A silver-catalyzed domino route toward 1,2-dihydroquinoline derivatives from simple anilines and alkynes

Article abstract of DOI:10.1021/ol050826b

(Chemical Equation Presented) A silver-catalyzed domino reaction of simple anilines and alkynes generates 1,2-dihydroquinoline derivatives efficiently.

Full text of DOI:10.1021/ol050826b

ORGANIC
LETTERS
2005
Vol. 7, No. 13
2675-2678
A Silver-Catalyzed Domino Route toward
1,2-Dihydroquinoline Derivatives from
Simple Anilines and Alkynes
Yumei Luo,† Zigang Li,† and Chao-Jun Li*,†,‡
Department of Chemistry, Tulane UniVersity, New Orleans, Louisiana 70118, and
Department of Chemistry, McGill UniVersity, 801 Sherbrooke St. West,
Montreal QC, H3A 2K6 Canada
cj.li@mcgill.ca
Received April 15, 2005
ABSTRACT
A silver-catalyzed domino reaction of simple anilines and alkynes generates 1,2-dihydroquinoline derivatives efficiently.
The partially hydrogenated quinoline moiety bearing different
functional groups is an important building block in various
natural products. It has exhibited a broad range of biological
activities and potential pharmaceutical applications.1 Typical
biological reactivities of such compounds include psycho-
tropic,2 anti-allergenic3 anti-inflammatory,4 and estrogenic
activities.5 Since Povarov’s pioneering work in the mid
1960s, Lewis acid catalysis toward tetrahydroquinoline
derivatives has been extensively studied.6 Very recently, we
reported an indium trichloride catalyzed 2:1 coupling of
dihydropyran or dihydrofuran with aniline derivatives to
provide tetrahydroquinoline derivatives.7 On the other hand,
Skraup and Bischler-Napieralski reactions have been com-
monly utilized in the synthesis of dihydroquinolines; these
involve the use of aniline and a ketone or an intramolecular
condensation of an aromatic amide.8
† Tulane University.
‡ McGill University.
(1) (a) Ramesh, M.; Moham, P. S.; Shanmugam, P. Tetrahedron 1984,
40, 4041. (b) Witherup, K. M.; Ransom, R. W.; Varga, S. L.; Pitzenberger,
S. M.; Lotti, V. J.; Lumma, W. J. U.S. Patent 5,288,725, 1994. (c) Perry,
N. B.; Blunt, J. W.; McCombs, J. D.; G. Munro, M. H. J. Org. Chem.
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A.; Misra, R. N. U.S. Patent 4,843,082, 1989. (g) Mohamed, E. A. Chem.
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Miyakawa, M.; Nagata, N. PCT Int. Appl. WO 0127086, 2001; Chem. Abstr.
2001, 134, 295752.
For the synthesis of dihydroquinoline derivatives, Taylor
and co-workers reported a Diels-Alder intramolecular
addition of 1,2,4-triazines.9 Arduini and co-workers reported
(4) Faber, K.; Stueckler, H.; Kappe, T. J. Heterocycl. Chem. 1984, 21,
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(5) Akhmed, K. S.; Bessonova, I. A. Dokl. Akad. Nauk Uzh. SSR 1982,
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R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52, 15031. (c) Povarov,
L. S. Russ. Chem. ReV. Engl. Transl. 1967, 36, 656. (d) Boger, D. L.;
Weinreb, S. M. Hetero Diels-Alder Methodology in Organic Synthesis;
Academic: San Diego, 1987; Chapters 2 and 9.
(7) (a) Zhang, J. H.; Li, C.-J. J. Org. Chem. 2002, 67, 3969. (b) Li, Z.;
Zhang, J. H.; Li, C.-J. Tetrahedron Lett. 2003, 44, 153. (c) Chen, L.; Li, Z.
G.; Li, C. J. Synlett 2003, 5, 732.
(2) Nesterova, I. N.; Alekseeva, L. M.; Golovira, S. M.; Granik, V. G.
Khim.-Farm. Zh. 1995, 29, 31; Chem. Abstr. 1996, 124, 117128t.
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Pharmacol. 1992, 44, 1211.
(8) (a) Skraup, Z. H. Ber. 1880, 13, 2086. (b) Wahren, M. Tetrahedron
1964, 20, 2773. (c) Bischler, A.; Napieralski, B. Ber. 1893, 26, 1903. (d)
Fodor, G.; Nagubandi, S. Tetrahedron 1980, 36, 1279.
10.1021/ol050826b CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/27/2005

a synthesis via a reaction between lithium anilides and
phenylacetylene with a stoichiometric amount of tin(IV)
chloride to yield 2,4-diphenyl-2-methyl-1,2-dihydroquino-
line;10 Rana developed the synthesis of dihydroquinolines
by the reaction of anilines with alkyl vinyl ketones in the
presence of indium trichloride under microwave irradiation.11
Several examples of dihydroquinoline synthesis via transition
metal catalysis have also been reported very recently.
Nakagawa and co-workers described a method that used
ruthenium-catalyzed ring-closing metathesis for synthesizing
substituted quinolines;12 Ward and co-workers reported a
copper-catalyzed coupling of aniline with propargyl chloride
to generate 2,2-disubstitued-1,2-dihydroquinoline via an
interesting intramolecular hydroarylation of the alkyne.13
However, the substrate availability, cost, stoichiometric
amount of additives, and functional group tolerance are some
limitations of the current methods for dihydroquinoline
synthesis. Therefore, a simple and novel method for syn-
thesizing 1,2-dihydroquinoline, especially polysubstituted
ones, is highly desirable and has practical benefits.
Table 1. Hydroamination of Unactivated Alkynes
Herein we wish to present the first example of a silver-
catalyzed regioselective domino reaction using simple anilines
and alkynes, which are easily available from commercial
vendors, to give synthetically useful polysubstituted 1,2-
dihydroquinoline derivatives efficiently. The study was based
on both the Lewis acidity and the transition metal character
of the silver catalyst. Furthermore, as a general objective
toward the goal of green chemistry and atom-economical
synthesis, the process has been carried out under solvent-
free conditions.14
a Isolated yields were reported; all reactions were carried out with 1 mmol
alkyne and 1.5 mmol amine. b 5% AuCl3, room temperature. c 5% AuCl3/
15% AgOTf, 60 °C. d Same as c, 110 °C.
As a preliminary study, we explored the hydroamination
of unactivated alkynes by anilines with a gold/silver catalyst
system. Amines were obtained in high yields via a gold- and
silver-catalyzed hydroamination of alkynes followed by
reduction (Scheme 1). The results of this sequential hydro-
effective than the Au-catalyzed one under the same reaction
condititons. To our surprise, when an excess amount of
alkyne was used, the reaction of phenylacetylene and aniline
generated products 4a and 5a in 50% and 20% yield,
respectively, at 140 °C under solo AgBF4 catalyst. Aliphatic
alkynes could only afford 4a-type product.
Scheme 1
Scheme 2
amination-reduction are summarized in Table 1.15 Subse-
quently, we examined the catalytic activities of AgOTf alone
as the catalyst for this transformation. As we expected,
AgOTf catalysis for the hydroamination of alkynes is less
(9) Taylor, E. C.; Macor, J. E.; French, L. G. J. Org. Chem. 1991, 56,
1807.
(10) Arduini, A.; Bigi, F.; Casiraghi, G.; Casnati, G.; Sartori, G. Synthesis
1981, 975.
(11) Ranu, B. C.; Hajra, A.; Dey, S. S.; Jana, U. Tetrahedron 2003, 59,
813.
(12) Theeraladanon, C.; Arisawa, M.; Nishida, A.; Nakagawa, M.
Tetrahedron 2004, 60, 3017.
(13) (a) Hennion, G. F.; Hanzel, R. S. J. Am. Chem. Soc. 1960, 82, 4908.
(b) Cooper, M. A.; Lucas, M. A.; Taylor, J. M.; Ward, A. D.; Williamson,
N. M. Synthesis 2001, 621. (c) Williamson, N. M.; Ward, A. D. Tetrahedron
2005, 61, 155.
Interestingly, Au catalyst alone did not provide these
products. After subsequent optimization of the reaction
conditions (Supporting Information), compound 5 was
(14) (a) Trost, B. M. Science 1991, 254, 1471. (b) Trost, B. M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 259.
2676
Org. Lett., Vol. 7, No. 13, 2005

Scheme 3
Table 2. Silver-Catalyzed Tandem Reaction of Alkynes and
Anilinesa
major product, which indicated a possible step involving the
addition of phenylacetylene to the ketimine intermediates.17
As the corresponding propargylamine intermediates have not
been isolated or identified at the current stage, we could not
rule out the possibility of a 6e-electrocyclic process, which
will give a similar product. However, since only product 4aD
was observed in the model study (in Scheme 3), the latter
6e-electrocyclic process seems unlikely. To gain further
insight into the reaction mechanism, 1,2-dihydro-2-methyl-
2,4-diphenylquinoline (4a) reacted directly with phenylacety-
Scheme 4
lene under the same conditions. Compound 5a was isolated
in 62% yield, which suggested a highly regioselective
hydroarylation step during the reaction process.18 On the basis
of these experimental results, we tentatively propose a
a All reactions were carried out by employing aniline (1.0 mmol), alkyne
(4.0 mmol), AgBF4 (0,05 mmol), HBF4 (0.07 mmol, 54% solution in diethyl
ether). and BF3‚Et2O(0.08 mmol). b Stirred at 190 °C. c Stirred at 160 °C.
d Isolated yields.
(15) For recent examples of the hydroamination of alkynes, see: (a)
Heutling, A.; Pohlki, F.; Doye, S. Chem. Eur. J. 2004, 10, 3059 and
references therein. (b) Illack, A.; Jiao, H.; Castro, I. G.; Hartung, C. G.;
Beller, M. Chem. Eur. J. 2004, 10, 2409. (c) Pohlki, F.; Bytschkov, I.;
Siebeneicher, H.; Heutling, A.; Koenig, W. A.; Doye, S. Eur. J. Org. Chem.
2004, 1967. (d) Anderson, L. L.; Arnold, J.; Bergman, R. G. Org. Lett.
2004, 6, 2519. (e) Hong, S.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673.
(f) Lutete, L. M.; Kadaoto, I.; Yammaoto, Y. J. Am. Chem. Soc. 2004,
126, 1622. (g) Li, Y.; Shi, Y.; Odom, A. L. J. Am. Chem. Soc. 2004, 126,
1794. For early transition metal/lanthanide catalyzed hydroamination, see:
(h) Bu¨rgstein, M. R.; Berberich, H.; Roesky, P. W. Chem. Eur. J. 2001, 7,
3078. (i) Douglass, M. R.; Stern, C. L.; Marks, T. J. J. Am. Chem. Soc.
2001, 123, 10221. (j) Hong, S.; Marks, T. J. J. Am. Chem. Soc. 2002, 124,
7886. For Ag- and Au-catalyzed hydroamination, see: (k) Mizushima, E.;
Hayashi, T.; Tanaka, M. Org. Lett. 2003, 5, 3349. (l) Robinson, R. S.;
Dovey, M. C.; Gravestock, D. Eur. J. Org. Chem. 2005, 505. (m) Robinson,
R. S.; Dovey, M. C.; Gravestock, D. Tetrahedron Lett. 2004, 45, 6787.
(16) To avoid deuterium and hydrogen exchange during the prolonged
reaction time, this model study was carried out under microwave irradiation
at 140 °C with 100 W operating power for 20 min.
obtained in good yield using the combined AgBF4/HBF4
system. Various polysubstituted dihydroquinoline products
were obtained from alkynes and aniline via this reaction,
and the results are summarized in Table 2.
Good to excellent yields were obtained in almost all cases.
The catalyst system is quite insensitive to the electronic effect
of both alkynes and anilines. More electron-rich substrates
(compare entries 5 and 6) provided the product in a slightly
higher yield.
To investigate the possible mechanism of the reaction, an
isotope experiment was performed using deuterium-labeled
phenylcetylene with aniline at 140 °C catalyzed by AgBF4/
HBF4 (Scheme 3).16 Compound 4aD was observed as the
(17) (a) Wei, C.; Li, Z.; Li, C.-J. Org. Lett. 2003, 5, 4473. (b) Li, Z.;
Wei, C.; Chen, L.; Varma, R. S.; Li, C.-J. Tetrahedron Lett. 2004, 45, 2443.
(18) 1,2-Dihydro-2-methyl-2,4-diphenylquinoline is not stable under the
current reaction conditions, and the yield is lower than starting from aniline
and phenylacetylene directly.
Org. Lett., Vol. 7, No. 13, 2005
2677

In summary, we have developed a novel method to
generate polysubstituted 1,2-dihydroquinoline derivatives by
a one-pot domino process with high regioselectivity using a
silver catalyst. Hydroamination, alkyne addition, intramo-
lecular hydroarylation, and hydroarylation of a third molecule
of alkyne could be accomplished in a one-pot process with
100% atom economy.14 The scope, mechanism, and synthetic
applications of the reaction are currently under investigation.
Scheme 5
Acknowledgment. We thank NSF and the NSF-EPA
joint program for a sustainable environment for support of
our research.
Supporting Information Available: Representative ex-
perimental procedure and the characterization of all products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
domino process with three different types of reactions to form
the dihydroquinoline core, which include the formation of
ketimine, a ketimine addition to form a propargylamine
intermediate, and an intramolecular hydroarylation. Then the
dihydroquinoline intermediate undergoes a neighboring-
group-directed hydroarylation to give the final product.19
OL050826B
(19) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93,
1307.
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Org. Lett., Vol. 7, No. 13, 2005