Angewandte
Communications
Chemie
removal of the directing group, providing straightforward
access to a wide array of meta-functionalized benzylamines.
Our experimental design was guided by the following
reasoning: a readily removable directing group is needed to
prepare benzyl amines; a 7-membered palladacycle inter-
mediate is known to be advantageous for this norbornene-
mediated multi-step catalytic cycle. Gratifyingly, a newly
designed removable pyridine-derived directing group that
form a 7-membered palladacycle allowed the formation of the
meta-arylated product in 25% yield with 10 mol% Pd(OAc)2
improved the reactivity, affording the desired meta-arylated
product in 67% yield. Methyl substitution at the 6-position
(L2) of the ligand scaffold led to a significant decrease in the
activity probably due to steric encumbrance of the ligand,
while methyl substitution at the 4- or 5-position does not
drastically alter the effectiveness of the ligand (L3 and L4).
Fluorinated ligand (L5) provided a slightly lower yield of the
[
3e]
desired product. Gratifyingly, the installation of a CF at the
3
5-position increased the yield to 74% (L6). A few acyl
protecting groups on amine based on the promising ligand L6
were evaluated, but no drastic changes in efficiency were
noticed (L7–L9). This is in contrast to our prior publications
concerning 3-acetylamino-2-hydroxypyridine ligands wherein
the protecting group on the amine can exert a significant
(
see the Supporting Information (SI) for more information).
The presence of a mono-protected 3-amino-2-hydroxypyri-
dine ligand L1 was essential. Notably, these substrates can be
easily synthesized in one step using the 2-(Boc-amino)-3-
methylpyridine with benzylic halides in the presence of base.
After a simple investigation of the substitution on the
pyridine directing group, it was found that substitution of
the 3-position on the pyridine ring with a methyl group
improved the yield to 99%. The efficiency of this reaction
prompted us to search for ligands that can reduce the Pd
catalyst loading. Hence, we evaluated a variety of ligands in
[3f]
influence on the reaction efficiency. Interestingly, simple 2-
hydroxypyridine (L10) also promoted this reaction smoothly,
providing slightly lower yield compared with the 3-acetyl-
amino-2-hydroxypyridine ligand L1. Thus we turned our
attention to the evaluation of the simple 2-pyridone ligands
(L10–L24). 5-methyl substituted hydroxypyridine ligand
(L11) led to a slight decrease of the efficiency of the ligand,
while the electron-withdrawing group at the 5-position of the
ligand scaffold gave higher yield (L12–L15). Similar to the
the presence of 2.5 mol% Pd(OAc) on 0.2 mmol scale. Based
2
on our previous findings in meta-CÀH functionalization of
anilines and phenols, the mono-protected 3-amino-2-hydroxy-
pyridine ligands (L1–L9) were investigated first (Table 1).
The 3-acetylamino-2-hydroxypyridine (L1) dramatically
ligand L2, the 6-CF substituted hydroxypyridine ligand L16
3
dramatically decreased the activity, while ligands containing
a CF group on the 3, or 4 positions provide promising results
3
(L16 vs. L17–L18). To our delight, the 3-CF3 substituted
[
a,b]
ligand L18 improved the yield to 81%. This result demon-
strates that the 3-acetylamino group is not likely playing
a fundamental role in our previously reported reactions, but
instead serves as a tunable substituent whose role is substrate
and transformation dependent. More electron deficient
hydroxypyridine ligands (L19–L21) containing the 3-CF3
substituent were tested and it was found that 3,5-ditrifluoro-
methyl hydroxypyridine L21 displays very similar activity
with L18. 3-Nitro-5-trifluoromethyl-2-hydroxypyridine (L22)
and 3,5-dichloro-2-hydroxypyridine (L23) were also efficient
for this transformation, providing the desired product in 74%
and 78% yields, respectively. 2-Hydroxyquinoline (L24) only
afforded the product in 9% yield, probably due to the steric
similarity of L2, L6, and L24. The yield of this reaction can be
further improved to either 96% or 95% in the presence of
L18 by use of 3.0 equivalents of aryl iodide or increasing the
loading of palladium catalyst to 5.0 mol% respectively.
With the optimal conditions in hand, we next examined
the scope of benzylic amine substrates. As shown in Table 2,
a broad range of functional groups are well tolerated in this
reaction. Benzylamines bearing electron-donating substitu-
ents at the 3-position (2a–c), such as methyl, methoxy, and
phenyl, are suitable substrates for the process providing the
desired products in high yields. Substrate 1d bearing an
alkynyl group on the 3-position afforded lower yield due to
the stability of the substrates under the standard conditions.
Electron-deficient benzylamines gave lower yields in the
presence of L18 (2e–k). For example, subjection of the 3-
bromo- and 3-trifluoromethyl-benzylamine to the standard
conditions afforded the corresponding products in 69% and
Table 1: Ligand evaluation for meta-CÀH arylation of benzylamines.
[
a] Conditions: 1a (0.2 mmol), Ar-I (2.0 equiv), Pd(OAc) (2.5 mol%),
L (5.0 mol%), AgOAc (100.2 mg, 3.0 equiv), NBE-CO Me (43.0 mg,
2
2
1
.5 equiv), HCCl (1.0 mL), 1008C, air, 24 h. [b] The yields were
3
1
determined by H NMR using acetylene tetrachloride as an internal
6
1% yields, respectively. Through optimizations of the ligand
standard. [c] Pd(OAc) (2.5 mol%), L18 (3.75 mol%), Ar-I (3.0 equiv)
2
were used. [d] Pd(OAc) (5 mol%), L18 (7.5 mol%) were used.
effects for the electron deficient substrates, we found that the
2
2
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!
Wang, Peng
