perspective. Unfortunately, the Larock protocol is not ap-
plicable to the indolization of acetylenes with 2-bromo or
chloroanilines, because the oxidative insertion requires
electron-rich palladium.3 In addition, the presence of iodide
was postulated to have a pronounced effect on the nature of
the products in these alkyne insertion processes, as previous
research on the reaction of ortho palladation complex with
alkynes demonstrated the exclusive formation of multiple
insertion products (eq 2).3b,5
Scheme 1. Mechanistic Working Model
The mechanism of the transformation is generally recog-
nized as involving the following three steps: (a) oxidation
insertion of carbon-halide bond to L2Pd, (b) coordination
and regioselective addition to the C-C alkyne bond, and
(c) subsequent Pd extrusion via reductive elimination (Scheme
1).3b,6 Recent developments have shown that bulky, electron-
rich phosphines readily allow previously unreactive aryl
chlorides to undergo cross-coupling and Heck chemistry,7
as well as amination reactions.8
These precedents therefore suggest that extension of the
Larock chemistry to highly deactivated o-chloroanilines may
be possible. However, it is not at all obvious that expected
side reactions such as multiple insertions (eq 2) and amina-
tion/dimerization of the substrates could be brought under
control. Indeed, one would expect that the ligands that are
necessary to activate aryl chlorides would also be capable
of promoting amination of the substrates, a reaction that is
never seen with the traditional Larock substrates under
“ligandless” conditions. Indeed, this side reaction proved to
be a major problem for the development of the new
indolization protocol, but suitable conditions could be found
that partially suppressed it. Therefore, we are pleased to
report herein on the first effective palladium-catalyzed
indolization of 2-bromo or chloroaniline derivatives with
internal alkynes.
To develop this protocol into a practical method, we had
to address another aspect in addition to chemoselectivity,
i.e., regioselectivity. Although regioselectivity is generally
attributed to the inherent steric hindrance of the alkyne
substrates, the use of ligands, introduced in order to activate
the C-Cl bond, will most likely lead to unpredictable
regiochemical issues, which have never been studied before
in this type of reaction. To this end, we first conducted a
ligand screen with a deactivated 2-chloroaniline and a
nonsymmetrical alkyne (Scheme 1). In addition to the desired
product, we observed that the major side reaction was indeed
the homocoupling of the 2-chloroaniline via two consecutive
amination reactions.9 Our primary objective became identify-
ing conditions that not only minimize formation of amination
byproduct 3 but also result in optimal regioselectivity.
Several types of well-documented, highly active phosphine
ligands such as trialkylphosphines (Cy3P, t-Bu3P), ferrocenyl
phosphines (4-6), and biaryl phosphines (7-10) were
examined, among which 1,1′-bis(di-tert-butylphosphino)
ferrocene (6) gave superior results, albeit with formation of
19% of 3 (entry 5a). With tricyclohexylphosphine, the
reaction was clean and no byproduct 3 was formed. However,
this ligand negatively affected the desired regioselectivity
(entry 1). With either biaryl ligands (7-10) or t-Bu3P, the
unwanted amination reaction occurred to a large extent
(entries 2, 6-9). With DtBPF (6) as the ligand, several bases,
both inorganic and organic, were evaluated. K2CO3 proved
to be the best choice with regards to reaction rate, reaction
profile, and regioselectivity. Further optimization indicated
that lower temperature or nonpolar solvents had little
influence in reducing formation of side product 3. Eventually,
(5) (a) Maassarani, F.; Pfeffer, M.; Borgne, G. L. Organometallics 1987,
6, 2029. (b) Maassarani, F.; Pfeffer, M.; Borgne, G. L. Organometallics
1987, 6, 2043. (c) Maassarani, F.; Pfeffer, M.; Spencer, J.; Wehman, E. J.
Organomet. Chem. 1994, 466, 265.
(6) Roesch, K. R.; Larock, R. C. J. Org. Chem. 2001, 66, 412.
(7) For oxidative insertion to aryl chlorides: (a) Littke, A. F.; Dai, C.;
Fu, G. C. J. Am. Chem. Soc. 2000, 122, 4020. (b) Littke, A. F.; Fu, G. C.
Angew. Chem., Int. Ed. 1998, 37, 3387. (c) Wolf, J. P.; Buchwald, S. L.
Angew. Chem., Int. Ed. 1999, 38, 2413. (d) Wolf, J. P.; Singer, R. A.; Yang,
B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 9550. (e) Zhang,
C.; Huang, J.; Trudell, M. L.; Nolan, S. P. J. Org. Chem. 1999, 64, 3804.
(f) Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem., Int. Ed. 2000, 39,
4153.
(8) (a) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.;
Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575. (b) Beller, M.;
Riermeier, T. H.; Reisinger, C.-P.; Herrmann, W. A. Tetrahedron Lett. 1997,
38, 2073. (c) Kuwano, R.; Utsunomiya, M.; Hartwig, J. F. J. Org. Chem.
2002, 67, 6479.
(9) Application of this double-amination reaction to the preparation of
dihydrophenazine and analogues is under current investigation.
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Org. Lett., Vol. 6, No. 22, 2004