Synthesis of Isoquinolines and Pyridines via Palladium-Catalyzed Iminoannulation of Internal Acetylenes

Full text of DOI:10.1021/jo980871f

5306
J . Org. Chem. 1998, 63, 5306-5307
Syn th esis of Isoqu in olin es a n d P yr id in es via
P a lla d iu m -Ca ta lyzed Im in oa n n u la tion of
In ter n a l Acetylen es
The reaction conditions employed in the present heterocycle
synthesis are similar to those that we previously reported
for the annulation of alkynes.2-5 The reaction of the tert-
butylimines with 2 equiv of an alkyne in the presence of 5
mol % Pd(OAc)2, 10 mol % PPh3, and 1 equiv of Na2CO3 in
DMF as the solvent at 100 °C affords the desired heterocyclic
products in good to excellent yields in short reaction times.
The annulation of a variety of aryl-substituted alkynes
by the tert-butylimine of o-iodobenzaldehyde (1) affords the
desired disubstituted isoquinoline heterocycles in moderate
to excellent yields with high regioselectivity (Table 1, entries
1-4). The regiochemistry of the products is based on
analogy with our previous alkyne annulation chemistry2-5
and comparison of the spectral and physical data for
compounds 36 and 49 with those already in the literature.
The annulation of a relatively unhindered diyne and
enyne by imine 1 also affords the anticipated isoquinoline
products in good yields, although mixtures of regioisomers
are obtained (Table 1, entries 5 and 6). This is interesting
due to the fact that the products 2-5 are all isolated as
single regioisomers. In addition, the diyne annulation gives
an unexpected major product bearing the more hindered
phenyl group in the 4-position (Table 1, entry 5).
It is interesting to note that the attempted annulation of
many alkyl-substituted alkynes, namely 4-octyne, 3-hexyne,
4,4-dimethyl-2-butyne, and 3,3-dimethyl-1-phenyl-1-butyne,
by imine 1 fails to produce any of the desired heterocycles.
On the basis of the observations of Heck,7 it is presumed
that multiple alkyne insertion products are being formed
from these alkynes, although none of these products have
been identified. Alternatively, the presumed vinylpalladium
intermediate generated upon alkyne insertion (see the latter
mechanistic discussion) may simply be undergoing â-hydride
elimination to afford allenes.
Surprisingly, when a more electron-rich imine 10 is
employed in a reaction that previously gave only a single
regioisomer, a mixture of regioisomers is observed (compare
Table 1, entries 3 and 7). In the case of the imine 13 bearing
an electron-withdrawing group, only a single regioisomer is
obtained, with hydrolysis of the imine presumably occurring
during the workup of the reaction.
This annulation chemistry has also been extended to
vinylic imines. For example, the tetrahydroisoquinoline
derivative 16 and the pyrindine derivative 18 have been
synthesized by annulation with the cyclic vinylic imines 15
and 17, respectively (Table 1, entries 9 and 10). Acyclic
vinylic imines have also been successfully employed in this
annulation process to produce highly substituted pyridine
derivatives (Table 1, entries 11 and 12). It is interesting to
note that the compounds derived from the vinylic imines are
all isolated as single regioisomers. Surprisingly, the imine
21 works quite well in this pyridine synthesis, whereas the
corresponding ethyl ester (Z-PhCIdCHCO2Et) fails to un-
dergo annulation of this same alkyne to produce the corre-
sponding pyrone, a process with which we have recently had
considerable success.10
Kevin R. Roesch and Richard C. Larock*
Department of Chemistry, Iowa State University,
Ames, Iowa 50011
Received May 8, 1998
Annulation processes have found numerous applications
in organic synthesis, primarily due to the ease with which
a wide variety of complicated hetero- and carbocycles can
be rapidly constructed.1 In our own laboratories, it has been
demonstrated that palladium-catalyzed annulation meth-
odology can be effectively employed for the synthesis of
indoles,2 benzofurans,3 isocoumarins,3 indenones,4 and poly-
cyclic aromatic hydrocarbons.5
Substituted isoquinolines have previously been synthe-
sized by employing palladium methodology. For instance,
Pfeffer reported the formation of a disubstituted isoquinoline
derivative from a cyclopalladated N,N-dimethylbenzylamine
complex,6 and Heck observed the formation of 3,4-diphenyl-
isoquinoline in 22% yield by the reaction of cyclopalladated
N-tert-butylbenzaldimine tetrafluoroborate with diphenyl-
acetylene.7 Widdowson has also reported an isoquinoline
synthesis based on cyclopalladated N-tert-butylaryl-
aldimines.8 These examples, however, suffer the major
disadvantage that they are stoichiometric with respect to
palladium, and in the latter synthesis, a final pyrolysis step
greatly limits the synthetic utility.
Our own interest in these types of annulation reactions
has prompted us to investigate a catalytic version of these
isoquinoline syntheses. We now report that the palladium-
catalyzed iminoannulation of internal alkynes readily affords
a wide variety of nitrogen heterocycles, including isoquino-
lines, tetrahydroisoquinolines, pyrindines, and pyridines.
Our preliminary results are summarized in Table 1.
Our initial studies focused on the palladium-catalyzed
annulation of internal alkynes employing the methyl imine
of o-iodobenzaldehyde. However, this substrate failed to
produce any of the desired isoquinoline even at elevated
temperatures. Furthermore, use of the corresponding iso-
propyl, allyl, and benzyl imines also afforded none of the
desired heterocyclic products. The reaction of the R-meth-
ylbenzyl imine with diphenylacetylene did produce the
desired product, 3,4-diphenylisoquinoline, albeit in low yields
(6-11%). By employing the tert-butylimine, however, we
obtained substantially improved results with a variety of
alkynes, after optimization of the reaction conditions (eq 1).
(1) (a) Schore, N. E. Chem. Rev. 1988, 88, 1081. (b) Pfeffer, M. Recl. Trav.
Chim. Pays-Bas 1990, 109, 567. (c) Negishi, E.; Cope´ret, C.; Ma, S.; Liou,
S.; Liu, F. Chem. Rev. 1996, 96, 365. (d) Ojima, I.; Tzamarioudaki, M.; Li,
Z.; Donovan, R. J . Chem. Rev. 1996, 96, 635.
(2) (a) Larock, R. C.; Yum, E. K. J . Am. Chem. Soc. 1991, 113, 6689. (b)
Larock, R. C.; Yum, E. K.; Refvik, M. D. Submitted.
(3) Larock, R. C.; Yum, E. K.; Doty, M. J .; Sham, K. K. C. J . Org. Chem.
1995, 60, 3270.
(4) Larock, R. C.; Doty, M. J .; Cacchi, S. J . J . Org. Chem. 1993, 58, 4579.
(5) Larock, R. C.; Doty, M. J .; Tian, Q.; Zenner, J . M. J . Org. Chem. 1997,
62, 7536.
(6) Maassarani, F.; Pfeffer, M.; Le Borgne, G. J . Chem. Soc., Chem.
Commun. 1987, 565.
We propose a mechanism for this process that is similar
to our other alkyne annulation chemistry. Specifically,
oxidative addition of the aryl or vinylic halide to Pd(0)
(7) (a) Wu, G.; Rheingold, A. L.; Geib, S. J .; Heck, R. F. Organometallics
1987, 6, 1941. (b) Wu, G.; Geib, S. J .; Rheingold, A. L.; Heck, R. F. J . Org.
Chem. 1988, 53, 3238.
(9) Brooks, J . R.; Harcourt, D. N.; Waigh, R. D. J . Chem. Soc., Perkin
Trans. 1 1973, 2588.
(10) Larock, R. C.; Han, X.; Doty, M. J . Tetrahedron Lett., in press.
(8) Girling, I. R.; Widdowson, D. A. Tetrahedron Lett. 1982, 23, 4281.
S0022-3263(98)00871-8 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/17/1998

Communications
J . Org. Chem., Vol. 63, No. 16, 1998 5307
Ta ble 1. Syn th esis of Nitr ogen Heter ocycles by th e P d -Ca ta lyzed An n u la tion of In ter n a l Acetylen esa
a
A representative procedure for the annulation of internal acetylenes: 5 mol % Pd(OAc)2, 10 mol % PPh3, Na2CO3 (0.5 mmol), the
acetylene (1.0 mmol), the imine (0.5 mmol), and DMF (10 mL) were placed in a 4 dram vial and were heated at 100 °C for the indicated
b
time. Isolated in an 85:15 ratio of 8 to 9 as an inseparable mixture of isomers.
produces an organopalladium intermediate, which then
inserts the acetylene, producing a vinylic palladium inter-
mediate, which then reacts with the neighboring imine
substituent to form a seven-membered palladacyclic am-
monium salt. Subsequent reductive elimination produces
a tert-butylisoquinolinium salt and regenerates Pd(0). As
previously suggested by Heck,7 the tert-butyl group appar-
ently fragments to relieve the strain resulting from interac-
tion with the substituent present in the 3-position.
In conclusion, we have developed an efficient, palladium-
catalyzed synthesis of nitrogen heterocycles, including iso-
quinolines, tetrahydroisoquinolines, pyrindines, and py-
ridines. A wide variety of aryl acetylenes undergo this
process in moderate to excellent yields, with high regio-
selectivity being observed in most cases. Further detailed
studies into the scope and limitations of this annulation
process are currently under investigation.
Ack n ow led gm en t. We gratefully acknowledge the
donors of the Petroleum Research Fund, administered by
the American Chemical Society, for partial support of this
research, Johnson Matthey, Inc., and Kawaken Fine Chemi-
cals Co., Ltd. for donation of the palladium acetate, and
Merck and Co., Inc., for an Academic Development Award
in Chemistry.
Su p p or tin g In for m a tion Ava ila ble: General experimental
procedure, copies of 1H and 13C spectra for compounds 5-9, 12,
and 14, and characterization data for all products (18 pages).
J O980871F