Redox-Neutral Imination of Alcohol with Azide: A Sustainable Alternative to the Staudinger/Aza-Wittig Reaction

Article abstract of DOI:10.1021/acscatal.1c00379

The traditional Staudinger/aza-Wittig reaction represents one of the most powerful tools for imine formation. However, for this multistep procedure, the sacrificial phosphine has to be used, resulting in difficulties in the purification process and waste disposal at the same time. Here, we report a redox-neutral azide-alcohol imination methodology enabled by a base-metal nickel PN3 pincer catalyst. The one-step, waste-free, and high atom-economical features highlight its advantages further. Moreover, mechanistic insight suggests a non-metal-ligand cooperation pathway based on the observation of an intermediate and density functional theory calculations.

Full text of DOI:10.1021/acscatal.1c00379

pubs.acs.org/acscatalysis
Letter
Redox-Neutral Imination of Alcohol with Azide: A Sustainable
Alternative to the Staudinger/Aza-Wittig Reaction
Huaifeng Li,* Daniel Lupp, Pradip K. Das, Li Yang, Théo P. Gonca
̧ lves, Mei-Hui Huang,
Marwa El Hajoui, Lan-Chang Liang,* and Kuo-Wei Huang*
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ABSTRACT: The traditional Staudinger/aza-Wittig reaction
represents one of the most powerful tools for imine formation.
However, for this multistep procedure, the sacrificial phosphine
has to be used, resulting in difficulties in the purification process
and waste disposal at the same time. Here, we report a redox-
neutral azide−alcohol imination methodology enabled by a base-
metal nickel PN3 pincer catalyst. The one-step, waste-free, and
high atom-economical features highlight its advantages further.
Moreover, mechanistic insight suggests a non-metal−ligand
cooperation pathway based on the observation of an intermediate and density functional theory calculations.
KEYWORDS: imination, redox-neutral process, base-metal catalysis, atom and step economy, PN3 pincer
Scheme 1. Methods of Imine Synthesis with Organic Azides
mines are essential intermediates and precursors in the
Isynthesis of various dyes, pigments, polymers, natural
products, agrochemicals, and pharmaceuticals.1 The conven-
tional method for the synthesis of imines is the acid-catalyzed
condensation of aldehydes or ketones with amines. Recently,
several alternative approaches of imine synthesis have been
reported,1e such as oxidation of amines,2 oxidative or accept-
orless dehydrogenative coupling of alcohols and amines,2e,3
hydroamination of alkynes by amines,4 hydrogenative coupling
of nitriles and amines,5 transfer hydrogenative cross-coupling of
nitriles and alcohols,6 and hydrogenation of nitriles.7 Generally,
most of the methods for imine synthesis employ either an amine
or a nitrile as a nitrogen source, along with using stoichiometric
amounts of sacrificial oxidants or reductants.
Organic azides offer another alternative and fascinating
nitrogen source for the synthesis of various N-containing
compounds because of their versatile reactivity.8 Prominent
examples are the Schmidt reaction,9 Staudinger ligation,10 C−H
bond amination,11 and azide−alkyne cycloaddition.12 Con-
currently, a wide range of organic azides are readily available,
primarily due to the development of “click” azide−alkyne
cycloaddition. Despite these significant advances in azide
chemistry, to date, there are only a few methods on the use of
organic azides as the nitrogen source for imine synthesis. In this
regard, the classical Staudinger/aza-Wittig reaction, which starts
from an azide and a suitable phosphine, via iminophosphorane
formation, followed by the reaction with aldehydes or ketones,
has provided a powerful tool to prepare imines (Scheme 1a).13
However, the phosphine has to be used as a sacrificial reagent
during this multistep process. At the same time, the formation of
phosphine oxide byproduct leads to difficulties in the separation
and waste disposal.14 In addition to the traditional Staudinger/
aza-Wittig reactions,15 there are only two reports on the
transformation of azides to imines.16 Nevertheless, both of them
are limited to self-coupling of benzyl azides to the corresponding
Received: January 27, 2021
Revised: March 12, 2021
Published: March 17, 2021
© 2021 The Authors. Published by
American Chemical Society
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Letter
symmetric imines with narrow substrate scopes. Therefore, the
development of efficient, waste-free, and environmentally
benign synthetic methodologies for the imine synthesis using
readily available azides as the nitrogen source remains
challenging and attractive.
A highly desirable goal is the direct conversion of alcohols and
azides into imines without adding any external redox reagents
because it is a redox-neutral, waste-free, and highly atom- and
step-economical process (Scheme 1b). Furthermore, the use of
alcohols as reaction partners for this azide−alcohol imination
protocol are of highly practical advantage due to their availability
and stability compared to that of carbonyl compounds, which
might allow access to a great variety of imines from these very
simple substrates.3g,17 Herein, we describe such a redox-neutral
azide−alcohol imination reaction catalyzed by an abundant
base-metal nickel PN3 pincer complex, leading to various cross-
imines.
As part of our ongoing interest in the PN3(P) pincer
chemistry,18 the bipyridine- and phenanthroline-based PN3−Ni
pincer complexes Ni1, Ni2, and Ni3 (Figure 1) were synthesized
Figure 1. Bipyridine- and phenanthroline-based PN3−Ni pincer
complexes Ni1, Ni2, and Ni3.
readily by the treatment of NiCl2 with the corresponding pincer
ligands at 110 °C in toluene in high yields. The solid-state
structures of complexes Ni1, Ni2, and Ni3 were determined by
single-crystal X-ray diffraction crystallography. The Ni(II)
centers in the three complexes featured square-planar
coordination spheres with a meridional tridentate bipyridine-
based pincer ligand, one chloride ligand, and a non-coordinating
chloride anion. Similar geometrical parameters have been
observed in these three complexes, as well. While the Cl1−
Ni1−N2 angles are linear, the P1−Ni1−N3 angles are deviated
from linearity (Figure 2).
We began our catalytic studies for the azide−alcohol
imination reaction with benzyl alcohol (1a) and phenyl azide
(2a) as the model substrates to optimize the reaction conditions.
Unprecedented chemoselectivity was shown upon heating a
solution of 1a and 2a in the presence of Ni1 (2 mol %) and
KOtBu (8 mol %) in toluene at 130 °C for 24 h. N-
Benzylideneaniline (3a) was afforded as the major product
together with only a trace amount of the amidation product N-
phenylbenzamide (4a), albeit in a lower conversion (55%)
(Table 1, entry 1). A control experiment without the catalyst
resulted in no reaction under these conditions (Table 1, entry
2). A lower yield of 3a was observed when complex Ni2 was
employed as the catalyst (Table 1, entry 3).
Figure 2. X-ray structures of complexes Ni1, Ni2, and Ni3 at 30%
ellipsoid probability. Hydrogen atoms (except for pincer arms) are
omitted for clarity. Selected bond lengths (Å). Ni1: Ni1−Cl1
2.1843(1), C1−N1 1.335(3). Ni2: Ni1−Cl1 2.1348(2), C1−N1
1.363(3). Ni3: Ni1−Cl1 2.1470(8), C1−N1 1.358(3). Selected bond
angles (deg). Ni1: Cl1−Ni1−N2 179.79(1), P1−Ni1−N3 168.01(1).
Ni2: Cl1−Ni1−N2 177.26(1), P1−Ni1−N3 169.76(1). Ni3: Cl1−
Ni1−N2 179.43(8), P1−Ni1−N3 167.08(7).
The phenanthroline-based PN3−Ni pincer complex Ni3 also
demonstrated a lower catalytic reactivity, despite the high
selectivity in this transformation (Table 1, entry 4). Encouraged
by such unique catalytic performances, we carried out further
optimization to increase the conversion and yield. Changing the
solvent to p-xylene or benzene led to lower yields of 3a under
otherwise analogous conditions (Table 1, entries 5 and 6). In
contrast, the formation of amidation product 4a was favored
over formation of the imination product 3a at higher conversion
of 2a (83%) while using more polar solvent, THF (Table 1, entry
7). Notably, increasing the amount of 1a to 2 equiv under
otherwise identical conditions furnished the desired product 3a
in 71% yield at 77% conversion of 2a (Table 1, entry 8).
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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 CN 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
full characterization, see the Supporting Information). In
addition, the dearomatized complex Ni4 was found to still be
stable upon heating at 130 °C in toluene-d8 for 24 h as
determined by 31P NMR (see Supporting Information for more
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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Figure 4. Proposed catalytic cycle for the main reaction steps.
populating its starting point Ni5 as highly as possible, by
employing the 3-fold excess of alcohol, should facilitate the
reaction. The next step, TS6,7, is the insertion of the azide into
the Ni−H bond to form Ni7, which can expel nitrogen via the
water-mediated TS7,8 to form the amide complex Ni8.20 The
final step is a ligand exchange,21 liberating benzylamine and
coordinating benzylalkoxide (see the Supporting Information
for details). The formed amine reacts with the aldehyde to give
the imine and water. One interesting difference in this
mechanism is the absence of the rearomatization processes. In
other words, after the initial activation, the catalyst remains in its
“dearomatized” state throughout the reaction, presumably due
to the square-planar geometry combined with the bulky
phosphine ligand, effectively shielding the nitrogen linker.
In summary, we have developed a redox-neutral azide−
alcohol imination protocol catalyzed by an abundant base-metal
nickel PN3 pincer complex. Intermolecular and intramolecular
variants of this reaction were demonstrated, and a wide range of
imines were prepared. Compared with the traditional
Staudinger/aza-Wittig reaction, this one-step process generates
no waste, which circumvents the need for a sacrificial reagent.
Employing more available and stable alcohols as reaction
partners instead of carbonyl compounds constitutes another
attractive feature of our protocol. Therefore, this nickel-
catalyzed azide−alcohol imination process would provide a
straightforward and sustainable alternative to the traditional
Staudinger/aza-Wittig reaction. A plausible non-MLC catalytic
mechanism is proposed, supported by the observation of some
plausible intermediates and DFT studies. Further investigations
on the applications of this methodology are underway.
Figure 3. Synthesis of the complexes Ni4 and Ni5 and their X-ray
structures at 30% ellipsoid probability. Hydrogen atoms are omitted for
clarity. Selected bond lengths (Å). Ni4: Ni1−Cl1 2.1568(12), C1−N1
1.320(4). Ni5: Ni1−O1 1.8464(18), C1−N1 1.327(3). Selected bond
angles (deg). Ni4: Cl1−Ni1−N2 174.30(8), P1−Ni1−N3 164.67(10).
Ni5: O1−Ni1−N2 177.90(9), P1−Ni1−N3 165.22(6).
benzyl alcohol resulted in the formation of a new dearomatized
complex Ni5, whereas the expected rearomatization of the
pyridine ring of the PNN ligand did not occur. The shorter bond
length of C1−N1 (1.327 Å) in the X-ray structure of Ni5
1
together with its high-field signals of both H NMR and 13C
NMR spectra clearly demonstrated the dearomatic nature of the
pyridine moiety (Figure 3; for full characterization, see the
Supporting Information). When the reaction of 1a and 2a was
carried out with complex Ni5 as a catalyst under the optimal
reaction conditions (Table 1, entry 10) but without a base, the
imine product 3a could be obtained in 87% yield. These
observations, together with the results from density functional
theory (DFT) studies allowed us to suggest the non-MLC
catalytic cycle shown in Figure 4 (see Supporting Information).
The reaction of Ni4 to Ni5 was found to be reversible, and an
excess of alcohols was required to drive the equilibrium toward
formation of the dearomatized complex at approximately 83%
yield. This may explain why a 3-fold excess of alcohol is required
to maintain good conversions for this azide−alcohol imination
protocol. Starting from Ni5, the first step of the reaction is β-
hydrogen elimination to give benzaldehyde and the hydride
complex Ni6. Since TS5,6, the dehydrogenation of the
alcoholate, seems to be the step with the highest energy barrier,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.1c00379.
■
sı
Experimental procedures, characterization data, spectra of
new compounds (PDF)
X-ray structural information for Ni1 (CIF)
X-ray structural information for Ni2 (CIF)
X-ray structural information for Ni3 (CIF)
X-ray structural information for Ni4 (CIF)
X-ray structural information for Ni5 (CIF)
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AUTHOR INFORMATION
Corresponding Authors
■
Huaifeng Li − State Key Laboratory for Chemistry and
Molecular Engineering of Medicinal Resources, School of
Chemistry and Pharmaceutical Sciences, Guangxi Normal
University, Guilin 541004, China; Email: huaifengli@
gxnu.edu.cn
Lan-Chang Liang − Department of Chemistry, National Sun
Yat-sen University, Kaohsiung 80424, Taiwan; Department of
Medicinal and Applied Chemistry and School of Pharmacy,
Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
orcid.org/0000-0002-8185-2824; Email: lcliang@
mail.nsysu.edu.tw
Kuo-Wei Huang − Division of Physical Sciences and
Engineering, King Abdullah University of Science and
Technology, Thuwal 23955-6900, Saudi Arabia;
orcid.org/0000-0003-1900-2658; Email: hkw@
kaust.edu.sa
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Authors
Daniel Lupp − Division of Physical Sciences and Engineering,
King Abdullah University of Science and Technology, Thuwal
23955-6900, Saudi Arabia
Pradip K. Das − Division of Physical Sciences and Engineering,
King Abdullah University of Science and Technology, Thuwal
23955-6900, Saudi Arabia
Li Yang − Division of Physical Sciences and Engineering, King
Abdullah University of Science and Technology, Thuwal
23955-6900, Saudi Arabia
Théo P. Gonca̧ lves − Division of Physical Sciences and
Engineering, King Abdullah University of Science and
Technology, Thuwal 23955-6900, Saudi Arabia
Mei-Hui Huang − Division of Physical Sciences and
Engineering, King Abdullah University of Science and
Technology, Thuwal 23955-6900, Saudi Arabia
Marwa El Hajoui − Division of Physical Sciences and
Engineering, King Abdullah University of Science and
Technology, Thuwal 23955-6900, Saudi Arabia
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.1c00379
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support from the King Abdullah
University of Science and Technology (KAUST), the Ministry
of Science and Technology of Taiwan (MOST 109-2113-M-
110-004), Guangxi Natural Science Foundation of China (No.
2020GXNSFAA297213), and the State Key Laboratory for
Chemistry and Molecular Engineering of Medicinal Resources
(No. CMEMR2020-A12) in China. The service of Ibex,
Shaheen 2 High Performance Computing Facilities was
provided by KAUST.
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DEDICATION
■
This work is dedicated to Professor Tien-Yau Luh on the
occasion of his 75th birthday.
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