Angewandte
Chemie
well to give the corresponding lactams in above 80% yield.
2
Intramolecular amination of the ortho C(sp )ÀH bonds of aryl
acetamides such as 34 and 37 also occurred to provide
indolinone products in good to excellent yield under further-
optimized conditions in the presence of PhI(OAc)2
(
1.3 equiv) at 608C. As compared with the corresponding
AQ-coupled aryl acetamides, PM-coupled substrates usually
gave slightly higher cyclization yields and produced less of the
acetoxylated side product (see products 35 and 36).
Substrate 27 without a b-Me group was much less reactive
than 18 Val under the same reaction conditions (< 10%
conversion); in this case, no CÀN cyclized products were
generated, and the acetoxylation side product was formed in
less than 5% yield. Deuterium-exchange experiments per-
formed on 27 revealed that its b-methylene CÀH bonds were
readily deuterated within 1 h (ca. 40%), whereas the Me
[
19]
group was mostly unaffected [Eq. (8)]. Interestingly, the
tert-butyl-substituted acetamide 30 bearing three Me groups g
to the carbonyl group and no competing b CÀH bond cyclized
well even at a lower temperature (708C) to give 31 in good
[
20]
yield. This result indicates the relatively facile oxidation
and CÀN reductive elimination of the putative six-membered
palladacycle intermediate. Overall, both AQ- and PM-
3
Scheme 4. AQ-directed sequential C(sp )ÀH functionalization reac-
3
directed intramolecular g-C(sp )ÀH amination reactions
tions involving A) b methylation and g amination and B) g arylation
and g amination (benzylic CÀH). Reagents and conditions: a) MeI
proceeded well if the kinetic inertness of the initial g-CÀH
II/IV
palladation could be overcome effectively. A Pd
catalytic
(2 equiv), Pd(OAc) (10 mol%), AgOAc (2 equiv), (BnO) PO H
2 2 2
manifold is most likely operative for these CÀH lactamization
(
20 mol%), 2-methylbutan-2-ol, 1108C, 22 h; b) ArI (1.5 equiv), Pd-
OAc) (10 mol%), AgOAc (1.5 equiv), (BnO) PO H (20 mol%), 2-
methylbutan-2-ol, 1108C, 22 h. Bn=benzyl, Ts=p-toluenesulfonyl.
(
2
2
2
reactions. However, the underlying mechanism that favors the
CÀN over the CÀOAc reductive-elimination pathway is
[21]
unclear.
3
The utility of this intramolecular g-C(sp )ÀH amination
[
24]
reaction can be further improved when applied in conjunction
group, was also obtained from 48. Similar acetoxylated side
products were obtained in less than 5% yield for substrates
bearing an electron-deficient g arene group (e.g. 45).
3
with other AQ-directed C(sp )ÀH functionalization reactions
(
Scheme 4). For example, substrate 41 was readily methylated
at the b-methylene position with MeI (2 equiv) by our
Finally, we addressed the last critical issue regarding this
intramolecular CÀH lactamization method: removal of the
auxiliary group. Cleavage of the ArÀN bond under mild
3
previously reported palladium-catalyzed C(sp )ÀH alkylation
[
22]
procedure to give 42.
Compound 42 then underwent
cyclization at the g position to give 43 in moderate yield
under the standard CÀH amination conditions. Furthermore,
conditions is inherently difficult and has long restricted the
synthetic utility of many auxiliary-mediated CÀH functional-
b-substituted N-quinolylbutanamides, such as 10 Ile, can also
undergo CÀH monoarylation with ArI at the g position to
ization reactions. Inspired by the para-methoxyphenyl (PMP)
protecting group for amines, we envisioned that the installa-
tion of a methoxy group at the para and/or ortho positions of
the parent auxiliary groups could enable their removal with
give g-aryl butanamides (in this case 45 and 48) in good yield
under palladium catalysis in the presence of (BnO) PO H
2
2
[23]
[25]
(
Scheme 4B).
The resulting g-aryl butanamides can
ceric ammonium nitrate (CAN) under mild conditions.
undergo intramolecular CÀH amination at the 28 benzylic
CÀH position to form g-arylated pyrrolidinones in good yield
under the standard conditions. For example, compounds 46
and 49, which contain three contiguous stereogenic centers,
were obtained in good yield with excellent diastereoselectiv-
ity (Ar trans to the b substituent) from the corresponding
arylated Ile precursors. Interestingly, pyrrolidone 50, which
contains an additional ortho acetate functionality on the AQ
Among the five modified auxiliary groups tested (Sche-
me 5A), 8-amino-5-methoxyquinoline (MQ, 51) performed
best in both cyclization and deprotection steps. Compound 51
can be readily prepared in three steps from the commercially
available aniline precursor 56 through a sequence involving
a Skraup reaction, S Ar substitution with NaOMe, and
N
[
26]
reduction of the NO group to NH . The MQ group could
2
2
be installed readily on carboxylic acid substrates through
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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