One-Pot Access towards 4,5-Disubstituted 2-Amino-1H-imidazoles Starting from Mannich Substrates and their Transformation Utilities

Article abstract of DOI:10.1002/ejoc.202001253

An efficient protocol for the preparation of 4,5-functionalised 2-amino-1H-imidazoles as fragment-like structures was developed in isolated yields up to 95 %. The demonstrated one-pot manner includes an intramolecular oxidative annulation and ring cleavage sequence starting from Mannich precursors. The suggested one-pot sequential synthetic methodology is easy to apply in automatic and robotic chemistry laboratories for which a rapidly increasing demand is foreseen because of the ongoing revolution in the field of continuous manufacturing of pharmaceutical drug substances and products. Further transformation utilities such as Groebke–Blackburn–Bienaymé 3CR and the formation of marine alkaloid analogs were also represented.

Full text of DOI:10.1002/ejoc.202001253

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: One-pot access towards 4,5-disubstituted 2-amino-1H-imidazoles
starting from Mannich substrates and their transformation utilities
Authors: Zsófia Makra, Attila Bényei, László G. Puskás, and Ivan
Kanizsai
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001253
Link to VoR: https://doi.org/10.1002/ejoc.202001253
01/2020

10.1002/ejoc.202001253
European Journal of Organic Chemistry
FULL PAPER
One-pot access towards 4,5-disubstituted 2-amino-1H-imidazoles
starting from Mannich substrates and their transformation
utilities
Zsófia Makra,a Dr. Attila Bényei,b Dr. László G. Puskás,a Dr. Iván Kanizsaia,*
[a]
[b]
AVIDIN Ltd., Alsó kikötő sor 11/D, Szeged, H-6726, Hungary
University of Debrecen, Department of Physical Chemistry, Laboratory for X-ray Diffraction, Egyetem tér 1, Debrecen, H-4032, Hungary
Correspondence: Dr. Iván Kanizsai, AVIDIN Ltd., Alsó kikötő sor 11/D, Szeged H-6726, Hungary; Tel.: +3662202107; Fax: +3662202108
E-mail: i.kanizsai@avidinbiotech.com, URL: https://avidinbiotech.com/
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: An efficient protocol for the preparation of 4,5-
difunctionalised 2-amino-1H-imidazoles as fragment-like
Among various synthetic approaches, formation of the 4,5-
disubstituted 2-AI scaffold has attracted a great deal of attention
due to the encoded biological potential and importance for drug
design (examples E–G, Figure 1)[4] including several
condensation reactions[5-7] as well as cleavage of the imidazo[1,2-
structures was developed in isolated yields up to 95%. The
demonstrated one-pot manner includes an intramolecular
oxidative annulation and ring cleavage sequence starting from
Mannich precursors. The suggested one pot sequential synthetic
methodology is easy to apply in automatic and robotic chemistry
laboratory for which a rapidly increasing demand is foreseen
because of the ongoing revolution in the field of continuous
manufacturing of pharmaceutical drug substances and products.
Further transformation utilities such as Groebke–Blackburn–
Bienaymé 3CR and formation of marine alkaloid analogues were
also represented.
a]pyrimidine
ring.[8-11]
For
condensation
procedures,
iminophosphorane-mediated or base-catalysed annulation of
vinyl azides have been presented exploiting isocyanates,[5a]
imidates or thioamidium reagents[5b] as well as cyanamide under
conventional heating[5c] or microwave and visible light
irradiations[5d] (Entry 1, Scheme 1). The treatment of diaryl or
dialkyl diketones with N,N-dimethylguanidine followed by Pd-
catalysed hydrogenation led to 4,5-substituted 2-AI analogues.[6a]
Similar condensation procedures including the reaction of α-
haloketones,[6b-c] alkenones[6d] (Entry 2, Scheme 1) or diaryl α-
hydroxyketones (aroins)[6e] with N-acetylguanidine or guanidine
salts have also been reported. A three-component condensation
was also described by the assembly of 1,3-dimethylbarbituric acid,
arylglyoxal hydrates and guanidine salts (Entry 3, Scheme 1).[7]
The 2-amino-1H-imidazole (2-AI) core is a general motif occurring
in various marine alkaloids isolated from sponges (representative
examples A–D, Figure 1),[1] possessing a broad range of
pharmaceutical properties such as cytotoxic behaviour and
antibacterial and antiviral activities. For some related structures
incorporating 2-AI, adrenergic, serotonine and histamin receptor
antagonist and enzyme-inhibition effects were found depending
on the substitution pattern.[2] In addition, they may act as
organocatalysts, due to their hydrogen bond donor and/or
acceptor ability.[3]
Condensation methods
(1)
Et3N
or
R1
KOAc
R2
H2N
H2N
N
C
EtOH, heating
or
N3
µ
tBuOH, W or led light
R1
(2)
O
·HCl
NH
H
, MnO
R
K2CO3
MeO
2
O
HN
N
R2
R2
R1
NH2
OMe
abs.1,4-dioxane, heating
N
H2N
N
NH
Br
R
NH
H2N
N
H
1= COOMe, COOEt, COOtBu,
N
R
(3)
N
O
O
N
Br
AcOH
COAryl, COmorpholyl, Aryl
NH
R
H2N
·HCO
N
NH
N
H
2= Alkyl, Aryl, Heteroaryl,
3
H2N
µ
W
N
EtOH,
R
HO
H
Br
H2N
NH2
O
R=Br : Oroidin
(A)
1,3-dimethylbarbituric acid substituent
O
O
R=H : Clathrodin (B)
OH
Naamine D
(D)
Hymenin
(C)
Alkaloid isolated from the sponge Marine sponge alkaloid
from the Leucetta family
Marine sponge alkaloids
from the Agelas family
Hymeniacidon sp.
Adrenergic receptor antagonist
iNOS inhibitor
Cl
Antibacterial agents
Scheme 1. Condensation procedures for the synthesis of 4,5-disubstituted 2-AI
compounds.
3
O
S
O
Br
O
NC
H
N
O
N
Cl
N
H2N
N
HN
F
O
H2N
H
N
N
N
N
4
The first method to form the 2-AI core via the fused systems
based on 2-aminopyrimidines condensation and the deprotection
of the resulted bicycles to afford 4-benzoyl-substituted 2-AI
derivatives was demonstrated by Tišler and co-workers (Entry 1,
OMe
N
N
O
H2N
H
H
MeO
OMe
(E)
Anticancer agent
(F)
Antibacterial agent
(G)
Antiviral activity
Figure 1. Representative examples of natural and synthetic bioactive 2-AI
Scheme 2).[8] Afterwards, Van der Eycken published
microwave-assisted one-pot, two-step protocol for the synthesis
a
frameworks.
1
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10.1002/ejoc.202001253
European Journal of Organic Chemistry
FULL PAPER
of 1,4-, 1,5- and 1,4,5-substituted 2-AI compounds.[9] First,
imidazo[1,2-a]-pyrimidine salts were formed by condensation of
2-aminopyrimidines and α-bromocarbonyl reagents. The desired
compounds were obtained by opening the heterocycle salts by
means of hydrazine. Later, they tested secondary amines for the
controlled cleavage of fused imidazopyrimidines.[10] Similar
results involving a microwave-assisted procedure were also
demonstrated for the preparation of 4,5-disubstituted 2-AI starting
from 2-arylimidazo[1,2-a]pyrimidines[11] (Entry 2, Scheme 2). Van
der Eycken also reported a multi-step process to introduce C4
ester or amide functions (R1 = OR, NHR) and C5 aryl (R2)
substituents. This latter arylation step was carried out via a Pd-
mediated reaction.[12]
O
O
O
O
-CHO
R2
PTA or TMSCl
R1
R
R1
NH2
R
MeCN or H2O, 60 or 80 °C
HN
R2
R=Me, Ph
1=OEt, Me, Ph
N
N
R
N
N
2=Alkyl, Aryl
R
, 20-90%
1a-w
Scheme 3. The synthetic protocol for the preparation of Mannich precursors.
Before the investigation of the sequential one-pot procedure, the
formation of key intermediate 1ab was investigated.[13] For this
study,
ethyl
2-benzoyl-3-phenyl-3-(pyrimidin-2-yl)amino-
In our previous report, we described the synthesis of imidazo[1,2-
a]pyrimidine frameworks by oxidative annulation of Mannich
precursors.[13] As a continuation of our research, herein we
demonstrate an efficient, sequential, one-pot synthetic protocol
for the preparation of structurally diverse 4,5-disubstituted 2-AI
scaffolds via Mannich three-component reaction (3CR) starting
from β-ketoesters, 2-aminopyrimidine and aldehydes followed by
an oxidative annulation and a ring cleavage sequence (Entry 3,
Scheme 2). Our concept is based on achieving valuable, unique
and easily transformable 2-AI fragments as precursors for the
construction of pharmacologically relevant, highly diverse and
more complicated structures.
propanoate 1a was selected as model substrate for optimisation.
Utilising slightly modified reaction conditions, the reaction of 1a
with iodoxybenzoic acid (IBX) and N-iodophtalimide (IPT) in 4.75
mL dimethylacetamide (DMA) at 80°C led to the desired
heterocycle in an excellent isolated yield of 94% (Scheme 4).
O
O
O
OEt
IBX (1.1 equiv.)
IPT (1.5 equiv.)
Ph
HN
OEt
N
4.75 mL DMA,
80 °C, 30 min
N
1ab
N
, 94%
N
N
1a
Ring cleavage
Scheme 4. Preparation of the crucial intermediate 1ab
Tišler et al., 1986 "pioneering work"
(1)
O
O
Ph
Ph
N2H4
or NH
HN
2OH
N
Afterwards, exploiting the observed optimal parameters for the
generation of 1ab (see Table S1.), both the ring cleavage
procedure and the one-pot protocol could be studied. Repeating
the ring-closing assembly followed by the addition of 4 equivalents
of hydrazine hydrate afforded the desired 2-AI product 2a isolated
in an overall yield of 58% (X-ray structure on Figure 2.). However,
full conversion could not be achieved even after 48 hours (Entry
1, Table 1). Increasing the amount of hydrazine hydrate up to 6 or
8 equivalents improved the yields of 2a (74 and 78%) in shorter
reactions (Entry 2 and 3). Because of the unfavourable properties
of hydrazine monohydrate, we investigated the applicability of the
hydrochloride salt of hydroxylamine. Because of the low boiling
point of the hydroxylamine base (liberated by TEA; 58 °C), the
reaction temperature was decreased from 80 °C to 50 °C, which
improved the yield of 2a to 80% from 67% (Entries 4 and 5). Of
other bases tested (Entries 6–8), Na2CO3 gave the best result
(82%, Entry 8). Any efforts such as the use of further additives
were not successful to increase the yield (Entries 9, 10). Finally,
applying a mixture of NH2OH·HCl and the base in an increased
amount (10 equivalents each) led to a superior result (92% yield,
Entry 11). When the model reaction was carried out either at room
temperature or using an about two-fold amount of DMA solvent or
10 equivalents of methyl hydrazine (control experiment), lower
yields were experienced (Entries 12-15).
N
EtOH, reflux
N
H2N
N
Van der Eycken et al., 2009
(2)
O
O
O
O
R1
Incorporating of R2
R1
R2
R1
R2
Br
R1
N
µ
N
N
HN
20% N2H4,
W
O
Pd-mediated
Condensation
step
Ring-cleavage
H2N
step
N
NH2
N
R
N
N
−
N
N
Aryl C C coupling
1= OEt, NHPh, NHBn; R2=Aryl
Ref [12]
Our retrosynthetic strategy
Sequential one-pot procedure
(3)
O
O
O
R1
R2
O
O
1. Oxidative annulation
2. Ring cleavage
R
R1
Mannich-3RC
R
R1
HN
OHC-R2
R2
N
HN
H2N
N
N
N
N
NH2
1= OEt, Me, Ph; R2= Alkyl, Aryl
R= Ph or Me; R
Scheme 2. Ring cleavage procedures towards 4,5-disubstituted 2-AI.
For construction of the desired chemical library, the M-3CR
reactions
aminopyrimidine with some β-keto esters and either aliphatic or
aromatic aldehydes affording Mannich substrates 1a–w as
diastereomeric mixtures in yields up to 90% (Scheme 3).
[13],[14]
were accomplished by the treatment of 2-
2
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10.1002/ejoc.202001253
European Journal of Organic Chemistry
FULL PAPER
Table 1. Optimisation of one-pot protocol, ring-cleavage reaction conditions.
Table 2. Substrate scope.
1. IBX (1 equiv.), IPT (1.5 equiv.)
DMA, 80 °C, 30 min
2. NH2OH·HCl/Na2CO3
1. IBX (1 equiv.), IPT (1.5 equiv.)
O
O
O
R1
R2
4.75 mL DMA, 80 °C, 30 min
.
O
O
O
OEt
(10 equiv.)
R
R1
HN
2. Reagent (equiv.)
temperature, time
DMA, 50 °C, 16 h
Ph
HN
OEt
HN
−
HN
R2
H2N
N
32 95%
N
−
H2N
w
2b
N
N
N
N
2a
−
w
1b
1a
Entry
Reagent(s) (equiv.)
Temp.
[°C]
Time
[h]
Yield
[%][a]
Substrate
Product
R1
R2
Yield
[%][a]
1[b]
2
NH2NH2·H2O (4)
80
80
80
80
50
50
50
50
50
50
50
rt
48
16
1
58
74
78
67
80
50
65
82
78
72
92
40
60
84
1b
1c
1d
1e
1f
2b
2c
2d
2e
2f
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Me
3-FC6H4
88
75
90
70
94
60
78
84
90
94
62
32
50
67
52
48
62
51
77[b]
95[b]
62
40
NH2NH2·H2O (6)
3-ClC6H4
3-BrC6H4
3-IC6H4
3
NH2NH2·H2O (8)
4
NH2OH·HCl/TEA (8/8)
NH2OH·HCl/TEA (8/8)
NH2OH·HCl/DIPEA (8/8)
NH2OH·HCl/DBU (8/8)
NH2OH·HCl/Na2CO3 (8/8)
NH2OH·HCl/Na2CO3 (8/8)
NH2OH·HCl/Na2CO3 (8/8)
NH2OH·HCl/Na2CO3 (10/10)
NH2OH·HCl/Na2CO3 (10/10)
NH2OH·HCl/Na2CO3 (10/10)
MeNHNH2 (10)[h]
16
16
16
16
16
16
16
16
24
16
1
5
3-NO2C6H4
2-CF3C6H4
3-CF3C6H4
4-CF3C6H4
6
1g
1h
1i
2g
2h
2i
7
8
9[c]
10[d]
11
12[e]
13[f]
14[g]
1j
2j
2,4-diCF3C6H3
3,5-diCF3C6H3
3-MeOC6H4
1k
1l
2k
2l
1m
1n
1o
1p
1q
1r
1s
2m
2n
2o
2p
2q
2r
2s
3,4,5-triMeOC6H2
2-MeC6H4
3-MeC6H4
4-MeC6H4
3,5-diMeC6H3
cPro
50
50
Reaction conditions: 0.25 mmol of 1a. [a] Isolated overall yields after column
chromatography, full conversion (TLC), [b] 75% conversion, [c] Addition of
sodium dithionite/TEA (3/3 equiv.), [d] Addition of sodium thiosulfate
pentahydrate/TEA (3/3 equiv.), [e] 60% conversion, [f] Reaction carried out in
10 ml DMA. [g] 0.125 mmol of 1a, 2.4 mL DMA. [h] according to the Ref. [15]
cHex
With the optimal conditions in hand, the sequential one-pot
strategy was extended for the synthesis of other 4,5-disubstituted
2-AI scaffolds (Table 2). In terms of substitution effect, the
presence of EWG groups in meta/ortho/para position afforded
higher yields in comparison with those of the ED groups. Target
compounds 2b–2k were obtained in good to excellent yields up
to 94% for 2f and 2k (R2 = 3-NO2C6H4 and 3,5-diCF3C6H3). The
introduction of ED functions on phenyl and/or changing R1 = OEt
into phenyl resulted in lower yields (2l–2q, 32–67%, 2v, 40% and
2w, 62%). In addition, the lowest yield was observed in the
combination of R1 = OEt, R2 = 3,4,5-triOMePh (2m, 32%). For R2
= alkyl, medium yields were observed (2r, 62%, 2s, 51%) similar
to other ED-substituted variants. A superior isolated yield was
achieved when R1 = Me and R2 = 3-NO2Ph substituents were
used (2u, 95%).
1t
2t
4-CF3C6H4
3-NO2C6H4
4-CF3C6H4
3-NO2C6H4
1u
1v
1w
2u
2v
2w
Me
Ph
Ph
Reaction conditions: 0.25 mmol of 1a, 4.75 mL DMA. [a] Isolated overall yields
after column chromatography, full conversion (TLC), [b] R = Me.
Seven analogues (2a, 2f, 2i, 2j, 2s, 2u and 2w) were furnished in
gram-scale synthesis with similar results.
3
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10.1002/ejoc.202001253
European Journal of Organic Chemistry
FULL PAPER
Figure 2. ORTEP view of structure of 2a at 50% probability level with partial
numbering scheme. Selected bond lengths (Å) and angles (o): C(2)–N(3)
1.331(4), C(4)–C(5) 1.380(4), N(1)–C(2) 1.336(4), N(2)–C(2) 1.347(4), C(51)–
O(1) 1.203(4), N(3)–C(4) 1.382(4), C(2)–N(1)–C(5) 107.3(3), C(5)–C(51)–O(1)
123.1(3), N(3)–C(2)–N(2) 124.0(3).
Figure 3. ORTEP view of structure of 3c at 50% probability level with partial
numbering scheme. Selected bond lengths (Å) and angles (o): C(2)–C(3)
1.400(6), N(4)–C(5) 1.417(5), N(1)–C(2) 1.371(6), N(1)–C(8) 1.343(6), C(31)–
O(32) 1.224(5), C(5)–C(6) 1.358(7), C(8)–N(7)–C(6) 107.1(4), C(3)–C(31)–
O(32) 124.8(4), C(2)–N(1)–C(8) 103.2(4).
To highlight the importance of the structural entity of 4,5-
disubstituted 2-AI, representative synthetic routes were
introduced towards bicyclic 5:5 ring systems such as the unique
1H-imidazo[1,2-a]imidazole scaffold utilising the multicomponent
Groebke–Blackburn–Bienaymé (GBB-3CR, 3a–d) reaction
(Scheme 5).
Inspired by the results of medicinal chemistry research,[2b,2d]
a
simple and convenient synthetic route was developed by
utilisation of selected 3-nitrophenyl-substituted 2-AI compounds
2f, 2u and 2w as precursors for the preparation of structurally
modified marine sponge alkaloid analogues with diverse
substitution patterns at the C4 and C5 positions (Scheme 6). First,
the reduction step (A) was carried out induced by SnCl2 in
concentrated HCl to form the corresponding 3-aminophenyl
intermediates (4a–c, 77–78%). In the next step, amine coupling
(B) mediated by TEA/TBTU gave target amides 5a–f containing
both indole and quinoline units in yields up to 86%.
For GBB-3CR, compounds 2a, 2i, 2k and 2s were reacted with
aryl aldehydes and alkyl isocyanides in the presence of HClO4 as
catalyst
(20
mol%)
to
afford
highly
substituted
1H-imidazo[1,2-a]imidazole analogues 3a–d in yields of 23–40%.
Noteworthy is the successful exploitation of 4,5-disubstituted 2-
aminoimidazoles for the construction of 2,3,5,6-tetrasubstituted
1H-imidazo[1,2-a]imidazoles via GBB-3CR. It is in sharp contrast
to previous findings,[16] that a substituent on the C4 atom hinders
the ring-closing step affording no conversion. On the other hand,
the scope and limitation revealed, that neither alkyl aldehydes
(pivalaldehyde or cyclohexyl carbaldehyde) nor aryl/benzyl
isocyanides was effective in this GBB methodology. The structure
of product 3c was further confirmed by X-ray analysis (Figure 3).
R2
O
O
O
R1
R1
2 equiv. HOOC-R2
2 equiv. TEA
1.1 equiv. TBTU
R1
NH2
HN
NO2
9 equiv. SnCl2
O
·2H
2O
HN
HN
HN
4.5 mL DCM,
rt, 72 h
6 mL cc. HCl,
reflux, 24 h
N
N
N
H2N
H2N
H2N
−
,
,
c
5a-f
4a
2f 2u 2w
(B)
(A)
−
−
, R
, R
, R
1=OEt, 78% (to
1=Me, 77% (to
1=Ph, 77% (to
50 86%
6 examples
4a
4b
4c
5a
5c
b
)
OEt
−
−
d
)
R3
R4
O
C
R2
O
O
0.3 mmol
0.3 mmol
R1
R2
5e
f
)
N
H
N
N
N
N
,
R4
20 mol% HClO4
O
O
OEt
OEt
H
H
O
O
N
NH
MeCN, 60 °C, 24 h
simple filtration
H2N
N
N
R3
H
HN
HN
−
,
,
2a 2i 2j 2s
3a d
N
23
−
NH
NH
H2N
H2N
N
N
OH
40%
23-40%
0.2 mmol
−
−
Groebke Blackburn Bienaymé
Reaction
, 60%
5b
, 61%
5a
=OEt
R1
O
O
H
H
O
F
O
OEt
OEt
N
N
HN
HN
O
O
NH
H2N
H2N
N
N
H
H
N
N
N
N
N
N
, 66%
5c
, 63%
5d
NH
NH
MeO
MeO
O
, 23%
, 40%
3b
3a
O
O
Ph
Ph
H
H
O
N
N
HN
HN
CF3
CF3
N
NH
H2N
H2N
N
N
OEt
OEt
O
O
, 50%
5e
, 86%
5f
H
H
CF3
N
N
N
N
N
N
MeO
NH
NH
, 35%
3d
, 28%
3c
F
Scheme 6. Synthesis of marine sponge alkaloid analogues 5a–f.
F
Scheme 5. Representation of synthetic routes to the preparation of 1H-
imidazo[1,2-a]imidazoles 3.
4
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10.1002/ejoc.202001253
European Journal of Organic Chemistry
FULL PAPER
A convenient, sequential one-pot access was demonstrated
towards the preparation of C4/C5-functionalised 2-AI structures
as valuable fragment-like heterocycles. Utilisation of Mannich
precursors and exploiting the IBX/IPT-mediated intramolecular
oxidative annulation as well as hydroxylamine-induced ring
cleavage sequence, a highly diverse 2AI chemical library was
generated. Further modifications have also been performed
including the Groebke–Blackburn–Bienaymé 3CR process
towards unique 1H-imidazo[1,2-a]imidazoles with four diversity
points. Other efforts to synthesize potential pharmacones such as
structurally modified marine alkaloid analogues were also carried
out.
diastereoisomers δ 193.40 (s; Cquat), 192.48 (s; Cquat), 167.47 (s;
Cquat), 166.87 (s; Cquat), 162.37 (dd, JC-F = 243.3, 20.0 Hz; Cquat),
161.76 (s; Cquat), 161.75 (s; Cquat), 144.28 (d, J = 6.6 Hz; Cquat),
144.13 (d, J = 6.6 Hz; Cquat), 136.42 (s; Cquat), 136.11 (s; Cquat),
134.57 (s; Ar-CH), 130.54 (s; Ar-CH), 130.48 (s; Ar-CH), 130.41
(s; Ar-CH), 129.45 (s; Ar-CH), 129.15 (s; Ar-CH), 128.75 (s; Ar-
CH), 124.50 (s; Ar-CH), 114.89 (s; Ar-CH), 114.72 (s; Ar-CH),
114.69 (d, J = 21.2 Hz; Ar-CH), 114.48 (d, J = 20.9 Hz; Ar-CH),
111.50 (s; Ar-CH), 111.43 (s; Ar-CH), 61.63 (s; CH2), 61.56 (s;
CH2), 59.32 (s; CH), 58.94 (s; CH), 54.02 (s; CH), 53.91 (s; CH),
14.21 (s; CH3), 13.94 (s; CH3). HRMS (ESI) m/z: [M + H]+ Calcd
for C22H21FN3O3+ 394.1562 (100%); Found 394.1559.
Ethyl 2-benzoyl-3-(3-chlorophenyl)-3-(pyrimidin-2-ylamino)
propanoate (1c)
Mannich precursors (1a-w)[13], [14]
White solid, 69% yield; Silica gel TLC Rf = 0.65 (Toluene/MeCN
3:1) Diastereoisomers ratio: 60:40. 1H NMR (500 MHz, DMSO-d6)
maior diastereoisomer δ 8.29 (d, J = 4.7 Hz, 2H; Ar-H), 8.05 (d, J
= 7.3 Hz, 2H; Ar-H), 7.80 (d, J = 9.1 Hz, 1H; Ar-H), 7.72 (t, J = 7.4
Hz, 1H; Ar-H), 7.62 – 7.57 (m, 3H; Ar-H), 7.45 (d, J = 7.6 Hz, 1H;
Ar-H), 7.36 (t, J = 7.7 Hz, 1H; Ar-H), 7.31 (d, J = 8.5 Hz, 1H; Ar-
H), 6.59 (t, J = 4.9 Hz, 1H; Ar-H), 5.86 (dd, J = 10.8, 9.1 Hz, 1H),
5.30 (d, J = 10.8 Hz, 1H; CH), 3.81 (q, J = 7.1 Hz, 2H; CH2), 0.82
Ethyl 2-benzoyl-3-phenyl-3-(pyrimidin-2-ylamino)propanoate
(1a)
White solid, 75% isolated yield; Silica gel TLC Rf = 0.63
(Toluene/MeCN 3:1) Diastereoisomers ratio: 54:46. 1H NMR (500
MHz, DMSO-d6) maior diastereoisomer δ 8.27 (d, J = 4.8 Hz, 2H;
Ar-H), 8.04 (dd, J = 8.3, 1.2 Hz, 2H; Ar-H), 7.78 (d, J = 9.2 Hz, 1H;
Ar-H), 7.71 (t, J = 7.4 Hz, 1H, Ar-H), 7.52 – 7.47 (m, 4H; Ar-H),
7.31 (t, J = 7.6 Hz, 2H; Ar-H), 7.23 (t, J = 7.3 Hz, 1H; Ar-H), 6.56
(t, J = 4.8 Hz, 1H), 5.89 (dd, J = 10.4, 9.3 Hz, 1H), 5.31 (d, J =
10.7 Hz, 1H; CH), 3.77 (q, J = 7.1 Hz, 2H; CH2), 0.79 (t, J = 7.1
Hz, 3H; CH3). 1H NMR (500 MHz, DMSO-d6) minor
diastereoisomer δ 8.27-8.17 (m, 2H; Ar-H), 7.83 (dd, J = 8.4, 1.3
Hz, 2H; Ar-H), 7.74 (d, J = 9.7 Hz, 1H; Ar-H), 7.66 – 7.59 (m, 1H;
Ar-H), 7.59 (t, J = 7.1 Hz, 2H), 7.44 (d, J = 6.9 Hz, 2H), 7.16 (t, J
= 7.7 Hz, 2H), 7.07 (t, J = 7.4 Hz, 1H; Ar-H), 6.58 (t, J = 4.8 Hz,
1H), 5.95 (t, J = 10.1 Hz, 1H), 5.45 (d, J = 10.6 Hz, 1H; CH), 4.12
– 3.95 (m, 2H; CH2), 0.98 (t, J = 7.1 Hz, 3H; CH3). 13C NMR (126
MHz, DMSO) mixture of two diastereoisomers δ 193.52 (s; Cquat),
192.72 (s; Cquat), 167.66 (s; Cquat), 167.00 (s; Cquat), 161.87 (s;
Cquat), 161.85 (s; Cquat), 141.31 (s; Cquat), 141.26 (s; Cquat), 136.54
(s; Cquat), 136.25 (s; Cquat), 134.47 (s; Ar-CH), 134.41 (s; Ar-CH),
129.42 (s; Ar-CH), 129.39 (s; Ar-CH), 129.11 (s; Ar-CH), 128.72
(s; Ar-CH), 128.49 (s; Ar-CH), 128.46 (s; Ar-CH), 128.23 (s; Ar-
CH), 128.18 (s; Ar-CH), 127.78 (s; Ar-CH), 127.57 (s; Ar-CH),
111.24 (s; Ar-CH), 111.15 (s; Ar-CH), 61.51 (s; CH2), 61.41 (s;
CH2), 59.58 (s; CH), 59.07 (s; CH), 54.38 (s; CH), 54.25 (s; CH),
14.22 (s; CH3), 13.92 (s; CH3). HRMS (ESI) m/z: [M + H]+ Calcd
for C22H22N3O3+ 376.1656 (100%); Found 376.1653.
1
(t, J = 7.1 Hz, 3H; CH3). H NMR (500 MHz, DMSO-d6) minor
diastereoisomer δ 8.27 – 8.21 (m, 2H; Ar-H), 7.85 (d, J = 7.3 Hz,
2H; Ar-H), 7.76 (d, J = 9.6 Hz, 1H; Ar-H), 7.64 (t, J = 7.4 Hz, 1H;
Ar-H), 7.55 – 7.48 (m, 3H; Ar-H), 7.39 (d, J = 7.7 Hz, 1H; Ar-H),
7.21 (t, J = 7.8 Hz, 1H; Ar-H), 7.15 (d, J = 8.0 Hz, 1H; Ar-H), 6.64
– 6.58 (m, 1H; Ar-H), 5.92 (t, J = 10.1 Hz, 1H), 5.44 (d, J = 10.6
Hz, 1H; CH), 4.12 – 3.96 (m, 2H; CH2), 0.98 (t, J = 7.1 Hz, 3H;
CH3). 13C NMR (126 MHz, DMSO-d6) mixture of two
diastereoisomers δ 193.41 (s; Cquat), 192.37 (s; Cquat), 167.46 (s;
Cquat), 166.84 (s; Cquat), 161.72 (s; Cquat), 161.70 (s; Cquat), 143.86
(s; Cquat), 143.73 (s; Cquat), 136.38 (s; Cquat), 136.08 (s; Cquat),
134.59 (s; Ar-CH), 133.27 (s; Cquat), 133.16 (s; Cquat), 130.48 (s;
Ar-CH), 130.39 (s; Ar-CH), 129.46 (s; Ar-CH), 129.16 (s; Ar-CH),
128.76 (s; Ar-CH), 128.03 (s; Ar-CH), 127.98 (s; Ar-CH), 127.87
(s; Ar-CH), 127.65 (s; Ar-CH), 127.16 (s; Ar-CH), 127.08 (s; Ar-
CH), 111.54 (s; Ar-CH), 111.47 (s; Ar-CH), 61.65 (s; CH2), 61.60
(s; CH2), 59.32 (s; CH), 58.90 (s; CH), 54.00 (s; CH), 53.92 (s;
CH), 14.21 (s; CH3), 13.93 (s; CH3). HRMS (ESI) m/z: [M + H]+
Calcd for C22H21ClN3O3+ 410.1266 (100%), 412.1237 (32.0%);
Found 410.1263, 412.1227.
Ethyl 2-benzoyl-3-(3-bromophenyl)-3-(pyrimidin−2-ylamino)
propanoate (1d)
Ethyl 2-benzoyl-3-(3-fluorophenyl)-3-(pyrimidin-2-ylamino)
propanoate (1b)
White solid, 74% yield; Silica gel TLC Rf = 0.65 (Toluene/MeCN
3:1) Diastereoisomers ratio: 60:40. 1H NMR (500 MHz, DMSO-d6)
maior diastereoisomer δ 8.29 (d, J = 4.7 Hz, 2H; Ar-H), 8.05 (d, J
= 7.3 Hz, 2H; Ar-H), 7.80 (d, J = 9.1 Hz, 1H; Ar-H), 7.74 – 7.69
(m, 2H; Ar-H), 7.60 (t, J = 7.8 Hz, 2H; Ar-H), 7.55 – 7.47 (m, 3H;
Ar-H), 6.59 (t, J = 4.9 Hz, 1H), 5.85 (dd, J = 10.8, 9.1 Hz, 1H),
5.30 (d, J = 10.8 Hz, 1H; CH), 3.81 (q, J = 7.2 Hz, 2H; CH2), 0.82
White solid, 66% yield; Silica gel TLC Rf = 0.61 (Toluene/MeCN
3:1) Diastereoisomers ratio: 58:42. 1H NMR (500 MHz, DMSO-d6)
maior diastereoisomer δ 8.28 (d, J = 4.7 Hz, 2H; Ar-H), 8.04 (d, J
= 7.0 Hz, 2H; Ar-H), 7.80 – 7.69 (m, 3H; Ar-H), 7.60 (t, J = 7.8 Hz,
2H, Ar-H), 7.39 – 7.28 (m, 4H; Ar-H), 7.07 (tdd, J = 7.9, 2.7, 1.3
Hz, 1H; Ar-H), 6.59 (t, J = 5.0 Hz, 1H), 5.89 (dd, J = 10.6, 9.2 Hz,
1H), 5.31 (d, J = 10.7 Hz, 1H; CH), 3.81 (q, J = 7.1 Hz, 2H; CH2),
0.82 (t, J = 7.1 Hz, 3H; CH3). 1H NMR (500 MHz, DMSO-d6) minor
diastereoisomer δ 8.25 (d, J = 9.5 Hz, 2H; Ar-H), 7.85 (d, J = 7.3
Hz, 2H; Ar-H), 7.64 (t, J = 7.4 Hz, 1H; Ar-H), 7.51 (t, J = 7.8 Hz,
2H; Ar-H), 7.28 – 7.19 (m, 2H; Ar-H), 6.91 (tdd, J = 8.9, 2.6, 1.1
Hz, 1H; Ar-H), 6.64 – 6.58 (m, 1H), 5.95 (t, J = 10.1 Hz, 1H), 5.44
(d, J = 10.6 Hz, 1H; CH), 4.12 – 3.95 (m, 2H, CH2), 0.98 (t, J = 7.1
Hz, 3H; CH3). 13C NMR (126 MHz, DMSO-d6) mixture of two
1
(t, J = 7.1 Hz, 3H; CH3). H NMR (500 MHz, DMSO-d6) minor
diastereoisomer δ 8.26 – 8.23 (m, 2H; Ar-H), 7.85 (d, J = 7.3 Hz,
2H; Ar-H), 7.76 (d, J = 9.6 Hz, 1H; Ar-H), 7.67 – 7.62 (m, 2H; Ar-
H), 7.44 (t, J = 8.8 Hz, 2H; Ar-H), 7.29 (t, J = 7.9 Hz, 2H; Ar-H),
7.14 (t, J = 7.8 Hz, 1H; Ar-H), 6.64 – 6.58 (m, 1H), 5.90 (t, J = 10.1
Hz, 1H), 5.43 (d, J = 10.7 Hz, 1H; CH), 4.12 – 3.96 (m, 2H; CH2),
0.98 (t, J = 7.1 Hz, 3H; CH3). 13C NMR (126 MHz, DMSO-d6)
mixture of two diastereoisomers δ 193.43 (s; Cquat), 192.34 (s;
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001253
European Journal of Organic Chemistry
FULL PAPER
Cquat), 167.45 (s; Cquat), 166.84 (s; Cquat), 161.70 (s; Cquat), 161.68
(s; Cquat), 144.11 (s; Cquat), 143.97 (s; Cquat), 136.37 (s; Cquat),
136.08 (s; Cquat), 134.59 (s; Ar-CH), 130.92 (s; Ar-CH), 130.85 (s;
Ar-CH), 130.77 (s; Ar-CH), 130.69 (s; Ar-CH), 130.54 (s; Ar-CH),
129.47 (s; Ar-CH), 129.16 (s; Ar-CH), 128.76 (s; Ar-CH), 127.56
(s; Ar-CH), 127.46 (s; Ar-CH), 121.90 (s; Cquat), 121.82 (s; Cquat),
111.55 (s; Ar-CH), 111.48 (s; Ar-CH), 61.65 (s; CH2), 61.61 (s;
CH2), 59.36 (s; CH), 58.90 (s; CH), 53.97 (s; CH), 53.90 (s; CH),
14.21 (s; CH3), 13.94 (s; CH3). HRMS (ESI) m/z: [M + H]+ Calcd
for C22H21BrN3O3+ 454.0761 (100.0%), 456.0741 (97.3%); Found
454.0756, 456.0734.
136.31 (s; Ar-CH), 135.97 (s; Ar-CH), 135.37 (s; Ar-CH), 135.32
(s; Ar-CH), 134.68 (s; Ar-CH), 134.66 (s; Ar-CH), 130.21 (s; Ar-
CH), 130.07 (s; Ar-CH), 129.48 (s; Ar-CH), 129.46 (s; Ar-CH),
129.23 (s; Ar-CH), 128.78 (s; Ar-CH), 123.02 (s; Ar-CH), 122.88
(s; Ar-CH), 122.74 (s; Ar-CH), 111.74 (s; Ar-CH), 111.68 (s; Ar-
CH), 61.78 (s; CH2), 61.74 (s; CH2), 59.11 (s; CH), 58.86 (s; CH),
53.98 (s; CH), 53.90 (s; CH), 14.21 (s; CH3), 13.90 (s; CH3).
HRMS (ESI) m/z: [M + H]+ Calcd for C22H21N4O5+ 421.1507
(100.0%); Found 421.1506.
Ethyl 2-benzoyl-3-(pyrimidin-2-ylamino)-3-(2-(trifluoro-
methyl)phenyl)propanoate (1g)
Ethyl 2-benzoyl-3-(3-iodophenyl)-3-(pyrimidin-2-ylamino)
propanoate (1e)
White solid, 41% isolated yield; Silica gel TLC Rf = 0.67, 0.63
(Toluene/MeCN 3:1) Diastereoisomers ratio: 64:36. 1H NMR (500
MHz, DMSO-d6) maior diastereoisomer δ 8.27 (d, J = 4.7 Hz, 1H;
Ar-H), 8.19 (d, J = 4.8 Hz, 2H; Ar-H), 8.03 (d, J = 7.9 Hz, 1H; Ar-
H), 7.96 (d, J = 7.2 Hz, 2H; Ar-H), 7.79 (d, J = 8.2 Hz, 1H; Ar-H),
7.71 – 7.43 (m, 10H; Ar-H), 6.54 (t, J = 4.8 Hz, 1H), 6.46 – 6.39
(m, 1H), 5.32 (d, J = 10.0 Hz, 1H; CH), 3.73 (qd, J = 7.1, 4.3 Hz,
2H; CH2), 0.71 (t, J = 7.1 Hz, 3H; CH3). 1H NMR (500 MHz,
DMSO-d6) minor diastereoisomer δ 7.89 (d, J = 7.9 Hz, 1H; Ar-H),
7.72 – 7.42 (m, 10H; Ar-H), 7.33 (t, J = 7.6 Hz, 1H; Ar-H), 6.60 (t,
J = 4.8 Hz, 1H), 6.45 – 6.38 (m, 1H), 5.49 (d, J = 9.6 Hz, 1H; CH),
4.05 – 3.84 (m, 2H; CH2), 0.94 (t, J = 7.1 Hz, 3H; CH3). 13C NMR
(126 MHz, DMSO-d6) mixture of two diastereoisomers δ 193.36
(s; Cquat), 192.96 (s; Cquat), 167.99 (s; Cquat), 166.91 (s; Cquat),
161.53 (s; Cquat), 161.40 (s; Cquat), 158.26 (s; Cquat), 140.38 (s;
Cquat), 139.78 (s; Cquat), 136.69 (s; Cquat), 136.31 (s; Cquat), 134.30
(s; Ar-CH), 134.21 (s; Ar-CH), 132.82 (s; Ar-CH), 132.79 (s; Ar-
CH), 130.35 (s; Ar-CH), 129.36 (s; Ar-CH), 129.35 (s; Ar-CH),
129.21 (s; Ar-CH), 128.85 (s; Ar-CH), 128.47 (s; Ar-CH), 128.34
(s; Ar-CH), 128.24 (s; Ar-CH), 127.89 – 127.13 (m; Cquat), 127.54
(q, J = 29.3 Hz; Cquat), 126.48 (q, J = 5.5 Hz; Ar-CH), 126.27 (q, J
= 5.4 Hz; Ar-CH), 125.97 (s; Cquat), 125.82 (s; Cquat), 111.44 (s; Ar-
CH), 111.41 (s; Ar-CH), 61.67 (s; CH2), 61.32 (s; CH2), 59.10 (s;
CH), 58.85 (s; CH), 49.78 (s; CH), 49.76 (s; CH), 14.03 (s; CH3),
White solid, 42% isolated yield; Silica gel TLC Rf = 0.63
(Toluene/MeCN 3:1) Diastereoisomers ratio: 60:40. 1H NMR (500
MHz, DMSO-d6) mixture of two diastereoisomers δ 8.29 (d, J =
4.8 Hz, 2H; Ar-H), 8.27 – 8.20 (m, 2H; Ar-H), 8.04 (d, J = 7.3 Hz,
2H; Ar-H), 7.89 (s, 1H; Ar-H), 7.84 (d, J = 7.0 Hz, 2H; Ar-H), 7.78
(d, J = 9.1 Hz, 1H; Ar-H), 7.74 (d, J = 9.9 Hz, 1H; Ar-H), 7.71 (d,
J = 7.4 Hz, 1H; Ar-H), 7.65 (t, J = 7.4 Hz, 1H; Ar-H), 7.63 – 7.57
(m, 3H; Ar-H), 7.55 – 7.48 (m, 2H; Ar-H), 7.44 (d, J = 7.8 Hz, 1H;
Ar-H), 7.13 (t, J = 7.8 Hz, 1H; Ar-H), 6.98 (t, J = 7.8 Hz, 1H; Ar-
H), 6.62 – 6.60 (m, 1H), 6.59 (t, J = 4.9 Hz, 1H), 5.86 (t, J = 10.1
Hz, 1H), 5.85 – 5.77 (m, 1H), 5.41 (d, J = 10.6 Hz, 1H; CH), 5.27
(d, J = 10.8 Hz, 1H; CH), 4.12 – 3.96 (m, 2H; CH2), 3.81 (q, J =
7.0 Hz, 2H; CH2), 0.98 (t, J = 7.1 Hz, 3H; CH3), 0.83 (t, J = 7.1 Hz,
3H; CH3). 13C NMR (126 MHz, DMSO-d6) mixture of two
diastereoisomers δ 193.50 (s; Cquat), 192.34 (s; Cquat), 167.48 (s;
Cquat), 166.84 (s; Cquat), 161.69 (s; Cquat), 161.68 (s; Cquat), 143.94
(s; Cquat), 143.78 (s; Cquat), 136.79 (s; Ar-CH), 136.69 (s; Ar-CH),
136.59 (s; Ar-CH), 136.38 (s; Cquat), 136.35 (s; Ar-CH), 136.12 (s;
Cquat), 134.57 (s; Ar-CH), 130.78 (s; Ar-CH), 130.68 (s; Ar-CH),
129.46 (s; Ar-CH), 129.43 (s; Ar-CH), 129.15 (s; Ar-CH), 128.75
(s; Ar-CH), 127.92 (s; Ar-CH), 127.80 (s; Ar-CH), 111.51 (s; Ar-
CH), 111.44 (s; Ar-CH), 95.06 (s; Cquat), 95.03 (s; Cquat), 61.62 (s;
CH2), 61.61 (s; CH2), 59.42 (s; CH), 58.86 (s; CH), 53.86 (s; CH),
53.79 (s; CH), 14.22 (s; CH3), 13.97 (s; CH3). HRMS (ESI) m/z:
[M + H]+ Calcd for C22H21IN3O3+ 502.0623 (100.0%); Found
502.0620.
13.67 (s; CH3). HRMS (ESI) m/z: [M
C23H21F3N3O3+ 444.1530 (100.0%); Found 444.1529.
+
H]+ Calcd for
Ethyl 2-benzoyl-3-(pyrimidin-2-ylamino)-3-(3-(trifluoro-
methyl)phenyl)propanoate (1h)
Ethyl 2-benzoyl-3-(3-nitrophenyl)-3-(pyrimidin-2-ylamino)
propanoate (1f)
White solid, 40% yield; Silica gel TLC Rf = 0.63 (Toluene/MeCN
3:1) Diastereoisomers ratio: 64:36. 1H NMR (500 MHz, DMSO-d6)
mixture of two diastereoisomers δ 8.29 (d, J = 4.7 Hz, 2H; Ar-H),
8.25 (d,J = 7.6 Hz, 2H; Ar-H), 8.05 (d, J = 7.2 Hz, 2H; Ar-H), 7.89
(s, 1H; Ar-H), 7.88 – 7.84 (m, 2H; Ar-H), 7.84 – 7.78 (m, 3H; Ar-
H), 7.72 (t, J = 7.4 Hz, 2H; Ar-H), 7.65 – 7.54 (m, 5H; Ar-H), 7.49
(t, J = 7.8 Hz, 1H; Ar-H), 7.46 – 7.39 (m, 1H; Ar-H), 6.62 (t, J = 4.8
Hz, 1H), 6.59 (t, J = 4.8 Hz, 1H), 6.02 – 5.97 (m, 1H), 5.96 – 5.91
(m, 1H), 5.49 (d, J = 10.6 Hz, 1H; CH), 5.36 (d, J = 10.8 Hz, 1H;
CH), 4.14 – 3.95 (m, 2H; CH2), 3.77 (q, J = 7.1 Hz, 2H; CH2), 0.99
(t, J = 7.1 Hz, 3H; CH3), 0.77 (t, J = 7.1 Hz, 3H; CH3). 13C NMR
(126 MHz, DMSO-d6) mixture of two diastereoisomers δ 193.62
(s; Cquat), 192.28 (s; Cquat), 167.45 (s; Cquat), 166.84 (s; Cquat),
142.72 (s; Cquat), 142.53 (s; Cquat), 136.35 (s; Cquat), 136.09 (s;
Cquat), 134.62 (s; Ar-CH), 134.57 (s; Ar-CH), 132.66 (s; Ar-CH),
132.59 (s; Ar-CH), 129.70 (s; Ar-CH), 129.57 (s; Ar-CH), 129.48
(s; Ar-CH), 129.40 (s; Ar-CH), 129.16 (s; Ar-CH), 128.70 (s; Ar-
CH), 124.70 (dq, J = 8.4, 4.4 Hz; Ar-CH), 124.44 (q, J = 3.7 Hz;
Ar-CH), 111.61 (s; Ar-CH), 111.54 (s; Ar-CH), 61.68 (s; CH2),
61.59 (s; CH2), 59.30 (s; CH), 58.79 (s; CH), 54.17 (s; CH), 54.04
White solid, 62% isolated yield; Silica gel TLC Rf = 0.57, 0.55
(Toluene/MeCN 3:1) Diastereoisomers ratio: 62:38. 1H NMR (500
MHz, DMSO-d6) maior diastereoisomer δ 8.46 (t, J = 1.9 Hz, 1H;
Ar-H), 8.30 (d, J = 4.8 Hz, 2H; Ar-H), 8.13 (ddd, J = 8.2, 2.3, 1.0
Hz, 1H; Ar-H), 8.07 (d,J = 7.2 Hz, 2H; Ar-H), 7.98 – 7.91 (m, 3H;
Ar-H), 7.73 (t, J = 7.4 Hz, 1H; Ar-H), 7.53-7.47 (m, 2H; Ar-H), 7.61
(t, J = 7.8 Hz, 2H; Ar-H), 6.60 (t, J = 4.8 Hz, 1H), 5.98 (dd, J =
10.8, 9.0 Hz, 1H), 5.40 (d, J = 10.9 Hz, 1H; CH), 3.85 – 3.75 (m,
2H; CH2), 0.79 (t, J = 7.1 Hz, 3H; CH3).1H NMR (500 MHz, DMSO-
d6) minor diastereoisomer δ 8.39 (t, J = 1.9 Hz, 1H; Ar-H), 8.29 –
8.20 (m, 2H; Ar-H), 7.98 – 7.91 (m, 3H; Ar-H), 7.89 (d, J = 7.8 Hz,
1H; Ar-H), 7.84 (d, J = 7.2 Hz, 2H; Ar-H), 7.67 – 7.63 (m, 2H; Ar-
H), 6.63 (t, J = 4.8 Hz, 1H), 6.02 (dd, J = 10.6, 9.8 Hz, 1H), 5.52
(d, J = 10.7 Hz, 1H; CH), 4.15 – 3.97 (m, 2H; CH2), 0.99 (t, J = 7.1
Hz, 3H; CH3). 13C NMR (126 MHz, DMSO-d6) mixture of two
diastereoisomers δ 193.43 (s; Cquat), 192.25 (s; Cquat), 167.35 (s;
Cquat), 166.79 (s; Cquat), 161.62 (s; Cquat), 161.58 (s; Cquat), 148.20
(s; Cquat), 148.01 (s; Cquat), 143.69 (s; Cquat), 143.51 (s; Cquat),
6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001253
European Journal of Organic Chemistry
FULL PAPER
(s; CH), 14.21 (s; CH3), 13.79 (s; CH3). HRMS (ESI) m/z: [M + H]+
Calcd for C23H21F3N3O3+ 444.1530 (100.0%); Found 444.1528.
Ar-CH), 129.53 (s; Ar-CH), 129.50 (s; Ar-CH), 129.42 (s; Ar-CH),
129.39 (s; Ar-CH), 129.12 (s; Ar-CH), 128.75 (s; Ar-CH), 120.58
(s; Ar-CH), 120.54 (s; Ar-CH), 114.08 (s; Ar-CH), 113.98 (s; Ar-
CH), 112.91 (s; Ar-CH), 112.83 (s; Ar-CH), 111.27 (s; Ar-CH),
111.20 (s; Ar-CH), 61.50 (s; CH2), 61.43 (s; CH2), 59.48 (s; CH),
58.97 (s; CH), 55.48 (s; CH3), 55.34 (s; CH3), 54.31 (s; CH), 54.20
(s; CH), 14.22 (s; CH3), 13.96 (s; CH3). HRMS (ESI) m/z: [M + H]+
Calcd for C23H24N3O4+ 406.1762 (100.0%); Found 406.1758.
Ethyl 2-benzoyl-3-(pyrimidin-2-ylamino)-3-(4-(trifluoro-
methyl)phenyl)propanoate (1i)
The substrate has been characterized in the previous work.[13]
Ethyl 2-benzoyl-3-(2,4-bis(trifluoromethyl)phenyl)-3-
(pyrimidin-2-ylamino)propanoate (1j)
White solid, 22% isolated yield; Silica gel TLC Rf = 0.69, 0.65
(Toluene/MeCN 3:1) Diastereoisomers ratio: 69:31. 1H NMR (500
MHz, DMSO-d6) maior diastereoisomer δ 8.31 (d, J = 8.4 Hz, 1H;
Ar-H), 8.20 (d, J = 4.8 Hz, 2H; Ar-H), 8.15 (d, J = 8.3 Hz, 2H; Ar-
H), 7.98 (d, J = 7.2 Hz, 2H; Ar-H), 7.95 (s, 1H; Ar-H), 7.57 (t, J =
7.8 Hz, 2H; Ar-H), 7.48 (t, J = 7.8 Hz, 1H; Ar-H), 6.57 (t, J = 4.8
Hz, 1H), 6.43 (dd, J = 10.1, 8.5 Hz, 1H), 5.36 (d, J = 10.2 Hz, 1H;
CH), 3.74 (qd, J = 7.1, 4.5 Hz, 2H; CH2), 0.69 (t, J = 7.1 Hz, 3H;
CH3).1H NMR (500 MHz, DMSO-d6) minor diastereoisomer δ 8.29
(d, J = 4.8 Hz, 2H; Ar-H), 7.97 (d, J = 8.3 Hz, 2H; Ar-H), 7.91 (d,
J = 8.4 Hz, 1H; Ar-H), 7.88 (s, 1H; Ar-H), 7.78 (d, J = 7.2 Hz, 2H;
Ar-H), 7.69 (t, J = 7.4 Hz, 2H; Ar-H), 7.62 (t, J = 7.4 Hz, 1H; Ar-
H), 6.63 (t, J = 4.8 Hz, 1H), 6.45 (t, J = 9.5 Hz, 1H), 5.55 (d, J =
9.6 Hz, 1H; CH), 4.04 – 3.87 (m, 2H; CH2), 0.94 (t, J = 7.1 Hz, 3H;
CH3). 13C NMR (126 MHz, DMSO-d6) mixture of two
diastereoisomers δ 193.46 (s; Cquat), 192.52 (s; Cquat), 167.81 (s;
Cquat), 166.80 (s; Cquat), 161.43 (s; Cquat), 161.26 (s; Cquat), 145.62
(s; Cquat), 144.63 (s; Cquat), 136.56 (s; Cquat), 136.14 (s; Cquat),
134.38 (s; Ar-CH), 134.34 (s; Ar-CH), 131.90 (s; Ar-CH), 130.75
(s; Ar-CH), 129.76 (q, J = 4.0 Hz; Ar-CH), 129.39 (s; Ar-CH),
129.36 (s; Ar-CH), 128.99 (q, J = 44.9, 39.6 Hz; Cquat), 128.90 (s;
Ar-CH), 128.52 (s; Ar-CH), 123.32 – 123.09 (m; Ar-CH), 111.74
(s; Ar-CH), 61.84 (s; CH2), 61.50 (s; CH2), 58.82 (s; CH), 58.68
(s; CH), 49.75 (s; CH), 14.00 (s; CH3), 13.51 (s; CH3). HRMS (ESI)
m/z: [M + H]+ Calcd for C24H20F6N3O3+ 512.1404 (100.0%); Found
512.1385.
Ethyl 2-benzoyl-3-(pyrimidin-2-ylamino)-3-(3,4,5-trimethoxy-
phenyl)propanoate (1m)
Pale yellow solid, 25% isolated yield; Silica gel TLC Rf = 0.47,
0.42 (Toluene/MeCN 3:1) Diastereoisomers ratio: 55:45. 1H NMR
(500 MHz, DMSO-d6) mixture of two diastereoisomers δ 8.03 (d,
J = 7.4 Hz, 2H), 7.97 (d, J = 7.4 Hz, 2H; Ar-H), 7.88 (d, J = 7.2 Hz,
2H; Ar-H), 7.83 (d, J = 7.4 Hz, 2H; Ar-H), 7.70 (t, J = 7.4 Hz, 1H;
Ar-H), 7.60 – 7.47 (m, 5H; Ar-H), 7.45 (t, J = 7.5 Hz, 2H; Ar-H),
6.84 (s, 2H; Ar-H), 6.73 (s, 2H; Ar-H), 6.57 (ddt, J = 19.3, 6.2, 4.7
Hz, 3H), 5.88 (td, J = 10.1, 4.4 Hz, 2H), 5.60 (td, J = 9.0, 4.6 Hz,
1H), 5.42 (d, J = 10.6 Hz, 1H; CH), 5.30 (d, J = 10.4 Hz, 1H; CH),
4.04 (dddd, J = 18.0, 10.9, 7.1, 3.8 Hz, 2H; CH2), 3.91 – 3.82 (m,
2H; CH2), 3.77 (s, 3H; CH3), 3.75 (s, 3H; CH3), 3.65 (s, 3H; CH3),
3.62 (s, 3H; CH3), 3.61 (s, 3H; CH3), 3.48 (s, 3H; CH3), 1.00 (t, J
= 7.1 Hz, 3H; CH3), 0.86 (t, J = 7.0 Hz, 3H; CH3). 13C NMR (126
MHz, DMSO) mixture of two diastereoisomers δ 193.87 (s; Cquat),
193.01 (s; Cquat), 167.70 (s; Cquat), 167.02 (s; Cquat), 162.14 (s;
Cquat), 161.89 (s; Cquat), 158.46 (s; Ar-CH), 158.33 (s; Ar-CH),
153.00 (s; Cquat), 152.85 (s; Cquat), 137.38 (s; Cquat), 137.24 (s;
Cquat), 136.96 (s; Cquat), 136.69 (s; Cquat), 136.60 (s; Cquat), 136.54
(s; Cquat), 134.42 (s; Ar-CH), 134.23 (s; Ar-CH), 129.40 (s; Ar-CH),
129.24 (s; Ar-CH), 129.14 (s; Ar-CH), 129.07 (s; Ar-CH), 128.69
(s; Ar-CH), 128.65 (s; Ar-CH), 128.52 (s; Ar-CH), 127.91 (s; Ar-
CH), 111.28 (s; Ar-CH), 111.25 (s; Ar-CH), 105.85 (s; Ar-CH),
105.68 (s; Ar-CH), 61.43 (s; CH2), 61.41 (s; CH2), 60.36 (s; CH3),
60.25 (s; CH3), 59.63 (s; CH), 59.01 (s; CH), 56.57 (s; CH3), 56.41
(s; CH3), 56.32 (s; CH3), 56.25 (s; CH3), 54.75 (s; CH), 54.54 (s;
CH), 14.24 (s; CH3), 14.03 (s; CH3). HRMS (ESI) m/z: [M + H]+
Calcd for C25H28N3O6+ 466.1973 (100.0%); Found 466.1978.
Ethyl 2-benzoyl-3-(3,5-bis(trifluoromethyl) phenyl)-3-
(pyrimidin-2-ylamino)propanoate (1k)
The substrate has been characterized in the previous work.[13]
Ethyl 2-benzoyl-3-(pyrimidin-2-ylamino)-3-(o-tolyl)
Ethyl 2-benzoyl-3-(3-methoxyphenyl)-3-(pyrimidin-2-yl
amino)propanoate (1l)
propanoate (1n)
White solid, 48% isolated yield; Silica gel TLC Rf = 0.63, 0.59
(Toluene/MeCN 3:1) Diastereoisomers ratio: 84:16. 1H NMR (500
MHz, DMSO-d6) maior diastereoisomer δ 8.27 (d, J = 4.2 Hz, 1H;
Ar-H), 7.80 (d, J = 7.2 Hz, 2H; Ar-H), 7.71 (d, J = 9.5 Hz, 1H; Ar-
H), 7.60 (d, J = 7.3 Hz, 2H; Ar-H), 7.48 (t, J = 7.8 Hz, 2H; Ar-H),
6.96 (t, J = 7.7 Hz, 2H; Ar-H), 6.94 – 6.90 (m, 1H; Ar-H), 6.56 (t, J
= 4.8 Hz, 1H), 6.20 – 6.12 (m, 1H), 5.51 (d, J = 10.8 Hz, 1H; CH),
4.10 – 3.97 (m, 2H; CH2), 2.59 (s, 3H; CH3), 0.98 (t, J = 7.1 Hz,
3H; CH3). 1H NMR (500 MHz, DMSO-d6) minor diastereoisomer δ
8.21 (d, J = 4.8 Hz, 2H; Ar-H), 8.05 (d, J = 7.2 Hz, 2H; Ar-H), 7.68
(d, J = 8.2 Hz, 1H; Ar-H), 7.19 (t, J = 8.1 Hz, 1H; Ar-H), 7.12 –
7.06 (m, 2H; Ar-H), 6.53 (t, J = 4.8 Hz, 1H), 6.21 – 6.13 (m, 1H),
5.33 (d, J = 10.7 Hz, 1H; CH), 3.72 (qq, J = 10.9, 7.1 Hz, 2H; CH2),
2.61 (s, 3H; CH3), 0.69 (t, J = 7.1 Hz, 3H; CH3). 13C NMR (126
MHz, DMSO-d6) maior diastereoisomer δ 193.61 (s; Cquat), 167.78
(s; Cquat), 161.86 (s; Cquat), 140.06 (s; Cquat), 136.57 (s; Cquat),
136.34 (s; Cquat), 134.31 (s; Ar-CH), 130.26 (s; Ar-CH), 129.31 (s;
Ar-CH), 128.69 (s; Ar-CH), 127.37 (s; Ar-CH), 127.29 (s; Ar-CH),
126.29 (s; Ar-CH), 111.04 (s; Ar-CH), 61.48 (s; CH2), 58.83 (s;
CH), 49.97 (s; CH), 20.07 (s; CH3), 14.23 (s; CH3). 13C NMR (126
White solid, 30% isolated yield; Silica gel TLC Rf = 0.59, 0.53
(Toluene/MeCN 3:1) Diastereoisomers ratio: 68:32. 1H NMR (500
MHz, DMSO-d6) maior diastereoisomer δ 8.27 (d, J = 4.7 Hz, 2H;
Ar-H), 8.04 (d, J = 7.2 Hz, 1H; Ar-H), 7.85 (d, J = 7.2 Hz, 2H; Ar-
H), 7.73 – 7.57 (m, 4H; Ar-H), 7.51 (t, J = 7.8 Hz, 2H; Ar-H), 7.12
– 7.01 (m, 3H; Ar-H), 6.98 (d, J = 7.7 Hz, 1H; Ar-H), 6.64 (ddd, J
= 8.1, 2.6, 0.9 Hz, 1H; Ar-H), 6.59 (t, J = 4.8 Hz, 1H), 5.93 (t, J =
10.2 Hz, 1H), 5.44 (d, J = 10.7 Hz, 1H; CH), 4.14 – 3.94 (m, 2H;
CH2), 3.63 (s, 3H; CH3), 0.98 (t, J = 7.1 Hz, 3H; CH3). 1H NMR
(500 MHz, DMSO-d6) minor diastereoisomer δ 8.23 (d, J = 4.7 Hz,
2H; Ar-H), 7.74 – 7.57 (m, 4H; Ar-H), 7.22 (t, J = 7.9 Hz, 1H; Ar-
H), 7.11 – 7.03 (m, 3H; Ar-H), 6.80 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H;
Ar-H), 6.56 (d, J = 4.8 Hz, 1H), 5.90 – 5.84 (m, 1H), 5.30 (d, J =
10.6 Hz, 1H; CH), 3.80 (q, J = 7.1 Hz, 2H; CH2), 3.73 (s, 3H; CH3),
0.82 (t, J = 7.1 Hz, 3H; CH3). 13C NMR (126 MHz, DMSO-d6)
mixture of two diastereoisomers δ 193.44 (s; Cquat), 192.80 (s;
Cquat), 167.63 (s; Cquat), 166.97 (s; Cquat), 161.87 (s; Cquat), 159.50
(s; Cquat), 159.37 (s; Cquat), 142.89 (s; Cquat), 142.76 (s; Cquat),
136.56 (s; Cquat), 136.27 (s; Cquat), 134.47 (s; Ar-CH), 134.41 (s;
7
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10.1002/ejoc.202001253
European Journal of Organic Chemistry
FULL PAPER
MHz, DMSO-d6) minor diastereoisomer δ 193.58 (s; Cquat), 166.97
(s; Cquat), 161.84 (s; Cquat), 140.02 (s; Cquat), 136.51 (s; Cquat),
136.22 (s; Cquat), 134.45 (s; Ar-CH), 129.41 (s; Ar-CH), 129.10 (s;
Ar-CH), 128.09 (s; Ar-CH), 127.51 (s; Ar-CH), 126.29 (s; Ar-CH),
110.98 (s; Ar-CH), 61.32 (s; CH2), 59.63 (s; CH), 49.65 (s; CH),
19.88 (s; CH3), 13.75 (s; CH3). HRMS (ESI) m/z: [M + H]+ Calcd
for C23H24N3O3+ 390.1813 (100.0%); Found 390.1811.
129.10 (s; Ar-CH), 128.96 (s; Ar-CH), 128.72 (s; Ar-CH), 125.92
(s; Ar-CH), 125.90 (s; Ar-CH), 111.15 (s; Ar-CH), 111.05 (s; Ar-
CH), 61.42 (s; CH2), 61.37 (s; CH2), 59.82 (s; CH), 59.12 (s; CH),
54.15 (s; CH), 54.05 (s; CH), 21.44 (s; CH3), 21.35 (s; CH3), 14.21
(s; CH3), 13.92 (s; CH3). HRMS (ESI) m/z: [M + H]+ Calcd for
C24H26N3O3+ 404.1969 (100.0%); Found 404.1965.
Ethyl 2-benzoyl-3-cyclopropyl-3-(pyrimidin-2-yl
Ethyl 2-benzoyl-3-(pyrimidin-2-ylamino)-3-(m-tolyl)
propanoate (1o)
amino)propanoate (1r)
Colourless solid, 15% isolated yield; Silica gel TLC Rf = 0.63, 0.57
(Toluene/MeCN 3:1) Diastereoisomers ratio: 62:38. 1H NMR (500
MHz, Chloroform-d) mixture of diastereoisomers δ 8.29 (d, J = 4.9
Hz, 1H; Ar-H), 8.27 (d, J = 4.8 Hz, 2H; Ar-H), 8.24 (d, J = 4.8 Hz,
1H; Ar-H), 8.15 (d, J = 4.8 Hz, 1H; Ar-H), 8.09 (d, J = 7.1 Hz, 2H;
Ar-H), 8.02 (d, J = 7.0 Hz, 1H; Ar-H), 7.94 (d, J = 7.0 Hz, 1H; Ar-
H), 7.89 (d, J = 7.0 Hz, 1H; Ar-H), 7.62 – 7.52 (m, 3H; Ar-H), 7.49
(t, J = 7.7 Hz, 2H; Ar-H), 7.46 – 7.42 (m, 1H), 6.61 (t, J = 4.8 Hz,
1H), 6.56 – 6.47 (m, 2H), 6.45 (t, J = 4.8 Hz, 1H), 4.98 (d, J = 4.8
Hz, 1H; CH), 4.91 (d, J = 5.6 Hz, 1H; CH), 4.17 – 4.05 (m, 4H; 2
CH2), 1.55 – 1.45 (m, 2H; CH2), 1.42 – 1.35 (m, 2H; CH2), 1.18 (t,
J = 7.1 Hz, 3H; CH3), 1.11 (t, J = 7.1 Hz, 3H; CH3), 1.01 – 0.94
(m, 1H; CH), 0.79 – 0.73 (m, 1H; CH), 0.55 – 0.43 (m, 4H; 2 CH2).
13C NMR (126 MHz, CDCl3) mixture of two diastereoisomers δ
194.89 (s; Cquat), 194.10 (s; Cquat), 168.84 (s; Cquat), 168.69 (s;
Cquat), 158.03 (s; Ar-CH), 158.00 (s; Ar-CH), 136.80 (s; Cquat),
136.73 (s; Cquat), 133.56 (s; Ar-CH), 133.47 (s; Ar-CH), 133.27 (s;
Ar-CH), 133.03 (s; Ar-CH), 128.82 (s; Ar-CH), 128.55 (s; Ar-CH),
128.35 (s; Ar-CH), 128.25 (s; Ar-CH), 110.76 (s; Ar-CH), 110.57
(s; Ar-CH), 61.41 (s; CH2), 61.30 (s; CH2), 57.78 (s; CH), 57.04
(s; CH), 55.88 (s; CH), 54.98 (s; CH), 15.90 (s; CH), 14.93 (s; CH),
13.90 (s; CH3), 13.88 (s; CH3), 4.86 (s; CH2), 4.68 (s; CH2), 3.63
(s; CH2), 3.58 (s; CH2). HRMS (ESI) m/z: [M + H]+ Calcd for
C19H22N3O3+ 340.1656 (100.0%), Found 340.1662.
The substrate has been characterized in the previous work.[13]
Ethyl 2-benzoyl-3-(pyrimidin-2-ylamino)-3-(p-tolyl)
propanoate (1p)
White solid, 35% isolated yield; Silica gel TLC Rf = 0.61
(Toluene/MeCN 3:1) Diastereoisomers ratio: 51:49. 1H NMR (500
MHz, DMSO-d6) mixture of two diastereoisomers δ 8.26 (d, J =
4.6 Hz, 2H; Ar-H), 8.22 (d, J = 4.7 Hz, 2H; Ar-H), 8.04 (d, J = 7.2
Hz, 2H; Ar-H), 7.84 (d, J = 7.2 Hz, 3H; Ar-H), 7.74 – 7.65 (m, 3H;
Ar-H), 7.63 (t, J = 7.4 Hz, 1H; Ar-H), 7.59 (t, J = 7.8 Hz, 2H; Ar-
H), 7.51 (t, J = 7.8 Hz, 2H; Ar-H), 7.38 (d, J = 8.1 Hz, 2H; Ar-H),
7.33 (d, J = 8.1 Hz, 2H; Ar-H), 7.11 (d, J = 7.9 Hz, 2H; Ar-H), 6.97
(d, J = 7.9 Hz, 2H; Ar-H), 6.57 (t, J = 4.8 Hz, 1H; Ar-H), 6.55 (t, J
= 4.8 Hz, 1H), 5.92 (t, J = 10.2 Hz, 1H), 5.85 (dd, J = 10.6, 9.2 Hz,
1H), 5.43 (d, J = 10.6 Hz, 1H; CH), 5.29 (d, J = 10.7 Hz, 1H; CH),
4.02 (ddq, J = 35.5, 10.9, 7.1 Hz, 2H; CH2), 3.78 (q, J = 7.1 Hz,
2H; CH2), 2.24 (s, 3H; CH3), 2.13 (s, 3H; CH3), 0.97 (t, J = 7.0 Hz,
3H; CH3), 0.81 (t, J = 7.1 Hz, 3H; CH3). 13C NMR (126 MHz,
DMSO-d6) mixture of two diastereoisomers δ 193.40 (s; Cquat),
192.84 (s; Cquat), 167.68 (s; Cquat), 167.00 (s; Cquat), 161.88 (s;
Cquat), 161.86 (s; Cquat), 138.35 (s; Cquat), 138.33 (s; Cquat), 136.83
(s; Cquat), 136.61 (s; Cquat), 136.57 (s; Cquat), 136.25 (s; Cquat),
134.44 (s; Ar-CH), 134.41 (s; Ar-CH), 129.40 (s; Ar-CH), 129.12
(s; Ar-CH), 129.02 (s; Ar-CH), 128.75 (s; Ar-CH), 128.11 (s; Ar-
CH), 128.08 (s; Ar-CH), 111.17 (s; Ar-CH), 111.09 (s; Ar-CH),
61.48 (s; CH2), 61.39 (s; CH2), 59.57 (s; CH), 59.13 (s; CH), 54.06
(s; CH), 53.95 (s; CH), 21.14 (s; CH3), 21.02 (s; CH3), 14.22 (s;
CH3), 13.94 (s; CH3). HRMS (ESI) m/z: [M + H]+ Calcd for
C23H24N3O3+ 390.1813 (100.0%); Found 390.1809.
Ethyl 2-benzoyl-3-cyclohexyl-3-(pyrimidin-2-ylamino)
propanoate (1s)
Colourless solid, 23% isolated yield; Silica gel TLC Rf = 0.69, 0.63
(Toluene/MeCN 3:1) Diastereoisomers ratio: 50:50. 1H NMR (500
MHz, Chloroform-d) mixture of two diastereoisomers δ 8.22 (d, J
= 4.7 Hz, 2H; Ar-H), 7.94 (d, J = 8.2 Hz, 2H; Ar-H), 7.83 (d, J =
8.1 Hz, 2H; Ar-H), 7.60 – 7.51 (m, 3H; Ar-H), 7.52 – 7.37 (m, 2H;
Ar-H), 6.44 (t, J = 4.7 Hz, 1H), 6.37 (t, J = 4.7 Hz, 1H), 6.26 (d, J
= 10.5 Hz, 1H), 5.95 (d, J = 10.6 Hz, 1H), 4.89 – 4.79 (m, 2H;
CH2), 4.77 (d, J = 5.3 Hz, 1H; CH), 4.72 (d, J = 4.3 Hz, 1H; CH),
4.22 – 4.10 (m, 2H; CH2), 3.95 (q, J = 7.1 Hz, 2H; CH2), 1.99 –
1.92 (m, 1H), 1.90 – 1.80 (m, 2H), 1.80 – 1.57 (m, 9H), 1.17 (t, J
= 7.1 Hz, 3H; CH3), 1.17 – 1.00 (m, 8H), 0.98 (t, J = 7.1 Hz, 3H;
CH3). 13C NMR (126 MHz, CDCl3) mixture of two
diastereoisomers δ 195.16 (s; Cquat), 194.40 (s; Cquat), 169.05 (s;
Cquat), 168.95 (s; Cquat), 162.69 (s; Cquat), 162.45 (s; Cquat), 158.26
(s; Ar-CH), 157.97 (s; Ar-CH), 136.97 (s; Cquat), 136.28 (s; Cquat),
133.55 (s; Ar-CH), 133.22 (s; Ar-CH), 128.79 (s; Ar-CH), 128.69
(s; Ar-CH), 128.33 (s; Ar-CH), 128.19 (s; Ar-CH), 110.39 (s; Ar-
CH), 110.30 (s; Ar-CH), 61.56 (s; CH2), 61.35 (s; CH2), 55.95 (s;
CH), 54.69 (s; CH), 53.70 (s; CH), 41.86 (s; CH), 41.31 (s; CH),
31.68 (s; CH2), 30.61 (s; CH2), 29.81 (s; CH2), 29.12 (s; CH2),
26.19 (s; CH2), 26.15 (s; CH2), 26.04 (s; CH2), 25.97 (s; CH2),
25.95 (s; CH2), 24.97 (s; CH2), 13.97 (s; CH3), 13.70 (s; CH3).
Ethyl 2-benzoyl-3-(3,5-dimethylphenyl)-3-(pyrimidin-2-yl
amino)propanoate (1q)
White solid, 21% isolated yield; Silica gel TLC Rf = 0.65
(Toluene/MeCN 3:1) Diastereoisomers ratio: 56:44. 1H NMR (500
MHz, DMSO-d6) maior diastereoisomer δ 8.26 (d, J = 4.8 Hz, 2H;
Ar-H), 8.03 (d, J = 7.3 Hz, 2H; Ar-H), 7.70 (t, J = 9.4 Hz, 2H; Ar-
H), 7.58 (t, J = 7.8 Hz, 2H; Ar-H), 7.10 (s, 2H; Ar-H), 6.85 (s, 1H;
Ar-H), 6.56 – 6.54 (m, 1H), 5.85 – 5.80 (m, 1H), 5.23 (d, J = 10.7
Hz, 1H; CH), 3.79 (q, J = 7.1 Hz, 2H; CH2), 2.24 (s, 6H; 2 CH3),
0.82 (t, J = 7.1 Hz, 3H; CH3). 1H NMR (500 MHz, DMSO-d6) minor
diastereoisomer δ 8.22 (d, J = 4.7 Hz, 2H; Ar-H), 7.83 (d, J = 7.3
Hz, 2H; Ar-H), 7.64 – 7.60 (m, 2H; Ar-H), 7.50 (t, J = 7.7 Hz, 2H;
Ar-H), 7.03 (s, 2H; Ar-H), 6.69 (s, 1H; Ar-H), 6.58 – 6.56 (m, 1H),
5.88 (t, J = 10.0 Hz, 1H), 5.38 (d, J = 10.4 Hz, 1H; CH), 4.09 –
3.95 (m, 2H; CH2), 2.11 (s, 6H; 2 CH3), 0.98 (t, J = 7.1 Hz, 3H;
CH3). 13C NMR (126 MHz, DMSO-d6) mixture of two
diastereoisomers δ 193.69 (s; Cquat), 192.71 (s; Cquat), 172.14 (s;
Cquat), 167.82 (s; Cquat), 167.00 (s; Cquat), 161.84 (s; Cquat), 141.26
(s; Cquat), 141.09 (s; Cquat), 137.31 (s; Cquat), 137.27 (s; Cquat),
136.54 (s; Cquat), 136.34 (s; Cquat), 134.41 (s; Ar-CH), 134.28 (s;
Ar-CH), 129.39 (s; Ar-CH), 129.29 (s; Ar-CH), 129.16 (s; Ar-CH),
HRMS (ESI) m/z: [M + H]+ Calcd for C22H28N3O3 382.2126
(100.0%), Found 382.2125.
+
8
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10.1002/ejoc.202001253
European Journal of Organic Chemistry
FULL PAPER
3-((pyrimidin-2-ylamino)(4-(trifluoromethyl)phenyl)
methyl)pentane-2,4-dione (1t)
Cquat), 148.00 (s; Cquat), 142.85 (s; Cquat), 136.70 (s; Cquat), 135.96
(s; Cquat), 135.41 (s; Ar-CH), 134.51 (s; Ar-CH), 130.06 (s; Ar-CH),
129.46 (s; Ar-CH), 129.33 (s; Ar-CH), 129.06 (s; Ar-CH), 128.95
(s; Ar-CH), 123.10 (s; Ar-CH), 122.77 (s; Ar-CH), 111.65 (s; Ar-
CH), 60.18 (s; CH), 55.04 (s; CH). HRMS (ESI) m/z: [M + H]+
Calcd for C26H21N4O4+ 453.1558 (100.0%); Found 453.1552.
White solid, 47% isolated yield; Silica gel TLC Rf = 0.53
1
(Toluene/MeCN 3:1) Diastereoisomers ratio: <95. H NMR (500
MHz, DMSO-d6) δ 8.27 (d, J = 4.7 Hz, 2H; Ar-H), 7.85 (d, J = 9.5
Hz, 1H; Ar-H), 7.70 – 7.63 (m, 4H; Ar-H), 6.61 (t, J = 4.8 Hz, 1H),
5.78 (dd, J = 11.0, 9.5 Hz, 1H), 4.71 (d, J = 10.9 Hz, 1H), 2.26 (s,
3H; CH3), 1.98 (s, 3H; CH3). 13C NMR (126 MHz, DMSO-d6) δ
202.21 (s; Cquat), 201.81 (s; Cquat), 161.68 (s; Cquat), 146.28 (s;
Cquat), 128.88 (s; Ar-CH), 128.30 (q, J = 31.5 Hz; Cquat), 125.63 (q,
J = 3.5 Hz; Ar-CH), 127.93 – 120.94 (m; Cquat), 111.64 (s; Ar-CH),
71.91 (s; CH), 53.86 (s; CH), 31.13 (s; CH3), 30.98 (s; CH3).
HRMS (ESI) m/z: [M + H]+ Calcd for C17H17F3N3O2+ 352.1268
(100.0%); Found 352.1271.
General procedure for the preparation of 4,5-disubstituted 2-
amino-1H-imidazole compounds (2a-w)
To a solution of the Mannich precursor 1a-w (0.25 mmol) in DMA
(4.75 mL), IBX (0.25 mmol, 1 equiv. (156 mg), 45 wt%) and IPT
(0.38 mmol, 1.5 equiv. (102 mg)) were added. The reaction
mixture was stirred at 80 ºC for 30 minutes. Afterwards, the
mixture was cooled to room temperature and NH2OH·HCl (2.5
mmol, 10 equiv. (174 mg)) was added to the reaction mixture.
After addition of Na2CO3 (2.5 mmol, 10 equiv. (265 mg)), the
mixture was stirred at ambient temperature for 15 min, then at
50 °C for 16 hours. When TCL indicated that the reaction was
completed, the solution was poured into water and extracted with
ethyl acetate (2x10 mL). The organic layer was washed with
saturated sodium bicarbonate solution (10 mL) and brine (10 mL).
The combined organic layers were dried over Na2SO4 and
evaporated to dryness. The crude material was subjected to
column chromatographic separation (silica gel, eluent:
toluene/methanol from 50:1 to 10:1) and recrystallized in diethyl
ether/methanol observing the pure products 2a-w.
3-((3-nitrophenyl)(pyrimidin-2-ylamino)methyl)pentane-2,4-
dione (1u)
White solid, 30% isolated yield; Silica gel TLC Rf = 0.44
1
(Toluene/MeCN 3:1) Diastereoisomers ratio: <95. H NMR (500
MHz, DMSO-d6) δ 8.39 (t, J = 2.0 Hz, 1H; Ar-H), 8.28 (d, J = 4.8
Hz, 2H; Ar-H), 8.08 (ddd, J = 8.2, 2.4, 1.0 Hz, 1H; Ar-H), 7.95 (d,
J = 9.5 Hz, 1H; Ar-H), 7.87 (d, J = 7.7 Hz, 1H; Ar-H), 7.59 (t, J =
7.9 Hz, 1H; Ar-H), 6.62 (t, J = 4.8 Hz, 1H), 5.81 (dd, J = 11.0, 9.5
Hz, 1H), 4.75 (d, J = 11.0 Hz, 1H), 2.30 (s, 3H; CH3), 2.00 (s, 3H;
CH3). 13C NMR (126 MHz, DMSO-d6) δ 202.08 (s; Cquat), 201.69
(s; Cquat), 161.59 (s; Cquat), 148.28 (s; Cquat), 143.95 (s; Cquat),
135.19 (s; Ar-CH), 130.12 (s; Ar-CH), 122.81 (s; Ar-CH), 122.56
(s; Ar-CH), 111.79 (s; Ar-CH), 71.88 (s; CH), 53.70 (s; CH), 31.21
(s; CH3), 31.18 (s; CH3). HRMS (ESI) m/z: [M + H]+ Calcd for
C16H17N4O4+ 329.1245 (100.0%); Found 329.1246.
Ethyl 2-amino-4-phenyl-1H-imidazole-5-carboxylate (2a)
White solid, 92% yield (53 mg); Silica gel TLC Rf = 0.52
(toluene/2-propanol 3:1); m.p.: 228.4-228.9 °C; 1H NMR (500
MHz, DMSO-d6) δ 10.82 (s, 1H; NH), 7.92 (d, J = 7.1 Hz, 2H; Ar-
H), 7.35 (t, J = 7.5 Hz, 2H; Ar-H), 7.29 (t, J = 7.3 Hz, 1H; Ar-H),
5.77 (s, 2H; NH2), 4.18 (q, J = 7.1 Hz, 2H; CH2), 1.24 (t, J = 7.1
Hz, 3H; CH3). 13C NMR (126 MHz, DMSO) δ 159.88 (s; Cquat),
152.11 (s; Cquat), 146.48 (s; Cquat), 134.64 (s; Cquat), 129.18 (s; Ar-
CH), 128.05 (s; Ar-CH), 127.89 (s; Ar-CH), 111.89 (s; Cquat), 59.77
(s; CH2), 14.79 (s; CH3). FTIR-ATR: υ~ = 1149 (s) cm-1 (C-N), 1299
(s) cm-1 (C-O) 1590 (m) cm-1 (N-H), 1636 (s) cm-1 (C=C), 3059 (m)
1,3-diphenyl-2-((pyrimidin-2-ylamino)(4-(trifluoromethyl)
phenyl)methyl)propane-1,3-dione (1v)
White solid, 20% isolated yield; Silica gel TLC Rf = 0.65
1
(Toluene/MeCN 3:1) Diastereoisomers ratio: <95. H NMR (500
MHz, DMSO-d6) δ 8.23 (d, J = 4.7 Hz, 2H; Ar-H), 8.03 (d, J = 7.3
Hz, 2H; Ar-H), 7.81 (d, J = 7.3 Hz, 2H; Ar-H), 7.78 (d, J = 9.2 Hz,
1H; Ar-H), 7.70 (d, J = 8.1 Hz, 2H; Ar-H), 7.63 (t, J = 7.4 Hz, 1H;
Ar-H), 7.58 – 7.49 (m, 5H; Ar-H), 7.42 (t, J = 7.8 Hz, 1H; Ar-H),
6.61 – 6.57 (m, 2H), 6.13 (t, J = 9.5 Hz, 1H). 13C NMR (126 MHz,
DMSO-d6) δ 194.26 (s; Cquat), 193.69 (s; Cquat), 161.70 (s; Cquat),
146.13 (s; Cquat), 136.79 (s; Cquat), 136.06 (s; Cquat), 134.35 (q, 3J
= 2.3 Hz; Ar-CH), 129.44 (s; Ar-CH), 129.33 (s; Ar-CH), 129.09
(s; Ar-CH), 129.04 (s; Ar-CH), 128.85 (s; Ar-CH), 128.14 (q, J =
32.0 Hz; Cquat), 125.38 (q, J = 3.7 Hz; Ar-CH), 127.64 – 121.65
(m; Cquat), 111.60 (s; Ar-CH), 60.29 (s; CH), 55.14 (s; CH). HRMS
(ESI) m/z: [M + H]+ Calcd for C27H21F3N3O2+ 476.1581 (100.0%);
Found 476.1574.
cm-1 (C-H). HRMS (ESI) m/z: [M + H]+ Calcd for C12H14N3O2
+
232.1081 (100.0%); Found 232.1088. These spectroscopic data
correspond to the reported data in reference[5b]
.
Ethyl 2-amino-4-(3-fluorophenyl)-1H-imidazole-5-carboxylate
(2b)
White solid, 88% yield (55 mg); m.p.: 191.3-194.0 °C; Silica gel
TLC Rf = 0.60 (toluene/2-propanol 3:1). 1H NMR (500 MHz,
DMSO-d6) δ 10.93 (s, 1H; NH), 7.84 (s, 1H; Ar-H), 7.85 – 7.79 (m,
1H; Ar-H), 7.40 (td, J = 8.1, 6.3 Hz, 1H; Ar-H), 7.13 (td, J = 8.2,
2.3 Hz, 1H; Ar-H), 5.82 (s, 2H; NH2), 4.20 (q, J = 7.1 Hz, 2H; CH2),
1.26 (t, J = 7.1 Hz, 3H; CH3). 13C NMR (126 MHz, DMSO-d6) δ
162.16 (d, J = 240.9 Hz; Cquat), 159.80 (s; Cquat), 152.10 (s; Cquat),
144.75 (d, J = 2.4 Hz; Cquat), 136.89 (d, J = 8.9 Hz; Cquat), 129.85
(d, J = 8.4 Hz; Ar-CH), 125.04 (d, J = 2.4 Hz; Ar-CH), 115.50 (d,
J = 23.1 Hz; Ar-CH), 114.73 (d, J = 21.1 Hz; Ar-CH), 112.48 (s;
Cquat), 60.02 (s; CH2), 14.74 (s; CH3). FTIR-ATR: υ~ = 1137 (s) cm-
1 (C-F), 1298 (s) cm-1 (C-O) or (C-N), 1590 (m) cm-1 (N-H). HRMS
2-((3-nitrophenyl)(pyrimidin-2-ylamino)methyl)-1,3-
diphenylpropane-1,3-dione (1w)
White solid, 90% isolated yield, applying method from [14]; Silica
gel TLC Rf = 0.60 (Toluene/MeCN 3:1) Diastereoisomers ratio:
<95. 1H NMR (500 MHz, DMSO-d6) δ 8.48 (t, J = 2.0 Hz, 1H; Ar-
H), 8.45 (d, J = 9.2 Hz, 1H; Ar-H), 8.35 (d, J = 4.9 Hz, 2H; Ar-H),
8.03 (d, J = 7.3 Hz, 2H; Ar-H), 7.94 – 7.88 (m, 2H; Ar-H), 7.84 (d,
J = 7.3 Hz, 2H; Ar-H), 7.61 (t, J = 7.4 Hz, 1H; Ar-H), 7.53 (t, J =
7.5 Hz, 1H; Ar-H), 7.49 (t, J = 7.7 Hz, 2H; Ar-H), 7.45 (t, J = 8.0
Hz, 1H; Ar-H), 7.39 (t, J = 7.7 Hz, 2H; Ar-H), 6.81 (d, J = 9.7 Hz,
1H), 6.71 (t, J = 4.9 Hz, 1H), 6.19 (t, J = 9.3 Hz, 1H). 13C NMR
(126 MHz, DMSO) δ 194.36 (s; Cquat), 193.63 (s; Cquat), 159.52 (s;
(ESI) m/z: [M + H]+ Calcd for C12H13FN3O2 250.0987 (100.0%);
+
Found 250.0995.
9
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001253
European Journal of Organic Chemistry
FULL PAPER
Ethyl 2-amino-4-(3-chlorophenyl)-1H-imidazole-5-
carboxylate (2c)
(s; Cquat), 60.26 (s; CH2), 14.69 (s; CH3). FTIR-ATR: υ~ = 1302 (s)
cm-1 (C-N), 1523 (s) cm-1 (N-O), 1583 (m) cm-1 (N-H). HRMS
(ESI) m/z: [M + H]+ Calcd for C12H13N4O4 277.0932 (100.0%);
+
White solid, 75% yield (50 mg); m.p.: 196.1-197.3 °C; Silica gel
TLC Rf = 0.62 (toluene/2-propanol 3:1). 1H NMR (500 MHz,
DMSO-d6) δ 10.95 (s, 1H; NH), 8.06 (s, 1H; Ar-H), 7.93 (d, J = 7.5
Hz, 1H; Ar-H), 7.39 (t, J = 7.8 Hz, 1H; Ar-H), 7.36 (d, J = 8.1 Hz,
1H; Ar-H), 5.83 (s, 2H; NH2), 4.20 (q, J = 7.1 Hz, 2H; CH2), 1.27
(t, J = 7.0 Hz, 3H; CH3). 13C NMR (126 MHz, DMSO-d6) δ 159.80
(s; Cquat), 152.18 (s; Cquat), 144.46 (s; Cquat), 136.61 (s; Cquat),
132.75 (s; Cquat), 129.90 (s; Ar-CH), 128.71 (s; Ar-CH), 127.79 (s;
Ar-CH), 127.55 (s; Ar-CH), 112.56 (s; Cquat), 60.05 (s; CH2), 14.73
(s; CH3). FTIR-ATR: υ~ = 1152 (m) cm-1 (C-N), 1294 (s) cm-1 (C-
N), 1588 (m) cm-1 (N-H), 3073 (m) cm-1 (C-H), 3305 (m) cm-1 (N-
H). HRMS (ESI) m/z: [M + H]+ Calcd for C12H13ClN3O2+ 266.0691
(100.0%), 268.0662 (32.0%), 267.0725 (13.0%); Found
266.0700, 268.0670, 267.0731.
Found 277.0941.
Ethyl 2-amino-4-(2-(trifluoromethyl)phenyl)-1H-imidazole-5-
carboxylate (2g)
White solid, 60% yield (45 mg); m.p.: 231.8-232.8 °C; Silica gel
TLC Rf = 0.54 (toluene/2-propanol 3:1). 1H NMR (500 MHz,
DMSO-d6) δ 11.06 (s, 1H; NH), 7.74 (d, J = 7.8 Hz, 1H; Ar-H),
7.64 (t, J = 7.5 Hz, 1H; Ar-H), 7.57 (t, J = 7.7 Hz, 1H; Ar-H), 7.39
(d, J = 7.6 Hz, 1H; Ar-H), 5.73 (s, 2H; NH2), 3.93 (q, J = 7.1 Hz,
2H; CH2), 0.92 (t, J = 7.1 Hz, 3H; CH3). 13C NMR (126 MHz,
DMSO-d6) δ 159.65 (s; Cquat), 152.07 (s; Cquat), 144.57 (s; Cquat),
135.13 (s; Cquat), 132.75 (s; Ar-CH), 131.78 (s; Ar-CH), 128.58 (s;
Ar-CH), 128.78 – 127.85 (m; Cquat), 131.53 – 123.31 (m; Cquat),
126.01 (q, J = 5.0 Hz; Ar-CH), 113.87 (s; Cquat), 59.31 (s; CH2),
14.29 (s; CH3). FTIR-ATR: ν~ = 1146 (s) cm-1 (C-F), 1313 (s) cm-
1 (C-N), 1034 (m) cm-1 (C-N), 1635 (m) cm-1 (C=C), 1676 (m) cm-
Ethyl 2-amino-4-(3-bromophenyl)-1H-imidazole-
5-carboxylate (2d)
(C=N), 3323 (m) cm-1 (N-H). HRMS (ESI) m/z: [M + H]+ Calcd
1
Light yellow solid, 90% yield (70 mg); m.p.: 200.0-201.4 °C; Silica
1
gel TLC Rf = 0.62 (toluene/2-propanol 3:1). H NMR (500 MHz,
for C13H13F3N3O2+ 300.0955 (100.0%); Found 300.0966.
DMSO-d6) δ 10.95 (s, 1H; NH), 8.19 (s, 1H; Ar-H), 7.97 (d, J = 7.8
Hz, 1H; Ar-H), 7.49 (dd, J = 7.9, 2.2 Hz, 1H; Ar-H), 7.33 (t, J = 7.9
Hz, 1H; Ar-H), 5.82 (s, 2H, NH2), 4.20 (q, J = 7.1 Hz, 2H; CH2),
1.27 (t, J = 7.1 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) δ 159.80
(s; Cquat), 152.18 (s; Cquat), 144.33 (s; Cquat), 136.88 (s; Cquat),
131.59 (s; Ar-CH), 130.65 (s; Ar-CH), 130.20 (s; Ar-CH), 127.92
(s; Ar-CH), 121.34 (s; Cquat), 112.56 (s; Cquat), 60.06 (s; CH2),
14.75 (s; CH3). FTIR-ATR: υ~ = 676 (s) cm-1 (C-Br), 1292 (s) cm-
1 (C-O) or (C-N), 1585 (m) cm-1 (N-H), 3054 (m) cm-1 (C-H), 3310
Ethyl 2-amino-4-(3-(trifluoromethyl)phenyl)-1H-imidazole-
5-carboxylate (2h)
White solid, 78% yield (58 mg); m.p.: 218.2-219.8 °C; Silica gel
TLC Rf = 0.62 (toluene/2-propanol 3:1). 1H NMR (500 MHz,
DMSO-d6) δ 11.01 (s, 1H; NH), 8.35 (s, 1H; Ar-H), 8.27 (d, J = 7.8
Hz, 1H; Ar-H), 7.66 (d, J = 7.9 Hz, 1H; Ar-H), 7.61 (t, J = 7.8 Hz,
1H; Ar-H), 5.87 (s, 2H; NH2), 4.21 (q, J = 7.0 Hz, 2H; CH2), 1.25
(t, J = 7.1 Hz, 3H; CH3). 13C NMR (126 MHz, DMSO-d6) δ 159.83
(s; Cquat), 152.31 (s; Cquat), 144.27 (s; Cquat), 135.47 (s; Cquat),
(m) cm-1 (N-H). HRMS (ESI) m/z: [M
+
H]+ Calcd for
3
C12H13BrN3O2+ 310.0186 (100.0%), 312.0166 (97.3%), 311.0220
(13.0%), 313.0199 (12.6%); Found 310.0198, 312.0178,
311.0228, 313.0207.
132.79 (s; Ar-CH), 129.18 (s; Ar-CH), 128.94 (q, J = 31.7 Hz;
Cquat), 125.45 (q, J = 3.5 Hz; Ar-CH), 128.26 – 121.39 (m; Cquat),
124.52 (q, J = 3.8 Hz; Ar-CH), 112.73 (s; Cquat), 60.13 (s; CH2),
14.67 (s; CH3). FTIR-ATR: ν~ = 1112 (s) cm-1 (C-F), 1289 (s) cm-
1
(C-O), 1584 (m) cm-1 (N-H), 1646 (s) cm-1 (C=C). HRMS (ESI)
Ethyl 2-amino-4-(3-iodophenyl)-1H-imidazole-5-carboxylate
(2e)
m/z: [M + H]+ Calcd for C13H13F3N3O2+ 300.0955 (100.0%); Found
300.0966.
Light yellow solid, 70% yield (63 mg); m.p.: 205.8-206.0 °C; Silica
gel TLC Rf = 0.64 (toluene/2-propanol 3:1). H NMR (500 MHz,
1
Ethyl 2-amino-4-(4-(trifluoromethyl)phenyl)-1H-imidazole-5-
carboxylate (2i)
DMSO-d6) δ 10.93 (s, 1H; NH), 8.35 (s, 1H; Ar-H), 7.98 (d, J = 7.9
Hz, 1H; Ar-H), 7.66 (d, J = 7.8 Hz, 1H; Ar-H), 7.17 (t, J = 7.8 Hz,
1H; Ar-H), 5.81 (s, 2H; NH2), 4.19 (q, J = 7.1 Hz, 2H; CH2), 1.27
(t, J = 7.1 Hz, 3H; CH3). 13C NMR (126 MHz, DMSO-d6) δ 159.82
(s; Cquat), 152.18 (s; Cquat), 144.30 (s; Cquat), 137.51 (s; Ar-CH),
136.81 (s; Cquat), 136.48 (s; Ar-CH), 130.23 (s; Ar-CH), 128.34 (s;
Ar-CH), 112.45 (s; Cquat), 94.33 (s; Cquat), 60.03 (s; CH2), 14.82 (s;
CH3). FTIR-ATR: υ~ = 1295 (s) cm-1 (C-O), 1587 (m) cm-1 (N-H),
3301 (m) cm-1 (N-H). HRMS (ESI) m/z: [M + H]+ Calcd for
C12H13IN3O2+ 358.0047 (100.0%); Found 358.0061.
Off-white solid, 84% yield (63 mg); m.p.: 253.7-254.9 °C; Silica
1
gel TLC Rf = 0.58 (toluene/2-propanol 3:1). H NMR (500 MHz,
DMSO-d6) δ 11.03 (s, 1H; NH), 8.16 (d, J = 8.0 Hz, 2H; Ar-H),
7.71 (d, J = 8.1 Hz, 2H; Ar-H), 5.86 (s, 2H; NH2), 4.20 (q, J = 7.1
Hz, 2H; CH2), 1.26 (t, J = 7.1 Hz, 3H; CH3). 13C NMR (126 MHz,
DMSO-d6) δ 159.75 (s; Cquat), 152.32 (s; Cquat), 144.46 (s; Cquat),
138.59 (s; Cquat), 129.65 (s; Ar-CH), 128.10 (q, J = 31.8 Hz; Cquat),
124.88 (q, J C-F= 272.0 Hz; Cquat), 124.86 (q, J = 3.4 Hz; Ar-CH),
113.02 (s; Cquat), 60.09 (s; CH2), 14.73 (s; CH3). FTIR-ATR: υ~ =
1105 (s) cm-1 (C-F), 1159 (m) cm-1 (C-N), 1303 (s) cm-1 (C-O),
1317 (s) cm-1 (C-N), 1586 (m) cm-1 (N-H), 1636 (m) cm-1 (C=C),
1662 (m) cm-1 (C=C). HRMS (ESI) m/z: [M + H]+ Calcd for
C13H13F3N3O2+ 300.0954 (100%); Found 300.0965.
Ethyl 2-amino-4-(3-nitrophenyl)-1H-imidazole-5-carboxylate
(2f)
Orange solid, 94% yield (65 mg); m.p.: 251.2-252.8 °C; Silica gel
TLC Rf = 0.58 (toluene/2-propanol 3:1). 1H NMR (500 MHz,
DMSO-d6) δ 11.08 (s, 1H; NH), 8.91 (t, J = 2.1 Hz, 1H; Ar-H), 8.46
(dt, J = 7.9, 1.4 Hz, 1H; Ar-H), 8.16 (ddd, J = 8.2, 2.4, 1.1 Hz, 1H;
Ar-H), 7.67 (t, J = 8.0 Hz, 1H; Ar-H), 5.90 (s, 2H; NH2), 4.23 (q, J
= 7.1 Hz, 2H; CH2), 1.27 (t, J = 7.1 Hz, 3H; CH3). 13C NMR (126
MHz, DMSO-d6) δ 159.79 (s; Cquat), 152.36 (s; Cquat), 147.96 (s;
Cquat), 143.43 (s; Cquat), 136.09 (s; Cquat), 135.22 (s; Ar-CH),
129.66 (s; Ar-CH), 123.45 (s; Ar-CH), 122.66 (s; Ar-CH), 113.11
Ethyl 2-amino-4-(2,4-bis(trifluoromethyl)phenyl)-1H-
imidazole-5-carboxylate (2j)
Light orange solid, 90% yield (82 mg); Silica gel TLC Rf = 0.63
(toluene/2-propanol 3:1); m.p.: 182.9-183.9 °C. 1H NMR (500
MHz, DMSO-d6) δ 11.24 (s, 1H; NH), 8.09 – 8.02 (m, 2H; Ar-H),
7.68 (d, J = 7.9 Hz, 1H; Ar-H), 5.83 (s, 2H; NH2), 3.95 (q, J = 7.1
10
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001253
European Journal of Organic Chemistry
FULL PAPER
Hz, 2H; CH2), 0.93 (t, J = 7.1 Hz, 3H; CH3). 13C NMR (126 MHz,
DMSO-d6) δ 159.40 (s; Cquat), 152.43 (s; Cquat), 142.93 (s; Cquat),
139.59 (s; Cquat), 134.35 (s; Ar-CH), 129.30 (q, J = 33.0 Hz; Cquat),
129.77 – 128.95 (m; Cquat), 128.76 (q, J = 4.0 Hz; Ar-CH), 127.07
CH2), 2.19 (s, 3H; CH3), 1.06 (t, J = 7.0 Hz, 3H; CH3). 13C NMR
(126 MHz, DMSO) δ 136.93 (s; Cquat), 130.83 (s; Ar-CH), 129.79
(s; Ar-CH), 127.96 (s; Ar-CH), 125.12 (s; Ar-CH), 59.31 (s; CH2),
20.21 (s; CH3), 14.59 (s; CH3). FTIR-ATR: ν~ = 1141 (s) cm-1 (C-
N), 1312 (s) cm-1 (C-N), 1635 (m) cm-1 (N-H), 1671 (m) cm-1
(C=N), 3319 (m) cm-1 (N-H). HRMS (ESI) m/z: [M + H]+ Calcd for
C13H16N3O2+ 246.1238 (100.0%); Found 246.1244.
6
– 120.24 (m; Cquat), 127.38 – 120.11 (m; Cquat), 123.06 (dt, J =
9.4, 4.3 Hz; Ar-CH), 114.24 (s; Cquat), 59.56 (s; CH2), 14.19 (s;
CH3). FTIR-ATR: ν~ = 1064 (m) cm-1 (C-N), 1123 (s), 1264 (s),
1342 (s) cm-1 (C-F), 1582 (s) cm-1 (N-H), 1632 (m) cm-1 (C=C),
1689 (m) cm-1 (C=N). HRMS (ESI) m/z: [M + H]+ Calcd for
C14H12F6N3O2+ 368.0829 (100.0%); Found 368.0841.
Ethyl 2-amino-4-(m-tolyl)-1H-imidazole-5-carboxylate (2o)
Off-white solid, 67% yield (41 mg); m.p.: 202.8-203.9 °C; Silica
1
gel TLC Rf = 0.48 (toluene/2-propanol 3:1). H NMR (500 MHz,
Ethyl 2-amino-4-(3,5-bis(trifluoromethyl)phenyl)-1H-
imidazole-5-carboxylate (2k)
DMSO-d6) δ 10.80 (s, 1H; NH), 7.75 (s, 1H; Ar-H), 7.73 (d, J = 8.0
Hz, 1H; Ar-H), 7.23 (t, J = 7.6 Hz, 1H; Ar-H), 7.11 (d, J = 8.1 Hz,
1H; Ar-H), 5.75 (s, 2H; NH), 4.17 (q, J = 7.0 Hz, 2H; CH2), 2.32
(s, 3H; CH3), 1.25 (t, J = 7.1 Hz, 3H; CH3). 13C NMR (126 MHz,
DMSO-d6) δ 159.92 (s; Cquat), 152.06 (s; Cquat), 146.52 (s; Cquat),
136.72 (s; Cquat), 134.57 (s; Cquat), 129.84 (s; Ar-CH), 128.66 (s;
Ar-CH), 127.79 (s; Ar-CH), 126.39 (s; Ar-CH), 111.87 (s; Cquat),
59.75 (s; CH2), 21.58 (s; CH3), 14.77 (s; CH3). FTIR-ATR: υ~ =
1186 (m) cm-1 (C-N), 1310 (s) cm-1 (C-O), 1592 (m) cm-1 (N-H),
1692 (m) cm-1 (N-H), 3335 (m) cm-1 (N-H). HRMS (ESI) m/z: [M +
H]+ Calcd for C13H16N3O2+ 246.1238 (100.0%); Found 246.1246.
White solid, 94% yield (86 mg); Silica gel TLC Rf = 0.67
(toluene/2-propanol 3:1); m.p.: 234.9-235.1 °C. 1H NMR (500
MHz, DMSO-d6) δ 11.20 (s, 1H; NH), 8.73 (s, 2H; Ar-H), 8.03 (s,
1H; Ar-H), 5.97 (s, 2H; NH2), 4.24 (q, J = 7.1 Hz, 2H; CH2), 1.27
(t, J = 7.1 Hz, 3H; CH3). 13C NMR (126 MHz, DMSO-d6) δ 159.80
(s; Cquat), 152.48 (s; Cquat), 142.12 (s; Cquat), 136.78 (s; Cquat),
130.32 (q, J = 32.6 Hz; Cquat), 128.99 (s; Ar-CH), 123.95 (q, J C-F
= 273.0 Hz; Cquat), 121.26 (p, J = 3.9 Hz; Ar-CH), 113.72 (s; Cquat),
60.51 (s; CH2), 14.59 (s; CH3). FTIR-ATR: ν~ = 1119 (s) cm-1 (C-
F), 1281 (s) cm-1 (C-O), 1649 (s) cm-1 (C=C), 1670 (w) cm-1 (C=C),
1587 (m) cm-1 (N-H). HRMS (ESI) m/z: [M + H]+ Calcd for
C14H12F6N3O2+ 368.0829 (100.0%); Found: 368.0843.
Ethyl 2-amino-4-(p-tolyl)-1H-imidazole-5-carboxylate (2p)
Light yellow solid, 52% yield (32 mg); m.p.: 221.5-221.8 °C; Silica
1
gel TLC Rf = 0.55 (toluene/2-propanol 3:1). H NMR (500 MHz,
Ethyl 2-amino-4-(3-methoxyphenyl)-1H-imidazole-5-
carboxylate (2l)
DMSO-d6) δ 10.73 (s, 1H; NH), 7.83 (d, J = 7.8 Hz, 2H; Ar-H),
7.16 (d, J = 8.0 Hz, 2H; Ar-H), 5.71 (s, 2H; NH2), 4.17 (q, J = 7.1
Light yellow solid, 62% yield (41 mg); m.p.: 173.5-174.0 °C; Silica
Hz, 2H; CH2), 3.32 (s, 3H; CH3), 1.25 (t, J = 7.1 Hz, 3H; CH3). 13
C
1
gel TLC Rf = 0.44 (toluene/2-propanol 3:1). H NMR (500 MHz,
NMR (126 MHz, DMSO) δ 151.96 (s; Cquat), 137.31 (s; Cquat),
129.08 (s; Ar-CH), 128.51 (s; Ar-CH), 59.67 (s; CH2), 21.34 (s;
CH3), 14.81 (s; CH3). FTIR-ATR: ν~ = 1059 (m) cm-1 (C-N), 1297
(s) cm-1 (C-O), 1588 (m) cm-1 (N-H), 3314 (m) cm-1 (N-H). HRMS
DMSO-d6) δ 10.82 (s, 1H; NH), 7.59 (s, 1H; Ar-H), 7.57 (d, J = 8.2
Hz, 1H; Ar-H), 7.26 (t, J = 7.9 Hz, 1H; Ar-H), 6.87 (dd, J = 7.9, 2.3
Hz, 1H; Ar-H), 5.79 (s, 2H; NH2), 4.19 (q, J = 7.1 Hz, 2H; CH2),
3.77 (s, 3H; CH3), 1.25 (t, J = 7.1 Hz, 3H; CH3). 13C NMR (126
MHz, DMSO-d6) δ 159.88 (s; Cquat), 159.06 (s; Cquat), 151.98 (s;
Cquat), 146.17 (s; Cquat), 135.88 (s; Cquat), 128.89 (s; Cquat), 121.60
(s; Ar-CH), 114.35 (s; Ar-CH), 113.95 (s; Ar-CH), 112.03 (s; Cquat),
59.82 (s; CH2), 55.41 (s; CH3), 14.82 (s; CH3). FTIR-ATR: ν~ =
1279 (s) cm-1 (C-O), 1300 (s) cm-1 (C-N), 1586 (m) cm-1 (N-H),
1635 (m) cm-1 (C=C), 3082 (m) cm-1 (C-H). HRMS (ESI) m/z: [M
+ H]+ Calcd for C13H16N3O3+ 262.1187 (100.0%); Found 262.1194.
(ESI) m/z: [M + H]+ Calcd for C13H16N3O2 246.1238 (100.0%),
+
247.1271 (14.1%), 247.1208 (1.1%); Found 246.1247.
Ethyl 2-amino-4-(3,5-dimethylphenyl)-1H-imidazole-5-
carboxylate (2q)
White solid, 48% yield (31 mg); m.p.: 235.7-237.0 °C; Silica gel
TLC Rf = 0.57 (toluene/2-propanol 3:1). 1H NMR (500 MHz,
DMSO-d6) δ 10.77 (s, 1H; NH), 7.54 (s, 2H; Ar-H), 6.93 (s, 1H; Ar-
H), 5.73 (s, 2H; NH2), 4.17 (q, J = 7.1 Hz, 2H; CH2), 2.28 (s, 6H;
2 CH3), 1.24 (t, J = 7.1 Hz, 3H; CH3). 13C NMR (126 MHz, DMSO-
d6) δ 159.95 (s; Cquat), 152.00 (s; Cquat), 146.56 (s; Cquat), 136.55
(s; Cquat), 134.50 (s; Cquat), 129.41 (s; Ar-CH), 127.09 (s; Ar-CH),
111.84 (s; Cquat), 59.72 (s; CH2), 21.48 (s; CH3), 14.74 (s; CH3).
FTIR-ATR: ν~ = 1241 (m) cm-1 (C-N), 1599 (m) cm-1 (N-H), 1669
(s) cm-1 C=C), 3325 (m) cm-1 (N-H). HRMS (ESI) m/z: [M + H]+
Calcd for C14H18N3O2+ 260.1394 (100.0%); Found 260.1403.
Ethyl 2-amino-4-(3,4,5-trimethoxyphenyl)-1H-imidazole-5-
carboxylate (2m)
White solid, 32% yield (26 mg); m.p.: 219.8-220.2 °C; Silica gel
TLC Rf = 0.38 (toluene/2-propanol 3:1). 1H NMR (500 MHz,
DMSO-d6) δ 10.74 (s, 1H; NH), 7.48 (s, 2H; Ar-H), 5.81 (s, 2H;
NH2), 4.21 (q, J = 7.1 Hz, 2H; CH2), 3.79 (s, 6H; CH3), 3.69 (s, 3H;
CH3), 1.26 (t, J = 7.1 Hz, 3H; CH3). 13C NMR (126 MHz, DMSO-
d6) δ 159.97 (s; Cquat), 152.53 (s; Cquat), 151.80 (s; Cquat), 146.22
(s; Cquat), 137.72 (s; Cquat), 129.89 (s; Cquat), 106.53 (s; Ar-CH),
60.51 (s; CH3), 59.85 (s; CH2), 56.20 (s; CH3), 14.94 (s; CH3).
FTIR-ATR: υ~ = 1068 (m) cm-1 (C-N), 1586 (m) cm-1 (N-H), 1649
(m) cm-1 (C=C), 3092 (m) cm-1 (C-H). HRMS (ESI) m/z: [M + H]+
Calcd for C15H20N3O5+ 322.1398 (100.0%); Found 322.1410.
Ethyl 2-amino-4-cyclopropyl-1H-imidazole-5-carboxylate (2r)
White solid, 62% yield (30 mg); Silica gel TLC Rf = 0.45
(toluene/2-propanol 3:1); m.p.: 220.3-221.4 °C. 1H NMR (500
MHz, DMSO-d6) δ 10.39 (s, 1H; NH), 5.61 (s, 2H; NH2), 4.17 (q, J
= 7.1 Hz, 2H; CH2), 1.26 (t, J = 7.1 Hz, 3H; CH3), 0.83 – 0.74 (m,
5H; CH, 2 CH2).13C NMR (126 MHz, DMSO-d6) δ 160.58 (s; Cquat),
152.43 (s; Cquat), 151.59 (s; Cquat), 112.07 (s; Cquat), 59.20 (s; CH2),
15.03 (s; CH3), 9.44 (s; CH), 8.52 (s; CH2). FTIR-ATR: ν~ = 1062
(m) cm-1 (C-N), 1170 (s) cm-1 (C-O), 1625 (s) cm-1 (C=C), 1585
(m) cm-1 (N-H), 3071 (m, broad) cm-1 (C-H). HRMS (ESI) m/z: [M
+ H]+ Calcd for C9H14N3O2+ 196.1081 (100.0%); Found 196.1081.
Ethyl 2-amino-4-(o-tolyl)-1H-imidazole-5-carboxylate (2n)
Light orange solid, 50% yield (31 mg); m.p.: 223.2-224.1 °C; Silica
1
gel TLC Rf = 0.44 (toluene/2-propanol 3:1). H NMR (500 MHz,
DMSO-d6) δ 10.92 (s, 1H; NH), 7.29 – 7.17 (m, 3H; Ar-H), 7.14 (t,
J = 6.4 Hz, 1H; Ar-H), 5.67 (s, 2H; NH2), 4.01 (q, J = 7.0 Hz, 2H;
11
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001253
European Journal of Organic Chemistry
FULL PAPER
Ethyl 2-amino-4-cyclohexyl-1H-imidazole-5-carboxylate (2s)
White solid, 50% yield (30 mg); Silica gel TLC Rf = 0.47
(toluene/2-propanol 3:1); m.p.: 231.9-233.0 °C. 1H NMR (500
MHz, DMSO-d6) δ 10.45 (s, 1H; NH), 5.60 (s, 2H; NH2), 4.14 (q, J
= 7.0 Hz, 2H; CH2), 1.74 (dt, J = 12.9, 3.2 Hz, 2H; CH2), 1.66 (d,
J = 8.5 Hz, 3H; CH2, CH), 1.46 (qd, J = 12.5, 3.2 Hz, 2H; CH2),
1.33 – 1.22 (m, 6H; CH3, CH2, CH), 1.18 (tt, J = 12.7, 3.1 Hz, 1H;
CH). 13C NMR (126 MHz, DMSO-d6) δ 59.13 (s; CH2), 36.86 (s;
CH), 32.44 (s; CH2), 26.68 (s; CH2), 26.26 (s; CH2), 14.91 (s; CH3).
FTIR-ATR: ν~ = 1091 (s) cm-1 (C-N), 1589 (m) cm-1 (N-H), 1628
(s) cm-1 (C=C), 1657 (w) cm-1 (C-H), 2852 (m) cm-1 (C-H). HRMS
Hz, 1H; Ar-H), 7.82 (d, J = 7.8 Hz, 1H; Ar-H), 7.49 – 7.40 (m, 3H;
Ar-H), 7.37 (t, J = 7.5 Hz, 1H; Ar-H), 7.23 (t, J = 7.6 Hz, 2H; Ar-
H), 6.13 (s, 2H; NH2). 13C NMR (126 MHz, DMSO-d6) δ 183.56 (s;
Cquat), 153.59 (s; Cquat), 147.44 (s; Cquat), 146.39 (s; Cquat), 139.36
(s; Cquat), 136.54 (s; Cquat), 135.64 (s; Ar-CH), 131.51 (s; Ar-CH),
129.49 (s; Ar-CH), 129.04 (s; Ar-CH), 128.47 (s; Ar-CH), 124.03
(s; Ar-CH), 123.00 (s; Cquat), 122.51 (s; Ar-CH). FTIR-ATR: υ~ =
1187 (m) cm-1 (C-N), 1318 (s) cm-1 (C-N), 1522 (s) cm-1 (N-O),
1584 (m) cm-1 (N-H), 1647 (m) cm-1 (C=C). HRMS (ESI) m/z: [M
+ H]+ Calcd for C16H13N4O3+ 309.0983 (100.0%); Found 309.0987.
(ESI) m/z: [M + H]+ Calcd for C12H20N3O2 238.1551 (100.0%);
General procedure for the synthesis of 3a-d
+
Found 238.1556.
To a 4 mL vial equipped with a magnetic stir bar containing 4,5-
disubstituted 2-AI 2a, 2i, 2k, 2s (0.2 mmol), concentrated
perchloric acid (3.4 µL, 0.04 mmol) and MeCN (0.2 mL), the
corresponding aldehyde (0.3 mmol, 1.5 equiv.) and isocyanide
(0.3 mmol, 1.5 equiv.) were consecutively added and the reaction
mixture was stirred at 60 °C for 24 hours. Upon completion of
reaction, white crytals were precipitated. Following a simple
filtration and recrystallization in MeCN/aceton mixture (4:1), the
pure products 3a-d were observed.
1-(2-amino-4-(4-(trifluoromethyl)phenyl)-1H-imidazol-5-yl)
ethanone (2t)
Light orange solid, 77% yield (52 mg); m.p.: 258.3-259.8 °C; Silica
1
gel TLC Rf = 0.48 (toluene/2-propanol 3:1). H NMR (500 MHz,
DMSO-d6) δ 11.15 (s, 1H; NH), 7.98 (d, J = 8.0 Hz, 2H; Ar-H),
7.74 (d, J = 8.2 Hz, 2H; Ar-H), 5.90 (s, 2H; NH2), 2.20 (s, 3H; CH3).
13C NMR (126 MHz, DMSO-d6) δ 152.44 (s; Cquat), 130.12 (Ar-
CH), 128.50 (q, J = 32.1 Hz; Cquat), 125.07 (q, J = 3.4 Hz; Ar-CH),
124.80 (q, J C-F = 272.0 Hz; Cquat), 28.28 (s; CH3). FTIR-ATR: υ~ =
1065 (s) cm-1 (C-F), 1172 (m) cm-1 (C-N), 1319 (s) cm-1 (C-N),
1587 (m) cm-1 (N-H), 1655 (m) cm-1 (C=C). HRMS (ESI) m/z: [M
+ H]+ Calcd for C12H11F3N3O+ 270.0849 (100.0%); Found
270.0859.
Ethyl 5-(tert-butylamino)-2,6-diphenyl-1H-imidazo[1,2-a]
imidazole-3-carboxylate (3a)
White solid, 40% yield (32 mg); Silica gel TLC Rf = 0.84
(toluene/2-propanol 3:1); m.p./b.p. 186.0-187.6 °C; 1H NMR (500
MHz, DMSO-d6) δ 12.25 (s, 1H; NH), 7.97 (d, J = 6.9 Hz, 2H; Ar-
H), 7.73 – 7.66 (m, 2H; Ar-H), 7.44 (t, J = 7.8 Hz, 2H; Ar-H), 7.43
– 7.36 (m, 3H; Ar-H), 7.30 (t, J = 7.4 Hz, 1H; Ar-H), 4.77 (s, 1H;
NH), 4.20 (q, J = 7.1 Hz, 2H; CH2), 1.15 (t, J = 7.1 Hz, 3H; CH3),
0.94 (s, 9H; 3 CH3). 13C NMR (126 MHz, DMSO-d6) δ 161.41 (s;
Cquat), 146.15 (s; Cquat), 135.41 (s; Cquat), 131.45 (s; Cquat), 130.37
(s; Ar-CH), 128.81 (s; Ar-CH), 128.53 (s; Ar-CH), 127.78 (s; Ar-
CH), 127.14 (s; Ar-CH), 122.88 (s; Cquat), 110.27 (s; Cquat), 60.62
(s; CH2), 57.39 (s; Cquat), 29.69 (s; CH3), 14.43 (s; CH3). FTIR-
ATR: υ~ = 1615 (m) cm-1 (N-H), 1669 (m) cm-1 (C=C), 2971 (m)
cm-1 (C-H), 3307 (m) cm-1 (N-H). HRMS (ESI) m/z: [M + H]+ Calcd
for C24H27N4O2+ 403.2129 (100.0%); Found 403.2135.
1-(2-amino-4-(3-nitrophenyl)-1H-imidazol-5-yl)ethanone (2u)
Yellow solid, 95% yield (58 mg); m.p.: 235.1-237.0 °C; Silica gel
TLC Rf = 0.50 (toluene/2-propanol 3:1). 1H NMR (500 MHz,
DMSO-d6) δ 11.24 (s, 1H; NH), 8.78 (s, 1H; Ar-H), 8.35 (d, J = 7.8
Hz, 1H; Ar-H), 8.18 (dd, J = 8.3, 2.3 Hz, 1H), 7.68 (t, J = 8.0 Hz,
1H; Ar-H), 5.99 (s, 2H; NH2), 2.28 (s, 3H; CH3). 13C NMR (126
MHz, DMSO) δ 152.41 (s; Cquat), 148.05 (s; Cquat), 135.51 (s; Ar-
CH), 129.72 (s; Ar-CH), 123.67 (s; Ar-CH), 122.91 (s; Ar-CH),
28.50 (s; CH3). FTIR-ATR: υ~ = 1321 (s) cm-1 (C-N), 1526 (s) cm-
(N-O), 1642 (m) cm-1 (C=C). HRMS (ESI) m/z: [M + H]+ Calcd
1
for C11H11N4O3+ 247.0826 (100.0%); Found 247.0833.
Ethyl 5-(tert-butylamino)-2-cyclohexyl-6-(3-methoxyphenyl)-
1H-imidazo[1,2-a]imidazole-3-carboxylate (3b)
(2-amino-4-(4-(trifluoromethyl)phenyl)-1H-imidazol-5-yl)
(phenyl)methanone (2v)
White solid, 23% yield (20 mg) m.p.: 163.0-164.2 °C; Silica gel
TLC Rf = 0.86 (toluene/2-propanol 3:1). 1H NMR (500 MHz,
DMSO-d6) δ 12.03 (s, 1H; NH), 7.56 – 7.47 (m, 2H; Ar-H), 7.31 (t,
J = 8.0 Hz, 1H; Ar-H), 6.83 (d, J = 5.8 Hz, 1H; Ar-H), 4.83 (s, 1H;
NH), 4.30 (q, J = 7.1 Hz, 2H; CH2), 3.79 (s, 3H; CH3), 1.81 (qd, J
= 8.9, 7.2, 3.0 Hz, 4H; 2 CH2), 1.71 (d, J = 12.5 Hz, 1H; CH), 1.56
(qd, J = 13.3, 12.7, 3.5 Hz, 2H; CH2), 1.40 – 1.18 (m, 7H; 2 CH2,
CH3), 0.92 (s, 9H; 3 CH3). 13C NMR (126 MHz, DMSO-d6) δ
161.70 (s; Cquat), 159.52 (s; Cquat), 129.82 (s; Ar-CH), 123.09 (s;
Cquat), 119.22 (s; Ar-CH), 113.09 (s; Ar-CH), 112.36 (s; Ar-CH),
109.50 (s; Cquat), 60.30 (s; CH2), 57.44 (s; CH2), 55.49 (s; CH),
32.77 (s; CH2), 29.61 (s; CH3), 26.69 (s; CH2), 26.23 (s; CH2),
14.80 (s; CH3). FTIR-ATR: υ~ = 1233 (m) cm-1 (C-N), 1600 (m)
cm-1 (N-H), 1669 (m) cm-1 (C=N), 2852 (m) cm-1 (C-H), 2991 (m)
Vivid yellow solid, 62% yield (52 mg); m.p.: 274.2-276.9 °C; Silica
1
gel TLC Rf = 0.58 (toluene/2-propanol 3:1). H NMR (500 MHz,
DMSO-d6) δ 11.17 (s, 1H; NH), 7.51 (d, J = 8.1 Hz, 2H; Ar-H),
7.45 – 7.40 (m, 4H; Ar-H), 7.38 (t, J = 7.5 Hz, 1H; Ar-H), 7.21 (t, J
= 7.6 Hz, 2H; Ar-H), 6.10 (s, 2H; NH2). 13C NMR (126 MHz,
DMSO-d6) δ 183.58 (s; Cquat), 153.54 (s; Cquat), 147.34 (s; Cquat),
139.37 (s; Cquat), 139.16 (s; Cquat), 131.47 (s; Ar-CH), 130.12 (s;
Ar-CH), 129.08 (s; Ar-CH), 128.32 (s; Ar-CH), 128.52 – 127.49
(m; Cquat), 124.59 (q, J = 4.2 Hz; Ar-CH), 127.65 – 121.34 (m;
Cquat), 123.00 (s; Cquat). FTIR-ATR: υ~ = 1105 (s) cm-1 (C-F), 1321
(s) cm-1 (C-N), 1302 (s) cm-1 (C-O), 1584 (m) cm-1 (N-H), 1652 (m)
cm-1 (C=C). HRMS (ESI) m/z: [M + H]+ Calcd for C17H13F3N3O+
332.1006 (100.0%); Found 332.1016.
cm-1 (C-H). HRMS (ESI) m/z: [M + H]+ Calcd for C25H35N4O3
+
439.2704 (100.0%); Found 439.2712.
(2-amino-4-(3-nitrophenyl)-1H-imidazol-5-yl)(phenyl)
methanone (2w)
Vivid yellow solid, 29% yield (23 mg); m.p.: 246.7-251.1 °C; Silica
1
gel TLC Rf = 0.60 (toluene/2-propanol 3:1). H NMR (500 MHz,
DMSO-d6) δ 11.20 (s, 1H; NH), 8.14 (s, 1H; Ar-H), 8.01 (d, J = 8.4
12
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001253
European Journal of Organic Chemistry
FULL PAPER
Ethyl 6-(4-fluorophenyl)-2-(4-(trifluoromethyl)phenyl)-5-
((2,4,4-trimethylpentan-2-yl)amino)-1H-imidazo[1,2-a]
imidazole-3-carboxylate (3c)
(s; Cquat), 128.18 (s; Ar-CH), 117.47 (s; Ar-CH), 115.16 (s; Ar-CH),
113.90 (s; Ar-CH), 111.56 (s; Cquat), 59.59 (s; CH2), 14.80 (s; CH3).
FTIR-ATR: υ~ = 1021 (m) cm-1 (C-N), 1615 (m) cm-1 (N-H), 1636
(m) cm-1 (N-H), 1662 (m) cm-1 (C=N), 3343 (m) cm-1 (N-H). HRMS
White solid, 28% yield (31 mg) m.p.: 230.2-233.6 °C; Silica gel
TLC Rf = 0.90 (toluene/2-propanol 3:1). 1H NMR (500 MHz,
DMSO-d6) δ 12.28 (s, 1H; NH), 7.97 – 7.88 (m, 4H; Ar-H), 7.77
(d, J = 8.0 Hz, 2H; Ar-H), 7.30 (t, J = 8.6 Hz, 2H; Ar-H), 4.64 (s,
1H; NH), 4.22 (q, J = 7.1 Hz, 2H; CH2), 1.47 (s, 2H; CH2), 1.16 (t,
(ESI) m/z: [M + H]+ Calcd for C12H15N4O2 247.1190 (100.0%);
+
Found 247.1199.
1-(2-amino-4-(3-aminophenyl)-1H-imidazol-5-yl)ethanone
(4b)
J = 7.1 Hz, 3H; CH3), 0.99 (s, 9H; 3 CH3), 0.88 (s, 6H; 2 CH3). 13
C
NMR (126 MHz, DMSO-d6) δ 161.85 (d, J C-F = 245.3 Hz; Cquat),
161.16 (s; Cquat), 146.20 (s; Cquat), 139.54 (s; Cquat), 131.03 (s; Ar-
CH), 129.85 (d, J = 8.0 Hz; Ar-CH), 128.76 (q, J = 31.6 Hz; Cquat),
128.01 (s; Cquat), 128.45 – 121.10 (m; Cquat), 124.69 (q, J = 3.6 Hz;
Ar-CH), 123.08 (s; Cquat), 122.46 (s; Cquat), 115.81 (d, J = 21.6 Hz;
Ar-CH), 110.92 (s; Cquat), 61.50 (s), 60.85 (s; CH2), 55.81 (s),
32.08 (s; CH3), 31.77 (s), 28.75 (s; CH3), 14.38 (s; CH3). FTIR-
ATR: υ~ = 1147 (s) cm-1 (C-F), 1321 (s) cm-1 (C-N), 2946 (m) cm-
1 (C-H), 3312 (m) cm-1 (N-H). HRMS (ESI) m/z: [M + H]+ Calcd for
C29H33F4N4O2+ 545.2535 (100.0%); Found 545.2531.
Orange solid, 77% yield (250 mg) m.p.: 196.1-198.6 °C; Silica gel
TLC Rf = 0.33 (toluene/2-propanol 3:1). 1H NMR (500 MHz,
DMSO-d6) δ 10.71 (s, 1H; NH), 7.03 (t, J = 7.7 Hz, 1H; Ar-H), 6.75
(s, 1H; Ar-H), 6.68 (d, J = 7.5 Hz, 1H), 6.57 (d, J = 7.3 Hz, 1H),
5.82 (s, 2H; NH2), 5.10 (s, 2H; NH2), 2.03 (s, 3H; CH3). 13C NMR
(126 MHz, DMSO-d6) δ 184.66 (s; Cquat), 152.64 (s; Cquat), 149.57
(s; Cquat), 148.59 (s; Cquat), 136.33 (s; Cquat), 128.68 (s; Ar-CH),
123.79 (s; Cquat), 117.72 (s; Ar-CH), 115.69 (s; Ar-CH), 114.15 (s;
Ar-CH), 27.40 (s; CH3). FTIR-ATR: υ~ = 1248 (m) cm-1 (C-N), 1620
(m) cm-1 (N-H), 3063 (m) cm-1 (C-H), 3326 (m) cm-1 (N-H). HRMS
(ESI) m/z: [M + H]+ Calcd for C11H13N4O+ 217.1084 (100.0%);
Found 217.1085.
Ethyl 2-(2,4-bis(trifluoromethyl)phenyl)-6-(4-fluorophenyl)-5-
((2,4,4-trimethylpentan-2-yl)amino)-1H-imidazo[1,2-a]
imidazole-3-carboxylate (3d)
(2-amino-4-(3-aminophenyl)-1H-imidazol-5-yl)(phenyl)
methanone (4c)
White solid, 35% yield (43 mg) m.p.: 208.5-210.3 °C; Silica gel
1
TLC Rf = 0.92 (toluene/2-propanol 3:1). H NMR (500 MHz,
Yellow solid, 77% yield (322 mg) m.p.: 247.0-248.1 °C; Silica gel
1
DMSO-d6) δ 12.33 (s, 1H; NH), 8.24 – 8.07 (m, 2H; Ar-H), 7.98 –
7.87 (m, 2H; Ar-H), 7.78 (d, J = 8.3 Hz, 1H; Ar-H), 7.31 (t, J = 8.9
Hz, 2H; Ar-H), 4.66 (s, 1H; NH), 3.95 (q, J = 7.1 Hz, 2H; CH2),
1.45 (s, 2H; CH2), 0.97 (s, 9H; 3 CH3), 0.89 (s, 6H; 2 CH3), 0.77
(t, J = 7.1 Hz, 3H; CH3). 13C NMR (126 MHz, DMSO-d6) δ 161.89
(d, J C-F= 245.4 Hz; Cquat), 160.70 (s; Cquat), 148.70 (s; Cquat),
145.94 (s; Cquat), 139.61 (s; Cquat), 134.18 (s; Ar-CH), 129.91 (d, J
= 8.0 Hz; s; Ar-CH), 129.57 (d, J = 33.2 Hz; Cquat), 129.49 (d, J =
30.7 Hz; Cquat), 128.81 (q, J = 2.8 Hz; Cquat), 129.94 – 129.36 (m;
Cquat), 129.91 – 122.32 (m; Cquat), 129.52 – 122.75 (m; Cquat),
122.99 (dt, J = 8.0, 4.4 Hz; Ar-CH), 122.18 (s; Cquat), 115.84 (d, 1J
= 21.6 Hz; Ar-CH), 112.14 (s; Cquat), 61.62 (s), 60.21 (s; CH2),
55.57 (s), 32.05 (s; CH3), 31.73 (s), 28.62 (s; CH3), 13.72 (s; CH3).
FTIR-ATR: υ~ = 1069 (s) cm-1 (C-F), 1136 (s) cm-1 (C-F), 1155 (s)
cm-1 (C-F), 1629 (m) cm-1 (C=C), 2962 (m) cm-1 (C-H), 3318 (m)
TLC Rf = 0.38 (toluene/2-propanol 3:1). H NMR (500 MHz,
DMSO-d6) δ 10.87 (s, 1H; NH), 7.41 (d, J = 7.0 Hz, 2H; Ar-H),
7.34 (t, J = 7.5 Hz, 1H; Ar-H), 7.19 (t, J = 7.6 Hz, 2H; Ar-H), 6.65
(s, 1H; Ar-H), 6.61 (t, J = 7.7 Hz, 1H; Ar-H), 6.32 (d, J = 5.6 Hz,
1H; Ar-H), 6.26 (d, J = 7.5 Hz, 1H; Ar-H), 5.95 (s, 2H; NH2), 4.83
(s, 2H; NH2). 13C NMR (126 MHz, DMSO-d6) δ 183.50 (s; Cquat),
153.17 (s; Cquat), 150.24 (s; Cquat), 148.22 (s; Cquat), 139.65 (s;
Cquat), 135.56 (s; Cquat), 131.16 (s; Ar-CH), 129.00 (s; Ar-CH),
128.05 (s; Ar-CH), 127.91 (s; Ar-CH), 122.13 (s; Cquat), 118.24 (s;
Ar-CH), 115.28 (s; Ar-CH), 113.72 (s; Ar-CH). FTIR-ATR: υ~ =
1582 (m) cm-1 (N-H), 1653 (m) cm-1 (C=C). HRMS (ESI) m/z: [M
+ H]+ Calcd for C16H15N4O+ 279.1241 (100.0%); Found 279.1245.
cm-1 (N-H). HRMS (ESI) m/z: [M + H]+ Calcd for C30H32F7N4O2
+
General procedure for the synthesis of 5a-f
613.2408 (100.0%); Found 613.2414.
The corresponding carboxylic acid (0.2 mmol,
2 equiv.),
triethylamine (28 µL, 0.2 mmol, 2 equiv.) and TBTU (35.3 mg, 0.11
mmol, 1.1 equiv.) were dissolved in dichloromethane (4.5 mL) and
stirred at room temperature for 1 h. Then, 0.1 mmol of 4a, 4b or
4c were added. Afterwards, the reaction mixture was stirred at
ambient temperature for 72 hours then the mixture was poured
into water (10 mL) and extracted with ethyl-acetate (2x10 mL).
The combined organic extracts were then washed with saturated
NaHCO3 solution (1x20 mL) and brine (1x20 mL). The organic
phase was dried over Na2SO4, the solvent was removed at
reduced pressure and the residue was subjected to the flash
column chromatography (silica gel; gradient of toluene:MeOH,
30:1/ 15:1 /9:1) and crystallization from diethyl ether/MeOH
mixture affording the 5a-f crystals.
General procedure for the synthesis of 4a-c
1.5 mmol of 2f, 2u, 2w and tin (II) chloride dihydrate (3091 mg,
13.7 mmol, 9 equiv.) were solved in conc. HCl (10 mL). The
reaction mixture was refluxed for 24 hours and then allowed to
cool at room temperature. After 6 h, the precipitate was filtered off
and subsenquently dissolved in 10% NaOH (5 ml). The solvent
was evaporated under reduced pressure and the residue was
extracted with EtOAc (4x8 ml). The organic phase was dried over
Na2SO4, and then the solvent was evaporated to dryness. The
resulting residue was used in the next step without any further
purification.
Ethyl 2-amino-4-(3-aminophenyl)-1H-imidazole-5-
carboxylate (4a)
Ethyl 4-(3-(1H-indole-2-carboxamido)phenyl)-2-amino-1H-
imidazole-5-carboxylate (5a)
Orange solid, 78% yield (288 mg) m.p.: 209.3-211.6 °C; Silica gel
TLC Rf = 0.35 (toluene/2-propanol 3:1).1H NMR (500 MHz,
DMSO-d6) δ 10.69 (s, 1H; NH), 7.17 – 7.07 (m, 2H; Ar-H), 6.97 (t,
J = 7.7 Hz, 1H; Ar-H), 6.50 (d, J = 7.3 Hz, 1H; Ar-H), 5.69 (s, 2H;
NH2), 4.95 (s, 2H; NH2), 4.16 (q, J = 7.1 Hz, 2H; CH2), 1.24 (t, J =
7.1 Hz, 3H; CH3). 13C NMR (126 MHz, DMSO-d6) δ 159.91 (s;
Cquat), 151.81 (s; Cquat), 148.21 (s; Cquat), 147.42 (s; Cquat), 135.17
Yellow solid, 61% yield (24 mg) m.p.: 238.9-240.8 °C; Silica gel
1
TLC Rf = 0.55 (toluene/2-propanol 3:1). H NMR (500 MHz,
DMSO-d6) δ 11.71 (s, 1H; NH), 10.85 (s, 1H; NH), 10.23 (s, 1H;
NH), 8.27 (s, 1H), 7.78 (d, J = 8.2 Hz, 1H; Ar-H), 7.71 (d, J = 7.9
Hz, 1H; Ar-H), 7.68 (d, J = 8.0 Hz, 1H; Ar-H), 7.48 (d, J = 8.7 Hz,
13
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10.1002/ejoc.202001253
European Journal of Organic Chemistry
FULL PAPER
1H; Ar-H), 7.46 (s, 1H; Ar-H), 7.34 (t, J = 7.9 Hz, 1H; Ar-H), 7.23
(t, J = 7.6 Hz, 1H; Ar-H), 7.08 (t, J = 7.4 Hz, 1H; Ar-H), 5.78 (s,
2H; NH2), 4.19 (q, J = 7.1 Hz, 2H; CH2), 1.25 (t, J = 7.1 Hz, 3H;
CH3). 13C NMR (126 MHz, DMSO-d6) δ 160.12 (s; Cquat), 159.90
(s; Cquat), 152.09 (s; Cquat), 146.34 (s; Cquat), 138.68 (s; Cquat),
137.25 (s; Cquat), 135.17 (s; Cquat), 132.04 (s; Cquat), 128.09 (s; Ar-
CH), 127.55 (s; Cquat), 124.83 (s; Ar-CH), 124.19 (s; Ar-CH),
122.21 (s; Ar-CH), 121.40 (s; Ar-CH), 120.35 (s; Ar-CH), 120.18
(s; Ar-CH), 112.85 (s; Ar-CH), 112.05 (s; Cquat), 104.29 (s; Ar-CH),
59.82 (s; CH2), 14.75 (s; CH3). FTIR-ATR: υ~ = 1103 (m) cm-1 (C-
N), 1641 (m) cm-1 (N-H), 3313 (m) cm-1 (N-H), 3385 (m) cm-1 (N-
5H; Ar-H), 7.10 (td, J = 9.2, 2.5 Hz, 1H; Ar-H), 5.90 (s, 2H; NH2),
2.13 (s, 3H; CH3). 13C NMR (126 MHz, DMSO-d6) δ 159.96 (s;
Cquat), 159.75 (s; Cquat), 157.70 (d, J C-F = 233.5 Hz; Cquat), 138.84
(s; Cquat), 134.04 (s; Cquat), 133.60 (s; Cquat), 128.66 (s; Ar-CH),
127.60 (s; Cquat), 127.52 (s; Cquat), 126.25 (s; Cquat), 121.84 (s; Ar-
CH), 120.32 (s; Ar-CH), 115.65 (s; Cquat), 114.12 (s; Ar-CH),
114.04 (s; Ar-CH), 113.03 (d, J = 26.8 Hz; Ar-CH), 106.36 (d, J =
22.8 Hz; Ar-CH), 104.39 (d, J = 5.1 Hz; Ar-CH). FTIR-ATR: υ~ =
1233 (s) cm-1 (C-F), 1167 (m) cm-1 (C-N), 1204 (m) cm-1 (C-N),
1380 (m) cm-1 (C-H), 1608 (m) cm-1 (C-N), 1633 (m) cm-1 (C=C),
3396 (m) cm-1 (N-H). HRMS (ESI) m/z: [M + H]+ Calcd for
C20H17FN5O2+ 378.1361 (100.0%); Found 378.1366.
H). HRMS (ESI) m/z: [M + H]+ Calcd for C21H20N5O3 390.1561
+
(100.0%); Found 390.1567.
N-(3-(2-amino-5-benzoyl-1H-imidazol-4-yl)phenyl)-5-
Ethyl 2-amino-4-(3-(8-hydroxyquinoline-2-carboxamido)
phenyl)-1H-imidazole-5-carboxylate (5b)
methoxy-1H-indole-2-carboxamide (5e)
Yellow solid, 50% yield (23 mg) m.p.: 270.7-273.8 °C; Silica gel
TLC Rf = 0.63 (toluene/2-propanol 3:1). 1H NMR (500 MHz,
DMSO-d6) δ 11.54 (s, 1H; NH), 11.02 (s, 1H; NH), 10.00 (s, 1H;
NH), 7.86 (s, 1H; Ar-H), 7.63 (d, J = 8.8 Hz, 1H; Ar-H), 7.43 (d, J
= 7.2 Hz, 2H; Ar-H), 7.36 (d, J = 8.9 Hz, 1H; Ar-H), 7.37 – 7.30
(m, 2H; Ar-H), 7.19 (t, J = 7.7 Hz, 2H; Ar-H), 7.14 (d, J = 2.4 Hz,
1H; Ar-H), 6.99 (t, J = 7.9 Hz, 1H; Ar-H), 6.92 – 6.85 (m, 2H; Ar-
H), 6.04 (s, 2H; NH2), 3.79 (s, 3H; CH3). 13C NMR (126 MHz,
DMSO-d6) δ 183.62 (s; Cquat), 159.92 (s; Cquat), 154.32 (s; Cquat),
153.39 (s; Cquat), 149.20 (s; Cquat), 139.57 (s; Cquat), 138.83 (s;
Cquat), 135.47 (s; Cquat), 132.57 (s; Cquat), 132.25 (s; Cquat), 131.25
(s; Ar-CH), 129.07 (s; Ar-CH), 128.15 (s; Ar-CH), 127.86 (s; Ar-
CH), 127.83 (s; Cquat), 125.11 (s; Ar-CH), 122.43 (s; Cquat), 121.23
(s; Ar-CH), 119.47 (s; Ar-CH), 115.49 (s; Ar-CH), 113.68 (s; Ar-
CH), 103.95 (s; Ar-CH), 102.57 (s; Ar-CH), 55.77 (s; CH3). FTIR-
ATR: υ~ = 1164 (m) cm-1 (C-N), 1591 (m) cm-1 (N-H), 1634 (m)
cm-1 (C=C) or (N-H), 1657 (w) cm-1 (C=C), 3326 (m) cm-1 (N-H).
White solid, 60% yield (25 mg) m.p.: 266.6-269.0 °C; Silica gel
1
TLC Rf = 0.65 (toluene/2-propanol=3/1). H NMR (500 MHz,
DMSO-d6) δ 11.20 (s, 1H), 10.87 (s, 1H; NH), 10.48 (s, 1H), 8.58
(d, J = 8.5 Hz, 1H; Ar-H), 8.37 (s, 1H; Ar-H), 8.29 (d, J = 8.5 Hz,
1H; Ar-H), 7.91 (d, J = 8.3 Hz, 1H; Ar-H), 7.82 (d, J = 7.7 Hz, 1H;
Ar-H), 7.62 (t, J = 7.9 Hz, 1H; Ar-H), 7.53 (d, J = 7.0 Hz, 1H; Ar-
H), 7.41 (t, J = 7.9 Hz, 1H; Ar-H), 7.23 (d, J = 7.5 Hz, 1H; Ar-H),
5.79 (s, 2H; NH2), 4.20 (q, J = 7.1 Hz, 2H; CH2), 1.25 (t, J = 7.1
Hz, 3H; CH3). 13C NMR (126 MHz, DMSO-d6) δ 162.56 (s; Cquat),
159.91 (s; Cquat), 154.27 (s; Cquat), 152.10 (s; Cquat), 147.86 (s;
Cquat), 146.13 (s; Cquat), 138.60, 138.11 (s; Cquat), 136.90 (s; Cquat),
135.25 (s; Cquat), 130.22 (s; Ar-CH), 130.19 (s; Cquat), 128.23 (s;
Ar-CH), 125.37 (s; Ar-CH), 121.76 (s; Ar-CH), 120.56 (s; Ar-CH),
119.48 (s; Ar-CH), 118.13 (s; Ar-CH), 112.15 (s; Cquat), 59.86 (s;
CH2), 14.75 (s; CH3). FTIR-ATR: υ~ = 1119 (m) cm-1 (C-N), 1152
(m) cm-1 (C-N), 1284 (s) cm-1 (C-N), 1570 (m) cm-1 (C=C), 1648
(s) cm-1 (C=C), 3102 (w, br), cm-1 (O-H), 3288 (s) cm-1 (O-H).
HRMS (ESI) m/z: [M + H]+ Calcd for C26H22N5O3 452.1718
(100.0%); Found 452.1726.
+
HRMS (ESI) m/z: [M + H]+ Calcd for C22H20N5O4 418.1510
+
(100.0%), 419.1544 (23.8%); Found 418.1515, 419.1551.
N-(3-(2-amino-5-benzoyl-1H-imidazol-4-yl)phenyl)quinoline-
2-carboxamide (5f)
N-(3-(5-acetyl-2-amino-1H-imidazol-4-yl)phenyl)-5-methoxy-
1H-indole-2-carboxamide (5c)
Vivid yellow solid, 86% yield (37 mg) m.p.: 301.6-303.9 °C; Silica
1
Light orange solid, 66% yield (26 mg) m.p.: 213.9-215.0 °C; Silica
gel TLC Rf = 0.48 (toluene/2-propanol 3:1). 1H NMR (500 MHz,
DMSO-d6) δ 11.59 (s, 1H; NH), 10.87 (s, 1H; NH), 10.22 (s, 1H;
NH), 8.05 (s, 1H; Ar-H), 7.83 (d, J = 7.8 Hz, 1H; Ar-H), 7.40 (t, J
= 7.7 Hz, 1H; Ar-H), 7.38 – 7.34 (m, 3H; Ar-H), 7.14 (d, J = 2.4
Hz, 1H; Ar-H), 6.89 (dd, J = 8.9, 2.4 Hz, 1H; Ar-H), 5.90 (s, 2H;
NH2), 3.79 (s, 3H; CH3), 2.12 (s, 3H; CH3). 13C NMR (126 MHz,
DMSO-d6) δ 184.78 (s; Cquat), 160.21 (s; Cquat), 154.34 (s; Cquat),
152.77 (s; Cquat), 148.02 (s; Cquat), 138.98 (s; Cquat), 136.12 (s;
Cquat), 132.63 (s; Cquat), 132.18 (s; Cquat), 128.62 (s; Ar-CH),
127.82 (s; Cquat), 125.14 (s; Ar-CH), 123.92 (s; Cquat), 121.77 (s;
Ar-CH), 120.26 (s; Ar-CH), 115.56 (s; Ar-CH), 113.70 (s; Ar-CH),
104.12 (s; Ar-CH), 102.58 (s; Ar-CH), 55.77 (s; CH3), 27.82 (s;
CH3). FTIR-ATR: υ~ = 1214 (m) cm-1 (C-N), 1602 (m) cm-1 (N-H),
1638 (m) cm-1 (C=C). HRMS (ESI) m/z: [M + H]+ Calcd for
C21H20N5O3+ 390.1561 (100.0%); Found 390.1564.
gel TLC Rf = 0.70 (toluene/2-propanol 3:1). H NMR (500 MHz,
DMSO-d6) δ 11.05 (s, 1H; NH), 10.50 (s, 1H; NH), 8.65 (d, J = 8.5
Hz, 1H; Ar-H), 8.28 (d, J = 8.5 Hz, 1H; Ar-H), 8.24 (d, J = 8.5 Hz,
1H; Ar-H), 8.14 (d, J = 8.0 Hz, 1H; Ar-H), 7.99 – 7.94 (m, 1H; Ar-
H), 7.95 – 7.92 (m, 1H; Ar-H), 7.78 (t, J = 8.0 Hz, 1H; Ar-H), 7.72
(d, J = 7.1 Hz, 1H; Ar-H), 7.44 (d, J = 7.0 Hz, 2H; Ar-H), 7.31 (t, J
= 7.4 Hz, 1H; Ar-H), 7.19 (t, J = 7.7 Hz, 2H; Ar-H), 7.05 (t, J = 7.9
Hz, 1H; Ar-H), 6.97 (d, J = 7.7 Hz, 1H; Ar-H), 6.06 (s, 2H; NH2).
13C NMR (126 MHz, DMSO-d6) δ 183.62 (s; Cquat), 162.82 (s;
Cquat), 153.44 (s; Cquat), 150.43 (s; Cquat), 149.14 (s; Cquat), 146.33
(s; Cquat), 139.64 (s; Cquat), 138.71 (s; Ar-CH), 137.97 (s; Cquat),
135.61 (s; Cquat), 131.19 (s; Ar-CH), 129.84 (s; Ar-CH), 129.41 (s;
Cquat), 129.06 (s; Ar-CH), 128.86 (s; Ar-CH), 128.61 (s; Ar-CH),
128.17 (s; Ar-CH), 128.03 (s; Ar-CH), 125.63 (s; Ar-CH), 122.55
(s; Cquat), 121.34 (s; Ar-CH), 119.57 (s; Ar-CH), 119.14 (s; Ar-CH).
FTIR-ATR: υ~ = 1583 (m) cm-1 (N-H), 1648 (m) cm-1 (N-H) or
(C=C), 3396 (m) cm-1 (N-H). HRMS (ESI) m/z: [M + H]+ Calcd for
C26H20N5O2+ 434.1612 (100.0%); Found 434.1617.
N-(3-(5-acetyl-2-amino-1H-imidazol-4-yl)phenyl)-5-fluoro-1H-
indole-2-carboxamide (5d)
Light orange solid, 63% yield (24 mg) m.p.: 257.0-259.2 °C; Silica
gel TLC Rf = 0.51 (toluene/2-propanol 3:1). 1H NMR (500 MHz,
DMSO-d6) δ 11.86 (s, 1H; NH), 10.88 (s, 1H; NH), 10.32 (s, 1H;
NH), 8.05 (s, 1H), 7.82 (d, J = 7.5 Hz, 1H; Ar-H), 7.52 – 7.35 (m,
14
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001253
European Journal of Organic Chemistry
FULL PAPER
Y. Yu, Tetrahedron 2014, 70, 1418−1421; d) L. Man, R. C. B. Copley, A.
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Acknowledgements
The research was supported by the EU and co-financed by the
European Regional Development Fund under the projects
GINOP-2.3.2-15-2016-00008 and GINOP-2.3.3-15-2016-00004.
[7] N. N. Kolos, N. V. Chechina, L. L. Zamigailo, E. V. Vashchenko, Chem. Het.
Comp. 2013, 6, 872–881.
Keywords: 2-aminoimidazole • Groebke–Blackburn–Bienaymé
reaction • Mannich-type substrate • one-pot process • ring
cleavage
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.202001253
European Journal of Organic Chemistry
FULL PAPER
Table of Contents
Marine alkaloid precursor/pharmacophore architecture
1. intramolecular oxidative
annulation step
O
O
O
R1
R2
Sequential one-pot reaction
Mild reaction conditions
up to 95% yield
R
R1
2. ring cleavage of the formed
imidazo[1,2-a]pyrimidine
N
HN
R2
DMA
N
further transformations towards
H2N
R1
H
80 °C
30 min.
50 °C
16 h
a
H-imidazo[1,2-
unique 1
]imidazoles
and marine alkaloid analogues
N
N
=OEt, Me, Ph
R2=Alkyl, Aryl
We disclose an efficient one-pot process towards sophistically decorated, C4/C5-functionalised 2-AI structures as valuable fragment-
like frameworks starting from the corresponding Mannich-type substrates. The IBX/IPT-mediated intramolecular oxidative annulation
and hydroxylamine-induced ring cleavage sequence were carried out under mild conditions, affording the desired heterocycles in up to
95% yield. In addition, further modifications were also executed including GBB-3CR and preparation of structurally modified marine
alkaloid analogues.
16
This article is protected by copyright. All rights reserved.