Diversely substituted imidazo[1,2-a]pyrazine-8-oxo-3-carbaldehydes: An iodine-mediated cyclization/oxidation approach

Article abstract of DOI:10.1002/ejoc.201201150

A mild and efficient iodine-mediated intramolecular heteroannulation approach for the construction of the imidazo[1,2-a]pyrazinone core has been developed. Under ambient conditions, this metal-free protocol allows easy access to densely functionalized imidazo[1,2-a]pyrazinone-3-carbaldehydes or (aminomethyl)imidazo[1,2-a]pyrazinones from substrates containing terminal alkynes by cyclization and subsequent oxidation or amination. Further diversification may be introduced by using substrates containing an internal alkyne and/or Suzuki coupling after cyclization to generate polysubstituted (dihydro)imidazo[1,2-a]pyrazinones. An iodine-mediated heteroannulation approach for the construction of (dihydro)imidazo[1,2-a]pyrazinone motifs have been developed. For terminal alkynes, a hydrolysis/oxidation sequence or an amination gives direct access to imidazo[1,2-a]pyrazin-3-carbaldehydes or aminomethyl-imidazo-[1,2-a]pyrazinones in a one-pot process. Copyright

Full text of DOI:10.1002/ejoc.201201150

FULL PAPER
DOI: 10.1002/ejoc.201201150
Diversely Substituted Imidazo[1,2-a]pyrazine-8-oxo-3-carbaldehydes: An Iodine-
Mediated Cyclization/Oxidation Approach
Nigam M. Mishra,[a] Dipak D. Vachhani,[a] Sachin G. Modha,[a] and
Erik V. Van der Eycken*[a]
Keywords: Synthetic methods / Nitrogen heterocycles / Iodine / Oxidation / Cyclization / Cross-coupling / Alkynes
A mild and efficient iodine-mediated intramolecular het-
eroannulation approach for the construction of the imid-
substrates containing terminal alkynes by cyclization and
subsequent oxidation or amination. Further diversification
azo[1,2-a]pyrazinone core has been developed. Under ambi- may be introduced by using substrates containing an internal
ent conditions, this metal-free protocol allows easy access to
densely functionalized imidazo[1,2-a]pyrazinone-3-carbal-
dehydes or (aminomethyl)imidazo[1,2-a]pyrazinones from
alkyne and/or Suzuki coupling after cyclization to generate
polysubstituted (dihydro)imidazo[1,2-a]pyrazinones.
biologically interesting heterocycles,[3,11] we developed an
iodine-mediated intramolecular heteroannulation approach
for the synthesis of the imidazo[1,2-a]pyrazinone core.
Introduction
Imidazo[1,2-a]pyrazinones[1] are a very important class
of heterocyclic compounds, as many of them have been de-
veloped into, for example, GABAA agonists,[1a,1d] antiar-
rhythmic agents,[1e] and kinase modulators.[1c] As a result,
imidazo[1,2-a]pyrazinones have generated considerable
interest in the last two decades, and different synthetic ap-
proaches have been reported. However, most of these ap-
proaches rely on long synthetic sequences[1b,1e] and lack the
possibility to generate diversity.[1]
Results and Discussion
Following on from our recent report on the chemoselec-
tive AgI- and AuI-catalyzed synthesis of pyrazino[2,1-b]-
quinazolines and 3-indolylpyrazin-2(1H)-ones,[4b] we envi-
sioned that iodine may be used for this heteroannulation.
To investigate this idea, we synthesized starting compound
2a by treatment of readily available 3,5-dichloropyrazin-
2(1H)-one[12] 1a with propargylamine and diisopropylethyl-
amine (DIPEA) in acetonitrile at 70 °C for 6 h (Table 1).
Compound 2a was stirred with I2 (3 equiv.) in CH2Cl2 at
room temp. TLC and MS analysis indicated that 2a was
entirely consumed after 12 h. Surprisingly, MS and NMR
spectroscopic analysis of the purified product showed that
aldehyde[7a,7b,13] 3a had been formed (Table 1, entry 1),
whereas MS analysis during the reaction had shown the
presence of iodine-containing compound 3aЈ, as well as the
corresponding hydrolyzed compound (i.e., 3aЈЈ). We con-
cluded that oxidation of this primary alcohol (i.e., 3aЈЈ) to
aldehyde 3a due to the presence of air during the reaction
and column chromatography must have occured. Further
optimization of the conditions was required to exploit the
tendency of this alcohol to be oxidized. To our satisfaction,
the yield of 3a increased dramatically to 80%, when hydro-
gen peroxide (50% in water, 8.0 mmol) was added after
complete consumption of 2a (Table 1, entry 2). Importantly,
the amount of iodine could be decreased to 2 equiv. without
a significant drop in the yield. However a further decrease
seemed to be deleterious for the reaction (Table 1, entries 3
Metal-catalyzed[2] intra- or intermolecular carbocycliza-
tions[3] and heteroannulations[4] of alkynes have been exten-
sively used in recent years for the construction of diversely
substituted heterocycles.[5] Although selective and high-
yielding, such metal-catalyzed approaches have a drawback,
which is that traces of the metals must be removed after
the reaction. This has inspired organic chemists to develop
metal-free approaches for the synthesis of such biologically
important heterocycles.[6] Iodine activates alkynes very well,
and most often, an iodo group will remain in the molecule
after cyclization, allowing the introduction of additional
functionalities.[4a,7] Thus, iodine-mediated metal-free ap-
proaches are generating interest in organic chemistry.[8] As
part of our continuing research into transformations of the
3,5-dichloropyrazinone[9,10] skeleton and the development
of diversity-orientated concise routes for the synthesis of
[a] Laboratory for Organic & Microwave-Assisted Chemistry
(LOMAC), Department of Chemistry, KU Leuven,
Celestijnenlaan 200F, Heverlee 3001, Leuven, Belgium
Fax: +32-16-327-990
E-mail: erik.vandereycken@chem.kuleuven.be
Homepage: http://chem.kuleuven.be/organ/lomac/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201150.
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E. V. Van der Eycken et al.
FULL PAPER
and 4). To further enhance the reaction performance, dif- Table 2. One-pot sequential cyclization/oxidation approach
towards imidazo[1,2-a]pyrazinone-3-carbaldehyde.[a]
ferent solvents were evaluated, and THF was found to be
the best solvent (Table 1, entries 5–7). Using iodine mono-
chloride (ICl) or N-iodosuccinimide (NIS) as the iodine
source resulted in lower yields (Table 1, entries 8 and 9).
Finally, of the different oxidants examined, H2O2 was found
to be the best (Table 1, entries 10, 12, and 13). The amount
of oxidant could be decreased from 8.0 mmol to 5.0 mmol
Entry
Product
R1
R2
Yield[b] [%]
without compromising the yield (Table 1, entries 10 and
11).
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
PMP
Ph
Me
Me
Bn
PMB
PMP
Ph
H
Me
Me
Ph
H
H
PMP
2-MeOC6H4
PMP
99
72
72
72
80
72
88
99
74
Table 1. Optimization of the iodine-mediated intramolecular het-
eroannulation.[a]
PMB
[a] Conditions: 2 (0.3 mmol) and I2 (2 equiv.) in THF, room temp.,
12–14 h, then H2O2 (50% in water, 5.0 mmol), room temp., 2–4 h.
[b] Isolated yields.
To further evaluate the utility of the protocol on alkyne-
substituted propynylaminopyrazinones, substrates 5a–c
were synthesized by Sonogashira coupling of 2a,b with the
aryl iodides iodobenzene (4a) and 1-iodo-4-methoxyben-
zene (4b) by treatment with Pd(PPh3)2Cl2 (2 mol-%) and
CuI (3 mol-%) in a mixture of Et3N/DMSO (3:1) at 40 °C
for 1 h. When the resulting (arylpropynylamino)pyraz-
inones 5a–c were subjected to the reaction conditions, the
iodine-mediated heteroannulation proceeded very well, and
we were able to isolate the 3-iodomethylene 2,3-dihydro-
imidazo[1,2-a]pyrazin-8(7H)-ones 6a–c containing an (E)-
configured exocyclic double bond (Table 3).[14] However,
upon addition of an oxidant, these compounds decomposed
completely.
Entry Solvent
Iodine source Oxidant
(equiv.)
Yield[b] of
3a [%]
1
2
3
4
5
6
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
acetone
THF
I2 (3)
–
30
80
75
45
95
50
99
65
74
99
80
50
57
I2 (3)
I2 (2)
I2 (1.5)
I2 (2)
I2 (2)
H2O2 (8.0 mmol)
H2O2 (8.0 mmol)[c]
H2O2 (8.0 mmol)
H2O2 (8.0 mmol)
H2O2 (8.0 mmol)
H2O2 (8.0 mmol)
H2O2 (8.0 mmol)
H2O2 (8.0 mmol)
H2O2 (5.0 mmol)
H2O2 (3.0 mmol)
aq. K2Cr2O3 (2 equiv.)
aq. mCPBA (2 equiv.)
I2 (2)
8
THF
ICl (2)
NIS (2)[d]
I2 (2)
I2 (2)
I2 (2)
9
THF
Table 3. Iodine-mediated heteroannulation of (arylpropynylamino)-
pyrazinones 5a–c.[a]
10
11
12
13
THF
THF
THF
THF
I2 (2)
[a] All reactions were carried out with 2a (0.3 mmol) in the indi-
cated solvent (5 mL) at room temp. for 12 h. Then the oxidant was
added, and the mixture was stirred for 2–4 h. [b] Isolated yields.
[c] H2O2 (50% in water). [d] NIS = N-Iodosuccinimide.
Entry
Product R1
R2
R
Yield[b] [%]
1
2
3
6a
6b
6c
PMP
Ph
PMP
H
CH3
H
H
H
OCH3
68
48
91
With the optimum conditions established (Table 1, en-
try 10), the scope of this newly developed process was
evaluated. A set of diversely substituted propynylaminopyr-
azinones 2b–i was synthesized from the corresponding 3,5-
dichloropyrazin-2(1H)-ones (i.e., 1b–i), and was subjected
to the reaction conditions. In most cases, complete conver-
sion was obtained in 12–14 h at room temp., yielding imid-
[a] Conditions: 5 (0.3 mmol) and I2 (2 equiv.) in THF, room temp.,
12–15 h. [b] Isolated yields.
On the basis of literature reports[7] and our experimental
azo[1,2-a]pyrazinone-3-carbaldehydes 3b–i in good to excel- observations, a plausible mechanism for the iodine-medi-
lent yields, regardless of the substitution pattern of the pyr- ated heteroannulation is shown in Scheme 1. Nucleophilic
azinone (Table 2).
attack of nitrogen on the activated alkyne generates inter-
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Iodine-Mediated Cyclization/Oxidation
mediate A, which, after deprotonation and subsequent Table 4. One-pot sequential cyclization/amination approach
towards aminomethyl-imidazo[1,2-a]pyrazinone.[a]
isomerization of the double bond, produces B. This inter-
mediate produces the final carbaldehydes (i.e., 3) by hydrol-
ysis and subsequent oxidation. However, in case of an in-
ternal alkyne 5, deprotonation of intermediate A results in
6, without further hydrolysis.
Scheme 1. Plausible mechanism for the iodine-mediated regioselec-
tive 5-exo-dig heteroannulation of propynylaminopyrazinones.
Next, we became interested in using highly reactive inter-
mediate B to generate amino-substituted imidazo[1,2-a]pyr-
azinones. To our delight, when the reaction mixture was
treated with an excess (3 equiv.) of cyclic secondary amines
after the cyclization step was complete, the reaction worked
well and amino-substituted products 8a–c were formed
(Table 4). However, only traces of product or even no reac-
tion was observed when the reaction was attempted with an
[a] Conditions: 2a (0.3 mmol) and I2 (3 equiv.) in CH2Cl2, room
temp., 12–15 h, then amine 7 (3 equiv.), room temp., 3–5 h. Isolated
yields.
acyclic secondary amine (i.e, diisobutylamine) or a primary
amine (i.e., benzylamine).
Table 5. Synthesis of polysubstituted imidazo[1,2-a]pyrazin-3-
carbaldehydes.[a]
Finally, to further decorate the synthesized imidazo[1,2-
a]pyrazin-3-carbaldehydes 3a,b,e, the 5-Cl group was used
as a convenient synthetic handle. It is worth mentioning
that such a Suzuki coupling could not be performed before
the heteroannulation had been done.[15] Using imidazopyr-
azinone 3 (1 equiv.), boronic acid 9 (1.5 equiv.), Pd(OAc)2
(5 mol-%), S-Phos (10 mol-%), and K2CO3 (2 equiv.) in
THF/water (7:3) at 110 °C for 30 min under microwave irra-
diation, we could generate further diversity at the 5-position
(Table 5). This newly developed protocol allowed the instal-
lation of diverse substituents on both the 5- and 6-positions
of the imidazo-pyrazinone, which is rather difficult to
achieve otherwise.[1] However, when compound 6c was sub-
jected to Suzuki coupling, diarylated product 11 was iso-
lated in 65% yield as the sole product (Scheme 2).
Entry
Product
R1
R2
R3
Yield[b] [%]
1
2
3
4
10a
10b
10c
10d
PMP
Bn
Ph
H
H
CH3
H
OC2H5
H
H
53
85
32
63
PMP
CH3
[a] Isolated yield. [b] 3 (0.3 mmol), boronic acid 9 (1.5 equiv.),
Pd(OAc)2 (5 mol-%), S-Phos (10 mmol-%) and K2CO3 (2 equiv.) in
THF/water (7:3; 2 mL), 110 °C, 30 min.
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E. V. Van der Eycken et al.
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1 equiv.) in THF (25 mL). The reaction mixture was stirred at 60 °C
for 6–10 h. After the reaction was complete, THF was removed
under reduced pressure, and the mixture was partitioned between
ethyl acetate (2ϫ 50 mL) and water (50 mL). The organic phase
was separated, washed with brine, and dried with Na2SO4. The
solvent was distilled off, and the residue was subjected to silica gel
chromatography (30–60% ethyl acetate in heptane) to give com-
pounds 2a–i.
5-Chloro-1-(4-methoxyphenyl)-3-(prop-2-ynylamino)pyrazin-2(1H)-
1
one (2a): Pale yellow solid, 84% yield, m.p. 170–172 °C. H NMR
(300 MHz, CDCl3): δ = 7.30 (d, J = 8.8 Hz, 2 H), 6.99 (d, J =
8.8 Hz, 2 H), 6.68 (s, 1 H), 6.52 (s, 1 H, NH), 4.26 (dd, J = 2.4,
5.5 Hz, 2 H, CH2), 3.85 (s, 3 H), 2.28 (s, 1 H, alkyne-CH) ppm.
13C NMR (75 MHz, CDCl3): δ = 154.4, 144.8, 144.5, 126.4, 121.5,
121.3, 109.4, 109.1, 73.7, 66.7, 50.3, 25.6 ppm. HRMS (EI): calcd.
for C14H12ClN3O2 289.0618; found 289.0591.
Scheme 2. Synthesis of polysubstituted dihydroimidazo[1,2-a]-
pyrazinone 11.
Conclusions
5-Chloro-6-methyl-1-phenyl-3-(prop-2-ynylamino)pyrazin-2(1H)-
one (2b): Pale yellow solid, 66% yield, m.p. 165–167 °C. H NMR
In summary, we have developed an efficient and mild iod-
ine-mediated approach for the synthesis of (dihydro)imid-
azo[1,2-a]pyrazinones using a 5-exo-dig intramolecular het-
eroannulation strategy. For terminal alkynes, a hydrolysis
and oxidation sequence or an amination gives direct access
to imidazo[1,2-a]pyrazinone-3-carbaldehydes or amino-
methylimidazo[1,2-a]pyrazinones in a one-pot process. Mild
reaction conditions, good to excellent yields, and tolerance
of a range of substituents are merits of this protocol. More-
over, the above approach also allowed convenient access to
polysubstituted (dihydro)imidazo[1,2-a]pyrazinones by Su-
zuki coupling.
1
(300 MHz, CDCl3): δ = 7.56–7.48 (m, 3 H), 7.17 (d, J = 6.5 Hz, 2
H), 6.29 (s, 1 H, NH), 4.23 (dd, J = 2.4, 5.3 Hz, 2 H, CH2), 2.25
(t, J = 2.49 Hz, 1 H, alkyne-CH), 1.93 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 151.4, 147.8, 137.3, 129.9, 129.4, 127.4,
125.0, 120.5, 79.3, 71.6, 30.6, 16.9 ppm. HRMS (EI): calcd. for
C14H12ClN3O 273.0668; found 273.0662.
5-Chloro-1,6-dimethyl-3-(prop-2-ynylamino)pyrazin-2(1H)-one (2c):
White solid, 30 % yield, m.p. 151–153 °C. 1H NMR (300 MHz,
CDCl3): δ = 6.25 (s, 1 H, NH), 4.19 (dd, J = 2.4, 5.5 Hz, 2 H,
CH2), 3.53 (s, 3 H), 2.35 (s, 3 H), 2.25 (t, J = 2.4 Hz, 1 H, alkyne-
CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 151.3, 147.1, 125.0,
120.5, 79.4, 71.6, 32.0, 30.6, 15.9 ppm. HRMS (EI): calcd. for
C9H10ClN3O 211.0512; found 211.0514.
Experimental Section
5-Chloro-1-methyl-6-phenyl-3-(prop-2-ynylamino)pyrazin-2(1H)-
one (2d): Yellow solid, 90 % yield, m.p. 119–121 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.60–7.45 (m, 3 H), 7.33–7.28 (m, 2 H),
6.41 (br. s, 1 H, NH), 4.27 (dd, J = 2.5, 5.5 Hz, 2 H, CH2), 3.22 (s, 3
H), 2.28 (t, J = 2.3 Hz, 1 H, alkyne-CH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 151.0, 148.2, 132.2, 130.2, 129.4, 129.0, 125.7, 124.8,
79.2, 71.8, 34.2, 30.7 ppm. HRMS (EI): calcd. for C14H12ClN3O
273.0669; found 273.0680.
1
General Remarks: H and 13C NMR spectra were recorded with a
Bruker Avance 300 MHz instrument using CDCl3 or [D6]DMSO
as solvent unless otherwise stated. The 1H and 13C NMR chemical
shifts are reported in parts per million (ppm) relative to tetrameth-
ylsilane using the residual solvent signal as an internal reference.
Mass spectra were recorded using a Kratos MS50TC and a Kratos
Mach III system. The ion source temperature was 150–250 °C, as
required. High-resolution electron impact (EI) mass spectra were
performed with a resolution of 10000. The low-resolution spectra
were obtained with a HP5989A MS instrument. For TLC, analyti-
cal TLC plates (Alu-gram SIL G/UV254) and 70–230 mesh silica
gel (E. M. Merck) were used.
1-Benzyl-5-chloro-3-(prop-2-ynylamino)pyrazin-2(1H)-one (2e): Off-
white solid, 80 % yield, m.p. 170–172 °C. 1H NMR (300 MHz,
CDCl3): δ = 7.37–7.32 (m, 3 H), 7.31–7.27 (m, 2 H), 6.53–6.50 (m,
2 H, NH, Ar), 5.01 (s, 2 H, CH2Ar), 4.21 (dd, J = 2.4, 5.4 Hz, 2
H, CH2NH), 2.26 (t, J = 2.4 Hz, 1 H, alkyne-CH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 150.1, 149.5, 134.7, 129.0, 128.6, 128.3,
126.7, 112.9, 78.9, 72.0, 51.8, 30.8 ppm. HRMS (EI): calcd. for
C14H12ClN3O 273.0668; found 273.0668.
Microwave Irradiation Experiments: All microwave irradiation ex-
periments were carried out in a dedicated CEM-Discover monom-
ode microwave apparatus, operating at a frequency of 2.45 GHz
with continuous irradiation with a maximum power of 300 W. The
reactions were carried out in 10 mL glass vials sealed with a Tef-
lon® septum and placed in the microwave cavity. Initially, the tem-
perature was raised to the desired reaction temperature. Once this
temperature was reached, the reaction mixture was held at the same
temperature for the required time. The reaction mixture was mag-
netically stirred continuously during the reaction. The temperature
was measured with an IR sensor on the outer surface of the vial.
After the irradiation was complete, the reaction vessel was cooled
rapidly to ambient temperature by an air jet.
5-Chloro-1-(4-methoxybenzyl)-3-(prop-2-ynylamino)pyrazin-2(1H)-
1
one (2f): Pale yellow solid, 85% yield, m.p. 197–199 °C. H NMR
(300 MHz, CDCl3): δ = 7.24 (d, J = 8.4 Hz, 2 H), 6.88 (d, J =
8.4 Hz, 2 H), 6.52 (s, 1 H), 6.44 (br. s, 1 H, NH), 4.94 (s, 2 H,
CH2Ar), 4.21 (dd, J = 2.4, 5.4 Hz, 2 H, CH2NH), 3.80 (s, 3 H),
2.26 (s, 1 H, alkyne-CH) ppm. . 13C NMR (100 MHz, [D6]DMSO):
δ = 159.7, 150.2, 150.1, 130.1, 128.5, 125.3, 114.7, 113.9, 81.1, 72.9,
55.7, 51.0, 30.3 ppm. HRMS (EI): calcd. for C15H14ClN3O2
303.0774; found 303.0771.
5-Chloro-1,6-bis(4-methoxyphenyl)-3-(prop-2-ynylamino)pyrazin-
2(1H)-one (2g): Yellow solid, 88% yield, m.p. 137–139 °C. 1H NMR
(300 MHz, CDCl3): δ = 6.98 (d, J = 8.6 Hz, 2 H), 6.87 (d, J =
8.7 Hz, 2 H), 6.75–6.67 (m, 4 H), 6.50 (t, J = 5.4 Hz, 1 H, NH),
4.29 (dd, J = 2.4, 5.6 Hz, 2 H, CH2), 3.72 (s, 6 H), 2.28 (t, J =
General Procedure for the Synthesis of 3-(Prop-2-ynylamino)pyrazin-
2(1H)-ones 2a–i: Propargylamine (3 mmol, 1.5 equiv.) and diisopro-
pylethylamine (DIPEA; 6 mmol, 3 equiv.) were added to a solution
of substituted 3,5-dichloropyrazine-2(1H)-one (1) (2 mmol,
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Iodine-Mediated Cyclization/Oxidation
1
2.4 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 159.2, 159.0,
151.3, 148.6, 132.2, 130.0, 129.1, 126.0, 125.1, 124.5, 114.2, 113.4,
79.3, 71.7, 55.3, 55.1, 30.71 ppm. HRMS (EI): calcd. for
C21H18ClN3O3 395.1036; found 395.1030.
313 °C. H NMR (300 MHz, CDCl3): δ = 10.63 (s, 1 H), 8.28 (s, 1
H), 7.65–7.55 (m, 3 H), 7.40 (t, J = 7.31 Hz, 2 H), 3.29 (s, 3 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 179.6, 152.8, 140.3, 139.8,
132.0, 131.8, 130.8, 130.6, 129.6, 129.4, 108.7, 34.2 ppm. HRMS
(EI): calcd. for C14H10ClN3O2 287.0461; found 287.0460.
5-Chloro-6-(2-methoxyphenyl)-1-phenyl-3-(prop-2-ynylamino)-
pyrazin-2(1H)-one (2h): Yellow solid, 78% yield, m.p. 223–225 °C.
1H NMR (300 MHz, CDCl3): δ = 7.28–7.11 (m, 5 H), 7.09 (d, J =
1.8 Hz, 1 H), 7.07 (d, J = 1.7 Hz, 1 H), 6.90 (d, J = 4.7 Hz, 1 H),
6.61 (d, J = 8.2 Hz, 1 H), 6.49 (br. s, 1 H, NH), 4.31 (dd, J = 2.4,
5.6 Hz, 2 H, CH2), 3.64 (s, 3 H), 2.29 (t, J = 2.4 Hz, 1 H, alkyne-
CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 156.7, 151.0, 148.8,
137.2, 132.5, 130.8, 128.5, 128.3, 128.2, 127.9, 127.5, 126.2, 122.1,
121.1, 120.1, 110.5, 79.3, 71.8, 55.0, 30.7 ppm. HRMS (EI): calcd.
for C21H18ClN3O2 365.0931; found 365.0875.
7-Benzyl-5-chloro-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazine-3-carb-
aldehyde (3e): Yellow solid, 80% yield, m.p. 181–183 °C. H NMR
1
(300 MHz, CDCl3): δ = 10.60 (s, 1 H), 8.24 (s, 1 H), 7.45–7.32 (s,
5 H), 6.92 (s, 1 H), 5.19 (s, 2 H, CH2Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 179.0, 152.0, 140.4, 140.2, 134.6, 131.8, 129.2, 128.9,
128.5, 119.6, 109.2, 51.0 ppm. HRMS (EI): calcd. for
C14H10ClN3O2 287.0461; found 287.0460.
5-Chloro-7-(4-methoxybenzyl)-8-oxo-7,8-dihydroimidazo[1,2-a]-
pyrazine-3-carbaldehyde (3f): Yellow solid, 72% yield, m.p. 188–
1
190 °C. H NMR (300 MHz, CDCl3): δ = 10.60 (s, 1 H), 8.26 (s, 1
5-Chloro-1-(4-methoxybenzyl)-6-(4-methoxyphenyl)-3-(prop-2-ynyl-
amino)pyrazin-2(1H)-one (2i): Yellow solid, 35% yield, m.p. 113–
115 °C. 1H NMR (300 MHz, CDCl3): δ = 7.01 (d, J = 8.6 Hz, 2
H), 6.89 (d, J = 8.6 Hz, 2 H), 6.74 (m, 4 H), 6.50 (t, J = 5.5 Hz, 1
H, NH), 4.94 (s, 2 H, CH2Ar), 4.26 (dd, J = 2.4, 5.4 Hz, 2 H,
CH2NH), 3.84 (s, 3 H), 3.75 (s, 3 H), 2.28 (t, J = 2.3 Hz, 1 H,
alkyne-CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 160.1, 159.0,
151.1, 148.6, 132.1, 128.8, 127.8, 126.6, 124.4, 124.0, 113.9, 113.7,
79.2, 71.9, 55.3, 55.2, 48.8 ppm. HRMS (EI): calcd. for
C22H20ClN3O3 409.1193; found 409.1200.
H), 7.31 (d, J = 8.6 Hz, 2 H), 6.91 (d, J = 8.6 Hz, 2 H), 6.85 (s, 1
H), 5.12 (s, 2 H, CH2Ar), 3.81 (s, 3 H) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 180.4, 158.9, 151.5, 138.6, 129.5, 128.1, 120.9,
113.9, 108.3, 55.0, 49.8 ppm. HRMS (EI): calcd. for C15H11ClN2O3
317.0567; found 317.0607.
5-Chloro-6,7-bis(4-methoxyphenyl)-8-oxo-7,8-dihydroimidazo[1,2-a]-
pyrazine-3-carbaldehyde (3g): Yellow solid, 94% yield, m.p. 228–
1
230 °C. H NMR (300 MHz, CDCl3): δ = 10.68 (s, 1 H), 8.30 (s, 1
H), 7.08 (d, J = 8.6 Hz, 2 H), 6.96 (d, J = 8.8 Hz, 2 H), 6.76 (t, J
= 8.8 Hz, 4 H), 3.77 (s, 3 H), 3.73 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 179.8, 160.1, 159.2 152.9, 140.3, 140.2,
132.3, 132.2, 131.7, 129.8, 129.3, 122.9, 114.3, 113.9, 108.9, 55.3,
55.2 ppm. HRMS (EI): calcd. for C22H17ClN3O4 409.0825; found
409.0829.
General Procedure for the Synthesis of Imidazo[1,2-a]pyrazinone-3-
carbaldehydes 3a–i: Compound 2 (0.3 mmol, 1 equiv.) was dis-
solved in THF (5 mL) in a 25 mL round-bottomed flask fitted with
a condenser, and iodine (0.6 mmol, 2 equiv.) was added. The mix-
ture was stirred at room temp. for 12–14 h. After complete con-
sumption of 2, H2O2 (50% in H2O, 5.0 mmol) was added, and stir-
ring was continued for 2–4 h at room temp. After completion of
the reaction, the reaction mixture was concentrated under reduced
pressure. Na2S2O3 (satd. aq., 25 mL) was added to the resulting
crude material, and the mixture was extracted with ethyl acetate
(2ϫ 25 mL). The organic extracts were washed with water (25 mL)
and brine (25 mL), and dried with Na2SO4. The solvent was dis-
tilled off, and the residue was subjected to silica gel chromatog-
raphy (50–70% ethyl acetate in heptane) to give compounds 3a–i.
5-Chloro-6-(2-methoxyphenyl)-8-oxo-7-phenyl-7,8-dihydroimidazo-
[1,2-a]pyrazine-3-carbaldehyde (3h): Yellow solid, 99% yield, m.p.
Ͼ 320 °C. 1H NMR (300 MHz, CDCl3): δ = 10.71 (s, 1 H), 8.33
(s, 1 H), 7.30–7.15 (m, 5 H), 7.13–7.09 (m, 2 H), 6.87 (t, J = 7.5 Hz,
1 H), 6.71 (d, J = 8.2 Hz, 1 H), 3.73 (s, 3 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 183.1, 159.0, 154.9, 142.8, 141.9,
139.7, 134.7, 134.5, 134.3, 131.6, 131.2, 131.1, 130.8, 122.9, 122.6,
114.0, 111.2, 58.1 ppm. HRMS (EI): calcd. for C21H15ClN3O3
379.0723; found 379.0717.
5-Chloro-7-(4-methoxybenzyl)-6-(4-methoxyphenyl)-8-oxo-7,8-di-
hydroimidazo[1,2-a]pyrazine-3-carbaldehyde (3i): Yellow solid, 74%
yield, m.p. 185–187 °C. 1H NMR (300 MHz, CDCl3): δ = 10.61 (s,
1 H), 8.29 (s, 1 H), 7.06 (d, J = 8.6 Hz, 2 H), 6.97 (d, J = 8.6 Hz,
2 H), 6.78 (d, J = 8.6 Hz, 2 H), 6.69 (d, J = 8.6 Hz, 2 H), 5.06 (s,
2 H, CH2Ar), 3.89 (s, 3 H), 3.74 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 179.7, 160.9, 159.2, 153.1, 140.3, 140.1, 132.1, 131.6,
131.5, 129.1, 127.9, 122.4, 114.4, 113.7, 109.4, 55.4, 55.2, 48.4 ppm.
HRMS (EI): calcd. for C22H18ClN3O4 423.0985; found 423.0972.
5-Chloro-7-(4-methoxyphenyl)-8-oxo-7,8-dihydroimidazo[1,2-a]-
pyrazine-3-carbaldehyde (3a): Yellow solid, 99% yield, m.p. 263–
265 °C. H NMR (300 MHz, [D6]DMSO): δ = 10.63 (s, 1 H), 8.28
(s, 1 H), 7.83 (s, 1 H), 7.48 (d, J = 8.1 Hz, 2 H), 7.14 (d, J = 8.1 Hz,
2 H), 3.88 (s, 3 H) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
180.4, 159.0, 151.6, 140.4, 138.8, 131.4, 131.2, 127.9, 121.9, 114.2,
108.2, 55.4 ppm. HRMS (EI): calcd. for C14H10ClN3O3 303.0410;
found 303.0409.
1
5-Chloro-6-methyl-8-oxo-7-phenyl-7,8-dihydroimidazo[1,2-a]-
pyrazine-3-carbaldehyde (3b): Yellow solid, 86% yield, m.p. 211–
General Procedure for the Synthesis of Compounds 5a–c: Com-
pound 2 (0.7 mmol, 1 equiv.), aryl iodide 4 (0.77 mmol, 1.1 equiv.),
Pd(PPh3)2Cl2 (2 mol-%), and CuI (3 mol-%) were added to an
oven-dried 25 mL two-necked flask equipped with a stirrer-bar un-
der argon. The flask was evacuated and refilled with argon (3ϫ).
Dry Et3N/DMSO (4:1; 10 mL) were added by syringe, and the re-
sulting suspension was allowed to stir at 45 °C for 1 h. After com-
pletion of reaction, as indicated by TLC and MS analysis, the mix-
ture was cooled to room temperature. The crude mixture was di-
luted with ethyl acetate (50 mL), and washed with H2O (50 mL).
The organic phase was washed with brine (50 mL), and dried with
anhydrous Na2SO4. The solvent was removed under reduced pres-
sure, and the crude sample was purified by silica gel column
1
213 °C. H NMR (300 MHz, CDCl3): δ = 10.69 (s, 1 H), 8.26 (s, 1
H), 7.60–7.52 (m, 3 H), 7.27–7.23 (m, 2 H), 2.13 (s, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 179.8, 152.7, 140.2, 139.8, 136.7,
132.0, 130.1, 129.8, 128.1, 127.8, 107.6, 17.9 ppm. HRMS (EI):
calcd. for C14H10ClN3O2 287.0461; found 287.0481.
5-Chloro-6,7-dimethyl-8-oxo-7,8-dihydroimidazo[1,2-a]pyrazine-3-
carbaldehyde (3c): Yellow solid, 72% yield, m.p. 241–243 °C. 1H
NMR (300 MHz, CDCl3): δ = 10.64 (s, 1 H), 8.23 (s, 1 H), 3.66 (s,
3 H), 2.56 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 179.7,
152.9, 140.2, 139.4, 131.8, 127.7, 107.4, 31.9, 16.7 ppm. HRMS
(EI): calcd. for C9H8ClN3O2 225.0305; found 225.0306.
5-Chloro-7-methyl-8-oxo-6-phenyl-7,8-dihydroimidazo[1,2-a]- chromatography (35–40% ethyl acetate in heptane) to give com-
pyrazine-3-carbaldehyde (3d): Yellow solid, 82% yield, m.p. 311– pounds 5a–c.
Eur. J. Org. Chem. 2013, 693–700
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
697

E. V. Van der Eycken et al.
FULL PAPER
5-Chloro-1-(4-methoxyphenyl)-3-(3-phenylprop-2-ynylamino)-
pyrazin-2(1H)-one (5a): Yellow solid, 72 % yield, m.p. 95 °C. H
NMR (300 MHz, CDCl3): δ = 7.45–7.39 (m, 2 H), 7.35–7.27 (m, 5
General Procedure for the Synthesis of 3-Aminomethylimidazo[1,2-
a]pyrazinones 8a–c: Compound 2 (0.3 mmol, 1 equiv.) was dis-
solved in CH2Cl2 (5 mL) in a 25 mL round-bottomed flask fitted
1
H), 6.98 (d, J = 8.5 Hz, 2 H), 6.66–6.63 (m, 2 H, Ar, NH), 4.27 (d, with a condenser, and iodine (0.9 mmol, 3 equiv.) was added. The
J = 5.5 Hz, 2 H, CH2), 3.83 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 159.7, 150.2, 149.7, 131.7, 128.4, 128.3, 126.8, 126.7,
mixture was stirred at room temp. for 12–15 h. After complete con-
sumption of 2, amine (0.9 mmol, 3 equiv.) was added, and the mix-
122.5, 114.66, 114.1, 84.2, 83.7, 55.6, 31.7 ppm. HRMS (EI): calcd. ture was stirred for 3–5 h at room temp. After completion of the
for C20H16N3O2 365.0931; found 365.0930.
reaction, the mixture was diluted with CH2Cl2 (25 mL) and washed
with Na2S2O3 (satd. aq., 25 mL). The organic phase was washed
with brine and dried with Na2SO4. The solvent was distilled off,
and the residue was purified by silica gel chromatography (2–4%
methanol in CH2Cl2) to give pure product 8a–c.
5-Chloro-6-methyl-1-phenyl-3-(3-phenylprop-2-ynylamino)pyrazin-
2(1H)-one (5b): Yellow solid, 80 % yield, m.p. 128–130 °C. 1H
NMR (300 MHz, CDCl3): δ = 7.56–7.48 (m, 3 H), 7.47–7.41 (m, 2
H), 7.31–7.28 (m, 3 H), 7.17 (d, J = 6.7 Hz, 2 H), 6.35 (br. s, 1 H,
NH), 4.46 (d, J = 5.2 Hz, 2 H, CH2), 1.93 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 151.5, 147.8, 137.4, 131.7, 129.9, 129.3,
128.3, 128.2, 127.4, 125.1, 122.6, 120.3, 84.6, 83.5, 31.5, 16.9 ppm.
HRMS (EI): calcd. for C20H16ClN3O 349.0982; found 349.0961.
5-Chloro-7-(4-methoxyphenyl)-3-(morpholinomethyl)imidazo-
[1,2-a]pyrazin-8(7H)-one (8a): Yellow solid, 78% yield, m.p. 200–
1
202 °C. H NMR (300 MHz, CDCl3): δ = 7.45 (s, 1 H), 7.33 (d, J
= 8.8 Hz, 2 H), 6.98 (d, J = 8.8 Hz, 2 H), 6.83 (s, 1 H), 3.88 (s, 2
H, CH2Ar), 3.84 (s, 3 H), 3.69 (t, J = 4.3 Hz, 4 H), 2.51 (t, J =
4.3 Hz, 4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 159.5, 152.1,
139.3, 135.2, 131.4, 128.1, 127.4, 119.3, 114.7, 109.7, 66.9, 55.6,
53.2, 52.8 ppm. HRMS (EI): calcd. for C18H19ClN4O3 374.1145;
found 374.1146.
5-Chloro-1-(4-methoxyphenyl)-3-[3-(4-methoxyphenyl)prop-2-ynyl-
amino]pyrazin-2(1H)-one (5c): Yellow solid, 84% yield, m.p. 130–
132 °C. 1H NMR (300 MHz, CDCl3): δ = 7.37 (d, J = 8.8 Hz, 2
H), 7.30 (d, J = 9.0 Hz, 2 H), 6.98 (d, J = 9 Hz, 2 H), 6.82 (d, J =
8.6 Hz, 2 H), 6.66–6.61 (m, 2 H, NH, Ar), 4.45 (d, J = 5.4 Hz, 2
H, CH2), 3.83 (s, 3 H), 3.79 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 159.7, 159.6, 150.1, 149.7, 133.2, 131.7, 126.8, 126.6,
114.6, 114.5, 114.0, 113.9, 83.7, 82.8, 55.5, 55.2, 31.8 ppm. HRMS
(EI): calcd. for C21H18ClN3O3 395.1036; found 395.1023.
5-Chloro-7-(4-methoxyphenyl)-3-(piperidin-1-ylmethyl)imidazo-
[1,2-a]pyrazin-8(7H)-one (8b): Yellow solid, 72 % yield, m.p. 96–
98 °C. 1H NMR (300 MHz, CDCl3): δ = 7.44 (s, 1 H), 7.33 (d, J =
8.8 Hz, 2 H), 6.99 (d, J = 8.8 Hz, 2 H), 6.79 (s, 1 H), 3.84 (s, 3 H),
3.83 (s, 2 H, CH2Ar), 2.49–2.40 (m, 4 H), 1.62–1.44 (m, 6 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 159.5, 152.2, 139.0, 135.0, 131.5,
129.3, 127.5, 119.1, 114.7, 109.6, 55.6, 54.3, 53.3, 25.9, 24.2 ppm.
HRMS (EI): calcd. for C19H21ClN4O2 372.1353; found 372.1360.
General Procedure for the Synthesis of Dihydroimidazo[1,2-a]-
pyrazinones 6a–c: Compound 5 (0.3 mmol, 1 equiv.) was dissolved
in THF (5 mL) in a 25 mL round-bottomed flask fitted with a con-
denser, and iodine (0.6 mmol, 2 equiv.) was added. The mixture was
stirred at room temp. for 12–15 h. After complete consumption of
5, the reaction mixture was concentrated under reduced pressure.
Na2S2O3 (satd. aq., 25 mL) was added to the resulting crude mate-
rial, and the mixture was extracted with ethyl acetate (2ϫ 25 mL).
The organic phase was washed with water (25 mL) and brine
(25 mL), and dried with Na2SO4. The solvent was distilled off, and
the residue was subjected to silica gel chromatography (60–70%
ethyl acetate in heptane) to give compounds 6a–c.
5-Chloro-7-(4-methoxyphenyl)-3-(pyrrolidin-1-ylmethyl)imidazo-
[1,2-a]pyrazin-8(7H)-one (8c): Yellow solid, 50% yield, m.p. 142–
1
144 °C. H NMR (300 MHz, CDCl3): δ = 7.47 (s, 1 H), 7.32 (d, J
= 8.8 Hz, 2 H), 6.98 (d, J = 8.8 Hz, 2 H), 6.80 (s, 1 H), 4.07 (s, 2
H, CH2Ar), 3.83 (s, 3 H), 2.66–2.53 (m, 4 H), 1.84–1.77 (m, 4 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 159.5, 152.2, 138.8, 134.4,
131.5, 130.0, 127.5, 119.2, 114.7, 109.6, 55.6, 54.0, 50.4, 23.5 ppm.
HRMS (EI): calcd. for C18H19ClN4O2 358.1196; found 358.1222.
(E)-5-Chloro-3-[iodo(phenyl)methylene]-7-(4-methoxyphenyl)-2,3-di-
hydroimidazo[1,2-a]pyrazin-8(7H)-one (6a): Yellow solid, 68% yield,
m.p. 122–124 °C. H NMR (300 MHz, CDCl3): δ = 7.44–7.42 (m,
3 H), 7.34–7.31 (m, 4 H), 6.98 (d, J = 9 Hz, 2 H), 6.09 (s, 1 H),
4.75 (s, 2 H, CH2), 3.84 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 159.3, 155.2, 146.0, 138.3, 134.8, 131.5, 129.6, 129.3, 128.5,
126.9, 114.7, 113.8, 112.8, 73.6, 59.8, 55.5 ppm. HRMS (EI): calcd.
for C20H15ClIN3O2 490.9897; found 490.9879.
General Procedure for the Synthesis of Polysubstituted Imidazo[1,2-
a]pyrazine-8(7H)-ones by Suzuki Coupling 10a–d: Boronic acid 9
(0.45 mmol, 1.5 equiv.), Pd(OAc)2 (0.015 mmol, 5 mol-%), S-Phos
(0.03 mmol, 10 mol-%), and K2CO3 (0.6 mmol, 2 equiv.) were
added to a 10 mL reaction vial containing compound 3 (0.3 mmol,
1 equiv.). Then a THF/water mixture (7:3; 2 mL) was added, and
the vial was sealed tightly with a Teflon® cap. The mixture was
irradiated for 30 min at a pre-selected temperature of 110 °C, with
a maximum irradiation power of 300 W. After the reaction was
complete, as monitored by TLC and MS analysis, water (25 mL)
was added, and the crude mixture was extracted with ethyl acetate
(2 ϫ 30 mL). The combined organic extracts were washed with
brine (25 mL), and dried with Na2SO4. After filtration, the solvent
was evaporated under reduced pressure, and the crude product was
subjected to silica gel column chromatography (70–80% ethyl acet-
ate in heptane) to give compounds 10a–d.
1
(E)-5-Chloro-3-[iodo(phenyl)methylene]-6-methyl-7-phenyl-2,3-di-
hydroimidazo[1,2-a]pyrazin-8(7H)-one (6b): Yellow solid, 48% yield,
1
m.p. 175–177 °C. H NMR (300 MHz, CDCl3): δ = 7.53–7.42 (m,
7 H), 7.33–7.31 (m, 2 H), 7.24 (s, 1 H), 4.72 (s, 2 H, CH2), 1.68 (s,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 156.5, 146.0, 138.8,
136.9, 134.9, 130.0, 129.6, 129.2, 129.0, 128.4, 128.1, 118.6, 112.2,
72.7, 59.9, 16.5 ppm. HRMS (EI): calcd. for C20H15ClIN3O
474.9948; found 474.9966.
(E)-5-Chloro-3-[iodo(4-methoxyphenyl)methylene]-7-(4-methoxy- 5-(4-Ethoxyphenyl)-7-(4-methoxyphenyl)-8-oxo-7,8-dihydroimid-
phenyl)-2,3-dihydroimidazo[1,2-a]pyrazin-8(7H)-one (6c): Yellow so-
azo[1,2-a]pyrazine-3-carbaldehyde (10a): Light yellow solid, 53%
yield, m.p. 66–68 °C. H NMR (300 MHz, CDCl3): δ = 8.87 (s, 1
1
lid, 91% yield, m.p. 188–190 °C. 1H NMR (300 MHz, CDCl3): δ =
7.32 (d, J = 9 Hz, 2 H), 7.24 (d, J = 8.6 Hz, 2 H), 6.96 (t, J = H), 8.19 (s, 1 H), 7.45 (d, J = 8.6 Hz, 2 H), 7.39 (d, J = 8.8 Hz, 2
8.4 Hz, 4 H), 6.09 (s, 1 H), 4.72 (s, 2 H, CH2), 3.85 (s, 3 H), 3.83 H), 7.07–6.97 (m, 4 H), 6.81 (s, 1 H), 4.09 (q, J = 6.9 Hz, 2 H),
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 160.2, 159.3, 155.3,
3.84 (s, 3 H), 1.46 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR (75 MHz,
145.9, 138.1, 131.6, 130.9, 126.99, 126.90, 114.7, 113.9, 113.8, CDCl3): δ = 179.2, 160.8, 159.7, 152.4, 140.6, 140.0, 131.5, 130.9,
112.7, 72.4, 59.8, 55.5, 55.3 ppm. HRMS (EI): calcd. for
C21H17ClIN3O3 521.0003; found 521.0021.
130.8, 127.4, 122.8, 121.9, 119.6, 115.8, 114.8, 63.8, 55.6, 14.6 ppm.
HRMS (EI): calcd. for C22H19N3O4 389.1375; found 389.1375.
698
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 693–700

Iodine-Mediated Cyclization/Oxidation
7-Benzyl-8-oxo-5-phenyl-7,8-dihydroimidazo[1,2-a]pyrazine-3-carb-
1
aldehyde (10b): Yellow solid, 85% yield, m.p. 98–100 °C. H NMR
[1]
a) S. G. Goodacre, D. J. Hallett, R. W. Carling, J. L. Castro,
D. S. Reynolds, A. Pike, K. A. Wafford, R. Newman, J. R. At-
ack, L. J. Street, Bioorg. Med. Chem. Lett. 2006, 16, 1582–1385;
b) D. D. Davey, J. Org. Chem. 1987, 52, 4379–4381; c) Q. Liu,
D. G. Batt, G. V. Delucca, Q. Shi, A. J. Tebben, U. S. Patent
US 2010/0160303 A1, 2010; d) W. R. Carling, J. L. Castro-Pi-
neiro, S. C. Goodacre, D. J. Hallett, L. J. Street, PCT Int. Appl.
WO 2004/041826 A1, 2004; e) B. Plouvier, D. Fedida, G. N.
Beatch, D. Chou, A. Yifru, G. Jung, PCT Int. Appl. WO 2005/
034837 A2, 2005; f) D. D. Vachhani, S. G. Modha, A. Sharma,
E. V. Van der Eycken, Tetrahedron 2013, 69, 359–365.
a) A. De Meijere, F. Diederich (Eds.), Metal-Catalyzed Cross-
Coupling Reactions, 2nd ed., Wiley-VCH, Weinheim, Germany,
2004; b) E. I. Negishi, Acc. Chem. Res. 1982, 15, 340–348; c)
P. Knochel, M. I. Calaza, E. Hupe, in: Metal-Catalyzed Cross-
Coupling Reactions, (Eds.: A. de Meijere, F. Diederich), Wiley-
VCH, Weinheim, Germany, 2004, chapter 11; d) M. Beller, C.
Bolm (Eds.), Transition Metals for Organic Synthesis 2nd ed.,
Wiley-VCH, Weinheim, Germany, 2004; e) E. A. V. Kentchev,
C. J. O’Brien, M. G. Organ, Angew. Chem. 2007, 119, 2824–
2870; Angew. Chem. Int. Ed. 2007, 46, 2768–2813.
(300 MHz, CDCl3): δ = 8.80 (s, 1 H), 8.17 (s, 1 H), 7.55–7.42 (m,
5 H), 7.41–7.30 (m, 5 H), 6.68 (s, 1 H), 5.22 (s, 2 H, CH2Ar) ppm.
13C NMR (75 MHz, CDCl3): δ = 178.7, 152.7, 140.6, 140.2, 135.2,
131.2, 130.8, 130.6, 129.9, 129.2, 129.1, 128.6, 128.5, 120.4, 120.2,
50.8 ppm. HRMS (EI): calcd. for C20H15N3O2 329.1164; found
329.1147.
6-Methyl-8-oxo-5,7-diphenyl-7,8-dihydroimidazo[1,2-a]pyrazine-
3-carbaldehyde (10c): Yellow solid, 32% yield, m.p. 240–242 °C. 1H
NMR (300 MHz, CDCl3): δ = 8.20 (s, 1 H), 8.16 (s, 1 H), 7.66–
7.46 (m, 8 H), 7.34–7.29 (m, 2 H), 1.76 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 179.6, 153.6, 139.9, 139.8, 136.9, 132.4,
131.1, 130.9, 130.7, 130.5, 130.0, 129.4, 128.3, 127.8, 116.7,
17.8 ppm. HRMS (EI): calcd. for C20H15N3O2 329.1164; found
329.1159.
[2]
7-(4-Methoxyphenyl)-8-oxo-5-(p-tolyl)-7,8-dihydroimidazo[1,2-a]-
pyrazine-3-carbaldehyde (10d): Yellow solid, 63% yield, m.p. 152–
154 °C. H NMR (300 MHz, CDCl3): δ = 8.87 (s, 1 H), 8.20 (s, 1
1
[3]
[4]
H), 7.45–7.32 (m, 6 H), 7.00 (d, J = 8.6 Hz, 2 H), 6.82 (s, 1 H),
3.84 (s, 3 H), 2.44 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
179.1, 159.7, 152.4, 141.2, 140.7, 140.1, 131.5, 130.8, 130.7, 129.1,
128.1, 127.4, 121.9, 119.8, 114.8, 55.6, 21.4 ppm. HRMS (EI):
calcd. for C21H17N3O3 359.1269; found 359.1259.
a) P. A. Donets, K. Van Hecke, L. Van Meervelt, E. V.
Van der Eycken, Org. Lett. 2009, 11, 3618–3621; b) V. A. Pes-
kov, S. Van Hove, P. A. Donets, O. P. Pereshivko, K.
Van Hecke, L. Van Meervelt, E. V. Van der Eycken, Eur. J. Org.
Chem. 2011, 1837–1840.
a) V. P. Mehta, S. G. Modha, D. Ermolat’ev, K. Van Hecke, L.
Van Meervelt, E. Van der Eycken, Aust. J. Chem. 2009, 62, 27–
41; b) D. D. Vachhani, V. P. Mehta, S. G. Modha, K.
Van Hecke, L. Van Meervelt, E. V. Van der Eycken, Adv. Synth.
Catal. 2012, 354, 1593–1599.
3-[bis(4-Methoxyphenyl)methylene]-5,7-bis(4-methoxyphenyl)-2,3-di-
hydroimidazo[1,2-a]pyrazin-8(7H)-one (11): (p-Methoxyphenyl)-
boronic acid (9d) (0.44 mmol, 2.2 equiv.), Pd(PPh3)4 (0.01 mmol,
5 mol-%), and Na2CO3 (0.4 mmol, 2 equiv.) were added to a 10 mL
reaction vial containing compound 6c (0.2 mmol, 1 equiv.). Then a
mixture of dioxane/water (7:3; 2 mL) was added, and the vial was
sealed tightly with a Teflon® cap. The mixture was irradiated for
30 min at a pre-selected temperature of 110 °C, with maximum irra-
diation power of 300 W. After the reaction was complete, as moni-
tored by TLC and MS analysis, water (25 mL) was added, and the
mixture was extracted with ethyl acetate (2ϫ 30 mL). The com-
bined organic extracts were washed with brine (25 mL), and dried
with Na2SO4. After filtration, the solvent was evaporated under
reduced pressure, and the crude product was subjected to silica gel
column chromatography (70–80% ethyl acetate in heptane) to give
compound 11. Yellow solid, 65% yield, m.p. 53–55 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.42 (d, J = 9.0 Hz, 2 H), 7.0 (d, J =
9.0 Hz, 2 H), 6.90 (d, J = 2.1 Hz, 2 H), 6.87 (d, J = 2.1 Hz, 2 H),
6.6–6.5 (m, 6 H), 6.47 (d, J = 9 Hz, 2 H), 6.03 (s, 1 H), 3.84 (s, 3
H), 3.72 (s, 2 H), 3.71 (s, 3 H), 3.68 (s, 3 H), 3.67 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 159.1, 158.7, 158.1, 156.3, 147.8,
134.3, 132.6, 130.9, 130.7, 129.8, 127.5, 127.2, 126.9, 124.6, 116.1,
114.9, 114.6, 116.1, 113.6, 113.4, 113.1, 112.0, 55.5, 55.2, 55.1, 55.0,
52.1 ppm. HRMS (EI): calcd. for C35H31N3O5 573.2263; found
573.2272.
[5]
[6]
For a thematic special issue on coinage metals in organic Syn-
thesis see: Chem. Rev. 2008, 108, 2793–3442.
a) P. T. Parvatkar, P. S. Parameswaran, S. G. Tilve, Chem. Eur.
J. 2012, 18, 5460–5489; b) C. Chen, S. Yang, M. Wu, J. Org.
Chem. 2011, 76, 10269–10274; c) A. Sniady, K. A. Wheeler, R.
Dembinski, Org. Lett. 2005, 7, 1769–1772; d) D. W. Knight,
A. L. Redfern, J. Gilmore, J. Chem. Soc. Perkin Trans. 1 2001,
2874–2883; e) D. Yue, R. C. Larock, Org. Lett. 2004, 6, 1037–
1040.
a) S. Li, Z. Li, Y. Yuan, D. Peng, Y. Li, L. Zhang, Y. Wu,
Org. Lett. 2012, 14, 1130–1133; b) D. Sucunza, A. Samadi, M.
Chioua, D. B. Silva, C. Yunta, L. Infantes, M. C. Carreiras, E.
Soriano, J. Marco-Contelles, Chem. Commun. 2011, 47, 5043–
5045; c) S. K. Sharma, A. K. Mandadapu, B. Kumar, B.
Kundu, J. Org. Chem. 2011, 76, 6798–6805; d) M. J. Mphahlele,
Molecules 2009, 14, 4814–4837; e) H. Togo, S. Iida, Synlett
2006, 2159–2175; f) F. M. da Silva, J. J. Junior, M. C. S.
de Mattos, Curr. Org. Synth. 2005, 2, 393–414; g) S. Mehta,
R. C. Larock, J. Org. Chem. 2010, 75, 1652–1658; h) R. Man-
cuso, S. Mehta, B. Gabriele, G. Salerno, W. S. Jenks, R. C. Lar-
ock, J. Org. Chem. 2010, 75, 897–901.
a) B. Alcaide, P. Almendros, G. Cabrero, R. Callejo, M. P. Ruiz,
M. Arno, L. R. Domingo, Adv. Synth. Catal. 2010, 352, 1688–
1700; b) W. Lee, H. Shen, W. Hu, W. Lo, C. Murali, J. K. Van-
davasi, J. Wang, Adv. Synth. Catal. 2012, 354, 2218; c) K. Xu,
Y. Hu, S. Zhang, Z. Zha, Z. Wang, Chem. Eur. J. 2012, 18,
9793–9797; d) S. Das, R. Borah, R. R. Devi, A. J. Thakur, Syn-
lett 2008, 18, 2741–2762.
For an early review, see: a) G. Hoornaert, Bull. Soc. Chim. Belg.
1994, 103, 583–589; for a recent review, see: b) V. G. Pawar,
W. M. De Borggraeve, Synthesis 2006, 2799–2814; using micro-
wave irradiation, see: c) V. P. Mehta, P. Appukkuttan, E.
Van der Eycken, Curr. Org. Chem. 2011, 15, 265–283; d) E.
Van der Eycken, C. O. Kappe (Eds.), Topics in Heterocyclic
Chemistry, Springer, Berlin, 2006, vol. 1, p. 267; e) N. Kaval,
K. Bisztrav, W. Dehaen, C. O. Kappe, E. Van der Eycken, Mol.
Diversity 2003, 7, 125–134; f) N. Kaval, B. K. Singh, D. S. Erm-
[7]
[8]
[9]
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C spectra of all new compounds.
Acknowledgments
The authors wish to thank the Fund for Scientific Research, Flan-
ders, Belgium (FWO) and the Research Fund of the University of
Leuven (KU Leuven) for financial support. N. M. and D. V. are
grateful to the Erasmus Mundus External Cooperation Window
(EMECW), Lot 13) for a doctoral scholarship. The authors thank
Ir. B. Demarsin for HRMS measurements.
Eur. J. Org. Chem. 2013, 693–700
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
699

E. V. Van der Eycken et al.
FULL PAPER
olat’ev, S. Claerhout, J. Van der Eycken, E. Van der Eycken, J.
Comb. Chem. 2007, 9, 446–453.
[12]
[13]
a) J. Vekemans, C. Pollers-Wieërs, G. Hoornaert, J. Heterocycl.
Chem. 1983, 20, 919–923; for recent microwave-assisted Syn-
thesis see: b) J. Gising, P. Örtqvist, A. Sandström, M. Larhed,
Org. Biomol. Chem. 2009, 7, 2809–2815.
I. Kim, S. G. Kim, J. Y. Kim, G. H. Lee, Tetrahedron Lett.
2007, 48, 8976–8981.
[10] a) V. P. Mehta, A. Sharma, E. Van der Eycken, Adv. Synth. Ca-
tal. 2008, 350, 2174–2178; b) V. P. Mehta, A. Sharma, E.
Van der Eycken, Org. Lett. 2008, 10, 1147–1150; c) V. P. Mehta,
S. G. Modha, E. Van der Eycken, J. Org. Chem. 2009, 74, 6870–
6873; d) N. M. Mishra, V. A. Peshkov, O. P. Pereshivko, S. G.
Modha, E. V. Van der Eycken, Tetrahedron Lett. 2012, 53,
4676–4678.
[11] a) S. G. Modha, D. D. Vachhani, J. Jacobs, L. Van Meervelt,
E. V. Van der Eycken, Chem. Commun. 2012, 48, 6550–6552; b)
S. G. Modha, A. Kumar, D. D. Vachhani, J. Jacobs, S. K.
Sharma, V. S. Parmar, L. Van Meervelt, E. V. Van der Eycken,
Angew. Chem. Int. Ed. 2012, 51, 9572–9575; c) S. G. Modha,
A. Kumar, D. D. Vachhani, S. K. Sharma, V. S. Parmar, E. V.
Van der Eycken, Chem. Commun. 2012, 48, 10916–10918.
[14] The geometry of the double bond was confirmed by 2D NMR
spectroscopy (NOESY). For more details, see Supporting In-
formation.
[15] a) V. P. Mehta, A. Sharma, K. Van Hecke, L. Van Meervelt, E.
Van der Eycken, J. Org. Chem. 2008, 73, 2382–2388; b) R. Az-
zam, W. De Borggraeve, F. Compernolle, G. Hoornaert, Tetra-
hedron Lett. 2004, 45, 1885–1888.
Received: August 22, 2012
Published Online: December 11, 2012
700
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 693–700