New Access to 2,3-disubstituted Quinolines through Cyclization of o-Alkynylisocyanobenzenes

Article abstract of DOI:10.1021/ol991133w

(Matrix Presented) o-Alkynylisocyanobenzenes underwent nucleophile-induced intramolecular cyclization to give 2,3-disubstituted quinoline derivatives in high yields. In addition to the oxygen and nitrogen nucleophiles such as methanol and diethylamine, the nucleophilic carbon of the enolate of malonate induced the cyclization effectively. Reaction of 1,4-di(trimethylsilylethynyl)-2,3-diisocyanobenzene with methanol afforded 2,9-dimethoxy-1,10-phenanthroline in good yield.

Full text of DOI:10.1021/ol991133w

ORGANIC
LETTERS
1999
Vol. 1, No. 12
1977-1979
New Access to 2,3-Disubstituted
Quinolines through Cyclization of
o-Alkynylisocyanobenzenes
Michinori Suginome, Takeshi Fukuda, and Yoshihiko Ito*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of
Engineering, Kyoto UniVersity, Kyoto 606-8501, Japan
yoshi@sbchem.kyoto-u.ac.jp
Received October 8, 1999
ABSTRACT
o-Alkynylisocyanobenzenes underwent nucleophile-induced intramolecular cyclization to give 2,3-disubstituted quinoline derivatives in high
yields. In addition to the oxygen and nitrogen nucleophiles such as methanol and diethylamine, the nucleophilic carbon of the enolate of
malonate induced the cyclization effectively. Reaction of 1,4-di(trimethylsilylethynyl)-2,3-diisocyanobenzene with methanol afforded 2,9-dimethoxy-
1,10-phenanthroline in good yield.
Cyclization of ortho-functionalized aryl isocyanides has been
an attractive strategy for the synthesis of nitrogen-containing
heterocyclic aromatic compounds. This protocol has provided
an effective synthetic method for five-membered heterocyclic
aromatics including indole derivatives.1-3 On the other hand,
six-membered ring formation with ortho-functionalized aryl
isocyanides has only been reported quite recently.4,5
In a very recent paper, Rainier and co-workers reported
the synthesis of indole derivatives by radical cyclization of
o-alkynylisocyanobenzenes.6 They briefly described the
formation of quinolines as undesired byproducts of the radical
cyclization. The appearance of this paper prompted us to
publish our quinoline synthesis by the cyclization of o-
alkynylisocyanobenzenes.7 Herein, we report a new and
versatile synthesis of substituted quinolines through nucleo-
phile-triggered 6-endo cyclization of o-alkynylisocyano-
benzenes, which are readily available from o-iodoaniline and
alkynes.
o-(Trimethylsilylethynyl)isocyanobenzene (3a) was pre-
pared in high yield from o-iodoaniline (1) and trimethyl-
silylacetylene via Sonogashira-Hagihara coupling and N-
formylation, followed by dehydration (Scheme 1).8 The
compound 3a could be isolated by silica gel column
chromatography.
Scheme 1. Synthesis of
o-(Trimethylsilylethynyl)isocyanobenzene 3a
(1) For anionic cyclizations, see: Ito, Y.; Kobayashi, K.; Saegusa, T. J.
Am. Chem. Soc. 1977, 99, 3532. Ito, Y.; Kobayashi, K.; Saegusa, T.
Tetrahedron Lett. 1979, 20, 1039. Haefliger, W.; Knecht, H. Tetrahedron
Lett. 1984, 25, 289. Orita, A.; Fukudome, M.; Ohe, K.; Murai, S. J. Org.
Chem. 1994, 59, 477.
(2) For Lewis acid mediated cyclization, see: Ito, Y.; Kobayashi, K.;
Saegusa, T. Chem. Lett. 1980, 1563.
(3) For radical cyclizations, see: Fukuyama, T.; Chen, X.; Peng, G. J.
Am. Chem. Soc. 1994, 116, 3127. Shinada, T.; Miyachi, M.; Itagaki, Y.;
Naoki, H.; Yoshihara, K.; Nakajima, T. Tetrahedron Lett. 1996, 37, 7099.
(4) Kobayashi, K.; Matoba, T.; Irisawa, S.; Matsumoto, T.; Morikawa,
O.; Konishi, H. Chem. Lett. 1998, 551.
(5) Synthesis of quinolines by radical reaction of aryl isocyanide with
o-alkynyliodobenzenes was reported. See: Josien, H.; Ko, S.-B.; Bom, D.;
Curran, D. P. Chem. Eur. J. 1998, 4, 67 and references therein.
10.1021/ol991133w CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/12/1999

The compound 3a was stirred in methanol in the presence
of potassium carbonate at room temperature. Six-membered
ring formation accompanied by the cleavage of the silicon-
carbon bond was completed within 6 h, giving 2-methoxy-
quinoline (4a) in 86% yield (eq 1). The reaction was
(entry 1). The cyclization reactions of other isonitriles 3b-f
with Et2NH proceeded at room temperature in the absence
of potassium carbonate. An isocyanide bearing an enynyl
group at the ortho position (3f) also provided the corre-
sponding alkenylquinoline 5f in high yield (entry 6).
To gain insight into the reaction mechanism, the reaction
of o-isocyanobenzonitrile (6) was examined under similar
conditions used for 3. Interestingly, 2-diethylaminoquinazo-
line (7) was formed in high yield through the diethylamine-
induced cyclization in the same manner as the reaction of 3
(eq 2).
significantly retarded in the absence of the base (36%
conversion after 48 h). No trace of the indole derivative was
observed in the reaction mixture.
Reactions of internal alkynes 3b-e other than TMS
derivative 3a proceeded in the absence of base at 50 °C to
afford the corresponding 3-substituted 2-methoxyquinolines
in good yields (Table 1).
On the basis of this finding, the mechanism shown in
Scheme 2 is presumed. Initial attack of the nucleophile to
Table 1. Synthesis of 2-Methoxyquinolines by Cyclization of
o-Alkynylisocyanobenzenes with Methanola
Scheme 2. Possible Mechanism of the Cyclization of
o-Alkynylisocyanobenzenes and o-Isocyanobenzonitrile Induced
by Nucleophiles
entry
3 (R)
product (yield, %)
1
2
3
4
3b (t-Bu)
4b (76)
4c (71)
4d (66)
4e (86)
3c (c-Hex)
3d (CH2OCH3)
3e (Ph)
a A mixture of 3 (0.5 mmol) and methanol (0.5 mL) was stirred for 20
h at 50 °C.
Use of diethylamine as the nucleophile rather than
methanol resulted in the formation of 3-substituted 2-(di-
ethylamino)quinolines 5 in better yields (Table 2). Note that
5a was produced in high yield even in the presence of K2CO3
Table 2. Synthesis of 2-(Diethylamino)quinolines by
Cyclization of o-Alkynylisocyanobenzenes with Et2NHa
the isocyano carbon of 3 (E ) CR) or 6 (E ) N) produces
the corresponding imidoyl anion. The intermediate undergoes
a 6π electrocyclization to give a bicyclic allene or a
ketenimine intermediate,9 which is rapidly protonated to
afford the corresponding product 4, 5, or 7.10 Although the
addition11 of alcohols and amines to ordinary isonitriles is
known to be very sluggish in the absence of catalysts, the
facile electrocyclization following the reversible attack of
the nucleophile may have favorably driven 3 to the formation
entry
3 (R)
product (yield, %)
1b
2
3
4
5
3a (TMS)
3b (t-Bu)
3c (c-Hex)
3d (CH2OCH3)
3e (Ph)
5a (92)
5b (86)
5c (80)
5d (65)
5e (94)
5f (86)
(6) Rainier, J. D.; Kennedy, A. R.; Chase, E. Tetrahedron Lett. 1999,
40, 6325.
(7) A part of this paper was presented at the 76th Chemical Society of
Japan National Meeting, March, 1999, Yokohama, 4C303.
(8) For the use of 3a in a palladium-mediated cyclization, see: Onitsuka,
K.; Segawa, M.; Takahashi, S. Organometallics 1998, 17, 4335.
(9) Intermediacy of reactive cyclic allenes was discussed. See: Wills,
M. S. B.; Danheiser, R. L. J. Am. Chem. Soc. 1998, 120, 9378.
6
3f (1-c-hexenyl)
a A mixture of 3 (1 mmol) and diethylamine (5 mL) was stirred for 24
h at room temperature unless otherwise noted. b In the presence of potassium
carbonate (0.5 mmol).
1978
Org. Lett., Vol. 1, No. 12, 1999

of the quinolines. It is worth noting that deuterium was
quantitatively incorporated at the 3- and 4-positions of the
quinoline 4a produced, when the cyclization of 3a was
carried out in CH3OD in the presence of potassium carbonate.
The incorporation of the deuterium to the 3-position indicates
that deuteriodesilylation with CH3OD/K2CO3 may be in-
volved prior to the cyclization reaction.
cross-coupling reaction with Grignard reagents as exempli-
fied in eq 4.12
The new cyclization was successfully applied to the
synthesis of phenanthroline derivatives 9. The treatment of
dialkynyldiisocyanobenzene 8 with methanol in the presence
of potassium carbonate afforded the double cyclization
product 9 in good yield (eq 3).
A further synthetic application of the present reaction is
demonstrated by the cyclization of o-alkynylisocyano-
benzenes (3) induced by carbon nucleophiles. Thus, the
sodium enolate of diethylmalonate reacted with 3b at room
temperature to give 11 in 87% yield via C-C bond formation
at the isocyano carbon (eq 5).
This example demonstrates the potential utility of this
cyclization reaction for the efficient synthesis of a variety
of quinoline derivatives. Investigations to explore cyclizations
induced by other carbon nucleophiles are now underway.
The 2-methoxyquinoline derivative 4a prepared by this
method was synthetically elaborated using Ni-catalyzed
(10) One of the reviewers suggested a mechanism involving a initial 6π
cyclization of 3, which affords a cyclic allenyl intermediate with a carbene
site at the 2-position, followed by trapping with methanol or diethylamine.
Although we also considered this alternative mechanism, the mechanism
proposed by us may be more likely at this moment, if it is taken into account
that each alkynylisocyanobenzene 3 exhibited different reaction rates toward
the two different reactants, i.e., methanol and dimethylamine. Indeed, we
would expect very similar reaction rate for the two reactions, if the
generation of the highly reactive allenyl carbene intermediate is involved
in the reaction.
Supporting Information Available: Experimental pro-
cedures and characterization data for the new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL991133W
(11) Saegusa, T.; Ito, Y. In Isonitrile Chemistry; Ugi, I., Ed.; Academic
Press: New York, 1971; p 65.
(12) Wenkert, E.; Michelotti, E. L.; Swindell, C. S. J. Am. Chem. Soc.
1979, 101, 2246.
Org. Lett., Vol. 1, No. 12, 1999
1979