Palladium-catalyzed carbonylative heck-type reactions of alkyl iodides

Article abstract of DOI:10.1021/ja1053913

A palladium-catalyzed carbonylative Heck-type cyclization of alkyl halides is described. Treatment of a range of primary and secondary alkyl iodides with catalytic palladium(0) under CO pressure forms a variety of synthetically versatile enone products. The reactivity described represents a rare example of a palladium-catalyzed Heck-type cyclization involving unactivated alkyl halides with β-hydrogens. Alkene substitution is well tolerated, and mono-and bicyclic carbocycles may be easily accessed.

Full text of DOI:10.1021/ja1053913

Published on Web 08/30/2010
Palladium-Catalyzed Carbonylative Heck-Type Reactions of Alkyl Iodides
Kayla S. Bloome and Erik J. Alexanian*
Department of Chemistry, UniVersity of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290
Received June 20, 2010; E-mail: eja@email.unc.edu
in carbonylative Heck reactions with aryl or vinyl electrophiles.9
Upon heating to 130 °C in toluene for 5 h under 50 atm CO in the
presence of 10 mol % Pd(PPh3)4 and 2.0 equiv of iPr2EtN,
cyclohexenyl substrate 1 provided cyclized enone 2 and minor
isomer 3 in 79% combined yield (Table 1, entry 1). Reactions
utilizing a variety of other palladium catalyst systems resulted in
decreased yields (entries 2-4), and no product formed in the
Abstract: A palladium-catalyzed carbonylative Heck-type cycliza-
tion of alkyl halides is described. Treatment of a range of primary
and secondary alkyl iodides with catalytic palladium(0) under CO
pressure forms a variety of synthetically versatile enone products.
The reactivity described represents a rare example of a palladium-
catalyzed Heck-type cyclization involving unactivated alkyl halides
with ꢀ-hydrogens. Alkene substitution is well tolerated, and mono-
and bicyclic carbocycles may be easily accessed.
absence of Pd(PPh3)4 (entry 5). Performing the reaction at lower
temperature (entry 6) or at lower CO pressure (entry 7) hampered
reaction efficiency. We also found that inorganic bases such as
Cs2CO3 (entry 8) proved inferior to amine bases. Substrate
dehydrohalogenation was not a significant side reaction in these
experiments. Polar solvent systems are much less effective (entry
9), which we attribute to increased formation of phosphonium salt
byproducts.11
The use of palladium catalysts in organic synthesis has resulted
in numerous methods for carbon-carbon bond construction of
exceptional value.1 The palladium-catalyzed Heck reaction is among
the premier methods in this class and is broadly applicable using
aryl or vinyl halide or sulfonate electrophiles.2 Despite the
impressive scope of the Heck reaction, unactivated alkyl halides
are generally not viable electrophiles.3 Recently, the first example
of a palladium-catalyzed intramolecular alkyl-Heck reaction was
reported,4 although this process is limited to primary alkyl
electrophiles and monosubstituted alkene substrates. Several other
research groups have developed useful Heck-type processes using
other transition metals that generally involve free radical intermedi-
ates.5
Table 1. Influence of Reaction Conditions on the Carbonylative
Cyclization
The development of general methods capable of extending
palladium-catalyzed Heck-type processes to alkyl electrophiles
could result in powerful synthetic transformations; however, there
are a number of significant challenges impeding such developments.
These include the general reluctance of sp3-hybridized alkyl
electrophiles to undergo oxidative addition6 and the marked
tendency of alkylpalladium species to undergo ꢀ-hydride elimina-
tion,7 resulting in dehydrohalogenation products. Despite this
instability of alkylpalladium species containing ꢀ-hydrogens, migra-
tory insertion of CO ligands is capable of outcompeting this
process.8 We envisioned the carbonylative cyclization of alkyl
halides as a potential approach to accessing alkyl-Heck-type
transformations (eq 1). Carbonylative Heck-type reactions facilitate
the preparation of diverse carbocyclic structures; however, these
processes are currently limited to the use of aryl or vinyl
electrophiles.9 In addition, carbonylative cyclizations of alkyl
electrophiles would provide synthetically valuable enone products,
which are important building blocks for organic synthesis.10 Herein,
we report that readily available palladium catalysts are capable of
catalyzing carbonylative Heck-type reactions of unactivated alkyl
iodide electrophiles.
a Determined through GC analysis.
We examined the scope of the reaction using a wide variety of
unsaturated alkyl iodides and the optimized reaction conditions
(Table 2). The reaction performs well using simple linear substrates,
as predominantly (E)-disubstituted alkyl iodide 4 (85:15 E:Z) (entry
1) provided cyclopentenone 5 in 77% yield as a 10:1 mixture of
E:Z isomers. Conjugated alkenes are also useful substrates, as (Z)-
styrenyl substrate 6 (entry 2) provided (E)-disubstituted cyclopen-
tenone 7 in 55% yield. We next explored the capability of the
carbonylative alkyl-Heck-type reaction to construct a variety of ring
systems. The carbonylative cyclization is capable of furnishing
bicyclo[3.3.0]octenones (entry 3) and bicyclo[4.3.0]nonenones
(entry 4), as demonstrated in the reactions of substrates 8 and 1.
We also found that both secondary alkyl electrophiles and trisub-
stituted alkenes participate in the process, as cyclohexyl substrate
11 cyclized to tetrasubstituted enone 12 (1.2:1 dr) in 91% yield
(entry 5). The bicyclo[5.3.0]decenone framework was easily
accessed from cycloheptyl substrate 13 (entry 6). Neopentyl iodide
We began our studies using the commercially available pal-
ladium(0) source Pd(PPh3)4 as catalyst, which is commonly used
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C O M M U N I C A T I O N S
15 was efficiently transformed to spirocyclic product 16 in 90%
yield, demonstrating that R-disubstitution of the alkyl iodide is well
tolerated. Notably, this process is also not limited to the synthesis
of five-membered carbocycles, as cyclohexenyl alkyl iodide 17
underwent 6-endo cyclization to yield bicyclo[4.4.0]decenone
derivative 18 in 69% yield (entry 8).
involvement of carbon-centered radicals in the reaction.15,16 Further
detailed studies to elucidate the precise reaction pathway are
underway.
Table 2. Palladium-Catalyzed Carbonylative Cyclizationa
In conclusion, we have developed a palladium-catalyzed in-
tramolecular carbonylative Heck-type reaction of unactivated alkyl
iodides. This reaction proceeds efficiently with primary or secondary
alkyl iodides to deliver a variety of synthetically valuable mono-
cyclic and bicyclic enones. Further studies will extend this mode
of alkyl halide activation in the discovery of other synthetic
transformations and explore applications in complex molecule
synthesis.
Acknowledgment. This work was supported by generous start-
up funds provided by UNC Chapel Hill.
Supporting Information Available: Detailed experimental proce-
dures and spectral data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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a All reactions run 0.5 M in PhMe at 130 °C under 50 atm CO in the
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The capability of palladium(0) to react with alkyl iodides via
SN212 as well as single-electron13 pathways opens the door to a
number of mechanistic possibilities for this process. Subjecting
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cyclization conditions in the presence of 1 equiv of persistent radical
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