A Novel Approach to 2-Arylated Quinolines: Electrocyclization of Alkynyl Imines via Vinylidene Complexes

Article abstract of DOI:10.1021/ol036190a

(Matrix presented) Alkynyl imines underwent [4 + 2] electrocyclization in the presence of 20 mol % W(CO)₅(THF) to give 2-arylated quinolines in good yields. A deuterium labeling study suggests that the reaction proceeds via a tungsten vinylidene complex.

Full text of DOI:10.1021/ol036190a

ORGANIC
LETTERS
2004
Vol. 6, No. 3
353-355
A Novel Approach to 2-Arylated
Quinolines: Electrocyclization of
Alkynyl Imines via Vinylidene
Complexes
Kenichiro Sangu, Kohei Fuchibe, and Takahiko Akiyama*
Department of Chemistry, Faculty of Science, Gakushuin UniVersity,
1-5-1 Mejiro Toshima-ku, Tokyo 171-8588, Japan
takahiko.akiyama@gakushuin.ac.jp
Received November 7, 2003
ABSTRACT
Alkynyl imines underwent [4 + 2] electrocyclization in the presence of 20 mol % W(CO)5(THF) to give 2-arylated quinolines in good yields. A
deuterium labeling study suggests that the reaction proceeds via a tungsten vinylidene complex.
Quinoline skeletons play important roles as components of
biologically active compounds.1 In particular, 2-arylated
quinolines are naturally present and occur in structures of
5-lipoxygenase inhibitors,2 leucotriene antagonists,3 LTD4
receptor antagonists,4 and other biologically active molecules.
Although a variety of condensation reactions such as the
Skraup synthesis were reported for quinoline construction,5
development of novel and expeditious methods is still
desired.6
As a part of our continuing interest in the reaction of
imines and group 6 metal complexes,7 we recently found a
novel catalytic electrocyclization method of N-aryl alkynyl
imines. In this communication, we describe a novel quinoline
synthesis that proceeds via catalytically generated tungsten
vinylidene complexes.
At first, we examined the reaction of M(CO)6 (M ) Cr,
Mo, W) and an alkynyl imine. A mixture of an alkynyl imine
1a and an equimolar amount of M(CO)6 was irradiated in
toluene for 9-10 h, and the reaction mixtures were purified
by preparative TLC to give 2-phenylquinoline 2a (Table 1,
entries 1-3). Among the three metals examined, W(CO)6
gave the most favorable result (34% yield, entry 3). Further
optimization of the reaction conditions revealed that use of
W(CO)5(THF)8 and THF as a solvent increased the yield up
to 52% (entry 5).
(6) Recent transition metal-catalyzed synthetic methods: (a) Amii, H.;
Kishikawa, Y.; Uneyama, K. Org. Lett. 2001, 3, 1109. (b) Mahanty, J. S.;
De, M.; Das, P.; Kundu, N. G. Tetrahedron 1997, 53, 13397. (c) Takahashi,
T.; Li, Y.; Stepnicka, P.; Kitamura, M.; Liu, Y.; Nakajima, K.; Kotora, M.
J. Am. Chem. Soc. 2002, 124, 576. (d) Cho, C. S.; Kim, B. T.; Kim, T.-J.;
Shim, S. C. Chem. Commun. 2001, 2576 and references therein.
(7) Our recent reports on reactions of group 6 metal carbene complexes
with imines: (a) Kagoshima, H.; Akiyama, T. J. Am. Chem. Soc. 2000,
122, 11741. (b) Kagoshima, H.; Okamura, T.; Akiyama, T. J. Am. Chem.
Soc. 2001, 123, 7182. (c) Sangu, K.; Kagoshima, H.; Fuchibe, K.; Akiyama,
T. Org. Lett. 2002, 4, 3967.
(1) (a) Michael, J. P. Nat. Prod. Rep. 2001, 18, 543. (b) Funayama, S.;
Murata, K.; Noshita, T. Heterocycles 2001, 54, 1139.
(2) Musser, J. H,; Chakraborty, U. R.; Sciortino, S.; Gordon, R. J.;
Khandwala, A.; Neiss, E. S.; Pruss, T. P.; Van Inwegen, R.; Weinryb, I.;
Coutts, S. M. J. Med. Chem. 1987, 30, 96.
(3) Van Inwegen, R. G.; Khandwala, A.; Gordon, R.; Sonnino, P.; Coutts,
S.; Jolly, S. J. Pharm. Exp. Therapeut. 1987, 24, 117.
(4) Gauthier, J. Y.; Jones, T.; Champion, E.; Charette, L.; Dehaven, R.;
Ford-Hutchinson, A. W.; Hoogsteen, K.; Lord, A.; Masson, P.; Piechuta,
H.; Pong, S. S.; Springer, J. P.; Therien, M.; Zamboni, R.; Young, R. N. J.
Med. Chem. 1990, 33, 2841.
(8) W(CO)5(THF) was prepared just before use by irradiating a slurry
of W(CO)6 in dry THF under Ar for 2 h using a high-pressure mercury
lamp (450W).
(5) Jones, G. In ComprehensiVe Heterocyclic Chemistry; Katritzky, A.
R., Rees, A. R., Eds.; Pergamon: New York, 1984; Vol. 2, p 395.
10.1021/ol036190a CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/14/2004

sequently, electrocyclization of 4 takes place to give unstable
tungsten carbene complex 5, which gives 2a and regenerates
W(CO)5.
Table 1. Examination of Reaction Conditions
Although it was quite difficult to isolate or capture the
vinylidene intermediate 4, experimental results described
below (Scheme 3) support the [1,2]-hydrogen migration-
entry
M(CO)5(L)
conditions
yield/%
Scheme 3
1
2
3
4
5
Cr(CO)6
Mo(CO)6
W(CO)6
W(CO)6
W(CO)5(THF)
toluene, hν, rt, 10 h
toluene, hν, rt, 9 h
toluene, hν, rt, 9 h
THF,hν, rt, 9 h
18
13
34
16
52
THF, reflux, 3 h
Oxidative treatment of the crude mixture improved the
yield. Thus, after the reaction had completed, the crude
mixture was treated with 3 molar amounts of NMO (N-
methylmorpholine N-oxide) in dichloromethane at room
temperature for 1 h and purified by preparative TLC to give
2a in 70% yield (Scheme 1).9 Furthermore, this reaction
proceeded even with 20 mol % W(CO)5(THF), although the
rate of the reaction decreased (60% yield, 24 h).
a Deuterium incorporation was determined by relative intensity
on mass spectroscopy.
Scheme 1
vinylidene formation mechanism. First, phenyl-ethynyl imine
6 did not react under the reaction conditions and was
recovered in 75% yield. Second, deuterated alkynyl imine 8
gave 3-deuterated quinoline 9 in 59% yield.
Under the optimized conditions described in Scheme 1,11
we examined the generality of this reaction (Table 2).
Alkynyl imines 1b and 1c possessing electron-donating
substituents on the aniline ring provided 2b and 2c in good
yields. Imines 1d and 1e bearing electron-withdrawing
substituents on the aniline ring afforded 2d and 2e in
moderate yields.
Presumably, this reaction proceeds as follows (Scheme
2): alkynyl imine 1a complexes with W(CO)5(THF) to
Scheme 2
This reaction could be applied not only to para-substituted
substrates such as 1a-e but also to ortho- and meta-
(10) For reviews on vinylidene complexes, see: (a) Bruneau, C.; Dixneuf,
P. H. Acc. Chem. Res. 1999, 32, 311. (b) Bruce, M. I. Chem. ReV. 1991,
91, 197. (c) Bruce, M. I.; Swincer, A. G. AdV. Organomet. Chem. 1983,
22, 59. For synthetic use of vinylidene intermediates of group 6 metals,
see for examples: (d) McDonald, F. E.; Schultz, C. C. J. Am. Chem. Soc.
1994, 116, 9363. (e) McDonald, F. E. Chem. Eur. J. 1999, 5, 3103. (f)
Maeyama, K.; Iwasawa, N. J. Am. Chem. Soc. 1998, 120, 1928. (g)
Maeyama, K.; Iwasawa, N. J. Org. Chem. 1999, 64, 1344. (h) Iwasawa,
N.; Maeyama, K.; Kusama, H. Org. Lett. 2001, 3, 3871. (i) Kusama, H.;
Yamabe, H.; Iwasawa, N. Org. Lett. 2002, 4, 2569. (j) Iwasawa, N.; Shido,
M.; Maeyama, K.; Kusama, H. J. Am. Chem. Soc. 2000, 122, 10226. (k)
Miura, T.; Iwasawa, N. J. Am. Chem. Soc. 2002, 124, 518. (l) Miki, K.;
Nishino, F.; Ohe, K.; Uemura, S. J. Am. Chem. Soc. 2002, 124, 5260 and
references therein.
(11) Typical Procedure. A slurry of tungsten hexacarbonyl (70 mg, 0.20
mmol) in dry THF (2 mL) was irradiated for 2 h using a high-pressure
mercury lamp (450W). To the resulting yellow solution was added 1a (41
mg, 0.20 mmol) in THF (1 mL), and the solution was refluxed for 2 h.
After confirmation that alkynyl imine 1a was consumed completely by TLC
analysis, the solvent was removed in vacuo and a solution of NMO (70
mg, 0.60 mmol) in dichloromethane was added and stirred at room
temperature for 1 h. The reaction mixture was filtered through a small pad
of silica gel using ethyl acetate as an eluent. The filtrate was concentrated
and purified by preparative TLC (silica gel, 10:1 hexane/ethyl acetate) to
afford the quinoline derivative 2a as a yellow solid (28.6 mg, 70%).
generate π-alkyne complex 3, which reversibly produces
vinylidene complex 4 by [1,2]-hydrogen migration.10 Sub-
(9) This fact suggests that tungsten was complexed to 2a and was lost
during workup or purification.
354
Org. Lett., Vol. 6, No. 3, 2004

Finally, we examined the generality on imine carbon
(Table 3). Alkynyl imines 1i-l, which possess electron-
Table 2. Reaction with Various Alkynyl Imines (1)
Table 3. Reaction with Various Alkynyl Imines (2)
yield (%)
entry
Ar
Ph (1a )
p-CH3OC6H4 (1i)
p-CH3C6H4 (1j)
m-CH3C6H4 (1k )
p-ClC6H4 (1l)
x ) 1.0
x ) 0.2a
1
2
3
4
5
70
65
71
67
63
60
61
68
63
58
a Reaction was carried out over 24 h.
donating and electron-withdrawing groups on the benzylidene
ring, afforded the corresponding 2-arylated quinoline deriva-
tives in good yields.12,13
In summary, we have developed a novel synthesis of
2-substituted quinoline derivatives utilizing electrocyclization
of alkynyl imines via tungsten vinylidene complex.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Reseach on Priority Areas (A) “Ex-
ploitation of Multi-Element Cyclic Molecules” from the
Ministry of Education, Culture, Sports, Science, and Tech-
nology, Japan.
Supporting Information Available: Spectral data (1H
NMR, 13C NMR, IR, and elemental analysis) for all of the
products listed in Tables 2 and 3. This material is available
free of charge via the Internet at http://pubs.acs.org.
a Reaction was carried out over 24 h. b Reaction was carried out in a
scale 25 times larger than usual. 1a was recovered in 12% yield. c Products
were obtained as 97/3 regioisomeric mixtures.
OL036190A
substituted substrates: reaction of o-tolyl alkynyl imine 1f
afforded the corresponding quinoline 2f in 73% yield. The
m-tolyl substrate 1g gave the corresponding product 2g as a
97/3 regioisomeric mixture, which is apparently due to steric
effects. Furthermore, N-(1-naphthyl) alkynyl imine 1h worked
well to give the corresponding benzoquinoline derivative 2h
in 82% yield.
(12) N-[1-(2-Methylphenyl)prop-2-yn-1-ylidene]aniline (ortho isomer of
compound 1j) afforded the corresponding quinoline derivative in 21% yield
under the reaction conditions. Steric hindrance of the methyl group might
decrease the planarity of the vinylidene intermediate and retard the
electrocyclization step.
(13) Reactions of alkyl- or alkenyl-substituted alkynyl imines (not aryl
alkynyl imines) have not been examined yet due to their difficulties of
preparation.
Org. Lett., Vol. 6, No. 3, 2004
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