Phosphine Catalyzed α-Arylation of Enones and Enals Using Hypervalent Bismuth Reagents: Regiospecific Enolate Arylation via Nucleophilic Catalysis

Article abstract of DOI:10.1021/ja048987i

Exposure of enones and enals to 20 mol % tributylphosphine in the presence of triarylbismuth(V) dichlorides results in regiospecific aryl transfer to the α-position of the enone or enal pronucleophile. These results represent the first examples of enolate

Full text of DOI:10.1021/ja048987i

Published on Web 04/07/2004
Phosphine Catalyzed r-Arylation of Enones and Enals Using Hypervalent
Bismuth Reagents: Regiospecific Enolate Arylation via Nucleophilic
Catalysis
Phillip K. Koech and Michael J. Krische*
Department of Chemistry and Biochemistry, UniVersity of Texas at Austin, Austin, Texas 78712
Received February 23, 2004; E-mail: mkrische@mail.utexas.edu
Table 1. Phosphine Catalyzed Arylation of Cyclohexenone Using
The development of catalytic methods for the regiospecific
generation and capture of enolates via tandem conjugate addition-
electrophilic trapping is currently under investigation in our lab.
Here, enone hydrometallation (1,4-reduction),1 enone carbometal-
lation (1,4-addition),2 and nucleophilic catalysis3 have been applied
to the regiospecific generation of enolate nucleophiles, which are
found to engage in subsequent additions to aldehyde,1a-c ketone,1d,e,2
ester,2c nitrile,2c activated alkene,1a,b,3a,b and Pd(II)-π-allyl3c partners.
Further development based on this enone-electrophile template is
potentially enabled through the use of arenes as terminal electro-
philes. Indeed, while considerable effort has been devoted to
transition metal catalyzed enolate arylation by way of ketone
pronucleophiles,4,5 general catalytic methods for the R-arylation of
enones have not been described.6,7 Here, we report a method for
the regiospecific R-arylation of enones and enals under the
conditions of nucleophilic catalysis. Specifically, exposure of cyclic
enones or enals to 1 equiv of BiAr3Cl2 and Hunig’s base in the
presence of substoichiometric tributylphosphine results in aryl
transfer to afford the corresponding R-aryl enones and R-aryl enals
in good to excellent yield.
BiAr3Cl2 Reagentsa,b
Scheme 1. Proposed Mechanism for Catalytic Enone R-Arylation
under the Conditions of Nucleophilic Catalysis
a
b
See Supporting Information for a detailed experimental procedure.
Isolated yields after purification by silica gel chromatography.
Table 2. Phosphine Catalyzed Arylation of Cyclopentenone Using
BiAr3Cl2 Reagentsa,b
Triarylbismuth(V) reagents8 such as BiPh3Cl2 are well-known
to effect the arylation of alcohols9 and amines,10 as well as the
C-arylation of phenols,11 â-dicarbonyl compounds,12 preformed
alkali-enolates,13 and enol silanes.14 A catalytic mechanism for
enone R-arylation under the conditions of nucleophilic catalysis
using triarylbismuth(V) reagents is easily envisioned (Scheme 1).
However, the feasibility of phosphine catalyzed enone R-arylation
using triarylbismuth(V) reagents requires compatibility between
tributylphosphine, a Lewis base, with the triarylbismuth(V) reagent,
a Lewis acid. Additionally, Bi(V)-mediated phosphine oxidation
should be slow with respect to aryl transfer pathways. To assess
the feasibility of applying nucleophilic catalysis to the R-arylation
enones, cyclohexenone 1 (100 mol %) was exposed to BiPh3Cl2
(100 mol %) in the presence of tributylphosphine (20 mol %) and
Hunig’s base (100 mol %) at ambient temperature in CH2Cl2-t-
BuOH solvent. Gratifyingly, the R-arylation product 1a was
obtained in 93% isolated yield as a single regioisomer, as
determined by 1H NMR analysis. Under these conditions, the
a
See Supporting Information for a detailed experimental procedure.
b
Isolated yields after purification by silica gel chromatography.
catalytic R-arylation of cyclohexenone 1 (Table 1) and cyclopen-
tenone 2 (Table 2) was explored using diverse triarylbismuth(V)
dichlorides. As demonstrated by the formation of R-arylation
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J. AM. CHEM. SOC. 2004, 126, 5350-5351
10.1021/ja048987i CCC: $27.50 © 2004 American Chemical Society

C O MMU N I C A T I O N S
Table 3. Phosphine Catalyzed Arylation of Crotonaldehyde Using
(CS0927), the Alfred P. Sloan Foundation, the Camille and Henry
Dreyfus Foundation, Eli Lilly, and the UT-Austin Center for
Materials Research (CMC) for partial support of this research.
BiAr3Cl2 Reagentsa,b
Supporting Information Available: Spectral data for all new
compounds (1H NMR, 13C NMR, IR, HRMS) (PDF). This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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See Supporting Information for a detailed experimental procedure.
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substituted triaryl bismuth(V) dichlorides. However, it was found
that strong π-donating substituents in the para-position diminish
the efficiency of aryl transfer. For example, transfer of para-
methoxy-substituted arenes occurs in greatly diminished yield. As
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efficiently, even in the case methoxy-substituted systems. Finally,
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To further probe the scope of this transformation, alternative
pronucleophiles were examined. The collective experiments reveal
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R-arylated enals 3a-d in modest to good yields.
In summation, cyclic enones and â-substituted enals undergo
regiospecific R-arylation under the conditions of nucleophilic
catalysis using triarylbismuth(V) dichlorides. This approach comple-
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regiospecific enolate generation, bromo-substituted arenes are
readily transferred, and finally, preservation of the enone moiety
in the product facilitates subsequent elaboration of the arylated
products. Future studies will focus on the development of related
reagents for aryl transfer under the conditions of nucleophilic
catalysis and the application of such methods toward the total
synthesis of therapeutically relevant target molecules.
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Acknowledgment. Acknowledgment is made to the NIH (RO1
GM65149-01), the Research Corporation Cottrell Scholar Award
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