Angewandte
Communications
Chemie
In general, the associative relay pathway is difficult to identify
because of the tendency to embrace, even without much
evidence, the deceptively simple dissociative relay mecha-
nism. For example, the dissociative relay can be a perfectly
legitimate proposal for the [Ni{P(O-o-Tol)3}3]-catalyzed
alkene hydrocyanation reaction until proven otherwise, to
be, an associative dative relay event (Scheme 1c).[2] Herein,
through detailed mechanistic studies, we report an intriguing
example of associative covalent relay in the context of
À
transition
metal
catalyzed
C H
functionalization
(Scheme 1d).
À
Transition-metal-catalyzed, directed C H functionaliza-
tion has recently become an actively pursued step- and atom-
economic strategy for improving organic synthesis efficiency
(e.g., imine, oxime, amide, and phenol as directing groups for
[3–5]
À
alkenyl C H activation).
Despite the great success,
a typical synthetic protocol can only target either the
construction of molecular skeletons or the generation of
functional appendages, which are largely considered two
distinct domains of synthesis thus far. We are interested in the
merger of these two types of transformations into a single
synthetic scheme for the creation of broadly useful functional-
group-bearing molecular skeletons. In particular, our initial
targets of interest are azaheterocycles containing a syntheti-
cally versatile functionality, a primary amine. Simultaneous
installation of a strongly coordinating functionality along with
the generation of a molecular skeleton represents a significant
synthetic challenge because the strongly coordinating func-
tionality can, either alone or together with the directing
Scheme 2. Strategies for the synthesis of a) primary pyridinylamines
(reported herein) and b) pyridines and N-substituted 2-aminopyridines
À
(previous work) by C H activation.
We began our investigations by evaluating synthetic
conditions for a reaction between (E)-3-styryl-1,2,4-oxadia-
zol-5(4H)-one (1a) and 1,2-diphenylacetylene (2a). Initial
experiments suggest [{RhCp*Cl2}2] as an effective catalyst for
the synthesis of 3a (structure confirmed by single-crystal
X-ray analysis[10]) only in the presence of a base (KOAc,
NaOAc, or CsOAc; see the Supporting Information). The
yield is not substantially affected by a change of the type or
amount of the base. The reaction comes to a complete stop
with the participation of an acid additive (HOAc). The
reaction medium is critical as 1,4-dioxane gives a much higher
yield than other solvents (e.g., 1,2-dichloroethane, methanol).
Addition of a typical chloride abstraction reagent, AgSbF6,
provides no beneficial effect. Under the optimized reaction
conditions (5 mol% [{RhCp*Cl2}2], 50 mol% KOAc, 1,4-
dioxane, 808C, and 24 h), 3a could be obtained in 69% yield.
The high reactivity for oxadiazolone, as demonstrated
previously, ensures a broad substrate scope for both 1,2,4-
oxadiazol-5(4H)-ones and alkynes. For the former substrates
(Scheme 3), aryl substitution with both electron-donating
(1b, 1c, 1g, 1h) and electron-withdrawing groups (1d–f, 1i)
proves synthetically compatible. The synthetic efficiency can
be slightly compromised by the di- and trisubstitution (1j–n),
and an elevated temperature is generally required for the
achievement of sufficient reactivity. (E)-3-(2-(furan-2-
yl)vinyl)-1,2,4-oxadiazol-5(4H)-one (1o) is also a suitable
substrate for the transformation. For the latter substrates,
both electron-rich (2b, 2c, 2 f) and electron-poor (2d, 2e, 2g)
diarylalkynes can react in good yields. The synthesis is also
viable for di(thiophen-2-yl)acetylene (2h). The regioselectiv-
ity for the reaction involving an unsymmetrically substituted
alkyne is generally high (2i–p), and a variety of synthetically
versatile functional groups [alkene (2k), hydroxyl (2l),
aldehyde (2m), ester (2n–p)] can be installed in the respec-
tive target products. Importantly, (E)-3-(2-styrylvinyl)-1,2,4-
oxadiazol-5(4H)-one (1p) and (E)-3-(2-cyanovinyl)-1,2,4-
oxadiazol-5(4H)-one (1q) can react with 2p to allow the
incorporation of a non-aryl substituent at the C4 position.
À
group, interfere in the target C H activation process. We have
devised a cyclic surrogate strategy to address both the
transition-metal docking and functionality generation issues.
With this strategy, 1,2,4-oxadiazol-5(4H)-one (abbreviated as
oxadiazolone herein) has been used as an effective synthon
À
for cobalt(III)-catalyzed activation of aromatic C H bond
and synthesis of primary isoquinolinylamines.[6] As a further
demonstration of the utility of this handy structural motif, we
communicate herein the application of oxadiazolone in
synthetically more challenging yet highly useful alkenyl
À
C H activation for rhodium(III)-catalyzed synthesis of pri-
mary pyridinylamines (Scheme 2a).
Primary pyridinylamines are versatile intermediates for
diverse synthetically and pharmaceutically important com-
pounds but remain an elusive target based on transition metal
catalyzed C H functionalization reactions.[7] Indeed as
À
expected, virtually all of the pyridine synthesis protocols
developed thus far focused exclusively on the construction of
six-membered ring skeleton (Scheme 2b, left).[8] Only
recently has there been a documented synthetic effort
aimed at the preparation of amine-derivatized pyridines
(Scheme 2b, right).[9] The cumbersome reaction system for
the tandem approach, however, translates directly to several
inevitable drawbacks: 1) bulky substituent left intact on the
amino group, 2) synthetic restriction to secondary amine,
3) required use of an external oxidant, and 4) not being step
and atom economic. The plight calls for a revamping of the
synthetic scheme and oxadiazolone proves to be the ideal
choice for addressing the issues, which allows for efficient
synthesis of primary pyridinylamines.
2
ꢀ 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!
Yu, Xiaolong
