Copper-Catalyzed Synthesis of Fused Imidazopyrazine N-Oxide Skeletons

Article abstract of DOI:10.1055/s-0037-1610859

N-Propargyl-2-aroylimidazoles synthesized and converted into the corresponding ketoximes. Under various conditions, several mono- and diketoxime imidazole derivatives were formed by converting the carbonyl or carbonyl and propargyl groups into oxime groups. N -Propargyl monooxime imidazole derivatives were cyclized by treatment with CuI to give various imidazopyrazine N -oxides. Several copper salts, such as CuOAc, CuSO ₄, and CuOTf, formed the same cyclization product. This cyclization reaction occurred only in the presence of Cu(I) or Cu(II) salts; other transition metals such as Au, Ag, In, and Fe did not yield cyclic products. The nucleus-independent chemical shift method was used to calculate the aromaticity of the bicyclic rings.

Full text of DOI:10.1055/s-0037-1610859

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–D
letter
A
en
V. Taşdemir et al.
Letter
Synlett
Copper-Catalyzed Synthesis of Fused Imidazopyrazine N-Oxide
Skeletons
Volkan Taşdemira
Burak Kuzub,c
Meltem Tanb,c
Hasan Gençd
Nurettin Menges*b,c
0
0
0
0-0
0
0
2-5
9
9
0-6
2
7
5
a Science Research and Applied Center, Van Yüzüncü Yıl University,
65080, Van, Turkey
b SAFF Chemical Reagents R&D Lab. YYU-TEKNOKENT, 65080, Van,
Turkey
nurettinmenges@yyu.edu.tr
c Pharmaceutical Chemistry Section, Van Yüzüncü Yıl University,
65080, Van, Turkey
d Faculty of Education, Chemistry Section, Van Yüzüncü Yıl University,
65080, Van, Turkey
Received: 29.11.2018
Accepted after revision: 21.12.2018
Published online: 22.01.2019
O
Ph
N
Ar
Ph
O
N
N
Ar
N
O
N
N
N
O
O
N
DOI: 10.1055/s-0037-1610859; Art ID: st-2018-k0554-l
O
N
N
Ph
Bz
Imidazolo-
pyrazine
N-Oxide
Pyrrolo-
Pyrazine
N-Oxide
Abstract N-Propargyl-2-aroylimidazoles synthesized and converted
into the corresponding ketoximes. Under various conditions, several
mono- and diketoxime imidazole derivatives were formed by convert-
ing the carbonyl or carbonyl and propargyl groups into oxime groups.
N-Propargyl monooxime imidazole derivatives were cyclized by treat-
ment with CuI to give various imidazopyrazine N-oxides. Several copper
salts, such as CuOAc, CuSO4, and CuOTf, formed the same cyclization
product. This cyclization reaction occurred only in the presence of Cu(I)
or Cu(II) salts; other transition metals such as Au, Ag, In, and Fe did not
yield cyclic products. The nucleus-independent chemical shift method
was used to calculate the aromaticity of the bicyclic rings.
Isoquinoline
N-Oxide
Pyrazole
N-Oxide
Benzopyrazole
N-Oxide
(This Work)
Figure 1 Examples of N-oxide derivatives
example of an imidazo N-oxide reported in the literature, a
carbaldehyde group attached at the C-2 position of the im-
idazole ring of an imidazopyrazine N-oxide was cyclized to
an ethyne group by using hydroxylamine.14 The addition of
various groups to heterocyclic rings can change their phar-
macological properties and the side-effects of candidate
drugs; consequently, expedient strategies for synthesizing
heterocyclic molecules are a welcome development. For ex-
ample, the functional differences between zolpidem and al-
pidem derive from the different affinities of the peripheral
benzodiazepine receptor subtype.15 Efficient atom-eco-
nomic synthetic routes that permit desirable diversification
of such cores are proving to be of tremendous value, as they
permit structure–activity relationship and quantitative
structure–activity relationship studies to be performed
more effectively.
Our research group has synthesized pyrrolo- and indol-
opyrazine N-oxide derivatives by a gold-catalyzed reac-
tion.10 In addition, we aimed to extend the range of hetero-
cyclic N-oxides by replacing the heterocyclic ring in these
compounds (i.e., pyrrole and indole) with imidazole.
We hypothesized that unknown imidazopyrazine N-ox-
ides might be synthesized through a metal-catalyzed reac-
tion of an oxime group with a propargyl group . This is the
first report of synthesis of highly substituted imidazopyra-
Keywords alkynes, cyclization, copper catalysis, imidazopyrazine
oxides, oximes
Fused bicyclic imidazole molecules have attracted con-
siderable attention from researchers owing to their impor-
tance in the design of drugs, for example, zolpidem and alp-
idem. Despite the fact that many important compounds
contain an imidazole ring, for example, protein kinase in-
hibitors,1 antitubercular agents,2 and cannabinoid receptor
ligands,3 certain members of this class are virtually unex-
plored, including substituted imidazopyrazine N-oxides.
Heterocyclic N-oxide molecules are important structural
moieties, because they are present in numerous natural and
pharmacological compounds that display significant biolog-
ical activities (Figure 1).4a,b To access such moieties, cycliza-
tion reactions of alkynes are of particular interest.4c,5–7
Although some heterocyclic N-oxide derivatives, such as
isoquinoline N-oxides,8,9 pyrrolo- and indolopyrazine N-ox-
ides,10 pyrazole N-oxides,11 benzopyrazole N-oxides,12 and
benzimidazole N-oxides,13 have been documented, this is
the first study to report the synthesis of the highly substi-
tuted imidazo[1,2-a]pyrazine N-oxide skeleton. In the only
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

B
V. Taşdemir et al.
Letter
Synlett
Ar
Ar
O
N
HO
N
OH
N
N
Ar
NH2OH·HCl
N
N
N
N
Ar
Ar
+
pyridine, reflux
Ar
N
a: Ar = Ph
HO
b: Ar = 4-MeOC6H4
c: Ar = 3,4-(MeO)2C6H4
d: Ar = 4-BrC6H4
e: Ar = 4-FC6H4
f: Ar = 4-PhC6H4
g: Ar = 2-naphthyl
h: Ar = 2-thienyl
1a–g
2a–g
25–80%
2aa–ga
20–75%
O
HO
N
N
N
OH
N
N
NH2OH·HCl
N
N
N
Ar
Ar
+
pyridine, reflux
Ar
N
HO
3a, 3h
4a,4h
66–62%
4aa,4ha
38–34%
Scheme 1 Synthesis of the desired condensation products.
zine N-oxide derivatives in which an oxime group is used as
a nucleophile to attack the propargyl group in a catalytic
reaction.
Table 1 Optimization Experiments for the Cyclizationa
Ph
N
N
N
OH
Ph
N
N
Ph
catalyst
N-Propargyl 2,4-disubstituted imidazoles 1a–g and N-
propargyl 2-substituted imidazoles 3a and 3h were synthe-
sized by methods reported in the literature [for details of
the reactions, see the Supplementary Information (SI),
Scheme S3].16–18 During the propargylation reaction to form
1a–g, 3a, and 3h, the N-1 atom was propargylated exclu-
sively. To determine the structure of the favored N-propar-
gylated isomer, we calculated their relative enthalpies and
Gibbs free energies (SI; Figure S1).19
The N-propargylated derivatives 1a–g, 3a, and 3h were
converted into the corresponding N-propargylated ketox-
imes 2a–g, 4a, and 4h in moderate yields by treatment with
hydroxylamine under basic condition (Scheme 1). However,
the attempted ketoximation of 1a by using triethylamine as
a base instead of pyridine did not give 2a, but instead gave a
mixture of products (SI; Scheme S1).
The cyclization reaction of the oxime derivative 2a was
optimized by screening various catalysts, bases, and sol-
vents (Table 1). Gold salts did not catalyze the reaction (Ta-
ble 1, entries 1–5, and 13), although they have been used
for similar reactions reported in the literature. Most Lewis
acids and bases were also unreactive except for the copper
salts CuI, CuSO4, CuOTf, and CuOAc (entries 15–17, 19, and
20).20a Both Cu(I) and Cu(II) salts gave a cyclized product 5a,
although CuCl2 was ineffective (entry 18).20b Use of a hy-
drated copper salt decreased the yield of 5a (entry 17).
Moving from CuI to other counterions such as SO42–, OTf–,
OAc– had little effect on the yield of reaction.20c The ob-
served yields of product 5a suggest that the iodide ion
might play an important role as a stabilizing ligand in the
copper complex, thereby extending the lifetime of the
formed intermediate.20d The choice of solvent was also
found to be crucial for the efficiency of this process, and
PrOH was found to be optimal (entry 14).
Ph
N
O
solvent, reflux
2a
5a
Entry
Catalyst
Solvent
DCE
Yield (%)
1
2
AuCl + AgSbF6
AuCl3
NDb
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
ND
83
acetone
MeCN
CHCl3
CHCl3
acetone
CHCl3
MeCN
MeOH
MeCN
MeCN
MeOH
PrOH
3
AuCl3
4
AuCl3
5
AuBr3
6
InCl3
7
InCl3
8
InCl3
9
InCl3
10
11
12
13
14
15
16
17
18
19
20
21
22
AgOTf
Yb(OTf)3
Cs2CO3
AuCl
CuI
PrOH
CuI
MeCN
PrOH
59
CuSO4
CuSO4·5H2O
CuCl2·2H2O
CuOTf
69
PrOH
49
PrOH
ND
66
PrOH
CuOAc
FeCl3·6H2O
FeCl3·6H2O
PrOH
63
MeCN
PrOH
ND
ND
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

C
V. Taşdemir et al.
Letter
Synlett
did not see any sign of the starting material. This might be
due to the formation of a coordination complex of gold(III)
with a reaction intermediate, which might occur as a result
of the presence of the internal alkyne unit. A similar reduc-
tion has been reported for a reaction between benzothi-
azole and AuCl3.22
Entry
23c
Catalyst
TiCl4
Solvent
MeCN
Yield (%)
ND
24c
25
BF3·OEt2
CuI
MeCN
CHCl3
ND
48%
a 10 mol% of the metal salt was used. All reactions were performed in the
refluxing solvent.
b ND = not detected.
c An equivalent amount of the Lewis acid was used.
CuI
n-PrOH
Ph
SM
N
N
N
OH
(a)
(b)
Ph
AuCl3
+ Au0
unidentified
As an alternative cyclization route, we attempted to car-
ry out the oxime formation before the propargylation reac-
tion. All attempts at cyclization of a dipropargylated ketox-
ime derivative with various catalysts and bases failed to
give any cyclic product (SI; Scheme S2).
n-PrOH or CHCl3 reaction mixture
7
Scheme 3 Testing of an internal alkyne for cyclization. SM = starting
material.
Next, we examined the scope of the cyclization reaction,
and various unknown imidazopyrazine N-oxide derivatives
were obtained (Scheme 2).21 The diphenyl, bis(4-methoxy-
phenyl), bis(4-bromophenyl), bis(4-fluorophenyl), and di-
2-naphthyl derivatives 5a, 5b, 5d, 5e, and 5g, respectively,
and the monophenyl N-oxide derivatives 6a were obtained
in moderate yields. Other products (not shown) were ob-
tained only as crude products. The scope of this cyclization
reaction was limited to aryl substituents, because the reac-
tion by which we prepared the N-propargyl-2-aroylimidaz-
ole derivatives did not permit the preparation of alkyl-sub-
stituted (ketone or aldehyde) imidazole derivatives.
Our cyclization reaction gave pyrazine N-oxides con-
taining two different aromatic rings. We therefore desired
to investigate the aromaticity of these rings by means of the
nucleus-independent chemical shift (NICS) index method.
The aromaticities of bicyclic compounds 5a, 5b, 5e, 5g, and
6a were therefore calculated by using the NICS meth-
od.19,23,24 NICS(1) values were chosen for this investigation.
The imidazole and the pyrazine N-oxide rings were found to
possess aromatic character (Table 2). The bicyclic disubsti-
tuted N-oxide derivatives 5a, 5b, 5e, and 5g all displayed
similar aromatic properties, even though they possess dif-
ferent functional groups with different electronic proper-
ties. The imidazole rings exhibited more-aromatic charac-
ter than did the N-oxide rings. The monosubstituted imid-
azopyrazine N-oxide 6a exhibited the most aromatic traits
for the imidazole ring; conversely, it showed the least aro-
matic character for the pyrazine N-oxide ring among the
various cyclic derivatives (Table 2).
Ar
N
Ar
N
N
OH
N
N
Ar
CuI 10 mol%
Ar
N
O
Propanol, reflux, 24 h
OMe
Br
MeO
Br
N
N
N
N
N
Table 2 Aromaticities of the Imidazopyrazine N-Oxidesa
N
N
O
N
O
N
O
5b, 49%
5d, 33%
Ring
5a
5b
5e
5g
6a
5a, 83%
F
F
imidazole
N-oxide
a Values are expressed in ppm.
–12.0
–11.0
–11.9
– 6.2
–12.6
– 6.2
–12.7
– 5.2
N
N
N
N
N
N
– 5.9
– 6.1
N
O
N
O
N
O
5g, 28%
6a, 33%
5e, 66%
It is obvious that there are marked differences between
the two aromatic rings. To test the effects of this variation
on a cyclization reaction, we attempted a simple [3+2] cy-
clization reaction of compound 5a with dimethyl acety-
lenedicarboxylate (DMAD) (SI; Scheme S4). However, this
reaction did not proceed in refluxing xylene, and the start-
ing material was recovered. Note that the phenyl ring adja-
cent to the quaternary nitrogen atom might cause steric
hindrance resulting in an unfavorable geometrical position
for the DMAD molecule. With this knowledge, this reaction
might be fully optimized by adopting different reaction
conditions.25
Scheme 2 Extension of the cyclization reaction to various derivatives
To examine the effect of an internal alkyne on the cy-
clization, we treated compound 7 with CuI under the same
cyclization conditions as discussed above; however, only
the starting material was obtained (Scheme 3; Path a).
When we attempted to cyclize compound 7 with AuCl3 in
PrOH or CHCl3, as in our previous work,10 we obtained a
yellow precipitate. Extended stirring at room temperature
led to further reduction of the Au(III) to Au(0) (Scheme 3;
Path b) and, although we checked all the reaction media, we
© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D

D
V. Taşdemir et al.
Letter
Synlett
In conclusion, we investigated the oximation of N-prop-
argyl-2 aroylimidazole derivatives. When pyridine was
used as both base and solvent, the product of oximation of
the carbonyl group was obtained exclusively. Monooxime
derivatives were subjected to alkyne cyclization by copper
salts to yield imidazopyrazine N-oxides. Both copper(I) and
copper(II) salts gave the same cyclization products in differ-
ent yields. However, the optimal reaction was achieved
with CuI, which is a cheap and low-toxicity catalyst. Silver,
gold, and iron salts were ineffective for the cyclization, pos-
sibly because of the higher catalytic activity of copper in C–
X (X = C, N, O) coupling reactions. The developed cyclization
protocol afforded novel bicyclic imidazole skeletons con-
taining aryl substituents. Aromaticity values were calculat-
ed, and the aromaticities of the imidazole and N-oxide rings
were found to be different. This feature of these bicyclic
molecules might provide an opportunity for selective reac-
tions.
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Funding Information
(19) Gaussian 09, Revision D.01; Gaussian, Inc: Wallingford, 2009.
(20) (a) Liu, Y.; Wan, J.-P. Org. Biomol. Chem. 2011, 9, 6873. (b) Ge, Q.;
Zong, J.; Li, B.; Wang, B. Org. Lett. 2017, 19, 6670. (c) Aradi, K.;
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(21) Imidazo[1,2-a]pyrazine N-Oxides 5a–g and 6a; General Pro-
cedure
This study was funded by Scientific and Technologic Research Agency
of Turkey (TÜBİTAK) (grant numbers:115Z894).()
Acknowledgment
The appropriate N-propargylimidazole oxime derivative 2a–g,
4a, or 4h (1 mmol) was dissolved in PrOH (5 mL) in a 25 mL
flask. A catalytic amount of CuI (10 mol%) was added, and the
mixture was refluxed for the appropriate time until the reac-
tion was completed (TLC). The mixture was then extracted with
EtOAc–H2O (3 × 40 mL). The organic layer was dried (MgSO4)
and concentrated under reduced pressure to give a crude
product that was purified by column chromatography. The
products were further purified by preparative TLC (hexane–
EtOAc, 5:1).
Authors thank to TUBİTAK for funding and Van Yüzüncü Yıl Universi-
ty, Faculty of Pharmacy and Science Research and Applied Center for
their research laboratories.
Authors also thank to graphic artist Gül Menges for designing the
graphical abstract.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610859.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orti
n
gInformati
o
n
6-Methyl-2,8-diphenylimidazo[1,2-a]pyrazine 7-Oxide (5a)
Reaction time:
3 h; eluent for column chromatography:
hexane–EtOAc (1:1).
References and Notes
Brown solid; yield: 250 mg (83%); mp 193–195 °C. FTIR (ATR):
3140, 3038, 2969, 2925, 2163, 1732, 1660, 1604, 1576, 1496,
1489 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.23 (d, J = 6.91 Hz, 2
H, Ar-H), 7.93–7.89 (m, 3 H, Ar-H), 7.78 (s, 1 H, Ar-H), 7.55–7.48
(m, 4 H, Ar-H), 7.41 (t, J = 7.36 Hz, 2 H, Ar-H), 2.51 (s, 3 H, CH3).
13C NMR (100 MHz, CDCl3): δ = 148.9, 132.6, 131.0, 130.3, 128.7,
128.6, 127.9, 127.8, 126.3, 116.9, 108.8, 15.5. LCMS: m/z [M +
H]+ Calcd for C19H16N3O: 302.12879; found: 302.12958.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2019, 30, A–D