Angewandte
Communications
Chemie
regardless of the steric hindrance. Moreover, heteroaryl-
sulfonyl azides, 1-naphthylsulfonyl azides, and alkylsulfonyl
azides were also amenable to this transformation and
produced the corresponding sulfonylamidation products 3j–
versatile synthetic units for assembling biologically active
molecules.
Several control experiments, as well as DFT studies
[13]
(Supporting Information), were designed to elucidate the
III
3
m in 63–75% yields.
plausible reaction mechanism for this Ir -catalyzed g-sulfo-
Subsequently, we prepared the 5- and 6-substituted
nylamidation of amidoalkanes (Scheme 2). It was found that
the treatment of N-butyl-benzamide (1s) with tosyl azide (2a)
under our standard conditions only provided the ortho-phenyl
pyridine-2-carboxylic acid butylamides, and found their
3
corresponding secondary Csp ꢀH sulfonylamidation efficien-
2
[14]
cies were still maintained, irrespective of the type of
substituents and the substituent positions on the pyridyl
rings (3n–3r). For example, 5-chloropyridine-2-carboxylic
acid butylamide and 5-nitropyridine-2-carboxylic acid buty-
lamide furnished the corresponding sulfonylamidation prod-
ucts 3o and 3q in 82% and 89% yields, respectively.
Csp ꢀH bond sulfonylamidation product (4) in 95% yield,
3
and no alkyl Csp ꢀH bond amidation product was observed
[Eq. (a)]. Moreover, the reaction of the amido N-blocked
pyridine-2-carboxylic acid dibutylamide (1t) with 2a did not
3
produce the corresponding alkyl Csp ꢀH bond amidation
product 5 [Eq. (b)]. These results clearly demonstrate that the
Finally, the scope of the present procedure with regard to
different types of N-amido alkanes has also been established
systematically. Compared with the N-n-butyl-substituted
amide (1a), the longer straight chain n-amyl amine-based
amide and N-n-hexyl amide was amenable to regioselective
installation of a secondary CꢀN bond into the g-position of
pyridyl group and amide nitrogen played a significant biche-
3
late-directing role in forming the remote secondary Csp ꢀN
bond.
the alkylamine moiety in 75% and 77% yields (3s and 3t),
respectively. We also observed that the intermolecular
3
secondary Csp ꢀH amidation of 3-aryl-propylamine amides
proceeded well to give yields of 52–89%, but an electron rich
phenyl ring from 3-(4-methoxylphenyl)-propylamine amide
made the reaction a little sluggish, possibly because the lower
3
pKa of the Csp ꢀH bonds benefits the nitrene insertion
(
compare 3w with 3x). We further performed Hammett
correlation studies with compounds 3u–3x, which showed
a linear free energy relationship (R = 0.99); the Hammett
constant sI and the value 1I was found to be + 0.28
(
Supporting Information, Figure S-14). This result is remark-
II
ably different to those described for Rh -catalyzed nitrene
3
insertion into activated Csp ꢀH bonds, in which the yields
[
10]
decrease with the electron deficiency of the substituents. To
our surprise, the present reaction was also applicable to an
alkenyl functional group containing amidoalkane, in which
[11]
the C=C double bond could be kept intact (3y, 55% yield).
Scheme 2. Preliminary mechanistic studies.
More importantly, in addition to the linear N-alkylamides, the
branched-chain N-alkylamides were also amenable to the
reaction, and furnished the desired g-sulfonylamido substi-
tuted alkanes in 32–81% yields (3z, 3az and 3bz), in which
On the other hand, when the H/D exchange of amide (1a)
III
was conducted in a Ir -CH CO D system at 608C for 24 h in
3
2
1
,3-cis-3z (cis/trans = 9:1) and 1,2-cis-3az (cis/trans = 1.2:1)
the absence of 2a, the degree of deuterium incorporation into
the alkyl chain of 1a was 0% [Eq. (c)]. Therefore, the
belong to the major products based on the combined NOE
[12]
3
NMR and DFT calculations. Furthermore, the scope of the
present procedure with regard to shorter carbon chains
substituted with N-alkylamide has also been evaluated, and
possibility of a bichelate-directed Csp ꢀH activation process
could be ruled out. DFT study also excluded the CꢀH
activation pathway, which has a high activation free energy of
3
ꢀ1
we were pleased to find that the unactivated Csp ꢀH bond
31.7 kcalmol (Supporting Information, Figure S-10). Sub-
amidation could also occur at the beta-position on the
amidoalkanes in acceptable yields (3cz and 3dz). Unfortu-
nately, N-cyclohexylamide was not allowed for this trans-
formation, possibly because of steric hindrance (3ez).
Further removal of the directing group and the newly
sequently, the competitive sulfonamidation of d-1k and 1k
with tosyl azide did not exhibit a kinetic isotope effect
[
15]
([Eq. (d)]; k /k = 1.1). Furthermore, a competitive inter-
H
D
3
molecular Csp ꢀH sulfonamidation between tosyl azides
differing in electronic effects implied that an electron-poor
azide tended to easily form iridium nitrene at a higher rate
[Eq. (e)]. Meanwhile, the kinetic experiments also indicated
that the concentration of tosyl azide governed the reaction
rate of the intermolecular amidation of N-alkyl amides with
azides (Supporting Information, Table S-7 and S-8). These
experiments further suggest that the formation of the metal-
3
introduced sulfonyl group from the Csp ꢀH amidation
product 3s allowed the construction of pentane-1,3-diamine
in a one-pot procedure, and the corresponding diamine could
be easily cyclized with glyoxylic acid and arylaldehyde to
afford good yields of 2-carboxyl- and 2-aryl-substituted
hexahydro-pyrimidines (Supporting Information), which are
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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