Month 2015 Chemistry of 2-Aminoimidazoles

Aleš Žula, Danijel Kikelj, and Janez Ilaš*

Faculty of Pharmacy, University of Ljubljana, Aškerčeva 7, 1000 Ljubljana, Slovenia
*E-mail: janez.ilas@ffa.uni-lj.si
Received December 1, 2014
DOI 10.1002/jhet.2415
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).

The 2-aminoimidazole (2-AI) ring is used widely as a building block in the design of new biologically
active compounds, because of its good physico-chemical properties and potent activity in various test sys-
tems. Many marine alkaloids contain the 2-AI moiety. As a consequence, many synthetic routes have been
developed in the total synthesis of natural compounds. The review covers all synthetic procedures for con-
struction of 2-AI in particular and its analogs up to December 2014.

J. Heterocyclic Chem., 00, 00 (2015).

INTRODUCTION exchange reactions. In the fourth class, the 2-AI ring is

introduced to the other molecule. We describe the
2-Aminoimidazole (2-AI) moiety is common in medici-
applicability of each method and its appropriateness
nal chemistry [1] and in isolated marine alkaloids from dif-
regarding the desired substituents. No synthetic method
ferent species of sponge [2]. The pyrrole-2-aminoimidazole
yet exists that would proceed under mild reaction condi-
marine alkaloids family contains more than 150 members
tions in good yield. Existing syntheses of unsubstituted
[3]. Members of this group of marine alkaloids possess var-
and substituted 2-AIs are often carried out under harsh
ious biological activities, varying from purealidin A, a po-
conditions, starting from labile precursors and using com-
tent inhibitor of mycothiol-S-conjugate amidase [4],
mon condensation strategies, frequently resulting in low
stylissadines A that inhibit P2X7 receptors [5], to
overall yields.
palau’amine, that show potent immunosuppressive activity
(Fig. 1) [6]. Compounds containing the 2-AI fragment are Elementary condensation approaches to the
2-aminoimidazole ring. Lawson’s, Lancini/Lazzari’s, and
active against various targets, making it a good building
Kreutzberger’s condensations constitute the basis of the
block [7–12] in the design of new compounds. Their wide
synthetic procedures to the 2-AI ring. In the first approach
application is the result of its basic and spatial properties,
to the unsubstituted 2-AI ring, introduced by Lawson in
because the active sites of many biological targets contain
1956, acetic acid-catalyzed nucleophilic addition of amino
aspartate and glutamate residues with which the 2-AI ring
group of aminoacetaldehyde diethylacetal (1) to nitriles of
interacts with four hydrogen bonds. In addition, 2-AI is
cyanamide (2) gave protected guanidine acetaldehyde 3.
increasingly used as a bioisostere replacement of
Hydrochloric acid then catalyzed cyclization to produce
guanidine in the design of thrombin inhibitors [13],
the 2-AI heterocycle 4 (Scheme 1) [17,18].
acylguanidine in the design of the sodium hydrogen
This route has been employed in the synthesis of the 1-
exchanger isoform-1 (NHE-1) inhibitors [14], and
substituted-2-aminoimidazoles 7 by Lowe et al. and in the
benzamidine and triazole groups in the design of com-
synthesis of 2-(arylamino)imidazoles 11 by Munk et al.
pounds with antibacterial activity [15,16]. More than
Lowe and co-workers used substituted aminoacetaldehyde
10 different syntheses of the 2-AI ring have been pub-
diethylacetal 6, which undergoes cyclization with cyana-
lished, their utility varying mainly according to the
mide (2) to generate the corresponding 1-carboxymethyl-
substituents on the 2-AI core. This review is focused
2-aminoimidazole 7 (Scheme 2) [18]. Munk et al. used
on the syntheses reported up to January 2014 and their
N-(2,2-diethoxyethyl)carbodiimide (8) to convert amines
applicability to the synthesis of new compounds.
9 to the substituted N-(diethoxyethyl)guanidine intermedi-
ate 10 in the presence of methanesulfonic acid as a catalyst.
In the last step, in the presence of HCl in water, the 2-
SYNTHESIS OF THE 2-AMINOIMIDAZOLE RING
substituted amino imidazole 11 was obtained in 60% over-
Approaches to synthesizing the 2-AI ring can be di- all yield (Scheme 3) [19].
vided into four classes. The first comprises methods using In the second approach to the 2-AI ring, Kreutzberger
condensation strategies, the second contains methods by condensated amino groups of 1,2-hydrazinedicarboxamidine
which the amino group is introduced directly to the (12) with the carbonyl groups of benzoin derivatives 13 in
imidazole ring, and the third class combines heterocyclic alkaline media to generate 4,4′,5,5′-aryl (Ph, 2-naphthyl,

© 2015 HeteroCorporation
 A. Žula, D. Kikelj, and J. Ilaš
Figure 1. Bioactive marine natural products containing 2-AIs.
2-Py, 2-Me-6-Py)-substituted azoimidazoles 14 within 6 h
in 40–90% yield. Air oxygen (O2) is responsible for the ox-
idation of intermediate 2,2′-hydrazoimidazoles to generate
conjugated double bond of compound 14. Cleavage of the
azo group by catalytic hydrogenation afforded two mole
equivalents of the 4,5-diaryl substituted 2-aminoimidazoles
15 (70–90% yield) (Scheme 4) [20].
Kreutzberger’s procedure [20] was used to introduce a 2-
amino group into the imidazole ring, utilizing imidazole-4-
acetic acid (16) protected as a methyl ester 17. This was
then coupled to (4-methoxycarbonylphenyl)diazonium salt
(18) to form a diazo compound 19 that, on catalytic reduc-
tion, afforded the 2-AI product 20 in 31% overall yield.
This procedure was used to prepare the γ-aminobutyric acid
agonists (Scheme 5) [21].
Another approach to produce 2-AI via direct introduc-
tion of the 2-amino group to the N-protected imidazole ring
was through different mechanisms achieved and reported
by Wang and co-workers in the synthesis of marine natural
product oroidin 21. The synthesis started from urocanic
acid, which was N-protected using trityl protecting group,
esterified, and finally, reduced to alcohol 22. In the next
step, hydroxyl group of 22 was protected with TBS
protecting group and then treated with tosyl azide in the
presence of a strong base, such as n-butyl lithium, to pro-
duce the 2-azido imidazole ring 23 with 94% yield. Ob-
tained amino group, prepared from hydroxyl group
Scheme 1
Journal of Heterocyclic Chemistry
Vol 000
Scheme 2
through phthalimido protecting group, was then acylated
with 4,5-dibro-2-trichloroacetylpyrrole to generate com-
pound 23b. The trityl protecting group was cleaved, and
the azido group was quantitatively reduced to free amino
group by catalytic hydrogenation to generate oroidin 21
(Scheme 6) [22]. Lindel and co-workers used the same pro-
cedure to introduce an amino group into the imidazole at
position 2, in which N-protected alkynylimidazoles were
used as a starting material instead of urocanic acid. The in-
troduction of an azide group was again introduced to the
imidazole ring using tosyl azide and n-butyl lithium [23].
Kawasaki and co-workers used the same procedure as
Wang to generate 2-AI in the synthesis of marine alkaloid
ageliferin. The same strong base (n-BuLi) was used with a
different azidation reagent (trisyl azide) to generate 2-azido
imidazole ring in 55% yield. This was followed by reduc-
tion of the azido group with Pd/C to the corresponding 2-
AI derivative [24].
In a synthesis of 2-AI, similar to that of Wang [22],
Cole et al. prepared 1-substituted 2-aminoimidazoles, as
inhibitors of thymidine phosphorylase. Commercially
available 2-nitroimidazole (25) was substituted at position
1, followed by reduction of nitro group to amino group
with NaBH4 and Pd/C to give 27 (60–70% yield). NaBH4
was used in this reaction as a donor of hydrogen
(Scheme 7) [25,26].
DOI 10.1002/jhet
Month 2015 Chemistry of 2-Aminoimidazoles
Scheme 3
The third elementary synthesis of the 2-AI ring was de-
scribed by Lancini and Lazzari in 1966. They prepared the
1,4-disubstituted 2-AI ring by cyclization of N-methyl α-
aminoketones 28 with cyanamide (2). It was found that a
pH of 4.5 is crucial for the success of this reaction [27].
This approach is one of the most commonly used in the to-
tal synthesis of marine alkaloids with a 2-AI moiety. Horne
et al. used it for the total synthesis of mauritiamine,
hymenidin, and clathrodin marine alkaloids [28,29]; Stoltz
et al. for the total synthesis of dragmacidin D and F alka-
loids [30–32]; and Watson and co-workers for the concise
total synthesis of naamidine A alkaloid (Scheme 8) [33].
Horne’s procedure to 2-AI moiety starting from α-
aminoesters is widely used in the synthesis of antibacterial
compounds [34].
In terms of yield, the number of synthetic steps and
the complexity of the reactions elementary condensation
approach described by Lancini and Lazzari proved to
be the best (Scheme 8). This method is conducted in rel-
atively few steps with good yield (62%) of the condensa-
tion towards 2-AI. Moreover, the reactions are carried
out under mild conditions, which are of a great impor-
tance to the functional groups optionally present in the
side chains. The best modified method proved to be the
direct introduction of amino group to the position 2 of
imidazole ring, described by Wang and co-workers
(Scheme 6). The important advantage of this approach
is because an amino group on the imidazole ring leads
to more polar molecule and consequently to difficulties
in purification, which is avoided by introducing the
amino group to the imidazole ring in the last step.
Scheme 4
Journal of Heterocyclic Chemistry
Scheme 5
Despite this advantage and a good yield, the reaction has
certain limitations. The introduced azido group is also a
good leaving group and can lead to the dimerization
products. Moreover, the catalytic hydrogenation of the
azido group in the last step can cause reduction of the
other groups in the molecule.
Approaches to 4,5-disubstituted-2-aminoimidazole rings.
Weber and Little in 1994 designed a new approach of
wide applicability to 4,5-disubstituted-2-AI ring, which
could be already considered as elementary route to 2-AI
as the previously mentioned Lawson’s, Lancini/Lazzari’s,
and Kreutzberger’s routes. Weber and Little showed in
1994 that condensation of N-acetylguanidine (30) with α-
haloketones 31, followed by the removal of the acetyl
group with hydrazine or sulphuric acid, generates 4,5-
disubstituted-2-aminoimidazoles 33 (Scheme 9) [35]. The
first step resulted in 32–92% yield within 16 h, while the
acetyl group was cleaved off in 67–86% yield in 24 h.
The substituents R1 and R2 were, respectively, both short
and long alkyl and aryl chains such as ethyl, tert-butyl,
phenyl, 4-Br-phenyl, 3-NO2-phenyl, and 4-MeO-phenyl
(Scheme 9). Weber′s procedure is currently a commonly
used procedure to prepare 2-AI ring [34–40]. Because of
the harsh conditions needed to remove the acetyl group at
position 2 of the 2-AI ring, several research groups have
used a modified Weber′s procedure, in which the acetyl
guanidine moiety is replaced by Boc-protected guanidine
[16,41–43].
DOI 10.1002/jhet
 A. Žula, D. Kikelj, and J. Ilaš
Scheme 6
Scheme 7
An alternative approach to 4,5-disubstituted-2-
aminoimidazoles via nitroenolates was used by Su et al.
starting from free carboxylic acid 34. Carboxylic acids 34 ac-
tivated with 1,1′-carbonyldiimidazole were reacted with the
methylene group of nitroalkyl derivatives 35 in alkali media
to give α-nitro ketones 36 in 20–50% yield. In the next step,
their nitro group was reduced to the corresponding α-amino
ketone using catalytic hydrogenation over Pd/C in hydro-
chloric acid. The α-amino ketone was then treated with
cyanamide (2) at pH 4.5, as used by Lancini, to yield
4,5-disubstituted-2-aminoimidazoles 37 (Scheme 10) [44].
The 4,5-disubstituted-2-aminoimidazoles 41 can also be
prepared via bromination of the respective ketone 38 and
subsequent reaction of the resulting α-bromoketone 39
with N-acetylguanidine (30) to 1-acetyl-4,5-disubstituted-
2-aminoimidazoles 40 (1 h, 15–40% yield,) followed by
acid deprotection of the amino group. The substituents
used were aryl moieties, such as 2-pyridyl, 6-quinoxalyl,
and 6-triazolopyridinyl (Scheme 11) [37].
Journal of Heterocyclic Chemistry
Vol 000
4,5-Disubstituted-2-aminoimidazoles were also prepared
using Nishimura’s diketone condensation. Substituted
α-diketones 42 with guanidine (43) gave 2-aminoimidazo-
4-oles 44 with 83–91% yield in 30 min, which can then be
reduced, by catalytic hydrogenation, to 4,5-disubstituted-
2-aminoimidazoles 45 [45]. The reaction worked with aryl
as well as alkyl R1 and R2 substituents (Scheme 12).
Another simple approach to 4,5-disubstituted-
2-aminoimidazoles utilizes ring rearrangement of 1,2,
4-oxadiazole derivatives, where starting N-(1,2,4-oxadiazol-
3-yl)-β-enaminoketones 46, prepared by acylation of
5-phenyl-1,2,4-oxadiazol-3-amine with substituted β-
dicarbonylic compounds, undergo a three-atom side chain
rearrangement under basic conditions to give the corres-
ponding 2-(N-acylamino)imidazoles 47 in 50–75% yield.
Cleavage of the acyl group is achieved under acidic condi-
tion (HClaq) in 50–90% yield to give compound 48
(Scheme 13) [46].
The most appropriate approach for the synthesis of 4,5-
disubstituted-2-aminoimidazoles proved to be Nishimura’s
diketone condensation (Scheme 12). This synthesis starts
from commercially available reagents and is carried out
in only two steps resulting in an excellent yield in a short
time under mild conditions. Again, there are restrictions
imposed by the groups, which can be reduced during cata-
lytic hydrogenation in the last step.
Approaches to the 1,4,5-trisubstituted-2-aminoimidazole
ring. Synthesis of 1,4,5-trisubstituted-2-aminoimidazoles
was explored by Steenackers et al. using trisubstituted
propargylamines 49, which were guanylated with N,N′-bis-
Boc-protected thiourea (50) in the presence of activating
agent 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and
diisopropylethylamin [47]. The resulting propargylguanidines
51 underwent cyclization in the presence of silver nitrate in
acetonitrile to produce the desired Boc-protected 1,4,5-
DOI 10.1002/jhet
Month 2015 Chemistry of 2-Aminoimidazoles

Scheme 8

Scheme 9 Scheme 11

Scheme 10 Scheme 12

1,4,5-trisubstituted-2-aminoimidazoles 52b in good yield

(75–95%) (Scheme 14).
trisubstituted-2-aminoimidazoles 52a in good overall Similar to this methodology, Zavesky and co-workers
yield (70–98%). The cleavage of Boc protection groups explored that starting N-propargyl guanidines via
was achieved under acidic conditions to obtain desired Pd-catalyzed carboamination reaction with aryl triflates

Journal of Heterocyclic Chemistry DOI 10.1002/jhet

 A. Žula, D. Kikelj, and J. Ilaš
Scheme 13
Scheme 14
generate 2-AI heterocycle. This new one-step approach to
2-aminoimidazoles is rapid (3 h), with good overall yield
(49–97%), and different aryl groups are well-tolerated.
The reaction was conducted using 1.0 eqiuv of N-propargyl
guanidines, 2.0 equiv of Ar-OTf, 2.4 equiv of base LiOtBu,
4 mol % Pd(OAc)2, and 8 mol % RuPhos in PhCF3 as a sol-
vent (Scheme 15), where C–N and C–C bonds were gener-
ated during the annulation step. This new method for the
synthesis of 2-AI was used in the total synthesis of marine
natural products preclathridine A, preclathridine B, and
dorimidazole B [48].
An alternative approach to 1,4,5-trisubstituted-
2-aminoimidazoles by Steenackers et al. uses
2-aminopyrimidines (53) that reacted with the α-
Scheme 15
Journal of Heterocyclic Chemistry
Vol 000
bromocarbonyl compounds 54 under microwave irradia-
tion to afford 2-hydroxy-2,3-dihydro-1H-imidazo[1,2-a]
pyrimidin-4-ium salts 55 (80–90% yield). These were
treated with hydrazine to give the 1,4,5-trisubstituted-2-
aminoimidazole rings 56 (62–76% yield) via an unusual
Dimroth-type rearrangement based on microwave irradia-
tion (Scheme 16). The proposed mechanism of rearrange-
ment was the following. The 2-hydroxy-2,3-dihydro-1H-
imidazo[1,2-a]pyrimidin-4-ium salts 55 were cleaved with
hydrazine to produce pyrazole and 2-amino-5-
hydroxyimidazolidines, where the latter cyclize to the iso-
meric 2-amino-5(4)-hydroxyimidazolidines. In the final
step, the dehydration caused by microwave irradiation led
to 1,4,5-trisubstituted-2-aminoimidazole rings 56 [49,50].
This procedure was widely employed to prepare the 4-
substituted and 4,5-disubstituted-2-aminoimidazoles series
[51] as well as a large library of 1,4-disubstituted-2-
aminoimidazoles as beta-site amyloid precursor protein
cleaving enzyme 1 (BACE-1) inhibitors as potential anti-
Alzheimer’s drugs [52], 1,4-disubstituted-2-aminoimidazoles
as a scaffold of the marine alkaloids preclathridines A and
C; isonaamine A, C, D, and E [53]; and 4,5-disubstituted-2-
aminoimidazoles as a new biofilm formation inhibitors[54]
and also 4-phenyl-2-aminoimidazoles as voltage-gated
sodium channel modulators [55]. Again, synthesis started
from substituted 2-aminopyrimidines (53), which were
treated with appropriately substituted α-bromoaldehydes 57
in a microwave reactor, followed by cleavage of the
corresponding intermediates 58 with hydrazine to afford
the corresponding 1,4-disubstituted-2-aminoimidazoles 59
(55–90% yield) through an unusual Dimroth-type rearrange-
ment based on microwave irradiation (Scheme 17).
Boehm et al. prepared 1,4,5-trisubstituted-2-
aminoimidazoles by opening the symmetrical disubsti-
tuted epoxides 60 with the primary amines 61 (49–84%
yield within 38 h) and oxidation of the resulting amino al-
cohols 62 to the amino ketone 63 with pyridinium dichro-
mate (50–56% yield). Cyclization with cyanamide (2) led
to 1,4,5-trisubstituted-2-aminoimidazoles 64 (76–89%
Scheme 16
DOI 10.1002/jhet
Month 2015 Chemistry of 2-Aminoimidazoles
Scheme 17
yield) by using previously employed protocol [27]
(Scheme 18) [56].
Boehm’s procedure for preparing the 1,4,5-trisubsti-
tuted-2-aminoimidazole motif was also used in preparing
a series of antibacterial compounds in which the 2-AI ring
is part of the tetrahydrobenzimidazole ring 67 (Scheme 19).
Prepared epoxide 65 was opened with a mixture of aque-
ous ammonium hydroxide and methanol to produce
aminoalcohol, which was Boc-protected and oxidized in
the presence of pyridinium dichromate to obtain Boc-
protected α-aminoketone 66. In the next steps, Boc
protecting group of compound 66 was cleaved under acidic
conditions and cyclized with cynamide (2) to produce
tetrahydrobenzimidazole ring 67 in very good overall
yield, 61% for over steps [57].
From the perspective of yield, implementation, reagent
availability, number of steps, and the length of the synthe-
sis, the best route to 1,4,5-trisubstituted-2-aminoimidazole
core is the procedure described by Steenackers et al.
(Scheme 16) although the substituents on the 2-AI building
block require some attention as they may undergo nucleo-
philic reactions with hydrazine.
Scheme 18
Journal of Heterocyclic Chemistry
Approaches to the 1,2,4,5-tetrasubstituted-2-aminoimidazole
ring. The first and rapid three-step procedure towards the
1,2,4,5-tetrasubstituted-2-aminoimidazole ring was
described by Giles and co-workers. A three-component
coupling reaction, using secondary amines 68, aldehydes
69, and alkynes 70 and catalyzed by copper(I), generated
tertiary amines 71. Introduction of the cyano group, using
von Braun condition, gave trisubstituted propargyl
cyanamides 72 with yields for both steps from 61% to
93%. In the last step, La(OTf)3 promoted hydroamination–
isomerization of prepared cyanamides 72 with secondary
amines RR4NH 73 in propan-2-ol as a solvent to produce
2-AI ring 74 in good yield (54–96%) (Scheme 20). Other
catalysts, such as Zn2+ and Cu2+ salts, were also used,
wherein La(OTf)3 proved to be in the terms of yield the
most appropriate [58]. The major contribution of this
approach is in wide applicability in the synthesis of multi
substituted 2-AI compounds, because of mild reagents and
simple and relatively rapid synthesis with an excellent
overall yield. The great advantage of this procedure is also
in the usage of various substituents from short alkyl and
aryl to long or basic moiety.
Approaches to the 1,4-disubstituted-2-aminoimidazoles.
1,4-Disubstituted-2-aminoimidazoles were synthesized
from N-Boc-protected α-amino acids 75 and N,O-
dimethylhydroxylamine (76) and (Benzotriazol-1-yloxy)
tris(dimethylamino)phosphonium hexafluorophosphate
(BOP) as coupling agent to give first N-methoxy-N-
methylamides (Weinreb amides) 77 in 45–60% yield,
which were then reduced with diisobutylaluminum
hydride (DIBAL-H) in THF to their corresponding
aldehydes 78 (60–70% yield). Finally, Boc protecting
group of aldehydes 78 was removed quantitatively
under acidic conditions and in the next step reacted with
cyanamide (2) (pH = 4.3) to form 1,4-disubstituted-2-
aminoimidazoles 79 (23–59% yield). Substituents such as
alkyl, Bn, and aryl are well-tolerated (Scheme 21) [59].
Another concise synthesis of 1,4-disubstituted-2-
aminoimidazoles from α-azido esters 80 was described by
Molina et al. in the synthesis of marine alkaloids isonaamine
Scheme 19
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 A. Žula, D. Kikelj, and J. Ilaš Vol 000

Scheme 20

Scheme 21 conversion from α-azido esters 80 to protected-2-

A, dorimidazole A, and preclathridine. As a starting
material, different α-azido esters 80 were used, which were
converted with triphenylphosphine to the corresponding
iminophosphoranes 81 under Staudinger conditions. In the
next step, iminophosphoranes 81 were treated with tosyl iso-
cyanate to give carbodiimides 82, which were reacted with
different amines 83 to afford guanidine-substituted interme-
diates 84 that underwent spontaneous cyclization to form the
corresponding protected-2-aminoimidazolones 85. The
aminoimidazolones 85 was achieved in 50–60% yield.
Protected-2-aminoimidazolones 85 were easily converted
into protected-2-aminoimidazoles 87 by two steps with the
treatment with DIBAL-H and then with methanesulfonyl
chloride in 31–67% yield for both steps. In the last step,
tosyl-protected group was cleaved in the presence of samar-
ium diiodide in 90–95% yield (Scheme 22) [60].
The most useful procedure reported so far towards 1,4-
disubstituted-2-aminoimidazoles proved to be the proce-
dure demonstrated in Scheme 21. The great advantages
of this procedure are in the commercially availability of
Boc-protected starting compound, such as natural or unnat-
ural Boc-protected amino acids and in simple and rapid
synthetic steps under mild conditions. The advantage of
this procedure is also in various substituents, tolerated be-
tween short or long alkyl and aryl moiety and protected
amino acid side chains.
Other approaches to 2-aminoimidazole ring. An elegant
path to 4-substituted-2-aminoimidazoles with a potential for
simple conversion to 1,4-disubstituted-2-aminoimidazoles
from asymmetric ketones was disclosed by Baran in the
synthesis of marine alkaloid sceptrin 89 (Scheme 23). First,
dimethylacetal 90 was formed from ketone then treated
with dichloroiodate to generate α-chloroketone 91. Further

Scheme 22

Journal of Heterocyclic Chemistry DOI 10.1002/jhet

Month 2015 Chemistry of 2-Aminoimidazoles
Scheme 23
conversion to the α-aminoketone 92 was achieved with
sodium diformylamide followed by acid-catalyzed
hydrolysis. From here, the Lancini’s procedure with
cyanamide (2) was used to produce 4-monosubstituted-2-
aminoimidazole moiety 89 [61].
Similar to the synthesis presented in Scheme 21 is the
preparation of 4-substituted-2-aminoimidazoles introduced
by Ilies et al. Here, N-protected α-amino esters 93 were re-
duced with DIBAL-H in ether to aldehydes 94 (89–90%
yield), which were Boc-deprotected and cyclized with cy-
anamide (2) (pH 4.5) to 2-aminoimidazoles 95 in 30–40%
yield. Short and long alkyl chains with protected groups
are tolerated as the substituents (Scheme 24) [62]. The 4-
substituted-2-aminoimidazole can be prepared in similar
fashion to this reaction from α-amino ester by the reduction
of ester to the corresponding aldehyde with sodium
amalgam, followed by Lancini/Lazzari’s condensation pro-
cedure with cyanamide. This approach is favorable, be-
cause the usage of unprotected α-amino esters in the
reduction of ester is tolerated, because of acidic reaction
conditions [28].
A general and efficient synthesis of 4-substituted-2-
aminoimidazoles starting from carboxylic acids 96 com-
prises their conversion with oxalyl chloride to the corre-
sponding acyl chlorides 97 (88–90% yield) followed by
Scheme 24
Journal of Heterocyclic Chemistry
α-bromo homologation with diazomethane and bromine
to produce the respective α-bromoketones 98 (87–91%
yield), which then undergo condensation with Boc-
guanidine 99 (49–63% yield) and quantitatively Boc-
deprotected in acidic conditions. The substituents include
short and longer alkyl chains and protected functionalized
alkyl groups (Scheme 25) [42,16].
The simple and concise synthesis of 4-substituted-2-
aminoimidazole ring, illustrated by the formation of the
marine alkaloids hymenin 101 and girolline 102, was
achieved through ambivalent additions of 2-AI to 103
and 105. In the synthesis of racemic (+/ )girolline 102,
2-AI was added directly to the α-chloroaldehyde 103
through the position 4 of the 2-AI in the presence of so-
dium carbonate, but the yield of this step is quite low be-
cause of the instability of the β-phtalimido-α-
chloroaldehyde 103 under basic conditions (17%)
(Scheme 26) [63]. Sosa’s approach to hymenin 101 has re-
vealed that 2-AI can be added directly to the prepared al-
kene 106 in the presence of methanesulfonic acid in 60%
yield (Scheme 27). Intermediate 106 was prepared from
compound 105 via deprotection of aldehyde protection
group in acidic conditions, followed by intramolecular ring
closure by aldol condensation. In the next step,
pyrroloazepinone 106 was coupled with 2-AI through
acid-facilitated coupling reaction to afford hymenin 101
in good yield [64].
Scheme 25
Scheme 26
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 A. Žula, D. Kikelj, and J. Ilaš
Scheme 27
N-2,C-4-disubstituted 2-aminoimidazoles 107 were syn-
thesized in good yield from disubstituted cyanohydrazones
108 with trimethylsilyl trifluoromethanesulfonate and
1,1,1,3,3,3-hexafluoroisopropanol (Scheme 28) [65].
N-substituted 4-(3-amino-propen-1-yl)-2-aminoimidazoles
109 can also be formed in about 50% yield from N-
substituted-1,2-dihydropyridines 110 through formation
of the bicyclic products 111 with Boc-guanidine (99) in
the presence of bromine (36–40% yield) in the first step.
In the next step, the opening of bicyclic products 111 with
6N hydrochloric acid led to corresponding 2-AI 109
(Scheme 29) [66,67].
2-AI can be easily prepared with good overall yield from
carboxylic acid via acyl chlorides and α-bromoketones.
The intermediate amino aldehyde, needed for the cycliza-
tion with cyanamide towards 2-AI, can be easily prepared
from N-protected amino acid esters. The condensation re-
agents, which are used for the preparation of 2-AI, are cy-
anamide or guanidine. 4-Substituted 2-AI with unsaturated
Scheme 28
Scheme 29
Journal of Heterocyclic Chemistry
Vol 000
side chain is easily prepared in two synthetic steps and
good overall yield from 1,2-dihydropyridines.
CONCLUSION
Lawson’s, Lancini/Lazzari’s, Kreutzberger’s, and
Weber’s condensation procedures serve as the basis for
the current approaches to the monosubstituted, disubsti-
tuted, and trisubstituted 2-AI ring. There is now an increas-
ing focus on the synthesis of the trisubstituted (1,4,5) and
multiply substituted (1,2,4,5) 2-AI ring as new
pharmacophores or central scaffolds. No general method
existed for the synthesis of 2-AI under mild conditions
and in satisfactory yield for many years. Many recently de-
veloped syntheses of 2-AI are, however, conducted in a rel-
atively few steps and in good yields. Moreover, the
reactions are carried out under mild conditions, which are
of a great importance to the functional groups present in
the side chains. Compounds with promising biological ac-
tivity and discovery of novel marine alkaloids possessing
the 2-AI ring will increase the demand for effective syn-
thetic approaches for the synthesis of 2-aminomidazoles.
Acknowledgments. This work was supported by the European
Union FP7 Integrated Project MAREX: Exploring Marine
Resources for Bioactive Compounds: From Discovery to
Sustainable Production and Industrial Applications (Project
No. FP7-KBBE-2009-3-245137). The authors thank Prof.
Roger Pain for the critical reading of the manuscript.
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