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amino-oxazoline auxiliary.[8d] Hong and co-workers reported
the Pd-catalyzed diastereoselective b-methylene C(sp3)ÀH ary-
lation of cyclopropanes enabled by the isoleucine NH2 direct-
ing group.[8e] More recently, Yu and co-workers developed
a ligand-enabled strategy for the arylation of b-methylene
C(sp3)ÀH bonds with aryl iodides by using simple monoden-
tate amide auxiliaries, such as CONHOMe[10] and CONHArF
(ArF =para-CF3C6F4).[11]
5 mol% Pd(OAc)2 as a catalyst (Table 1). We were delighted to
find that the desired arylation product 3a was obtained in
40% yield when 2 equivalents of Ag2CO3 were used as a halide
scavenger (Table 1, entry 1). A thorough screening of solvents
indicated that 1,2-dichloroethane was the optimal solvent
(Table 1, entries 2–4). Other silver salts, including AgF, AgOAc,
and Ag3PO4, were less efficient than Ag2CO3 (Table 1, entries 5–
7). It is well known that carboxylic acids could significantly im-
prove the reactivity of C(sp3)ÀH functionalization reactions.[19]
Thus, we turned our attention to test the effect of carboxylic
acid additives. As expected, when 2,4,6-trimethylbenzoic acid,
pivalic acid, and (BnO)2PO2H were used as additives, the yields
of 3a were improved to 52, 64, and 67%, respectively (Table 1,
entries 8–10). Finally, we found that 1-adamantane carboxylic
acid gave the best result, thus affording 3a in 73% yield
(Table 1, entry 11).
Despite these elegant precedents in the b-methylene
C(sp3)ÀH arylation of carboxylic acid derivatives, the direct ary-
lation of g-methylene C(sp3)ÀH bonds of amine derivatives still
remains undeveloped (Scheme 1A). A seminal study complet-
ed in 2005 by Daugulis and co-workers first reported an exam-
ple of a Pd-catalyzed g-methylene C(sp3)ÀH arylation that em-
ployed picolinamide as a bidentate auxiliary under extremely
harsh conditions (i.e., ArI (4 equiv), neat, 1508C) and the selec-
tive monoarylation of methyl groups was achieved in most
cases.[5] In 2011, He and Chen further studied the synthetic ap-
plication and scope of picolinamide-directed palladium-cata-
lyzed C(sp3)ÀH arylation.[12a] Consistent with the findings of
Daugulis and co-workers, a highly selective monoarylation of
methyl C(sp3)ÀH bonds was achieved to provide the monoary-
lated products; however, g-methylene C(sp3)ÀH arylation only
happened with several specific substrates, such as cy-
clohexylamino acid and exo-2-aminonorborane deriv-
atives.[12] Later, a number of bidentate auxiliaries, in-
cluding N-(2-pyridyl)sulfonyl by Carretero and co-
workers[13] and 2-methoxyiminoacetyl by Fan and
Ma,[14] were successfully employed for the selective
monoarylation of the g-methyl C(sp3)ÀH bond of
amine derivatives. Very recently, Yu and co-workers
reported the selective monoarylation of a g-methyl
C(sp3)ÀH bond directed by a monodentate triflate
auxiliary enabled by a mono-N-protected amino
acid.[15] However, these auxiliaries were only applied
to the arylation of g-methyl C(sp3)ÀH bonds. Thus,
the development of a new type of auxiliary that
could efficiently promote the arylation of unactivated
g-methylene C(sp3)ÀH bonds is highly desirable. As
part of our continuing study into C(sp3)ÀH functional-
ization assisted by bidentate auxiliaries,[16] we envi-
sioned that a suitable bidentate auxiliary could facili-
tate this process.
We carried out control experiments with alternative direct-
ing groups under the optimized reaction conditions (Table 1,
entries 12 and 13). The use of picolinamide as the directing
group (1a,b) led to the arylated product 3a,b in a moderate
yield (58%; Table 1, entry 12). No reaction occurred when
2-methoxyiminoacetyl was used as the directing group
(Table 1, entry 13).
Herein, we report the development of a powerful
and removable oxazoline-carboxylate auxiliary, which
could be used in the arylation of unactivated g-meth-
ylene C(sp3)ÀH bonds (Scheme 1B). Meanwhile, the
protocol is also efficient for the arylation of remote
d-CÀH bonds, which has been seldom reported.[6c,17]
Furthermore, preliminary results of a diastereoselec-
tive arylation that uses chiral oxazoline-carboxylate
auxiliaries are also reported.[18]
Figure 1. Pd-catalyzed arylation of g-methylene C(sp3)ÀH bonds with ArI. Reaction condi-
tions: 1a (0.15 mmol, 1 equiv), 2 (3 equiv), Pd(OAc)2 (5 mol%), Ag2CO3 (2 equiv), and
1-AdCO2H (0.5 equiv) in DCE (2 mL) at 1108C under N2 for 24 h. The yields of the isolated
Results and Discussion
We initiated our investigations by the reaction of
amide 1a with para-iodoacetophenone (2a) with product are given. [a] 10 mol% Pd(OAc)2.
Chem. Eur. J. 2015, 21, 17503 – 17507
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