.
Angewandte
Communications
3
À
C(sp ) H amination is a distinct challenge. We initiated our
The observed significant ligand effect prompted us to screen
various phosphine and NHC ligands which have been
previously used for palladium(0)-catalyzed coupling reac-
3
À
investigation into the palladium(0)-catalyzed C(sp ) H ami-
nation of the amide 1a (for structure see Table 1), as the
weakly coordinating N-arylamide auxiliary has been shown to
tions. Somewhat surprisingly, the optimal electron-rich NHC
0
3
3
À
À
be able to direct Pd /PAr3-catalyzed C(sp ) H arylation and
alkynylation.[16,17] We selected O-benzoyl hydroxylmorpho-
line (2a) as the aminating reagent,[4c,7b] which can be readily
prepared using a known procedure.[19] We anticipated that
oxidative addition of 2a to Pd0 could occur in the presence of
and phosphine ligands for our previous C(sp ) H arylation
and alkynylation reactions[16,17] proved to be ineffective for
3
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this C(sp ) H amination (entries 4–6). These results indicate
II
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that the required ligand properties of the LnPd NR2
intermediate for cleaving the C(sp ) H bonds may be differ-
3
À
II
II
À
À
phosphine ligands. However, identification of suitable ligands
ent from LnPd aryl and LnPd alkynyl species. We there-
fore began to investigate electron-deficient phosphine ligands
(entries 7–9; for detailed ligand screening see the Supporting
Information). We found that tris(4-fluorophenyl)phosphine
improved the yield to 28% (entry 7). Replacement of the
fluorine by the more electron-withdrawing trifluoromethyl
group in the phosphine ligand led to further improvement,
thus affording 3a in 41% yield (entry 8). Remarkably, when
we utilized the tris[3,5-bis(trifluoromethyl)phenyl]phosphine
ligand, the reaction proceeded to give 3a in 83% yield
(entry 9). Although further modification of triarylphosphine
ligands did not improve this reaction (entries 10–14), these
experiments provided further insights into the ligand effect:
1) electron-withdrawing substituents on the aryl groups were
crucial to the reactivity (entry 10); 2) substitution at the 2-
position of the aryl ring was detrimental to the reaction
(entries 11 and 12); 3) electron-withdrawing groups at 3-
positions are more effective than those at the 4-position of the
aryl ring (entries 13 and 14); 4) monodentate, rather than
bidendate ligands, are required for this reaction (entry 15).
The control experiment also illustrated that triarylphosphine
oxides were ineffective for promoting the reaction, thus
confirming that the triarylphosphine is the active ligand
(entry 16).
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and reaction conditions to ensure that the LnPd NR2 species
would be able to coordinate with the amide substrate and
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subsequently activate the b-C(sp ) H bonds presents a sig-
nificant challenge.
Our early experimentation employed the commonly used
combination of Pd(OAc)2 and triphenylphosphine as the
precatalyst to explore reaction conditions that would lead to
the formation of the amination product. We found the
reaction of 1a with amine coupling partner 2a in the presence
of this precatalyst and Cs2CO3 in dichloromethane at 1208C
gave the desired amination product 3a in 10% yield (Table 1,
3
[a,b]
À
Table 1: Ligand optimization for C(sp ) H amination.
Entry
Ligand
Yield [%]
1[c]
2
3
PPh3
PPh3
–
10
15
5
Amides derived from various aliphatic acids were sub-
jected to these optimized reaction conditions (Table 2).
Amination of 1a and 1b provided the corresponding products
3a and 3b in 77 and 73% yields, respectively. The amide 1c of
the parent drug gemfibrozil was also aminated to give 3c in
75% yield. The amination of the amide 1d afforded a valuable
b-amino-acid derivative containing a trifluoromethyl group
(3d) in 52% yield. A variety of aryl groups on the b- and g-
positions were well tolerated (3e–i). In comparison to other b-
C(sp3)-H functionalization reactions, this amination protocol
displays exclusive monoselectivity in the presence of two or
three a-methyl groups (1a–i). The newly installed amino
group appears to prevent palladium catalysts from activating
the remaining methyl groups through bidentate coordination.
Amides containing a single a-methyl group are also reactive,
thus affording the desired amination products in good yields
4
IAd·HBF4
5
5
6
7
8
PCy3·HBF4
tBuXPhos·HBF4
P(4-FC6H4)3
P(4-CF3C6H4)3
PAr3
2
3
28
41
83
39
12
24
72
46
0
9
10
11
12
13
14
15[d]
16
PAr2Ph
PAr2(2,6-F2C6H3)
PAr2(2-CF3C6H4)
PAr2(3-CF3C6H4)
PAr2(4-CF3C6H4)
1,2-(PAr2)2C6H4
OPAr3
3
[a] Experiments were performed with 1a (0.1 mmol), 2a (0.4 mmol),
[{Pd(allyl)Cl}2] (0.005 mmol), ligand (0.02 mmol), Cs2CO3 (0.4 mmol),
and 4 ꢀ molecular sieves (M.S.; 50 mg) in CH2Cl2 (1.5 mL) for 16 h at
1208C under N2 atmosphere. [b] The yield was determined by 1H NMR
analysis of the crude reaction mixture using CH2Br2 as the internal
standard. [c] Pd(OAc)2 (0.01 mmol) was used. [d] The bidentate ligand
(0.01 mmol) was used. Ar=3,5-(CF3)2C6H3.
(3j–o). Substrates containing a-protons are incompatible with
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the reaction conditions, presumably because the basic LnPd
amido species generated in situ will react with the acidic a-
carbon center.
Intriguingly, aminating reagents derived from pyrrolidine
and acyclic dialkylamines were not effective coupling part-
ners and resulted in poor yields. Encouragingly, batchwise
addition of the more challenging amine coupling partners
improved the reaction yield from 14 to 27% (see the
Supporting Information). We thus explored the scope of the
entry 1). Through extensive screening of palladium sources
and bases, we identified [{Pd(allyl)Cl}2] to be the most
effective precatalyst, thus affording 3a in 15% yield
(entry 2). The yield decreased to 5% when the reaction was
carried out in the absence of triphenylphosphine (entry 3).
2
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
These are not the final page numbers!
He, Jian
