Palladium-catalyzed α-arylation of esters and protected amino acids [2]

Full text of DOI:10.1021/ja016032j

8410
J. Am. Chem. Soc. 2001, 123, 8410-8411
Scheme 1
Palladium-Catalyzed r-Arylation of Esters and
Protected Amino Acids
Sunwoo Lee, Neil A. Beare, and John F. Hartwig*
Department of Chemistry
Yale UniVersity, P.O. Box 208107
New HaVen, Connecticut 06520-8107
ReceiVed April 17, 2001
ReVised Manuscript ReceiVed July 1, 2001
Table 1. Palladium-Catalyzed R-Arylation of Estersa
R-Aryl carboxylic acids and R-aryl amino acids are among the
most important carbonyl compounds. These molecules include
the profen family of drugs,1 as well as R-aryl amino acid and
acetic acid building blocks.2,3 Naproxen and ibuprofen are
prepared by multistep syntheses.1 R-Aryl amino acids are gener-
ally prepared by Strecker chemistry, which forms the linkage
between the R carbon and the final carboxylic acid unit.4 R-Aryl
acetic acids are generally formed from one of several classical
reactions that lack functional group tolerance or regiospecificity.
The direct R-arylation of esters and protected amino acids could
provide a short, general route to these molecules. One paper 25
years ago described catalytic (20 mol %) coupling of tert-butyl
acetate with phenyl iodide using BuLi and NiBr2;5 others describe
coupling of Reformatsky reagents6 or copper enolates,7 which
were generated in two steps from the ester. Although the
palladium-catalyzed, direct R-arylation of carbonyl compounds
now encompasses many substrates,8-18 the intermolecular R-ary-
lation of monocarbonyl compounds at the carboxylic acid
oxidation level has not been conducted in a general fashion.10
We report a set of R-arylations of esters and protected amino
acids that reveals both important concepts for direct arylation of
carbonyl compounds and useful catalytic systems. First, we show
by the choice of ester and base that the formation of the palladium
enolate complexes controls the reaction scope as much as the
chemistry of the palladium enolate, and second we show that
glycinates are activated for direct coupling by unsaturated amine
protective groups. Using this information, we uncovered two
readily available catalyst systems that provide a general, pal-
ladium-catalyzed reaction of esters with aryl halides to form tert-
butyl- or methyl-protected R-aryl carboxylic acids, and a general,
palladium-catalyzed reaction of imine-protected glycinates with
aryl halides to form protected, R-aryl amino acids (Scheme 1).
Recently, we showed that the rates for reductive elimination
from arylpalladium ketone, ester, and amide enolate complexes
were nearly identical.19 These results implied that the arylation
of esters was deterred by the instability of the alkali metal enolate
a Reactions were conducted for 12 h at room temperature on a 1
mmol scale using 1.1 equiv of ester and 2.3 equiv of Li- (entries 1-8
and 17) or NaN(SiMe3)2 (entries 9-15) as base. The catalyst consisted
of a 1:1 mixture of Pd(dba)2 and ligand. Yields are for isolated material
of >95% purity by GC or combustion analysis. b Reaction conducted
with K3PO4 as base at 100 °C. c Two equiv of ester.
and slow formation of the palladium enolate complex, not by
unfavorable reductive elimination. Thus, reactions should occur
using more stable ester enolates and a strong enough base to
generate the alkali metal and subsequent palladium enolate
efficiently. Therefore, we focused initially on reactions of tert-
butyl esters. We evaluated reactions using tert-butoxide and
ultimately hexamethyldisilazide (HMDS) bases, which we had
shown previously to induce some successful arylation of amides.10
Neither base can reduce the palladium by â-hydrogen elimination.
Table 1 summarizes our results from reactions of esters. An
evaluation of several simple and inexpensive ligands showed that
a combination of Pd(dba)224 and tri-tert-butylphosphine (1) or the
hindered carbene precursor 2 (Scheme 1)21-23 generated catalysts
that couple esters with aryl halides. Although tert-butoxide was
a strong enough base to couple ketones with aryl halides, low
conversions of aryl halide were observed from reactions of esters.
Instead, HMDS bases were more effective and led to reactions
of aryl bromides at room temperature. The use of lithium HMDS
(1) Harrington, P. J.; Lodewijk, E. Org. Process Res. DeV. 1997, 1, 72.
(2) Yamada, T.; Omote, Y.; Yamanaka, Y.; Miyazawa, T.; Kuwata, S.
Synthesis 1998, 991.
(3) Crisma, M.; Valle, G.; Bonora, G. M.; Toniolo, C.; Lelj, F.; Barone,
V.; Fraternali, F.; Hardy, P. M.; Maia, H. L. Biopolymers 1991, 31, 637.
(4) Yet, L. Angew. Chem., Int. Ed. 2001, 40, 875.
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(8) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382.
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1998, 63, 6546.
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(19) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 5816.
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10.1021/ja016032j CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/03/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 34, 2001 8411
Table 2. Palladium-Catalyzed Arylation of Protected Amino
Scheme 2
Acidsa
effective because of the lower pKa. Alternatively, coordination
of the substrate nitrogen may assist formation of the enolate, as
suggested by the coupling of ethyl N,N-dimethylglycinate, but
not other esters when using K3PO4. Electron-rich, ortho-
substituted, and sterically unhindered aryl halides all reacted in
high yields with benzophenone ethyl or tert-butyl glycinate. In
addition, reactions of pyridyl halides and aryl chlorides provided
good yields of isolated product.
Because benzophenone imine is more expensive than aromatic
aldehydes, we investigated the R-arylation of ethyl N-benzylidene
glycinates. Reaction of phenyl bromide with the conveniently
crystalline26 ethyl N-(p-chlorobenzylidene) glycinate (Scheme 2)
gave two products: one the desired product from R-arylation and
the other from coupling at the imine carbon. The latter product
formed the corresponding diarylmethylamine upon hydrolysis.
We reasoned that the undesired product was formed by
reductive elimination from the iminobenzylic tautomer of the
expected palladium enolate (Scheme 2). To disfavor this undesired
tautomer, we conducted the reaction with a more electron-rich
aldimine. By increasing the electron density of the aryl group,
the iminobenzylic anion would be less stable, and the R-imino
ester enolate would be more favored. As shown in entries 23-
33 of Table 2, this strategy was effective. Reactions of aryl
bromides with the p-methoxy aldimine of ethyl glycinate formed
the free, neutral R-aryl glycinate upon workup. Reactions of this
substrate with aryl chlorides were less favorable than reactions
of benzophenone ethyl glycinate, but they did occur to give
substantial yields of the coupled products (entries 24 and 32).
Thus far, reactions to form quaternary amino acids have not
occurred.
The R-arylations described here most likely occur by oxidative
addition of aryl halide, formation of arylpalladium enolate
complexes, and reductive elimination. As mentioned in the
introductory paragraphs, the reductive elimination rate is relatively
insensitive to enolate electronic properties.19 Thus, the yields are
most dependent on the stability of alkali ester enolates and the
formation of palladium ester enolates.
The turnover-limiting step of coupling reactions involving
chloro- and bromoarenes is often oxidative addition. Indeed, the
reactions of protected amino acids with bromo or chloroarenes
catalyzed by palladium complexes of P(t-Bu)3 showed Pd[P(t-
Bu)3]2 as the major phosphine complex in solution during the
reaction. In most cases, these data would imply that oxidative
addition is turnover-limiting. Yet, these reactions are much slower
than those of the simple esters or of other nucleophiles when the
same catalyst and aryl halide are used. Reversible oxidative
addition and turnover-limiting formation of the palladium enolate
could account for these observations. Alternatively, oxidative
addition could occur to an anionic palladium enolate complex.
These mechanistic issues will be the subject of future studies.
a For entries 23-33 the free, neutral R-aryl glycinate was isolated.
Yields are for reactions conducted on a 1 mmol scale using 2 mol %
Pd(dba)2, 4 mol % P(t-Bu)3, 3 equiv of K3PO4 in 2 mL of toluene.
Reactions of aryl bromides were conducted at 100 °C for 20 h and of
aryl chlorides at 120 °C. b tert-Butyl diphenylmethyleneglycinate used
as protected amino acid.
led to fast reactions and high selectivity for monoarylations of
tert-butyl acetate; the use of the sodium salt led to high yields
for reactions of tert-butyl propionate. Potassium HMDS was
ineffective for either ester. Reaction of tert-butyl acetate with the
unhindered aryl halides in entries 1, 2, 4, and 7 occurred without
competing diarylation when using LiHMDS. Only bromoanisole
showed any diarylation product by GC, and this side product was
formed in <2% yield. The selectivity for monoarylation was
achieved, as it was for reactions of methyl ketones,9 by using 2
equiv of base. This ratio of base to substrate encourages
deprotonation of both product and reactant and, therefore,
discourages quenching of the starting ester enolate by the more
acidic product. Reactions of sterically hindered substrates gave
high selectivity for monoarylation with either Li or NaHMDS.
Complexes of ligand 2 also catalyzed reactions of tert-butyl
propionate with aryl halides under appropriate conditions. Reac-
tions of this ester with aryl bromides (entries 9, 11-13) and even
chlorobenzene (entry 10) occurred in high yields at room
temperature, but this time using excess NaHMDS. Hydrode-
halogenation of the haloarene was the major competing reaction
when using other ligands for reactions of this ester. Reaction of
the most hindered bromide in entry 12 occurred in higher yield
when using P(t-Bu)3. Coupling of esters with branching at the
â-position (entries 14-16) was accomplished using ethyl or
methyl esters. For example, essentially quantitative yields were
obtained from reaction of ethyl 3-methylbutyrate and methyl
cyclohexyl acetate with a representative aryl bromide. The
sterically similar ethyl N,N-dimethylglycinate also gave the
R-arylation product in high yield, even when using K3PO4 as base.
Finally, the use of P(t-Bu)3 instead of carbene precursor 2 as
ligand led to construction of quaternary carbons, for example by
reaction of 4-bromo-t-butylbenzene with methyl isobutyrate in
the presence of LiHMDS (entry 17).
The reaction of N,N-dimethylglycinate led us to evaluate the
R-arylation of amino acids with more convenient nitrogen
protection.25 We focused our studies on N-(diphenylmethylene)-
glycinate and N-benzylideneglycinate. These materials are con-
venient to prepare, and the imine unit can modulate the acidity
of the R C-H bond.20 The results from these reactions are shown
in Table 2. High yields of coupled product were obtained using
P(t-Bu)3 as ligand and K3PO4 as base. The weaker base may be
Acknowledgment. We thank the NIH (RO1-GM58108-02-04) for
support and Dr. Motoi Kawatsura and Morten Jørgensen for helpful
suggestions.
Supporting Information Available: Reaction procedures and spectral
and analytical data for reaction products (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA016032J
(25) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic Synthesis,
3rd ed.; John Wiley and Sons: New York, 1991; p 587.
(26) Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc.
2000, 122, 5228.