Organic Letters
Letter
palladium-catalyzed allylic rearrangements could occur through
an N-allyl ketenimine intermediate. This approach would
provide a unique method for the synthesis of quaternary nitriles
bearing two independent allyl groups.8 More importantly, we
hypothesized that both allylic rearrangements could be
performed by a single palladium catalyst through two distinct
mechanisms, one π-allylic and one sigmatropic. Although the
uncatalyzed thermal ketenimine aza-Claisen rearrangement has
been previously reported,9 we reasoned that a catalyst-
accelerated variant could be developed. While electrophilic
Pd(II) complexes have been reported to promote a range of
sigmatropic rearrangements,10 these proceed via a π-Lewis
acidic pathway, requiring either a strongly nucleophilic
migrating group or a strongly electrophilic palladium π-Lewis
acid.11 Tunge has reported a suite of Pd-catalyzed π-allylic
rearrangements to form nitriles; these generate π-allyl
intermediates and nitrile α-anions in situ (via decarboxylative
and deacylative routes).12 While the use of protonated allyl
amines as π-allyl donors has been established,13 the activation of
neutral allyl amines has not been reported and represents a new
mode of reactivity. The rearrangement of butyl derivative 1a was
optimized with a Pd(OAc)2/BINAP catalyst system, with
Et2B(OMe) and N,O-BSA proving optimal (Table 1). Both
similar efficiency as 1a. This reaction provided quaternary nitrile
2o with high levels of linear regioselectivity.
As uncatalyzed sigmatropic ketenimine aza-Claisen rearrange-
ments were previously reported,9 we examined whether both
rearrangement reactions were indeed catalyzed by a single
palladium catalyst. Two distinct substrate classes were chosen,
with butyl (1a) and phenyl (1e) substrates being the focus of our
studies (Scheme 2). Deuterium-labeled analogues (3 and 4)
Scheme 2. Substrate Scope
Table 1. Optimization Studies
a
entry
change from optimized conditions
yield (%)
b
1
2
3
4
5
6
7
none
no N,O-BSA
72 (56 )
24
42
n.r.
32
n.r.
63
BEt3 instead of Et2B(OMe)
no borane (Et2B(OMe) or BEt3)
(S)-SEGPHOS as the ligand
Trost ligands (ANDEN or DACH)
Xantphos as the ligand
a
Determined by 1H NMR analysis with mesitylene as an internal
a
b
b
Average isolated yield over two reactions. The reaction was
standard. Isolated yield.
c
performed on a 1 mmol scale. Isolated as a 10:1 mixture of
regioisomers.
the N,O-BSA and Et2B(OMe) additives were crucial for high
efficiency. Et3B provided products in lower yield, and the
absence of borane led to no reaction. Other bidentate ligands,
such as SEGPHOS or Xantphos, were effective, whereas both
Trost ligand scaffolds led to no reaction.
were prepared in which CH2 was independently replaced with
CD2 at the N-allyl (3) and N-alloc (4) positions. These were
then subjected to the optimized reaction conditions, and the
position of the deuterium was tracked (Scheme 3a). When the
deuterated N-allyl analogues (3) were utilized, two reactivity
patterns were observed. The butyl substrate (3a) provided a
single regioisomer 5a with the deuterium exclusively at the
terminal vinylic position. With the phenyl analogue (3b),
deuterium scrambling was observed in a 5b:6b ratio of 1.2:1.
These results clearly demonstrate a divergence in mechanisms
between the two substrates (3a and 3b) and indicate that a
dissociative allylic pathway occurs for 3b that is not accessible to
3a. Of note is the slight excess of the terminal vinylic deuterium
isomer (5b). The origin of the selectivity in 3b could be
produced by either two competing (concerted and dissociative)
mechanisms or a secondary kinetic isotope effect in a rapidly
isomerizing (Curtin−Hammett) system. In the latter case, it
would suggest the facile formation of a π-allyl intermediate
followed by a higher-energy C−C bond-forming step with
Following optimization, we embarked on a substrate scope
study to examine the generality of the reaction. Quaternary
nitriles bearing unsubstituted alkyl groups (2a, 2b), highly
substituted alkyl groups (2c), and phenethyl (2d) were formed
in good yields. Aryl alkyne substrates (1e−m) were particularly
efficient for this reaction. Interestingly, there was little difference
in efficiency between aryl alkynes substituted by electron-neutral
(1e), σ-donating (1f, 1g), or σ-withdrawing (1h−j) groups.
When mesomeric π-withdrawing groups were present (1k, 1l),
enhanced reactivity was observed, and excellent yields of the
products were obtained. The use of polyaromatic-substituted
alkynes was demonstrated, with 2-naphthyl-substituted 1m and
the more hindered 1-naphthyl analogue 1n reacting with similar
reactivity. Substitution at R2 could also be tolerated, with 1o
bearing a cinnamyl-substituted N-alloc group reacting with
560
Org. Lett. 2021, 23, 559−564
Alexander, Juliana R.
