Palladium-catalyzed α-arylation of esters and amides under more neutral conditions

Article abstract of DOI:10.1021/ja036792p

Two procedures for the ∞-arylation of carbonyl compounds under conditions that are more neutral than those of reactions of aryl halides with alkali metal enolates are reported. The first procedure rests upon the development of catalysts bearing the hindered pentaphenylferrocenyl di-tert-butylphosphine (Q-phos) and the highly reactive dimeric Pd(I) complex {P(t-Bu)₃]PdBr}₂. By this procedure, zinc enolates prepared from ∞-bromo esters and amides react with aryl halides to form ∞-aryl esters and amides in high yields under mild conditions with 1-2 mol % catalyst and with remarkable functional group tolerance. By the second procedure, silyl ketene and silyl ketimine acetals react with aryl bromides in the presence of substoichiometric zinc fluoride, 1 mol % Pd(dba)₂, and 2 mol % P(t-Bu)₃ in DMF solvent at 80 °C. Reactions of zinc tert-butyl acetate and propionate enolates and trimethylsilyl ketene acetals of tert-butyl propionate and methyl isobutyrate with aryl bromides bearing electron-donating and potentially reactive, base-sensitive electron-withdrawing groups and with pyridyl bromides are reported. In addition, the diastereoselective coupling of phenyl bromide with an imide enolate bearing the Evans auxiliary is reported, and this study shows that racemization of base-sensitive stereocenters does not occur during the coupling process under these more neutral conditions. Copyright

Full text of DOI:10.1021/ja036792p

Published on Web 08/21/2003
Palladium-Catalyzed r-Arylation of Esters and Amides under More Neutral
Conditions
Takuo Hama, Xiaoxiang Liu, Darcy A. Culkin, and John F. Hartwig*
Department of Chemistry, Yale UniVersity, P.O. Box 208107, New HaVen, Connecticut 06520-8107
Received June 19, 2003; E-mail: John.Hartwig@yale.edu
Table 1. Reactions of Reformatsky Reagents with Bromoarenes
Bearing Potentially Reactive Functional Groups
The palladium-catalyzed reaction of aryl halides with alkali metal
enolates has become a convenient synthetic method.1-4 These
procedures are simple to conduct, but a number of drawbacks result
from the basic reaction conditions. Reactions of substrates bearing
nitro, cyano, carboxyl, and keto groups, which react with strong
bases and nucleophiles, occurred in low yield. Also, coupling at
the more hindered of two enolizable positions was not possible.
Moreover, the basic conditions limit control of stereochemistry.
Products with new tertiary stereocenters would be racemized
because of the greater acidity of the product, and substrates with
auxiliary, base-sensitive stereocenters can undergo racemization.
Finally, the strong base required to generate amide enolates has
limited the scope of the coupling of amides even with unfunction-
alized bromoarenes.5,6
We report two procedures for the R-arylation of carbonyl
compounds under conditions that are more neutral than those for
reactions of aryl halides with alkali metal enolates. The first
procedure involves the use of zinc enolates and rests upon the
development of catalysts bearing the hindered pentaphenylferrocenyl
di-tert-butylphosphine (Q-phos)7,8 and the highly reactive dimeric
Pd(I) complex {P(t-Bu)3]PdBr}2.9 Previous studies on the cross-
coupling of zinc enolates included reactions of only acetate enolates
with a small set of aryl halides in modest yields.10-15 The second
procedure involves palladium-catalyzed reactions of silyl ketene
and silyl ketimine acetals in the presence of zinc fluoride cocatalyst.
Previous palladium-catalyzed couplings of these enolates with aryl
halides were conducted with tin fluoride additives to generate the
tin enolates16-18 or with suprastoichiometric amounts of both enolate
and copper fluoride additive.19 Tin halides generate toxic byprod-
ucts, and an excess of copper complicates product separation. These
previous reports included only acetate enolates.
Palladium catalysts bearing hindered alkyl phosphines catalyzed
the coupling of Reformatsky reagents prepared from activated zinc
and R-bromo esters with a wide variety of base-sensitive substrates,
as summarized in Table 1. The chemistry with Reformatsky reagents
in Table 1 was conducted in the presence of 1 or 2 mol % of a
combination of Pd(dba)2 and Q-phos or 0.5 mol % {P(t-Bu)3]-
PdBr}2. In most cases, both catalysts provided good yields, but,
with the exception of aryl halides with acidic protons, the catalyst
with Q-phos created a more general process. The broad scope and
high yields were not obtained with triarylphosphine catalysts.12,13
Our study on the coupling of zinc ester enolates focused on the
reactions of aryl and heteroaryl halides that did not undergo
palladium-catalyzed couplings with alkali metal enolates.20,21 For
example, bromonitrobenzenes, bromobenzonitriles, aryl halides with
enolizable hydrogens, and aryl halides of electrophilic ketones did
not undergo palladium-catalyzed coupling with lithium acetate or
propionate enolates. However, coupling of these aryl bromides with
the Reformatsky reagent of tert-butyl acetate or propionate occurred
in high yield at room temperature (entries 1, 2, 5-9, 11-13).
Reactions of zinc enolates with aryl halides bearing protic
a Standard conditions: (A) 1 mol % Pd(dba)2, 1 mol % Ph5FcP(t-Bu)2,
1.1 equiv of enolate, THF; (B) 0.5 mol % {P(t-Bu)3]PdBr}2, 1.1 equiv of
enolate, THF; (C) 2 mol % Pd(dba)2, 2 mol % Ph5FcP(t-Bu)2, 1.2 equiv of
enolate, dioxane; (D) 1.05 equiv of KH, 0.5 mol % {P(t-Bu)3]PdBr}2, 1.1
equiv of enolate, THF. b 2 mol % Pd(dba)2 and Q-phos were used. c 2 equiv
of enolate. d Yields are for pure isolated material and are an average of
two runs.
functionality (entries 15-20) also occurred if 2 equiv of the
Reformatsky reagent was added or if 1 equiv of KH was added
before the Reformatsky reagent. For example, most combinations
of the two enolates and 2- or 4-bromophenol and 4-bromoaniline
formed the R-aryl ester in high yield. In contrast to the reactions
of alkali metal ester enolates,20,21 no products from diarylation of
zinc acetate or propionate enolates were observed.
Reactions of halopyridines also did not form R-heteroaryl esters
in previous work with lithium enolates of acetates or propi-
onates.20,21 However, reaction of the corresponding zinc enolates
with bromopyridines generated the products in high yields in several
cases (entries 21-23). The Reformatsky reagent of tert-butyl acetate
reacted with both 3- and 4-bromopyridine in high yield. Moreover,
the zinc enolate of tert-butylpropionate coupled with 3-bromopy-
ridine in high yield.
To test if the less basic conditions improved the scope and yields
for the R-arylation of the amides, we conducted reactions of the
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10.1021/ja036792p CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Coupling of Silyl Ketene Acetals with Bromoarenes
Scheme 1
isomer. To determine if the more neutral conditions generated a
kinetic ratio of diastereomers, we conducted the arylation of the
silyl enolate of one imide in the presence of a diastereomerically
pure R-aryl imide 1 and its epimer at the R-aryl position epi-1
(Scheme 1). This reaction formed the same ratio of diastereomers
as the reaction conducted without added R-aryl amide, and the
stereochemistry of the added imides remained unaltered. Thus, the
conditions for the R-arylation of the silyl enolates are neutral enough
to prevent silyl group migration and epimerization of base-sensitive
stereocenters.
In summary, two advances in catalyst and reaction design have
significantly expanded the scope of the R-arylation of carbonyl
compounds. Highly reactive catalysts based on Q-phos or Pd(I)
dimers, in combination with zinc enolates or silicon enolates with
ZnF2 additive, allow the preparation of R-aryl esters and amides
from substrates that bear functionality or stereochemistry that is
sensitive to the basicity or nucleophilicity of alkali metal enolates.
Further studies that exploit the broad scope and lack of racemization
are in progress.
a Yields are for pure isolated material and are an average of two runs.
Reformatsky reagents generated from R-bromodiethylacetamide and
R-bromodiethylpropionamide with bromoarenes. Indeed, coupling
occurred with broad scope at room temperature (Table 1, entries
3, 4, 10, 14, 24-29). The reaction scope encompassed aryl halides,
such as 4-bromobenzotrifluoride, 4-bromobenzonitrile, and the
electron-rich bromoanisole, that failed to react in high yield with
potassium amide enolates in the presence of palladium and BINAP.5
The zinc enolates formed none of the diarylation product that
reduced yields of reactions of potassium enolates.5
Alkali metal enolates of propionamides reacted in low yields
with all aryl halides in published work5 conducted with palladium
catalysts bearing monodentate or bidentate ligands. However,
coupling of the zinc enolate generated from R-bromodiethylpro-
pionamide occurred in high yield at room temperature with a variety
of aryl bromides, including those with electron-donating or
potentially reactive, base-sensitive electron-withdrawing groups.
The second protocol resulted from conditions that improve the
rate of transmetalation of silyl enolate without use of toxic tin
additives or an excess of copper halide and enolate. Silicon enolates
can be advantageous over Reformatsky reagents because they are
prepared directly from the ester and they are even less basic than
Reformatsky reagents. Silyl ketene acetals and silyl enol ethers react
in the presence of Lewis acidic transition metal catalysts,22,23 but
the rate for transmetalation of the enolate from the hard main group
metal to soft late metals could be slow.
Yet, we found that the silyl ketene acetal of tert-butyl propionate
or methyl isobutyrate reacted in high yield at 80 °C with
bromoarenes to form the corresponding R-aryl esters in the presence
of palladium catalysts ligated by P(t-Bu)3 and ZnF2 as cocatalyst.
Reaction yields were higher with zinc fluoride than with other zinc
halides.
Coupling of the silyl ketene acetals with bromoarenes occurred
with broad scope, as summarized in Table 2. Aryl halides containing
enolizable hydrogens, as well as electrophilic and base-sensitive
functionality, all reacted in high yield. Even substrates, such as
methyl ketones, that underwent attack at the carbonyl group by
zinc enolates faster than they underwent coupling, produced the
R-aryl esters from reactions of silyl ketene acetals.
Acknowledgment. We thank the NIH-NIGMS (GM58108),
Merck Research Laboratories, and Johnson-Matthey for support.
Supporting Information Available: Reaction procedures and
characterization of products (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
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Palladium-catalyzed R-arylation of imides bearing chiral auxil-
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carbonyl compounds. In the presence of strong base at room
temperature or above, this process would provide an equilibrium
ratio of products. Moreover, the alkoxide base of the coupling
chemistry cleaves the auxiliary from the enolate.24
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