Pd-catalyzed alkyl to aryl migration and cyclization: An efficient synthesis of fused polycycles via multiple C-H activation

Article abstract of DOI:10.1021/ja047980y

A novel palladium migration methodology for the synthesis of complex fused polycycles has been developed. This process involves 1,4-palladium alkyl to aryl migrations via through-space C-H activation, followed by intramolecular arylation or an intermolecu

Full text of DOI:10.1021/ja047980y

Published on Web 05/26/2004
Pd-Catalyzed Alkyl to Aryl Migration and Cyclization: An Efficient Synthesis
of Fused Polycycles via Multiple C-H Activation
Qinhua Huang, Alessia Fazio, Guangxiu Dai, Marino A. Campo, and Richard C. Larock*
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011
Received April 7, 2004; E-mail: larock@iastate.edu
Table 1. Synthesis of Fused Polycycles via 1,4-Palladium Alkyl to
Metal-catalyzed C-H bond activation is an area of considerable
Aryl Migration, Followed by Intramolecular Arylationa
current interest.1 In particular, the ability of palladium to activate
C-H bonds has been used extensively in organic synthesis.1b,2
Furthermore, the cyclopalladation of a pendant aromatic ring, a
process that constitutes a good model for C-H activation, has led
to many useful synthetic applications.3,4 For example, Lautens,5
Catellani,6 and Ca´mpora7 have previously reported interesting trans-
formations that proceed through alkyl/aryl palladacycles. To date,
only a couple of examples of complete alkyl to aryl palladium rear-
rangements via intramolecular C-H activation have been reported.4c,8
We have previously reported that intramolecular C-H activation
in organopalladium intermediates derived from o-halobiaryls leads
to a 1,4-palladium aryl to aryl migration and shown that such
intermediates can be trapped by Heck reactions and intramolecular
arylation.9 Herein, we wish to report 1,4-palladium alkyl to aryl
migrations via through-space C-H activation, followed by in-
tramolecular arylation or an intermolecular Heck reaction, which
provide a very efficient way to synthesize fused ring systems.
Our first attempts to effect 1,4-palladium alkyl to aryl migration
employed compound 1. Under our usual palladium migration
conditions reported earlier9 [0.25 mmol of aryl halide, 5 mol %
Pd(OAc)2, 5 mol % bis(diphenylphosphino)methane (dppm), and
2 equiv of CsO2CCMe3 in DMF (4 mL)], aryl iodide 1 afforded an
88% yield of chromene 2 (entry 1, Table 1).10 This reaction appears
to proceed as shown in Scheme 1 by a process that involves
Scheme 1
a The reaction was carried out under our standard reaction conditions
employing 0.25 mmol of aryl halide, 5 mol % Pd(OAc)2, 5 mol % dppm,
and 2 equiv of CsO2CCMe3 in DMF (4 mL) at 100 °C unless otherwise
noted. b Isolated yield. c The seven-membered Heck reaction product was
obtained in a 5-10% yield. d The reaction was carried out at 90 °C.
to react under our standard migration conditions. The results indicate
that this migration/arylation process proceeds well with either an
N or a C linkage (entries 2 and 3). We have also studied the
palladium C-H activation with simultaneous 1,4-palladium alkyl
to aryl migration via key arylpalladium intermediate A or B and
subsequent intramolecular arylation by another Pd-catalyzed C-H
activation. This through-space migration of a metal moiety between
an alkyl and an aryl position amounts to an overall 1,4-palladium
alkyl to aryl shift, which may involve an intermediate hydridopallada-
(IV)cycle4c,d generated by insertion of palladium into a neighboring
C-H bond. Alternatively, Pd migration may proceed by generation
of a pallada(II)cycle and subsequent protonation,7 although this
seems unlikely in the present base and should proceed by cleavage
of the arylpalladium bond. This process represents a very powerful
new tool for the preparation of complex molecules, which may be
difficult to prepare by any other present methodology.
regioselectivity of this migration by employing naphthalene deriva-
tives 7, 9, and 11 (entries 4-6). The palladium migration/arylation
occurs exclusively at the less sterically congested 3-position of these
naphthalenes. The data in entries 4-6 indicate that the substituents
on the aryl halide ring have a strong influence on the yield in this
migration/arylation process. This migration process works best with
electron-rich aromatics. Our finding that electron-rich arenes are
superior to electron-deficient arenes in this alkyl to aryl migration
via C-H activation is consistent with literature reports indicating
that the ease of C-H activation by palladium parallels that of
electrophilic aromatic substitution.11 It is important to note that this
sequential migration/arylation reaction works well with more
complex polycyclic aromatic compounds. For example, the reaction
of compound 13 afforded pentacycle 14 in a 95% yield (entry 7),
and tetrahydroquinoline 16 containing a 5,5-ring juncture has been
successfully synthesized by this process in a 76% yield (entry 8).
To test the effect of the linkage between the carbon-carbon
double bond and the halide-substituted arene on this 1,4-palladium
alkyl to aryl migration chemistry, aryl halides 3 and 5 were allowed
9
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10.1021/ja047980y CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
An interesting example of this migration involves the rearrange-
ment of diaryl ether 17 to dibenzofuran 18 (entry 9). Mechanisti-
cally, the palladium must undergo a 1,4-palladium shift from an
alkyl position to the 2-position of the diaryl ether, followed by
arylation at the 2′-position of the diaryl ether (Scheme 2). This
unique high yielding migration/arylation process provides a very
powerful and efficient way to prepare complex fused benzofurans,
carbazoles, and indenes.
is much slower and less efficient than intramolecular arylation of
the migrated arylpalladium intermediates.
In conclusion, we have developed novel palladium alkyl to aryl
migration methodology for the synthesis of complex fused poly-
cycles, which employs sequential Pd-catalyzed C-H activation
processes. The chemistry developed here works best with electron-
rich aromatics, which is in agreement with the idea that these
palladium-catalyzed C-H activation reactions parallel electrophilic
aromatic substitution. We are presently examining more closely
the mechanism of this 1,4-palladium alkyl to aryl shift and further
synthetic applications.
Scheme 2
We have also carried out the Pd-catalyzed double migration/
arylation of easily prepared aryl halide 19 and the complex fused
dioxarubicenes 20 and 21 have been obtained in good yields (eq
1). This example further illustrates the efficiency of this migration/
Acknowledgment. We thank the donors of the Petroleum Re-
search Fund, administered by the American Chemical Society, and
the National Science Foundation, for partial support of this research.
We are also grateful to Johnson Matthey, Inc. and Kawaken Fine
Chemicals Co. for providing the palladium salts and Frontier
Scientific Co. for donating the arylboronic acids used to prepare
the starting materials.
Supporting Information Available: General experimental proce-
dures and spectroscopic characterization of all new products (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
arylation process for the construction of complex heterocycles and
carbocycles using easily prepared starting materials.
References
Another example of a reaction involving an alkyl to aryl
palladium migration to generate a functionalized polycycle has been
obtained from the reaction of 3-iodo-1-p-tosylindole (22) with
norbornene under our standard Pd migration conditions (Scheme
3). The first step of this reaction involves the cis addition of an
indol-3-ylpalladium iodide to norbornene,5-7 generating a stable
alkylpalladium intermediate lacking cis â-hydrogens properly
aligned for â-hydride elimination. This intermediate in turn
undergoes a 1,4-palladium alkyl to aryl shift to the 2-position of
the indole, followed by intramolecular cyclization onto the p-
toluenesulfonyl moiety.12 This successful migration/arylation pro-
cess indicates that the incorporated carbon-carbon double bonds
can be introduced from external sources, which broadens the scope
of this alkyl to aryl migration chemistry.
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Scheme 3
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A mechanistically interesting question is whether the migrated
arylpalladium(II) intermediate can be trapped by other traditional
organopalladium chemistry and still affect synthetically useful
chemistry. Thus, aryl halide 24 was allowed to react with ethyl
acrylate and methyl vinyl ketone, and olefinated chromenes have
been generated in good yields (eq 2). It appears that the intermo-
lecular trapping of migrated arylpalladium intermediates by olefins
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Am. Chem. Soc. 2000, 122, 10464-10465.
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