perfluorinated arylamides, to direct a wide range
of C(sp3)–H activation reactions by weak coor-
dination to palladium catalysts (4, 5). However,
to date we have found that these auxiliaries
are incompatible with the functionalization of
the C(sp3)–H bonds of a–amino acids (4, 5).
We recently demonstrated that the use of an
alkoxypyridine ligand can match the weak co-
ordination of the amide auxiliary (CONHArF)
and facilitate secondary C(sp3)–H activation
(albeit, with only simple aliphatic amides) (21),
indicating that pyridine-based ligands are ca-
pable of lowering the transition state energy of
C(sp3)–H activation. This finding prompted us
to test a diverse array of monodentate pyridine-
derived ligands for their ability to selectively pro-
mote primary C(sp3)–H activation, thereby allowing
for highly monoselective arylation of alanine-
derived amide 1.
To obtain preliminary information regarding
the reactivity of the CONHArF amide auxiliary
with amino acid substrates, we initiated our experimental efforts by studying C(sp3)–H arylation
of 1 under a variety of different reaction conditions in the absence of an ancillary ligand.
Through extensive screening, we found that the
use of 20 mol trifluoroacetic acid (TFA) prevented substrate decomposition, which had been
observed with 1 under previously developed
basic conditions (21). Under the best conditions
from this initial screen, monoarylated product
2 could be obtained in 47% yield, along with
full recovery of the remaining starting material
(Fig. 2A). Additional attempts to fine-tune var-
ious reaction parameters, including increasing
the catalyst loading to 30 mol %, failed to improve
the reaction conversion. The low conversion was
found to result primarily from product inhibition
(see supplementary materials: table S2, entry 16).
Alternative aryl iodide coupling partners reacted
in even lower yields (Fig. 2A, 2m to 2p). These
findings point to the need for the identification of
a ligand that will promote the activation of pri-
mary b-C(sp3)–H bonds exclusively but not the
secondary b-C(sp3)–H bonds in the product. Hence,
a library of pyridine ligands was tested for their
efficiency of promoting monoarylation in the pres-
ence of TFA. Pyridine and 4-dimethylaminopyridine
(L1 and L2) are highly selective for monoaryla-
tion, but neither enhances conversion substantial-
ly relative to the ligand-free catalyst. In contrast,
we found that 2,6-dimethoxypyridine, acridine,
2,6-lutidine, and 2-picoline (L4 to L7) promote
substantially higher conversion, though the use
of L4 to L6 leads to appreciable quantities of
the undesired diarylated product 3 as well. The
2-picoline ligand (L7) seems to possess an op-
timal balance of steric and electronic properties
to provide 2 in high yield with an excellent level
of selectivity for monoarylation [nuclear mag-
netic resonance (NMR) yield of 94%]. The mono-
arylation reaction also proceeded in the presence
of 5 mol of Pd(TFA)2 and 10 mol of L7 to
give the desired product 2 in 79% yield (table
S2, entry 4).
The applicability of this ligand-controlled monoarylation protocol in the preparation of diverse
chiral b-Ar-b-Ar′-a–amino acids is shown in Fig.
2A: Phenylalanine derivatives with electron-rich
or electron-poor groups in the ortho, meta, or
para positions can be synthesized in high yields.
This reaction is tolerant of halide substituents and
a wide range of polar functional groups. Arylation
with 4-methylthiophenyl iodide also proceeds to
give the arylated product (2p) in a synthetically
useful yield, indicating that the pyridine ligand
is able to out-compete the methylthio group
for coordination at Pd(II). The reaction of 1 with
2-iodonaphthalene to give 2q is particularly
useful, as the resulting product could be applied
to synthesis of bioactive peptides that block cell
cycle progression in HeLa cells (22). Arylation
with disubstituted aryl iodides is also efficient,
giving 2r to 2t in >85% yields.
When conducted at 100°C, these reactions
are typically complete within 20 hours, and no
racemization of the a-chiral center is observed.
Subsequent removal of the auxiliary can be accomplished under mild conditions without loss
of enantiomeric purity (Fig. 2B), and the monoarylated products are readily converted to the corresponding N-fluorenylmethyloxycarbonyl–protected
unnatural amino acids following literature procedures (see supplementary materials). The auxiliary 2,3,5,6-tetrafluoro-4-(trifluoromethyl)aniline is
readily prepared from octafluorotoluene ($0.47/g)
on a 100-g scale or purchased directly from Aldrich.
Fig. 2. Palladium-catalyzed arylation of primary C(sp3)–H bonds. (A) Ligand-promoted monoarylation of auxiliary-substituted alanine. Phth, phthalimido; DCE, 1,2-dichloroethane (B) Removal of amide
auxiliary and determination of enantiomeric purity of N-Phth–protected chiral a–amino acid. Ac, acetyl; RT,
room temperature; ee, enantiomeric excess; HPLC, high-performance liquid chromatography.