Reactions 04 00007 v2

reactions
Review
A Brief Review: Advancement in the Synthesis of Amine
through the Leuckart Reaction
Qasim Umar and Mei Luo *
Department of Chemistry and Chemical Engineering, Hefei University of Technology, Hefei 230002, China
* Correspondence: luomei@pku.edu.cn; Tel.: +86-18256000981
Abstract: This review presents a summary of reactions that take place during the “Leuckart-type
reaction”. The significance of, as well as recent advancements in, the synthesis of amines through
simple and inexpensive methods using readily available raw materials is discussed. This review
includes all catalytic and noncatalytic reactions that involve the Leuckart method. Recent studies have
shown that at least a quarter of C–N bond-forming reactions in the pharmaceutical industry are occur
with the support of reductive amination. Recently, experimental conditions have achieved excellent
yields. The “Leuckart-type reaction” is technically associated with Eschweiler–Clarke methylation.
Compounds are grouped in accordance with the precept of action. This includes drugs affecting the
central nervous system, cardiovascular system and gastrointestinal tract; anticancer drugs, antibiotics,
antiviral and antifungal drugs; drugs affecting anxiety; convulsant, biotic, and HIV drugs; and
antidiabetic drugs. Therefore, this review supports the development of the Leuckart-type preparation
of nitrogenous compounds, as well as their advancement in other areas of human development.
Keywords: Leuckart-type reaction; synthesis of amines; catalytic and noncatalytic reaction;

Leuckart method
1. Introduction
1.1. Background
Citation: Umar, Q.; Luo, M. A Brief
The Leuckart reaction is a process commonly known for its use in the reductive
Review: Advancement in the
amination of aldehydes and ketones [1–4]. The Leuckart reaction is a very famous and
Synthesis of Amine through the
Leuckart Reaction. Reactions 2023, 4,
unique method used for the synthesis of amines and one-pot reductive amination [5–7].
117–147. https://doi.org/10.3390/
In 1885, Leuckart first discovered this reaction, and as a result of his experimental work,
reactions4010007 he concluded that heating a mixture of benzaldehyde and formamide results in the produc-
tion of various kinds of benzalamine, instead of his sought product. Wallach explained the
Academic Editor: Annamaria
preliminary steps of the reaction [8], and Ingersoll and his colleagues used this reaction
Deagostino
in the preparation of a series of substituted α-phenethylamine compounds. As a result,
Received: 31 October 2022 this method has been widely used and become well known. The most famous applications
Revised: 17 January 2023 of this method include the preparation of “trimethylamine” from NH3 , “formaldehyde”
Accepted: 24 January 2023 and “formic acid”, and the “Eschweiler–Clarke” method for the methylation of 1◦ and 2◦
Published: 29 January 2023 amine [3]. Recently, this reaction has been used to synthesize a large number of amines and
useful drugs [8].
Nitrogen heterocycles exhibit various organic and pharmacological activities due to
their similarities to many herbal and artificial molecules with acknowledged biological
Copyright: © 2023 by the authors.
activity [9]. Thus, they play a key role in the synthesis of “polyamides”, “polyureas”,
Licensee MDPI, Basel, Switzerland.
and “polyepoxydes”, which are all useful in automotive, aerospace, building and health
This article is an open access article
applications [10]. Reductive amination plays an important role in pharmaceutical and
distributed under the terms and
medicinal chemistry. According to research performed by Roughley et al. a quarter of C–N
conditions of the Creative Commons
bond-forming reactions in pharmaceutical applications are carried out using the reductive
Attribution (CC BY) license (https://
amination method [11]. Thus, reductive amination has attracted much attention throughout
creativecommons.org/licenses/by/
4.0/).
the 20th century [12]. Reductive amination in the presence of formic acid is called the
Reactions 2023, 4, 117–147. https://doi.org/10.3390/reactions4010007 https://www.mdpi.com/journal/reactions

Reactions 2023, 4 118
“Leuckart Wallach reaction”, wherein formic acid serves as a reducing agent by supplying
a hydride ion [13]. This reaction is also known as the “Leuckart reaction”, sometimes called
“Leuckart reductive amination”, “Leuckart alkylation”, “Leuckart synthesis” or “Leuckart
reduction”. It requires a carbonyl-containing center and a formamide reagent. It has been
reported that using a formamide instead of an ammonium format produces good yields,
and ammonium formate is the prime reactant. A “Leuckart-type reaction” is not affected
by the presence of water (other than formamide). Similarly, at a lower reaction temperature,
a higher yield of 2◦ amine can be obtained by reacting with a higher concentration of
“formic acid”. However, the concentration of formic acid at high reaction temperatures
is not as effective as that at low temperatures [4]. According to Roughleg’s analysis of
reactions used in the production of medicines, 25% of C–N bond-forming reactions include
“reductive aminations”. Common reducing agents that influence “reductive amination”
include NaBH4 , NaBH3 CN”, and NaBH(OAc)3 , and more precise operations include the
“Leuckart” and “Eschweiler–Clarke reactions” [14]. The use of formic acid as a “reducing
agent” has already been well explored for its use in mono-catalytic reductive amination,
i.e., the Leuckart–Wallach and Eschweilar–Clarke reactions [15].
Very recently, the reductive amination of “carbonyl compounds” has been very effec-
tive in synthesis because ketones or aldehydes are convertible into the corresponding alkyl
amines in a single reaction step. Compared with previous methods, the LW reaction is easy
and clean. It achieves higher productivity and high purity [16]. When ammonium formate
or formamide is used as a reducing agent, reductive amination is called the “Leuckart
reaction” [17]. This reaction appears to be very suitable for the “stereoselective synthesis”
of (amine precursors), i.e., “bicyclic amines”, “amino alcohols”, and “diamines”, all of
which have numerous uses in pharmaceuticals and in asymmetric synthesis [18]. The
“Leuckart-type reaction” is particularly recognized for the conversion of certain aldehydes
and ketones and their derivatives into amines. It is a form of amination reaction that
involves the transformation of carbonyl groups to amines through intermediate carbon
double-bond nitrogen groups of compounds (imine compounds), sometimes called Schiff
bases. It is considered a simple and important method for the synthesis of amines, and
most of the pharmaceutical industry uses this method to produce amines. This reaction
requires a mixture of carbonyl compounds and formate or amine in the presence of heat [3].
The “Leuckart reaction” has two types [17], including indirect reductive amination, in
which the imine is separated from the product of the corresponding carbonyl compound
and amine and reduced with a suitable reducing agent to obtain the “corresponding
amine” (Scheme 1a), and direct reductive amination (Scheme 1b) or the “one-pot reaction”,
wherein the intermediate imine is not separated, but a “reducing agent” is added to the
same reaction tank to form a carbonyl compound and amine [17]. “Leuckart’s reaction”
was not widely used as a preparation method until 1936, when Ingersoll and colleagues
developed a procedure with high yields derived from various ketones. Novelli showed
that under similar experimental procedures, N-alkyl formamide was able to achieve a
comparable secondary amine yield on some alternative acetophenones when using the
same experimental method [19].
3
tions 2023, 4, 3
(a)
(a)
(b)
(b)
Scheme 1. Mode of reductive amination. (a) Indirect reductive amination. (b) Direct reductive
amination.
Scheme 1. Mode of reductive amination. (a) Indirect reductive amination. (b) Direct reductive
Scheme 1. Mode of reductive amination. (a) Indirect reductive amination. (b) Direct
amination. reductive amination.
1.2. Related Reactions
1.2. Related Reactions
1.2. Related ReactionsThis reaction correlates to the “Eschweiler–Clarke methylation” reaction [20].
This reaction correlates to the “Eschweiler–Clarke methylation” reaction [20]. Primary
Primary and secondary amines are aminated into tertiary amines. When the ketone is
and secondary
This reaction correlates
replaced to amines
by formaldehyde,
are aminated into tertiary amines.
the “Eschweiler–Clarke
the “Eschweiler–Clarke
When the ketone
methylation”
reductive”
is replaced
reaction
alkylation [20].by takes
of amines
formaldehyde, the “Eschweiler–Clarke reductive” alkylation of amines takes over [13,21].
Primary and secondary Someamines
over [13,21]. are aminated
Some reactions
related related reactions into
are given inare tertiary
given
(Figure amines.
1).in (Figure 1). When the ketone is
replaced by formaldehyde, the “Eschweiler–Clarke reductive” alkylation of amines takes
over [13,21]. Some related reactions are given in (Figure 1).
Figure
Figure 1. 1. Leuckart’s
Leuckart’s relatedrelated reactions.
reactions.
The Eschweiler–Clarke process is the reductive methylation of primary and

secondary amines using formaldehyde and formic acid [17].
Figure 1. Leuckart’s
1.3. related reactions.
Mechanism
The Eschweiler–Clarke process is the reductive methylation of primary and secondary

Reactions 2023, 4, amines using formaldehyde and formic acid [17].
1.3. Mechanism
The “Leuckart-type reaction” process can be divided into two random steps (Figure 2),
namely, the formation
cyclohexenes inofan
N–C bonds andto
attempt theestablish
reduction ofan intermediates by formic
appropriate acid. The
mechanism [23]
◦
maximum rate of reaction was observed at 166–169 C [22]. Musseron studied the effects of
for the reaction
formamide, N-mono andwas proposed by Wallach
N,N-dialkylformamides and reiterated
on cyclopentanones by Crossley
and cyclohexenes in an
Courtois,
an Daviesan
attempt to establish and Rogersmechanism
appropriate proposed that
[23]. Thein this reaction,
mechanism the primary
for the reaction
was proposed by Wallach and reiterated by Crossley and Moore. Doevre, Courtois, Davies
of formamide on the carbonyl center [24]. The formed base can rea
and Rogers proposed that in this reaction, the primary step is the attack of formamide on
compounds
the carbonyl centerto[24].
yieldTheadditional
formed base products.
can react with These arecompounds
carbonyl then reducedto yieldby form
and react with more formamide to form salts or amides. Thesemore
additional products. These are then reduced by formic acid to amines and react with conversio
formamide to form salts or amides. These conversions seem to be the only transitions
only transitions related to the formation of tertiary amines by fo
related to the formation of tertiary amines by formats or formyl derivatives of carbonyl
derivatives
compounds of carbonyl
and secondary aminescompounds
[3]. and secondary amines [3].
Figure
Figure 2. Leuckart’s
2. Leuckart’s reaction reaction
two randomtwo random
steps. steps.
However, the first objection to these proposed mechanisms is to the acceptance of
formamideHowever, the first
as a nucleophile objection
for the carbonyl to these
group proposed
of the mechanisms
substrate, and the claim of is to
the reduced nucleophilic toxicity achieved with amines. The
formamide as a nucleophile for the carbonyl group of the substrate, second objection is to the an
suggestion of transferring the hydride from the nitric acid formed in the reaction [25].
reduced nucleophilic
First, formic acid and ammonia toxicity achieved
are formed with amines.
by the dissociation of ammonium Theformate
second ob
suggestion
(hygroscopic of transferring
crystalline solid). Due to the
thehydride
existence offrom
a lonethe
pair,nitric
ammonia acid
(anformed
electron- in the
rich species) acts as a nucleophilic attacker on carbonyl carbon, and the hydroxyl form, such
First, formic acid and ammonia are formed by the dissociation of am
as oxygen, deprotonates hydrogen from nitrogen. Since hydrogen ions are a good leaving
(hygroscopic
group crystalline
(OH2 ), this hydroxyl groupsolid). Duemolecules
allows water to the existence
to be used byofthe
a lone pair, amm
protonated
rich species)
hydrogen acts
from formic asResonance-stable
acid. a nucleophilic attacker ionization
carbon-positive on carbonyl(RRNH2C+)carbon,
forms,and th
which provide more space for unoccupied electrons, reduce the energy of the molecule and
such as oxygen, deprotonates hydrogen from nitrogen. Since hydroge
form a more stable molecule in addition to having high energy. Carbon dioxide and amines
leaving
are formed by group (OH
the attack ), thisacid
of 2formic hydroxyl group
[8]. As formic acid isallows
added towater molecules
formamide, the to
yield can be improved
protonated over that obtained
hydrogen with ammonia
from formic acid.andResonance-stable
formic acid reagents showncarbon-po
in (Scheme 2) [5].
(RRNH2C+) forms, which provide more space for unoccupied elect
energy of the molecule and form a more stable molecule in addition to ha
Carbon dioxide and amines are formed by the attack of formic acid [8].
added to formamide, the yield can be improved over that obtained w
formic acid reagents shown in (Scheme 2) [5].
protonated hydrogen from formic acid. Resonance-stable carbon-positive ionization
(RRNH2C+) forms, which provide more space for unoccupied electrons, reduce the
energy of the molecule and form a more stable molecule in addition to having high energy.
Carbon dioxide and amines are formed by the attack of formic acid [8]. As formic acid is
added
Reactions 2023, 4 to formamide, the yield can be improved over that obtained with ammonia and 121
formic acid reagents shown in (Scheme 2) [5].
NH2
H3C CH3 CO2 H2O

propan-2-amine
Scheme 2. MechanismScheme Mechanism of thereaction”.

of the 2.“Leuckart-type “Leuckart-type reaction”.
1.4. Kinetic Study of the Leuckart–Wallach Reaction

1.4. Kinetic Study of the Leuckart–Wallach Reaction
Ostovari and Zahedi in 2018 successfully identified all stationary points of a five-step
mechanism,
Ostovari and Zahedi which
in 2018 included identified all stationary points of a five-step
successfully
(i) Dissociation of ammonium formate into HCOOH and NH3 ;
mechanism, which included
(ii) Nucleophilic attack of ammonia on the carbonyl carbon;
(i) Dissociation of(iii)
ammonium formate into HCOOH and NH3;
Dehydration;
(ii) Nucleophilic attack of ammonia
(iv) Trans on the carbonyl
to cis isomerization carbon;
of the formic acid;
(iii) Dehydration; (v) Formation of amphetamine by the reduction of the produced 1-phenyl propane-2-
(iv) imine. The reaction is
Trans to cis isomerization of the formic acid;spontaneous, and the reaction kinetics are of the first order [26].
(v) Formation of amphetamine

2. Significance ofbythethe reduction Reaction
Leuckart-Type of the produced 1-phenyl propane-2-
imine. The reactionSince
is spontaneous,
the beginningand the reaction
of medical science,kinetics
scientistsare
andof the first
chemists order
have tried[26].
to synthe-
size or extract pharmaceutically active compounds to benefit mankind and protect the
natural
2. Significance of the environment, Reaction
Leuckart-Type ultimately promoting a safe and healthy human life and reducing
the chance of disease. In modern medicinal chemistry, “amines” are the most essential
Since the beginning of medical
building blocks. In both science, scientists
pure and applied and the
chemistry, chemists
synthesishave tried
of 2◦ and to
3◦ amines is
synthesize or extractbecoming
pharmaceutically
increasingly active compounds
significant. to benefit
Synthetic chemists have mankind
paid closeand protect
attention in recent
years to the
the natural environment, functional procedures
ultimately promoting usedafor the production
safe and healthyof tertiary
humanamines, owing
life andto their
wide range of uses in catalysis [17]. The “Leuckart-type reaction”
reducing the chance of disease. In modern medicinal chemistry, “amines” are the most is a characteristic one-pot
reaction method that has been widely used for the production of a variety of products,
essential building blocks. In both pure and applied chemistry, the synthesis of 2° and 3°
including medicinally useful compounds such as 1◦ , 2◦ , and 3◦ amines. For example, the
amines is becoming“Leuckart-type
increasingly reaction”
significant. Synthetic
is used to producechemists have paid
“abemaciclib”, close attention
“cyclin-dependent kinase in-
in recent years to the functional
hibitor”, procedures
“bromantane used
analogues”, for the production
“1H-pyrrolo”, and “quinolineof tertiary amines,
derivatives”. These have
owing to their wide range of uses in catalysis [17]. The “Leuckart-type reaction” is a
characteristic one-pot reaction method that has been widely used for the production of a
variety of products, including medicinally useful compounds such as 1°, 2°, and 3°
amines. For example, the “Leuckart-type reaction” is used to produce “abemaciclib”,
antibiotic activities and anti-inflammatory effects and can also be used to treat pain failure
and reduce fever [8]. Additionally, this method appears to be suitable for the production of
aromatic aldehydes and water-insoluble ketones. For this reaction, ammonium formate or
formamide is not limited, and methyl formate has been used with some primary amines.
Substituted ammonium formate, such as monomethyl ammonium or dimethyl ammonium
formate, will react satisfactorily and lead to the formation of mixed secondary and ter-
tiary amines that cannot be easily obtained by other methods [3]. The isocyanide-based
multicomponent reaction (IMCR) is one of the most commonly used chemical reactions
for increasing molecular diversity. Isocyanates are usually made in two stages, beginning
with primary amines. The Leuckart–Wallach reaction produces isocyanide with greater
variability [27]. Chiral, enantiomerically pure vicinal diamines and their derivatives have
been increasingly used in asymmetric catalysis reactions. One of the classic methods used
for the synthesis of amine derivatives is the “Leuckart–Wallach reaction”, which is based
on the reductive amination of carbonyl compounds with a mixture of formamide, formic
acid, or ammonium formate. In all cases, the final product is a formamide derivative, which
can then be reduced or hydrolyzed in an alkaline or acidic medium to obtain the desired
free amine [28]. The Leuckart–Wallach reaction, which yielded almost exclusively anomers
with Z-configurations, and then isocyanide. These represent a fascinating class of sugar
and organic moiety chimeric compounds with important applications in medicine and
with great potential for drug discovery. In the case of D-glucose, the method’s stereose-
lectivity is notable, as enantiomeric D-glucose is commonly used [29]. For many years,
the “Leuckart-type reaction” has been the most popular method used for the synthesis of
illicit amphetamines in the United States, the United Kingdom, and the Netherlands. The
reductive amination of benzyl methyl ketone is very important, and in Sweden and the
United States, the nitro propene route is used, similar to the phenyl oxime route used in
the United States. The Leuckart route was also used for the synthesis of amphetamine [30].
Many studies have shown that amines contain most of the MDMA-HCl contaminants. As a
result, extraction appears to be more effective in alkaline environments [31–33].
The Leuckart reaction is the most common route used to produce the amphetamine-
type stimulant ATS [34–36] and to synthesize thiophenols [37], as well as N-alkylaminom-
ethylanthracenes [38]. Amines are universal and valuable compounds in synthetic chem-
istry, with a wide range of applications in organic catalysis, organometallic complexes [39],
organocatalysis in organic synthesis [40], biological processes, and the pharmaceutical
chemistry [41]. The reductive amination of carbonyls is one of the most popular processes
used for making amines [42,43]. Numerous legal methods for the synthesis of amphetamine
have been reported, including Hofmann, Curtius, and Schmidt rearrangements, heteroge-
neous reduction, Friedel–Crafts alkylation, the Henry reaction, Knoevenagel condensation,
the Ritter reaction, and the Leuckart–Wallach reductive amination reaction. However,
due to the simplicity, speed and safety of the procedure, characterized high efficiency, the
Leuckart–Wallach is more useful [26,30]. A prominent example of the Leuckart reaction is
its use in the synthesis of tetrahydro-1,4 benzodiazepin-5-one, a molecule that is part of ben-
zodiazepine [6]. Many compounds in this family are central nervous system suppressants
and are associated with therapeutic uses and a variety of medications, such as antibiotics,
antiulcer, and anti-HIV agents. Researchers have synthesized tetrahydro-1,4-benzodiazepin-
5-ones with excellent yields and high purity by utilizing the Leuckart reaction, and they
have performed the reaction via solid-phase synthesis using formic acid as the reduc-
ing agent [6]. The “Leuckart-type reaction” provides a useful way to prepare numerous
formamides, amines, and bulky compounds that are pharmaceutically useful. In 2018,
Skachilova et al. first synthesized 5-(N-piperidine)-1-arylpentan-1-ones, and then, using a
modified Leuckart method, synthesized 5-(N-piperidine)-1-aryl-1-aminopentanes [22]. In
2017, Frederick et al. successfully synthesized abemaciclib via the Leuckart reaction [44,45].
The synthesis process of some important drugs through the Leuckart reductive method is
summarized and given below.
2.1. Synthesis of Animated Graphene and Amphetamine

The “Leuckart-type reaction” was used to reduce graphite oxide (Scheme 3). This work
ctions 2023, 4, reported the first use of the “Leuckart-type reaction” to reduce GO and obtain animated
graphene [46]. Barba, Recio, and Batanero (2013) reported that, when formamide is used in
the reaction, N-formyl derivatives of amines can be obtained instead of free amines [25].
The most popular synthetic drug type in Europe is amphetamine-type substances, a cat-
ctions 2023, 4, egory which includes amphetamine (shown in Scheme 4), methamphetamine, and 3,4-
7
methylenedioxymethamphetamine (MDMA). Hauser et al. (2020) used the “Leuckart-type
reaction” pathway, the most commonly used method for synthesizing amphetamine [47].
Scheme 3. Possible structures of GO and rGO-Am.
Scheme
Scheme 3. Possible 3. Possible
Scheme
structures of GOstructures
3. Possible structures
and of GOand
of GO
rGO-Am. and rGO-Am.
rGO-Am.
Scheme 4. Synthesis of amphetamine through the LW method.
2.2. Synthesis of Tetrahydro-1,4-benzodiazepine-5-one and Arylamine

SchemeIn 2006,
Scheme
Lee and
4. Synthesis
4. Synthesis
Park
ofthrough synthesized
ofamphetamine
amphetamine through
through
tetrahydro-1,4-benzodiazepine-5-one
thethe
LW LW method.
method.
(Scheme
Scheme 4. Synthesis of amphetamine the LW method.
(a member of the benzodiazepine family) through a “Leuckart-type reaction” using
2.2. Synthesis of Tetrahydro-1,4-benzodiazepine-5-one and Arylamine
2.2. Synthesis ofsingle
2.2. step instead
Synthesis of the multiple steps Arylamine
of Tetrahydro-1,4-benzodiazepine-5-one
Tetrahydro-1,4-benzodiazepine-5-one
In 2006, Lee and Park synthesizedand
previouslyand reported
Arylamine [48,49]. It can be used as
tetrahydro-1,4-benzodiazepine-5-one (Scheme 5) (a
antibiotic,
In 2006,anti-ulcer,
Lee andand Park anti-HIV agent.tetrahydro-1,4-benzodiazepine-5-one
synthesized Sung Chen li et al. introduced bromoacetal re
In 2006, Lee and member
Parkofsynthesized
the benzodiazepine family) through a “Leuckart-type reaction”
tetrahydro-1,4-benzodiazepine-5-one using a5)single(Scheme
(Scheme
as a solid support for the in situ generation of iminium intermediates during the acidoly
(a member of (athemember
step of of
instead
benzodiazepine the
thebenzodiazepine
multiple
family) steps family)
previously
through through
reported
a “Leuckart-type a It“Leuckart-type
[48,49]. can be used as
reaction” reaction”
an antibiotic,
using a usin
cleavage
singleofstep step,
anti-ulcer, andwhich
instead anti-HIV increased
ofsteps agent.
the multiple Sungthe product
Chen
steps li et al. and scope
introduced
previously of the
bromoacetal
reported LWresin
[48,49]. reaction
as
Itascana be used asT
solid [46].
single step instead the multiple previously reported [48,49]. It can be used an
“Leuckart-type
support for the
antibiotic, reaction”
anti-ulcer, offers aof fast
in situ generation
and anti-HIV andintermediates
iminium
agent. convenient
Chen li etmethod for synthesizing
during the acidolytic cleavage vario
antibiotic, anti-ulcer, and
step, anti-HIV
which increasedagent.
the Sung Chen
product and li etSung
scope al.the
of introduced
LW reaction
al. introduced
bromoacetal
[46]. The
bromoacetal
resin
“Leuckart-type
re
formamides
as afor
solid (an important class of compounds in synthesis) [50], amines, and lar
as a solid support thesupport
reaction”in situ for theand
offersgeneration
a fast in convenient
situ generation
of iminium offor
iminium
intermediates
method intermediates
during
synthesizing during the
the acidolytic
various formamides (an acidoly
numbers of biologically active compounds and pharmaceuticals. New 5-(N-piperidin
cleavage step,cleavage
which step,class
important
increased which
ofthe increased
compounds
product the scope
product
in synthesis)
and [50],of and
amines,
the andscope
LW large ofnumbers
reaction the [46].
LW reaction
of biologically
The [46]. T
1-arylpentan-1-one
active compounds and
and 5-(N-piperidine)-1-aryl-1-amino
pharmaceuticals. New pentane
5-(N-piperidine)-1-arylpentan-1-onesynthesizing6)vario
(Scheme and w
“Leuckart-type“Leuckart-type
reaction” offers reaction”
a fast and offers a fast and
convenient convenient
method method for various
for synthesizing
synthesized [22].
5-(N-piperidine)-1-aryl-1-amino pentane (Scheme 6) were synthesized [22].
formamides
formamides (an important(an important
class of compounds class ofincompounds
synthesis) [50], in synthesis)
amines, [50],
and large amines, and la
numbers ofactive
numbers of biologically biologically
compounds activeand compounds and pharmaceuticals.
pharmaceuticals. New 5-(N-piperidine)-New 5-(N-piperidin
1-arylpentan-1-one and 5-(N-piperidine)-1-aryl-1-amino
1-arylpentan-1-one and 5-(N-piperidine)-1-aryl-1-amino pentane (Scheme 6) were pentane (Scheme 6) w
synthesized [22].synthesized [22].
Scheme 5. Synthetic
Scheme route
5. Synthetic routeofoftetrahydro-1,4 benzodiazepin-5-one.
tetrahydro-1,4 benzodiazepin-5-one.
Scheme
Scheme 5. Synthetic 5. of
route Synthetic route ofbenzodiazepin-5-one.
tetrahydro-1,4 tetrahydro-1,4 benzodiazepin-5-one.
Scheme 5. Synthetic route of tetrahydro-1,4 benzodiazepin-5-one.
Reactions 2023, 4, 8
Scheme 6. Synthesis
Synthesis of
of 5-(N-piperidino)-1-phenyl-1-aminopentanones.
5-(N-piperidino)-1-phenyl-1-aminopentanones.
2.3. Synthesis of 4-methylthioamphetamine (4-MTM), (PMMA) and Heterocycles

2.3. Synthesis of 4-methylthioamphetamine (4-MTM), (PMMA) and Heterocycles
Dariusz Bachut et al. (2012) experimentally proved that 4-methylthioamphetamine can
Dariusz Bachut et al. (2012) experimentally proved that 4-methylthioamphetamine
be obtained via the
can be obtained via Leuckart
the Leuckartmethod [51].
method J. Kochana
[51]. et et
J. Kochana al. al.
(2003) explained
(2003) explainedthe
thesynthesis
of
synthesis of PMMA obtained by the Leuckart method (Scheme 7). They can be dividedinto two
PMMA obtained by the Leuckart method (Scheme 7). They can be divided
groups
into two(Scheme 8) [52]. 8) [52].
groups (Scheme
Scheme 7.
Scheme 7. Chemical
Chemical structures
structures of
of PMMA,
PMMA, substrates
substrates of
of Leuckart
Leuckart synthesis,
synthesis, and
and synthesized
synthesized markers.
markers.
Reactions 2023, 4 Scheme 7. Chemical structures of PMMA, substrates of Leuckart synthesis,
125and syn
markers.
trifluoromethylbenzyl ketone
Scheme
Scheme under
Synthesis
8. 8. ofLeuckart–Wallach
Synthesis l-methyl and/orand/or
of l-methyl reaction conditions (Scheme 9).
3-hydroalkylmethyl-1,3-heterocycles.
3-hydroalkylmethyl-1,3-heterocycles.
However, they did not 2.4. find any ofamines
Synthesis in the
Trifluoromethyl product
Alcohol [53–56]. Neochoritis et al. (2015)
and Isocyanides
2.4. Synthesis
Vasiliy M. of Trifluoromethyl
proposed that through the reductive amination reaction of
Muzalevskiy et al. Alcohol
(2008) studiedand Isocyanides
formamide
a new experimentaland
method formic acid, a
for preparing
trifluoromethanol from
Vasiliy M.(Scheme tert-butoxy-b-(trifluoromethyl)
Muzalevskiy can et al.be (2008) styrene and trifluoromethylbenzyl
studied a [56].
new experimental met
variety of oxygenated ketone
isocyanates
under Leuckart–Wallach10) synthesized
reaction conditions (Scheme 9). However, Neochoritis,
they did not
preparing trifluoromethanol from tert-butoxy-b-(trifluoromethyl) styren
Zhang, et al. (2015) introduced a short
find any amines and
in the convenient
product method
[53–56]. Neochoritis for(2015)
et al. theproposed
synthesis of glycosyl
that through the
reductive amination reaction of formamide and formic acid, a variety of oxygenated iso-
and arabinosyl isocyanides, directly from sugar, via a two-step modified Leuckart–
cyanates (Scheme 10) can be synthesized [56]. Neochoritis, Zhang, et al. (2015) introduced
Wallach procedure [29].a short and convenient method for the synthesis of glycosyl and arabinosyl isocyanides,
directly from sugar, via a two-step modified Leuckart–Wallach procedure [29].
(a)
(b)
(c)
Scheme 9. (a) Synthesis of Scheme
tert-butoxy-b-(Trifluoromethyl) styrene. (b)
9. (a) Synthesis of tert-butoxy-b-(Trifluoromethyl) Synthesis
styrene. of of
(b) Synthesis trifluoromethyl
trifluoromethyl
alcohols. (c) Preparation ofalcohols. (c) Preparation of trifluoromethyl alcohols via trifluoromethyl ketones.
trifluoromethyl alcohols via trifluoromethyl ketones.
Br
(c)
Reactions 2023, 4 Scheme 9. (a) Synthesis of tert-butoxy-b-(Trifluoromethyl) styrene. (b) Synthesis of trifluoromethyl 126
alcohols. (c) Preparation of trifluoromethyl alcohols via trifluoromethyl ketones.
Br
HN O
N O
NH2 O
F N
R1 R2
O N
O L.W procedure NHCHO N
R1 R2 H
R1 R2 N
Meo O
Br Meo
NC
R1 R2
O
O N
O N O
H
N
N
Reactions 2023, 4, H 10
N
Cl
Scheme
Scheme 10. Synthesis
10. Synthesis of isocyanides
of isocyanides directly
directly fromfrom the sugar
the sugar viaLeuckart–Wallach
via the the Leuckart–Wallach reaction.
reaction.
2.5. Synthesis of cis- and trans-l-Methyl-2,5-diphenylpyrrolidines

In 1972, Brkukr and Melumad synthesized a mixture of cis- and trans-l-benzoyl-2-
In 1972, Brkukr and Melumad synthesized a mixture of cis- and trans-l-benzoyl-2-
phenylcyclopropane (Scheme 11) from the reaction of two compounds, benzylacetophenone
phenylcyclopropane (Scheme 11) from the reaction of two compounds,
benzylacetophenone and dimethylsulfoxonium methylidene, in the presence of catalytic
quantities of magnesium chloride for 25 h. Two products were obtained with 50% yield
[57].
Scheme 10. Synthesis of isocyanides directly from the sugar via the Leuckart–Wallach reac

In 1972, Brkukr and Melumad synthesized a mixture of cis- and trans-l-ben
phenylcyclopropane (Scheme 11) from the reaction of two comp
benzylacetophenone and dimethylsulfoxonium methylidene, in the presence of c
quantities of magnesium
and dimethylsulfoxonium chloridein for
methylidene, 25 h. Two
the presence products
of catalytic wereofobtained
quantities magnesiumwith 50
[57].
chloride for 25 h. Two products were obtained with 50% yield [57].
Scheme
Scheme 11.11. of cis- and
Synthesis
Synthesis of trans-l-methyl-2,5-diphenylpyrrolidines
cis- and trans-l-methyl-2,5-diphenylpyrrolidines using the L
using the Leuckart method.
method.
2.6. Synthesis of Racemic Tert-Leucine and Polyether Amines and PPGs
Brian M. Adger et al. (1997) used the Leuckart reaction method of reduction for the
2.6. Synthesis
synthesis of Racemic
of tert-leucine Tert-Leucine
(Scheme and Polyether
12). This method Aminescompared
is more favorable and PPGsto previous
methods dueM.
Brian to the need et
Adger foral.
high-pressure
(1997) used hydrogenation
the Leuckart or the use of environmentally
reaction method of reduction
ctions 2023,
ctions 2023, 4,
4, unfriendly reagents [58]. Kulyk et al. (2020) used the Leuckart reaction (with CO2 and H2 O
synthesis of tert-leucine (Scheme 12). This method is more favorable comp
as the only byproducts), which appeared to be more environmentally friendly than other
previous methods
routes for the aminationdue to the need
of polypropylene for(PPGs)
glycols high-pressure
(Scheme 13) hydrogenation
[59]. or the
environmentally unfriendly reagents [58]. Kulyk et al. (2020) used the Leuckart r
(with CO2 and H2O as the only byproducts), which appeared to be more environm
friendly than other routes for the amination of polypropylene glycols (PPGs) (Sch
[59].

Scheme ofofracemic
12. Synthesis racemic tert-leucine from
tert-leucine from trimethylpyruvic.
trimethylpyruvic.
Scheme 13. Optimization

Scheme 13. Optimizationof
ofthe Leuckart–Wallach
the Leuckart–Wallach reductive
reductive amination
amination reaction.reaction.
2.7. Synthesis of Tertiary Amines

2.7. Synthesis of Tertiary Amines
The Eschweiler–Clarke process is based on the reductive methylation of primary and
The Eschweiler–Clarke
secondary process isand
amines using formaldehyde based on acid.
formic the reductive
Araminta De methylation of primary
et al. established in a
secondary amines
2018 that, using both
by modifying formaldehyde and formic
amines and aldehydes, it is acid. Araminta
feasible De etofal.
to make a range established
tertiary
2018 amines (Scheme
that, by 14) [17]. both
modifying Smith and John McDonnell
amines (1950) investigated
and aldehydes, the preparation
it is feasible to make ofa range
triamide, and Bonnet and Max also reported this work with slight modifications. They did
tertiary amines (Scheme 14) [17]. Smith and John McDonnell (1950) investigated t
not use excessive amounts of formic acid or other catalysts, such as magnesium chloride,
preparation of triamide,
and achieved good resultsand Bonnet and
[60]. Abbruscato and Max
Trippier also reported
(2018) found thatthis work with slig
amphetamine,
modifications.
synthesizedThey did
through thenot use excessive
Leuckart method, is amounts of formic
a better stimulant [35].acid or other catalysts, su
as magnesium chloride, and achieved good results [60]. Abbruscato and Trippier (20
found that amphetamine, synthesized through the Leuckart method, is a better stimula stimul
[35].
The formation of mono-methylated (R2NMe) or dimethylated amines (RNMe2):
modifications. They did not use excessive amounts of formic acid or other catalysts, such
as magnesium chloride, and achieved good results [60]. Abbruscato and Trippier (2018)
found that amphetamine, synthesized through the Leuckart method, is a better stimulant
[35].
Chemoselective Synthesis of Tertiary Amines
Scheme 14. Synthesis of tertiary amines.

Scheme 14. Synthesis of tertiary amines.
2.8. Synthesizing a 12β-Amino Derivative of Allopregnanolone
2023, 4, 2.8. Synthesizing a 12β-Amino Derivative of Allopregnanolone
Slavikova et al. (2013) reported
Slavikova Leuckart–Wallach’s
et al. (2013) reductivereductive
reported Leuckart–Wallach’s amination for the
amination for the pro-
production of a 12β-amino
ductionderivative of allopregnanolone
of a 12β-amino (Scheme (Scheme
derivative of allopregnanolone 15) [61].15) [61].
SchemeScheme 15. Synthesis

15. Synthesis of 12β-amino derivative
of 12β-amino derivativeof allopregnanolone.
of allopregnanolone.
2.9. Synthesis of Abemaciclib, Chiral Bis and Racemic Methamphetamine
2.9. Synthesis of Abemaciclib,
Reizman Chiral Bis
et al. (2019) reported thatand Racemic Methamphetamine
the Leuckart–Wallach reaction of aldehyde and
ethyl piperazine leads to the synthesis of abemaciclib (LY2835219) (Scheme 16) [62]. In 2011,
Reizman
Wilckens, et al. and
Lentz, (2019) reported
Czekelius that applied
successfully the Leuckart–Wallach
the LW reaction methodreaction of aldehy
to synthesize
ethyl piperazine leads17)to[63].
chiral Bis (Scheme theInsynthesis of abemaciclib
2018, Abbruscato (LY2835219)
and Trippier reported (Scheme
the synthesis of 16)
racemic methamphetamine (Scheme 18) from a phenyl-2-propanone
2011, Wilckens, Lentz, and Czekelius successfully applied the LW reaction me precursor using the
Leuckart method [35].
synthesize chiral Bis (Scheme 17) [63]. In 2018, Abbruscato and Trippier repo
synthesis of racemic methamphetamine (Scheme 18) from a phenyl-2-pro
precursor using the Leuckart method [35].
2.9. Synthesis of Abemaciclib, Chiral Bis and Racemic Methamphetamine
Reizman et al. (2019) reported that the Leuckart–Wallach reaction of aldehyde and
ethyl piperazine leads to the synthesis of abemaciclib (LY2835219) (Scheme 16) [62]. In
2011, Wilckens, Lentz, and Czekelius successfully applied the LW reaction method to
synthesize chiral Bis (Scheme 17) [63]. In 2018, Abbruscato and Trippier reported the
synthesis of racemic methamphetamine (Scheme 18) from a phenyl-2-propanone
precursor using the Leuckart method [35].
ctions 2023, 4, 13
Scheme 16. Synthesis of chiral bis (tetrahydroisoquinoline).

Scheme of chiral
Scheme 17.bis tetra-hydro
17. Synthesis chiralisoquinoline.
ofofchiral
Synthesis bis tetra-hydro
bis tetra-hydro isoquinoline.
isoquinoline.

Scheme of racemic
Scheme methamphetamine.
18. Synthesis ofofracemic
18. Synthesis racemic methamphetamine.
methamphetamine.
2.10. Synthesis of Hydro naphthylamines

2.10. Synthesis of Hydronaphthylamines
Hydronaphthylamines (Scheme 19) are ubiquitous structural motifs that widely exist in
Hydronaphthylamines (Scheme
Hydronaphthylamines
natural products, 19) are(Scheme
ubiquitous
pharmaceuticals, and19) structural
are motifs
ubiquitous
biologically active that widely
structural
molecules, exist
and motifs
the LW that widely ex
reaction
in natural products, suffers from its harsh
pharmaceuticals,
in natural products, reaction conditions,
and biologically
pharmaceuticals, multiple
andactive steps, andactive
molecules,
biologically narrow substrate
the LWscope
andmolecules, and the L
when synthesizing such compounds [64]. The monoterpene amine bornylamine was first
reaction suffersreaction
from itssuffers
harsh from
reaction conditions,
its harsh multiple
reaction steps,multiple
conditions, and narrow substrate
steps, and narrow substr
scope when synthesizing
scope whensuch compounds
synthesizing such[64]. The monoterpene
compounds [64]. The amine bornylamine
monoterpene amine bornylami
was first synthesized
was first by Leuckart in
synthesized by 1887 through
Leuckart the reaction
in 1887 through of thecamphor
reaction andof camphor a
formamide, and then, by the
formamide, andreduction
then, by ofthecamphor
reduction oxime by Forster
of camphor in 1898.
oxime However,
by Forster in 1898. Howev
Hydronaphthylamines (Scheme 19) are ubiquitous structural motifs that widely exis
in natural products, pharmaceuticals, and biologically active molecules, and the LW
reaction suffers from its harsh reaction conditions, multiple steps, and narrow substrat
scope when synthesizing such compounds [64]. The monoterpene amine bornylamin
was first synthesized by Leuckart in 1887 through the reaction of camphor and
synthesized by Leuckart in 1887 through the reaction of camphor and formamide, and
formamide,
then, and then,ofby
by the reduction the reduction
camphor oxime byofForster
camphor oxime
in 1898. by Forster
However, withinthe1898. However
recent
with the recent preparation of terpene amines by reducing oximes, the “Leuckart-typ
preparation of terpene amines by reducing oximes, the “Leuckart-type reaction” and the
reaction”amination
reductive and the reductive
reaction amination reaction
of carbonyl-containing of carbonyl-containing
terpene compounds have shown good terpen
potential [65].
compounds have shown good potential [65].
Scheme 19.Synthesis
Scheme19. Synthesisof hydronaphthylamines.
of hydronaphthylamines.
2.11.
2.11. Synthesis
Synthesis of
of N-Alkylated-l,
N-Alkylated-l, 2-Phenylethylamine
2-Phenylethylamine and and Some
Some High-MW
High-MW Compounds
Goodson, Wiegand,and
Goodson, Wiegand, andSplitter
Splitter (1946)
(1946) synthesized
synthesized 12 novel
12 novel substituted
substituted 1,2-
1,2-phenyl-
phenylethylamine
ethylamine compounds compounds that all
that were were all produced
produced usingusing the “Leuckart-type
the “Leuckart-type reaction”
reaction” [66].
[66]. The “Leuckart-type
The “Leuckart-type reaction”
reaction” has beenhasfruitfully
been fruitfully
applied applied to someofketones
to some ketones of high
high molecular
molecular weight to give the corresponding amines [67]. Ingersoll
weight to give the corresponding amines [67]. Ingersoll and coworkers successively studied and coworkers
successively
the behaviorstudied the behavior
of 1,5-diketones whenof 1,5-diketones when used
used to synthesize to synthesize
1,5-diamines 1,5-diamines
in relation to the
in relation toformate–formamide
ammonium the ammonium formate–formamide reagent et
reagent [68]. Afanasyev [68].
al. Afanasyev
(2019) used et drug-type
al. (2019)
used drug-type
molecule molecule diversity-oriented
diversity-oriented synthesis (DOS), synthesis
which can(DOS),
improve which can improve
the synthesis the
of useful
drug-like compounds
synthesis with a high
of useful drug-like degree ofwith
compounds molecular
a highdiversity.
degree of Leuckart-type reactions
molecular diversity.
were successfully
Leuckart-type applied
reactions werehere to synthesize
successfully polyheterocyclic
applied scaffolds
here to synthesize in high yields
polyheterocyclic
with excellent stereo- and regioselectivity [11]. Jaekel and Antonietti
scaffolds in high yields with excellent stereo- and regioselectivity [11]. Jaekel (2021) usedand
the
Leuckart reagent to achieve reactivity towards the reductive amination
Antonietti (2021) used the Leuckart reagent to achieve reactivity towards the reductiveof carbonyl groups
in celluloseof
amination chains during
carbonyl a one-step
groups method for
in cellulose the preparation
chains of cationic
during a one-step nanocellulose
method for the
seen in (Scheme
preparation 20) [54].
of cationic nanocellulose seen in (Scheme 20) [54].
Scheme
Scheme 20.
20. Reduction
Reduction of
of cellulosic
cellulosic carbonyl.
carbonyl.
2.12. Enantiospecific
2.12. Enantiospecific Synthesis
Synthesis
Garcia Martinez
Garcia Martinez et et al.
al. (1999)
(1999) reported
reported experiments
experiments on
on the
the formation
formation of
of rearranged
rearranged
(1S,2S)-N-(3,3-dimethyl-2-carboxamideamino-1-norbornyl) acetamide, and according
(1S,2S)-N-(3,3-dimethyl-2-carboxamideamino-1-norbornyl) acetamide, and according to to
Garcia Martinez et al. (1999), no alcohol is created during the reduction process
Garcia Martinez et al. (1999), no alcohol is created during the reduction process (Scheme
(Scheme 21) [69].
21) [69].
2.12. Enantiospecific Synthesis
Garcia Martinez et al. (1999) reported experiments on the formation of rearranged
(1S,2S)-N-(3,3-dimethyl-2-carboxamideamino-1-norbornyl) acetamide, and according to
Reactions 2023, 4
Garcia Martinez et al. (1999), no alcohol is created during the reduction process (Scheme
131
21) [69].
Scheme 21. Enantiospecific synthesis.

Scheme 21. Enantiospecific synthesis.
3. Recent Advancement
The “Leuckart-type reaction” has been fruitfully applied to some ketones of high
molecular weight, producing the corresponding amines that are desired for pharmacody-
namics and chemotherapeutic studies [67]. It has also been suggested that an alternative
approach to “primary” and “secondary” alkyl ammonium formats may involve reducing
imines formed from the loss of water in carbonyl ammonia [70]. As formic acid is added to
formamide, the yield can be improved over that obtained with ammonia and formic acid
reagents [5]. The yield is affected by the temperature at which condensation is carried out,
and the yield was twice that achieved at 160–170 ◦ C and twice that at 190–200 ◦ C [5]. The
higher alkyl-substituted ammonium format is more difficult to condense with ketones, and
it may be desirable to use higher temperatures in these reactions [5]. However, using a 6.6%
NaOH solution or concentrated HCl also significantly affected the yield [5].
3.1. Catalytic Advancement

3.1.1. Rh(III) Complex Catalysis
In recent years, many catalytic systems used for the reductive amination of carbonyls
to synthesize C–N bonds have been reported [71–75]. However, only a few precious
metal (e.g., Rh, Ru, and Ir) catalytic systems have been reported for the Leuckart-type
reductive amination of carbonyl compounds that have usually using ammonium formate or
formamide as a nitrogen source [76–78]. Additionally, noble metal catalysts have achieved
acceptable results in “Leuckart-type reactions”, and it is desirable to replace them with non-
noble metals (e.g., Cu, Ni, Co, Fe, and Mn) to reduce the overall production costs. However,
it is a major challenge to eliminate the defects of non-noble metals in organic synthesis,
such as inferior catalytic activity, poor selectivity, thermal instability, metal agglomeration,
and easily reaction with acid [79–81]. Kitamura et al. (2002) applied the Cp*Rh(III) complex
to catalyze the reductive amination of ketones, using the ammonium format at 50–70 ◦ C
to give the relevant 1◦ amines in a 99% yield (Scheme 22) [16]. Senthamarai et al. (2018)
reported the synthesis of a class of amines by Ru-catalyzed reductive amination with
H2 , starting with carbonyls and NH3 [82]. In 2003, Kadyrov and Riermeier successfully
investigated rhodium-catalyzed asymmetric reductive amination with hydrogen as the
Cp*Rh(III) complex to catalyze the reductive amination of ketones, using the amm
format at 50–70 °C to give the relevant 1° amines in a 99% yield (Scheme 2
Senthamarai et al. (2018) reported the synthesis of a class of amines by Ru-ca
reductive amination with H2, starting with carbonyls and NH3 [82]. In 2003, Kady
Reactions 2023, 4 Riermeier successfully investigated rhodium-catalyzed asymmetric reductive 132 am
with hydrogen as the reducing agent, and a highly active and enantioselective c
system was constructed (Scheme 23) [83]. Santos et al. (2013) identified th
reducing agent, and
combination a highly
of an active and
aldehyde or enantioselective
ketone with catalytic system was constructed
a 2° amine-free base in the pres
(Scheme 23) [83]. Santos et al. (2013) identified the direct combination of an aldehyde
“ammonium tetra fluoroborate”, “ammonium perchlorate”, or “ammonium hex
or ketone with a 2◦ amine-free base in the presence of “ammonium tetra fluoroborate”,
phosphate” as a high-yielding
“ammonium perchlorate”, “one-pot
or “ammonium procedure”
hexa fluoro foras
phosphate” the preparation“one-
a high-yielding of a wide r
iminium
pot saltsfor
procedure” (Scheme 24) [84].
the preparation of aTo manage
wide the
range of chemoselectivity
iminium salts (Scheme via reductive
24) [84]. To am
manage the chemoselectivity via reductive amination, Tanaka et al.
Tanaka et al. (2019) used formic acid and formate salts as potential hy (2019) used formic acid
and formate salts as potential hydrogen replacements. Kitamura and coworkers reported
replacements. Kitamura and coworkers reported that using ammonium formate
that using ammonium formate instead of ammonia in the transfer of hydrogenative DRA is
aofhighly
ammonia
selectiveinmethod
the transfer of hydrogenative
for the preparation DRA in
of primary amines is the
a highly
presenceselective
of catalyticmethod
preparation
amounts of primary
of [Cp*RhCl 2 ]2 [85].amines in the presence of catalytic amounts of [Cp*RhCl2]
ctions 2023, 4, 16
Scheme 22. Reductive amination of acetophenone using a Cp*Rh(III) catalyst.

Scheme 22. Reductive amination of acetophenone using a Cp*Rh(III) catalyst.
Scheme Scheme
23. Asymmetric reductive amination withwith
hydrogen using a rhodium catalyst.
23.Asymmetric
Scheme23. Asymmetricreductive amination
reductive amination hydrogen
with using
hydrogen ausing
rhodium catalyst. catalyst.
a rhodium
“One-pot preparation of iminium salts”

“One-pot preparation of iminium salts”
Scheme 24. One-pot Leuckart-type preparation of amines.

Scheme 24. One-pot Leuckart-type preparation of amines.
Scheme
3.1.2. 24. Complex
Ir(III) One-pot Leuckart-type preparation Iridium
Catalysis (Half-Sandwich of amines.
Complexes)
3.1.2. Ir(III) Complex Catalysis
Dai et al. (2021) (Half-Sandwich
identified Iridium
a series of Ir(III) Complexes)
complexes bearing an amidato bidentate
3.1.2. Ir(III) Complex Catalysis (Half-Sandwich Iridium Complexes)
ligand capable of catalyzing the “Leuckart–Wallach reaction”
Dai et al. (2021) identified a series of Ir(III) complexes bearing withan
high efficiency,
amidato and at-
bidentate
Daiasymmetric
tempted et al. (2021) identified a series
transformations of Ir(III)
with several complexes
chiral bearing(Scheme
Ir(III) complexes an amidato bidentate
25) [86].
ligand capable of catalyzing the “Leuckart–Wallach reaction” with high efficiency, and
ligandet capable
Falus al. (2011)ofexplored
catalyzing the method
a useful “Leuckart–Wallach
for the reductivereaction” with
amination of high efficiency,
ketones. The and
attempted asymmetric transformations with several chiral Ir(III) complexes (Scheme 25)
attempted asymmetric transformations with several chiral Ir(III) complexes (Scheme 25
[86]. Falus et al. (2011) explored a useful method for the reductive amination of ketones.
[86]. Falus et al. (2011) explored a useful method for the reductive amination of ketones
The methods use ammonium formate as the hydrogen source, but the application of Zn
dust or a 10% Pd/C-catalyst (Scheme 26) in methanol makes the Leuckart method
smoother and generally more favorable [87].
3.1.2. Ir(III) Complex Catalysis (Half-Sandwich Iridium Complexes)
Dai et al. (2021) identified a series of Ir(III) complexes bearing an amidato bidentate
ligand capable of catalyzing the “Leuckart–Wallach reaction” with high efficiency, and
attempted
Reactions 2023, 4 asymmetric transformations with several chiral Ir(III) complexes (Scheme 25) 133
[86]. Falus et al. (2011) explored a useful method for the reductive amination of ketones.
methods use ammonium formate as the hydrogen source, but the application of Zn dust or
a 10% Pd/C-catalyst (Scheme 26) in methanol makes the Leuckart method smoother and
smoother and generally generally more favorable[87].
more favorable [87].
17
s 2023, 4, 17
O H2NOH·HCl
NOH
Scheme 25. Asymmetric reductive amination with Ir(III) Zn Dust
complexes. NH2
Scheme 25. Asymmetric reductive amination with Ir(III) complexes.
R R HCOONH4, MeOH R R reflux 5 hr R R
O H2NOH·HCl
NOH Zn Dust NH2
R R HCOONH4, MeOH R R reflux 5 hr R R
Scheme 26. Reductive amination of ketones in a packed-bed continuous-flow reactor at 40 °C and a

0.2 mL/min flow rate.
Scheme 26. Reductive amination of ketones in a packed-bed continuous-flow reactor at 40 ◦ C and a
Polishchuk
Scheme 26. etmL/min
al. (2021)
0.2 Reductive
catalyzed
flowamination
rate.
Leuckart–Wallach
of ketones (NH4COOH) reactor
in a packed-bed continuous-flow using at half-
40 °C and a
sandwich iridium complexes
0.2 mL/min flow rate. bearing bidentate urea–phosphorus ligands in order to
Polishchuk et al. (2021) catalyzed Leuckart–Wallach
catalyze the direct reductive amination of aromatic and aliphatic (NH 4 COOH) using half-sandwich
ketones under mild
iridium complexes bearing bidentate urea–phosphorus ligands in order to catalyze the
conditions atPolishchuk
0.5 mol% loading, with high
et al.amination
(2021) selectivity
catalyzed towards primary
Leuckart–Wallach amines
(NH 4COOH) (Scheme
using
direct reductive of aromatic and aliphatic ketones under mild conditions at half-
27) [78].sandwich 0.5 iridium complexes
mol% loading, with highbearing
selectivitybidentate urea–phosphorus
towards primary amines (Schemeligands
27) [78]. in order to
catalyze the direct reductive amination of aromatic and aliphatic ketones under mild
conditions at 0.5 mol% loading, with high selectivity towards primary amines (Scheme
27) [78].
Scheme
Scheme 27. Reductive 27. Reductive
amination amination
using using half-sandwich
half-sandwich iridium complexes.
iridium complexes.
3.1.3. Synthesis of Chiral Amine under Ru and H2 Catalysis

BaScheme
and Ku27.(2003) showed
Reductive the reaction
amination of ketones iridium
using half-sandwich with NH 4OAc as the ammonia
complexes.
Scheme 27. Reductive amination using half-sandwich iridium complexes.
3.1.3. Synthesis of Chiral Amine under Ru and H2 Catalysis

Ba and Ku (2003) showed the reaction of ketones with NH4OAc as the ammonia
source, and the use of the ligand (R, R)-iPr-DUPHOS resulted in the high chiral purity of
the product, with a 1 3.1.3.
mole% Ru catalyst (Scheme 28). Changing the ammonia source to
Synthesis of Chiral Amine under Ru and H2 Catalysis
NH3/NH4Cl leads to a dramatic
Ba and Kuincrease in chiral
(2003) showed [88]. ofInketones
the reaction the absence
with NH4ofOAc a as
solvent and
the ammonia
under argon at normal pressure,
source, theof researchers
and the use found that dramatically
the ligand (R, R)-iPr-DUPHOS resulted in the highreducing the
chiral purity of
the product, with a 1 mole% Ru catalyst (Scheme 28). Changing
catalyst loading had no significant effect on a reaction outcome. Despite the presence of a the ammonia source to
NH3 /NH4 Cl leads to a dramatic increase in chiral [88]. In the absence of a solvent and under
0.05 mol% Ru catalyst,argon
the atproduct was still
normal pressure, theformed infound
researchers appropriate amounts
that dramatically (Scheme
reducing 29)
the catalyst
[89]. loading had no significant effect on a reaction outcome. Despite the presence of a 0.05 mol%
Ru catalyst, the product was still formed in appropriate amounts (Scheme 29) [89].
Ligand Optimization for the NH3/NH4Cl System
ctions 2023, 4,
Scheme 28. Synthesis of chiral amines.

Scheme 28. Synthesis of chiral amines.
Scheme
Scheme 29. Effect
29. Effect of of
thethecatalyst
catalyst loading.
loading.
3.1.4. “Leuckart-Type Reaction” under CHT
3.1.4. “Leuckart-Type Reaction”
Hanson (1997) reported thatunder CHT are not reduced and aryl halides are not
nitro groups
cleaved
Hansonunder Leuckart
(1997) conditions,
reported as they
that nitro are under
groups arecatalytic transfer and
not reduced hydrogen
aryl (CTH)
halides are n
conditions (Scheme 30). Similarly, while aryl amines or their N-formyl
cleaved under Leuckart conditions, as they are under catalytic transfer hydrogenderivatives are stable (CT
under Leuckart conditions, they appear to hydrogenize under CTH conditions. Moore’s
conditions
analysis(Scheme 30). Similarly,
of the “Leuckart-type while
reaction” aryl that
suggests amines or their
ammonium N-formyl
formate derivatives
dissociates at
stablehigh
under Leuckart
temperatures conditions,
(Figure 3) [90]. they appear to hydrogenize under CTH conditio
Moore’s analysis of the “Leuckart-type reaction” suggests that ammonium form
dissociates at high temperatures (Figure 3) [90].
Figure 3. Ammonium formate dissociates at high temperatures.
R1 OH HCO2H R1 H
R C NH2
Moore’s
Figure 3. Ammonium formate analysis at
dissociates of high
the “Leuckart-type
temperatures. reaction” suggests that ammonium formate
dissociates at high temperatures (Figure 3) [90].
Scheme 29. Effect

R1 of
OHthe HCO
catalyst R1 H
H loading.
R1Reactions 2023, 4 2 C NH2
C O NH3 C R2 135
R2 Figure 3. AmmoniumRformate
2 NH 2
dissociates at high temperatures.
3.1.4. “Leuckart-Type Reaction” under CHT
-Hreported H
Hanson
R1 (1997) 20 R1 OH HCO2H
that nitro R1
groups
C NH2are not
C O NH3 C R2
R2 R2 NH2
cleaved under Leuckart conditions, HCOas 2H
they are under c
-H20
conditions (Scheme R 30).
1 Similarly, while aryl amines o
stable under Leuckart C NH theyHCO 2H
R2 conditions, R1
appear to hyd
Moore’s analysis of the “Leuckart-type R2
C NH reaction” su
Scheme 30. “Leuckart-type reaction” under catalytic hydrogen transfer.
dissociates
Scheme30.
Scheme
at high
30.“Leuckart-type
“Leuckart-typereaction”
temperatures
reaction” under
under catalytic
catalytic
(Figure
hydrogen
hydrogen transfer.
transfer.
3) [90].
The resulting ammonia reacts with the carbonyl compound to form a hydroxylamine,
The resulting ammonia reacts with the carbonyl compound to form a hydroxylamine,
which can be reduced directly by formic acid or indirectly through an imine.
3.1.5.
3.1.5. Synthesis of Tertiary Synthesisby
Amines of Tertiary
BronstedAmines
Acidby Bronsted
and LewisAcid and
AcidLewis Acid Catalysts
Catalysts
FigureMohanad A. formate
Hussein et al. (2020) demonstrated a new experimental method to
Mohanad A. Hussein Figure 3. (2020)
et tertiary
al. Ammonium
3. Ammonium
formate dissociates
dissociates at high temperatures.
at high method temperature
prepare aminesdemonstrated
through Lewis acidacatalysis new experimental
(Scheme 31) [41]. Webers to
and Bruce
prepare tertiary amines (1948)The
through resulting
showedLewis ammonia
that acid reacts with
catalysis
the addition the carbonyl
(Schemesalts
of ammonium compound
31) of [41].to form
Webers
sulfuric a hydroxylamine,
and Bruce
acid, formic acid and
(1948) showed that the anhydrous
additionmagnesium
of ammonium chloride (acidsaltsin ofthe sulfuric
Lewis sense) can significantly
acid, formic acid increase
andthe
conversion rate to 95.5% yield [24]. Zhang et al. (2018) developed Ra ZrO OH
1 increase the
(OH) HCO
catalyst to
R
2
anhydrous magnesium 3.1.5. Synthesis of Tertiary Amines by Bronsted Acid and Lewis Acid Catalysts
chloride
1Mohanad (acid in the Lewis sense) can significantly
synthesize anA.
C(Scheme aromatic
Oamines Hussein “tertiary
et al.NH amine”,
(2020) with 98%a new
demonstrated yieldexperimental
and 100% C selectivity
method to of the
conversion rate to 95.5%prepare
Ryieldtertiary
product
2
[24]. Zhang
32) [91]. et al.
Yang et 3
(2018)
al. developed
(2018) reported the
through Lewis acid catalysis (Scheme 31) [41]. a ZrO
zinc R2WebersNH
(OH)
acetate catalyst
dihydrate-catalyzed
2 and 2
Bruce to
reductive
synthesize an aromatic(1948)
“tertiary amination
showed that the of
amine”, various
withof98%
addition carbonyl
ammoniumyield compounds
and
salts with acid,
100%
of sulfuric DMF and dimethylamino
selectivity
formic acid of
andthe
(Me2N) source
anhydrous reductant
magnesium and solvent.
chloride (acid in With Zn(OAc)
the Lewis 2 orcan
sense) ZrO(OH) 2 as Lewis
significantly acidthe
increase catalysts,
product (Scheme 32) [91]. Yang et al. (2018) reported the zinc acetate dihydrate-catalyzed
conversion rate to 95.5% yield [24]. Zhang et al. (2018) developed
carbonyl compounds can efficiently react with DMF at 150–160 °C to produce a ZrO (OH) 2 catalyst to0
-H2dimethyl
reductive amination ofsynthesize
various
tertiary amine carbonyl
an aromatic
(Scheme 33)compounds
“tertiary amine”,
[92]. The with
previouswith
98% yield DMF
and
reductive 100% and dimethylamino
selectivity
animation of the product
method:
(Scheme 32) [91]. Yang et al. (2018) reported the zinc acetate dihydrate-catalyzed reductive
(Me2N) source reductantamination
and solvent. With Zn(OAc)2 or ZrO(OH)2 as Lewis acid catalysts,
of various carbonyl compounds with DMF and dimethylamino (Me2N) source
carbonyl compounds can efficiently
reductant reactWith
and solvent. with DMF
Zn(OAc) 2 orat 150–160
ZrO(OH) °C toacid
2 as Lewis produce dimethyl
catalysts, carbonyl
compounds can efficiently react with DMF at 150–160 ◦ C to produce dimethyl tertiary
tertiary amine (Scheme 33) [92]. The previous reductive animation method:
amine (Scheme 33) [92]. The previous reductive animation method:
R1
C
R2
19
Scheme 30. “Leuckart-type reaction” under catalytic hydrogen
The resulting ammonia reacts with the carbonyl com

which can be reduced directly by formic acid or indirect
3.1.5. Synthesis of Tertiary Amines by Bronsted Acid an

Scheme 31. Synthesis of tertiary amine through Lewis acid catalysis.
Mohanad A. Hussein et al. (2020) demonstrated
prepare tertiary amines through Lewis acid catalysis (Sc
(1948) showed that the addition of ammonium salts o
anhydrous magnesium chloride (acid in the Lewis sen
conversion rate to 95.5% yield [24]. Zhang et al. (2018) d
synthesize an aromatic “tertiary amine”, with 98% y
Scheme 32. Synthesis of aromatic tertiary amine.

Scheme 32. of aromatic
Synthesis tertiary
of aromatic amine.
tertiary amine.
Scheme 32. Synthesis of Synthesis
Scheme 32. aromatic of aromatic
tertiarytertiary amine.
amine.
Scheme 33. Synthesis of tertiary amine using DMF and Lewis acid catalyst.
3.1.6. 33.
Scheme Multiple
Synthesis ofSynthesis
Scheme 33.Catalysis
3.1.6. Relay
Multiple tertiaryoffor
tertiary
amine theamine
Relay Catalysis usingusing DMF Synthesis
Asymmetric
for theDMF
and Lewis acid
and
Asymmetric Lewis catalyst.
ofacid
SynthesisAmines
ofcatalyst.
Amines
3.1.6. Multiple Relay Catalysis for the Asymmetric Synthesis of Amines
AccordingAccording
to Palo-Nieto et al. (2016),
to Palo-Nieto et al. reagents, catalysts,
(2016), reagents, and diverse
catalysts, conditions
and diverse can can
conditions
be Multiple
3.1.6. introduced According
via
Relay
be introduced viatothe
theCatalysis
one-pot Palo-Nieto et technique,
technique,
for the
one-pot al.Asymmetric
(2016), reagents,
including catalysts,
multistep
Synthesis
including and diverse
catalytic
multistep conditions
operations,
ofcatalytic
Amines can
and and
operations,
3.1.6. Multiple
then usedthen Relay
be Catalysis
introduced
to synthesize via the for
one-potthe
differentdifferent
used to synthesize Asymmetric
technique,
amines amines including
with good Synthesis
multistep
with yields of Amines
catalytic
shownshown
good yields
operations,
in (Scheme and
34) and
in (Scheme 34) and
According
(Scheme 35) to
then
[78].
(Scheme
Palo-Nieto
used
35)
to synthesize
[78].
et al. (2016),
different reagents,
amines with good catalysts,
yields shownand diverse
in (Scheme conditio
34) and
According to Palo-Nieto
(Scheme 35) [78]. et al. (2016), reagents, catalysts, and diverse conditio
be introduced via the one-pot technique, including multistep catalytic operation
be introduced via the one-pot technique, including multistep catalytic operation
then used to synthesize different amines with good yields shown in (Scheme 3
then used to synthesize different amines with good yields shown in (Scheme 34
(Scheme 35) [78].
(Scheme 35) [78].
Scheme 34.34.
Scheme One-pot
One-potreductive
reductive amination/direct amination
amination/direct amination relay
relay sequence.
sequence.
Scheme 34. One-pot reductive amination/direct amination relay sequence.

Scheme
Scheme 35.35. Reductiveamination/amination
Reductive amination/amination catalytic
catalyticrelay.
relay.
Scheme 35. Reductive amination/amination catalytic relay.

3.1.7. Synthesis of Amines by Catalysis with Cp*Ir(III) Complexes

20

Tanaka et al. (2019) explained that Cp*Ir complexes with a 2-picolinamide moiety
tions 2023, 4, Tanaka et al. (2019)
work wellexplained
as catalyststhat Cp*Ir
in the directcomplexes with a of
reductive amination 2-picolinamide
ketonic compoundsmoiety
to produce20
work well as catalysts in theamines
primary direct(Scheme
reductive amination
36) [84]. Morisaki,of ketonic and
Morimoto, compounds to produce
Ohshima (2020) presented an
primary amines (Scheme 36) [84]. Morisaki, Morimoto, and Ohshima (2020) presented different
Ir-catalyzed “Leuckart Wallach” reaction of many ketones, which synthesized an
primary amines with excellent chemoselectivity (Scheme 37) [93]. Afanasyev et al. (2019) re-
Ir-catalyzed “Leuckart
TanakaWallach”
et al. (2019)reaction
explained of many ketones,
that Cp*Ir which with
complexes synthesized differentmoiety
a 2-picolinamide
ported that stoichiometric amounts of chemicals such as TiCl4 can promote the reaction [11].
work
primary amines with well as catalysts
excellent
Kulyk in the direct
chemoselectivity
et al. (2020) reductive amination
(Scheme of
explored the preparation of
37)primary ketonic
[93]. Afanasyev compounds
et al.
amines and the to produce
(2019)
optimization of
reported thatprimary the reaction conditions for the Leuckart–Wallach reductive amination of ketones usingan
amines
stoichiometric (Scheme
amounts 36)of [84]. Morisaki,
chemicals Morimoto,
such as TiCl 4 and
can Ohshima
promote (2020)
the presented
reaction
Ir-catalyzed
[11]. Kulyk et “Leuckart
ammonium
al. (2020) explored Wallach”
formate
the [59].
preparationreaction of many amines
of primary ketones,and whichthesynthesized
optimization different
Chuanhui Li et al. (2021) reported inexpensive and 37)
easily recoverable heterogeneous
of the reaction conditions for the Leuckart–Wallach reductive amination of ketones using (2019)
primary amines with excellent chemoselectivity (Scheme [93]. Afanasyev et al.
Co/NC-T catalysts viaamounts
the one-step pyrolysis ofsuch
ZIF-67as precursors in an N2 atmosphere.
ammonium reported that stoichiometric
formateIt[59]. of chemicals TiCl4 can promote
was reported to have a great influence on the catalyst performance in the Leuckart-
the reaction
[11]. Kulyk et al. (2020) explored the preparation of primary amines and the optimization
type reductive amination of biomass-derived FUR to NFMF. Among them, Co/NC-800
of the reaction conditions for the Leuckart–Wallach reductive amination of ketones using
exhibited the best catalytic activity, with an FUR conversion of 99% and an NFMF yield of
ammonium formate38)
86% (Scheme [59].
[94].
Cl Ir
N N R2
Cl Ir
ON N R2 NH2
O R1
HCOONH4
R R AcOH or HCOOH O R R NH2
O R1
HCOONHCH
4 3OH
R R
R R refluxAcOH or HCOOH
CH3OH
reflux
Scheme 36. “Reductive amination”

Scheme catalyzed
36. “Reductive by Cp*Ir
amination” (III) complexes.
catalyzed by Cp*Ir (III) complexes.
Scheme 36. “Reductive amination” catalyzed by Cp*Ir (III) complexes.
Typical examples of the products.

Typical examples of the products.
Scheme 37. Cont.
21
Scheme 37. Typical examples of the products of “reductive amination”.

Chuanhui Li et al. (2021) reported inexpensive and easily recoverable heterog
Co/NC-T catalysts
Chuanhui viaal.the
Li et one-step
(2021) pyrolysis
reported of ZIF-67
inexpensive precursors
and in an N2 atmosp
easily recoverable heterog
was
Co/NC-T catalysts via the one-step pyrolysis of ZIF-67 precursors in an N2 Leucka
reported to have a great influence on the catalyst performance in the atmosp
reductive amination
was reported to have of biomass-derived
a great FUR
influence on the to NFMF.
catalyst Amonginthem,
performance Co/
the Leuck
exhibited
reductive the best catalytic
amination activity, with an FUR
of biomass-derived FUR conversion
to NFMF. of 99% and
Among an NFM
them, Co/
of 86% (Scheme 38) [94].
exhibited the best catalytic activity, with an FUR conversion of 99% and an NFM
of 86% of
Scheme 37. Typical examples (Scheme 38) [94].
the products of “reductive amination”.
Chuanhui Li et al. (2021) reported inexpensive and easily recoverable heterogeneous

Co/NC-T catalysts via the one-step pyrolysis of ZIF-67 precursors in an N2 atmosphere. It
was reported to have a great influence on the catalyst performance in the Leuckart-type
reductive amination of biomass-derived FUR to NFMF. Among them, Co/NC-800
exhibited the best catalytic activity,
Scheme 38. withamination”
“Reductive an FUR conversion of 99%Co/NC-T.
by ZIF-67-derived and an NFMF yield
of 86% (Scheme 38) [94].
Scheme
Scheme “Reductive
38.38. amination”
“Reductive by ZIF-67-derived
amination” Co/NC-T.
by ZIF-67-derived Co/NC-T.
3.1.8. Pd/C Catalysis LW Reaction
3.1.8.Pan
Pd/Cet al,(2015) reported a Pd-based catalytic system, with 30% Pd/C loading
Pan et al.Catalysis LW Reaction
(2015) reported a Pd-based catalytic system, with 30% Pd/C loading at
and◦ 6
40 C Panatm
and et N2
6 atm atmosphere,
N2 atmosphere,
al,(2015) and
reported aand racemic
racemic 3-hydroxyadamantylglycine
Pd-based 3-hydroxyadamantylglycine
catalytic system, with 30% esterester
Pd/C was o
wasloading
with
and 6anatm
obtained 85%N2
with yield
an 85% (Scheme 39)
yield (Scheme
atmosphere, and[95].
39) [95].
racemic 3-hydroxyadamantylglycine ester was o
with an 85% yield (Scheme 39) [95].
Scheme 38. “Reductive amination” by ZIF-67-derived Co/NC-T.

Pan et al,(2015) reported a Pd-based catalytic system, with 30% Pd/C loading at 40 °C
Scheme 39.
Scheme
and 6 atm N2 atmosphere, Reductive
39.
andReductiveamination
racemic using Pd/C
amination usingcatalyst.
Pd/C catalyst. ester was obtained
3-hydroxyadamantylglycine
with an 85% yield (Scheme
3.2. 39) [95].
Noncatalytic
Scheme Advancement
39. Reductive amination using Pd/C catalyst.
3.2.
3.2.1. MW-Assisted Advancement
Noncatalytic Synthesis of Formylated Secondary Amines and Isocyanide
3.2.1.
3.2. InMW-Assisted Synthesis
technologyofhas
recent years,Advancement
Noncatalytic MW Formylated Secondary
improved organic Amines
synthesis shown and Isocyanide
in (Figure 4)
and (Table 1) [95]. Barba, Recio, and Batanero (2013) performed the reductive amina-
3.2.1. MW-Assisted Synthesis of Formylated Secondary Amines and Isocyanide
Scheme 41. MW synthesis of 1,2,6-triarylpiperidinesopen.

tion of several carbonyl compounds using N-methylformamide at 250 ◦ C under stirring
by microwave radiation for 10 min (Scheme 40) [25]. Rao, Poonguzhali, and Muthuku-
maran (2021) developed the facile MW-mediated synthesis (Scheme 41) of N-aryl-cis-2,6-
diphenylpiperidines using arylamine, formic acid, and 1,5-diphenylpentane-1,5-dione
through the novel application of microwaves to the classical Leuckart reaction [96]. D. G.
Hey et al. (1983) reported experimental work using 4-tert-butylcyclohexanone to develop
a convenient procedure for the preparation of secondary “amines” via a “Leuckart-type
reaction”, examining the stereochemical characteristics after changing the size of the pri-
mary amine used as the starting material [97]. Neochoritis and Dömling (2014) used the
Leuckart reaction (Scheme 42) for the reduction step during the synthesis of isocyanides.
Typical dehydrating conditions with POCl3 and Et3 N afforded the novel 1H-indole-methyl-
Scheme [55].
isocyanide 42. The Leuckart–Wallach reaction and preparation of isocyanide.
In recent
In recent years, years, MW technology
MW technology has improved
has improved organicorganic synthesis
synthesis shownshown in (Figure
in (Figure 4) 4)
and (Table 1) [95]. Barba, Recio, and Batanero (2013) performed
and (Table 1) [95]. Barba, Recio, and Batanero (2013) performed the reductive amination the reductive amination
of several
of several carbonyl carbonyl compounds
compounds using using N-methylformamide
N-methylformamide at 250at°C250 °C under
under stirringstirring
by by
microwave
microwave radiation for 10 min (Scheme 40) [25]. Rao, Poonguzhali, and Muthukumaran
Figureradiation for 10 min (Scheme
Microwave-assisted
4.developed Leuckart 40) [25].inRao,
reaction Poonguzhali, and Muthukumaran
N-methylformamide.
(2021)(2021)
Figure
developed the facile
4. Microwave-assisted
the facile MW-mediated
MW-mediated Leuckart
synthesissynthesis
reaction
(Scheme (Scheme
in of
41) 41) of N-aryl-cis-2,6-
N-methylformamide.
N-aryl-cis-2,6-
diphenylpiperidines
diphenylpiperidines using using arylamine,
arylamine, formic formic
acid, andacid, and 1,5-diphenylpentane-1,5-dione
1,5-diphenylpentane-1,5-dione
Table
through1. Obtained
the novel yields by MW radiation
application in methyl
of microwaves formamide.
through the novel application of microwaves to the to the classical
classical LeuckartLeuckart
reactionreaction
[96]. D.[96].
G. D. G.
Table
Hey et al.1. Obtained
(1983) reported
Hey et al. (1983) reported experimental
1
yields by
experimental MW work radiation
using in methyl formamide.
4-tert-butylcyclohexanone
work using 4-tert-butylcyclohexanone
Yield of 2% to develop to develop
a convenient
a convenient procedure procedure for the preparation of secondary
for the preparation of secondary “amines” via90% “amines” via a “Leuckart-type
a “Leuckart-type
a; cyclohexane
reaction”,
reaction”, examiningexamining the stereochemical characteristics after changing the size of the
b;the stereochemical
acetophenone characteristics after changing 85%the size of the
primary amine used
primary amine usedc;aspropophenone as the starting material [97]. Neochoritis
the starting material [97]. Neochoritis and Dömling and88% (2014)(2014)
Dömling used used
the Leuckart d; reaction (Scheme
2-Acetylepyradine 42) for the reduction
the Leuckart reaction (Scheme 42) for the reduction step during the synthesis of step during
85% the synthesis of
isocyanides. Typical dehydrating
e; thiophene—carbaldehyde conditions with POCl 3 and Et3N
isocyanides. Typical dehydrating conditions with POCl3 and Et3N afforded the novel 1H- afforded
92% the novel 1H-
f; benzaldehyde
indole-methyl-isocyanide 90%
indole-methyl-isocyanide [55]. [55].
Scheme 40. Microwave-assisted Leuckart reaction

reaction in
in N-methylformamide.
N-methylformamide.
Scheme 40. Microwave-assisted Leuckart reaction in N-methylformamide.
Scheme 41. MW
Scheme 41. MW synthesis
synthesis ofof 1,2,6-triarylpiperidinesopen.
1,2,6-triarylpiperidinesopen.
Scheme 41. MW synthesis of 1,2,6-triarylpiperidinesopen.
1 Yield of
a; cyclohexane 90%
Reactions 2023, 4
b; acetophenone
1 Yield
140
85%
of
Scheme 41. MW synthesisc;a;propophenone
of 1,2,6-triarylpiperidinesopen.
cyclohexane 88%
90%
d; b;
2-Acetylepyradine
acetophenone 85%
85%
e; thiophene—carbaldehyde
c; propophenone 92%
88%
f; benzaldehyde
d; 2-Acetylepyradine 90%
85%
e; thiophene—carbaldehyde 92%
Barba, Recio, and Batanero (2013b) obtained several secondary
f; benzaldehyde 90%
certain carbonyl imines via a microwave method using N-methyl form
Scheme
Scheme The Leuckart–Wallach
42.The reaction and preparation of isocyanide.
and 42.obtained
Barba, Leuckart–Wallach
the excellent
Recio, reaction
and Batanero yieldsand(Scheme
preparation
(2013b) of isocyanide.
43)
obtained[25].several secondary a
Barba,carbonyl
certain Recio, and Batanero
imines(2013b)
via a obtained
microwave several method
secondary amines
usingby reducing form
N-methyl
certain carbonyl imines via a microwave method using N-methyl formamide as a solvent,
andobtained
and obtained the excellent
the excellent yields
yields (Scheme (Scheme 43) [25].
43) [25].
Figure 4. Microwave-assisted Leuckart reaction in N-methylformamide.
Table 1. Obtained yields by MW radiation in methyl formamide.
Scheme 43. Microwave-assisted Leuckart-type synthesis of secondary amine
3.2.2.
Scheme
Scheme LW
43. 43.Reaction under
Microwave-assisted
Microwave-assisted MW
Leuckart-type in Solvent-Free
synthesis of secondary
Leuckart-type Conditions
amines.
synthesis of secondary amines
3.2.2. LW Reaction under
Microwave MW in Solvent-Free
irradiation Conditions
can boost the Leuckart reductive aminatio
3.2.2.
shown LW
Microwave
in Reaction
irradiation under
(Scheme can boostMW
44) in Solvent-Free
the Leuckart
[98]. Conditions
reductive amination yield by up to 95%
shown in (Scheme 44) [98].
Microwave irradiation can boost the Leuckart reductive aminatio
shown in (Scheme 44) [98].
Scheme 44. Leuckart-type reaction using MW in solvent-free conditions.

Scheme 44. Leuckart-type reaction using MW in solvent-free conditions.
3.2.3. Synthesis of Dimethylated Tertiary Amine and Ethyl Azetidin-2-ones under MW
Schaarschmidt
3.2.3.
Scheme Synthesis andofLang (2013) reported using
Dimethylated
44. Leuckart-type reaction that, using
Tertiary
MW theAmine
inparameters of the
and
solvent-free Eschweiler–
Ethyl Azetidin-
conditions.
Clark-modified Leuckart–Wallach reaction, 2-ferrocenylethylamine was transformed into
Schaarschmidt
the appropriate and amine
dimethylated tertiary Lang (2013)
(Scheme reported
45) [99]. that,
Re et al. (1998) using
produced 4-[1- the
3.2.3. Synthesis
(N-formylamino) of Dimethylated
(in a 55:20:25 Tertiary
molar ratio) within Amine
20 min using
Eschweiler–Clark-modified Leuckart–Wallach reaction, 2-ferroce and
a mixture of Ethyl Azetidin-2
15 equivalents
of formamide and 10 equivalents of formic acid as the amino formylating agent, with good
yields Schaarschmidt
transformed
of into
73% (Scheme 46)the and Lang (2013)
appropriate
[100]. reportedtertiary
dimethylated that, amine
using (Sche
the
Eschweiler–Clark-modified
(1998) Leuckart–Wallach
produced 4-[1-(N-formylamino) reaction,
(in a 55:20:25 molar2-ferrocen
ratio) w
mixture of 15 equivalents of formamide and 10 equivalents of(Schem
transformed into the appropriate dimethylated tertiary amine form
(1998) produced
formylating agent,4-[1-(N-formylamino) (in a(Scheme
with good yields of 73% 55:20:25 46)
molar ratio) wi
[100].
mixture of 15 equivalents of formamide and 10 equivalents of formi
formylating agent, with good yields of 73% (Scheme 46) [100].
Schaarschmidt and Lang (2013) reported that, using the parameters of the
Eschweiler–Clark-modified Leuckart–Wallach reaction, 2-ferrocenylethylamine was
transformed into the appropriate dimethylated tertiary amine (Scheme 45) [99]. Re et al,
(1998) produced 4-[1-(N-formylamino) (in a 55:20:25 molar ratio) within 20 min using a
Reactions 2023, 4
mixture of 15 equivalents of formamide and 10 equivalents of formic acid as 141
the amino
formylating agent, with good yields of 73% (Scheme 46) [100].
ctions 2023, 4,
45.Synthesis
Scheme 45.
Scheme Synthesisofof
dimethylated tertiary
dimethylated amine.
tertiary amine.
Scheme 46. 4-[1-(N-formylamino) ethyl] azetidin-2-one synthesis.

Scheme 46. 4-[1-(N-formylamino) ethyl] azetidin-2-one synthesis.
3.2.4. Metal-Free LW Synthesis

3.2.4. of DHQs
Metal-Free and Amino-Substituted
LW Synthesis Pyrrolidines
of DHQs and Amino-Substituted Pyrrolidines
In medicinal chemistry,
Scheme 46.In
Scheme the 3,4-dihydroquinazolinone
4-[1-(N-formylamino)
46.medicinal chemistry,
4-[1-(N-formylamino) ethyl]azetidin-2-one
ethyl] azetidin-2-one
the (DHQ) (Scheme 47)(DHQ)
synthesis.
3,4-dihydroquinazolinone
synthesis. moiety(Scheme
has been a favored hasscaffold
3.2.4. been aand
Metal-Free
has biological
favored
LW Synthesis scaffold
of DHQsand
activity against a broad
has biological
and Amino-Substituted activityvariety
Pyrrolidines againstofa broad
3.2.4. Metal-Free LW Synthesis of DHQsused and
therapeutic targets. Bokale-Shivale
therapeutic
In medicinal
et al.
targets.
chemistry,
(2021)
Bokale-Shivale et Amino-Substituted
the LW(2021)
al.
the 3,4-dihydroquinazolinone
method
(DHQ)used and
(Scheme
Pyrrolidines
thesynthesized
LW method
47) moiety has and s
DHQ at an 83% yield In
been
DHQ [101].
medicinal
a favored Bokale-Shivale
chemistry,
at an scaffold
83% yield and has the et al. (2020)
biological
[101]. reported
3,4-dihydroquinazolinone
activity against
Bokale-Shivale the
eta al.
broad synthesis
(DHQ)
variety
(2020) of 3,4-
(Scheme the47)
of therapeutic
reported moi
synthe
dihydroquinazolinonetargets.(DHQ,
has been favored
dihydroquinazolinonea good
aBokale-Shivale et al. anticancer
scaffold (2021)
andused
(DHQ, a product)
hasthe LW method[102]
biological
good activity
anticancer under
and synthesized
againstmetal-free
DHQ
product) a atbroad
an 83%variety
[102] under
conditions [103]. yield
Wei
therapeutic [101].
et al, Bokale-Shivale
(2014)
targets. reported et
Bokale-Shivaleal. (2020)
the reported
catalyst-free
et al. the
(2021) synthesis of 3,4-dihydroquinazolinone
transformation
used the LW of
methodlevulinic
and synthesiz
conditions
(DHQ, [103]. Wei
a good anticancer et al,[102]
product) (2014)
under reported
metal-freethe catalyst-free
conditions [103]. Weitransformation
et al. (2014) o
acid into pyrrolidinones
DHQreported
at an
acid intowith
83% formic
yield
the pyrrolidinones
acid,
[101]. and
catalyst-free transformation
showed
Bokale-Shivale
with formic theet effects
al.
acid,acid
of levulinic
(2020)
and of different
intoshowed
reported solvents
the
the effects
pyrrolidinones
synthesis of
of differen
with formic
3
[104]. Zhuangdihydroquinazolinone
et acid,
al, and
[104]. (2012)
showed
Zhuang synthesized(DHQ,
theeteffects amino-substituted
al, of(2012) a good
different anticancer
solvents
synthesized pyrrolidine
product)
[104]. amino-substituted
Zhuang derivatives
[102]
et al. (2012) under
synthesized metal-fd
pyrrolidine
conditions
(Schemes 48 and 49) with [103].
amino-substituted
(Schemes 48Wei
good et49)
yields al,(56%)
pyrrolidine
and (2014)via
with reported
derivatives
good theyields
(Schemesthe(56%)
catalyst-free
Leuckart–Wallach
48 and transformation
via the reaction
49) with good yields under of levuli
(56%)
Leuckart–Wallach via
reac
acid the
microwave irradiationintoLeuckart–Wallach
pyrrolidinones
and using NH reaction
with under
formic microwave
acid,
4COOH and R4NH2 at 120 °C [105]. and irradiation
showed and
the using NH
effects of
4 COOH and solve
different
Rmicrowave
NH2 at 120 ◦irradiation
C [105]. and using NH4COOH and R4NH2 at 120 °C [105].
[104]. 4 Zhuang et al, (2012) synthesized amino-substituted pyrrolidine derivati
(Schemes 48 and 49) with good yields (56%) via the Leuckart–Wallach reaction und
microwave irradiation and using NH4COOH and R4NH2 at 120 °C [105].
Scheme 47. Metal-free Leuckart–Wallach-style

Scheme Metal-free
47.47. reductive cyclization.
Leuckart–Wallach-style reductive cyclization.
Scheme Metal-free Leuckart–Wallach-style reductive cyclization.
Scheme 47. Metal-free Leuckart–Wallach-style reductive cyclization.
Scheme 48. SynthesisScheme

of amino-substituted pyrrolidine derivatives.
48. Synthesis of amino-substituted pyrrolidine derivatives.
Scheme 48. Synthesis of amino-substituted pyrrolidine derivatives.

Scheme 49. 49.

Scheme Synthesis
Synthesisof amino-substituted
of amino-substituted pyrrolidine
pyrrolidine derivatives
derivatives under irradiation
under microwave microwave and irradiat
and using NH44COOH.
using NH COOH.
Reactions 2023, 4, 3.2.5. Modified Leuckart–Wallach Formamide Procedure 25

3.2.5. Modified Leuckart–Wallach Formamide Procedure
Neochoritis, Stotani et al. (2015) used Leuckart–Wallach-produced formamides to
Neochoritis,
develop an in situ Stotani et al.multicomponent
isocyanide (2015) used Leuckart–Wallach-produced
reaction (IMCR) under MW in 3 min formamides
at
180 ◦ C without the tedious synthesis and isolation of foul-smelling and toxic isocyanides
develop
°C without anthein situ isocyanide
tedious synthesis andmulticomponent reaction
isolation of foul-smelling (IMCR)
and toxic under MW in 3 min at 1
isocyanides
(Scheme
(Scheme 50)The
50) [105]. [105]. Theamines
desired desiredin amines
(Schemein51)(Scheme 51) were
were obtained obtained
in excellent in excellent
yields of yields
97% inofa 97%
shortinreaction
a shorttime,
reaction
usingtime, using microwave
microwave technology technology
within 30 minwithin 30 with
aslong min aslong with
HCOOH and NHand
HCOOH 2-CHO.
NHThe best The
2 -CHO. voltage
bestwas foundwas
voltage to be 60 W to
found [106].
be 60 W [106].
SchemeScheme 50. Modified

50. Modified Leuckart–Wallach
Leuckart–Wallach formamide
formamide procedure
procedure and representative
and representative examples
examples with with yields.
yields.
Reactions 2023, 4 Scheme 50. Modified Leuckart–Wallach formamide procedure and representative examples
143 w
yields.
Scheme 51. Study

Scheme of of
51. Study Leuckart’s
Leuckart’s reductive amination
reductive amination under
under the microwave
the microwave condition.
condition.
Grunenberg et al. (2021) introduced amine-linked covalent organic frameworks. These

Grunenberg et enabling
serve as scaffolds, al. (2021) introduced
pore–wall amine-linked
modification and linkagecovalent organic
interconversion framewor
via new
ctions 2023, 4,
Thesesynthetic
servemethods
as scaffolds,
based onenabling pore–wall
Leuckart–Wallach modification
reduction with formicand
acidlinkage interconversi
and ammonium
via new synthetic methods based on Leuckart–Wallach reduction with formic acid a
formate (Scheme 52) [107].
ammonium formate (Scheme 52) [107].
Scheme 52. Amine-linked

Scheme 52. Amine-linkedcovalent organic
covalent organic frameworks
frameworks formed
formed through
through the “Leuckart
the “Leuckart reaction”. reaction”
4. Outlook and Conclusions

4. Outlook and Conclusions
In this study, the classical Leuckart–Wallach (LW) reaction is described. This reaction
In this study,worldwide
is well-known the classical Leuckart–Wallach
for the synthesis of a large(LW)number reaction is described.
of amines. This method This
is reacti
unique and environmentally friendly because
is well-known worldwide for the synthesis of a large number it produces only CO and NH
2 of amines.
3 byproducts.
This method
The Leuckart reaction is inexpensive, clean and productive. In this article, we collected
unique and environmentally friendly because it produces only CO2 and NH3 byproduc
all well-known reactions that involve the “Leuckart reaction”, as well as all synthesized
The Leuckart
drugs that reaction
have already is inexpensive,
been synthesized clean and
using thisproductive.
unique method. In this article,
To date, we collected
researchers
well-known reactions
have developed that involve
this method the “Leuckart
and successfully synthesizedreaction”, as well
different products withasexcellent
all synthesiz
yields and high enantioselectivity. All these methods have
drugs that have already been synthesized using this unique method. To date, been described in this article.
research
We collected all recent research advancements in using the “Leuckart-type reaction” for
have developed this method and successfully synthesized different products w
the synthesis of amines and bioactive drugs, including: drugs affecting the central nervous
excellent yields
system, and high enantioselectivity.
cardiovascular system and gastrointestinalAll thesetract;methods
anticancerhave been
drugs, described in t
antibiotics,
article. We and
antiviral collected
antifungalalldrugs;
recent drugsresearch
affecting advancements
anxiety; convulsant, inbiotic,
using andthe
HIV “Leuckart-ty
drugs,
reaction” for the synthesis
and antidiabetic drugs. We of hopeamines andwill
this review bioactive
support drugs, including:
the development drugs
of the affecting t
Leuckart-
central nervous system, cardiovascular system and gastrointestinal tract;ofantican
type preparation of nitrogenous compounds, as well their advancement into other areas
human development.
drugs, antibiotics, antiviral and antifungal drugs; drugs affecting anxiety; convulsa
Finally, the “Leuckart reaction” provides a convenient pathway towards the goal
biotic,
of and HIV drugs,
the green/easy and of
synthesis antidiabetic
amines, and is drugs.
strongly We hope this for
recommended review
use inwill support t
organic
development of The
preparations. the examples
Leuckart-type
cited abovepreparation of nitrogenous
are impressive and provide good compounds, as well th
insight into the
synthesis ofinto
advancement amines
otherthrough
areastheof LWhumanmethod. The benefits of Leuckart organic synthesis
development.
have increasingly attracted the attention of researchers worldwide. To achieve further de-
Finally, the “Leuckart reaction” provides a convenient pathway towards the goal
velopment in this field, novel instruments that offer reproducible performance in synthesis
the green/easy
should be used synthesis
instead of of amines,
domestic and is strongly recommended for use in orga
operations.
preparations. The examples cited above are impressive and provide good insight into t
synthesis of amines through the LW method. The benefits of Leuckart organic synthe
have increasingly attracted the attention of researchers worldwide. To achieve furth
development in this field, novel instruments that offer reproducible performance
Author Contributions: M.L. designed the work, analyzed the data and revised the article; Q.U.
searched all the available literature and wrote the final draft. All authors have read and agreed to the
published version of the manuscript.
Funding: This research received no external funding.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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Keywords: Leuckart-type reaction; synthesis of amines; catalytic and noncatalytic reaction;

Reactions 2023, 4, 117–147. https://doi.org/10.3390/reactions4010007 https://www.mdpi.com/journal/reactions

The Eschweiler–Clarke process is the reductive methylation of primary and

The Eschweiler–Clarke process is the reductive methylation of primary and secondary

H3C CH3 CO2 H2O

Scheme 2. MechanismScheme Mechanism of thereaction”.

1.4. Kinetic Study of the Leuckart–Wallach Reaction

(v) Formation of amphetamine

2.1. Synthesis of Animated Graphene and Amphetamine

Scheme 3. Possible structures of GO and rGO-Am.

Scheme 4. Synthesis of amphetamine through the LW method.

2.2. Synthesis of Tetrahydro-1,4-benzodiazepine-5-one and Arylamine

Scheme 5. Synthetic route of tetrahydro-1,4 benzodiazepin-5-one.

2.3. Synthesis of 4-methylthioamphetamine (4-MTM), (PMMA) and Heterocycles

2.5. Synthesis of cis- and trans-l-Methyl-2,5-diphenylpyrrolidines

2.5. Synthesis of cis- and trans-l-Methyl-2,5-diphenylpyrrolidines

Scheme 12. Synthesis

Scheme 13. Optimization

2.7. Synthesis of Tertiary Amines

Chemoselective Synthesis of Tertiary Amines

Scheme 14. Synthesis of tertiary amines.

SchemeScheme 15. Synthesis

Scheme 16. Synthesis of chiral bis (tetrahydroisoquinoline).

Scheme 17. Synthesis

Scheme 18. Synthesis

2.10. Synthesis of Hydro naphthylamines

Scheme 21. Enantiospecific synthesis.

3.1. Catalytic Advancement

Scheme 22. Reductive amination of acetophenone using a Cp*Rh(III) catalyst.

“One-pot preparation of iminium salts”

Scheme 24. One-pot Leuckart-type preparation of amines.

Scheme 26. Reductive amination of ketones in a packed-bed continuous-flow reactor at 40 °C and a

3.1.3. Synthesis of Chiral Amine under Ru and H2 Catalysis

3.1.3. Synthesis of Chiral Amine under Ru and H2 Catalysis

Ligand Optimization for the NH3/NH4Cl System

Scheme 28. Synthesis of chiral amines.

Figure 3. Ammonium formate dissociates at high temperatures.

Scheme 29. Effect

The resulting ammonia reacts with the carbonyl com

3.1.5. Synthesis of Tertiary Amines by Bronsted Acid an

Scheme 31. Synthesis of tertiary amine through Lewis acid catalysis.

Scheme 32. Synthesis of aromatic tertiary amine.

Scheme 34. One-pot reductive amination/direct amination relay sequence.

Scheme 35. Reductive amination/amination catalytic relay.

3.1.7. Synthesis of Amines by Catalysis with Cp*Ir(III) Complexes

3.1.7. Synthesis of Amines by Catalysis with Cp*Ir(III) Complexes

Scheme 36. “Reductive amination”

Typical examples of the products.

Scheme 37. Typical examples of the products of “reductive amination”.

Chuanhui Li et al. (2021) reported inexpensive and easily recoverable heterogeneous

Scheme 38. “Reductive amination” by ZIF-67-derived Co/NC-T.

3.1.8. Pd/C Catalysis LW Reaction

Scheme 41. MW synthesis of 1,2,6-triarylpiperidinesopen.

Scheme 40. Microwave-assisted Leuckart reaction

Figure 4. Microwave-assisted Leuckart reaction in N-methylformamide.

Table 1. Obtained yields by MW radiation in methyl formamide.

Scheme 43. Microwave-assisted Leuckart-type synthesis of secondary amine