ACS Catalysis
Letter
a
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Catalytic Azide−Alcohol Imination Reaction
b
yield (%)
entry catalyst
solvent
T (°C) t (h) conv (%)
3a
53
4a
1
2
3
4
5
6
7
8
9
Ni1
toluene
toluene
toluene
toluene
p-xylene
benzene
THF
toluene
toluene
toluene
toluene
130
130
130
130
130
130
130
130
130
130
120
24
24
24
24
24
24
24
24
24
18
24
55
<1
48
48
40
45
83
77
trace
trace
<5
trace
<5
<5
51
<5
<5
c
trace
44
30
33
36
27
71
93
92
80
Ni2
Ni3
Ni1
Ni1
Ni1
Ni1
Ni1
Ni1
Ni1
d
e
>99
>99
87
e
e
10
11
<5
<5
a
[Ni] complex (0.02 mmol), 1a (1.1 mmol), 2a (1 mmol), KOtBu
b
(0.08 mmol), solvent (6 mL). Determined by 1H NMR spectroscopy
of the crude reaction mixture using CH2Br2 as the internal standard or
GC-MS. Without catalyst. 1a (2 mmol). 1a (3 mmol).
c
d
e
Complete conversion of 2a to selectively produce imine 3a in
93% yield took place when 3 equiv of 1a was applied (Table 1,
entry 9). The reaction time could be shortened to 18 h with a
comparable yield of 3a. However, when the reaction temper-
ature was lowered to 120 °C, the conversion of 2a was decreased
(Table 1, entries 10 and 11).
a
Ni1 complex (0.02 mmol), 1 (3 mmol), 2 (1 mmol), KOtBu (0.08
mmol), toluene (6 mL), 130 °C, 18 h. Yields determined by 1H NMR
spectroscopy using CH2Br2 as the internal standard or GC-MS, with
isolated yield in the parentheses and conversion of azide in square
Having identified the optimal reaction conditions, we next
explored the scope of our unprecedented redox-neutral azide−
alcohol imination protocol, and the results are summarized in
Scheme 2. Various aromatic azides bearing either electron-
donating or electron-withdrawing groups furnished correspond-
ing imines (3a−3g) in good to excellent yields, though the latter
required longer reaction times. Notably, halides were tolerated
in these cases, which could be very useful for further
transformations. This catalytic protocol could also be applied
to an array of benzyl azides. For example, the reaction of p-
OCH3, p-CH3, and p-CF3 benzyl azides with benzyl alcohol (1a)
proceeded efficiently to afford imine products (3i, 3j, and 3k).
The aliphatic azides such as cyclohexyl azide, n-butyl azide, and
n-pentyl azide were also found to be suitable substrates to give
the desired imine products (3l, 3m, and 3n) in moderate yields
for this Ni1-catalyzed azide−alcohol imination process, albeit
with a higher catalyst loading.
b
c
d
brackets. 36 h. 6 mol % of catalyst, 12 mol % of KOtBu. 10 mol %
e
of catalyst, 15 mol % of KOtBu. THF as solvent.
Ni1 was capable of catalyzing the intramolecular azide−alcohol
imination reactions in one step. Synthesis of five-, six-, and
seven- membered cyclic imines (3w, 3x, and 3y), which are
privileged structural motifs in many pharmaceuticals, was
demonstrated. However, secondary alcohols remain difficult
substrates for this methodology. Even with a higher catalyst
loading (10 mol %) and longer reaction time (36 h), the reaction
of 1-phenylethanol with phenyl azide or benzyl azide resulted in
the corresponding ketimines (3z and 3aa) in only 11 and 8%
yields, respectively. Additionally, changing the solvent to THF
under otherwise identical conditions gave only a slightly higher
yield of 3aa. The lower catalytic efficiency might be due to the
steric hindrance of the secondary alcohols.
Subsequently, we examined the substrate scope of this
transformation with respect to various alcohols (Scheme 2).
The substrates, benzyl alcohols, containing both electron-
donating and electron-withdrawing groups on the benzene rings,
reacted with phenyl azide (2a) under the catalytic condition to
give the desired imine products (3o−3t) in good to excellent
yields. Halogens were fully compatible with this Ni1-catalyzed
azide−alcohol imination process. It is also notable that aliphatic
alcohols such as 1-butanol and 1-pentanol smoothly underwent
imination reaction with phenyl azide (2a) to afford the desired
products (3u and 3v) in moderate yields when using higher
catalyst loading (6 mol %) and extending the reaction time. In
addition, the water formed during the course of the azide−
alcohol imination does not hinder the reaction.
To gain insight into this catalytic reaction mechanism,
complex Ni1 was reacted with BuOK in THF at room
t
temperature to provide the dearomatized complex Ni4, and its
structure was confirmed by X-ray diffraction (Figure 3). A
shortened C1−N1 bond length (1.320 Å) of Ni4 was observed,
consistent with formation of a CN double bond. Meanwhile,
the upfield shifts in both 1H NMR and 13C NMR spectra of Ni4
compared to those of aromatic complex Ni1 agree with the
anticipated dearomatization of the pyridine ring (Figure 3; for
addition, the dearomatized complex Ni4 was found to still be
stable upon heating at 130 °C in toluene-d8 for 24 h as
details). It has been demonstrated that the dearomatized
pyridine-based pincer complexes readily react with alcohols and
undergo aromatization via metal−ligand cooperation
(MLC).3g,19 Surprisingly, treatment of the complex Ni4 with
One of the most important applications of the multistep
Staudinger/aza-Wittig chemistry is the synthesis of N-hetero-
cycles via intramolecular reaction.13b To our delight, complex
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ACS Catal. 2021, 11, 4071−4076