Organic Letters
Letter
incorporated at an elevated temperature as the pendant
substituent. This result implied that the gold-catalyzed N−C
bond formation between 1-azabutadiene 9i and the activated
propiolate induced the 6π-electrocyclization to form the
pyrazoline.
Scheme 5. Reaction Scope of 1,4-Dihydropyridine
formation
In parallel with our efforts on pyrazoline synthesis, we
attempted to exploit the potential of N-arylimines as simple
imine derivatives for autotandem Au-catalyzed reactions with
propiolates. As expected, the reaction of aryl imine 11a with
propiolate 2a proceeded with a 1:2 stoichiometry (one 11a to
two 2a molecules) in the presence of IPrAuCl and AgSbF6
(Scheme 4). Structural analyses revealed that the major
Scheme 4. Validation of Reaction Pathway for 1,4-
Dihydropiridine formation
product was fully substituted 1,4-dihydropyridine 13a. When
using XPhosAuNTf2,19 the reaction terminated at the aza-
enyne metathesis step to give 1-azabutadiene 12a, which could
be transformed into 13a by further exposure to the gold
catalyst. On the other hand, neither aza-enyne metathesis nor
annulation could proceed at all in the absence of the gold
catalyst. Thus, two distinct processes were catalyzed by a single
cationic gold autotandem catalyst, as in the case of pyrazoline
formation. After optimization of the autotandem catalysis
conditions for 1,4-dihydropyridine formation (see the
2a were converted into desired 13a (72%) in the presence of
was generated exclusively. The structures of the 1,2-
dihydropyridines were determined by comparison of their H
1
NMR spectra with that of 17x, the structure of which was
elucidated by X-ray crystallography. It is important to note that
the positions of the aromatic substituents (Ar2 and Ph) in 1,2-
dihydropyridines 17 are switched in 1,4-dihydropyridine 13,
indicating that 17 is not derived from 13 through a simple
isomerization of the double bond. Therefore, an independent
pathway for the formation of 1,2-dihydropyridines 17 should
be considered with a reasonable rationale for the observed
reaction outcome leading to 13 or 17 (vide infra).
20
IPrAuNTf2 at 65 °C within 24 h in THF (shown in Scheme
5).
With the optimal conditions in hand, we investigated the
scope and limitations of the transformation (Scheme 5). As for
Ar1, electron-rich or electron-deficient aryl groups were
introduced into the dihydropyridine nucleus in satisfactory
yields (13a−g). The substituent at the 3-position on the aryl
group did not influence the reaction efficiency (13b and 13h).
The structures were unambiguously determined by X-ray
crystallographic analyses of 13c and 13g. In particular, the
structure of 13g indicated that only the CN bond of the
imine was rearranged in the reaction. The propiolates
possessing not only electron-rich aromatic groups but also
halogenated or highly electron-deficient aromatic rings could
participate in the reaction (13a−p). Methyl tetrolate (R = Me)
gave the corresponding 2,5-dimehyl-1,4-dihydropyridine 13q
in satisfactory yield. Conversely, the electronic properties of
the aryl group on the imine carbon had a marked effect on the
reaction outcome (Ar2 scope in Scheme 5). While 11 with the
electron-donating group, phenyl, and sterically demanding β-
Naph groups uneventfully gave the 1,4-dihydropyridines 13r−s
in good yield, derivatives of 11 bearing electron-deficient
aromatic groups produced a mixture of 1,4-dihydropyridine
13t−v and 1,2-dihydropyridines 17t−v. Moreover, in the case
of a nitro-substituted aromatic ring, 1,2-dihydropyridine 17w
A plausible reaction mechanism is postulated in Scheme 6.
Propiolate 2 can be activated by cationic gold to generate 18,
which undergoes carbazate 8 (or imine 11) attack at the β-
position to give iminium 19.21 Then internal electron transfer
from vinyl Au to the iminium nitrogen of 19 generates
aziridine 20, which is rearranged to azetinium 21 with the
assistance of the electrophilic cationic gold carbenium
moiety.10a,22 The cationic gold catalyst is regenerated from
21 to give the azetine 22, the precursor for the 4π-ring opening
reaction23 that results in 1-azabutadienes 9 and 12. The
torquoselectivity in the ensuing 4π-ring opening step was
directed by the R substituents on the nitrogen atom in the
azetine 22. When R = −NHCO2Me (23), the stereoelectronic
effect dominates over the steric repulsion between R and R1,
and the lone pair on the exocyclic nitrogen atom stabilizes the
σ*N−C to accelerate outward selective ring opening and
generate 1-azabutadiene 9. 1-Azabutadiene 9 then attacks a
second molecule of 18 to yield 25, the subsequent
protodeauration of which gives ylide 26, which can be
smoothly isomerized into 27B via 27A. Finally, 6π-electro-
cyclization of the α,β-unsaturated hydrazone 27B and
subsequent isomerization of the pendant enamide moiety
3983
Org. Lett. 2021, 23, 3981−3985