Palladium-catalyzed alpha-arylation of azlactones to form quaternary amino acid derivatives.

Article abstract of DOI:10.1021/ol034570q

[reaction: see text] The synthesis of alpha-aryl-alpha-alkyl amino acid derivatives from alpha-amino acids by the arylation of azlactone derivatives is reported. Arylation of azlactones derived from alanine, valine, phenalanine, phenyl glycine, and leucin

Full text of DOI:10.1021/ol034570q

ORGANIC
LETTERS
2003
Vol. 5, No. 11
1915-1918
Palladium-Catalyzed r-Arylation of
Azlactones to Form Quaternary Amino
Acid Derivatives
Xiaoxiang Liu and John F. Hartwig*
Yale UniVersity, Department of Chemistry, New HaVen, Connecticut 06511
john.hartwig@yale.edu
Received April 1, 2003
ABSTRACT
The synthesis of r-aryl-r-alkyl amino acid derivatives from r-amino acids by the arylation of azlactone derivatives is reported. Arylation of
azlactones derived from alanine, valine, phenalanine, phenyl glycine, and leucine all provided good yields of the arylated product. Mechanistic
studies of this reaction revealed that a stable complex containing a ligand formed by reaction of dba with the azlactone accounts for a new
inhibiting effect of dba when reactions are initiated with Pd(dba)2.
The coupling between an sp2 carbon and an enolate has
emerged as a useful synthetic method only recently.1,2 Using
sterically hindered electron-rich phosphines as ligands, we
and others have developed efficient palladium-catalyzed
methods for the R-arylation of ketones,3,4 esters,5-7 amides,8,9
cyanoesters,10,11 malonates,3b,4b,11 and nitriles.12
molecular structure of receptors or enhance biological activity
by helping to preorganize peptides for binding.13,14 While a
variety of methods for the synthesis of R,R-dialkyl glycine
derivatives are available, methods for the synthesis of R-aryl-
R-alkyl amino acids, particularly from natural amino acids,
are more limited. For example, R-aryl-R-alkyl amino acids
can be prepared from the Strecker synthesis, but the linkages
between the R-carbon and the two side chains must be
present in the ketone prior to the Strecker reaction. Hydroly-
sis of the cyano group also requires harsh conditions.
Palladium-catalyzed R-arylation of suitably protected
amino acids could provide a general route to quaternary,
R-aryl amino acids by formation of the C-C bond linking
the aryl side chain to the R-carbon. We previously reported
the arylation of glycine derivatives by palladium-catalyzed
coupling of aryl bromides with diphenylmethylene-protected
glycinates,5 but no coupling with similarly protected R-sub-
stituted amino acids occurred. Intramolecular arylation of
Substitution at the R-carbon of R-amino acid derivatives
introduces conformational constraints that can probe the
(1) Culkin, D.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234.
(2) Miura, M.; Nomura, M. Top. Curr. Chem. 2002, 219, 211.
(3) (a) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382.
(b) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999, 121, 1473.
(4) (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108.
(b) Fox, J. M.; Huang, X. H.; Chieffi, A.; Buchwald, S. L. J. Am. Chem.
Soc. 2000, 122, 1360.
(5) Lee, S.; Beare, N. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123,
8410.
(6) Jorgensen, M.; Lee, S.; Liu, X. X.; Wolkowski, J. P.; Hartwig, J. F.
J. Am. Chem. Soc. 2002, 124, 12557.
(7) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7996.
(8) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem.
1998, 63, 6546.
(9) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402.
(10) Stauffer, S. R.; Beare, N. A.; Stambuli, J. P.; Hartwig, J. F. J. Am.
Chem. Soc. 2001, 123, 4641.
(11) Beare, N. A.; Hartwig, J. F. J. Org. Chem. 2002, 67, 541.
(12) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 9330.
(13) Obrecht, D.; Altorfer, M.; Lehmann, C.; Scho¨nholzer, P.; Mu¨ller,
K. J. Org. Chem. 1996, 61, 4080.
(14) Obrecht, D.; Bohdal, U.; Broger, C.; Bur, D.; Lehmann, C.; Ruffieux,
R.; Scho¨nholzer, P.; Spiegler, C.; Mu¨ller, K. HelV. Chim. Act. 1995, 78,
563.
10.1021/ol034570q CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/24/2003

R-substituted amino acid derivatives15 has been reported, but
the more versatile intermolecular arylation of protected amino
acids is unknown. Herein, we report the convenient synthesis
of R-aryl-R-alkyl amino acid derivatives from R-substituted
amino acids by the arylation of azlactone derivatives. Keys
to the development of this new transformation were the use
of an unexplored adamantyl phosphine and the discovery of
a new means by which dibenzylidene acetone (dba) inhibits
catalyst activity.
To develop the arylation of R-substituted amino acids, an
amino acid derivative that is more reactive toward palladium
coupling than benzophenone imine-protected amino acids
was needed. We considered that azlactones may be more
reactive because they are more acidic than imine-protected
amino acids and are less hindered because of their cyclic
structure. The sodium enolates of azlactones are stable for
hours at elevated temperatures.16 Indeed, Trost has recently
reported azlactones as pronucleophiles for asymmetric allylic
alkylation.16-18 Scheme 1 includes the simple preparation of
to lower conversions. For reasons described in detail below,
reactions initiated with Pd(OAc)2 instead of Pd(dba)2 or Pd2-
(dba)3 occurred under milder conditions and with a smaller
excess of azlactone. Thus, reactions conducted with a
combination of Pd(OAc)2 and Ad2P(t-Bu) as a catalyst with
1.5 equiv of azlactone and 3.3 equiv of K3PO4 generated
the quaternary aryl amino acid derivatives in good yields at
80 °C in 14 h.
Reactions of the azlactone of alanine are summarized in
Table 1. Reactions of electron-neutral aryl bromides (entries
Table 1. R-Arylation and Vinylation of the Alanine-Derived
Azlactone
Scheme 1
a Procedures: (A) 5% Pd(dba)2, 10% Ad2P(t-Bu), 3.3 equiv of K2CO3
and 2 equiv of azlactone in toluene, 100 °C, 14-36 h. (B) 5% Pd(OAc)2,
5% Ad2P(t-Bu), 3.3 equiv of K3PO4, 1.5 equiv of azlactone in toluene, 80
°C, 14 h. b Isolated yields are averages of at least two runs on a 1 mmol
scale.
azlactones from standard amino acids.13 The azlactone
derived from alanine was selected for a model study.
Several ligands, solvents, and bases were evaluated for
the reaction of PhBr with the azlactone derived from alanine.
Reactions were conducted at 100 °C in toluene with a
combination of Pd(dba)2 and a phosphine ligand as the
catalyst and K3PO4 as the base. Only reactions conducted
with sterically hindered electron-rich phosphines such as
P(t-Bu)3 gave substantial amounts of product. BINAP, DPPF,
and sterically hindered carbene ligands, which were effective
in related R-arylation chemistry,5,12 were ineffective in the
arylation of the azlactone. Reactions with catalysts generated
in situ from Ad2P(t-Bu) (2) occurred in the highest yield
and with the fastest rates. This ligand was prepared in 199419
but has not been exploited for catalysis previously.10,20
Reactions in aromatic solvents proceeded smoothly, but
those in THF, CH3CN, or DMF occurred in low yield.
Reactions conducted with K3PO4 as a base occurred in good
yield, but those conducted with Li3PO4 or Na3PO4 occurred
1 and 8) occurred in 77 and 83% yield. Reaction of the
electron-rich 4-bromoanisole (entry 3) gave 75% yield of
coupled product. Reactions of aryl halides with electron-
withdrawing trifluoromethyl, nitro, and cyano groups (entries
5, 10 and 11) also occurred, though the yields were slightly
lower than those of electron-neutral substrates. 4-Bromo-
styrene (entry 15), which could undergo Heck coupling to
deplete the aryl halide, formed the arylamino acid derivative
in good yield. Even somewhat hindered aryl bromides with
an ortho substituent such as 2-bromotoluene (entry 7) or
1-naphthyl bromide (entry 12) reacted to give 80 and 83%
yield of coupled product.
Some related vinyl and heteroaryl bromides were also
suitable substrates. For example, 1-bromo-2-methylpropene
(entry 13) reacted in good yield. Substrates with a pyridyl
nitrogen can deactivate palladium catalysts with monodentate
ligands,21 and 2-, 3-, and 4-bromopyridine did not react.
However, 3-bromoquinoline (entry 14) gave the desired
product in 40% yield.
(15) Gaertzen, O.; Buchwald, S. L. J. Org. Chem. 2002, 67, 465.
(16) Trost, B. M.; Dogra, K. J. Am. Chem. Soc. 2002, 124, 7256.
(17) Trost, B. M.; Xavier, A. J. Am. Chem. Soc. 1999, 121, 10727.
(18) Trost, B. M.; Lee, C. J. Am. Chem. Soc. 2001, 123, 12191.
(19) Lavrova, E. A.; Koidan, G. N.; Marchenko, A. P.; Pinchuk, A. M.
J. Gen. Chem. USSR (Engl. Transl.) 1994, 64, 1393; Zh. Obshch. Khim.
1994, 64, 1556.
To explore the steric sensitivity of the process toward
branched R-substituents on the amino acid derivative, we
explored the arylation of azlactones derived from phenyla-
(20) Stambuli, J. P.; Stauffer, S. R.; Shaughnessy, K. H.; Hartwig, J. F.
J. Am. Chem. Soc. 2001, 123, 2677.
(21) Paul, F.; Patt, J.; Hartwig, J. F. Organometallics 1995, 14, 3030.
Org. Lett., Vol. 5, No. 11, 2003
1916

Ad2P(t-Bu) as a ligand, we have isolated Pd[AdP(t-Bu)2](Ph)-
Br a related phenylpalladium bromide ligated by AdP-
(t-Bu)2.23 Treatment of this complex with the potassium
enolate of the azlactone derived from alanine generated the
coupled product in 40% yield by GC. The lower yield relative
to the catalytic reactions in Table 2 is due to the presence of
AdP(t-Bu)2 instead of Ad2P(t-Bu) on the palladium center.
Thus, oxidative addition of aryl bromide to Pd(0) and
reaction of the aryl palladium complex with the deprotonated
azlactone most likely accounts for the formation of coupled
product.
Table 2. Arylation of Azlactones
However, 31P NMR spectroscopy of the reaction between
the azlactone potassium enolate and phenyl bromide in the
presence of Pd(dba)2 and P(t-Bu)3 as catalysts showed a
single resonance at 70.6 ppm. This resonance does not
correspond to the Pd(0) species or the oxidative addition
product. X-ray crystallography revealed this complex to be
4 in Scheme 2 containing palladium, phosphine, and a ligand
a Procedures: (A) 5% Pd(OAc)2, 5% Q-phos 3, 3.3 equiv of K2CO3,
1.5 equiv of azlactone in toluene, 80 °C, 14 h. (B) 5% Pd(dba)2, 10% Ad2P(t-
Bu), 3.3 equiv of K2CO3 and 2 equiv of azlactone in toluene, 100 °C, 14
h. (C) 5% Pd(OAc)2, 5% Ad2P(t-Bu), 3.3 equiv of K3PO4, 1.5 equiv of
azlactone in toluene, 80 °C, 14 h. b Isolated yields are averages of at least
two runs on a 1 mmol scale. c Ad2P(t-Bu) (10%), GC yield. d Ad2P(t-Bu)
(10%), 36 h. e Temperature ) 100 °C.
Scheme 2
lanine, phenylglycine, leucine, and valine. As summarized
in Table 2, these azlactones also reacted to give quaternary
amino acid derivatives. The optimal catalyst for these
substrates depended on the type of side chain, but general
trends were observed. Reaction of the azlactone derived from
the more acidic and more hindered phenylglycine was best
conducted with Q-phos22 as a ligand. The azlactone derived
from phenylglycine reacted with electron-neutral, -poor, or
-rich bromoarenes in the presence of Pd(OAc)2 and Q-phos
(entries 1, 3, and 5). As shown in entry 2, analogous reactions
conducted with Ad2P(t-Bu) as a ligand occurred in lower
yields.
However, reactions of azlactones from naturally occurring
alkyl- and benzyl-substituted amino acids occurred in higher
yields with catalysts derived from Ad2P(t-Bu). Thus, the
azlactone derived from phenylalanine (entries 7 and 9)
reacted with electron-neutral or electron-poor bromoarenes
in good yields in the presence of Pd(OAc)2 and Ad2P(t-Bu).
In some cases, the azlactone containing a 2-tert-butyl
substituent instead of a 2-phenyl group reacted in higher
yield. For example, the 2-phenyl azlactone derived from
N-benzoyl leucine coupled in modest yields (entry 10), but
reaction of the 2-tert-butyl azlactone derived from the
pivaloyl amide of leucine gave 82% yield of the coupled
product (entry 11). Steric protection of the imine nitrogen
or electronic stabilization of the azlactone ring would account
for the higher yields with the tert-butyl derivative. Reaction
of the 2-tert-butyl azlactone derived from valine also
occurred in a much higher 63% yield (entry 13) than reaction
of the 2-phenyl azlactone from valine (29% yield, entry 12).
The arylation most likely occurs by oxidative addition,23
transmetalation, and reductive elimination.24 Though we have
not prepared arylpalladium halide complexes containing
generated from dba and the enolate of the azlactone. Complex
4 (5 mol %) catalyzed the reaction of PhBr with the azlactone
of alanine at 100 °C to give 66% yield of coupled product
by GC. However, complex 4 is more likely to be a precatalyst
than a true catalytic intermediate.
If 4 is a catalytic precursor and not an intermediate, then
the accumulation of 4 would siphon active catalyst from the
cycle, and a metal-ligand combination that forms the active
catalyst without formation of 4 would induce faster reactions.
Indeed, the results in Table 1 show that reactions initiated
with Ad2P(t-Bu) and Pd(OAc)2 instead of Pd(dba)2 occurred
at lower temperatures, in higher yields, with less catalyst,
and with less of an excess of azlactone. Further consistent
with a conventional mechanism involving oxidative addition
of aryl halide to Pd(0), 31P NMR spectroscopy of the reaction
of the azlactone enolate and phenyl bromide initiated by the
combination of Pd(OAc)2 and P(t-Bu)3 contained Pd[P-
(t-Bu)3]2 as the major palladium complex in solution. Finally,
reactions catalyzed by isolated Pd[P(t-Bu)3]2 occurred faster
than those initiated with P(t-Bu)3 and Pd(OAc)2 and occurred
in 76% yield.
Scheme 3
(22) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem.
2002, 67, 5553.
(23) Stambuli, J. P.; Buhl, M.; Hartwig, J. F. J. Am. Chem. Soc. 2002,
124, 9346.
(24) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 5816.
Org. Lett., Vol. 5, No. 11, 2003
1917

In summary, a new palladium-catalyzed method for the
R-arylation of azlactones was developed. The products of
these reactions can be hydrolyzed easily to generate R-aryl-
R-substituted amino acid derivatives.17 Moreover, resolution
of the quaternary azlactones has been accomplished previ-
ously by Mu¨ller by reaction with optically active amine as
shown in Scheme 3.14 Enantioselective versions of the
azlactone arylation are under investigation.
Acknowledgment. The authors thank the NIH (GM
58108) for funding.
Supporting Information Available: Procedures and
spectral data of products of all catalytic reactions and X-ray
data of complex 4. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL034570Q
1918
Org. Lett., Vol. 5, No. 11, 2003