and not the expected disubstituted heterocycle 4-phenyl-3-
trimethylsilyl)isoquinoline, was isolated in 85% yield from
the palladium-catalyzed reaction of N-(2-iodobenzylidene)-
tert-butylamine (1) and 1-phenyl-2-(trimethylsilyl)acetylene
Unfortunately, the attempted annulation of 1 and other
terminal acetylenes bearing simple alkyl groups, namely
cyclohexyl acetylene and 1-hexyne, afforded none of the
desired isoquinolines.
(
(eq 1). Herein, we report that monosubstituted isoquinolines
In an attempt to increase the generality of this annulation
process, we subsequently investigated the palladium-
catalyzed cyclization of the presumed intermediate imino-
alkynes 3a and 3c. Iminoalkyne 3a could be cyclized to
isoquinoline 2 in 88% yield by employing 5 mol % of PdCl
2
-
(
PhCN) and 1 equiv of Na CO in DMF at 100 °C for 14
2
2
3
h. However, 3c could not be cyclized using these reaction
conditions. Interestingly, by employing 10 mol % of CuI,
2 2
instead of PdCl (PhCN) , as the catalyst for the cyclization,
3-phenylisoquinoline could be obtained in quantitative yield
from the cyclization of 3a (eq 2). In addition, iminoalkynes
containing alkenyl, and most importantly alkyl substituents,
also cyclized to the desired monosubstituted isoquinolines
in excellent yields in short reaction times (eq 2).
and pyridines can be synthesized in good to excellent yields
by the coupling of terminal acetylenes with the tert-
butylimines of o-iodobenzaldehydes and 3-halo-2-alkenals
in the presence of a palladium catalyst and subsequent
copper-catalyzed cyclization of the intermediate imino-
alkynes.
The surprising results obtained from silyl acetylenes (eq
1) encouraged us to examine the mechanism of this interest-
ing transformation and to define the scope and limitations
of this new isoquinoline synthesis. On the basis of the
regiochemical outcome of much of our other alkyne annu-
lation chemistry in which the palladium adds to the more
hindered end of the alkyne,1-6 the expected products from
the reaction with trimethylsilyl-substituted alkynes were
either the 3,4-disubstituted products retaining the silyl group
or the corresponding 4-substituted isoquinoline arising from
desilylation of the 3,4-disubstituted isoquinoline. Since the
major product isolated from the reaction of 1 and 1-phenyl-
On the basis of this work, it was felt that a reasonable
mechanism for this terminal alkyne annulation process
involves coupling of the aryl halide and terminal acetylene
to produce the intermediate iminoalkyne, followed by
cyclization to the isoquinoline. The reaction conditions
employed for any one-pot synthesis must therefore be
compatible with both steps in the catalytic cycle. Since both
palladium and/or copper have been shown by us to effect
both of these individual steps, we felt it should be possible
to efficiently synthesize the desired monosubstituted iso-
quinolines in a single process.
2-(trimethylsilyl)acetylene possessed a phenyl substituent in
the 3-position of the isoquinoline, it seemed plausible that
desilylation and subsequent in situ coupling and cyclization
was taking place to give the observed products. This was
confirmed by the observation that 2-(2-phenylethynyl)-
benzaldehyde could be isolated, after hydrolysis of the imine
during workup, if the reaction was not allowed to proceed
to completion.
It was therefore anticipated that terminal acetylenes would
undergo this annulation. Indeed, phenylacetylene was sub-
sequently observed to participate in the palladium-catalyzed
reaction with 1 to afford an 85% yield of 2 when employing
We subsequently observed that the following reaction
conditions readily effect this isoquinoline synthesis. The
imine (0.5 mmol), the terminal acetylene (0.6 mmol), 2 mol
%
2 3 2 3
of PdCl (PPh ) , and 1 mol % of CuI in 2 mL of Et N
were heated at 55 °C until the coupling was judged complete
by thin-layer chromatography. The solvent and the precipi-
tates were subsequently removed (since they apparently
interfere in the subsequent cyclization), and DMF (5 mL)
and 10 mol % of CuI were added to the residue. The resulting
mixture was then heated at 100 °C until the cyclization was
judged complete by thin-layer chromatography. By employ-
ing this reaction sequence, a variety of isoquinolines have
been synthesized in good to excellent yields (Table 1).
A variety of terminal acetylenes have been employed in
this palladium/copper-catalyzed process. For example, the
reaction of imine 1 with aryl-, alkenyl-, and alkyl-substituted
acetylenes affords the desired isoquinolines in good to
excellent yields (Table 1, entries 1-4). Both electron-rich
aryl bromides (entry 5) and electron-poor heteroaryl bromides
1
equiv of 1, 1.1 equiv of phenylacetylene, 5 mol % of PdCl
2
-
(
PhCN) , and 1 equiv of Na CO in DMF at 100 °C for 14
2
2
3
h. By employing these same reaction conditions, 3-(cyclo-
hex-1-enyl)isoquinoline (3) was synthesized from 1 and
1-ethynylcyclohexene in 78% yield after a 78 h reaction time.
(
8) For recent leading references, see: (a) Monteiro, N.; Arnold, A.;
Balme, G. Synlett 1998, 1111. (b) Cacchi, S.; Fabrizi, G.; Moro, L. Synlett
1
5
998, 741. (c) Cacchi, S.; Fabrizi, G.; Moro, L. J. Org. Chem. 1997, 62,
327 and references therein. (d) Arcadi, A.; Anacardio, R.; D'Anniballe,
G.; Gentile, M. Synlett 1997, 1315. (e) Arcadi, A.; Cacchi, S.; Del Rosario,
M.; Fabrizi, G.; Marinelli, F. J. Org. Chem. 1996, 61, 9280 and references
therein. (f) Balme, G.; Bouyssi, D. Tetrahedron 1994, 50, 403. (g) Arcadi,
A.; Cacchi, S.; Carnicelli, V.; Marinelli, F. Tetrahedron 1994, 50, 437. (h)
Arcadi, A.; Burini, A.; Cacchi, S.; Delmastro, M.; Marinelli, F.; Pietroni,
B. R. J. Org. Chem. 1992, 57, 976. (i) Arcadi, A.; Cacchi, S.; Marinelli, F.
Tetrahedron Lett. 1992, 33, 3915.
(entry 6) have proven successful. Furthermore, pyridines can
be synthesized by employing vinylic imines. Pyrindine 10
and pyridine 12 have been synthesized in moderate yields
from vinylic imines 9 and 11, respectively (entries 7 and 8).
554
Org. Lett., Vol. 1, No. 4, 1999
Roesch, Kevin R.
