reaction conditions (Pd(OAc)2 (0.05 equiv), AgOAc
(1.0 equiv), ArI (4 equiv), 130–1508C, no solvent) were
required for this transformation.[12] Nonetheless, intrigued
by the unique remote directing ability of the PA moiety, we
screened various PA-based auxiliaries systematically in an
attempt to develop milder reaction conditions (Scheme 1B).
Thus, we carried out the arylation of the cyclohexylamino acid
substrates 1 and 1a–e with 4-iodoanisole (2; 1.5 equiv) at
808C with different combinations of PdII and AgI salts. Initial
screening revealed the optimal reaction conditions: the use of
Pd(OAc)2 (0.1 equiv) and Ag2CO3 (1.0 equiv) with tBuOH or
trifluoroethanol as the solvent. Stereoselectively monoary-
lated cyclohexane derivatives were obtained as the major
product in all cases. Interestingly, no products bisarylated at
both the g and g’ positions were observed. The structure of 3-
1b (p-NO2-PA) was confirmed by X-ray crystallography.[13]
The electronic properties of the substituents on the pyridine
ring of the PA had a clear effect on the arylation reaction: the
presence of electron-withdrawing substituents, as in 1b, 1c,
and 1d, led to a decrease in the arylation yield, whereas the
presence of an electron-donating substituent, as in substrate
1a, led to an increase in the yield. Owing to the advantages of
low cost and high performance, the unmodified PA was
employed for further exploratory studies.
A broad range of aryl iodides were used successfully in the
arylation of substrate 1 (Scheme 1B). O-TIPS, NO2, tosyl
amide, and CO2Me groups were tolerated well under the
reaction conditions. Even a free phenol, 2e, was incorporated
in moderate yield. However, the pyridine substrate 2 f failed
to give any arylated product. Although the arylation of 1 with
iodides 2 was complete within 24 h at 808C, the reaction also
proceeded smoothly at 608C in 48 h. Some 3-1 (ca. 15%) was
generated even at 408C with extended reaction times
(5 days).
Scheme 2. Substrate scope of the palladium-catalyzed picolinamide-
3
ꢀ
directed C(sp ) H arylation. Reaction conditions: a) amide substrate
(1.0 equiv), ArI (1.5 equiv), Pd(OAc)2 (0.1 equiv), Ag2CO3 (1.0 equiv),
tBuOH or trifluoroethanol, 0.2m (air and moisture were not strictly
excluded; yields refer to the isolated product); b) p-TsOH·H2O
(1.0 equiv), toluene, 82%. TBS=tert-butyldimethylsilyl, TsOH=p-tol-
uenesulfonic acid.
Encouraged by the excellent performance of substrate 1 in
ꢀ
this C H arylation system, we examined a variety of other
aliphatic amine scaffolds. Gratifyingly, excellent yields and
selectivities were observed for most substrates under mild
conditions (Scheme 2). For example, the exo-2-aminonorbor-
ꢀ
nane 4 gave the product 5 of arylation exclusively at the C7
Hb position, whereas the endo-2-aminonorbornane 6 gave the
reactions, presumably because of steric factors. Whereas the g
ꢀ
product 7 of arylation exclusively at the C2 Ha position. The
endo bornylamine substrate 8 was selectively arylated at the
regioselectivity was controlled by the five-membered pallada-
ꢀ
cycle intermediate, the relative conformation of the C H
ꢀ
C6 Ha position: the 1-CH3 group remained untouched. To
bond and the Pd center had a strong influence on the regio-
and stereoselectivity of the arylation reaction.
our surprise, acyclic substrates also reacted well under the
same arylation conditions. Threoninol 10 was arylated cleanly.
The threonine methyl ester 12 even underwent arylation with
ortho-substituted methyl 2-iodobenzoate at the g-CH3 posi-
tion to give 13 in moderate yield with complete chiral
integrity. Upon the heating of 13 with p-TsOH in toluene,
benzolactone 14 was obtained in excellent yield. The cis-2-
methylcyclohexylamine-derived substrate 15 was arylated
preferentially at the CH3 group to provide the monoarylated
product 16 along with bisarylated 17 as a minor product at
608C. The isoleucine-derived substrate 18 was arylated
preferentially at the g-CH3 position to give the monoarylated
product 19 (33%) and the bisarylated diastereomers 20 and
21 (17% combined yield) at 608C. No significant amount of
gem-diarylated products (< 3%) was observed in any of these
At the outset of our studies, the mechanism of this
ꢀ
pallladium-catalyzed PA-directed C H arylation was not well
understood. The original report suggested that the process
proceeded through a PdII/PdIV pathway.[9a,14] However, the
ꢀ
order of the C H activation and ArI-coupling steps remained
elusive. To address this question, we conducted some
preliminary mechanistic studies with substrate 4 (Sche-
me 3A). The dimeric Pd complex 22 was formed cleanly
within 30 min upon the mixing of 4 with Pd(OAc)2 (1.0 equiv)
in tBuOH at 808C (as confirmed by X-ray crystallography:
see the Supporting Information). Complex 22 reacted with 2
to give the arylated product 5 in excellent yield in the absence
of Ag2CO3. Furthermore, 22 acted as a competent catalyst for
the arylation of 4 with 2. Isolation of the speculative
Angew. Chem. Int. Ed. 2011, 50, 5192 –5196
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5193