Bioorg. Med. Chem. 2000, 8, 2629.
(3) Jones, G. In ComprehensiVe Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Eds.; Pergamon Press: New York, 1996; Vol. 5, p
167.
The cyclization of aryl-substituted alkynes via intramo-
lecular hydroarylation has proven to be an efficient method
for the construction of carbocycles and heterocycles.9 Our
work and that of others on the electrophilic cyclization of
functionally substituted alkynes has recently showed that this
is a very promising route to isoquinolines,10 benzothiophenes,11
polycyclic aromatics,12 indoles,13 naphthalenes,14 furopy-
(6) Trecourt, F.; Mongin, F.; Mallet, M.; Queguiner, G. Synth. Commun.
1995, 25, 4011.
(4) O’Dell, D. K.; Nicholas, K. M. J. Org. Chem. 2003, 68, 6427 and
refs cited therein.
(5) (a) Eisch, J. J. J. Org. Chem. 1961, 27, 1318. (b) Kress, T. J.;
Costantino, S. M. J. Heterocycl. Chem. 1973, 10, 409.
(7) Campos, P. J.; Tan, C. Q.; Rodriguez, M. A.; Anon, E. J. Org. Chem.
1996, 61, 7195.
(8) Baker, R. H.; Tinsley, S. W., Jr.; Butler, D.; Riegel, B. J. Am. Chem.
Soc. 1950, 72, 393.
10.1021/ol0476218 CCC: $30.25
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Table 1. Synthesis of Quinolines by Electrophilic Cyclization of N-(2-Alkynyl)anilines
a Reactions were run under the following conditions: 0.3 mmol of the propargylic aniline, 3 equiv of I2, and 2 equiv of NaHCO3 in 3 mL of CH3CN were
stirred at room temperature. b To 0.3 mmol of propargylic aniline and 2 equiv of NaHCO3 in 2 mL of CH3CN was added 2 equiv of ICl in 1 mL of CH3CN
dropwise at room temperature. c To 0.3 mmol of propargylic aniline and 2 equiv of NaHCO3 in 2 mL of CH3CN was added 2 equiv of PhSeBr in 1 mL of
CH3CN dropwise at room temperature.
ridines,15 and isochromenes.16 This encouraged us to examine
the cyclization of propargylic anilines by electrophiles in
order to obtain 3-haloquinolines and derivatives (Scheme 1).
The requisite N-(2-alkynyl)anilines can be easily prepared
by the reaction of propargylic mesylates or bromides with
anilines.17 We initially studied the reaction of N-(3-phen-
yl-2-propynyl)aniline (1) and I2. The reaction has been
examined with or without various bases such as NaHCO3,
NaOCO2CH3, triethylamine, and pyridine and in the presence
of different solvents and varying amounts of I2. The optimal
764
Org. Lett., Vol. 7, No. 5, 2005

reaction conditions developed thus far include stirring of 0.30
mmol of the propargylic aniline, 3 equiv of I2, and 2 equiv
of NaHCO3 in 3 mL of CH3CN at room temperature. The
reaction is complete in 0.5 h in all cases when finely ground
iodine powder is employed. The results are summarized in
Table 1.
The regioselectivity of this cyclization has also been
investigated. Very interestingly, 3-nitroaniline 17 afforded
regioisomers 18 and 19 in a 79% combined yield with
cyclization primarily ortho to the nitro group (9:1 ratio of
ortho to para) (entry 12). Only one isomer was observed in
the cyclization of 2-naphthylamine 20 with ring closure
occurring selectively in the less sterically hindered 3-position
of the naphthalene ring (entry 13).
The reaction of diamine 22 has also been examined (entry
14). Presumably, both the aromatic ring and the amino group
could attack the iodonium intermediate to form quinoline
23 and/or indole derivative 2413b as products. However, under
our reaction conditions, quinoline 23 is the only observed
product, being formed in a 55% isolated yield.
The stronger electrophile ICl has also been employed in
this cyclization. The ICl reaction conditions include stirring
of 0.30 mmol of the propargylic aniline, 2 equiv of ICl, and
2 equiv of NaHCO3 in 3 mL of CH3CN at room temperature.
Once again, good results were obtained at room temperature.
Thus, iodoquinolines 2 and 4 have been obtained in slightly
higher yields using ICl (entries 2 and 4). Lowering the
temperature to 0 or -78 °C did not improve the yields.
Yields comparable to those obtained using I2 (compare entry
1 with 2 and entry 3 with 4) have been obtained, and the
reactions are much faster, being complete in about 5 min.
PhSeBr has also been used as an electrophile in this
cyclization process. Satisfactory results have been obtained
using substrates bearing either an electron-donating group
on the phenyl ring of the side chain (entry 5) or an electron-
withdrawing group (entry 11) on the aniline ring.
We propose the following mechanism for this process: (1)
coordination of the carbon-carbon triple bond of the
propargylic aniline to the iodine cation, generating an
iodonium intermediate A, (2) intramolecular nucleophilic
attack of the aromatic ring of the aniline on the activated
triple bond to form dihydroquinoline B, and (3) in the
presence of I2 or ICl, oxidation of the dihydroquinoline B
to the corresponding quinoline18 (Scheme 3). It is possible
that the dihydroquinoline is not oxidized to the quinoline
until it is exposed to air during the workup.
We proceeded to examine the scope of the cyclization in
terms of the alkyne substituent. The iodocyclization of both
phenyl- (1) and 4-methoxyphenyl-substituted propargylic
anilines (3) using I2 generated the corresponding 3-iodo-
quinolines in 76 and 71% yields, respectively, with only a
trace of any side products (entries 1 and 3, Table 1). Good
results have also been obtained with the 4-fluorophenyl
substrate 6 (entry 6). In contrast, introducing a stronger
electron-withdrawing acetyl group in the para position of
the aromatic ring significantly lowered the yield to 57%
(entry 7). This reaction was accompanied by the formation
of 25% of the corresponding 3,6-diiodoquinoline and 14%
of the N-(3-aryl-2-propynyl)-4-iodoaniline. Cyclization with
I2 still proceeds when the terminus of the carbon-carbon
triple bond is substituted by an alkyl group. Thus, 4-butyl-
3-iodoquinoline can be synthesized in a moderate 43% yield
by the cyclization of aniline 10 (entry 8) together with a
26% yield of 3,6-diiodoquinoline. The reaction also pro-
ceeded smoothly with vinylic substitution on the alkyne
terminus. Thus, substrate 12 was cleanly converted to 4-(1-
cyclohexenyl)-3-iodo-2-methylquinoline in an 80% yield
(entry 9). In general, those alkyne substituents that can better
stabilize an iodonium intermediate (see the latter mechanistic
discussion) increase the reactivity of the carbon-carbon triple
bond and produce higher yields of the desired quinoline. The
n-butyl- and 4-acetylphenyl-substituted alkynes underwent
competitive electrophilic aromatic substitution on the acti-
vated aniline ring, followed by iodocyclization to produce
diiodoquinoline side products.
We continued to elucidate the scope of the reaction by
examining the effect of various substituents on the aniline
ring. Cyclization on relatively electron-poor anilines has also
been successful. For example, quinoline 15 was generated
exclusively in an 88% yield from substrate 14 bearing an
ester group (entry 10).
To obtain a dihydroquinoline, we have also examined the
cyclization on the mesyl-protected aniline 25 (Scheme 4).
(9) (a) Kitamura, T.; Takachi, T.; Kawasato, H.; Taniguchi, H. J. Chem.
Soc., Perkin Trans. 1 1992, 1969. (b) Barreau, M.; Ponsinet, G. Synthesis
1987, 262. (c) Barluenga, J.; Gonzalez, J. M.; Campos, P. J.; Asensio, G.
Angew. Chem., Int. Ed. Engl. 1988, 27, 1546. (d) Pastine, S. J.; Youn, S.
W.; Sames, D. Org. Lett. 2003, 5, 1055 and refs cited therein. (e) Nishizawa,
M.; Takao, H.; Yadav, V. K.; Imagawa, H.; Sugihara, T. Org. Lett. 2003,
5, 4563.
Scheme 2
(10) Huang, Q.; Hunter, J. A.; Larock, R. C. J. Org. Chem. 2002, 67,
3437.
(11) (a) Yue, D.; Larock, R. C. J. Org. Chem. 2002, 67, 1905. (b)
Hessian, K.; Flynn, B. Org. Lett. 2003, 5, 4377.
(12) Yao, T.; Campo, M. A.; Larock, R. C. Org. Lett. 2004, 6, 2677.
(13) (a) Yue, D.; Larock, R. C. Org. Lett. 2004, 6, 1037. (b) Barluenga,
J.; Trincado, M.; Rubio, E.; Gonzalez, J. M. Angew. Chem., Int. Ed. 2003,
42, 2406.
(14) Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez, J. M.
Org. Lett. 2003, 5, 4121.
(15) Arcadi, A.; Cacchi, S.; Giuseppe, S. D.; Fabrizi, G.; Marinelli, F.
Org. Lett. 2002, 4, 2409 and refs cited therein.
(16) (a) Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez, J.
M. J. Am. Chem. Soc. 2003, 125, 9028. (b) Yue, D.; Della Ca, N.; Larock,
R. C. Org. Lett. 2004, 6, 1581.
(17) Marshall, J. A.; Wolf, M. A. J. Org. Chem. 1996, 61, 3238.
Org. Lett., Vol. 7, No. 5, 2005
765

quinoline 27 in a 73% yield (Scheme 5). Iodoquinoline 23
readily undergoes an intramolecular palladium-catalyzed
Buchwald-Hartwig amination20 to produce the interesting
tetracyclic diamine 28 in a 65% yield.
Scheme 3
In summary, we have developed a new approach to
3-substituted quinolines, which are difficult to prepare using
previous methods. The reaction takes place under very mild
reaction conditions and tolerates considerable functionality.
The iodocyclization of propargylic anilines, followed by
palladium-catalyzed substitution, affords a rapid increase in
molecular complexity and provides a powerful tool for the
preparation of a wide range of functionalized, multisubsti-
tuted quinolines. Further work is in progress to extend this
method to the synthesis of more complex molecular struc-
tures.
Scheme 4
Acknowledgment. We gratefully acknowledge the donors
of the Petroleum Research Fund, administered by the
American Chemical Society, and the National Institute of
General Medical Sciences (GM 070620) for partial support
of this research and Kawaken Fine Chemicals Co., Ltd., and
Johnson Matthey, Inc., for donating the palladium acetate.
The boronic acid was contributed by Frontier Scientific, Inc.
Supporting Information Available: General experimen-
tal procedures and spectral data for all of the starting
materials and products. This material is available free of
charge via the Internet at http://pubs.acs.org.
Thus, the reaction of 25 with ICl at -78 °C for 1 h afforded
sulfonamide 26 in an 80% yield. Subsequent treatment with
NaOH in EtOH at 50 °C for 12 h in the presence of O2
converted this sulfonamide into the corresponding quinoline
2 in a 92% isolated yield.
OL0476218
3-Iodo- and selenoquinolines offer considerable potential
for further elaboration. For example, iodoquinoline 7 un-
dergoes a facile Suzuki reaction19 to afford styryl-substituted
(19) (a) Occhiato, E. G.; Trabocchi, A.; Guarna, A. J. Org. Chem. 2001,
66, 2459. (b) For a review, see: Miyaura, N.; Suzuki, A. Chem. ReV. 1995,
95, 2457.
(20) (a) Song, J. J.; Yee, N. K. Org. Lett. 2000, 2, 519. (b) For a review,
see: Wolfe, J. P.; Seble, W.; Marcoux, J. F.; Buchwald, S. L. Acc. Chem.
Res. 1998, 31, 805.
(18) Forrest, T. P.; Dauphinee, G. A.; Deraniyagala, S. A. Can. J. Chem.
1985, 63, 412.
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