Organic Letters
Letter
diverse cyclic frameworks, we envision that a α-iminol
rearrangement triggered by Pd-catalyzed C−H addition to
cyclobutanone derived O-acyl cyanohydrin sequence would be
feasible (Scheme 1b), in which the cleavage of C−O bond of
resultant tetrahedral intermediate I would deliver cyclobutane-
based α-iminol intermediate II with an activated functional
group (N-acyl group) and subsequently II undergoes 1,2-
carbon shift to afford the functionalized α-amino cyclo-
pentanone in an atom- and step-economic fashion. Moreover,
the readily availability and manipulation of reaction partners in
which heteroarenes are common feedstock chemicals, while
cyclobutanone-derived O-acyl cyanohydrins are readily pre-
pared from cyclobutanone derivatives, would enable this
transformation to access diverse α-fully substituted amino
cyclopentanones under redox-neutral and catalytic reaction
conditions, in contrast to well-established approaches of α-
amination of carbonyl compounds.10 Herein, we report this
preliminary work.
sequence proceeded more smoothly in the absence of HOAc
and furnished the desired product 3aa in excellent yield (entry
6). Further screening of Pd(II) catalysts and ligands revealed
that Pd(OAc)2/2,2′-bipyridine played a very important role in
this reaction, since other Pd(II) catalysts such as Pd(TFA)2,
Pd(acac)2, and PdCl2 did not afford any of the desired product
3aa at all in the presence of 2,2′-bipyridine, while Pd(OAc)2/
phen provided the desired product 3aa in slightly reduced yield
(entries 7−10). Decreasing the temperature led to the
dramatic reducing production of 3aa (entry 9). Both catalyst
and ligand are essential for this transformation, and removal of
either Pd(II) catalyst or ligand completely shut down the
reaction (entries 12 and 13) (for details see the Supporting
Information). It was noteworthy that further reducing the
loading of Pd(OAc)2/2,2′-bipyridine and the amount of N-
methylindole did not affect the efficiency of this trans-
formation, which provided product 3aa in the comparable
yield with that of Pd(OAc)2 (10 mol %)/2,2′-bipyridine (12
mol %) promoted reaction (entry 14).
With the optimized conditions in hand, the scope of the
reaction was investigated by employing various indoles 1 and
cyclobutanone-derived cyanohydrins 2 first (Scheme 2).
Except for N-unsubstituted and N-acetal indoles that were
ineffective, the benzyl group was compatible with the reaction,
providing the corresponding product 3ab in 94% yield. Then
the reactions between a broad range of N-methylindoles 2 with
1-cyanocyclobutyl benzoate 1a were examined. The sub-
stitution pattern and electronic nature of substitutions at the
benzene ring of the indole core were well tolerated and gave α-
indoyl-substituted α-amino cyclopentanones in high to
excellent yields (3af−3aj), except for 4-substituted indole
which gave the moderate yield (3ae), presumably due to the
steric hindered effect. Due to the ready availability and
manipulation of cyclobutanone-derived O-acyl cyanohydrins,
this transformation also can provide an efficient way to prepare
α-substituted amino cyclopentanones with diverse N-acyl
groups (R3) under the optimized reaction conditions. For
example, a range of N-acyl groups (R3) such as electron-rich or
electron-poor aromatic groups (3ba−3ha), heteroaromatic
groups (3ia−3ja), alkenyl (3ka), and linear alkyl (3la−3ma)
were well tolerated. However, O-branched alkylacyl cyanohy-
drin did not give the desired products (3na−3oa). In addition,
oxa- and azocyclobutane-based analogues were also examined.
It seemed that the reactions were sensitive to heteroatoms in
the cyclobutane ring. The reaction between the oxa-analogue
and 1a proceeded sluggishly under the optimized reaction
conditions, and an improved yield could be obtained with 10
mol % Pd(OAc)2 (3pa). N-Boc-substituted azo-analogue can
also give the desired product in good yield (3qa), while N-
benzhydryl analogue failed to deliver the desired product
(3ra).
Our investigation commenced with testing the feasibility of
this Pd-catalyzed C−H addition to nitrile/α-iminol rearrange-
ment sequences between 1-cyanocyclobutyl benzoate 1a and
N-methylindole 2a (Table 1) under the catalysis of Pd(OAc)2
a
Table 1. Optimal Reaction Conditions
b
T
yield of 3aa
entry
[Pd]
solvent
ligand additive (°C)
(%)
c
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(acac)2
PdCl2
NMP
DMA
NMA
THF
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
phen
bpy
bpy
HOAc
HOAc
HOAc
HOAc
HOAc
80
80
80
80
80
80
80
80
80
80
40
80
80
80
18
45
87
15
13
96
nd
nd
nr
87
9
nd
nd
95
c
2
cd
,
3
4
5
6
7
8
9
cd
,
c
toluene
NMA
NMA
NMA
NMA
NMA
NMA
NMA
NMA
NMA
10
11
12
13
14
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
e f
,
bpy
a
Reaction conditions: 1a (0.2 mmol), 2a (0.5 mmol), catalyst (10
b
mol %), and ligand (12 mol %) in solvent (c = 0.2 M). Isolated
yields. HOAc (40 mol %). 4a was obtained. Pd(OAc)2 (5 mol %),
bpy (6 mol %). 2a (0.4 mmol). bpy: 2,2′-bipyridine. phen: 1,10-
phenanthroline. NMA: N-methylacetamide. DMA: N, N-dimethyla-
c
d
e
f
cetamide.
Next different heteroarenes were surveyed (Scheme 3).
When N-methyl-2-phenylpyrrole was employed, the addition
of the 5- and 4-positions of the C−H bond of pyrrole to 1-
cyanocyclobutyl benzoate 1a was observed in the presence of
10 mmol % Pd(OAc)2 (6a and 6a′). 4-Pyrrolyl-substituted α-
amino cyclopentanone 6a′ was obtained in 46% yield as a
major product at the higher temperature. The reactions of 2-
substituted thiophenes and furan with 1a proceeded sluggishly
with 10 mmol % Pd(OAc)2 and provided 5-substituted
thiophenes or furan products in low yields (6b, 6c). No
reactions occurred when benzo[b]thiophene or benzofuran
(10 mol %)/2,2′-bipyridine (12 mol %) and HOAc (40 mol
%) in NMP at 80 °C, and the desired product 3aa was
obtained in 18% yield with low conversion (entry 1). The
evaluation on the influence of solvent was examined first
(entries 1−5). It turned out that NMA was the most effective
solvent for this transformation, while other solvents provided
inferior results, along with a small amount of bisindole adduct
4a as the byproduct. Unlike the previous results in which acid
promoted the Pd-catalyzed C−H addition to nitrile/cyclization
sequences,8a−d this Pd-triggered α-iminol rearrangement
1022
Org. Lett. 2021, 23, 1021−1025