Pharmaceuticals 13 00037 PDF

pharmaceuticals
Review
Synthesis of Imidazole-Based Medicinal Molecules
Utilizing the van Leusen Imidazole Synthesis
Xunan Zheng 1,2 , Zhengning Ma 1,3 and Dawei Zhang 1, *
1 College of Chemistry, Jilin University, Changchun 130012, China; zhengxn8217@mails.jlu.edu.cn (X.Z.);
2019203060028@whu.edu.cn (Z.M.)
2 College of Plant Science, Jilin University, Changchun 130062, China
3 Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Ministry of Education), School of
Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
* Correspondence: z_dw@jlu.edu.cn; Tel.: +86-431-8783-6471

Received: 10 February 2020; Accepted: 1 March 2020; Published: 3 March 2020
Abstract: Imidazole and its derivatives are one of the most vital and universal heterocycles
in medicinal chemistry. Owing to their special structural features, these compounds exhibit
a widespread spectrum of significant pharmacological or biological activities, and are widely
researched and applied by pharmaceutical companies for drug discovery. The van Leusen reaction
based on tosylmethylisocyanides (TosMICs) is one of the most appropriate strategies to synthetize
imidazole-based medicinal molecules, which has been increasingly developed on account of its
advantages. In this review, we summarize the recent developments of the chemical synthesis and
bioactivity of imidazole-containing medicinal small molecules, utilizing the van Leusen imidazole
synthesis from 1977.
Keywords: van Leusen; TosMICs; imidazole; synthesis
1. Introduction
Imidazole ring, which is widely found in natural products and medical molecules, is one of the most
prominent, five-membered, nitrogen-containing, heterocyclic scaffolds. Furthermore, imidazole-based
heterocyclic compounds, which possess a vital position in medicinal chemistry, have been playing a
central role in the treatment of numerous types of diseases, and new derivatives for medicinal use
are being energetically developed worldwide [1–5]. Due to the peculiar structural characteristic of
imidazole scaffold with a worthy electron-rich feature, it is advantageous for imidazole groups to
combine with various receptors and enzymes in biological systems, through diverse weak interactions,
thereby showing a variety of biological activities. At present, a legion of imidazole-containing
compounds with high a medical potential as a clinical drug have been widely used to treat diverse
types of illnesses, such as antibacterial [6,7], antifungal [8,9], anti-inflammatory [10,11], antiviral [12,13],
anti-parasitic [14,15], anticancer [16,17], antihistaminic [18,19], and enzyme inhibition [20,21]. Imidazole
and its derivatives encompass a vast range of medical activities, as shown in the following Table 1.
Pharmaceuticals 2020, 13, 37; doi:10.3390/ph13030037 www.mdpi.com/journal/pharmaceuticals

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Table 1. Various
Table
Various pharmacological
1. Various activities
pharmacological
pharmacological and and
activities
activities chemical structures
chemical of imidazole-based
structures molecules.
of imidazole-based
imidazole-based molecules.
Table 1. Table 1. Various pharmacological activitiesand
and chemical structures
chemical structures of
of imidazole-based molecules.
molecules.
Table 1. Various
Table pharmacological
1. Various activities
pharmacological andand
activities chemical structures
chemical of imidazole-based
structures molecules.
of imidazole-based molecules.
Pharmacological Activities
Pharmacological Activities Chemical Structures
Chemical Structures
Pharmacological
Activities Chemical
ChemicalStructures
Structures
Pharmacological Activities A
A
A Chemical Structures
Chemical Structures Cl Cl
Cl
AA A Cl
Cl Cl
1 1
1
OH OH
2 2
1 1 O2N O2N N
OH
N
CHOH CH
OH 3 OH3
Cl Cl
Cl 2
N 22 2
2
Antibacterial
Antibacterial O2N NN CH
N 3 Cl
Cl
N N Cl
HN HN
Antibacterial O22N
O N O22N N
CH
CHN 3 CH33
3
3 HN N
Antibacterial
2
Antibacterial
2 3
Antibacterial N
N HN HN
HN N N
N
MetronMeidN azoid
tron Nleazole
Metron
ronidazole
Meettron
M Meid azo
tron
id idllee
azo azole
1 1 2 2
1 2
N 11 N 1
1 N 22N 2
N N
N N
NN N
N NN NN
N N
NN OHN OH N
N N
N
OH
OH OH
OH 4 4
Antifungal
Antifungal 3 3 4
Antifungal 3 44 4
Antifungal
Antifungal
Antifungal 3 3
PhenePh enemthyli
thyli idazo midleazole Bif onazo le le
Bif onazo
Phenethylimmidazole Bif onazole
ene
Phene ene m azo
azo
m ee onazo l4ee le
Ph thyli
Phthyli
3 id
id
thyli 3 l azole
l
id Bifonazo
Bif 4Bif onazo
l
3 4 6 6
5 5 N 33 N 3 44 4 O O 6
5 Cl ClN N N O 6 6
5 5 Cl N N
N
Cl Cl N N
Cl
N
NN N
O O
O
N N N O O
N N
N N O
NN NO O O
F F
Anti-inflammatory
Anti-inflammatory F
Anti-inflammatory FF F SO2NH
Anti-inflammatory
Anti-inflammatory
Anti-inflammatory H3CO H3CO SO2NH2
SO22NH2
H3CO m cox m cox SO NH
SO222NH
SO22222NH
SO NH22 H3C H3C7
H333CO
H CO Ci i
H33COCimicoxibCi ib i ib H3C 7
mii5coxm H C 7
H33C
3 H33C777 6
Cim
Ci cox
Ci mib icox
ib 5
coxib 77 6
5 6
H3C 5H 5 C5 66 6
7 7 H3C 3CH CH3 CH3 A A
7 H33C
H C
3 H3CCH CH3333 CH3
A
A
7 7 N N S S
A A
N S N N O O
N N
O N O NNN S S
N S S Cl Cl NN SN S O
O
O O
H2N H2O N Cl N N
Antiviral
N N
N 8 8
Antiviral H2N O
O O O Cl Cl
Cl N S HN HN
Antiviral H N H N
H222N H2ON O N NS
N S HN
S 8
Antiviral
Antiviral
Antiviral O Cl Cl HN HN
HN HN 88 8
OO O Cl O2N O2N
N N Cl Cl Cl O2N
N O N O22N
O222N
aN
CNp CNravN r ne
aipiravirine 2 2
Caaprav
rav
irine 8 8
Capprav
C 7aiiprriirav
C ne
ne7 irine 8
7 88 8
77 7 N N
N
N
N N
N 10 10
N
9 9 O2N O2N N 10
9 O2N N
N 10 10
10
N
9 9 N O22N
O222N
O N
N
H3C H C
Antiparasitic
Antiparasitic H3C N 3 N
N N
Antiparasitic H33C
CH
N
Antiparasitic
Antiparasitic
Antiparasitic H 3 NH3CC
N N N
N
N
N N
N
O2N O2N NN O O
O2N N N
N Nimorazo leO
Nimorazo O leO
O
O NO
O222N O2N
N Nimorazo l e
9 9 Ni morazo
Ni morazo
Nimorazo
10 llee l e
morazo
10 e
9 10
N N 99 9 9 O O 10 10 10 10
N O NH2 NH2
11 11 NO NO2
N 2 N
N O O
O NH2 12 12
11 NO
N N
NO222NO22 NH
N N NH222 NH22CH CH3 CH3 12
11 11 N
NO N
N
2
O O N N NNNCH CH33N
N
12
12
12 12
12
N N 3 CH
CH33
Anticancer
Anticancer O CH3 CH3 N NN N
N NN N
N N
NN N NN CH33 CH3
Anticancer OH OHO CH
O CHO O3 NH H N CH3N
Anticancer
Anticancer
Anticancer OH
CH 3 CH3
33 3 HN N
N
H H
H
CH333 CH33
CH
OH
OHsonOH azoid
idson leazole azine
Mi Mi DacarDbacar bazine
Mison id azo le Dacarbazine
Mi son
Mison 11
Miid azo
idson
azo
son idlleeazo
11 azole e acar
Dacar
D D12 azi12
baz
bacar ne
ineb azine
11 12 14
a 11
11
11 a 12 12 O O
12 14
a 14
13 13 aa a
O
O O 14
14
14 14
14
13 O O
13 13 N CH
N CH3
N 3 CH3
N N N CH
N CH
N 333 CH
Antihistaminic
Antihistaminic N CH33 N N O O
Antihistaminic N N
N N NN N O
Antihistaminic
Antihistaminic
Antihistaminic NH H
N
N
N
N O
N Ciprox
O O
HN M
N NeethiM meethi
pip mepip NH H if an
Cip roxif an
H thime roxif an
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13 ethi
pip
13
pipmepip H
H H
H Cip 14
14
Cip 14 if an 3 of 19
13
13 13
13 13 14 14
14 14
A CH3
15 A CH3
15 16
N N N 16
N N N
N
N
Enzyme
EnzymeEnzyme inhibitor
inhibitor inhibitor N O
O
N
NO2
NO2
15 16
15 16
Owing
Owing to the significant
to the pharmacological
significant pharmacological or biological activities
or biological andand
activities the the
enormous
enormousmedicinal
medicinal
value of imidazole-based
value of imidazole-based molecules, the the
molecules, synthesis of the
synthesis imidazole-skeleton
of the imidazole-skeleton small molecule
small has has
molecule been been
paidpaid
attention to by pharmaceutical chemists and organic synthesis researchers.
attention to by pharmaceutical chemists and organic synthesis researchers. However, there However, there is is
stillstill
a need for aforsimple
a need andand
a simple efficient wayway
efficient to construct the the
to construct imidazole
imidazole heterocyclic skeleton.
heterocyclic In recent
skeleton. In recent
decades, there have been numerous classical strategies for synthesizing
decades, there have been numerous classical strategies for synthesizing this ring compoundthis ring compound in the
in the
laboratory, including
laboratory, includingvanvan
Leusen imidazole
Leusen imidazolesynthesis [22],[22],
synthesis Debus-Radziszewski
Debus-Radziszewski imidazole synthesis
imidazole synthesis
[23],[23],
Wallach
Wallachimidazole synthesis
imidazole [24],[24],
synthesis etc. etc.
Among
Among these synthetic
these syntheticstrategies, it isitwell-known
strategies, is well-known thatthat
the the
vanvanLeusen imidazole synthesis based on TosMICs, which is the cycloaddition
Leusen imidazole synthesis based on TosMICs, which is the cycloaddition reaction, is one reaction, is one of of
the the
most convenient and attractive protocols for the preparation of imidazole-based
most convenient and attractive protocols for the preparation of imidazole-based small molecules, small molecules,
15 16
N N N 16
N N N
N
N
Enzyme inhibitor
Enzyme inhibitor N O
O
N
NO
NO22
Pharmaceuticals 2020, 13, 37 15 16 3 of 19
15 16
Owing
Owing
Owing to to the significant
to the
the significant pharmacological
significant pharmacological or
pharmacological or biological activities
or biological
biological activities
activities andand the enormous
and the
the enormous medicinal
enormous medicinal
medicinal
value
value
value of of imidazole-based
ofimidazole-based molecules,
imidazole-basedmolecules,
molecules, the
thethesynthesis
synthesis
synthesis of the
of the imidazole-skeleton
imidazole-skeleton
of the imidazole-skeleton small molecule
smallsmall
molecule has been
has
molecule been
has
paid
paid attention
been attention to by pharmaceutical
to by pharmaceutical
paid attention to by pharmaceutical chemists
chemists and organic
and organic
chemists synthesis
synthesis
and organic researchers.
researchers.
synthesis However,
However,
researchers. there
there is
However, is
still
still a
therea isneed
need for
stillfor a simple
a simple
a need and
for aand efficient
efficient
simple way
and way to construct
to construct
efficient the imidazole
the imidazole
way to construct heterocyclic
heterocyclic
the imidazole skeleton.
skeleton. In
heterocyclic In recent
recent
skeleton.
decades, there have been numerous classical strategies for synthesizing
decades, there have been numerous classical strategies for synthesizing this ring compound in
In recent decades, there have been numerous classical strategies for this
synthesizing ring compound
this ring in the
compound the
laboratory,
laboratory, including
including
in the laboratory, van Leusen
van
includingLeusen imidazole
van imidazole
Leusen synthesissynthesis
synthesis
imidazole [22], Debus-Radziszewski
[22], Debus-Radziszewski
[22], Debus-Radziszewski imidazoleimidazole
imidazole synthesis
synthesis
[23],
[23], Wallach
Wallach
synthesis imidazole
[23],imidazole synthesis [24],
synthesissynthesis
Wallach imidazole etc. Among
[24], etc.[24],
Among these synthetic
these synthetic
etc. Among strategies,
strategies,
these synthetic it is well-known
it is well-known
strategies, it is well-knownthat
that
the
the van
thatvan Leusen
the Leusen
van Leusenimidazole
imidazole synthesis
synthesis
imidazole based
based
synthesis on TosMICs,
on TosMICs,
based on TosMICs, which
which is the
is the
which cycloaddition
cycloaddition
is the cycloaddition reaction,
reaction, is one
is one
reaction, of
of
is one
the
the
of themost
mostmostconvenient
convenient
convenient and
and
andattractive
attractive
attractiveprotocols
protocols
protocols for
for the
forthe preparation
thepreparation
preparationof ofofimidazole-based
imidazole-based
imidazole-basedsmall small molecules,
smallmolecules,
molecules,
due
due
due to to its
to its excellent advantages
excellent advantages
its excellent advantages likelike simple
like simple manipulation,
simple manipulation,
manipulation, easily easily obtained
easily obtained
obtained raw raw materials
raw materials
materials and and
and aaa wide
wide
wide
range
range
range of of substrates,
of substrates, which has
substrates, which
which has been
has been developed
been developed rapidly
developed rapidly in
rapidly in the
in the past
the past decades
past decades (Scheme
decades (Scheme 1).
(Scheme 1).
1).
R1
R3 H Base R2 R1
R1CH NR2 + R3 (H ) Base R2 N
R1CH NR2 + os ( ) N R3 H
T
Tos
NC
NC N R3((H))
N
Scheme 1. General van Leusen imidazole synthesis.

Scheme
Scheme 1.
1. General
General van
van Leusen
Leusen imidazole
imidazole synthesis.
synthesis.
TosMIC,
TosMIC, one
TosMIC, one of
one of the
of the most
the most significant
most significant reactants,
significant reactants, has
reactants, has many
has many good
many good features
good features
features at at room
at room temperature,
room temperature,
temperature,
including being
being aaa stable
including being
including stable solid
stable solid and being
solid and
and being odorless
being odorless and
odorless and colorless.
and colorless. Since
colorless. Since it
Since it was
it was introduced
was introduced
introduced and and applied
and applied
applied
in
in organic
organic synthesis
synthesis by
by the
the Dutch
Dutch professor
professor van
van Leusen
Leusen in
in 1972,
1972, this
this reagent
reagent
in organic synthesis by the Dutch professor van Leusen in 1972, this reagent is also known as is
is also
also known
known as van
as van
van
Leusen’s reagent.
Leusen’s reagent.
Leusen’s reagent. UpUp
Uptoto now,
to now, TosMIC
now, TosMIC
TosMIC andand its
and its derivatives
its derivatives have
derivatives have been
have been recognized
been recognized
recognized as as one
as one of
one of the
of the most
the most
most
significant
significant building
building blocks
blocks in
in nitrogen
nitrogen heterocyclic
heterocyclic synthesis,
synthesis, which
which have
have been
been fruitfully
fruitfully
significant building blocks in nitrogen heterocyclic synthesis, which have been fruitfully employed employed
employed
especially
especially in
especially in the
in the preparation
the preparation
preparation of of imidazole-based
of imidazole-based heterocycles
imidazole-based heterocycles [25–29].
heterocycles [25–29].
[25–29].
Therefore, this
Therefore, this
Therefore, review
this review will
review will summarize
will summarize
summarize the the developments
the developments
developments of of the synthesis
of the
the synthesis of
synthesis of imidazole-based
of imidazole-based
imidazole-based
molecules, utilizing
molecules, utilizing
molecules, the
utilizing the van
the van Leusen
van Leusen imidazole
Leusen imidazole synthesis,
imidazole synthesis, based
synthesis, based on
based on TosMICs
on TosMICs
TosMICs fromfrom 1977.
from 1977. It
1977. It is
It is expected
is expected
expected
that
that this
this review
review article
article will
will be
be beneficial
beneficial for
for new
new opportunities
opportunities to
to search
search for
for a
a reasonable
reasonable
that this review article will be beneficial for new opportunities to search for a reasonable design for design
design for
for
less toxic
less toxic
less and
toxic and higher
and higher bioactive imidazole-containing
higher bioactive
bioactive imidazole-containing drugs.
imidazole-containing drugs.
drugs.
2.
2. General
2.
General van
van Leusen
General van
Leusen Imidazole
Imidazole Synthesis
Leusen Imidazole
Synthesis
Synthesis
In
In 1977,
In
1977, van
1977, vanvan Leusen
Leusen et
Leusen et al.
et al. first
al. first
first published
published that
that TosMIC
published that
TosMIC and
TosMIC andand aldimine
aldimine undergo
aldimine undergo aaa base-induced
undergo base-induced
base-induced
cycloaddition
cycloaddition reaction
reaction inin aa proton
proton solvent,
solvent, meanwhile,
meanwhile, the
the effects
effects of
of RR11 and
1
and RR
cycloaddition reaction in a proton solvent, meanwhile, the effects of R and R2 on the formation of on the formation
22 on the formation
of
of 17
17
17
were qualitatively
were qualitatively analyzed.
qualitatively analyzed. They
analyzed. They They discovered
discovered that α-tosylbenzyl
discovered that α-tosylbenzyl isocyanate
that α-tosylbenzyl
isocyanate α-tosylethyl
isocyanate and
and α-tosylethyl
and α-tosylethyl
isocyanate
were
isocyanate
18 could form 18 could form 1,4,5-trisubstituted
1,4,5-trisubstituted imidazoles
imidazoles 19 (Scheme 2). 19
Based(Scheme
on the 2).
isocyanate 18 could form 1,4,5-trisubstituted imidazoles 19 (Scheme 2). Based on the Based
various on the various
advantages various
of this
advantages
reaction, it isofwidely
this reaction,
named it asisthe
widely named
van Leusen as the
imidazolevan Leusen
synthesis imidazole
[22].
advantages of this reaction, it is widely named as the van Leusen imidazole synthesis [22]. synthesis [22].
R1
R3 R2 R1
R3 base R2 N
R1CH NR2 + -base R3
R1CH NR2 + Tos NC osH
- Tos N
R3
Tos NC T H N
N
R H M ,Ph
3= , e
R3=H,Me,Ph
17 18 19
17 18 19
Scheme
Scheme 2.
2. The
The first
first example
example of
of van
van Leusen
Leusen imidazole
synthesis.
Scheme 2. The first example of van Leusen imidazole synthesis.
As shown
As shown in in Scheme
Scheme 3,3, the
the van
van Leusen
Leusen imidazole
imidazole synthesis
synthesis allows
allows the
the preparation
preparation of
of imidazole
imidazole
As
through shown
[3 + 2] in Scheme 3,
cycloaddition thereaction
van Leusen
from imidazole
aldimines synthesis
and a allowswith
reaction the preparation
TosMICs, of imidazole
which contain
through [3
through [3 ++ 2]
2] cycloaddition
cycloaddition reaction
reaction from
from aldimines
aldimines and
and aa reaction
reaction with
with TosMICs,
TosMICs, which
which contain
contain
reactive
reactive isocyanide
isocyanide carbons,
carbons, active
active methylene,
methylene, and
and leaving
leaving groups
groups such
such as
as C2N1
C2N1 “3-atom
“3-atom synthon”.
synthon”.
reactive
The cyano isocyanide
moiety can carbons, active methylene,
be a gradual andtoleaving
cycloaddition groups
polarize suchbond
a double as C2N1 “3-atom
under a base synthon”.
condition.
The elimination of p-TosOH forms the intermediate 4-tosyl-2-imidazoline to produce the target
1,4,5-trisubstituted imidazoles 19, accompanied by the elimination of p-TosOH, which is negative to
the obtained 1,5-disubstituted imidazoles.
The
The cyano
cyano moiety
moiety cancan be
be aa gradual
gradual cycloaddition
cycloaddition to
to polarize
polarize aa double
double bond
bond under
under aa base
base condition.
condition.
The
The elimination
elimination of of p-TosOH
p-TosOH forms
forms the
the intermediate
intermediate 4-tosyl-2-imidazoline
4-tosyl-2-imidazoline to
to produce
produce the
the target
target 1,4,5-
1,4,5-
trisubstituted
trisubstituted imidazoles
imidazoles 19,
19, accompanied
accompanied by
by the
the elimination
elimination of
of p-TosOH,
p-TosOH, which
which is
is negative
negative to
to the
Pharmaceuticals 2020, 13, 37 4 ofthe
19
obtained
obtained 1,5-disubstituted
1,5-disubstituted imidazoles.
imidazoles.
R11 O + R2 NH
R O + R2 NH22
R33 R33 R33 R11

Tos R N R N os R N --TosH R
2 R
Tos N b ase Tos N R1 N 2 Tos NC T os b ase T R2
Tos N C base Tos N C ++ R1 N R2 Tos N base Tos N TosH N
C C R
C N R 33
R33 N N R
R33 R11 N 1
R1 N2 R1
N2 N
R R R N R R1 N
R22 R2 R2
R R R
18 Ⅰ Ⅱ Ⅳ
18 Ⅰ Ⅱ Ⅲ Ⅳ 19
Ⅲ 19
Scheme 3. Mechanism
Mechanism of
of van Leusen imidazole synthesis.
Scheme 3.
Scheme 3. Mechanism of van Leusen
synthesis.
3.
3. Developments
3. Developments of
Developments of the
of the van
the van Leusen
van Leusen Imidazole
Leusen Imidazole Synthesis
Synthesis
Imidazole Synthesis
In known D-xylo-pentodialdose
In 1995,
In 1995, Frankowski
1995, Frankowski and
Frankowski and co-workers
and co-workers were
co-workers were reported
were reported to
reported to lead
lead the
the known D-xylo-pentodialdose to
to lead the known D-xylo-pentodialdose to
to
form
form imidazo-L-xylo-piperidinose
imidazo-L-xylo-piperidinose derivatives,
form imidazo-L-xylo-piperidinose
derivatives, based
based on
derivatives, based
on aa sequential
sequential eight-step
on a sequential
eight-step reaction.
reaction. In
eight-step reaction.
In this
In this process,
this
process,
process, the
the imidazole-base
imidazole-base molecule
the imidazole-base
molecule was
molecule was obtained
was obtained
obtained through
through aa van
through a van Leusen
van Leusen
reactionreaction
Leusen reaction as as aa key
as a key step.
key step.
step. As
As shown
As
shown
shown in
in Scheme
in Scheme
Scheme 4,
4,
4, applying
applying
applying this
this van
this van
van Leusen
Leusen
Leusen methodology,
methodology, 20
methodology, 20 and
20 and
and TosMIC
TosMIC
TosMIC 18
18 were
18 were
were transformed
transformed into the
transformed
into
into the
the imidazole
imidazole
imidazole derivative
derivative 21.
derivative 21. At last,
21. At
At last,
last, removal
removal
removal ofof the
the protecting
of the protecting
protecting group
group gave to thegave
group gave toto the
the target
target product
target product 22, which is
product
22, which
a kind is a kind
of bicyclic of bicyclic
azasugar andazasugar and
a glycosidase a glycosidase
inhibitor [30].inhibitor [30].
22, which is a kind of bicyclic azasugar and a glycosidase inhibitor [30].
B nnO OH
B O HO OH
O N steps HO
OHC O O .- O OH
OHC O + Tos 1 .t -Bu OK,,DME N O steps OH
+ Tos NC 1. t BuOK DME
O NC 2 .POCl3,,Et3N,,DME HN
HN O O N
BnnO O 2. POCl Et3N, DME O O N
B O 3 .NH3,,M3e OH DME N
3 NH3 MeOH,DME N
20 18 21 22
20 18 21 22
Scheme
Scheme 4.
Scheme 4. The
4. The van
The van Leusen
van Leusen methodology
Leusen methodology as
methodology as the
as the key
the key step
key step to
step to synthesize
to synthesize glycosidase
synthesize glycosidase inhibitor
glycosidase inhibitor 22.
inhibitor 22.
22.
In 1998,
In 1998, the
theSisko
Siskogroup
groupsynthesized
synthesized the the
1,4,5-trisubstituted imidazole
1,4,5-trisubstituted 25, which
imidazole 25, displayed
which potent
displayed
In 1998,
bindingbinding the
with p38with Sisko group
MAP kinase, synthesized
a recently the 1,4,5-trisubstituted imidazole 25, which displayed
potent
potent binding with p38
p38AsMAP
MAP kinase,
kinase, aadiscovered
recently
recently
protein kinase that participates
discovered
discovered protein kinase
kinase that
proteinimidazole that
in an inflammation
participates
participates in
in an
an
regulatory
inflammationmechanism.
regulatory shown
mechanism. in Scheme
As shown 5, 1,4,5-trisubstituted
in Scheme 5, 1,4,5-trisubstituted24 was accessed
imidazole 24 by
was
inflammation
a novel and regulatory mechanism. As shown in Scheme 5, 1,4,5-trisubstituted
α-ketoaldimine imidazole 24 was
accessed
accessed by
by aafacile
novel
novel
protocol,
and
and
based
facile
facile
on thebased
protocol,
protocol,
reaction
based on
on
of an
the
the reaction
reaction of
of an
an
23 with an aryl-substituted
α-ketoaldimine
α-ketoaldimine 23
23 with
with an
an aryl-
aryl-
TosMIC reagents
substituted TosMIC 18 as the key
reagents 18step
as [31].
the key step [31].
substituted TosMIC reagents 18 as the key step [31].
H H
H
N H
N
N N
O F O
O F O N
N N N
H3C N N
H3C H 3C steps N
N + K2CO3 H3C N steps H2N N N
N + K2CO3 N H2N N
NH
NH
Tos NC
Tos NC
F F
F F
23 18 24 25
23 18 24 25
Scheme
Scheme 5.
Scheme 5. Synthesis
5. Synthesis of
Synthesis of imidazole
of imidazole 25
imidazole 25 exhibiting
25 exhibiting potent
exhibiting potent binding
potent binding with
binding with p38
with p38 MAP
p38 MAP kinase.
MAP kinase.
kinase.
In
In 2000,
In 2000, they
2000, they also
they also described
also described an
described an active
active and
and gentle
an active and
gentle procedure
procedure for
gentle procedure
for preparing
preparing multisubstituted
for preparing multisubstituted
multisubstituted
imidazoles
imidazoles in one-pot, from an aryl-substituted TosMIC and a generated imine, in situ.
imidazoles in
in one-pot,
one-pot, from
from an
an aryl-substituted
aryl-substituted TosMIC
TosMIC and
and a
a generated
generated imine,
imine, in
in situ. One
situ. One of
One of the
the
of the
reactions
reactions is
reactions is shown
is shown in
shown in Scheme
in Scheme 6,
Scheme 6, cycloaddition
6, cycloaddition of
cycloaddition of imine
of imine 28,
imine 28, prepared
28, prepared imine
prepared imine in
imine in situ
in situ from
situ from aa 40%
from a 40% aqueous
40% aqueous
aqueous
solution
solution of pyruvaldehyde 26 and amine 27, then, ketone 29 was prepared in DMF, using aryl-
of
of pyruvaldehyde
pyruvaldehyde 26 26
andand
amineamine 27,
27, then, then,
ketoneketone
29 was29 was
prepared prepared in
in DMF, using DMF, using
aryl-substituted
aryl-
◦ C,
substituted
substituted TosMIC
TosMIC
TosMIC 18
18 and K2 CO
183and
and KK22CO
, with
CO33,, with
a 75%
with aa 75%
75% yield.
yield. Surprisingly,
yield. Surprisingly,
Surprisingly, when
when the
the reaction
when the reaction
reaction was
was carried
was carried
out at 0 out
carried out
at
the0 product
at 0 °C,
°C, the
the product
product 29
29 was
was blended
29 was blended
blended with
with 15–20% 15–20%
with 15–20% of of the
the 1,4-disubstituted
1,4-disubstituted imidazole
of the 1,4-disubstituted imidazole 30 [32]. 30 [32].
imidazole 30 [32].
CO2Et CO2Et
CO Et CO Et
N 2 N 2
F N N
CO2Et O F
CO2Et O O
O N O
O N DMF K2CO3 N N
+ DMF N + K2CO3 N + N
+ N + +
O N N
O NH2 NCO2Et Tos NC N N
NH2 NCO2Et Tos NC
F F
F F
26 27 28 18 29 30
26 27 28 18 29 30
Scheme 6. Synthesis of ketone 29 and 1,4-disubstituted imidazole 30.

Scheme
Scheme 6.
6. Synthesis
Synthesis of
of ketone
ketone 29
29 and
and 1,4-disubstituted
1,4-disubstituted imidazole
imidazole 30.
30.
In
In the
In the same
the same year,
same year, the Vanelle
the Vanelle
year, the group
Vanellegroup converted
groupconverted 6-nitropiperonal
converted6-nitropiperonal into
6-nitropiperonalinto the
intothe methylimine
methylimine3131
themethylimine through
31through
througha
aacondensation
condensation
condensation reaction
reaction
reaction withwith
with methylamine
methylamine
methylamine in ethanol.
in ethanol.
in ethanol. The molecule
The molecule
The molecule with imidazole
with imidazole
with imidazole ring
was 32
ring 32ring 32 was
was
formed
formed
by by
reacting reacting
equimolar equimolar quantities
quantities of TosMICof TosMIC
18 and 18 and
formed by reacting equimolar quantities of TosMIC 18 and aldimine 312 with
aldimine aldimine
31 with 31
K with
CO K
in 2CO3 in methanol
3 K2CO3 in methanol
methanol solvent,
solvent,
under a under
solvent, under aa refluxing
refluxing refluxing condition.
condition.
condition. Then,
Then, through
Then, through through the
the classical
classical
the classical Knoevenagel
Knoevenagel
Knoevenagel reaction,
reaction,
reaction, compound
compound
compound 33
33
33 were
were obtained, which displayed an effective in vitro leishmanicidal
were obtained, which displayed an effective in vitro leishmanicidal bioactivity (Scheme 7).
obtained, which displayed an effective in vitro leishmanicidal bioactivity bioactivity
(Scheme 7). (Scheme
Compound 7).
Compound
33a, higher in33a,
Compound 33a,
vitrohigher
higher in
in vitro
vitro leishmanicidal
leishmanicidal leishmanicidal bioactivity,
lead to a might
bioactivity,
bioactivity, might might lead to
to aa promising
leadsignificant
promising promising significant
significant
therapeutic agent
therapeutic
therapeutic
(Scheme agent (Scheme 8)
agent (Scheme 8) [33].
8) [33]. [33].
O O
O 2s teps O
O K2CO3 2 steps
O + K2CO3 O O
H + Tos NC O N O N
O H Tos NC CH3OH N N
C CH3 CH OH N N
O C N CH3 refl3ux
reflux H3C N H3C N R11
N H3C H3C R
H R22
H R
31 18 32 33
31 18 32 33
Scheme
Scheme 7.
7. Synthesis
Synthesis of
of the
the potential
potential significant
significant therapeutic
therapeutic agent
agent 33.
33.
Scheme 7. Synthesis of the potential significant therapeutic agent 33.
O
O
O
O N
N N
H3C N CH3
CH3
H3C
H NO2
H NO2
33a
33a
Scheme
Scheme 8.
8. High
High in
in vitro
vitro leishmanicidal
leishmanicidal activity
activity of
of compound
compound 33a.
33a.
Scheme 8. High in vitro leishmanicidal activity of compound 33a.
From 2005 to
From 2006, in order to access unusual imidazole-based heterocyclic structures, a series of
From 2005
experimental 2005 to
to 2006,
2006,
results were
in order
order to
inreported access
to by
access
the
unusual
unusualand
Gracias
imidazole-based
imidazole-based
Djuric group.
heterocyclic
heterocyclic structures,
structures, aa series
series
of
of experimental
experimental results
results were
were areported
reported by
by the
the Gracias
Gracias and
and theDjuric
Djuric group.
group.
Initially,
Initially, they
they reported
reported a new
new protocol
protocol employing
employing the van van Leusen
Leusen three-component
three-component reaction
reaction and
Initially,
andring-closing they
the ring-closing reported a
metatheticalnew protocol
reaction employing
in a sequence the van
method, Leusen
to formthree-component
a fused reaction
bicyclic imidazoleand
the
the ring-closing metathetical
metathetical reaction
reaction in
in a
a sequence
sequence method,
method, to
to form
form a
a fused
fused bicyclic
bicyclic imidazole
imidazole ring.
ring.
ring. general
The The general
method method
is is shown
shown in in Scheme
Scheme 9 (top),
99 (top), thethereaction
reactionunderwent
underwentsmoothly smoothly with with the
the
The general method
reaction ofis shown
of 4-pentenal in
4-pentenal 34 Scheme (top),
and allylamine
34 and allylamine 35, the reaction
in DMF at
35, in underwent
at room temperature, smoothly
temperature, to with
to give the
give the
condensation
condensation reaction of followed
4-pentenal 34 and allylamine 35, in DMF
DMF at room
room temperature, give the
toaccess the
imine
imine in
in situ,
situ, which
which was
was followed by
by the
the addition
addition of
of the
the TosMIC
TosMIC reagent
reagent 18
18 and
and a base,
aa base, to
to access the
the
imine
van in situ,
Leusen which
imidazole was followed
product 36 by
in the
high addition
yield. of
Next, thea TosMIC
ring-closing reagent 18
metathesis and base,
(RCM) to access
reaction the
was
van
Leusenthrough
imidazole product
product 36
36 in
in high
high yield.
yield. Next,
Next, aa ring-closing
ring-closing metathesis
metathesis (RCM)
(RCM) reaction
reaction was
was
performed
performed through the
the second-generation
second-generation Grubbs
Grubbs catalyst
catalyst to
to get
get imidazole
imidazole 37
37 and
and their
their derivatives
derivatives
performed
(Scheme 9, through
top) [34]. the second-generation Grubbs catalyst to get imidazole 37 and their derivatives
(Scheme
(Scheme 9, top)
top) [34].
9, they [34].
Next,
Next, they developed aa concise
developed concise route
route of of fused
fused imidazo
imidazo azepine
azepine analogs
analogs viavia thethe stepwise
stepwise van
van
Next, they developed
Leusen/intramolecular enyne a concise
enyne metathesis route of
metathesis synthesis. fused
synthesis. The imidazo azepine
The condensation
condensation reaction analogs
reaction of via the stepwise
of 4-pentenal
4-pentenal 34 van
34 with
Leusen/intramolecular
Leusen/intramolecular enyne metathesis synthesis. The condensation reaction ofadds
4-pentenal 34 with
with
but-2-yn-1-amine
but-2-yn-1-amine 38
38 in DMF
in DMF at room
at temperature
room temperature gives the
gives imine
the in
imine situ,
in and then
situ, and thenphenyl
adds TosMIC
phenyl
but-2-yn-1-amine
18 and K218 38
CO3 toKaccess in DMF at room
the van Leusen temperature
imidazole gives the
product 39productimine in
in high yield. situ, and then
Subsequent adds phenyl
cyclization
TosMIC
TosMIC 18 and
and K22CO to
to access
CO33enyne access the
the van Leusen
vanreaction imidazole
Leusenresults
imidazole product 39
39 in
in high
high yield.
yield. Subsequent
Subsequent
via the intramolecular
cyclization via the metathesis in the formation of the cyclized product 40
cyclization
containing the the intramolecular
via dieneintramolecular
functional
enyne
enyne
group and
metathesis
metathesis
their
reaction results
results in
reaction(Scheme
derivatives in
9,
the
the formation
formation
bottom) [35].
of
of the
the cyclized
cyclized
product 40 containing the diene functional group and their derivatives
product 40 containing the diene functional group and their derivatives (Scheme 9, bottom) [35]. (Scheme 9, bottom) [35].
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19
H2N
H N
H22N . - , Ph
35
35 Ph
Ph 11..pp--TTssOH
OH,CH CH2Cl Cl2 Ph
35 Ph N
N 1 .p TsOH,CH.2,2Cl22 Ph
N
, .
22. G ru
rubb s catt..,,CH
ca
K2 CO3 , DMF
K CO DMF N N Gru bbss ca CH22Cl
Cl2 N N
N
K 2CO 3 , DMF
2 3
N
N 2 G bb t CH2Cl22 N
N
36
36 37
37
Ph
Ph 36 37
OHC ++ Ph ++
OHC os
OHC + TTos NC
NC +
Tos NC
H CH
34
34 18
18 H2NN CH3
CH33
34 18 H22N Ph
CH
CH3 . - , Ph
38
38 CH33 Ph 11..pp--TTssOH
OH,,CH
CH22Cl
Cl22 Ph CH
CH3
38 , Ph s
1 .p T OH CH.2,Cl2 N CH33
Ph N . N
K CO33 ,, DMF
K22CO
N
N 22..G ru ss ca
Grubb bb catt. ,CH
CH2ClCl2
N
N N
K2CO3 DMF
DMF N
N 2 Grubbs cat ,CH22Cl22 N
N
39
39 40
40
39 40
Scheme
Scheme 9.
Scheme 9.
9. Synthesis
9. Synthesis
Synthesis of
Synthesis of
of the
of the
the fused
the fused
fused bicyclic
fused bicyclic
bicyclic 37
bicyclic 37 and
37 and
37 the
and the
and fused
the fused
the imidazo
fused imidazo
fused azepine
imidazo azepine
imidazo derivatives
azepine derivatives
azepine 40.
derivatives 40.
derivatives 40.
40.
Scheme
In late
In late 2005,
late2005, they
2005,they
they also
also reported
reported a facile
route route of fused triazolo imidazole derivatives via
via aaa
aa facile
facile route oftriazolo
fused triazolo
triazolo imidazole derivatives
In also reported a facile of fused imidazole derivatives via a sequential
In late 2005, they also reported route of fused imidazole derivatives via
sequential
van van
sequential van Leusen/alkyne–azide
van Leusen/alkyne–azide
Leusen/alkyne–azide cycloaddition cycloaddition
Leusen/alkyne–azide cycloaddition
reaction. Thereaction.
cycloaddition reaction.
use of The
reaction. The
an use
The use
azide of
use of an
of an azide
an azide functionality
azide functionality
functionality functionality on
on the on the
on the
aldehyde the
41
sequential
aldehyde
aldehyde
and 41
an alkyne and
41 and
and an alkyne
an alkyne functionality
on the amineon
alkyne functionality
functionality functionality 42the
on the amine
givesamine 42 gives
42 gives the
gives the
the bifunctional bifunctional
raw materialraw
the bifunctional
bifunctional for material
raw material
the for the
for the
van Leusenthe
aldehyde 41 an on the amine 42 raw material for
van Leusen
van Leusen
reaction reaction
Leusen reaction
resulting in resulting
reaction resulting
resulting in
substrate in
43. substrate
in substrate 43.
substrate 43.
Subsequent Subsequent
43. Subsequent cyclization
Subsequent cyclization
cyclization through
cyclization through
through the through thethe intramolecular
the intramolecular
intramolecular intramolecular
alkyne–azide
van
alkyne–azide
alkyne–azide
cycloaddition cycloaddition
cycloaddition will
will
will form the fused form
form the
the
triazolo fused
fused triazolo
triazolo
imidazole imidazole
imidazole
skeletons skeletons
skeletons
44 (Scheme 10)44
44 (Scheme
(Scheme
[36]. 10) [36].
10) [36].
[36].
alkyne–azide cycloaddition will form the fused triazolo imidazole skeletons 44 (Scheme 10)
1 R1
R
R1 R1
R1 iinnttramo
ramo lecu
ecullarar R1
nlky - lecu N
iaa tramone--az
ne lazid ear
CHO 3 R3
N lky idele R3
R3 N
NN
CHO R
R3 , R3 N3 accylky nedditi
ccloa az idon NN NN
1 CHO + NH
NH2 R3
K CO3 ,DMF
K2CO DMF R3 N33 oaddition
cyyclloadditi
R3 N
R
R1 + 2 NH22 ++ K22CO33,DMF on 2
R1 N + R
R2 + N
R
R2
N33 R2 N
N N R2
N3 TTos
os NC
NC N N N N
Tos NC N N
N R2 N
41 42 18 43 R2 44
41 42 18 43 R2 44
41 42 18 43 44
Scheme
Scheme 10.
Scheme 10.
10. Synthesis
10. Synthesis
Synthesis of
Synthesis of
of fused
of fused triazolo
fused triazolo
fused imidazoles
triazolo imidazoles
triazolo 44.
imidazoles 44.
imidazoles 44.
44.
Scheme
Then
Then
Then inin
in 2006,
in 2006, they
2006, theycontinued
they continuedto
continued publish
publishthe
totopublish
publish thethemethods
methods
methods for the
forfor fused
the
the fused
fused imidazole
imidazole
imidazole ring synthesis
ring
ring by
synthesis
synthesis by
Then 2006, they continued to the methods for the fused imidazole ring synthesis by
using
by the
using
using the tandem
the tandem
the tandem
tandem van van vanLeusen/RCM,
Leusen/RCM,
van Leusen/RCM,
Leusen/RCM, van van
van Leusen/enyne
Leusen/enyne
van Leusen/enyne metathesis,
metathesis,
Leusen/enyne metathesis,
metathesis, van van
Leusen/alkyne–azide
Leusen/alkyne–azide
using
cycloaddition,
cycloaddition,
cycloaddition, or
or
or van
van
van Leusen/Heck
Leusen/Heck
Leusen/Heck reaction,
reaction,
reaction, respectively.
respectively.
respectively.
cycloaddition, or van Leusen/Heck reaction, respectively.
Firstly,
Firstly, they
Firstly, they synthesized
they synthesized fused
synthesized fused imidazo-pyridine
fused imidazo-pyridine
imidazo-pyridine and and
and imidazo-azepine
and imidazo-azepine derivatives
derivatives
imidazo-azepine derivatives
derivatives by by
by using
using aaaa
using
by using
Firstly, they synthesized fused imidazo-pyridine imidazo-azepine
sequential
sequential van
van
sequential van Leusen/
Leusen/
van Leusen/ intramolecular
intramolecular
Leusen/ intramolecular
intramolecular Heck Heck
Heck route.
route.
Heck route. The
The imidazole
route. The
The imidazole 47
imidazole 47 and
47 and 49
and 49 were
were
49 were accessed
accessed
were accessed via
via
accessed via the
via the
the
sequential imidazole 47 and 49 the
condensation
condensation
reaction
reaction between
between
between an
an
an appropriate
appropriate
appropriate aldehyde-containing
aldehyde-containing
aldehyde-containing vinylogous
vinylogous
vinylogous bromide
bromide
bromide 45
45
45 and
and
and an
an
an
condensation reaction between an appropriate aldehyde-containing vinylogous bromide 45 and an
amine-containing
amine-containing
amine-containing doubledouble
double bond
bond
double bond 46,
46,
bond 46, respectively.
respectively.
46, respectively.
respectively. Then,Then,
Then, preformation
preformation
Then, preformation
preformation of of
of the
the
of the imine,
imine,
the imine, the
the
imine, the desired
desired
the desired TosMIC
TosMIC
desired TosMIC
TosMIC
amine-containing
reagent
reagent
reagent 18
18
18 and
and
and KK
K CO
222CO
CO were
333 were
were added,
added,
added, and
and
and the
the
the cyclization
cyclization
cyclization was
was
was allowed
allowed
allowed toto
to proceed
proceed
proceed atat room
room
at room temperature
temperature
temperature to
reagent 18 and K2CO3 were added, and the cyclization was allowed to proceed at room temperature
to
getget
to get imidazo-[1,5-a]pyridine
imidazo-[1,5-a]pyridine
get imidazo-[1,5-a]pyridine
imidazo-[1,5-a]pyridine 48 48 48
or or
48 or imidazo[1
imidazo[1
or imidazo[1 ,5-a]azepine
,5-a]azepine
imidazo[1 ,5-a]azepine 50 50 (Scheme
(Scheme
,5-a]azepine 50
50 (Scheme 11)
(Scheme 11)11) [37].
[37].
11) [37].
[37].
to
Ar Ar
Ar Ar
Ar Ar
Br
R
R Br Hec
Heckk ((CH
CH22))nn
R Br Heck
N
N (CH
CH22))nn
R
R N (CH2)n
N
N N ((CH R N
N 2)n N
N
N N
R 47 48
OHC
OHC Ar
Ar R(Ph
Ph) K
K2CO
47 48
OHC Ar ++ H R((Ph)) CO3
K22CO33
47 48
H2N CH2)nn ++
N (CH
B r + H22N ((CH22))n + TTos
os NC
NC DMF
Brr Tos NC DMF
B DMF r Ar
A
Ar Ar
45
45 46
46 18
18 Ar Br Ar
45 46 18 Ph Br Ph
Ph Br MW
MW Ph
Ph MW Ph
N
N N
N
N
N N N
N N
N N
49
49 50
50
49 50
Scheme 11.
Scheme 11. Synthesis of
Synthesis of the
the fused
fused imidazole
imidazole rings
rings 48 and 50.
48 and 50.
Scheme 11.
Scheme 11. Synthesis
Synthesis of
of the
the fused
fused imidazole
imidazole rings
rings 48
48 and
and 50.
50.
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Next,
Next, they
they described
described an an elegant
elegant method
method to to obtain
obtain aaaa fused
fused imidazole
imidazole ring,
ring, employing
employing the the van
van
Leusen Next,
Next, they
they described
described
three-component an
an elegant
elegant
reaction, method
method
followed to
to
byobtain
obtain
Pd/Cu fused
fused imidazole
imidazole
catalyzed ring,
ring, employing
employing
intramolecular the
the van
van
C-arylation.
Leusen
three-component reaction,
reaction,
reaction, followed
followed
followed by by Pd/Cu catalyzed intramolecular
by Pd/Cu catalyzed intramolecularsystem
Pd/Cu catalyzed intramolecular C-arylation. C-arylation.
C-arylation.
Meanwhile,
Meanwhile,
Meanwhile, another
another available
available protocol
protocol to
to form
form 5,6-dihydroimidazo[2,1-a]-isoquinoline
5,6-dihydroimidazo[2,1-a]-isoquinoline system 53,
53, via
via
Meanwhile,
another
aa radical another
available
cyclization available
protocol
reaction
to protocol
of tethered to form
aryl 5,6-dihydroimidazo[2,1-a]-isoquinoline
form 5,6-dihydroimidazo[2,1-a]-isoquinoline
halides onto the imidazole
system 53,system
ring, was also 53,
published. via
via a radical
In
radical
a radical
cyclization cyclization
cyclization
reaction reaction
reaction
of of
tethered tethered
of tethered
aryl aryl
halides halides
arylaccessed onto
halides onto
onto the the imidazole
the imidazole
imidazole ring, ring, was also
ring,chemistry,
was published.
was also published.
also published. In In
In
their
their
their article,
article, the
the imidazole
imidazole precursors
precursors were
were accessed through
through an
an alkylation
alkylation chemistry, and
and the
the van
van
their article,
article,
Leusen
the
reactionthe was
imidazole
imidazole
used toprecursors
precursors were
assemble were accessed
accessed
imidazole
through through
followed
an
aaan
alkylation
by alkylation chemistry,
chemistry,
transition metal
and the
catalyzed and
van thebond
C–C van
Leusen
Leusen
reaction reaction
Leusen reaction
was used was
to used
was 12) to assemble imidazole followed by transition metal
used to assemble imidazole followed by a transition metal catalyzed C–C bond
assemble imidazole followed by a transition metal catalyzed catalyzed
C–C bond C–C bond
framework
framework
framework (Scheme
(Scheme 12) [38].
[38].
framework
(Scheme 12)(Scheme
[38]. 12) [38].
R11
R
R33 R1
R3 N
. R N
NH2 + R33 1 . K2CO3,, DMF N N
R N
R11CHO ++ NH2 +
NH2 + os R 3 1.. K-2CO3, DMF N
1 K CO DMF
R CHO + NC 2 . C2-Arryl3aation
R1CHO X T os on
NC 2. C- Ar ylatition
R22 X
X T
Tos
NC 2 C A yl
R
R2 X==Brr,,I R22
R
X B I
X=Br,I R2
51 52 18 53
51 52 18 53
51 52 18 53
Scheme 12. Synthesis of fused imidazole rings 53.
Scheme 12.
Scheme
12. Synthesis of
Synthesis of fused
of fused imidazole
fused imidazole rings
imidazole rings 53.
rings 53.
53.
In 2006,
In 2006, Dömling’s
2006, Dömling’s
Dömling’sgroupgroup reported
groupreported that
reportedthat
that substituting
substituting
substituting pyrroloimidazoles
pyrroloimidazoles
pyrroloimidazoles 56
56 were
56 were were assembled
assembled
assembled by
by
by van
van In 2006,
Leusen Dömling’s
multicomponent group reported
reaction that
(MCR) substituting
of TosMIC pyrroloimidazoles
18, indole 56
carbaldehydes were
54,assembled
and by
primary
van Leusen
Leusen
van Leusen multicomponent
multicomponent
multicomponent reaction
reaction (MCR)
reaction (MCR) of
of TosMIC TosMIC
(MCR) of TosMIC 18,
18, indole indole carbaldehydes
carbaldehydes
18, indoleand
54, and54,
carbaldehydes and
primary primary
amines
54, and primary
amines
amines
55. They 55.
55. They
They
were were
were
interestedinterested
interested in
in
in bioactivity bioactivity
bioactivity of
of
of the productsthe
the products
products
and these and these
these imidazole-containing
imidazole-containing
imidazole-containing skeletons
amines 55.
skeletons They
were were interested
screened in a in bioactivity
phenotypic assay for of the products
neurite outgrowth. andThethese
test imidazole-containing
results indicated that
skeletons
were
skeletons were in
screened
were screened in aa phenotypic
a phenotypic
screened in phenotypic
assay forassay for outgrowth.
neurite
assay for neurite outgrowth.
neurite outgrowth.
The testThe test results
results
Theneurite
test results indicated
indicated that
that these
indicated that
these
these
small small
small molecules
molecules
molecules would would
would serve
serveserve as
as
as usefuluseful
useful chemical
chemical
chemical probesprobes
probes to
to research
research
to research neurite
neurite growth
growth
growth and
andand might
might
might be
these
be small
used as amolecules
therapeutic would serve asfor
application useful
axon chemical probes
regeneration of to research
lesions of neurite
the human growth
spinal and
cordmight
and
be used
used
be used as
as aas aa therapeutic
therapeutic application
therapeutic application for
application for for axon
axonaxon regeneration
regeneration of
regeneration of of lesions
lesionslesions of
of theof the
the human
human human spinal
spinal spinal cord
cord cord and
and and
brain
brain
brain
(Scheme(Scheme
(Scheme 13)
13)
13) [39]. [39].
[39].
brain (Scheme 13) [39].
O R
O O RN
R
O O O N
O O N N
N O N
N
N + + Tos base
ase N N
+ R NH2 base
NC b O N
+ R NH
NH2 + Tos
+ NC O N
R 2 Tos NC DCM O
DCM
DCM
CHO
CHO
CHO
54 55 18 56
54
54 55
55 18
18 56
56
Scheme
Scheme 13.
13. Synthesis
Synthesis of
of chemical
chemical probes
probes 56.
56.
Scheme 13.
Synthesis of
of chemical
chemical probes
probes 56.
56.
Based
Based on
on their
Based on their previous
on their
previous research,
research, they
previous research,
they also
they reported
reported aaa novel
also reported
also reported novel synthesis
synthesis route
route of
a novel synthesis
of potential
potential aspartyl-
route of potential
aspartyl-
Based
protease their
inhibitors previous
in 2007. research,
In their Inthey
2007.method, also novel
1,4,5-trisubstituted synthesis route of potential
1-(4-piperidyl)-imidazoles aspartyl-
1-(4-piperidyl)-imidazoles 59 59 could
aspartyl-protease inhibitors in their method, 1,4,5-trisubstituted 1-(4-piperidyl)-imidazoles
protease inhibitors
protease inhibitors in
in 2007.
2007. In
In their
their method,
method, 1,4,5-trisubstituted
1,4,5-trisubstituted 1-(4-piperidyl)-imidazoles 59 could
could
be
59 obtained
could be through
obtained an isocyanide-based
through an van Leusen
isocyanide-based MCR
van of
Leusen α-substituted
MCR of α-substituted
TosMICs 18, aldehydes
TosMICs 18,
be
be obtained
obtained through
through an
an isocyanide-based
isocyanide-based van
van Leusen
Leusen MCR
MCR of
of α-substituted
α-substituted TosMICs
TosMICs 18,
18, aldehydes
aldehydes
57,
57, and
and 4-aminopiperidine
aldehydes
4-aminopiperidine 58 58 (Scheme
(Scheme 14)
57, and 4-aminopiperidine
14) [40].
58 (Scheme
[40].
14) [40].
57, and 4-aminopiperidine 58 (Scheme 14) [40].
R22
R2
R
R33 R11 N
R3
R base
ase R1 N
N , N
R11 CHO ++ R22 NH2 ++ base R R22== N
R1 CHO + R2 NH2 + Tos NC
- osb
--T osSO2H N R2= N ,, N
R CHO R NH2 os
Tos NC TosSO
SO2HH N R N
H O O
T NC T 2 R33 N N
H O O
R 3
R 59 H O O
57 58 18
57
57 58
58 18
18 59
59
Scheme
Scheme 14.
14. Synthesis
Synthesis of
of potential
potential aspartyl-protease
aspartyl-protease inhibitors
inhibitors 59.
59.
Scheme 14.
Synthesis of
of potential
potential aspartyl-protease
aspartyl-protease inhibitors
inhibitors 59.
59.
In
In 2009,
2009, aa range
2009, aa range
In 2009, range of
of 1,5-disubstituted-4-methylimidazole
1,5-disubstituted-4-methylimidazole preparations
of 1,5-disubstituted-4-methylimidazole
preparations were
preparations were reported
reported by
were reported
by Fodili
reported by
Fodili
by Fodili
Fodili
and In
co-workers. range of
Compounds1,5-disubstituted-4-methylimidazole
63 were prepared from acetimine preparations
analogs 62, were
which were obtained
obtained from
and co-workers. Compounds 63 were prepared from acetimine analogs 62, which were obtained
and co-workers. Compounds
and Compounds 63 63 were prepared
prepared from
from acetimine
acetimine analogs
analogs 62,
62, which
which were
were obtained from
fromco-workers.
dehydroacetic acid
dehydroacetic 60 and
acid andwere
60primary amine
primary 61.
amine These were
61. These enabled
were to
enabledreact with
to react TosMIC
with 18
TosMIC from
in
18the
in
dehydroacetic
dehydroacetic acid
acid 60
60 and
and primary
primary amine
amine 61.
61. These
These were
were enabled
enabled to
to react
react with
with TosMIC
TosMIC 18
18 in
in the
the
presence
presence ofof catalytic
the presence
catalytic amounts
amounts of
of catalytic amounts
of bismuth
bismuth triflate.
of bismuth
triflate. A
triflate. Aplausible
plausible mechanism
plausible mechanismwas
A plausible mechanism was was put
was put forward
forward that
forward that
put forward that
presence
involved of
the catalytic
first amounts
formation of of
an bismuth
imidazolinetriflate. A
intermediate, mechanism
followed by methyl put
migration, and that
then
involved the
involved the first
first formation
formation ofof an
an imidazoline
imidazoline intermediate,
intermediate, followed
followed byby methyl
methyl migration,
migration, and
and then
then
subsequent
subsequent aromatization
aromatization provided
provided access
access to
to the
the target
target imidazole
imidazole ring
ring (Scheme
(Scheme 15)
15) [41].
[41].
subsequent aromatization provided access to the target imidazole ring (Scheme 15) [41].
involved the first formation of an imidazoline intermediate, followed by methyl migration, and then
Pharmaceuticals 2020, 13, x FOR PEER
subsequent aromatization REVIEW
provided access
to the target imidazole ring (Scheme 15) [41]. 8 of 19
R H3C
OH O OH N R H3C
OH N
OH O OH N R H
OH 3C N
- N
OH O CH
3
OH N CH
3
t- BuNH2,, Bi(OTf )3 OH N
CH3 + R NH2 CH3 + Tos NC t -BuNH2, Bi(OTf )3 N
H3C O
+
O CH3 + R NH2 H3C O
+ os
O CH3 + T NC t BuCH
NH2OH Bi(OTf )3 NR
R NH2 Tos NC 3 H3C O O R
H3C O O H3C O O CH3OH H3C O O R
H3C O O H3C O O CH3OH H3C O O
60 61 62 18 63
60 61 62 18 63
60 61 62 18 63
Scheme 15. Synthesis of 1,5-disubstituted-4-methyl imidazoles 63.
Scheme
Scheme 15.
15. Synthesis
Synthesis of
of 1,5-disubstituted-4-methyl
1,5-disubstituted-4-methyl imidazoles
imidazoles 63.
63.
Scheme 15. Synthesis of 1,5-disubstituted-4-methyl imidazoles 63.
In 2012, Hulme and Moliner reported a novel synthesis of two pharmacological relevant classes
In
In 2012,
2012, Hulme and Moliner
Hulme and Moliner reported
reportedaanovel
novelsynthesis
synthesisofoftwo
twopharmacological
pharmacological relevant
relevant classes
classes of
In 2012, Hulme
of molecules formingand
the Moliner reportedaline
imidazoquinox a novel synthesis
scafflod 66 andof68,
two pharmacological
respectively. relevantinvolves
This method classes
of molecules
molecules forming
forming theimidazoquinox
the imidazoquinoxaline
alinescafflod
scafflod6666and
and68,
68,respectively.
respectively. This
This method
method involves
involves
of
themolecules forming the imidazoquinox
use of 1,2-phenylenediamines 64 andaline scafflod
glyoxylic 66 derivatives,
acid and 68, respectively. This method
namely ethyl involves
glyoxylate 65 or
the
the use
use of
of 1,2-phenylenediamines
1,2-phenylenediamines 64 64 and
and glyoxylic
glyoxylic acid
acid derivatives,
derivatives, namely
namely ethyl
ethyl glyoxylate
glyoxylate 6565 or
or
the use of 1,2-phenylenediamines
benzylglyoxamide 64 and glyoxylic
67, along with TosMIC acid derivatives, namely
18 in a microwave-assisted ethylthree-component
van Leusen glyoxylate 65 or
benzylglyoxamide
benzylglyoxamide 67, 67, along
along with
with TosMIC
TosMIC 18 18 in
in aa microwave-assisted
microwave-assisted vanvan Leusen
three-component
benzylglyoxamide
condition. Then there67, along
was awith TosMIC 18 in a microwave-assisted
deprotection–cyclization step to form two vanbiological-activity-enticing
condition.
condition. Then
Then there
there was
was aa deprotection–cyclization
deprotection–cyclization step step to
to form two biological-activity-enticing
form two biological-activity-enticing
condition. Then there
imidazoquinoxaline was a (Scheme
families deprotection–cyclization
16) [42]. step to form two biological-activity-enticing
imidazoquinoxaline
imidazoquinoxaline families
families (Scheme
(Scheme 16)
16) [42].
[42].
imidazoquinoxaline families (Scheme 16) [42].
O
O
O
O CHO
O CHO
O65 CHO HN
65 HN
65,MW HN N
DMF O N
DMF,,MW O N
DMF MW O N
N
NH 66 N
NH22 O 66
Tos NC + NH2 + O 66
Tos NC + + O
Tos NC + NHBoc + N
N
CHO
NHBoc H CHO
NHBoc N
H CHO
18 64 H
18 64
18 64 67 N
67 N
. , 67 . . N N
1. DMF, MW or r. t. overnight H2N N
1
2... DMF,
10%TFAMW or r.t,. overnight H N
, DCE
r MW
or ,t overnight H N 2 N
2. DMF
1 10%TFA , DCE
MW MW 2 N
2 10%TFA, DCE, MW N
68 N
68
68
Scheme 16.
Scheme 16. Synthesis of
Synthesis of
16. Synthesis biologically
of biologically enticing
biologically enticing imidazoquinoxaline
enticing imidazoquinoxaline 66
imidazoquinoxaline 66 and 68.
and 68.
66 and 68.
Scheme
Scheme 16. Synthesis of biologically enticing imidazoquinoxaline 66 and 68.
In
In 2016,
2016,the thePirali’s
Pirali’sgroup
group reported
reporteda method
a methodfor synthesizing 4-PI analogues
for synthesizing via the via
4-PI analogues vanthe
Leusen
van
In 2016, the Pirali’s group reported a method for synthesizing 4-PI analogues via the van Leusen
MCR,
LeusenIn which
2016,
MCR, the Pirali’s
iswhich
by far isgroup
the
by far reported
mostthedirect
most a method for
methodmethod
direct forsynthesizing
obtaining 4-PI analogues
functionally
for obtaining rich
functionally viaimidazole.
the
richvan Leusen
This
imidazole.
MCR, which is by far the most direct method for obtaining functionally rich imidazole. This
MCR, which iscan
transformation
This transformation bybe far
canusedtheused
be tomost directfour
synthesize
to synthesize method for series
different obtaining
four different functionally rich imidazole. This
of compounds—1,4,5-trisubstituted
series of compounds—1,4,5-trisubstituted and
transformation can be used to synthesize four different series of compounds—1,4,5-trisubstituted and
transformation
1,5-, 1,4- and
and 1,5-, 1,4- and can be used
4,5-disubstituted to
4,5-disubstituted synthesize
imidazoles four
imidazoles different
71. 71.
Meanwhile, series
Meanwhile, of compounds—1,4,5-trisubstituted
4,5-diaryl imidazoles
4,5-diaryl imidazoles were analyzed
were analyzed and
by a
by
1,5-, 1,4- and 4,5-disubstituted imidazoles 71. Meanwhile, 4,5-diaryl imidazoles were analyzed by a
1,5-,
3D 1,4- and 4,5-disubstituted
a 3Dquantitative
quantitative structure-activity
structure-activity imidazoles 71. Meanwhile,
relationship
relationship (SAR).
(SAR).Based 4,5-diaryl
Based on
ontheirimidazoles
their docking were
scoreanalyzed
docking score and by a
and synthetic
synthetic
3D quantitative structure-activity relationship (SAR). Based on their docking score and synthetic
3D quantitative
feasibility,
feasibility, the structure-activity
the compounds
compounds were relationship
wereselected,
selected, (SAR).
synthesized,
synthesized, Based
and
and on theirevaluated.
biologically
biologically docking score
evaluated. and synthetic
Compared
Compared with
with 4-
4-PI,
feasibility, the compounds were selected, synthesized, and biologically evaluated. Compared with 4-
feasibility,
PI,
thethe
IDO1IDO1 theinhibitor
compounds
inhibitor products were
products selected,
through
through synthesized,
thisthis experimental
experimental and biologically
method
method havehave evaluated.
enhanced
enhanced theCompared
the potency.
potency. with 4-
Both
Both in
PI, the IDO1 inhibitor products through this experimental method have enhanced the potency. Both
PI, the IDO1 inhibitor products through this experimental method have
in enzymatic and cellular assays, the most active compounds showed lower micromolar potency, but
enzymatic and cellular assays, the most active compounds showed lower enhanced
micromolar the potency.
potency, Both
but no
in enzymatic and cellular assays, the most active compounds showed lower micromolar potency, but
in
no enzymatic
detectable
detectable and
cellular cellular
cellular assays,
toxicity.
toxicity. The The theanalysis
analysismost active compounds
displayed
displayed that athat ashowed
putative
putative lower micromolar
hydrogen
hydrogen bond potency,
bond between between but
the
the Ser167
no detectable cellular toxicity. The analysis displayed that a putative hydrogen bond between the
no detectable
Ser167
of the protein cellular
of the protein
and the toxicity.
andNH theofNH The
the of analysis displayed
the imidazole
imidazole that
ring might
ring might a be
putative hydrogen
responsible
be responsible bond
for improvement
for the the between
improvement of the
of
the
Ser167 of the protein and the NH of the imidazole ring might be responsible for the improvement of
Ser167 of the protein and the NH of the imidazole ring might be responsible
the potency, together with favorable interactions with the partially occupied pocket B. The results
potency, together with favorable interactions with the partially occupied for
pocket the
B. improvement
The results of
above
the potency, together with favorable interactions with the partially occupied pocket B. The results
the
abovepotency,
suggested
suggested together
that thethat with
the favorable
4,5-disubstituted
4,5-disubstituted interactions
imidazoleimidazole with
framework themight
frameworkpartially
might
give occupied pocket
give orientation
a new a new B.
forThe
the results
orientation for the
design
above suggested that the 4,5-disubstituted imidazole framework might give a new orientation for the
above
design
of IDO1 suggested
ofinhibitors, that
inthe
IDO1 inhibitors, 4,5-disubstituted
future in (Scheme
future (Scheme imidazole
17) [43].17) [43].framework might give a new orientation for the
design of IDO1 inhibitors, in future (Scheme 17) [43].
design of IDO1 inhibitors, in future (Scheme 17) [43].
R2 a. R1, R2≠H,, R3
R3 van Leusen MCR R1 R22 a.. R1,,=R2, ≠≠H≠ ,R
3
R33 van Leusen MCR R11 NR
N ab. R11=R H2, R22H≠ H3,, R33
R
R1 CHO + R2 NH + R R b . R H R ≠
c R21 H, R12≠ H,, R
, H R3
R11 CHO + R22 NH22 + Tos NCvan Leusen MCR N b =
R CHO + R NH2 + Tos NC R3 N c... R23=
=
=H,, R111≠, H2,≠ R33
Tos NC R33 N cd. R 2
R H H R R RH≠RH
69 70 18 R N
71 d. R33= H, R1, R2≠H
69 70 18 71 d R =H, R1, R2 H
69 70 18 71
Scheme
Scheme 17.
17. Synthesis
Synthesis of
of potential
potential IDO1
IDO1 inhibitors
inhibitors 71.
71.
Scheme 17. Synthesis of potential IDO1 inhibitors 71.
Scheme 17. Synthesis of potential IDO1 inhibitors 71.
At the same year, the Suresh group developed a direct, sequential, copper-catalyzed N-
At the same year, the Suresh group developed a direct, sequential, copper-catalyzed N-
At the same year,reaction
arylation–condensation the Suresh group
utilizing developed
chiral a direct, sequential,
cyclic 1,2-diamines copper-catalyzed
73 and ortho-haloaryl N-
aldehydes
arylation–condensation reaction utilizing chiral cyclic 1,2-diamines 73 and ortho-haloaryl aldehydes
arylation–condensation reaction utilizing chiral cyclic 1,2-diamines 73 and ortho-haloaryl aldehydes
or ketones 72. The corresponding chiral tricyclic 1,4-benzodiazepines 74 were synthesized in high
At the same year, the Suresh group developed a direct, sequential, copper-catalyzed
Pharmaceuticals 2020, 13, x FOR PEER
N-arylation–condensation REVIEW
reaction utilizing
chiral cyclic 1,2-diamines 73 and ortho-haloaryl aldehydes 9 of 19
Pharmaceuticals 2020,13,
Pharmaceuticals 13, x FORPEER
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of 19
Pharmaceuticals2020,
2020, 13,xx FOR
FOR PEERREVIEW
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19
yield. Subsequently,
yield. Subsequently, 1,4-diazapine
Subsequently, 1,4-diazapine 75
1,4-diazapine 75 was
75 was converted
was converted into
into aaaaa novel
converted into novel tetracyclic
novel tetracyclic N-fused ImBDs
N-fused ImBDs
tetracyclic N-fused through
ImBDs through
through
yield.
yield.
yield. Subsequently,
Subsequently, 1,4-diazapine
1,4-diazapine 75
75 was
was converted
converted into
into novel
novel tetracyclic
tetracyclic N-fused
N-fused ImBDs
ImBDs through
through
van
van Lusen
Lusen imidazole
imidazole synthesis
synthesis (Scheme
(Scheme 18)
18) [44].
[44].
van
van Lusen
van Lusen imidazole
Lusen imidazole synthesis
imidazole synthesis (Scheme
synthesis (Scheme 18)
(Scheme 18) [44].
18) [44].
[44].
N
N
N
H N
CuuII H
H
OHC
OHC * NH2 C C
Cuu,IDMSO
I * N N H * N N
*** NH Naa2CO *** N piperaz ne *** N
OHC
OHC + NH
NH222 CO33,,,DMSO
Naa 2CO
N DMSO N erazine
piperaz ne
iiine
N
+
++
N 22CO33 DMSO + Tos
+ Tos
os NC pip
piperaz
- u
* * N ++ NC t B OH
X
*** NH2 C4H N2 TTos NC tt--BBu℃
NC uOH
, * N R
X
XX R NH C H12 N2 *** NN R t Bu ℃OH *** N
N R
C444H 120 ℃OH
,,2h
12N
R
R NH
NH222 C ℃
H℃12 ,N 2 HN R
R 120℃ 2h H
N R
R
120 ,2h H
R 12 8h2 H R
120
120 ℃
℃ , , 8h HH 120 2h H
H
120 ,8h
120 8h
72 73 74 18 75
72
72 73
73 74
74 18
18 75
75
72 73 74 18 75
Scheme
Scheme 18.
18. Synthesis of N-fused
of
Synthesisof N-fused ImBDs
ImBDs 75.
75.
Scheme
Scheme 18.
18. Synthesis
Synthesis of N-fused
of N-fused ImBDs
N-fused ImBDs 75.
ImBDs 75.
75.
A range
A range
range of
range of
of 5-aryl-1-alkylimidazole
of 5-aryl-1-alkylimidazole
5-aryl-1-alkylimidazole derivantes
5-aryl-1-alkylimidazole derivantes
derivantes 79 79 were
79 were
79 synthetized
were synthetized
synthetized by by utilizing
by utilizing the
utilizing the van Leusen
van Leusen
the van
van Leusen
Leusen
A
A range of 5-aryl-1-alkylimidazole derivantes 79 were synthetized by utilizing the van Leusen
MCR
MCR by
MCR by
by Bojarski
by Bojarski
Bojarski and
Bojarski and
and co-workers,
and co-workers,
co-workers, in
co-workers, in
in 2017.
in 2017.
2017. The
2017. TheThe van
The van Leusen
van Leusen
van reaction
Leusen reaction
Leusen reaction was
reaction was performed
was performed
was performed by
performed by the
by the
by stepwise
the stepwise
the stepwise
stepwise
MCR
MCR by Bojarski and co-workers, in 2017. The van Leusen reaction was performed by the stepwise
cycloaddition
cycloaddition
cycloaddition of
of
of TosMIC
TosMIC
TosMIC 18
18
18 to
to
to the
the
the polarization
polarization
polarization double
double
double bond
bond
bond of
of
of aa preformed
a preformed
preformed imine
imine
imine 78.
78.
78. Imidazole
Imidazole
Imidazole is
is
is
cycloaddition
cycloaddition of TosMIC
ofthe
TosMIC 18
18 toto the polarization
thep-TosOH,
polarization double
double bond
bond of
of aa preformed
preformed imine
imine 78.
78. Imidazole
Imidazole is
is
synthetized
synthetized
synthetized by
by
by the
the elimination
elimination
elimination of
of
of p-TosOH,
p-TosOH, from
from
from the
the
the cyclic
cyclic
cyclic intermediate.
intermediate.
intermediate. Then,
Then,
Then, aromatic
aromatic
aromatic aldehydes
aldehydes
aldehydes
synthetized
synthetized
bind to the
by
by the
the elimination
elimination
appropriate amine. of p-TosOH,
of
Allp-TosOH,
compounds
from
from the cyclic
cyclic intermediate.
the highly
were intermediate.
selective to
Then,
Then, aromatic
5-HT5A. aromatic
These
aldehydes
aldehydes
compounds
bind
bind
bind to
to
to
bind to the
the
the appropriate
appropriate
appropriate
the appropriate amine.
amine.
amine.
amine. All
All
All compounds
compounds
compounds
All compounds were
were
were highly
highly
highly
were highly selective
selective
selective
selective to
to
to 5-HT5A.
5-HT5A.
5-HT5A.
to 5-HT5A. These
These
These compounds
compounds
compounds
These and
compounds
were
were metabolically
were metabolically stable
metabolicallystable in
stableinin human
inhuman
human liver
liver
liver microsome,
microsome,
microsome, showed
showed
showed less
less
lessless toxicity
toxicity
toxicity in HEK-293
in HEK-293
HEK-293
in HEK-293 HepG2
and HepG2
and and
HepG2 HepG2
cells
were
were metabolically
metabolically stable
stable in human
human liver
liver microsome,
microsome, showed
showed less toxicity
toxicity in
in HEK-293 and HepG2
cells
cells
and and
and
were were
were water-soluble
water-soluble
water-soluble (Scheme(Scheme
(Scheme
19) 19)
19)
[45]. [45].
[45].
cells
cells and
and were
were water-soluble
water-soluble (Scheme
(Scheme 19) 19) [45].
[45].
base
ase N
R11 CHO ++ H C NH CH3 + Tos base
NC bbase H3C N N N
R1 CHO ++ HH33CC NH NH2 R11 CH + Tos
N CH NC H3CC NN N
RR1 CHO
CHO H33C NH222 R1
R N CH333 ++ TT
N
os
os NC
NC H
H33C N
1= n o - - R1 N
R 1==i nd ol---3---yl R11
R1 in-ddool l 33 ylyl
R1=i5n
R i -me
d lth3ox yl ndol--3--yl R1
R
R1
5--me
methox oxyiyindo-l- 3-- yl
55 meth th yi
ox yinnddooll 33 yl
yl 78
76 77 18 79
7676 77
77 78
78 18
18 79
79
76 77 78 18 79
Scheme
Scheme 19.
19. Synthesis
Synthesis of 5-HT7
of5-HT7 receptor
5-HT7receptor agonists
agonists 79.
receptoragonists 79.
Scheme
Scheme 19.
19. Synthesis of
Synthesis of
of 5-HT7
5-HT7 receptor
receptor agonists 79.
agonists 79.
79.
In
In 2019,
In 2019,
2019, they
2019, they
they also
also
theyalso synthesized
synthesizedaaaarange
synthesized
alsosynthesized range
range of
rangeof fluorinated
ofoffluorinated
fluorinated
fluorinated indole-imidazoles
indole-imidazoles
indole-imidazoles to
totofind
find
findmore
more
more effective
effective 5-
5-
effective
In
In 2019, they also synthesized a range of fluorinated indole-imidazoles
indole-imidazoles to
to find
find more
more effective
effective 5-
5-
HT7
HT7
5-HT7 receptor
receptor
receptor selective
selective
selectiveagonists
agonists
agonists as
as
as molecular
molecular
molecular probes.
probes.
probes. As
As
Asshown
shown
shown in
in
in Scheme
Scheme
Scheme 20,
20,
20, the
the
the target
target
target compounds
compounds
compounds
HT7
HT7 receptor
receptor selective
selective agonists
agonists as
as molecular
molecular probes.
probes. As shown
Asthe
shown in
in Scheme
Scheme 20,
20, the
the target
target compounds
compounds
82
82 were
82were
were obtained
wereobtained
obtained from
obtainedfrom
from the
fromthethe relevant
therelevant
relevant indoles
relevantindoles
indoles undergoing
indolesundergoing
undergoingthe
undergoing formylation
theformylation
the process
formylationprocess
formylation processand
process and
andthe
and the stepwise
thestepwise
the stepwisevan
stepwise van
van
van
82
82 were obtained from the relevant indoles undergoing the formylation process and the stepwise van
Leusen
Leusen imidazole
Leusen imidazole
imidazole synthesis
imidazole synthesis
synthesis with
synthesis with
with TosMIC
with TosMIC
TosMIC 18.
TosMIC 18.
18. Meanwhile,
18. Meanwhile,
Meanwhile, they
Meanwhile, they indicated
they indicated
they that
indicated that
indicated compound
that compound
that compound 82a
compound 82a might
82a might
82a might
might
Leusen
Leusen imidazole synthesis with TosMIC 18. Meanwhile, they indicated that compound 82a might
be
be
be aaa potential
potential
potential analgesic
analgesic
analgesic or
or
or aaa long-sought
long-sought
long-sought tool
tool
tool for
for
for studying
studying
studying the
the
the receptor
receptor
receptor effect
effect
effect of
of
of 5-HT7,
5-HT7,
5-HT7, based
based
based on
on
on the
the
the
be
be aa potential
potential analgesic
analgesic or aa long-sought
oron long-sought tool
tooloffor studying
studying the
forneuropathic the receptor
receptor effect
effect of
of 5-HT7,
5-HT7, based
based onon the
the
anti-nociceptive
anti-nociceptive
anti-nociceptive function
function
function on
on a
aa murine
murine
murine model
model
model of
of neuropathic
neuropathic pain
pain
pain (Scheme
(Scheme
(Scheme 21)
21)
21) [46].
[46].
[46].
anti-nociceptive
anti-nociceptive function
function on on aa murine
murine model
model of of neuropathic
neuropathic painpain (Scheme
(Scheme 21)21) [46].
[46].
R11 R44 N N
O R4 N
R11
RR O R1R R4 NN NN
R22 O
O K2CO3 R11 N
RR
1
R11==H,,,F R22==CF3,,,OCF3,,,OEt,,,F,,,
RR22 + R44 NH2 ++ Tos K CO3
NC KK222CO R22 R1=HH,,FF RR22==CF
CF ,OCF
3,OCF OEt
, 33e,OEt F,
,CN,FF
R + RR44 NH
NH os
Tos NC CO33 R22 R
RR313==H ,FF R Cl
=H CF ,B
3rrOCF
,3B ,I,I,OM3 eOEt
N
++ R NH222 ++ TTos NC
NC M eOH
eOH
RR R3 == H,, F Cl, , r ,, , OMe ,,
,CN
R33 N MMe R
RR44==H
3 HeFF,,Et
M ClBBr IIOM
Cl OMeCN CN
R33
RR H
NN MeOH OH R33 N R44==M Me, Et
H
HH R33
RR H
NN
N
RR Mee,EtEt
H
HH
80 81 18 82
80
80 81
81 18
18 82
82
80 81 18 82
Scheme
Scheme 20.
20. Synthesis of
Synthesis of 5-HT7
of 5-HT7 receptor
5-HT7 receptor low-basicity
receptor low-basicity agonists
low-basicity agonists 82.
agonists 82.
82.
Scheme
Scheme 20.
20. Synthesis
Synthesis of
of 5-HT7
5-HT7 receptor
receptor low-basicity
low-basicity agonists
agonists 82.
82.
Et N
Et N
Et N
Et N
N NN
F N
F
FF
I
III
N
H
NN
N
H
- HH
AGH--192
AGH
AGH - 192
AGHa192
192
82 a
82aa
82
82
Scheme 21.
Scheme A potential
21. A potential analgesic
analgesic 82a.
82a.
Scheme 21.A
Scheme A potentialanalgesic
analgesic 82a.
Scheme 21.
21. A potential
potential analgesic 82a.
82a.
In 2017,
In 2017, Sharma
2017, Sharma and
Sharma and co-workers
and co-workers developed
developed aaaa brief,
co-workers developed brief, novel,
brief, novel, and
novel, and simple
and simple operational
simple operational van
operational van Leusen
van Leusen
Leusen
In
In 2017, Sharma and co-workers developed brief, novel, and simple operational van Leusen
method.
method. They
They presented
presented the
the first
first van
van Leusen
Leusen process
process towards
towards synthesis
synthesis of
of high
high functionalized
functionalized
method.
method. They
They presented
presented the
the first
first van
van Leusen
Leusen process
process 86, towards
towards synthesis
synthesis of high
high functionalized
of TosMICfunctionalized
dihydrodibenzo[b,f]imidazo[1,2-d][1,4]thia/oxazepine
dihydrodibenzo[b,f]imidazo[1,2-d][1,4]thia/oxazepine 86, by
by reacting
reacting TosMIC 18 and
18 andand
dihydrodibenzo[b,f]imidazo[1,2-d][1,4]thia/oxazepine
dihydrodibenzo[b,f]imidazo[1,2-d][1,4]thia/oxazepine 86, 86, byby reacting
reacting TosMIC
TosMIC 18 18 and
In 2017, Sharma and co-workers developed a brief, novel, and simple operational van Leusen
method. They
Pharmaceuticals
Pharmaceuticals 2020,presented
2020, 13, xx FOR
13, FOR PEERtheREVIEW
PEER first van Leusen process towards synthesis of high functionalized
REVIEW 10 of
10 of 19
19
dihydrodibenzo[b,f]imidazo[1,2-d] [1,4] thia/oxazepine 86, by reacting TosMIC 18 and dibenzo[b,f] [1,4]
dibenzo[b,f][1,4]thia/oxazepines
thia/oxazepines 85, which were85,obtained which were
fromobtained
compoundfrom83compound 83 anda84,
and 84, under under
basic a basic
condition
condition (Scheme 22)
condition (Scheme 22) [47].
(Scheme 22) [47]. [47].
R222
R R222
R
- ro ne
XH CHO C Cl,,LL-P
C-uuCl Proliline X
XH CHO ONaa,,DMF
tt-BBuuON DMF X R333
R KOH,,ACN ACN XX R333
++ R
R111 KOH R
++ TTos
os NC
NH2
NH Cl ℃ MW
MW R111 R444
NC rr..tt..,,55m
miinn 4
Cl R111 R44
120 ℃,,20
R 2
2 minn) R N
N R R N
N R
R ((120 20m i ) os
TTos
R H,,Cl
R111==H Cl R444==Cl
R Cl N
N
22==Cl,,CF = ,O
R Cl CF333 X=SS,O
R2 X
R NO2,,CF
R333==NO CF33
2 2 3
83
83 84 85 18 86
86
84 85 18
Scheme 22.
Scheme
22. Synthesis of
Synthesis of highly
of highly functionalized
highly functionalized molecules
functionalized molecules 86.
molecules 86.
86.
In 2018, the
In 2018, the Weaver
Weavergroupgroupreported
reported that
that twotwo corresponding
corresponding series
series of molecules
of molecules based
based on theonSAR
the
SAR design—N1-substituted
design—N1-substituted 5-indoleimidazoles
5-indoleimidazoles and and N1-substituted
N1-substituted 5-phenylimidazoles
5-phenylimidazoles
SAR design—N1-substituted 5-indoleimidazoles and N1-substituted 5-phenylimidazoles were were were
accessed.
accessed.
The The latter
latter The
accessed. (and latter (and more
more (and more
efficient) efficient)
series series were
were obtained
efficient) series were
by an obtained
accidental
obtained by rearrangement
by an accidental
an accidental rearrangement
rearrangement
of imines that are of
of
imines that
intermediate are
in intermediate
the van Leusenin the van
imidazole Leusen imidazole
synthesis synthesis
reaction. The reaction.
one-pot
imines that are intermediate in the van Leusen imidazole synthesis reaction. The one-pot synthesis The one-pot
synthesis of synthesis
compounds
of compounds
in two steps89
89 compounds
of 89 in two
twothe
utilizing
in steps utilizing
vanutilizing
steps the van
van Leusen
Leusen imidazole
the Leusen imidazole
synthesis synthesis
processsynthesis
imidazole process
is shownprocess
in Schemeis shown
is shown in
23. First,
in
Scheme 23. First,between
imine formation imine formation between 2-indolecarboxaldeyde
2-indolecarboxaldeyde 87 and the appropriate 87 and the amine
benzyl appropriate
88 tookbenzyl
place,
amine
which 88 took
then place,
reacted which
with then
TosMIC
amine 88 took place, which then reacted withreacted
18 and Kwith
2 CO TosMIC
to
TosMIC
3 give 18 and K CO
indoleimidazoles. to give indoleimidazoles.
They have also They
conducted
18 and K22CO33 to give indoleimidazoles. They
2 3
have also
SAR
have also conducted
conducted SAR
studies on their SAR studies
novel studies on
and on their
more their novel
potentnovel and
and more
compounds. more potent
potent compounds.
Compoundscompounds. Compounds
92 were Compounds 92
synthesized 92 were
were
starting
synthesized
from knownstarting
amine 91 from
andknown
aromatic amine 91 and
aldehyde 90aromatic
(Scheme aldehyde
24). These90 (Schemerepresent
inhibitors 24). These inhibitors
a promising
represent
represent a promising
future for athe promising
development future
future for the
of IDO1
for the development
inhibitors of IDO1
with specific
development of IDO1 inhibitors
physical with specific
and chemical
inhibitors with specific physical
properties
physical and
thatand
are
chemical properties
easy to synthesize
chemical properties that are
[48].
that are easy
easy toto synthesize
synthesize [48].
[48].
X
X
R
R
X
X DMF K2COCO33
DMF X N K 2 R
CHO ++ RCH
CHO
RCH2NH
2
NH2
2
X N ++ TTos
os NC
NC
2
℃
3 R
N
2 2
60 ℃ N N
N 60 N
H N
H
H N H
N
H
=Br or H H N
X= N
X Br or H
87
87 88
88 18
18 89
89
Scheme
Scheme 23. One-pot
Scheme 23.
23. One-pot synthesis
One-pot synthesis of
synthesis of potential
of potential IDO1
potential IDO1 inhibitors
IDO1 inhibitors 89.
inhibitors 89.
89.
Arr
A X
X
X
X
DMF X + os K22CO Arr
CO33 A
A CHO ++
ArrCHO DMF N
N X + TTos NC
K 2 3 N
N N
N
H22N
N N NC H
H
H N
2 H
H N N
N
N
H
H
90
90 91
91 18
18 92
92
Scheme 24. One-pot

Scheme 24.
Scheme 24. One-pot
One-pot synthesis
synthesis of
of potential
synthesis of
potential IDO1
IDO1 inhibitors
potential IDO1
inhibitors 92.
92.
inhibitors 92.
In the same year, Kondaparla et al. synthetized a range of short chain 4-aminoquinoline-imidazole
In the same year, Kondaparla et al. synthetized a range of short chain 4-aminoquinoline-
derivatives 95 using two
imidazole derivatives
derivatives steps,two
95 using
using in one-pot, invia
steps, in the van
one-pot, viaLeusen
the van
vanMCR standard
Leusen method. The
MCR standard
standard detailed
method. The
imidazole 95 two steps, one-pot, via the Leusen MCR method. The
synthetic protocol
detailed synthetic for the
synthetic protocol synthesis
protocol for
for the of target
the synthesis compounds
synthesis of of target 95 is shown
target compounds
compounds 95 in Scheme
95 is
is shown 25,
shown in compound
in Scheme
Scheme 25, 94
25,
detailed
as amine was utilized to react with TosMIC 18 and acetaldehyde 93 through a multicomponent
compound 94 as amine was utilized to react with TosMIC 18 and acetaldehyde 93 through a
cyclisation
multicomponentreaction. In the end,
cyclisation all synthesized
reaction. In the end,compounds
the end, werecompounds
all synthesized
synthesized screened against the chloroquine
were screened
screened against
multicomponent cyclisation reaction. In all compounds were against
sensitive and
the chloroquine chloroquine-resistant
chloroquine sensitive
sensitive and strains of
and chloroquine-resistant Plasmodium
chloroquine-resistant strains falciparum.
strains of In this
Plasmodium falciparum.
of Plasmodium study,
falciparum. In substitution
In this
this study,
study,
the
on the N-(2-(1H-imidazol-1-yl)ethyl)-7-chloroquinolin-4-amine moiety had greatly influenced the
substitution on the N-(2-(1H-imidazol-1-yl)ethyl)-7-chloroquinolin-4-amine moiety had greatly
antiplasmodial
influenced bioactivity [49].bioactivity [49].
the antiplasmodial
antiplasmodial
influenced the bioactivity [49].
Pharmaceuticals 2020, 13,
Pharmaceuticals 2020, 13, xx FOR
FOR PEER
PEER REVIEW
REVIEW 11
11 of
of 19
19
R
NH2 R
R
NH
NH22 N
N
N N
N
N
HN
HN
HN
NH
K CO3,,, DMF NH
NH
CHO + + os KK222℃
CO33 DMF
CO DMF
H3C CHO
CHO ++ ++ TT
Tos
os
NC
NC
NC 90℃ , overnight
℃,, overn
H
H33C
C Cl N 90
90 overnight
ight
Cl
Cl N
N
N Cl
N
N Cl
Cl
93 94 18 95
93
93 94
94 18
18 95
95
Scheme 25. One-pot synthesis of antiplasmodial compounds 95.

Scheme
Scheme 25.
Scheme 25. One-pot
25. One-potsynthesis
One-pot synthesisof
synthesis ofantiplasmodial
of antiplasmodial compounds
antiplasmodial compounds 95.
compounds 95.
95.
In the
In the
the same
same year,
year, Laali and
Laali and co-workers
co-workers reported
reported that
that an
an available
available route
route provided
provided access
access to
to
In
In the same
same year,
year, Laali
Laali and
and co-workers
co-workers reported
reported that
that an
an available
available route
route provided
provided access
access toto
various
various C5-substituted
C5-substituted imidazoles
imidazoles 97,
97, 98,
98, and
and 99,
99, through
through one-pot
one-pot tandem
tandem via
via the
the van
van Leusen-Suzuki,
Leusen-Suzuki,
various
various C5-substituted
imidazoles 97,
97, 98,
98, and
and 99,
99, through
through one-pot
one-pot tandemtandem viavia the
the van
van Leusen-Suzuki,
Leusen-Suzuki,
van
van Leusen-Heck,
Leusen-Heck, and van
and van Leusen-Sonogashira
van Leusen-Sonogashira methods,
Leusen-Sonogashira methods, respectively.
methods, respectively. Imidazolium-ILs
respectively. Imidazolium-ILs
Imidazolium-ILsas as solvents,
assolvents,
solvents,
van
van Leusen-Heck,
Leusen-Heck, andand van Leusen-Sonogashira methods, respectively. Imidazolium-ILs as solvents,
along with
along with
with piperidine-appended
piperidine-appended imidazolium [PAIM][NTf
[PAIM][NTf2222]]]] as
imidazolium [PAIM][NTf as task-specific
as task-specific basic
task-specific basic IL
basic IL and
IL and facile
and facile
facile
along
along with piperidine-appended
piperidine-appended imidazolium
imidazolium [PAIM][NTf as task-specific basic IL and facile
aldimines
aldimines 96,
96, and
and TosMIC
TosMIC 18 in
18 in the
the mild
mild condition,
condition, were
were employed
employed in in their
their article
article (Scheme
(Scheme 26)
26) [50].
[50].
aldimines
aldimines 96,
96, and
and TosMIC
TosMIC 18 18 in
in the
the mild
mild condition,
condition, were
were employed
employed in in their
their article
article (Scheme
(Scheme 26)26) [50].
[50].
R
RRN
N
N N
Suzu ki N
N
SSuzu
uzuki
ki Arr/Heet
AAr/H/Hett
Ar/Heet 97
AArr/H
/Hett 97
97
R
RRN
N
N N
R N
N
NRR r e
A /He t
N
N [BMIM][X X] eck
Hec AArr/H
/Hett
+ Tos NC [[BMIM
BMIM][][X]] Heckk
H
Arr/Heet H ++ TTos
os NC
NC [PAIM ][ NTf ]
AAr/H
/Hett H
H [[PAIM NTf222]]
PAIM][][NTf
Br
BBrr
98
R 98
96 18 R 98
R
96
96 18
18
R
RRN
ashira
Sonogas N
N N
SSono hira
onoggashi ra N
N
Arr/Heet
AAr/H
/Hett
R 99
R
R 99
99
Scheme
Synthesis of
26. Synthesis of C5-substituted
imidazoles 97,
97, 98,
98, and
and 99.
99.
Scheme
Scheme 26.
26. Synthesis of
of C5-substituted
imidazoles 97,
97, 98,
98, and
and 99.
99.
In
In the
the late
late 2018,
2018, Guan
Guan and
and co-workers
co-workers developed
developed aa novel
novel and
and highly
highly efficient
efficient synthesis
synthesis of
of
In
In the
the late
late 2018,
2018, Guan
Guan and
and co-workers
co-workers developed
developed aa novel
novel and
and highly
highly efficient
efficient synthesis
synthesis of
of
polysubstituted 1H-imidazo-[4,5-c]
polysubstituted 1H-imidazo-[4,5-c] quinoline
quinoline derivatives
derivatives through thethrough theLeusen/Staudinger/
stepwise van stepwise van
polysubstituted
polysubstituted 1H-imidazo-[4,5-c]
1H-imidazo-[4,5-c] quinoline
derivatives through
through the the stepwise
stepwise van van
Leusen/Staudinger/aza-Wittig/carbodiimide-mediated
aza-Wittig/carbodiimide-mediated cyclization method.cyclizationAzides 102method. Azides by
were accessed 102the
were
vanaccessed
Leusen
Leusen/Staudinger/aza-Wittig/carbodiimide-mediated
Leusen/Staudinger/aza-Wittig/carbodiimide-mediatedcyclization cyclization method.
method. Azides
Azides 102
102 were
were accessed
accessed
by the van
reaction Leusen reaction of 2-azidobenzaldehyde
of 2-azidobenzaldehyde 100, amine
100, amine 101, and TosMIC 101,1H-imidazole-[4,5-c]
18. Then, and TosMIC 18. Then, 1H-
quinoline
by
by the
the van
van Leusen
Leusen reaction
reaction of
of 2-azidobenzaldehyde
2-azidobenzaldehyde 100, 100, amine
amine 101,
101, and
and TosMIC
TosMIC 18. 18. Then,
Then, 1H-
1H-
imidazole-[4,5-c]
103 was formed quinoline
by a tandem103 aza-Wittig
was formedreaction
by a tandem aza-Wittig reaction
with isocyanate, with isocyanate,
in a moderate in a
to good yield
imidazole-[4,5-c]
imidazole-[4,5-c] quinoline 103 was formed by a tandem aza-Wittig reaction with isocyanate, in aa
quinoline 103 was formed by a tandem aza-Wittig reaction with isocyanate, in
moderate
(Scheme 27) to [51].
good yield (Scheme 27) [51].
moderate
moderate to to good
good yield
yield (Scheme
(Scheme 27)
27) [51].
[51].
R22 R22
R2 N
R R2N
R
N
N N NN N
CHO N One-pot
N
CHO
CHO K2CO3 - N
N
R11 + R2NH + Tos NC KK22CO
CO ,33 R11 O ne-ppoott
One R11
R1
R ++ R NH ++ TTos
R22NH os NC CH3OH,,DME
NC R1
R R1
R
N3 CH OH DME N3 N NHR33
N
N33 CH33re fluxDME
OH NN33 NN NHR3
NHR
re
reflflux
ux
100 101 18 102 103
100
100 101
101 18
18 102
102 103
103
Scheme
Scheme 27.
27. Synthesis
Synthesis of
of polysubstituted
polysubstituted quinoline
derivatives 103.
103.
Scheme
Scheme 27.
27. Synthesis
Synthesis of
of polysubstituted
polysubstituted quinoline
derivatives 103.
103.
In 2019,
In 2019, Lammi
Lammi et et al. reported an
al. reported an imidazolyl
imidazolyl peptidomimetic,
peptidomimetic, which which has
has shown
shown proprotein
proprotein
In
In 2019,
convertase2019, Lammi
Lammi et et al.
subtilisin/Kexin al.9reported
reported
(PCSK9) an
an imidazolyl
imidazolyl
inhibitor peptidomimetic,
peptidomimetic,
bioactivity in the which has
has shown
whichdosage
micromolar shown
range. proprotein
proprotein
As shown
convertase subtilisin/Kexin 9 (PCSK9) inhibitor bioactivity in the micromolar dosage range. As
convertase
convertase
in Scheme subtilisin/Kexin
subtilisin/Kexin
28, the first imidazole99 (PCSK9)
(PCSK9)
derivativeinhibitor
inhibitor
105 was bioactivity
bioactivity
accessed in in
in
good the
the micromolar
micromolar
yield, starting dosage
dosage
from range.
range. As
p-anisaldehydeAs
shown in Scheme 28, the first imidazole derivative 105 was accessed in good yield, starting from p-
shown
shown in
in Scheme
Scheme 28,
methylamine 28, the
andfirst
the first imidazole
imidazole
TosMIC derivative
derivative
Then, 105
105 was
compound was accessed
accessed
was in
in good
good
treated yield,
yield,
with starting
n-butyllithium from p-
starting from p-
104,
anisaldehyde 104, 77,
methylamine 77,18.and TosMIC 18. Then,105 compound 105 was treated withandn-
anisaldehyde
anisaldehyde 104, 104, methylamine
methylamine 77, 77, and
and TosMIC
TosMIC 18.18. Then,
Then, compound
compound 105 105 was
was treated with n-
treated with n-
butyllithium and DMF as a formylating reagent at low temperatures, to obtain the aldehyde
butyllithium
butyllithium and and DMF
DMF as as aa formylating
formylating reagent
reagent atat low
low temperatures,
temperatures, to to obtain
obtain thethe aldehyde
aldehyde
derivative 106 in high yield. The target compounds 107a RIm13 and 107b RIm14 were accessed via a
quasi-iterative protocol,
Pharmaceuticals 2020, 13, 37 with the emphasis on the alternating van Leusen three-component reactions 12 of 19
with two formylation steps. In the end, they found that RIm13 represents currently one of the most
potent proprotein
Pharmaceuticals convertase
2020, 13, x FOR PEERsubtilisin/kexin
REVIEW 9/low-density lipoprotein receptor, (PCSK9/LDLR) 12 of 19
protein−protein
Pharmaceuticals interaction
DMF as a formylating
2020, 13, x FOR of small
reagent
PEER REVIEW molecules
at low (Schemeto28)
temperatures, [52]. the aldehyde derivative 106 in
obtain 12 high
of 19
derivative 106 in high yield. The target compounds 107a RIm13 and 107b RIm14 were accessed via a
yield. The target compounds 107a RIm13 and 107b RIm14 were accessed via a quasi-iterative protocol,
derivative
with 106 inprotocol,
quasi-iterative
the emphasis high yield.
on the The
with thetarget
alternating vancompounds
emphasis on the
Leusen 107a
H3CRIm13
alternating
three-component vanand 107b RIm14
Leusen
reactions were accessed
three-component
with two via a
CHO
H3C reactions
formylation steps.
N
quasi-iterative
the end, they
CHO protocol,
found with
that the
with two formylation steps. In the end,K they
In RIm13 emphasis on
represents the alternating
currently one ofvan
Nthe Leusen
found that RIm13 .represents
most three-component
potent proprotein reactions
N
currently one of theNmost
convertase
2CO3 n-BuLi,THF, -78 ℃
with twoproprotein
potent formylation
subtilisin/kexin + CH3NH steps. + In
convertase
9/low-density2
the
os
end, they found
subtilisin/kexin
lipoprotein receptor, that RIm13 1lipoprotein
9/low-density
(PCSK9/LDLR) represents currently
receptor,
protein−protein one of the most
(PCSK9/LDLR)
interaction of small
T NC . , r.t.
potent
H3CO
proprotein
protein−protein
molecules (Scheme convertase
interaction subtilisin/kexin
28) [52]. of small molecules
DMF H3CO 9/low-density
(Scheme lipoprotein receptor,
2
28) [52].
DMF
H3CO (PCSK9/LDLR)
protein−protein
104 interaction
77 of small18 molecules (Scheme105 28) [52]. 106
H3C CHO
NHCH3 H3C
H C N N CHO
CHO 3
N
5 . - H3C
N - ℃ N N
CHO + +
K2CO3
N
NN 1 n BuLi,THF, 78 N
CH3NH2 os . - , , - ℃
H3CO T NC K2CO3 1N n
. BuLi, THF
r.t. 78
+ CH3NH2 + e 2 DMF
H3CO Tos NC DMF HM 3CO N . , r.t. H3CO
DMF H3CON 2 DMF
104 77 18 105
R H3CO 106
104 77 18 N 105 106
H3CO NHCH3
NHCH
5 3
107a RIm 13 R=CHN 2Ph
N
5
107b RIm 14 R=CH N
Me N2CH2Ph N
N N
Me N
N R
Scheme 28. Synthesis of inhibitory activity
N N molecules 107a and 107b.
R
H3CO N
In 2020, Rashamuse and co-workers H3COdescribed a microwave-assisted cycloaddition of TosMIC
18 with imines and aldehydes to form 1-substituted 13 R=CH2Ph

107a RIm5-aryl-1H-imidazoles. Imidazoles 110 were also
107 a RIRI
mm13 ==
14RR
107b CH
CH2Ph
2CH2Ph
obtained in a one-pot, two-steps reaction with a yield
107b RIm 14comparable
R=CH2CH2Ph to that obtained through step-by-
step irradiation of aldehyde Scheme28.
Scheme 108Synthesis
28. and aliphatic
Synthesis amineactivity
of inhibitory
of inhibitory 109, with
activity a neat107a
molecules
molecules microwave
107a 107b.at 60 °C for 4 min,
and107b.
and
followed by the addition Scheme of28.
TosMIC
Synthesis 18,ofKinhibitory
2CO3, and CH3CN,
activity and the
molecules 107areaction
and 107b.mixture was placed
under In microwave
In 2020, conditions
Rashamuse
2020, Rashamuse and
and(Scheme
co-workers29) [53].
co-workers described
described a microwave-assisted cycloaddition of
a microwave-assisted cycloaddition of TosMIC
TosMIC
18 In
18 with 2020,
Moreover,
with imines Rashamuse
iminestheand
and aldehydesand
antibacterial
aldehydes to co-workers
properties
to form described
1-substituted
form 1-substituted a microwave-assisted
of these fragments
5-aryl-1H-imidazoles.
5-aryl-1H-imidazoles. cycloaddition
in vitro were testedImidazolesby the
Imidazoles 110
110of TosMIC
minimum
were
were also
also
18 with
inhibitory
obtained imines
in a and
concentration
one-pot, aldehydes
(MIC)
two-steps to form
bioassay.
reaction 1-substituted
The
with results
a yield 5-aryl-1H-imidazoles.
showed
comparable that the
to that
obtained in a one-pot, two-steps reaction with a yield comparable to that obtained through step-by- MIC Imidazoles
value
obtained of 110
compound
through were also
110a
step-by-step
obtained
against
irradiation inof
a aldehyde
step irradiation one-pot,
Staphylococcus two-steps
aureus
of aldehyde108 and was
108 reaction
aliphatic
and with 109,
15.6aliphatic
μg/mL,
amine awhile
yield
with
amine comparable
110b
109, displayed
a neat
with to that
microwave
a neat obtained
at 60 ◦ C
amicrowave
similar MIC through
for
at 4value
60 min, step-by-
against
followed
°C for 4 min,
step
by irradiation
Bacillus
the
followedcereus,
addition
by the of
of aldehyde
andaddition
indicatedofthat
TosMIC 108
18, and
these
K
TosMIC 2 aliphatic
CO compounds
,
18,
3 and amine
CH CN,
K2CO3, 3and 109,
might CHbe
and with
the
3CN,
a
further neat microwave
and developed at
the reactiontomixture
reaction mixture 60 °C
specifically
was for 4placed
min,
wastarget
placed under
followed
microbial
microwave byconditions
the addition
pathogens
under microwave (Scheme of TosMIC
(Scheme
conditions 30). 18,
29) [53].
(Scheme 29)K[53].
2CO3, and CH3CN, and the reaction mixture was placed
underMoreover,
microwavethe conditions (Scheme 29) [53].
antibacterial properties of these fragments in vitro were tested by the minimum
Moreover, the antibacterial
inhibitory concentration (MIC) bioassay. propertiesThe of these fragments
results showed that in vitro were value
the MIC tested
N
ofbycompound
the minimum 110a
inhibitory concentration (MIC)
CHO bioassay.
against Staphylococcus aureus+ was 15.6+ μg/mL, R2 The results
while showed
K110b
2CO , that
3 displayed
CH 3CN the MICa value
similar of compound
N MIC value against 110a
Tos
BacillusStaphylococcus
against aureus that
was 15.6 μg/mL, while 110b bedisplayed a similar MIC value against
NH2 NC
cereus, and indicated these compounds might MW further developed R2to specifically target
Bacillus cereus, andR 1
indicated
microbial pathogens (Scheme 30). that these compounds might be further developed
R1
to specifically target
microbial pathogens (Scheme 108 30).109 18 110
N
Scheme
Scheme29.
29.Synthesis
Synthesisofofa anovel
novelclass
classofofpotential
potentialinhibitors
inhibitorsofofmicrobial
microbialpathogen
pathogen
N 110.
110.
CHO R2 K2CO3,CH3CN N
CHO + NH R2 + Tos
Moreover, the antibacterial properties
2 NC K2CO3,CHin
of these fragments 3CNvitro
N were tested
NR2 by the minimum
+ NH + N Tos NC MW
R1
inhibitory concentration
2
(MIC) bioassay. The results showed MWthat the MICR1 valueR2of compound 110a
R1 N N R1
against Staphylococcus aureus
108 was 15.6 109 µg/mL, while 18 110b displayed a similar 110 value against Bacillus
MIC
108 H3C 109 18 H3C 110
cereus, and indicated that these
H3C compounds might be further
H3C inhibitors of microbial pathogentarget
developed to specifically microbial
CHof a novel class of potential CH3 110.
pathogens Scheme
(Scheme29.
30). 3
Synthesis of a novel class of potential inhibitors of microbial pathogen 110.
110a N 110b N
N N
Scheme 30. Antimicrobial
N compounds 110a and 110b.
N
H C N H C N
3 3
In 2014, the Bunev group
HH3CC reported a novel process
3
HH3CC for the synthesis of 1,4,5-trisubstituted
3
H3C CH3 CH3
imidazole-containing trifluoromethyl
CH3 group 112, which
H 3C contained two-component condensation
CH3
110a 110b
110a 110b
Scheme 30. Antimicrobial compounds 110a and 110b.
Scheme 30.
Scheme Antimicrobial compounds
30. Antimicrobial compounds 110a and 110b.
110a and 110b.
In 2014, the Bunev group reported a novel process for the synthesis of 1,4,5-trisubstituted
In 2014, the Bunev
imidazole-containing group reported
trifluoromethyl a novel
group 112, process for the synthesis
which contained of 1,4,5-trisubstituted
two-component condensation
imidazole-containing trifluoromethyl group 112, which contained two-component condensation
reaction, N-aryltrifluoroacetimidoyl chlorides 111 reacted with TosMIC 18, as well as sodium hydride
in dry THF at2020,
Pharmaceuticals room13, 37temperature, under argon atmosphere (Scheme 31, top) [54]. 13 of 19
Then, in 2019, they also previously described a procedure, in which 1-imidoylbenzotriazoles [N-
aryl-1-(1H-benzotriazol-1-yl)-2,2,2-trifluoroethan-1-imines] 113 reacted with TosMIC 18, according to
In 2014, the Bunev group reported a novel process for the synthesis of 1,4,5-trisubstituted
the van Leusen
Pharmaceuticals 2020, 13, xreaction
FOR PEERto obtain a good yield of 1-aryl-4-(4-methylbenzenesulfonyl)-5-
REVIEW 13 of 19
imidazole-containing trifluoromethyl group 112, which contained two-component condensation
(trifluoromethyl)-1H-imidazoles 114, which is difficult to access. The yield of 114 almost did not
reaction, N-aryltrifluoroacetimidoyl chlorides
reaction, N-aryltrifluoroacetimidoyl chlorides 111 reacted with
111 reacted with TosMIC
TosMIC 18, as well
18, as well as
as sodium
sodiumhydride
hydride
depend on the substituent in the N-aryl fragment of initial imidoylbenzotriazole 113 (Scheme 31,
in
in dry
dry THF
THF at
at room
room temperature,
temperature, under
under argon
argon atmosphere
atmosphere (Scheme
(Scheme 31,
31, top)
top) [54].
[54].
bottom) [55].
Then, in 2019, they also previously described a procedure, in which 1-imidoylbenzotriazoles [N-
aryl-1-(1H-benzotriazol-1-yl)-2,2,2-trifluoroethan-1-imines]
N CF3
113 reacted with TosMIC 18, according to
R
the van Leusen reaction to obtain a good Clyield of Tos 1-aryl-4-(4-methylbenzenesulfonyl)-5-
N
(trifluoromethyl)-1H-imidazoles 114, which is111 difficult to access. The
N yield of 114 almost did not
depend on the substituent in the N-aryl fragment NaH,THF of initial imidoylbenzotriazole
F3C
R 113 (Scheme 31,
r.t.,2h
bottom) [55].
N 112
Tos NC + N N CF3
N
18 R Ar
ClN Tos N
F3111
C Tos N
N
NaH113,THF F3C
. ., R
Nar H
t 2hTHF F3C N
r.t. 1h Ar
N 112
Tos NC + N 114
N
31. Synthesis of imidazoles
imidazoles 112 Ar containing the trifluoromethyl group.
and 114
112 and 114
Scheme 18of
N containing the trifluoromethyl group.
F3C Tos
Then, in 2019, they also previously described a procedure, in N which 1-imidoylbenzotriazoles
A possible mechanism for synthesis of the113 imidazole-containing trifluoromethyl group is shown
[N-aryl-1-(1H-benzotriazol-1-yl)-2,2,2-trifluoroethan-1-imines]
NaH,THF 113 reacted with TosMIC 18, according
in Scheme 32. Initially, deprotonation of TosMIC . .
with sodiumF3hydride
C N
r
forms stabilized carbanion 18,
to the van Leusen reaction to obtain a rgood A
t 1h yield of 1-aryl-4-(4- methylbenzenesulfonyl)-5-
which attacks the carbon–nitrogen bond’s carbon atom of 115, to give the intermediate adduct 116.
(trifluoromethyl)-1H-imidazoles 114, which is difficult to access. 114 The yield of 114 almost did not
Elimination of the R ion from the latter generates intermediate 117, which undergoes intramolecular
depend on the substituent in the N-aryl fragment of initial imidoylbenzotriazole 113 (Scheme 31,
cyclization Scheme
and leads 31. to imidazole
Synthesis 118.
of imidazoles 112 and 114 containing the trifluoromethyl group.
bottom) [55].
A possible
A possible mechanism
mechanism for forsynthesis
synthesis ofof the imidazole-containingtrifluoromethyl
trifluoromethyl group isis shown
shown
Ar the imidazole-containing
Ar group
r Ar
F C R A N
in Scheme 32. Initially,
in Scheme 32. NInitially,
aH deprotonation Nof TosMIC with sodium hydride3forms stabilized carbanion
deprotonation of TosMIC with sodium
3 F
hydride forms stabilized carbanion 18,
C F3C N 18,
N
Tos attacks
which Tos NC +
NC - the carbon–nitrogen bond’s carbon atom of 115, to give the intermediate adduct 116.
which attacks the
H2 carbon–nitrogen F3Cbond’sR carbon T atom of 115, to
os -
R give Hthe intermediate
C adductN116.
Elimination of
of the
the RR ion
ion from
from the
the latter
latter generates
generates intermediate
intermediate which
117, which N
Tos undergoes Tos
intramolecular
Elimination NC
117, undergoes intramolecular
cyclization and
cyclization and leads
leads toto18
imidazole 118.
imidazole
115
118. 116 117 118
Scheme 32. A possible mechanism for the synthesis of imidazole-containing trifluoromethyl

r
group.
A
Ar Ar
N F3C R Ar F3C N F3C
4. Other van Leusen
NaH Imidazole Synthesis N N
Tos NC - Tos NC + -
H2 F3C R Tos R H C
In 2015, Fodili and collaborators described NCthe
synthesisTosof N a 1,4-disubstituted
Tos N
5-
methylimidazole 121. As 18 shown in Scheme
115 33, compound116 121 was prepared 117 by reacting enamine
118 119
with TosMIC 18, under the presence of tert-butylamine and a catalytic amount of bismuth (III) triflate
Scheme
Scheme32.
32.AApossible
possiblemechanism
mechanismforforthe
thesynthesis
synthesisof
ofimidazole-containing
imidazole-containingtrifluoromethyl
trifluoromethyl group.
group.
in methanol. In this research, it was the first example of a usual rearrangement in the van Leusen
imidazole
4. Other vansynthesis
Leusenand showedSynthesis
Imidazole that the imidazole ring system can be prepared through reaction
4. Other van Leusen Imidazole Synthesis
with TosMIC and a tautomeric enamine, to form a secondary ketamine. The possible mechanism
In 2015, Fodili and collaborators described the synthesis of a 1,4-disubstituted 5-methylimidazole
In 2015,
involves Fodili of
the formation and collaborators
the van describedintermediate,
Leusen imidazoline the synthesis of aby 1,4-disubstituted
followed 5-
a C–C bond cleavage
121. As shown in Scheme 33, compound 121 was prepared by reacting enamine 119 with TosMIC 18,
methylimidazole 121. As shown in Scheme
and then subsequent tosyl substitution [56]. 33, compound 121 was prepared by reacting enamine 119
under the presence of tert-butylamine and a catalytic amount of bismuth (III) triflate in methanol.
with TosMIC 18, under the presence of tert-butylamine and a catalytic amount of bismuth (III) triflate
In this research, it was the first example of a usual rearrangement in the van Leusen imidazole synthesis
in methanol. In this research, it was the first example of a usual rearrangement in the van Leusen
and showed that the imidazole ring system can be prepared through reaction with TosMIC and a
imidazole synthesis and showed that the imidazole ring system can be prepared through reaction
tautomeric enamine, to form a secondary ketamine. The possible mechanism involves the formation of
with TosMIC and a tautomeric enamine, to form a secondary ketamine. The possible mechanism
the van Leusen imidazoline intermediate, followed by a C–C bond cleavage and then subsequent tosyl
involves the formation of the van Leusen imidazoline intermediate, followed by a C–C bond cleavage
substitution [56].
and then subsequent tosyl substitution [56].
O HN OH N
O HN OH N
S N
Bi(OTf )3 N
CH3S - Bi(OTf )3
CH3 +
+ t -BuuNH2 ++ Tos NC ..
t B NH2 Tos NC MeeOH,,rr.t .,,48h CH3 S
H3C
H3C
O
O
O
O
M OH t 48h H3C O O CH3 S
H3C O O
119 120 18 121
119 120 18 121
Scheme
Scheme 33.
Scheme 33. The
33. The first
The first example
first example of
example of an
of an unusual
an unusual rearrangement
unusual rearrangement in
rearrangement in the
in the van
the van Leusen
Leusen imidazole synthesis.
synthesis.
In
In 2019,
In 2019, the
2019, theSuresh
the Sureshgroup
Suresh groupdemonstrated
group demonstratedthe
demonstrated theformation
the formationof
formation imidazoles
ofof
imidazoles
imidazolesin the
inin presence
thethe
presence
presenceof
of water
water
of as
as
water
aas solvent
a solvent and
andand
a solvent a base-free
a base-free condition.
condition.
a base-free The reaction
The The
condition. reaction of dihydro
of dihydro
reaction of dihydroβ-carboline imines
β-carboline
β-carboline imines 122 and
122122
imines p-
p-
andand
toluenesulfonylmethyl isocyanides 18 formed the corresponding substituted N-fused
toluenesulfonylmethyl isocyanides 18 formed the corresponding substituted N-fused imidazo 6,11-
p-toluenesulfonylmethyl isocyanides 18 formed the corresponding substituted imidazo
N-fused 6,11-
imidazo
dihydro β-carboline
dihydro
6,11-dihydro derivatives
β-carboline
β-carboline derivatives 123,
123, with
derivativeswith good
123,good
withyields
yields
goodunder
under mild
mild
yields and
and green
under mild condition
green condition
and green (Scheme
(Scheme 34)
34)
condition
[57].
[57].
(Scheme 34) [57].
General van Leusen imidazole reaction:

General van Leusen imidazole reaction:
R33 R11
R R
R11CH NR22 ++ Base
R CH NR Tos Base R22
Tos
NC
NC R N R33
organic solvent N R
organic solvent N
N
Sures h's work:
Suresh's work:
R22 R22
R R
N R33 N
N R Noo base N
+ os N base
R11 + T os NC .. R11 N
R
N T NC H2O,, rr.t . 2h R
N
N
N H2O t 2h N
H
H H R33
H R
122 18 123
122 18 123
Scheme
Scheme 34.
Scheme 34. The
34. The base-free
The base-free van
base-free van Leusen
Leusen imidazole synthesis
imidazole synthesis of
synthesis of cyclic
of cyclic imines
cyclic imines in
imines in water.
in water.
water.
A
A possible
possible mechanism for
mechanism for the
for the present
the present metal-
present metal- and
metal- and base-free
and base-free imidazole
base-free imidazole framework
imidazole framework is
framework is shown
is shown in
shown in
in
Scheme
Scheme 35.35. Initially,
Initially, the
the precursor dihydro β-carboline
precursor dihydro β-carboline imine
imine 122
122 acts
acts as
as aa base
base that
that captures
captures proton
proton
Scheme 35. Initially, the precursor dihydro β-carboline imine 122 acts as a base that captures proton
from the dihydro β-carboline
from TosMIC
from TosMIC 18, 18, to
to provide
provide aa C-nucleophile,
provide a C-nucleophile, which
C-nucleophile, which would
which would add
would add to
add to the
to the dihydro
dihydro β-carboline imine
β-carboline imine 122,
TosMIC 18, to imine 122,
122,
and
and then be cyclized to form the intermediate 125 through the intermediate 124. Another molecule of
then
and then be
be cyclized
cyclized totoform
form the
the intermediate
intermediate 125125 through
through thethe intermediate
intermediate 124.124. Another
Another molecule
molecule of the
of
the starting
starting dihydro
dihydro β-carboline
β-carboline imineimine 122 captures
122 captures a proton
a proton fromfrom intermediate
intermediate 125,
125, then
the starting dihydro β-carboline imine 122 captures a proton from intermediate 125, then removes the then removes
removes the
the tosyl
tosyl
group,group,
tosyl group, which
which mightmight
which might result
result inin the
the construction
construction of
result in the construction
of imidazole
of imidazole
imidazole derivative
derivative 123.
123. Subsequently,
Subsequently, the
derivative 123. Subsequently, the product
the
product
imidazoleimidazole
123 might123 might
also act asalso act
a base as a base
following following
the rational the rational
reaction reaction
mechanism,
product imidazole 123 might also act as a base following the rational reaction mechanism, as mechanism,
as described asin
described
described in
Scheme 35.
in Scheme
Scheme 35.35.
R22 R22 R22
R R H R H
C H H
N Tos N C N N
N Tos N N C N
N C N
H R N N
N H R N N H
R11 N
H R11 N Tos R
H R11 N
H H R Tos
R H R H Tos R R H R Tos
122
122 18 124 122 125
122 18 124 125
R22
R
- os N
-T osH N
T H 122 +
122 + N
N
N
R11 N
H
R H R
R
123
123
Scheme 35. A
Scheme mechanism for the
the base-free van
Scheme 35.
35. A possible
possible mechanism for
for the base-free
base-free van Leusen
Leusen imidazole synthesis.
synthesis.
At
At the
the same
same year,
year, Necardo
Necardo et
et al.
al. found
found an
an unusual
unusual multicomponent
multicomponent synthesis
synthesis of
of 4-tosyl-1-
4-tosyl-1-
arylimidazoles
arylimidazoles 127, by
127, by considering
considering aryl azides as the electrophilic partners for the TosMIC 18-
aryl azides as the electrophilic partners for the TosMIC 18-
At the same year, Necardo et al. found an unusual multicomponent synthesis of 4-tosyl-1-
Pharmaceuticals2020,
Pharmaceuticals 13,xxFOR
2020,13, FORPEER
PEERREVIEW
REVIEW 15 of
15 of 19
19
arylimidazoles 127, by considering aryl azides as the electrophilic partners for the TosMIC 18-mediated
mediated
mediated
van van
van
Leusen Leusen cycloaddition.
Leusen cycloaddition.
cycloaddition. In this
In this transformation,
transformation,
In this transformation, it is the firstititexample
is the
is the first
first example
of example
the of the
of
reaction thetwo
of reaction
reaction
TosMIC of
of
two TosMIC
two TosMIC molecules
molecules molecules participating
participating participating in
in van Leusen in van
van Leusen
Leusen imidazole
imidazole imidazole synthesis
synthesis (Scheme synthesis (Scheme
36) (Scheme 36)
[58]. 36) [58].
[58].
RR
NN33
--
++ 22 TTos OK,,DMF
tt BBuuOK DMF NN
os NC
NC ℃ o r.... m n
℃ NN
00 tto r tt 30
30min
i
RR os
TTos
126
126 18
18 127
127
Scheme
Scheme 36.
Scheme36. Synthesis
36.Synthesis of
Synthesisof 127
of127 by
127by van
byvan Leusen
vanLeusen imidazole
Leusenimidazole synthesis
imidazolesynthesis with
synthesiswith two
withtwo TosMIC.
twoTosMIC.
TosMIC.
AAplausible
A plausible scenariofor
plausible scenario
scenario forthe
for theMCR
the MCR
MCR is isshown
is shown
shownin in Scheme
inScheme
Scheme37. 37.
37.InIn the
Inthe initiation
theinitiation step,
initiationstep, the
step,the TosMIC
theTosMIC
TosMICanion anion
anion
attacks N-3
attacks
attacks N-3 of
N-3 of the
of the azide
the azide 128
azide 128 to
128 to produce
to produce intermediate
produce intermediate 129.
intermediate 129. Then,
129.Then, N-1
Then, N-1 intercepts
N-1 intercepts the
intercepts the isocyanide
isocyanide in
the isocyanide in ain
a 6-
6-
a
endo-trig cyclization
endo-trig
6-endo-trig cyclization to
cyclization to form
form anion
to form anion 130,
anion 130, which
130,which is
which is quenched
quenched by
is quenched by aa proton
by proton source
a proton source to
source to give
give 131.
to give131. Owing
131. Owing to
Owing to
its its
its
to instability,
instability,
instability, compound
compound
compound 131
131 processes
processes
131 processes a[4[4++ +
aa [4 2]2]cycloreversion
2] cycloreversion
cycloreversionto totoformation
formation
formation132, 132, with
withaaaloss
132,with loss
loss ofof
of
nitrogen. Subsequently,
nitrogen.
nitrogen. Subsequently,the
Subsequently, theimine
the imine
imine of
ofof 132
132132 passes
passes
passes through
through
through an attack
an
an attack attack by aa second
by
by a second second
molecule molecule
molecule of the
of
of the TosMIC the
TosMICanion,
TosMIC
anion, anion,followed
followed followedby
by ring byring
ringclosure,
closure, closure,to
to producetoproduce
produce133.
133. At 133.AtAtthis
this thispoint,
point, point,after
after afterprotonation,
protonation,intermediate
protonation, intermediate
intermediate 134
134 regains
134 regains
regains aromaticity
aromaticity
aromaticity via
via avia aa base-assisted
base-assisted
base-assisted mechanism,
mechanism,
mechanism, with
withwith the expulsion
the expulsion
the expulsion ofmost
of
of the the most
the most
acidic acidic
acidic
proton proton
proton
and
and loss
and
loss loss of
of of hydrogen
hydrogen hydrogen cyanide
cyanide cyanide and
and and sulfinate.
sulfinate. sulfinate. Under
Under Under strong
strong basicstrong basic
basic condition,
condition, condition, excess
excess t-BuOK excess t-BuOKt-BuOK
deprotonates
deprotonates
deprotonates
the newly formed the newly
the newly
hydrogen formed
formed hydrogen
hydrogen
cyanide, avoiding cyanide,
cyanide, avoiding
avoiding
the release the release
the
of toxic release
HCN. of ofis
It toxic
toxic
worth HCN.
HCN. ItIt is
noting isthat
worth
worth the
noting that
noting
two that the
molecules the twotwo molecules
of molecules of
TosMIC of TosMIC
partake TosMIC partake
in the partake in
reaction in the
the reaction
mechanism reaction mechanism
in mechanism in
two different in two
two different
paths, different paths,
with the paths,
second
with
with thesecond
the
molecule second
in Scheme molecule
molecule inScheme
in Schemea37
37 undergoing 37 undergoingaaresulting
undergoing
fragmentation fragmentation
fragmentation resultingin
in the resulting
incorporation inthe
theof incorporation
incorporation
a C−H into the of
of
a C−H
C−Hmolecule.
atarget into the
into the target
target molecule.
molecule.
NN
NN HH
NN OO OO --
NN NN t t BBuuOH
OH NN OO
128
128 NN SS CH33
CH NN SS CH33
CH NN SS CH33
CH
OO NN NN OO NN NN OO NN NN OO
SS NCNC
OO 129
129 130
130 131
131
HH33CC
18
18 HH
retro
re [4++22] ]
tro[4 NN22
NN HH NN
NN OO NN OO
OO OO SS SS NN OO
NN SS NN
NN OO NN OO SS CH33
CH
NN
CH33
CH CH33
CH OO
++ HCN
HCN ++ OO OO 132
132
OO SS SS SS OO
OO OO
OO --
t t BBuuOK
OK NN SS
CH33
CH OO
CH33
CH
CN
CN HH33CC HH33CC
HH33CC 135
135 134
134 133
133 18
18
Scheme37.
Scheme
Scheme 37.A
37. Aplausible
A plausiblescenario
plausible scenariofor
scenario forthe
for the van
thevan Leusen
vanLeusen imidazole
Leusenimidazole synthesis
imidazolesynthesis with
synthesiswith two
withtwo TosMIC
twoTosMIC molecules.
TosMICmolecules.
molecules.
In 2019,
In 2019,
In 2019, thethe one-pot
the one-pot three-component
one-pot three-component
three-component van van Leusen
van Leusen chemistry
Leusen chemistry
chemistry was was used
was used for
used for the
for the DNA-encoded
the DNA-encoded
DNA-encoded
libraries (DELs)
libraries (DELs)
libraries synthesis
(DELs) synthesis
synthesis by by the
by the Staz
the Staz group,
Staz group, which
group, which provided
which provided
provided the the first
the first published
first published DNA-compatible
published DNA-compatible
DNA-compatible
approach to
approach
approach to form
to form unusual
form unusual highly
unusual highly functionalized
highly functionalized imidazoles.
functionalized imidazoles.
imidazoles. TheThetarget
The targetDEL
target DELproductions
DEL productions138
productions 138 were
138 were
were
obtained from
obtained
obtained from the
from thethealdehyde
aldehydefunctionalized
aldehyde functionalizedDNA
functionalized DNAmolecule
DNA molecule136,
molecule 136,amine
136, amine
amine 137, and
137,
137, and
andTosMIC
TosMIC
TosMIC derivatives
derivatives
derivatives 18
by the
18 by
18 van
by the
the vanLeusen
van Leusen reaction.
Leusen reaction. Moreover,
reaction. Moreover, a wide
Moreover, aa wide variety
wide varietyof amines,
variety of commercial
of amines,
amines, commercial TosMIC
commercial TosMIC molecules
TosMIC molecules
moleculesand
aldehyde
and aldehyde
and as the
aldehyde as variety
as the element
the variety in
variety elementthe three
element inin theingredients
the three heterocyclization
three ingredients were
ingredients heterocyclization investigated
heterocyclization were under an
were investigated
investigated
optimized
under an
under condition,
an optimized respectively.
optimized condition, This transformation
condition, respectively.
respectively. This meaningfully
This transformation expanded
transformation meaningfully the application
meaningfully expanded
expanded of van
the
the
Leusen imidazole
application of
application of van synthesis
van Leusen and
Leusen imidazole DNA compatible
imidazole synthesis
synthesis and chemistries
and DNA (Scheme
DNA compatible 38)
compatible chemistries[59].
chemistries (Scheme
(Scheme 38)
38) [59].
[59].
O O R2
R3 O N
DNA + R2 NH2 + base N
N R1 DNA
H Tos NC aq. DMA N R1
H R3
136 137 18 138
Scheme 38.
Scheme DNA-compatible van
38. DNA-compatible van Leusen
Leusen imidazole
imidazole heterocyclization.
heterocyclization.
5. Conclusions
5. Conclusions
In summary, under the in-depth research and application in imidazole-based medicinal chemistry
In summary, under the in-depth research and application in imidazole-based medicinal
and the progress in other disciplines—such as cell biology, molecular biology, pharmacology, and organic
chemistry and the progress in other disciplines—such as cell biology, molecular biology,
chemistry—an increasing number of imidazole-containing drugs with lower toxic, better efficacy,
pharmacology, and organic chemistry—an increasing number of imidazole-containing drugs with
superior pharmacokinetic characteristics, effective pathologic probes and diagnostic agents would
lower toxic, better efficacy, superior pharmacokinetic characteristics, effective pathologic probes and
be used in clinics. This could make remarkable contributions for the protection of mankind’s health.
diagnostic agents would be used in clinics. This could make remarkable contributions for the
Therefore, the van Leusen imidazole synthesis based on TosMICs will play an increasingly central
protection of mankind’s health. Therefore, the van Leusen imidazole synthesis based on TosMICs
part in the synthesis of bioactive compounds as clinic drugs in drug design and synthesis. We could
will play an increasingly central part in the synthesis of bioactive compounds as clinic drugs in drug
focus on the changing of the various aldimine groups and TosMIC derivatives in the van Leusen
design and synthesis. We could focus on the changing of the various aldimine groups and TosMIC
reaction to modify the imidazole derivatives in future. Above all these have clearly indicated the
derivatives in the van Leusen reaction to modify the imidazole derivatives in future. Above all these
infinite potentiality of van Leusen imidazole synthesis in medicinal chemistry. Additionally, we hope
have clearly indicated the infinite potentiality of van Leusen imidazole synthesis in medicinal
this review would build a full foundation and reference source which would open up new thoughts
chemistry. Additionally, we hope this review would build a full foundation and reference source
for researchers to focus on in imidazole-based medicinal molecule design and synthesis chemistry.
which would open up new thoughts for researchers to focus on in imidazole-based medicinal
molecule design and synthesis
Author Contributions: All authorschemistry.
wrote the paper. All authors have read and agreed to the published version of
the manuscript.
Author
Funding:Contributions: All authors
Financial support wrote the
of this research paper. All
provided by authors have
the Science read
and and agreed
Technology to the published
Planning Project of version
the Jilin
of the manuscript.
Province (20160414015GH) is greatly acknowledged.
Funding:
Conflicts Financial support
of Interest: of this declare
The authors researchno
provided
conflict by the Science and Technology Planning Project of the Jilin
of interest.
Province (20160414015GH) is greatly acknowledged.
References
Conflicts of Interest: The authors declare no conflict of interest.
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© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).

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Keywords: van Leusen; TosMICs; imidazole; synthesis

Pharmaceuticals 2020, 13, 37; doi:10.3390/ph13030037 www.mdpi.com/journal/pharmaceuticals

Scheme 1. General van Leusen imidazole synthesis.

R33 R33 R33 R11

Scheme 6. Synthesis of ketone 29 and 1,4-disubstituted imidazole 30.

Scheme 24. One-pot

Scheme 25. One-pot synthesis of antiplasmodial compounds 95.

18 with imines and aldehydes to form 1-substituted 13 R=CH2Ph

Scheme 32. A possible mechanism for the synthesis of imidazole-containing trifluoromethyl

General van Leusen imidazole reaction:

31. Sisko, J. A one-pot synthesis of 1-(2,2,6,6-tetramethyl-4-piperidinyl)-4-(4-fluorophenyl)-5-(2-amino-4-

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