Rudolph et al.
secondary bromide substrate 48 with one equivalent each of
CsI and CsBr in acetonitrile at 140 °C for 20 min (eq 11). The
results of this experiment indicate the reaction conditions are
important for maintaining the levels of enantioenrichment in
the annulated products. Presumably due to the higher solubility
of CsI in acetonitrile, a portion of substrate 48 is converted to
the corresponding iodide 75, in nearly racemic form (8% ee).
Substrate 75 is also able to react under the palladium-catalyzed
conditions to form the same final product. The ee of remaining
48 was eroded at a much slower rate (71% ee remaining), within
the given reaction time.
with oxidative addition of palladium occurring by an SN2
mechanism.27
Conclusions
We have developed a route to polycyclic heterocycles using
a palladium-catalyzed norbornene-mediated domino process
involving the intramolecular or intermolecular ortho-alkylation
of aromatic carbon-hydrogen bonds with secondary alkyl
iodides and bromides. We have significantly expanded the scope
of this reaction to include a number of terminating reactions
such as a Heck reaction, direct arylation of heterocycles and a
Buchwald-Hartwig amination. The process creates up to two
new carbon-carbon bonds or a carbon-nitrogen bond in one
pot and can form products of medicinal value, with up to five
fused rings. The products are rapidly accessed within minutes
using microwave irradiation or heating in an oil bath. Further-
more, the reaction of enantioenriched substrates occurs in a
stereospecific manner to give the desired products with little
loss in ee. X-ray crystallography has shown that the reaction
proceeded with an overall inversion of configuration at the chiral
center, suggesting that oxidative addition of the alkyl halide to
our proposed Pd(II) intermediate occurred via an SN2 mechanism
and reductive elimination from Pd(IV) proceeds with retention
of configuration. To our knowledge, this is one of the few
stereochemical investigations of a Pd(II)/(IV) catalytic cycle,
outside of the pioneering discoveries of Stille. Investigations
toward the development of an asymmetric process from racemic
substrates is currently underway.
In order to determine whether the palladium-catalyzed
annulation proceeded with overall inversion or retention of
configuration, we aimed to obtain the crystal structures for an
enantioenriched substrate and the corresponding annulated
product. Derivatization of product 21 gave a crystalline product
77 (eq 12) that could be analyzed by X-ray crystallography.
Along with the X-ray structure of substrate 13, we determined
that the palladium-catalyzed annulation depicted in equation 7
proceeded with inversion of configuration at the chiral center.16a
Investigations on the stereochemical course of palladium-
catalyzed reactions are scarce in the literature and most are
restricted to oxidative addition to zerovalent palladium species.
From the pioneering work of Stille, it was shown indirectly that
oxidative addition to Pd(0) occurred with inversion of config-
uration at the stereogenic center.23 Further studies done by
Netherton and Fu24 on the Suzuki coupling of chiral primary
deuterated tosylates also showed that oxidative addition to Pd(0)
proceeds with inversion of configuration. Asensio and co-
workers reported that the Suzuki coupling of boronic acids to
chiral secondary 1-bromoethyl arylsulfoxides proceeded with
an overall inversion of configuration, although they were unable
to directly prove at which step of the catalytic cycle the inversion
of configuration occurs.9 Previous investigations of transmeta-
lation25 to Pd(II) and have shown that the stereochemistry may
depend on substrate class22a and/or reaction conditions.22b
To our knowledge, the only report in the literature on the
stereochemistry of oxidative addition/reductive elimination in
a Pd(II)/(IV) system, which is a proposed mechanistic pathway
for this reaction (intermediates 4-6, Scheme 1), is again limited
to the pioneering work of Stille.26 In his investigations, it was
found that oxidative addition of a chiral primary deuterated
benzyl bromide to Pd(II) proceeded with inversion of config-
uration while reductive elimination from Pd(IV) occurs with
retention of configuration. Regarding this investigation, if we
assume that reductive elimination from Pd(IV) species 5
(Scheme 1) of the palladium-catalyzed annulation also proceeds
with retention of configuration, then we propose that the
inversion of stereochemistry in this reaction likely occurs during
the oxidative addition of the secondary alkyl halide to Pd(II)
intermediate 4 to form Pd(IV) intermediate 5. This is consistent
Experimental Section
The following is a representative experimental procedure for the
palladium-catalyzed norbornene-mediated annulations reaction of
secondary alkyl halides. Specific experimental details and charac-
terization data for the aforementioned compounds and other new
compounds can be found in the Supporting Information.
General Procedure for the Palladium-Catalyzed Annu-
lation Reaction. To a 2-5 mL microwave vial was added the
substrate (0.1-0.2 mmol, 1 equiv), base (Cs2CO3 or K2CO3, 2-5
equiv), Pd(OAc)2 (10-20 mol%), ligand (22-44 mol%), nor-
bornene (2-7 equiv) and if applicable, a Heck acceptor (4 equiv)
or an aryl iodide (2 equiv). The vial was sealed with a septum and
flushed with nitrogen. Solvent (2-7 mL) was added and the reaction
mixture was stirred at room temperature for 2-5 min. The reaction
vessel was then placed in a preheated oil bath, or in a microwave
reactor and heated to 135-180 °C for 5 min to 16 h. The reaction
mixture was then cooled to ambient temperature, diluted with
(25) (a) Kells, K. W.; Chong, J. M. J. Am. Chem. Soc. 2004, 126, 15666–
15667. (b) Matos, K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461–470. (c)
Ridgway, B. H.; Woerpel, K. A. J. Org. Chem. 1998, 63, 458–460. (d) Ye, J.;
Bhatt, R. K.; Falck, J. R. J. Am. Chem. Soc. 1994, 116, 1–5. (e) Hatanaka, Y.;
Hiyama, T. J. Am. Chem. Soc. 1990, 112, 7793–7794. (f) Labadie, J. W.; Stille,
J. K. J. Am. Chem. Soc. 1983, 105, 6129–6137. (g) Ba¨ckvall, J. E.; Åkermark,
B. J. Chem. Soc., Chem. Commun. 1975, 82–83.
(26) For a review of oxidative addition and reductive elimination, including
stereochemical issues regarding Pd(II)-Pd(IV) intermediates, see: (a) Stille, J. K.
The Chemistry of the Metal-Carbon Bond; Vol. 2; Hartley, F. R., Patai, S., Eds.;
Wiley: New York, 1985; Chapter 9. (b) Milstein, D.; Stille, J. K. J. Am. Chem.
Soc. 1979, 101, 4981–4991. (c) Milstein, D.; Stille, J. K. J. Am. Chem. Soc.
1979, 101, 4992–4998.
(27) For a discussion regarding SN2 vs. direct insertion pathways of oxidative
addition, see: (a) Collman, J. P.; Hegedus, L. S. L. Principles and Applications
of Organotransition Metal Chemistry; University Science Books: Mill Valley,
CA, 1980; Chapter 4. See also: (b) Byers, P. K.; Canty, A. J.; Crespo, M.;
Puddephatt, R. J.; Scott, J. D. Organometallics 1988, 7, 1363–1367. (c) Aye,
K.-T.; Canty, A. J.; Crespo, M.; Puddephatt, R. J.; Scott, J. D.; Watson, A. A.
Organometallics 1989, 8, 1518–1522.
(23) (a) Lau, K. S. Y.; Fries, R. W.; Stille, J. K. J. Am. Chem. Soc. 1974,
96, 4983–4986. (b) Stille, J. K.; Lau, K. S. Y. J. Am. Chem. Soc. 1976, 98,
5841–5849.
(24) Netherton, M. R.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 3910–
3912.
296 J. Org. Chem. Vol. 74, No. 1, 2009