Efficient Access to Original 6-Substituted 5-Nitro-2,3-dihydro-imidazo[2,1- b ]oxazoles

Article abstract of DOI:10.1055/s-0036-1588984

A one-pot sequential intramolecular cyclization and Suzuki-Miyaura or Sonogashira reaction under microwave irradiation are reported in the 5-nitro-2,3-dihydroimidazo[2,1- b ]oxazole series. The intramolecular cyclization of 1-(2,4-dibromo-5-nitro-1 H -imidazol-1-yl)propan-2-ol between the hydroxyethyl group and the bromine atom at the 2-position is carried out first, followed by optimization and generalization of the Suzuki-Miyaura and Sonogashira cross-coupling reactions of the bromine atom at the 4-position. The various boronic acids and alkynyl derivatives used to perform these palladium-catalyzed cross-coupling reactions allowed to substitute the 6-position of 5-nitro-2,3-dihydroimidazo[2,1- b ]oxazole compounds.

Full text of DOI:10.1055/s-0036-1588984

SYNTHESIS
0
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8
1
1
4
3
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1
0
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©
Georg Thieme Verlag Stuttgart · New York
2017, 49, A–K
paper
A
en
Synthesis
F. Mathias et al.
Paper
Efficient Access to Original 6-Substituted 5-Nitro-2,3-dihydro-
imidazo[2,1-b]oxazoles
R
R(BOH)2 (1.3 equiv)
Fanny Mathias
N
Youssef Kabri
O2N
N
O
Maxime D. Crozet
Patrice Vanelle*
Br
Br
N
N
11 examples; isolated yield: 37–69%
R
O2N
Aix-Marseille Université, Institut de Chimie Radicalaire ICR,
UMR CNRS 7273, Laboratoire de Pharmaco-Chimie Radicalaire,
Faculté de Pharmacie, 27 Boulevard Jean Moulin – CS 30064,
O N
Br
2
N
O
N
OH
1
3385 Marseille Cedex 05, France
N
R
H
(1.3 equiv)
patrice.vanelle@univ-amu.fr
O2N
N
O
11 examples; isolated yield: 42–77%
Received: 25.01.2017
Accepted after revision: 08.03.2017
Published online: 04.04.2017
authors showed that cyclization with alcohol could occur in
good yields when a halogen, like a bromine, replaced the 2-
position of the nitro group. However, this protocol pro-
motes the formation of 6-nitroimidazooxazole, and 5-nitro-
imidazooxazole is only obtained in minor quantities. We fo-
cused our work on the synthesis of 5-nitro-2,3-dihydro-
imidazo[2,1-b]oxazole compounds with a bromine in the 6-
position able to react under palladium-catalyzed reactions.
Suzuki–Miyaura cross-coupling of an organoboron reagent
and an organohalide or organosulfonate is the most effi-
cient method of aryl–aryl bond formation, and is widely
used in the manufacturing of drug components in the phar-
DOI: 10.1055/s-0036-1588984; Art ID: ss-2017-t0048-op
Abstract A one-pot sequential intramolecular cyclization and Suzuki–
Miyaura or Sonogashira reaction under microwave irradiation are re-
ported in the 5-nitro-2,3-dihydroimidazo[2,1-b]oxazole series. The in-
tramolecular cyclization of 1-(2,4-dibromo-5-nitro-1H-imidazol-1-
yl)propan-2-ol between the hydroxyethyl group and the bromine atom
at the 2-position is carried out first, followed by optimization and gen-
eralization of the Suzuki–Miyaura and Sonogashira cross-coupling reac-
tions of the bromine atom at the 4-position. The various boronic acids
and alkynyl derivatives used to perform these palladium-catalyzed
cross-coupling reactions allowed to substitute the 6-position of 5-nitro-
6
2,3-dihydroimidazo[2,1-b]oxazole compounds.
maceutical industry. Sonogashira cross-coupling is a cop-
per and palladium co-catalyzed reaction of terminal
alkynes and aryl halides. The resulting compounds are
widely used for the synthesis of pharmaceutical com-
pounds.7
Key words 5-nitroimidazole, Suzuki–Miyaura reaction, Sonogashira
reaction, intramolecular cyclization, microwave, palladium
The biological interest of nitroimidazo[2,1-b]oxazole
derivatives was discovered by Agrawal et al. in 1979. They
described a series of compounds with radiosensitizing
A few examples of Suzuki–Miyaura and Sonogashira re-
actions performed on a 4-bromo-5-nitroimidazole were
described and showed good reactivity. The nitro group in
5-position increases the electrophilic properties of the C-4,
making this position very reactive toward cross-coupling
reactions.9 On the other hand, these palladium-catalyzed
cross-coupling were not yet carried out on a 6-bromo-5-ni-
troimidazooxazole.
8
1
properties. Thereafter, during a routine screening, Nagarajan
et al. showed that some 6-nitroimidazooxazoles had antitu-
2
bercular activity. Since this discovery, the search for alter-
native antitubercular molecules with a 6-nitroimidazo-
3
oxazole scaffold is ongoing. More recently, the Drugs for
Neglected Diseases initiative (DNDi) found that this class
had antileishmanial properties. Thus, current research is
turned toward the synthesis of 6-nitroimidazooxazole com-
pounds, and the 5-nitroimidazooxazole class remains unex-
plored.
We report herein an intramolecular cyclization of
the 1-(2,4-dibromo-5-nitro-1H-imidazol-1-yl)propan-2-ol
to form the 6-bromo-2-methyl-5-nitro-2,3-dihydroimid-
azo[2,1-b]oxazole. After undergoing Suzuki–Miyaura or
Sonogashira cross-coupling reactions, this allows 6-substi-
tuted 5-nitroimidazooxazoles to be obtained in a sequential
one-pot process.
4
Stable 6-nitroimidazo[2,1-b]oxazole can be synthesized
by alkylation of 2,4(5)-dinitroimidazole with oxirane to ob-
tain an ethanol chain, which can undergo intramolecular
cyclization by the displacement of 2-nitro function on heat-
The required starting material, compound 3, was syn-
thesized from the commercial product 4(5)-nitroimidazole
(1) in two steps as described in Scheme 1. For the first step,
1a
ing. To improve safety, a new approach was tried using 2-
5
10
bromo-4-nitroimidazole as the starting compound. The
we followed Pedada et al.’s methodology, who reported
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

B
Synthesis
F. Mathias et al.
Paper
the dibromination on 4(5)-nitro-1H-imidazole. Thus, the
reaction was carried out in water using bromine (3 equiv)
in the presence of sodium bicarbonate (3 equiv) and led to
two tautomeric forms 2a and 2b in 80% overall yield. The
first study of alkylation employed a mixture of 2,4(5)-di-
bromo-5(4)-nitroimidazole 2 (2a and 2b), propylene oxide
troimidazooxazoles are in accordance with our results and
have shown that the 4-nitro isomer always predominates
after alkylation of 4(5)-nitroimidazole with an epoxide.
3d,16
Table 1 Optimization of the Alkylation of Compound 2
(
1.5 equiv), and aluminum chloride as Lewis acid (1.5
Entry Solvent
AlCl3
Temp
Time
(h)
Yield of 3 Yield of 4
(%) (%)
(
equiv) (°C)
equiv) in ethyl acetate, according to the preparation method
of secnidazole and ornidazole in a temperature range be-
tween 0 and 10 °C for 2.5 hours. However, here we added
a short phase of optimization because our starting material
1
DME
0.5
0.3
0.2
0.1
0.5
–
MW, 150
MW, 150
MW, 150
MW, 150
150
1.5
1.5
1.5
1.5
72
30
46
11
2
DME
38
39
30
–
42
40
49
–
3
DME
2
was less reactive than 2-methyl-5-nitroimidazole used for
4
DME
the synthesis of secnidazole and ornidazole (probably due
to the steric hindrance of the 2-bromine atom as opposed
to the methyl group). Based on various approaches devel-
5a
6a
AcOH
Ac O + H PO
2
3
4
150
72
–
–
12
oped in our laboratory, we decided to adapt the synthesis
using microwave methodology. This enabled us to increase
the temperature to 150 °C under microwave irradiation us-
ing sealed vessels. These conditions led to the entire con-
sumption of the starting material 2. Unfortunately, the lat-
ter conditions using ethyl acetate as solvent led to the
acetylated alcohol of the side chain of compounds 3 and 4,
causing us to change the solvent. DME was tried next, and
was found to be very efficient in the synthesis promoted
under microwave irradiation. Thus, the reaction was per-
formed with compound 2, propylene oxide (1.5 equiv), and
aluminum chloride as Lewis acid. Furthermore, a short
phase of optimization led us to reduce the amount of AlCl3
to 0.2 equivalent to promote the formation of 5-nitro
isomer 3 in 39% yield (Table 1, entry 3). The decrease of the
a
Reaction progress was followed by LC/MS.
The structures of 3 and 4 were confirmed on the basis of
2D NMR (HMBC) (see the Supporting Information). A cor-
relation between the carbon (C–NO ) at 137.3 ppm and the
hydrogens (CH ) at 4.48 ppm of the alkyl chain of com-
pound 3 was observed, confirming the presence of the nitro
group at the 5-position. No correlation was observed be-
tween the carbon (C–NO ) at 144.6 ppm and the hydrogens
2
2
13
2
(CH ) of the alkyl chain of compound 4, confirming the
2
presence of the nitro group at the 4-position.
The 1-(2,4-dibromo-5-nitro-1H-imidazol-1-yl)propan-
2-ol (3) was subjected to intramolecular cyclization and
Suzuki–Miyaura cross-coupling with the purpose of identi-
fying reaction conditions, which would allow us to operate
in a sequential one-pot process. We started by trying to
achieve intramolecular cyclization (Scheme 2) under favor-
able conditions for Suzuki–Miyaura reaction, as described
amount of AlCl to 0.1 equivalent increased the yield of 4-
3
nitro isomer 4 (entry 4), probably due to the low acidity of
the medium. The use of acetic acid or phosphoric acid as
solvent (entries 5 and 6), found in the protocol of metroni-
dazole synthesis,14 did not improve the yield of compound
17
by Hodgetts et al. Thus, initial trials were performed using
3
. Indeed, the starting compound was in majority and only
3 equivalents of Na CO as base, 5 mol% of Pd(PPh ) as cat-
2
3
3 4
traces of compounds 3 and 4 were observed in LC/MS. We
did not try to operate in basic medium because some publi-
cations have shown that these conditions promoted forma-
alyst in a DME/H O (4:1, v/v) mixture as solvent (Table 2,
2
entry 1). However, in these conditions only 32% yield of
compound 5 was obtained because of the formation of side-
product following a nucleophilic aromatic substitution
with water. Thus, the following attempts were carried out
only in dimethoxyethane, which led us to increase the tem-
perature to 110 °C for 1.5 hours (entry 5) to obtain com-
pound 5 in a good yield of 80%. The presence of a catalyst
was not found to be essential for the cyclization and com-
pound 5 was obtained in equivalent yield without palladi-
um (entry 1 vs entry 2).
15
tion of the 4-nitro isomer. Current studies focused on ni-
Br
2
O N
Br2 (3 equiv)
O2N
N
N
N
NaHCO3 (3 equiv)
O2N
Br
Br
Br
N
H
N
H
N
H
H2O, 65 °C, 6 h
80%
1
2a
2b
O
(
1.5 equiv)
Br
O2N
After showing that 6-bromo-2-methyl-5-nitro-2,3-di-
hydroimidazo[2,1-b]oxazole (5) could be formed by intra-
molecular cyclization, our attention was focused on the
Suzuki–Miyaura cross-coupling and its optimization at the
6-position with bromine atom in a sequential one-pot two-
step process (Scheme 3). First, the cyclization step was per-
formed with Na CO at 110 °C under microwave irradiation
N
N
AlCl3 (0.2 equiv)
+
O2N
Br
Br
Br
N
N
DME, MW, 150 °C, 1.5 h
OH
OH
3
4
39%
40%
Scheme 1 Synthesis of 1-(2,4-dibromo-5-nitro-1H-imidazol-1-yl)pro-
pan-2-ol (3)
2
3
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C
Synthesis
F. Mathias et al.
Paper
Br
Br
The optimization of the Suzuki–Miyaura reaction on
-(2,4-dibromo-5-nitro-1H-imidazol-1-yl)propan-2-ol (5)
N
Na2CO3 (3 equiv)
N
1
O2N
Br
MW, Temp, Time
Solvent
O N
was performed with phenylboronic acid by screening palla-
dium sources, ligands, and solvents (Table 3). No side-prod-
ucts were observed. Several solvents were tested with
Pd(PPh ) as catalyst (Table 3, entries 1–6) and the best re-
N
2
N
O
OH
5
3
3
4
Scheme 2 Intramolecular cyclization of 1-(2,4-dibromo-5-nitro-1H-
imidazol-1-yl)propan-2-ol (3)
sult was obtained with DME/H O mixture. When the reac-
2
tion was carried out in DME, Suzuki–Miyaura cross-cou-
pling did not occur and only the cyclized compound 5 was
obtained. Thus, the addition of water during the second
step was found to be essential. Then, several sources of pal-
ladium were investigated (entries 7–12). From among all
the tested catalysts, Pd(PPh ) provided the highest conver-
Table 2 Optimization of the Intramolecular Cyclization Reaction of 3
Entry Solvent
Pd (0.05 equiv) Temp (°C)
Time (h) Yield of 5 (%)
3
4
1
DME/H
DME/H
DME
2
O
O
Pd(PPh
3
)
4
MW, 100
MW, 100
MW, 100
MW, 110
MW, 110
1
32
30
40
60
80
2
2
–
–
–
–
1
3a
4a
1
DME
1
Pd(PPh3)4 (0.05 equiv)
Na2CO3 (6 equiv)
Br
B(OH)2
5
DME
1.5
N
N
+
a
O2N
52%
LC/MS ratio.
O2N
Br
DME/H2O (4:1)
MW, 110 °C, 2 h
N
N
O
OH
(1.3 equiv)
3
6a
for 1.5 hours. Total consumption of starting material 3 was
monitored by LC-MS in all attempts, before adding the re-
agents for Suzuki–Miyaura reaction.
Scheme 4 One-pot intramolecular cyclization on 3 and Suzuki–Miyaura
reaction with phenylboronic acid
B(OH)2
Br
Na2CO3 (3 equiv)
Solvent
Br
N
N
N
(1.3 equiv)
O2N
Br
O2N
O2N
N
N
O
N
O
MW, 110 °C, 1.5 h
Pd (0.05 equiv)
6a
OH
3
5
Na2CO3 (3 equiv)
MW, Temp, Time
Scheme 3 One-pot sequential intramolecular cyclization of 3 and Suzuki–Miyaura reaction with phenylboronic acid
Table 3 Optimization of the Suzuki–Miyaura Reaction of 5
Entry
Solvent
Pd/Ligand
Temp (C)
Time (h)
Yield of 6a (%)
1
2
3
4
5
6a
7
8
9
DME
Pd(PPh
Pd(PPh
3
3
)
)
4
4
110
110
110
110
110
110
110
110
110
110
110
110
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
–
DME/EtOH/H
2
O
16
69
11
42
–
DME/H
DMF/H
1,4-dioxane/H
EtOH/H O/TBAB
2
O
3 4
Pd(PPh )
2
O
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
3
)
)
)
)
4
4
4
2
2
O
3
3
3
2
DME/H
DME/H
DME/H
DME/H
DME/H
DME/H
2
O
Cl
2
55
40
27
18
27
13
2
2
2
2
2
O
O
O
O
O
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
/PPh
3
1
0
1
2
/Xantphos
/BINAP
1
1
/JohnPhos
a
Reaction performed with 1 equiv of tetrabutylammonium bromide (TBAB) as the phase-transfer agent.
©
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D
Synthesis
F. Mathias et al.
Paper
H
Na2CO3 (3 equiv)
Br
Br
DME
N
(1.3 equiv)
N
N
O2N
O2N
5%
O2N
Br
MW, 110 °C, 1.5 h
N
Pd(PPh3)4 (0.05 equiv)
Et3N (2 equiv)
N
N
O
O
6
3
OH
5
CuI (0.1 equiv)
MW, 70 °C, 1 h
7a
Scheme 5 One-pot intramolecular cyclization and Sonogashira alkynylation of 1-(2,4-dibromo-5-nitro-1H-imidazol-1-yl)propan-2-ol (3)
sion into product (entry 3). The addition of ligands to
Pd(OAc) such as PPh , Xantphos, JohnPhos, or BINAP led to
coupling step. The reaction mixture was stirred for 1 hour
at 70 °C under microwave irradiation, yielding 65% of the
desired product 7a (Scheme 5).
2
3
a considerable decrease in the yield of 6a (entries 9–12).
Before generalizing this reaction to other boronic acids,
the best conditions described in Table 3 (entry 3) were used
in an attempt to achieve the cyclization and Suzuki–Miyaura
reaction in one step, as shown in Scheme 4. The reaction
was carried out with Na CO , Pd(PPh ) , and phenylboronic
Table 4 Scope of the One-Pot Intramolecular Cyclization and Suzuki–
Miyaura Reaction of 3a
R
Br
1) Na2CO3 (3 equiv)
2
3
3
4
N
N
acid (1.3 equiv) at 110 °C for 2 hours. The desired product
a was obtained in a lower yield than that observed when
the reaction was performed in two steps.
2
) RB(OH)2 (1.3 equiv)
O2N
O2N
Br
OH
3
N
N
O
6
6a–k
Having determined the best protocol, we tested the
scope of the intramolecular cyclization and Suzuki–Miyaura
cross-coupling reaction of 1-(2,4-dibromo-5-nitro-1H-im-
idazol-1-yl)propan-2-ol (3) (Table 4) in two steps. The first
step was performed with Na CO in DME at 110 °C under
Entry
RB(OH)
2
Product
Yield (%)
2
3
B(OH)2
microwave irradiation for 1.5 hours. In the second step, the
reaction was carried out with addition of water, Pd(PPh3)4
N
1
69
O2N
N
O
(
0.05 equiv), Na CO (3 equiv), and boronic acid (1.3 equiv)
2 3
at 110 °C under microwave irradiation for 1.5 hours. A vari-
ety of substituted (hetero)arylboronic acids (with electron-
donating or electron-withdrawing groups) were used to
give the corresponding coupling products 6a–k in moderate
to good yields (37–69%). The yield decreased below 50%
when hydroxymethylphenylboronic acid and boronic acids
substituted by an electron-withdrawing group such as NO2
was used. The structure of the 5-nitroimidazooxazole de-
rivative was confirmed for compound 6b with a methoxy-
phenyl group in the 6-position, on the basis of 2D NMR
MeO
B(OH)2
2
66
60
51
N
MeO
O2N
N
O
(NOESY) (see the Supporting Information). No correlation
B(OH)2
3
N
was observed between the protons of the aromatic ring and
the protons of the oxazole ring, confirming the presence of
the nitro group at the 5-position.
Thereafter, the reaction conditions of the second step
were modified to examine the Sonogashira alkynylation of
O2N
N
O
MeO
OMe
6
-bromo-2-methyl-5-nitro-2,3-dihydroimidazo[2,1-b]ox-
MeO
MeO
B(OH)2
MeO
azole (5). The first trial was performed with phenylacety-
lene (Scheme 5) under conditions previously described by
our group with the 4-bromo-1,2-dimethyl-5-nitro-1H-im-
4
N
O2N
OMe
N
O
8b
idazole. The reaction conditions of the first cyclization
step described above were used. After cooling, phenylacet-
ylene (1.3 equiv), Et N (2 equiv), CuI (0.1 equiv), and
3
Pd(PPh3)4 were added for the second Sonogashira cross-
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E
Synthesis
F. Mathias et al.
Paper
This protocol was extended to different terminal
alkynes (Table 5) to evaluate the scope and limitations of
this procedure. A variety of arylacetylenes (Table 5, entries
Entry
RB(OH)
2
Product
Yield (%)
OH
1–7), acetylenic alcohols (entries 8–10), and cyclopropyl-
B(OH)2
acetylene (entry 11) were reacted under this protocol and
afforded the corresponding coupled products 7a–k in mod-
erate to good yields. The best results were obtained with
arylacetylenes 7a–g, in particular when the aryl group car-
ried a fluorine atom at the para-position (7d, 78%). Howev-
er, a decrease in yield was observed when the reaction was
performed with acetylenic alcohols (compounds 7h–j).
5
37
N
OH
O2N
N
O
NO2
O2N
B(OH)2
Table 5 Scope of the One-Pot Intramolecular Cyclization and Sonogashira
Reaction of 3a
6
40
N
O2N
N
O
R
1) Na2CO3 (3 equiv)
Br
N
N
O
O2N
2)
R
H
(1.3 equiv)
B(OH)2
O2N
Br
N
O
N
N
7
8
57
60
OH
O
O2N
N
O
3
7a–k
Entry
R
H
Product
Yield (%)
B(OH)2
S
N
S
H
O2N
N
O
1
65
N
O2N
N
O
Cl
B(OH)2
9
63
63
56
N
Cl
O2N
N
O
H
2
70
F
N
O2N
N
O
B(OH)2
10
N
F
O2N
N
O
H
CF3
3
67
N
B(OH)2
O2N
11
N
N
O
O2N
N
O
a
Reaction conditions: Step 1: Na
.5 h. Step 2: H O (0.5 mL), boronic acid (1.3 equiv), Pd(PPh
CO
2
CO
3
(3 equiv), DME (4 mL), MW, 110 °C,
1
2
3 4
)
(0.05
equiv), Na
2
3
(3 equiv), MW, 110 °C, 1.5 h.
©
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F
Synthesis
F. Mathias et al.
Paper
Entry
R
H
Product
Yield (%)
Entry
R
H
H
Product
Yield (%)
F
H
HO
HO
10
45
4
78
N
N
F
O2N
O2N
N
O
N
O
H
H
11
N
58
5
60
N
O2N
N
O
O2N
N
O
a
Reaction conditions: Step 1: Na
2
CO
3
(3 equiv), DME, MW, 110 °C, 1.5 h.
(0.05 equiv), Et N (2 equiv), CuI (0.1
Step 2: alkyne (1.3 equiv), Pd(PPh
equiv), MW, 70 °C, 1 h.
3
)
4
3
OH
H
In conclusion, we have developed an efficient method to
design 5-nitroimidazooxazole compounds. We optimized a
one-pot sequential intramolecular cyclization and Suzuki–
Miyaura reaction to form the dihydrooxazole ring and func-
tionalized the 6-position of the heterocycle system with
various aryl and heteroaryl groups. Our strategy of choos-
ing a Sonogashira alkynylation to introduce arylacetylenes
and acetylenic alcohols in this 5-nitroimidazooxazole scaf-
fold allowed us to form the imidazooxazole cycle and sub-
stitute the 6-position with various alkynes in a one-pot
process. This method affords easy and rapid access to origi-
nal 5-nitroimidazooxazole compounds whose biological in-
terest remains to be determined.
6
67
N
OH
O2N
N
O
OMe
H
7
77
N
OMe
2
O N
N
O
Melting points were determined on Büchi B-540 and are uncorrected.
Elemental analyses and HRMS were carried out at the Spectropole,
HO
H
Faculté des Sciences et Techniques de Saint-Jérôme, Marseille. 250
1
MHz H NMR spectra (reference CDCl δ = 7.26, DMSO-d6 δ = 2.50)
3
HO
13
8
55
and 62.5 MHz C NMR spectra (reference CDCl δ = 77.0, DMSO-d δ =
N
3
6
3
9.7) were recorded at 24 °C on a Bruker ARX 200 spectometer in
O2N
OH
N
O
CDCl and DMSO-d solvents at the Faculté de Pharmacie de Marseille.
3
6
Solvents were dried by conventional methods. The following adsor-
bent was used for column chromatography: silica gel 60 (Merck, par-
ticle size 0.063–0.200 mm, 70–230 mesh ASTM). TLC was performed
on 5 cm × 10 cm aluminum plates coated with silica gel 60F-254
H
(Merck) in an appropriate eluent. HRMS spectra were recorded on
HO
9
42
QStar Elite (Applied Biosystems SCIEX) spectrometer. PEG was the
matrix for HRMS.
Microwave reactions were performed with a Biotage® Initiator Micro-
wave oven using 2–5 mL sealed vials; temperatures were measured
with an IR-sensor and reaction times are given as hold times.
N
O2N
N
O
1-(2,4-Dibromo-5-nitro-1H-imidazol-1-yl)propan-2-ol (3)
First Step: To a solution of 4(5)-nitro-1H-imidazole (1; 10 g, 88.5
mmol) and NaHCO3 (22.3 g, 3 equiv, 265.5 mmol) in H O (120 mL)
2
was added Br2 (13.5 mL, 3 equiv, 265.5 mmol) dropwise at 0 °C and
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

G
Synthesis
F. Mathias et al.
Paper
the reaction mixture was heated at 65 °C for 6 h after complete addi-
3 equiv), and H O (0.5 mL) were introduced under argon and the mix-
2
tion of Br . After cooling, the pH of the reaction mixture was adjusted
ture was heated at 110 °C for 1.5 h under microwave irradiation. After
2
to 2–3 by adding aq HCl. A yellow precipitate was formed, which was
cooling, H O (60 mL) was added and the solution was extracted with
2
filtered, washed with H O (3 × 100 mL), and dried in a vacuum drying
CH Cl (3 × 60 mL). The combined organic layers were dried (Na SO )
2
2
2
2
4
oven (desiccator cabinet). Compound 2,4(5)-dibromo-5(4)-nitroimid-
azole (2) was obtained as yellow solid in 80% yield (19.16 g); mp 175
and evaporated. The crude product was purified by column chroma-
tography (silica gel, PE/EtOAc, 7:3 (1:1 for 6d, 6e) and recrystallized
from i-PrOH.
°
C.
Second Step: To a solution of 2,4(5)-dibromo-5(4)-nitroimidazole (2;
.5 g, 1.9 mmol) and AlCl3 (0.12 g, 0.5 equiv, 0.92 mmol) in DME (5
mL) was added 2-methyloxirane (0.19 mL, 1.5 equiv, 2.78 mmol) at
0
2-Methyl-5-nitro-6-phenyl-2,3-dihydroimidazo[2,1-b]oxazole (6a)
Yield: 77 mg (69%); yellow solid; mp 66 °C.
0
1
°C under argon and the reaction mixture was heated at 150 °C for
.5 h under microwave irradiation. After cooling, EtOAc was added
1
H NMR (CDCl , 250 MHz): δ = 7.95–7.92 (m, 2 H, ArH), 7.51–7.43 (m,
3
2
3
3
H, ArH), 5.65–5.51 (m, 1 H, CH), 4.75 (dd, J = 10.7 Hz, J = 8.1
H,H H,H
and the solution was filtered on Celite and the solvent evaporated un-
der reduced pressure. The crude product was purified by column
chromatography (silica gel, PE/EtOAc, 7:3).
2
3
Hz, 1 H, CH ), 4.19 (dd, J = 10.5 Hz, J = 7.7 Hz, 1 H, CH ), 1.73 (d,
2
H,H
H,H
2
3
1
JH,H = 6.3 Hz, 3 H, CH3).
3
C NMR (CDCl , 62.5 MHz): δ = 158.3 (C ), 147.5 (C ), 131.2 (C ),
3
Ar
Ar
Ar
1
2
30.2 (CH ), 129.8 (2 × CH ), 128.1 (2 × CH ), 85.4 (CH), 52.7 (CH ),
Ar Ar Ar 2
1
-(2,4-Dibromo-5-nitro-1H-imidazol-1-yl)propan-2-ol (3)
0.5 (CH ); C–NO was not observed.
3
2
Yield: 238 mg (39%); yellow oil.
+
HRMS: m/z [M + H] calcd for C12H11N O : 246.0873; found: 246.0872.
3
3
1
H NMR (CDCl , 250 MHz): δ = 4.55–4.39 (m, 2 H, CH ), 4.19–4.07 (m,
3
2
3
1
H, CH), 2.09 (s, 1 H, OH), 1.34 (d, J = 6.3 Hz, 3 H, CH3).
H,H
6
-(4-Methoxyphenyl)-2-methyl-5-nitro-2,3-dihydroimidazo[2,1-
13
C NMR (CDCl , 62.5 MHz): δ = 137.3 (C ), 126.8 (C ), 120.0 (C ),
3
Ar
Ar
Ar
b]oxazole (6b)
6
6.7 (CH), 55.7 (CH ), 21.0 (CH ).
2
3
Yield: 77 mg (66%); yellow solid; mp 118 °C.
HRMS: m/z [M + H]+ calcd for C H Br N O : 328.8907; found:
6
7
2
3
3
1
3
H NMR (CDCl , 250 MHz): δ = 7.98 (d, J = 8.9 Hz, 2 H, ArH), 6.96 (d,
3
H,H
328.8908.
3J
2
= 8.9 Hz, 2 H, ArH), 5.60–5.49 (m, 1 H, CH), 4.73 (dd, J = 10.7
H-H
3
H,H
2
3
Hz, J = 8.4 Hz, 1 H, CH ), 4.17 (dd, J = 10.6 Hz, J = 7.7 Hz, 1 H,
CH ), 3.86 (s, 3 H, OCH ), 1.71 (d, J = 6.3 Hz, 3 H, CH3).
H,H
2
H,H
H,H
1-(2,5-Dibromo-4-nitro-1H-imidazol-1-yl)propan-2-ol (4)
3
2
3
H,H
Yield: 248 mg (40%); yellow oil.
13
C NMR (CDCl , 62.5 MHz): δ = 161.2 (C ), 158.4 (C ), 147.9 (C ),
3
Ar
Ar
Ar
1
H NMR (DMSO-d , 250 MHz): δ = 5.17 (d, 3JH,H = 4.4 Hz, 1 H, OH),
133.9 (C ), 131.6 (2 CH ), 123.7 (C ), 113.5 (2 CH ), 85.3 (CH), 55.4
(OCH ), 52.8 (CH ), 20.5 (CH ).
6
Ar
Ar
Ar
Ar
3
4
.07–3.89 (m, 3 H, CH and CH ), 1.16 (d, J = 5.5 Hz, 3 H, CH3).
2
H,H
3 2 3
13
C NMR (DMSO-d , 62.5 MHz): δ = 144.6 (C ), 121.9 (C ), 109.6 (C ),
Anal. Calcd for C13H13N O (275.26): C, 56.72; H, 4.76; N, 15.27.
3 4
6
Ar
Ar
Ar
6
4.5 (CH), 55.0 (CH ), 20.8 (CH ).
Found: C, 55.70; H, 4.66; N, 14.20.
2
3
HRMS: m/z [M + H]+ calcd for C H Br N O : 328.8907; found:
6
7
2
3
3
328.8907.
2-Methyl-5-nitro-6-p-tolyl-2,3-dihydroimidazo[2,1-b]oxazole (6c)
Yield: 71 mg (60%); yellow solid; mp 151 °C.
6
-Bromo-2-methyl-5-nitro-2,3-dihydroimidazo[2,1-b]oxazole (5)
1
3
H NMR (CDCl , 250 MHz): δ = 7.85 (d, J = 8.2 Hz, 2 H, ArH), 7.25 (d,
3
H,H
3J = 8.2 Hz, 2 H, ArH), 5.62–5.48 (m, 1 H, CH), 4.73 (dd, J = 10.6
Hz, J = 8.2 Hz, 1 H, CH ), 4.18 (dd, J = 10.6 Hz, J = 7.7 Hz, 1 H,
H,H 2 H,H H,H
CH ), 2.40 (s, 3 H, CH ), 1.71 (d, J = 6.3 Hz, 3 H, CH3).
2
A mixture of 1-(2,4-dibromo-5-nitro-1H-imidazol-1-yl)propan-2-ol
3; 0.2 g, 0.61 mmol) and Na CO (0.19 g, 1.82 mmol, 3 equiv) was
H
,
H
H
,
H
3
2
3
(
2
3
3
heated in DME (4 mL) for 1.5 h under microwave irradiation. After
2 3 H,H
cooling, H O was added (60 mL) and the aqueous mixture was ex-
13
2
C NMR (CDCl , 62.5 MHz): δ = 158.4 (C ), 147.8 (C ), 140.6 (C ),
3 Ar Ar Ar
tracted with CH Cl (3 × 60 mL). The combined organic layers were
2
2
129.7 (2 × CH ), 129.4 (C ), 128.8 (2 × CH ), 128.4 (C ), 85.4 (CH),
52.7 (CH ), 21.5 (CH ), 20.5 (CH ).
2 3 3
Ar Ar Ar Ar
dried (Na SO ) and evaporated under reduced pressure. Flash chroma-
2
4
tography (silica gel, PE/EtOAc, 6:4) provided 120 mg (80%) of 5 as a
yellow oil.
Anal. Calcd for C13H13N O (259.26): C, 60.22; H, 5.05; N, 16.21.
Found: C, 59.47; H, 4.91; N, 15.30.
3
3
1
2
H NMR (CDCl , 250 MHz): δ = 5.63–5.50 (m, 1 H, CH), 4.69 (dd, J
=
H,H
3
3
2
3
1
1
0.6 Hz, J = 8.2 Hz, 1 H, CH ), 4.12 (dd, J = 10.6 Hz, J = 7.9 Hz,
H,H 2 H,H H,H
2-Methyl-5-nitro-6-(3,4,5-trimethoxyphenyl)-2,3-dihydroimid-
3
H, CH ), 1.70 (d, J = 6.3 Hz, 3 H, CH3).
2
H,H
azo[2,1-b]oxazole (6d)
13
C NMR (CDCl , 62.5 MHz): δ = 157.7 (C), 121.6 (C), 85.7 (CH), 52.8
3
Yield: 78 mg (51%); yellow solid; mp 153 °C.
(
CH ), 20.3 (CH ); C–NO was not observed.
2
3
2
1
H NMR (CDCl , 250 MHz): δ = 7.34 (s, 2 H, ArH), 5.63–5.49 (m, 1 H,
3
2
HRMS: m/z [M
47.9665.
+
H]+ calcd for C H BrN O : 247.9665; found:
3
2
6
6
3
3
CH), 4.74 (dd, J = 10.8 Hz, J = 8.2 Hz, 1 H, CH ), 4.18 (dd, J
=
=
H,H
H,H
2
H,H
2
3
3
10.7 Hz, J = 7.7 Hz, 1 H, CH ), 3.90 (s, 9 H, 3 × OCH ), 1.72 (d, J
H,H 2 3
H,H
6
.3 Hz, 3 H, CH3).
One-Pot Sequential Intramolecular Cyclization and Suzuki–
Miyaura Reaction of 3 with Boronic Acids; General Procedure
13
C NMR (CDCl , 62.5 MHz): δ = 158.2 (C ), 152.6 (2 × C ), 147.2 (C ),
3
Ar
Ar
Ar
139.9 (C ), 129.6 (C ), 126.3 (C ), 107.2 (2 × CH ), 85.4 (CH), 60.9
Ar Ar Ar Ar
A solution of 1-(2,4-dibromo-5-nitro-1H-imidazol-1-yl)propan-2-ol
(CH ), 56.2 (2 × OCH ), 52.8 (OCH ), 20.5 (CH ).
2 3 3 3
(
3; 0.15 g, 0.45 mmol) and Na CO (0.15 g, 1.37 mmol, 3 equiv) in
2 3
Anal. Calcd for C15H17N O (335.31): C, 53.73; H, 5.11; N, 12.53.
Found: C, 53.67; H, 4.87; N, 12.22.
3
6
DME (4 mL) was heated at 110 °C under microwave irradiation for 1.5
h. After cooling, the appropriate boronic acid (0.59 mmol, 1.3 equiv),
Pd(PPh ) (28 mg, 0.02 mmol, 0.05 equiv), Na CO (0.15 g, 1.37 mmol,
3
4
2
3
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

H
Synthesis
F. Mathias et al.
Paper
1
3
4
-(2-Methyl-5-nitro-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)phe-
H NMR (CDCl , 250 MHz): δ = 7.90 (d, J = 8.7 Hz, 2 H, ArH), 7.41 (d,
3 H,H
3J = 8.7 Hz, 2 H, ArH), 5.64–5.50 (m, 1 H, CH), 4.74 (dd, J = 10.7
Hz, J = 8.2 Hz, 1 H, CH ), 4.18 (dd, J = 10.6 Hz, J = 7.7 Hz, 1 H,
CH ), 1.72 (d, J
2
nyl]methanol (6e)
H
,
H
H
,
H
3
2
3
Yield: 46 mg (37%); yellow solid; mp 163 °C.
H,H
2
H,H
H,H
3
2
H,H
= 6.5 Hz, 3 H, CH3).
1
H NMR (DMSO-d , 250 MHz): δ = 7.79 (d, 3J = 8.2 Hz, 2 H, ArH),
6
H,H
13
3
C NMR (CDCl , 62.5 MHz): δ = 158.3 (C ), 146.0 (C ), 136.2 (C ),
3 Ar Ar Ar
7
.40 (d, JH,H = 8.4 Hz, 2 H, ArH), 5.71–5.57 (m, 1 H, CH), 4.69 (dd,
2
3
131.1 (2 × CH ), 129.6 (C ), 129.4 (C ), 128.3 (2 × CH ), 85.5 (CH),
52.7 (CH ), 20.4 (CH ).
2 3
JH,H = 10.3 Hz, JH,H = 8.3 Hz, 1 H, CH ), 4.55 (s, 2 H, CH ), 4.18 (dd,
Ar Ar Ar Ar
2
2
2J
3
3
= 10.3 Hz, J = 7.7 Hz, 1 H, CH ), 1.59 (d, J = 6.3 Hz, 3 H, CH3).
H,H
H,H
2
H,H
1
3
Anal. Calcd for C12H10ClN O (279.68): C, 51.53; H, 3.60; N, 15.02.
3 3
Found: C, 51.46; H, 3.44; N, 14.55.
C NMR (DMSO-d , 62.5 MHz): δ = 158.5 (C ), 146.4 (C ), 144.7 (C ),
6
Ar
Ar
Ar
1
35.5 (C ), 130.1 (C ), 129.5 (2 × CH ), 126.0 (2 × CH ), 86.7 (CH),
Ar Ar Ar Ar
6
2.8 (CH ), 52.3 (CH ), 20.0 (CH ).
2
2
3
6
-(4-Fluorophenyl)-2-methyl-5-nitro-2,3-dihydroimidazo[2,1-
Anal. Calcd for C13H13N O (275.26): C, 56.72; H, 4.76; N, 15.27.
Found: C, 56.15; H, 4.57, N, 14.62.
3
4
b]oxazole (6j)
Yield: 75 mg (63%); yellow solid; mp 117 °C.
1
2
-Methyl-5-nitro-6-(3-nitrophenyl)-2,3-dihydroimidazo[2,1-b]ox-
H NMR (CDCl , 250 MHz): δ = 8.00–7.92 (m, 2 H, ArH), 7.17–7.07 (m,
3
2
3
azole (6f)
2 H, ArH), 5.63–5.49 (m, 1 H, CH), 4.73 (dd, J = 10.7 Hz, J = 8.2
H,H H,H
2
3
Hz, 1 H, CH ), 4.18 (dd, J = 10.7 Hz, J = 7.7 Hz, 1 H, CH ), 1.72 (d,
Yield: 53 mg (40%); yellow solid; mp 113 °C.
2
H,H
H,H
2
3
JH,H = 6.3 Hz, 3 H, CH3).
3
1
H NMR (CDCl , 250 MHz): δ = 8.83–8.81 (m, 1 H, ArH), 8.31–8.26 (m,
3
1
C NMR (CDCl , 62.5 MHz): δ = 163.7 (d, 2JC,F = 251.4 Hz, C ), 158.3
3
2
(
H, ArH), 7.62 (t, J = 8.1 Hz, 1 H, ArH), 5.69–5.58 (m, 1 H, CH), 4.79
3
Ar
H,H
4
dd, J = 10.8 Hz, 3J = 8.2 Hz, 1 H, CH ), 4.23 (dd, J = 10.9 Hz,
2
2
(C ), 146.4 (C ), 132.0 (d, J = 8.3 Hz, 2 × CH ), 129.5 (C ), 127.3 (d,
Ar
Ar
C,F
Ar
Ar
H,H
H,H
2
H,H
5
JC,F = 3.2 Hz, C ), 115.2 (d, 3JC,F = 22.1 Hz, 2 × CH ), 85.5 (CH), 52.7
3
3
JH,H = 7.7 Hz, 1 H, CH ), 1.75 (d, J = 6.3 Hz, 3 H, CH3).
Ar
Ar
2
H,H
(CH ), 20.4 (CH ).
13
2
3
C NMR (CDCl , 62.5 MHz): δ = 158.3 (C ), 148.0 (C ), 143.9 (C ),
3
Ar
Ar
Ar
Anal. Calcd for C12H10FN O (263.22): C, 54.75; H, 3.83; N, 15.96.
Found: C, 54.83, H, 3.61; N, 15.13.
135.6 (CH ), 132.8 (C ), 129.1 (CH ), 124.9 (CH ), 124.6 (CH ), 85.8
3
3
Ar
Ar
Ar
Ar
Ar
(CH), 52.7 (CH ), 20.5 (CH ); C–NO was not observed.
2 3 2
Anal. Calcd for C12H10N O (290.23): C, 49.66; H, 3.47; N, 19.30.
Found: C, 49.56; H, 3.30; N, 18.71.
4
5
2
-Methyl-5-nitro-6-[3-(trifluoromethyl)phenyl]-2,3-dihydroimid-
azo[2,1-b]oxazole (6k)
Yield: 80 mg (56%); yellow oil.
6
-(Furan-2-yl)-2-methyl-5-nitro-2,3-dihydroimidazo[2,1-b]oxaz-
1
3
ole (6g)
H NMR (CDCl , 250 MHz): δ = 8.20 (s, 1 H, ArH), 8.12 (d, J = 7.7 Hz,
3 H,H
3
3
1
H, ArH), 7.68 (d, J = 7.9 Hz, 1 H, ArH), 7.55 (t, J = 7.8 Hz, 1 H,
Yield: 61 mg (57%); yellow solid; mp 153 °C.
H,H
H,H
3
2
ArH), 5.64–5.50 (m, 1 H, CH), 4.74 (dd, J = 10.8 Hz, J = 8.2 Hz, 1
1
3
H,H
H,H
H NMR (CDCl , 250 MHz): δ = 7.75 (d, J = 3.6 Hz, 1 H, ArH), 7.62 (d,
3
H,H
2
3
3
H, CH ), 4.18 (dd, J = 10.7 Hz, J = 7.7 Hz, 1 H, CH ), 1.71 (d, J
=
3J
5
3
= 3.6 Hz, 3J
2
H,H
H,H
2
H,H
= 1.7 Hz, 1 H, ArH), 6.59 (dd, J
= 1.7 Hz, 1 H, ArH),
H,H
H,H
H,H
6
.3 Hz, 3 H, CH3).
.65–5.51 (m, 1 H, CH), 4.74 (dd, 2JH,H = 10.7 Hz, JH,H = 8.2 Hz, 1 H,
3
1
3
2
3
3
C NMR (CDCl , 62.5 MHz): δ = 158.3 (C ), 133.0 (C ), 132.0 (C ),
CH ), 4.18 (dd, J = 10.6 Hz, J = 7.7 Hz, 1 H, CH ), 1.71 (d, J =
3
Ar
Ar
4
Ar
2
H,H
H,H
2
H,H
3
1
×
30.5 (q, J = 32.6 Hz, C ), 128.5 (2 × CH ), 126.6 (q, J = 3.7 Hz, 2
6.5 Hz, 3 H, CH3).
C,F
Ar
Ar
C,F
2
CH ), 123.9 (q, JC,F = 272.6 Hz, C ), 85.7 (CH), 52.6 (CH ), 20.4
13
Ar
Ar
2
C NMR (CDCl , 62.5 MHz): δ = 159.0 (C ), 145.7 (C ), 145.2 (CH ),
3
Ar
Ar
Ar
(CH3).
137.7 (C ), 127.9 (C ), 117.0 (CH ), 112.4 (CH ), 85.8 (CH), 52.5
Ar Ar Ar Ar
HRMS: m/z [M + H]+ calcd for C13H10F N O : 314.0747; found:
(CH ), 20.4 (CH ).
3
3
3
2
3
314.0749.
Anal. Calcd for C10H N O (235.20): C, 51.07; H, 3.86; N, 17.87. Found:
9
3
4
C, 51.34; H, 3.68, N, 17.65.
One-Pot Sequential Intramolecular Cyclization and Sonogashira
Reaction of 3 with Terminal Alkynes; General Procedure
2-Methyl-6-(5-methylthiophen-2-yl)-5-nitro-2,3-dihydroimid-
A solution of 1-(2,4-dibromo-5-nitro-1H-imidazol-1-yl)propan-2-ol
azo[2,1-b]oxazole (6h)
(
3; 0.15 g, 0.45 mmol) and Na CO (0.15 g, 1.37 mmol, 3 equiv) in
2 3
Yield: 73 mg (60%); yellow solid; mp 173 °C.
DME (4 mL) was heated at 110 °C under microwave irradiation for 1.5
h. After cooling, the appropriate terminal alkyne (0.59 mmol, 1.3
equiv), Pd(PPh3)4 (28 mg, 0.02 mmol, 0.05 equiv), CuI (9 mg, 0.045
1
3
H NMR (CDCl , 250 MHz): δ = 8.15 (d, J = 3.8 Hz, 1 H, ArH), 6.84–
3
H,H
2
6
.82 (m, 1 H, ArH), 5.62–5.48 (m, 1 H, CH), 4.72 (dd, JH,H = 10.6 Hz,
3
2
3
JH,H = 8.1 Hz, 1 H, CH ), 4.15 (dd, JH,H = 10.3 Hz, JH,H = 7.7 Hz, 1 H,
2
mmol, 0.1 equiv), and Et N (0.12 mL, 0.91 mmol, 2 equiv) were intro-
3
3
CH ), 2.54 (s, 3 H, CH ), 1.70 (d, J
= 6.3 Hz, 3 H, CH3).
2
3
H,H
duced under argon and the mixture was heated at 70 °C for 1 h under
13
C NMR (CDCl , 62.5 MHz): δ = 158.6 (C ), 146.3 (C ), 142.5 (C ),
microwave irradiation. After cooling, H
solution was extracted with CH Cl (3 × 60 mL). The combined organ-
ic layers were washed with H O (3 × 100 mL), dried (Na SO ), and
2
O (60 mL) was added and the
3
Ar
Ar
Ar
1
32.5 (CH ), 132.1 (C ), 126.8 (CH ), 85.6 (CH), 52.6 (CH ), 20.4
2
2
Ar
Ar
Ar
2
(
CH ), 15.6 (CH ); C–NO was not observed.
2
2
4
3
3
2
evaporated. The crude product was purified by column chromatogra-
phy [silica gel, PE/EtOAc, 7:3 (1:1 for 7f, 7g, 7h, 7i)] and recrystallized
from i-PrOH.
Anal. Calcd for C11H11N O S (265.29): C, 49.80; H, 4.18; N, 15.84.
Found: C, 49.37; H, 3.99; N, 15.37.
3
3
6
-(4-Chlorophenyl)-2-methyl-5-nitro-2,3-dihydroimidazo[2,1-
2
-Methyl-5-nitro-6-(phenylethynyl)-2,3-dihydroimidazo[2,1-
b]oxazole (6i)
b]oxazole (7a)
Yield: 80 mg (63%); yellow solid; mp 127 °C.
Yield: 80 mg (65%); yellow solid; mp 168 °C.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

I
Synthesis
F. Mathias et al.
Paper
1
1
H NMR (DMSO-d , 250 MHz): δ = 7.55 (d, 3JH,H = 7.3 Hz, 1 H, ArH),
H NMR (CDCl , 250 MHz): δ = 7.65–7.61 (m, 2 H, ArH), 7.41–7.35 (m,
3
6
2
3
3
H, ArH), 5.63–5.49 (m, 1 H, CH), 4.70 (dd, J = 10.8 Hz, J = 8.1
7.43–7.35 (m, 2 H, ArH), 7.31–7.26 (m, 1 H, ArH), 5.71–5.57 (m, 1 H,
CH), 4.66 (dd, J = 10.3 Hz, J = 8.2 Hz, 1 H, CH ), 4.15 (dd, J
10.4 Hz, J = 7.6 Hz, 1 H, CH ), 2.50 (s, 3 H, CH ), 1.58 (d, J = 6.3
Hz, 3 H, CH
H,H
H,H
2
3
2
3
2
Hz, 1 H, CH ), 4.13 (dd, J = 10.7 Hz, J = 7.9 Hz, 1 H, CH ), 1.71 (d,
=
2
H,H
H,H
2
H,H
H,H
2
H,H
3
1
3
3
JH,H = 6.3 Hz, 3 H, CH3).
H,H 2 3 H,H
3
3
).
C NMR (CDCl , 62.5 MHz): δ = 158.3 (C ), 148.9 (C ), 134.2 (C ),
3
Ar
Ar
Ar
13
1
8
32.3 (2 × CH ), 129.7 (CH ), 128.5 (2 × CH ), 121.6 (C ), 98.1 (C),
C NMR (DMSO-d , 62.5 MHz): δ = 158.6 (C ), 140.9 (CH ), 134.7
Ar Ar Ar Ar
6
Ar
Ar
5.7 (CH), 81.8 (C), 52.1 (CH ), 20.4 (CH ).
(C ), 132.4 (CH ), 130.3 (C ), 130.1 (CH ), 126.9 (C ), 126.4 (CH ),
Ar Ar Ar Ar Ar Ar
2
3
1
20.9 (C ), 95.4 (C), 87.1 (CH), 86.4 (C), 51.8 (CH ), 20.3 (CH ), 20.0
Anal. Calcd for C14H11N O (269.26): C, 62.45; H, 4.12; N, 15.61.
Found: C, 62.13; H, 3.93; N, 14.97.
A
r
2
3
3
3
(
CH3).
Anal. Calcd for C15H13N O (283.28): C, 63.60; H, 4.63; N, 14.83.
3
3
Found: C, 63.31; H, 4.45; N, 14.53.
6-[(4-tert-Butylphenyl)ethynyl]-2-methyl-5-nitro-2,3-dihydroim-
idazo[2,1-b]oxazole (7b)
{
4-[(2-Methyl-5-nitro-2,3-dihydroimidazo[2,1-b]oxazol-6-
Yield: 104 mg (70%); yellow solid; mp 156 °C.
yl)ethynyl]phenyl}methanol (7f)
1
3
H NMR (CDCl , 250 MHz): δ = 7.57 (d, J = 8.4 Hz, 2 H, ArH), 7.39 (d,
3
H,H
3J
2
Yield: 91 mg (67%); yellow solid; mp 206 °C.
= 8.4 Hz, 2 H, ArH), 5.62–5.49 (m, 1 H, CH), 4.69 (dd, J = 10.7
H,H
3
H,H
2
3
1
H NMR (DMSO-d , 250 MHz): δ = 7.56 (d, 3JH,H = 8.1 Hz, 2 H, ArH),
Hz, J = 8.1 Hz, 1 H, CH ), 4.13 (dd, J = 10.7 Hz, J = 7.7 Hz, 1 H,
CH ), 1.71 (d, J = 6.3 Hz, 3 H, CH ), 1.32 (s, 9 H, 3 × CH ).
H,H
2
H,H
H,H
6
3
3
3
7.41 (d, J = 8.2 Hz, 2 H, ArH), 5.71–5.57 (m, 1 H, CH), 5.35 (t, J
=
2
H,H
3
3
H,H
H,H
2
3
13
5.4 Hz, 1 H, OH), 4.66 (dd, JH,H = 10.4 Hz, JH,H = 8.4 Hz, 1 H, CH ), 4.55
2
C NMR (CDCl , 62.5 MHz): δ = 158.4 (C ), 153.3 (C ), 132.1 (2 ×
3
Ar
Ar
d, J = 5.1 Hz, 2 H, CH ), 4.15 (dd, J = 10.3 Hz, 3J = 7.7 Hz, 1 H,
3
2
(
CH ), 128.8 (C ), 125.5 (2 × CH ), 118.6 (C ), 98.7 (C), 85.6 (CH, C),
H,H
2
H,H
H,H
Ar
Ar
Ar
Ar
3
CH ), 1.58 (d, J
= 6.3 Hz, 3 H, CH3).
8
1.4 (C), 52.1 (CH ), 35.0 (CH ), 31.1 (2 × CH ), 20.4 (CH ); C–NO was
2
H,H
2
3
3
3
2
13
not observed.
C NMR (DMSO-d , 62.5 MHz): δ = 158.6 (C ), 145.2 (C ), 134.8 (C ),
6 Ar Ar Ar
1
31.8 (2 × CH ), 127.0 (2 × CH ), 126.8 (C ), 119.1 (C ), 96.5 (C), 87.1
Anal. Calcd for C18H19N O (325.36): C, 66.45; H, 5.89; N, 12.91.
Found: C, 66.13; H, 5.82; N, 12.65.
Ar Ar Ar Ar
3
3
(
CH), 82.4 (C), 62.6 (CH ), 51.8 (CH ), 19.9 (CH ).
2 2 3
Anal. Calcd for C15H13N O (299.28): C, 60.20; H, 4.38; N, 14.04.
3
4
Found: C, 59.62; H, 4.20; N, 13.61.
2-Methyl-5-nitro-6-(p-tolylethynyl)-2,3-dihydroimidazo[2,1-b]ox-
azole (7c)
6
-[(3-Methoxyphenyl)ethynyl]-2-methyl-5-nitro-2,3-dihydroim-
Yield: 87 mg (67%); yellow solid; mp 234 °C.
idazo[2,1-b]oxazole (7g)
1
H NMR (DMSO-d , 250 MHz): δ = 7.49 (d, 3JH,H = 8.1 Hz, 2 H, ArH),
6
3
Yield: 105 mg (77%); yellow solid; mp 131 °C.
7
.29 (d, JH,H = 7.9 Hz, 2 H, ArH), 5.70–5.57 (m, 1 H, CH), 4.65 (dd,
2
3
2
3
1
JH,H = 10.3 Hz, J = 8.5 Hz, 1 H, CH ), 4.14 (dd, J = 10.4 Hz, J
=
H NMR (CDCl , 250 MHz): δ = 7.31–7.21 (m, 2 H, ArH), 7.15–7.14 (m,
H,H
2
H,H
H,H
3
3
7
.9 Hz, 1 H, CH ), 2.36 (s, 3 H, CH ), 1.58 (d, J = 6.3 Hz, 3 H, CH3).
1 H, ArH), 6.98–6.93 (m, 1 H, ArH), 5.64–5.50 (m, 1 H, CH), 4.70 (dd,
2
3
H,H
2
3
2
3
13
J
H,H = 10.7 Hz, JH,H = 8.1 Hz, 1 H, CH
2
), 4.14 (dd, JH,H = 10.7 Hz, JH,H
=
C NMR (DMSO-d , 62.5 MHz): δ = 158.6 (C ), 140.4 (C ), 134.7 (C ),
6
Ar
Ar
Ar
3
7.7 Hz, 1 H, CH ), 3.82 (s, 3 H, OCH ), 1.72 (d, J
H,H
= 6.5 Hz, 3 H, CH3).
1
31.9 (2 × CH ), 129.9 (2 × CH ), 126.9 (C ), 118.0 (C ), 96.6 (C), 87.1
2
3
Ar
Ar
Ar
Ar
13
(
CH), 82.3 (C), 51.8 (CH ), 21.4 (CH ), 20.0 (CH ).
C NMR (CDCl , 62.5 MHz): δ = 159.3 (C ), 158.3 (C ), 129.6 (CH ),
3 Ar Ar Ar
2
3
3
+
128.4 (CAr), 125.0 (CHAr), 122.5 (CAr), 116.8 (CHAr), 116.6 (CHAr), 98.1
HRMS: m/z [M + H] calcd for C15H13N O : 284.1030; found: 284.1031.
3
3
(
C), 85.7 (CH), 81.5 (C), 55.4 (OCH ), 52.1 (CH ), 20.4 (CH ); C–NO was
3 2 3 2
not observed.
6-[(4-Fluorophenyl)ethynyl]-2-methyl-5-nitro-2,3-dihydroimid-
+
HRMS: m/z [M + H] calcd for C15H N O : 300.0979; found: 300.0979.
azo[2,1-b]oxazole (7d)
13
3
4
Yield: 102 mg (78%); yellow solid; mp 199 °C.
4
-(2-Methyl-5-nitro-2,3-dihydroimidazo[2,1-b]oxazol-6-yl)-2-
1
H NMR (CDCl , 250 MHz): δ = 7.66–7.58 (m, 2 H, ArH), 7.11–7.02 (m,
3
phenylbut-3yn-2-ol (7h)
2
3
2
H, ArH), 5.64–5.50 (m, 1 H, CH), 4.70 (dd, J = 10.7 Hz, J = 8.1
H,H H,H
2
3
Yield: 79 mg (55%); brown oil.
Hz, 1 H, CH ), 4.14 (dd, J = 10.7 Hz, J = 7.7 Hz, 1 H, CH ), 1.72 (d,
2
H,H
H,H
2
3
1
(
1
JH,H = 6.3 Hz, 3 H, CH3).
H NMR (CDCl , 250 MHz): δ = 7.76–7.71 (m, 2 H, ArH), 7.41–7.28 (m,
3
2
3
3
C NMR (CDCl , 62.5 MHz): δ = 163.4 (d, 2J = 252.3 Hz, C ), 158.3
3 H, ArH), 5.60–5.46 (m, 1 H, CH), 4.64 (dd, JH,H = 10.7 Hz, JH,H = 8.2
Hz, 1 H, CH
3 H, CH
3
4
C,F
Ar
5
2
3
), 4.09 (dd, JH,H = 10.8 Hz, JH,H = 7.7 Hz, 1 H, CH
), 1.88 (s,
C ), 134.4 (d, J = 8.7 Hz, 2 × CH ), 128.3 (C ), 117.7 (d, J = 3.7
2
2
Ar
C,F
3
Ar
Ar
C,F
3
), 1.68 (d, JH,H = 6.3 Hz, 3 H, CH
).
Hz, C ), 115.9 (d, J = 22.5 Hz, 2 × CH ), 97.0 (C), 85.7 (CH), 81.6 (C),
3
3
Ar
C,F
Ar
13
5
2.1 (CH ), 20.4 (CH ); C–NO was not observed.
C NMR (CDCl , 62.5 MHz): δ = 158.2 (C ), 144.5 (C ), 128.4 (2 ×
3 Ar Ar
2
3
2
H]+ calcd for C14H10FN O : 288.0779; found:
CHAr), 127.9 (CHAr), 125.0 (2 × CHAr), 101.2 (CAr), 85.8 (CH, C), 76.8 (C),
0.4 (C), 52.0 (CH ), 32.8 (CH ), 20.3 (CH ); C–NO was not observed.
HRMS: m/z [M
+
3
3
7
288.0780.
2
3
3
2
+
HRMS: m/z [M + H] calcd for C16H15N O : 314.1135; found: 314.1136.
3
4
2-Methyl-5-nitro-6-(o-tolylethynyl)-2,3-dihydroimidazo[2,1-b]ox-
azole (7e)
4-Methyl-1-(2-methyl-5-nitro-2,3-dihydroimidazo[2,1-b]oxazol-
-yl)pent-1-yn-3-ol (7i)
Yield: 51 mg (42%); yellow solid; mp 118 °C.
6
Yield: 78 mg (60%); yellow solid; mp 158 °C.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

J
Synthesis
F. Mathias et al.
Paper
1
H NMR (CDCl , 250 MHz): δ = 5.59–5.51 (m, 1 H, CH), 4.70–4.65 (m, 1
Kawasaki, M.; Tsubouchi, H.; Sasaki, H.; Shimokawa, Y.;
Komatsu, M. PLoS Med. 2006, 3, 2131. (c) Sasaki, H.; Haraguchi,
Y.; Itotani, M.; Kuroda, H.; Hashizume, H.; Tomishige, T.;
Kawasaki, M.; Matsumoto, M.; Komatsu, M.; Tsubouchi, H.
J. Med. Chem. 2006, 49, 7854. (d) Kim, P.; Zhang, L.; Manjunatha,
U. H.; Singh, R.; Patel, S.; Keller, T.; Boshoff, H. I.; Barry, C. E.;
Dowd, C. S. J. Med. Chem. 2009, 52, 1317. (e) Sotgiu, G.; Migliori,
G. B. Lancet 2015, 385, 1703. (f) Dawson, R.; Diacon, A. H.;
Everitt, D.; van Niekerk, C.; Donald, P. R.; Burger, D. A.; Schall, R.;
Spigelman, M.; Conradie, A.; Eisenach, K.; Venter, A.; Ive, P.;
Page-Shipp, L.; Variava, E.; Reither, K.; Ntinginya, N. E.; Pym, A.;
von Groote-Bidlingmaier, F.; Mendel, C. M. Lancet 2015, 385,
1738. (g) Yempalla, K. R.; Munagala, G.; Singh, S.; Kour, G.;
Sharma, S.; Kumar, S.; Wazir, P.; Singh, G. D.; Raina, S.; Bharate,
S. S.; Khan, I. A.; Vishwakarma, R. A.; Singh, P. P. ACS Med. Chem.
Lett. 2015, 6, 1059. (h) Munagala, G.; Yempalla, K. R.; Singh, S.;
Sharma, S.; Kalia, N. P.; Rajput, V. S.; Kumar, S.; Sawant, S. D.;
Khan, I. A.; Vishwakarma, R. A.; Singh, P. P. Org. Biomol. Chem.
3
3
H, CH ), 4.44 (d, J = 5.6 Hz, 1 H, OH), 4.41–4.09 (m, 1 H, CH ), 2.07–
1
6
2
H,H
2
3
3
.96 (m, 2 H, 2 × CH), 1.70 (d, J = 6.4 Hz, 3 H, CH ), 1.09 (d, J
.7 Hz, 3 H, CH ), 1.06 (d, J = 6.9 Hz, 3 H, CH3).
=
H,H
3
H,H
3
3
H,H
13
C NMR (CDCl , 62.5 MHz): δ = 158.2 (C ), 134.3 (C ), 127.6 (C ),
3
Ar
Ar
Ar
9
8.4 (C), 85.8 (CH), 77.5 (C), 68.3 (CH), 52.1 (CH ), 34.4 (CH), 20.4
2
(CH ), 18.0 (CH ), 17.4 (CH ).
3 3 3
+
HRMS: m/z [M + H] calcd for C12H15N O : 266.1135; found: 266.1136.
3
4
9
-[(2-Methyl-5-nitro-2,3-dihydroimidazo[2,1-b]oxazol-6-
yl)ethynyl]-9H-fluoren-9-ol (7j)
Yield: 77 mg (45%); yellow solid; mp 152 °C.
1
H NMR (CDCl , 250 MHz): δ = 7.82–7.79 (m, 2 H, ArH), 7.64–7.61 (m,
3
2
H, ArH), 7.44–7.32 (m, 4 H, ArH), 5.57–5.43 (m, 1 H, CH), 4.66 (dd,
2
3
3
JH,H = 10.7 Hz, J = 8.1 Hz, 1 H, CH ), 4.62 (d, J = 5.1 Hz, 1 H, CH ),
H,H
2
H,H
2
2
= 10.8 Hz, 3J
3
4
3
.07 (dd, J
= 7.7 Hz, 1 H, CH ), 1.66 (d, J = 6.3 Hz,
H,H
H,H 2 H,H
H, CH3).
2015, 13, 3610.
13
C NMR (CDCl , 62.5 MHz): δ = 158.0 (C ), 146.0 (2 × C ), 139.3 (2 ×
3
Ar
Ar
(
4) (a) Shashiprabha, N.; Nayak, S. P.; Rao, K. S.; Nagarajan, K.;
C ), 129.9 (2 × CH ), 128.7 (2 × CH ), 127.2 (C ), 124.8 (2 × CH ),
1
C–NO was not observed.
Ar
Ar
Ar
Ar
Ar
Shridhara, K.; Torreele, E.; Trunz, B. B. Indian J. Pharm. Sci. 2014,
20.2 (2 × CH ), 98.0 (C), 75.0 (2 C), 85.8 (CH), 52.0 (CH ), 20.3 (CH );
A
r
2
3
76, 92. (b) Mukkavilli, R.; Pinjari, J.; Patel, B.; Sengottuvelan, S.;
2
Mondal, S.; Gadekar, A.; Verma, M.; Patel, J.; Pothuri, L.;
Chandrashekar, G.; Koiram, P.; Harisudhan, T.; Moinuddin, A.;
Launay, D.; Vachharajani, N.; Ramanathan, V.; Martin, D. Eur. J.
Med. Chem. 2014, 65, 147. (c) Gupta, S.; Yardley, V.;
Vishwakarma, P.; Shivahare, R.; Sharma, B.; Launay, D.; Martin,
D.; Puri, S. K. J. Antimicrob. Chemother. 2015, 70, 518.
+
HRMS: m/z [M + H] calcd for C21H15N O : 374.1135; found: 374.1136.
3
4
6
-(Cyclopropylethynyl)-2-methyl-5-nitro-2,3-dihydroimid-
azo[2,1-b]oxazole (7k)
Yield: 62 mg (58%); yellow oil.
1
(d) Patterson, S.; Wyllie, S.; Norval, S.; Stojanovski, L.; Simeons,
2
H NMR (CDCl , 250 MHz): δ = 5.59–5.45 (m, 1 H, CH), 4.64 (dd, J
=
H,H
3
F. R.; Auer, J. L.; Osuna-Cabello, M.; Read, K. D.; Fairlamb, A. H.
eLife 2016, 5.
3
2
3
1
1
0
0.6 Hz, J = 8.2 Hz, 1 H, CH ), 4.07 (dd, J = 10.6 Hz, J = 7.9 Hz,
H, CH ), 1.68 (d, JH,H = 6.3 Hz, 3 H, CH ), 1.59–1.49 (m, 1 H, CH),
H,H 2 H,H H,H
3
2
3
(
5) Thompson, A. M.; O’Connor, P. D.; Blaser, A.; Yardley, V.; Maes,
L.; Gupta, S.; Launay, D.; Martin, D.; Wan, B.; Wang, Y.; Ma, Z.;
Denny, W. A. J. Med. Chem. 2016, 59, 2530.
.97–0.94 (m, 4 H, 2 CH2).
13
C NMR (CDCl , 62.5 MHz): δ = 158.2 (C ), 134.1 (C ), 129.3 (C ),
3
Ar
Ar
Ar
1
04.6 (C), 85.5 (CH), 68.7 (C), 52.0 (CH ), 20.3 (CH ), 9.5 (2 × CH ), 0.7
(6) (a) Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111, 2177.
(b) Johansson Seechurn, C. C. C.; Kitching, M. O.; Colacot, T. J.;
Snieckus, V. Angew. Chem. Int. Ed. 2012, 51, 5062.
2
3
2
(CH).
+
HRMS: m/z [M + H] calcd for C11H11N O : 234.0873; found: 234.0875.
3
3
(7) (a) Mutel, V.; Peters, J.-U.; Wichmann, J. PCT Int. Appl
WO2002046166, 2002; Chem. Abstr. 2002, 137, 33292.
(
b) Buettelmann, B.; Ceccarelli, S. M.; Jaeschke, G.; Kolczewski,
S.; Porter, R. H. P.; Vieira, E. PCT Int. Appl WO2005118568,
005; Chem. Abstr. 2005, 144, 51579. (c) Jaeschke, G.;
Acknowledgment
2
This work was supported by the CNRS (Centre National de la Recher-
che Scientifique) and Aix-Marseille University. The authors thank V.
Remusat for NMR spectra recording and the Spectropole team for var-
ious analytical measurements.
Lindemann, L.; Vieira, E.; Wichmann, J. PCT Int. Appl
WO2011006910, 2011; Chem. Abstr. 2011, 154, 182550.
(
8) (a) Crozet, M. D.; Zink, L.; Remusat, V.; Curti, C.; Vanelle, P. Syn-
thesis 2009, 3150. (b) Neildé, K.; Crozet, M. D.; Terme, T.;
Vanelle, P. Synthesis 2013, 45, 1349. (c) Laroshenko, V. O.;
Gevorgyan, A.; Mkrtchyan, S.; Arakelyan, K.; Grigoryan, T.;
Yedoyan, J.; Villinger, A.; Langer, P. J. Org. Chem. 2014, 80, 2103.
Supporting Information
Supporting information for this article is available online at
(9) (a) Revesz, L.; Bonne, F.; Makavou, P. Tetrahedron Lett. 1998, 39,
5171. (b) Revesz, L.; Di Padova, F. E.; Buhl, T.; Feifel, R.; Gram, H.;
Hiestand, P.; Manning, U.; Wolf, R.; Zimmerlin, A. G. Bioorg.
Med. Chem. Lett. 2002, 12, 2109.
http://dx.doi.org/10.1055/s-0036-1588984.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
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