A facile diversity-oriented synthesis of imidazo[1,2-a]pyrazinones via gold-catalyzed regioselective heteroannulation of propynylaminopyrazinones

Article abstract of DOI:10.1016/j.tet.2012.10.019

A gold-catalyzed regioselective heteroannulation strategy has been developed for the concise and efficient synthesis of imidazo[1,2-a]pyrazinones. The protocol allows the introduction of diversity via the application of substituted propargyl amines or via Suzuki-coupling of the generated imidazo[1,2-a]pyrazinones with various (het)aryl boronic acids.

Full text of DOI:10.1016/j.tet.2012.10.019

Tetrahedron 69 (2013) 359e365
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Tetrahedron
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A facile diversity-oriented synthesis of imidazo[1,2-a]pyrazinones
via gold-catalyzed regioselective heteroannulation of
propynylaminopyrazinones
y
*
Dipak D. Vachhani, Sachin G. Modha, Abhishek Sharma , Erik V. Van der Eycken
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, KU Leuven, Celestijnenlaan 200F, B-3001 Leuven, Belgium
a r t i c l e i n f o
a b s t r a c t
Article history:
A gold-catalyzed regioselective heteroannulation strategy has been developed for the concise and
efficient synthesis of imidazo[1,2-a]pyrazinones. The protocol allows the introduction of diversity via the
application of substituted propargyl amines or via Suzuki-coupling of the generated imidazo[1,2-a]
pyrazinones with various (het)aryl boronic acids.
Received 14 June 2012
Received in revised form
29 September 2012
Accepted 5 October 2012
Available online 11 October 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Gold
Heteroannulation
Imidazopyrazinone
Alkyne
Suzuki
1. Introduction
2. Results and discussion
The imidazo[1,2-a]pyrazines1 and imidazo[1,2-a]pyrazine-
8(7H)-ones2 constitute important classes of heterocyclic com-
pounds possessing anticancer-,1c antiviral-,1d GABAA agonist2a,d
and antiarrhythmic2e activities. They are also known to inhibit
PI3K,1b cyclin-dependent kinase (CDK),1e and gastric secretion.1f
The prevalent synthetic approaches towards imidazo[1,2-a]pyr-
azinones predominantly involve multiple step sequences,2b,e harsh
conditions2a and are limited in scope of substitution pattern2 of the
pyrazinone ring. Consequently, it would be highly desirable to de-
velop more versatile and milder routes for these compounds.
The synthesis of fused heterocycles via transition metal-
catalyzed3 inter/intra-molecular carbocyclization4 or hetero-
annulation5 strategies, utilizing substituted propargyl amines as
substrates, has recently attracted considerable attention owing to
its selectivity and mild conditions.6 In view of our long-standing
interest in the synthesis and decoration of the pyrazin-2(1H)-one
scaffold,7,8 we became interested in exploring the utility of pyr-
azinones for accessing the imidazo[1,2-a]pyrazine-8(7H)-one
framework. Herein, we report a methodology via a Au-catalyzed
heteroannulation of propynylaminopyrazinones (Table 1).
We have recently reported a chemoselective Ag(I)9- and Au(I)10
-
catalyzed protocol for the synthesis of pyrazino[2,1-b]quinazolines
and 3-indolyl- pyrazin-2(1H)-ones.11 Now we were wondering if this
Ag-catalyst system could also afford the selective heteroannulation
of propynylaminopyrazinones 2aej into imidazo[1,2-a]pyrazinone.
Compounds 2aej were obtained in one-step by treatment of
readily synthesized 3,5-dichloro-pyrazin-2(1H)-ones12 1aej with
propargyl amine using diisopropylethylamine (DIPEA) as a base in
acetonitrile at 70 ꢀC for 8e24 h (Scheme 1).
Subsequently, 2a was treated at rt with 5 mol % of AgOTf and
trifluoroacetic acid (TFA) (2 equiv) in CDCl3. TLC and GC/MS analysis
indicated that 2a was entirely consumed within 60 min and two
different products were formed. 1H NMR analysis revealed that the
desired imidazo-pyrazinone 3a was formed in 62% yield via 5-exo-
dig cyclization (Table 1, entry 1), along with 2H-pyrazino[1,2-a]-
pyrimidine-9(8H)-one 4a in 38% yield.
Encouraged by these initial findings, a detailed optimization
study was undertaken. Various transition metal-catalysts and sol-
vents were evaluated (Table 1). Ag(I)-catalysts gave efficient con-
versions in short reaction times, although they resulted in a poor
selectivity towards the desired product (Table 1, entries 1, 4 and 6).
On the other hand, the Au(I)- and Au(III)-catalysts afforded higher
selectivities, but incomplete conversions, even after prolonged re-
action times (Table 1, entries 2, 5 and 8). Similarly, CuCl was not
* Corresponding author. Tel.: þ32 16 32 74 06; fax: +32 16 32 79 90; e-mail
address: erik.vandereycken@chem.kuleuven.be (E.V. Van der Eycken).
y
Current address: Department of Chemistry, University of Illinois at
Urbana-Champaign, Urbana, IL 61801, United States.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.019

360
D.D. Vachhani et al. / Tetrahedron 69 (2013) 359e365
Table 1
Having established the optimum conditions, the scope and
limitations of the process were evaluated. A diverse set of
substituted 3-(prop-2-ynylamino)-pyrazin-2(1H)-ones (2aej) un-
derwent complete conversion at rt to afford the corresponding
imidazo[1,2-a]pyrazine-8(7H)-ones 3aej in good to excellent yields
(Table 2). In the case of 6-methyl substituted pyrazinones (Table 2,
3e,h), an increase in catalyst loading was found to be necessary.
Optimization of the heteroannulation of propynyl-aminopyrazinonea
Table 2
Au-catalyzed heteroannulation of propynylamino-pyrazinonesa
Entry
Catalyst (mol %)
Reaction
time (h)
Solvent
Conv.
Yieldb (%)
3a:4a
1
2
3
4
5
6
7
8
AgOTf (5)
AuCl (5)
CuCl (5)
AgOCOCF3 (5)
Au(PPh3)Cl (5)
AgSbF6 (5)
Cu(OTf)2 (5)
AuCl3 (5)
1
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
MeOH
THF
100
81
41
100
85
100
76
62:38
77:23
44:56
61:39
91:9
62:38
82:18
77:23
92:8 (90)
93:7
15
15
1
15
1
15
15
1
1
15
8
90 min
15
15
15
48
Entry
Product 3
R1
R2
Yield (%)b
79
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
3e
3f
3g
3h
3i
p-OMe Ph
PMB
Bn
Me
Ph
p-OMe Ph
PMB
PMB
PMB
3-Ph Pr
H
H
H
Ph
Me
p-OMe Ph
i-Bu
Me
p-OMe Ph
H
90
87
82
72
71c
81
75
65c
79
78c
9
Au(PPh3)OTf (5)
Au(L)Cl (5)
100
100
16
100
100
89
29
27
nd
10
11
12
13
14
15
16
17
Au(PPh3)OTf (5)c
Au(L)Cl (2)
84:16
93:7
Au(PPh3)OTf (2)
Au(PPh3)OTf (1)
Au(PPh3)OTf (2)
Au(PPh3)OTf (2)
d
90:10 (87)
87:13
73:27
74:26
nd
CDCl3
10
3j
a
nd¼not detected.
Conditions: 2 (0.5 mmol), Au(PPh3)Cl (2 mol %), AgOTf (2 mol %) and TFA
L¼2-dicyclohexylphosphino-20,40,60-triisopropylbiphenyl.
(2 equiv) in CHCl3, rt.
a
b
Unless otherwise stated all reactions were carried out using 2a (0.2 mmol) and
Isolated yields.
Au(PPh3)Cl (4 mol %) and AgOTf (4 mol %) were used.
c
TFA (2 equiv) at rt.
b
Conversion and ratio of 3a:4a were determined by 1H NMR. Values in paren-
thesis represent isolated yields.
c
Reaction was carried out without TFA.
In order to further evaluate the utility of the protocol on 3-
(prop-2-ynylamino)-pyrazin-2(1H)-ones bearing
a substituted
acetylenic moiety, the corresponding substrates 6aee were syn-
thesized via Sonogashira-coupling of 2bed,f with various (het)aryl
iodides (1.1 equiv) in the presence of Pd(PPh3)2Cl2 (2 mol %) and CuI
(3 mol %) in a mixture of TEA/DMSO (4:1) at 40 ꢀC for 1 h. Having
successfully obtained (het)aryl-(3-phenylprop-2-ynylamino)pyr-
azin-2(1H)-ones 6aee, we were keen to investigate the subsequent
heteroannulation (Table 3). Gratifyingly, high regioselectivity was
observed in all cases. However the double bond remains outside
the ring with (Z)-configuration.14
Finally, we became interested to further decorate the synthe-
sized imidazo[1,2-a]pyrazine-8(7H)-ones using the 5-Cl group as
a convenient synthetic handle. It is noteworthy to mention that
such Suzuki-coupling could not be performed before the hetero-
annulation was done.13 The developed approach (Table 4) proved
beneficial, as it allowed to install diversity on both 5- and 6-
position of the imidazo[1,2-a]pyrazin-8(7H)-one skeleton, which
is rather difficult to achieve otherwise.2
R1
N
R1
N
R2
Cl
O
R2
Cl
O
DIPEA
H2N
ACN
N
H
N
N
C l
70 oC
2a- j
1a- j
R1 = Me, Ph, PMB, PMP, Bn, 3-Ph propyl
2 = H, Me, Ph, PMP, iso-butyl
Scheme 1.
65 -87%
R
found to be effective while Cu(OTf)2 failed to achieve complete
conversion (Table 1, entries 3 and 7). Interestingly the cationic gold
complex,10 formed in situ by mixing 5 mol % Au(PPh3)Cl and 5 mol %
AgOTf, dramatically improved the selectivity and also reduced the
reaction time (Table 1, entry 9). Importantly, the loading of the
above Au-catalyst could be reduced to 2 mol % without a significant
loss in reaction performance, upon extending the reaction time to
90 min (Table 1, entry 13). The combination of Au(I)-catalyst with
Buchwald phosphine ligand (2-dicyclohexylphosphino-20,40,60-
triisopropylbiphenyl, X-Phos) was also effective, but the catalyst
loading could not be sufficiently reduced in comparison with the
cationic gold complex (Table 1, entries 10, 12 and 13). In order to
further enhance the reaction performance, different solvents were
also evaluated (Table 1, entries 15 and 16), although with little
success. A very low conversion or no reaction was observed when
the cyclization was carried out without TFA or catalyst (Table 1,
entries 11 and 17).
A plausible mechanism for the cationic gold-catalyzed 5-exo dig
heteroannulation is depicted in Scheme 2. Nucleophilic attack of
nitrogen on the activated alkyne generates intermediate B, which on
subsequent deprotonation and protodeauration produces 7. How-
ever, in case of terminal alkyne, 1,3-proton shift led to product 3.
3. Conclusion
We have developed an efficient and mild approach for the
synthesis of biologically important (dihydro)imidazo[1,2-a]pyr-
azin-8(7H)-one via a cationic gold-catalyzed regioselective 5-exo
dig heteroannulation strategy. Low catalyst loading, good to ex-
cellent yields and tolerance towards a variety of functional groups

D.D. Vachhani et al. / Tetrahedron 69 (2013) 359e365
361
Table 3
Au-catalyzed heteroannulation
approach towards dihydroimidazo[1,2-a]
pyrazinonea
Scheme 2. Plausible mechanism for the gold-catalyzed regioselective 5-exo dig
heteroannulation.
signal as an internal reference. Mass spectra were recorded by using
a Kratos MS50TC and a Kratos Mach III system. The ion source
temperature was 150e250 ꢀC, as required. High-resolution electron
impact (EI) mass spectra were performed with a resolution of
10,000. The low-resolution spectra were obtained with a HP5989A
MS instrument. For, TLC, analytical TLC plates (Alu-gram SIL
G/UV254) and 70e230 mesh silica gel (E.M. Merck) were used.
4.2. Microwave irradiation experiments
All microwave irradiation experiments were carried out in
a dedicated CEM-Discover monomode microwave apparatus, op-
erating at a frequency of 2.45 GHz with continuous irradiation of
300 W maximum power. The reactions were carried out in 10 mL
glass tubes, sealed with a Teflon septum and placed in the micro-
wave cavity. Initially, microwave irradiation of required watts was
used and the temperature was ramped from room temperature to
the desired temperature. Once this was reached the reaction mix-
ture was held at this temperature for the required time. The reaction
mixture was continuously stirred with magnetic stirring during the
reaction. The temperature was measured with an IR sensor on the
outer surface of the process vial. After irradiation, air jet cooling
cooled the reaction vessel rapidly to ambient temperature.
a
Conditions: 6 (0.5 mmol), Au(PPh3)Cl (2 mol%), AgOTf (2 mol%) and
TFA (2 equiv) in CHCl3 , rt. Isolated yields.
Table 4
Synthesis of polysubstituted imidazo[1,2,a]pyrazin-8(7H)-onea
4.3. General procedure for the synthesis of 3-(prop-2-ynyl-
amino)pyrazin-2(1H)-ones (2aej)
To a solution of substituted 3,5-dichloro-pyrazine-2(1H)-one 1
(2 mmol) inTHF (25 mL) were added propargyl amine (1.5 equiv) and
diisopropylethylamine (DIPEA) (2 equiv). The reaction mixture was
stirred at 70 ꢀC for 8e24 h. After completion, THF was distilled under
reduced pressure and the mixture was partitioned between ethyl
acetate (2ꢁ50 mL) and water (50 mL). The organic layer was sepa-
rated, washed with brine and dried over MgSO4. The solvent was
distilled off and the residue was subjected to silica gel chromatog-
raphy (30e60% ethyl acetate in heptane) to afford compound 2aej.
Entry
Product 9
R1
R2
R3
Yield (%)b
1
2
3
4
9a
9b
9c
9d
p-OMe Ph
p-OMe Ph
Me
H
H
Ph
H
p-Tolyl
Ph
m-Cl Ph
3-Thiophene
94
75
60
89
PMB
a
Conditions: 3 (0.5 mmol), 8 (1.5 equiv), Na2CO3 (2 equiv), Pd(PPh3)4 (5 mol %),
dioxane/water (2:1) 2 mL, 110 ꢀC, MW, 30 min.
b
Isolated yields.
are the merits of this protocol. Importantly, the above hetero-
annulation also allowed installation of further diversity via Suzuki-
coupling, thereby, furnishing
4.3.1. 5-Chloro-1-(4-methoxyphenyl)-3-(prop-2-ynylamino)pyrazin-
2(1H)-one (2a). White solid, mp 170e172 ꢀC, yield 84%, 1H NMR
a convenient access to poly-
substituted imidazo[1,2-a]pyrazine-8(7H)-ones.
(300 MHz, CDCl3):
d
7.30 (d, J¼8.85 Hz, 2H), 6.99 (d, J¼8.85 Hz, 2H),
6.68 (s, 1H), 6.52 (bs,1H), 4.26 (dd, J¼2.39, 5.63 Hz, 2H), 3.85 (s, 3H),
4. Experimental section
4.1. General
2.28 (t, J¼2.39 Hz, 1H). 13C NMR (75 MHz, CDCl3):
d 154.4, 144.8,
144.5, 126.4, 121.5, 121.3, 109.4, 109.1, 73.7, 66.7, 50.3, 25.6. HRMS
(EI): calcd for C14H12ClN3O2: 289.0618, found: 289.0591.
NMR spectra were recorded on a Bruker Avance 300 MHz in-
strument using CDCl3 or DMSO-d6 as solvent unless otherwise
stated. The 1H and 13C NMR chemical shifts are reported in parts per
million relative to tetramethylsilane using the residual solvent
4.3.2. 5-Chloro-1-(4-methoxybenzyl)-3-(prop-2-ynylamino)pyrazin-
2(1H)-one (2b). White solid, mp 197e199 ꢀC, yield 87%, 1H NMR
(300 MHz, CDCl3):
d
7.28e7.20 (m, 2H), 6.88 (d, J¼8.49 Hz, 2H), 6.52
(s, 1H), 6.44 (bs, 1H), 4.94 (s, 2H), 4.21 (dd, J¼2.39, 5.57 Hz, 2H), 3.80

362
D.D. Vachhani et al. / Tetrahedron 69 (2013) 359e365
(s, 3H), 2.26 (t, J¼2.40 Hz, 1H). HRMS (EI): calcd for C15H14ClN3O2:
(bs,1H), 2.14e2.01 (m, 2H). 13C NMR (75 MHz, CDCl3):
d 150.0,149.4,
140.2,128.5,128.2,126.5,126.3,113.3, 79.0, 71.9, 48.8, 32.6, 30.7, 29.7.
HRMS (EI): calcd for C16H16ClN3O: 301.0982, found: 301.0974.
303.0775, found: 303.0771.
4.3.3. 1-Benzyl-5-chloro-3-(prop-2-ynylamino)pyrazin-2(1H)-one
(2c). White solid, mp 170e172 ꢀC, yield 67%, 1H NMR (300 MHz,
4.4. General procedure for the synthesis of substituted imi-
CDCl3):
4.26e4.16 (m, 2H), 2.27 (bs, 1H). 13C NMR (75 MHz, DMSO-d6):
149.6, 149.5, 136.0, 128.6, 127.9, 127.8, 124.8, 113.7, 80.7, 72.6, 51.0,
d
7.41e7.24 (m, 5H), 6.54 (s, 1H), 6.46 (bs, 1H), 5.01 (s, 2H),
dazo[1,2-a]pyrazin-8(7H)-ones (3aej)
d
To an oven dried 10 mL screw cap vial equipped with a stir-bar
and charged with 2 (0.5 mmol, 1 equiv) was added silver triflate
(2 mol %), Au(PPh3)Cl (2 mol %) and Trifluoroacetic acid (2 equiv).
Dry CHCl3 (2 mL) was added bysyringe and the reactionwas allowed
to stir at rt. After completion of the reaction as indicated by TLC
analysis, a saturated solution of K2CO3 (5 mL) was added and the
mixture was stirred for 5 min more. The resulting mixture was di-
luted with ethyl acetate (50 mL) and washed with water (50 mL) and
brine (50 mL). The organic phase was dried over anhydrous MgSO4,
filtered and concentrated under reduced pressure. The crude sample
was purified by silica gel column chromatography (5e20% dieth-
ylether in dichloromethane) to obtain compounds 3aej.
29.7. HRMS (EI): calcd for C14H12ClN3O: 273.0669, found: 273.0668.
4.3.4. 5-Chloro-1-methyl-6-phenyl-3-(prop-2-ynylamino)pyrazin-
2(1H)-one (2d). White solid, mp 119e121 ꢀC, yield 78%, 1H NMR
(300 MHz, CDCl3):
d 7.60e7.45 (m, 3H), 7.33e7.28 (m, 2H), 6.41 (b,
1H), 4.27 (q, J¼2.4 Hz, 2H), 3.22 (s, 3H), 2.28 (t, J¼2.3 Hz, 1H). 13C
NMR (75 MHz, CDCl3):
d 151.0, 148.2, 132.2, 130.2, 129.4, 129.0,
125.7, 124.8, 79.2, 71.8, 34.2, 30.7. HRMS (EI): calcd for C14H12ClN3O:
273.0669, found: 273.0680.
4.3.5. 5-Chloro-6-methyl-1-phenyl-3-(prop-2-ynylamino)pyrazin-
2(1H)-one (2e). Off white solid, mp 165e167 ꢀC, yield 79%, 1H NMR
(300 MHz, CDCl3):
(bs, 1H), 4.25 (dd, J¼2.27, 5.67 Hz, 2H), 2.26 (t, J¼2.40 Hz, 1H), 1.94
(s, 3H). 13C NMR (75 MHz, CDCl3):
151.4, 147.8, 137.4, 129.9, 129.3,
127.4, 124.9, 120.5, 79.4, 71.6, 30.6, 16.9. HRMS (EI): calcd for
C14H12ClN3O: 273.0669, found: 273.0662.
d
7.59e7.44 (m, 3H), 7.17 (d, J¼7.17 Hz, 2H), 6.23
4.4.1. 5-Chloro-7-(4-methoxyphenyl)-3-methylimidazo[1,2-a]pyr-
azin-8(7H)-one (3a). White solid, mp 197e199 ꢀC, yield 87%, 1H
d
NMR (300 MHz, CDCl3):
6.77 (s, 1H), 3.84 (s, 3H), 2.72 (s, 3H). 13C NMR (75 MHz, CDCl3):
159.5,152.2,138.2,133.5,131.5,128.0,127.5,118.8,114.7,109.5, 55.6,
d
7.35e7.28 (m, 3H), 6.99 (d, J¼8.85 Hz, 2H),
d
12.6. HRMS (EI): calcd for C14H12ClN3O2: 289.0618, found: 289.0619.
4.3.6. 5-Chloro-1,6-bis(4-methoxyphenyl)-3-(prop-2-ynylamino)
pyrazin-2(1H)-one (2f). Light yellow solid, mp 137e139 ꢀC, yield
4.4.2. 5-Chloro-7-(4-methoxybenzyl)-3-methylimidazo[1,2-a]pyr-
79%, 1H NMR (300 MHz, CDCl3):
d
6.99 (d, J¼8.46 Hz, 2H), 6.90 (d,
azin-8(7H)-one (3b). White solid, mp 241e242 ꢀC, yield 87%, 1H
J¼8.85 Hz, 2H), 6.80e6.65 (m, 4H), 6.47 (t, J¼5.57 Hz, 1H), 4.31 (dd,
NMR (300 MHz, CDCl3):
6.53 (s, 1H), 5.05 (s, 2H), 3.80 (s, 3H), 2.66 (s, 3H). 13C NMR (75 MHz,
CDCl3): 159.7, 152.6, 138.2, 133.3, 129.9, 127.8, 127.6, 116.8, 114.4,
d
7.31e7.22 (m, 2H), 6.88 (d, J¼8.64 Hz, 1H),
J¼2.24, 5.75 Hz, 2H), 3.73 (s, 3H), 2.30 (bs, 1H). 13C NMR (75 MHz,
CDCl3):
d
159.2, 159.0, 151.3, 148.7, 132.3, 130.1, 129.1, 126.0, 125.1,
d
124.5, 114.2, 113.4, 79.3, 71.8, 55.3, 55.1, 30.7. HRMS (EI): calcd for
C21H18ClN3O3: 395.1037, found: 395.1030.
109.6, 55.3, 49.7, 12.6. HRMS (EI): calcd for C15H14ClN3O2: 303.0775,
found: 303.0775.
4.3.7. 5-Chloro-6-isobutyl-1-(4-methoxybenzyl)-3-(prop-2-
4.4.3. 7-Benzyl-5-chloro-3-methylimidazo[1,2-a]pyrazin-8(7H)-one
ynylamino)pyrazin-2(1H)-one (2g). Orange viscous liquid, yield
(3c). White solid, mp 167e169 ꢀC, yield 82%, 1H NMR (300 MHz,
72%, 1H NMR (300 MHz, CDCl3):
d
7.04 (d, J¼8.49 Hz, 2H), 6.84 (d,
CDCl3):
d
7.40e7.30 (m, 4H), 7.29e7.24 (m, 1H), 5.12 (s, 2H), 2.67 (s,
152.6, 138.1, 135.6, 133.3, 129.0,
J¼8.49 Hz, 2H), 6.25 (t, J¼5.11 Hz, 1H), 5.21 (s, 2H), 4.22 (dd, J¼2.42,
5.42 Hz, 2H), 3.78 (s, 3H), 2.55 (d, J¼7.35 Hz, 2H), 2.26 (t, J¼2.44 Hz,
1H), 2.01e1.86 (m, 1H), 0.99 (d, J¼6.78 Hz, 6H). 13C NMR (75 MHz,
3H). 13C NMR (75 MHz, CDCl3):
d
128.4, 128.3, 127.8, 117.0, 109.7, 50.2, 12.6. HRMS (EI): calcd for
C14H12ClN3O: 273.0669, found: 273.0673.
CDCl3):
d 159.1, 151.6, 147.6, 127.8, 127.6, 126.8, 123.5, 114.3, 79.5,
71.7, 55.2, 47.5, 37.2, 30.6, 29.1, 22.3. HRMS (EI): calcd for
C19H22ClN3O2: 359.1401, found: 359.1388.
4.4.4. 5-Chloro-3,7-dimethyl-6-phenylimidazo[1,2-a]pyrazin-8(7H)-
one (3d). White solid, mp 242e243 ꢀC, yield 72%, 1H NMR
(300 MHz, CDCl3):
d
7.59e7.49 (m, 3H), 7.38e7.27 (m, 3H), 3.20 (s,
153.3, 137.7, 133.4,
4.3.8. 5-Chloro-1-(4-methoxybenzyl)-6-methyl-3-(prop-2-
3H), 2.70 (s, 3H). 13C NMR (75 MHz, CDCl3):
d
ynylamino)pyrazin-2(1H)-one (2h). White solid, mp 121e123 ꢀC,
131.7, 129.9, 129.8, 129.3, 128.9, 128.0, 109.1, 33.5, 13.3. HRMS (EI):
calcd for C14H12ClN3O: 273.0669, found: 273.0683.
yield 70%, 1H NMR (300 MHz, CDCl3):
d
7.10 (d, J¼8.10 Hz, 2H), 6.85
(d, J¼8.10 Hz, 2H), 6.25 (bs, 1H), 5.21 (s, 2H), 4.21 (d, J¼3.03 Hz, 2H),
3.78 (s, 3H), 2.31e2.25 (m, 4H). 13C NMR (75 MHz, CDCl3):
159.2,
d
4.4.5. 5-Chloro-3,6-dimethyl-7-phenylimidazo[1,2-a]pyrazin-8(7H)-
151.5,147.5,128.1,127.2,125.5,120.5,114.3, 79.4, 71.7, 55.3, 47.9, 30.7,
15.6. HRMS (EI): calcd for C16H16ClN3O2: 317.0931, found: 317.0932.
one (3e). White solid, mp 181e183 ꢀC, yield 71%, 1H NMR
(300 MHz, CDCl3):
d
7.56e7.42 (m, 3H), 7.28 (s, 1H), 7.25e7.18 (m,
153.1,
2H), 2.74 (s, 3H), 2.01 (s, 3H). 13C NMR (75 MHz, CDCl3):
d
4.3.9. 5-Chloro-1-(4-methoxybenzyl)-6-(4-methoxyphenyl)-3-(prop-
137.5, 137.4, 133.5, 129.8, 129.2, 128.5, 128.0, 124.5, 108.0, 17.3, 13.6.
HRMS (EI): calcd for C14H12ClN3O: 273.0669, found: 273.0645.
2-ynylamino)pyrazin-2(1H)-one (2i). Yellow solid, mp 113e115 ꢀC,
yield 81%, 1H NMR (300 MHz, CDCl3):
d
7.01 (d, J¼8.46 Hz, 2H), 6.89
(d, J¼8.49 Hz, 2H), 6.81e6.67 (m, 4H), 6.45 (t, J¼5.25 Hz,1H), 4.94 (s,
2H), 4.27 (dd, J¼2.37, 5.45 Hz, 2H), 3.85 (s, 3H), 3.75 (s, 3H), 2.29 (bs,
4.4.6. 5-Chloro-6,7-bis(4-methoxyphenyl)-3-methylimidazo[1,2-a]
pyrazin-8(7H)-one (3f). White solid, mp 201e203 ꢀC, yield 81%, 1H
1H).13C NMR (75 MHz, CDCl3):
d
160.1,159.0,151.1,148.6,132.1,128.6,
NMR (300 MHz, CDCl3):
(d, J¼8.85 Hz, 2H), 6.77e6.68 (m, 4H), 3.75 (s, 3H), 3.72 (s, 3H), 2.74
(s, 3H). 13C NMR (75 MHz, CDCl3):
159.6, 158.9, 153.3, 137.9, 133.7,
d
7.33 (s, 1H), 7.03 (d, J¼8.85 Hz, 2H), 6.93
127.8,126.6,124.4,124.0,113.9,113.6, 79.2, 71.8, 55.3, 55.2, 48.8, 30.7.
HRMS (EI): calcd for C22H20ClN3O3: 409.1193, found: 409.1200.
d
132.0,130.1 (2),129.3,128.4,123.8, 114.1,113.7,109.4, 55.3, 55.1,13.5.
HRMS (EI): calcd for C21H18ClN3O3: 395.1037, found: 395.1037.
4.3.10. 5-Chloro-1-(3-phenylpropyl)-3-(prop-2-ynylamino)pyrazin-
2(1H)-one (2j). Light yellow solid, mp 91e93 ꢀC, yield 65%, 1H NMR
(300 MHz, CDCl3):
(d, J¼4.46 Hz, 2H), 3.84 (t, J¼7.22 Hz, 2H), 2.68 (t, J¼7.52 Hz, 2H), 2.27
d
7.34e7.13 (m, 5H), 6.48 (s,1H), 6.42 (bs,1H), 4.20
4.4.7. 5-Chloro-6-isobutyl-7-(4-methoxybenzyl)-3-methylimidazo
[1,2-a]pyrazin-8(7H)-one (3g). Off white solid, mp 116e118 ꢀC, yield

D.D. Vachhani et al. / Tetrahedron 69 (2013) 359e365
363
75%, 1H NMR (300 MHz, CDCl3):
d
7.27 (s, 1H), 7.10 (d, J¼8.49 Hz,
125.5, 124.9, 124.5, 122.3, 114.2, 113.4, 88.3, 82.5, 55.3, 55.1, 31.8,
20.7. HRMS (EI): calcd for C28H24ClN3O3: 485.1506, found: 485.1513.
2H), 6.82 (d, J¼8.46 Hz, 2H), 5.31 (s, 2H), 3.76 (s, 3H), 2.71 (s, 3H),
2.61 (d, J¼7.35 Hz, 2H), 2.09e1.94 (m, 1H), 1.03 (d, J¼6.60 Hz, 6H).
13C NMR (75 MHz, CDCl3):
d
159.0, 153.8, 137.4, 133.6, 128.5, 128.0,
4.5.3. 5-Chloro-1-methyl-3-(3-(naphthalen-1-yl)prop-2-
127.9, 127.2, 114.2, 109.5, 55.2, 46.2, 36.6, 28.9, 22.2, 13.7. HRMS (EI):
calcd for C19H22ClN3O2: 359.1401, found: 359.1404.
ynylamino)-6-phenylpyrazin-2(1H)-one (6c). White solid, mp
172e174 ꢀC, yield 80%, 1H NMR (300 MHz, CDCl3):
d 8.36 (d,
J¼8.10 Hz, 1H), 7.88e7.78 (m, 2H), 7.68 (d, J¼6.96 Hz, 1H), 7.62e7.38
4.4.8. 5-Chloro-7-(4-methoxybenzyl)-3,6-dimethylimidazo[1,2-a]
(m, 6H), 7.34e7.28 (m, 2H), 6.60 (bs, 1H), 4.64 (d, J¼5.46 Hz, 2H),
pyrazin-8(7H)-one (3h). Off white solid, mp 116e119 ꢀC, yield 65%,
3.23 (s, 3H). 13C NMR (75 MHz, CDCl3):
d 151.1, 148.3, 133.4, 133.0,
132.2, 130.6, 130.2, 129.3, 128.9, 128.8, 128.1, 126.8, 126.4, 126.2,
125.9, 125.1, 124.7, 120.2, 89.5, 81.5, 34.2, 31.8. HRMS (EI): calcd for
C24H18ClN3O: 399.1139, found: 399.1149.
1H NMR (300 MHz, CDCl3):
d
7.27 (s, 1H), 7.16 (d, J¼8.28 Hz, 2H),
6.83 (d, J¼8.46 Hz, 2H), 5.30 (s, 2H), 3.77 (s, 3H), 2.70 (s, 3H), 2.35 (s,
3H). 13C NMR (75 MHz, CDCl3):
159.1, 153.6, 137.3, 133.5, 128.3,
d
128.1, 127.8, 124.4, 114.2, 108.1, 55.3, 46.8, 15.6, 13.6. HRMS (EI):
calcd for C16H16ClN3O2: 317.0931, found: 317.0927.
4.5.4. 3-(3-(1H-indol-5-yl)prop-2-ynylamino)-1-benzyl-5-chloropyra-
zin-2(1H)-one (6d). Light yellow solid, mp 160e162 ꢀC, yield 78%, 1H
4.4.9. 5-Chloro-7-(4-methoxybenzyl)-6-(4-methoxyphenyl)-3-
NMR (300 MHz, CDCl3): d 8.21 (s, 1H), 7.76 (s, 1H), 7.41e7.17 (m, 8H),
methylimidazo[1,2-a]pyrazin-8(7H)-one (3i). Light yellow solid, mp
6.61e6.48 (m, 3H), 5.02 (s, 2H), 4.45 (d, J¼5.10 Hz, 2H). 13C NMR
204e205 ꢀC, yield 79%, 1H NMR (300 MHz, CDCl3):
d
7.31 (s,1H), 6.99
(75 MHz, DMSO-d6): d 149.7, 149.6, 136.1, 135.4, 128.6, 127.9, 127.8,
(d, J¼8.34 Hz, 2H), 6.92 (d, J¼8.67 Hz, 2H), 6.77 (d, J¼8.67 Hz, 2H),
127.4, 126.4, 125.0, 124.3, 123.7, 113.5, 112.3, 111.6, 101.2, 83.3, 83.2,
51.0, 30.6. HRMS (EI): calcd for C22H17ClN4O: 388.1091, found:
388.1079.
6.67 (d, J¼8.67 Hz, 2H), 4.99 (s, 2H), 3.87 (s, 3H), 3.74 (s, 3H), 2.68 (s,
3H).13C NMR (75 MHz, CDCl3):
d 160.5,158.9,153.5,137.9,133.6,131.8,
128.9,128.8,128.5,128.1,123.3,114.1,113.6,109.8, 55.4, 55.2, 47.7,13.4.
HRMS (EI): calcd for C22H20ClN3O3: 409.1193, found: 409.1181.
4.5.5. 5-Chloro-3-(3-(2-chloropyridin-4-yl)prop-2-ynylamino)-1-(4-
methoxybenzyl)pyrazin-2(1H)-one (6e). Light yellow solid, mp
4.4.10. 5-Chloro-3-methyl-7-(3-phenylpropyl)-imidazo[1,2-a]pyr-
142e144 ꢀC, yield 92%, 1H NMR (300 MHz, CDCl3):
d 8.34 (d,
azin-8(7H)-one (3j). White solid, mp 114e116 ꢀC, yield 78%, 1H
J¼5.09 Hz, 1H), 7.33 (s, 1H), 7.30e7.17 (m, 3H), 6.89 (d, J¼8.10 Hz,
NMR (400 MHz, CDCl3):
(s, 1H), 3.94 (t, J¼7.33 Hz, 2H), 2.70 (t, J¼7.54 Hz, 2H), 2.67 (s, 3H),
2.15e2.05 (m, 2H). 13C NMR (75 MHz, CDCl3):
152.5, 140.5, 138.2,
d 7.30e7.24 (m, 3H), 7.21e7.15 (m, 3H), 6.49
2H), 6.60e6.45 (m, 2H), 4.96 (s, 2H), 4.46 (d, J¼5.28 Hz, 2H), 3.80 (s,
3H). 13C NMR (75 MHz, CDCl3):
d 159.8, 151.6, 150.1, 149.5, 149.4,
d
133.6, 129.9, 126.6 (2), 126.2, 124.4, 114.4, 113.0, 91.1, 79.8, 55.3, 51.5,
31.3. HRMS (EI): calcd for C20H16Cl2N4O2: 414.0650, found:
414.0666.
133.2, 128.4, 128.2, 127.7, 126.1, 117.6, 109.2, 47.6, 32.7, 30.2, 12.6.
HRMS (EI): calcd for C16H16ClN3O: 301.0982, found: 301.0983.
4.5. General procedure for the synthesis of 3-(prop-2-
4.6. General procedure for the synthesis of dihydroimidazo
ynylamino)pyrazin-2(1H)-ones (6aee)
[1,2-a]pyrazin-8(7H)-ones (7aee)
An oven dried 25 mL two necked flask equipped with a stir-bar
was charged with 2 (0.7 mmol, 1 equiv), (het)aryl iodide 5
(0.77 mmol, 1.1 equiv), PdCl2(PPh3)2 (2 mol %) and CuI (3 mol %)
under argon. The flask was evacuated and filled back with argon (ꢁ
three times). Dry TEA/DMSO (4:1) (10 mL) was added by syringe and
suspension was allowed to stir at 45 ꢀC for 30 min. After the com-
pletion of reaction as indicated by TLC and MS analysis, the mixture
was cooled to room temperature. The crude mixture was diluted
with ethyl acetate (50 mL) and organic phase was washed with H2O
(50 mL) and brine (50 mL). The organic phase was dried over anhy-
drous MgSO4, filtered and was concentrated under reduced pressure.
The crude sample was purified by silica gel column chromatography
(5e10% diethylether in DCM) to obtain compound 6aee.
To an oven dried 10 mL screw cap vial equipped with a stir-bar
and charged with 6 (0.5 mmol, 1 equiv) was added silver triflate
(2 mol %), Au(PPh3)Cl (2 mol %) and Trifluoroacetic acid (2 equiv).
Dry CHCl3 (2 mL) was added by syringe and the reaction was
allowed to stir at rt. After completion of the reaction as indicated by
TLC analysis, a saturated solution of K2CO3 (5 mL) was added and
the mixture was stirred for 5 min more. The resulting mixture was
diluted with ethyl acetate (50 mL) and washed with water (50 mL)
and brine (50 mL). The organic phase was dried over anhydrous
MgSO4, filtered and concentrated under reduced pressure. The
crude sample was purified by silica gel column chromatography
(5e20% diethylether in DCM) to obtain compounds 7aee.
4.6.1. (Z)-3-Benzylidene-5-chloro-6,7-bis(4-methoxyphenyl)-2,3-
4.5.1. 5-Chloro-1,6-bis(4-methoxyphenyl)-3-(3-phenylprop-2-
dihydroimidazo[1,2-a]pyrazin-8(7H)-one (7a). Off white solid, mp
ynylamino)pyrazin-2(1H)-one (6a). Off white solid, mp 179e181 ꢀC,
212e214 ꢀC, yield 78%, 1H NMR (300 MHz, CDCl3):
d 7.50e7.33 (m,
yield 89%, 1H NMR (300 MHz, CDCl3):
d
7.48e7.40 (m, 2H),
5H), 7.09 (d, J¼8.46 Hz, 2H), 6.98 (d, J¼8.28 Hz, 2H), 6.76 (d,
7.35e7.28 (m, 3H), 6.99 (d, J¼8.67 Hz, 2H), 6.91 (d, J¼9.03 Hz, 2H),
J¼8.49 Hz, 2H), 6.66 (d, J¼8.28 Hz, 2H), 5.23 (s,1H), 4.31 (s, 2H), 3.73
6.78e6.67 (m, 4H), 6.52 (t, J¼5.27 Hz, 1H), 4.53 (d, J¼5.46 Hz, 2H),
(s, 3H), 3.70 (s, 3H). 13C NMR (75 MHz, CDCl3):
d 159.2, 158.5, 157.1,
3.76e3.69 (m, 6H). 13C NMR (75 MHz, CDCl3):
d
159.2, 159.0, 151.3,
146.7, 138.6, 134.7, 132.0, 130.3, 129.3, 128.8, 128.7, 126.1, 123.9,
123.2, 113.9 (2), 113.3, 107.6, 55.2, 55.0, 46.4. HRMS (EI): calcd for
C27H22ClN3O3: 471.1350, found: 471.1353.
148.7, 132.3, 131.7, 130.1, 129.1, 128.4, 128.3, 126.1, 124.9, 124.5,122.6,
114.1, 113.4, 84.6, 83.5, 55.3, 55.0, 31.5. HRMS (EI): calcd for
C27H22ClN3O3: 471.1350, found: 471.1350.
4.6.2. (Z)-5-Chloro-6,7-bis(4-methoxyphenyl)-3-(2-methylbenzylid-
ene)-2,3-dihydroimidazo[1,2-a]pyrazin-8(7H)-one (7b). Light yel-
low solid, mp 100e102 ꢀC, yield 85%, 1H NMR (300 MHz, CDCl3):
4.5.2. 5-Chloro-1,6-bis(4-methoxyphenyl)-3-(3-o-tolylprop-2-
ynylamino)pyrazin-2(1H)-one (6b). White solid, mp 168e170 ꢀC,
yield 90%, 1H NMR (300 MHz, CDCl3):
7.24e7.09 (m, 3H), 7.00 (d, J¼8.67 Hz, 2H), 6.91 (d, J¼8.85 Hz, 2H)
6.78e6.67 (m, 4H), 6.53 (t, J¼5.32 Hz, 1H), 4.57 (d, J¼5.46 Hz, 2H),
d
7.42 (d, J¼7.32 Hz, 1H),
d
7.36e7.18 (m, 5H), 7.01 (d, J¼8.64 Hz, 2H), 6.91 (d, J¼8.46 Hz, 2H),
6.73 (d, J¼8.67 Hz, 2H), 6.63 (d, J¼8.49 Hz, 2H), 5.08 (t, J¼4.33 Hz,
1H), 4.32 (d, J¼3.51 Hz, 2H), 3.71 (s, 3H), 3.68 (s, 3H), 2.35 (s, 3H).
3.76e3.69 (m, 6H), 2.44 (s, 3H). 13C NMR (75 MHz, CDCl3):
d
159.2,
13C NMR (75 MHz, CDCl3):
d 159.2, 158.5, 156.8, 146.5, 138.7, 135.8,
159.0, 151.4, 148.7, 140.4, 132.3, 132.1, 130.1, 129.4, 129.1, 128.4, 126.1,
134.3, 132.0, 130.6, 130.3, 130.0, 129.2, 128.9, 126.0, 123.9, 123.1,

364
D.D. Vachhani et al. / Tetrahedron 69 (2013) 359e365
113.9, 113.8, 113.3, 108.3, 55.2, 55.0, 46.4, 19.2. HRMS (EI): calcd for
C28H24ClN3O3: 485.1506, found: 485.1496.
6.43 (s, 1H), 5.09 (s, 2H), 3.78 (s, 3H), 1.80 (s, 3H). 13C NMR (75 MHz,
CDCl3): 159.4, 153.2, 137.8, 133.0, 130.7, 130.1, 129.9, 128.2, 127.8,
d
126.9, 126.1, 118.7, 115.1, 114.2, 55.2, 49.5, 11.3. HRMS (EI): calcd for
C17H19ClN3O2S: 351.1041, found: 351.1052.
4.6.3. (Z)-3-((1H-Indol-5-yl)methylene)-7-benzyl-5-chloro-2,3-
dihydroimidazo[1,2-a]pyrazin-8(7H)-one (7d). Light brown solid,
mp>300 ꢀC, yield 58%, 1H NMR (300 MHz, DMSO-d6):
d 11.23 (s,
Acknowledgements
1H), 7.51e7.30 (m, 8H), 6.97 (d, J¼8.10 Hz, 1H), 6068 (s, 1H), 6.41 (s,
1H), 5.18 (s, 1H), 4.95 (s, 2H), 4.04 (s, 2H). 13C NMR (75 MHz, DMSO-
The authors wish to thank the F.W.O. [Fund for Scientific
ResearchdFlanders (Belgium)] and the Research Fund of the Uni-
versity of Leuven (KU Leuven) for financial support. D.V. is thankful
to the EMECW13 (Erasmus Mundus External Cooperation Window
Lot 13) for obtaining a doctoral scholarship. A.S. is thankful to the
F.W.O. for obtaining a postdoctoral fellowship. The authors thank Ir.
B. Demarsin for HRMS measurements.
d6): d 155.3,146.2,139.2,136.5,135.8,128.6, 128.0,127.7,127.6,127.5,
126.4, 125.1, 119.4, 117.8, 113.2, 111.6, 105.7, 101.4, 49.8, 45.5. HRMS
(EI): calcd for C22H17ClN4O: 388.1091, found: 388.1087.
4.6.4. (Z)-5-Chloro-3-((2-chloropyridin-4-yl)methylene)-7-(4-
methoxybenzyl)-2,3-dihydroimidazo[1,2-a]pyrazin-8(7H)-one
(7e). White solid, mp 151e153 ꢀC, yield 91%, 1H NMR (300 MHz,
CDCl3):
d
8.31 (d, J¼5.16 Hz, 1H), 7.35 (s, 1H), 7.30 (d, J¼8.28 Hz, 2H),
Supplementary data
7.05 (s, 1H), 6.96 (d, J¼4.62 Hz, 1H), 6.89 (d, J¼8.10 Hz, 2H), 6.56 (s,
1H), 5.06 (s, 2H), 4.44 (s, 2H), 3.80 (s, 3H). 13C NMR (75 MHz, CDCl3):
Complete experimental details and spectroscopic data of all com-
pounds are available online. Supplementary data related to this article
can be found online at http://dx.doi.org/10.1016/j.tet.2012.10.019.
d
159.8, 152.4, 152.1, 150.5, 150.0, 139.2, 134.9, 130.1, 127.2, 126.9,
123.7, 122.1, 117.6, 114.4, 108.7, 55.3, 49.9, 31.0. HRMS (EI): calcd for
C20H16Cl2N4O2: 414.0650, found: 414.0650.
References and notes
4.7. General procedure for the synthesis of polysubstituted
imidazo[1,2-a]pyrazine-8(7H)-one via Suzuki-coupling (9aed)
1. (a) Andrews, M. J. I.; Clase, J. A.; Bar, G.; Tricarico, G.; Edwards, P. J.; Brys, R.;
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Harris, J.; Self, A.; Nash, K.; Dixon, G. Bioorg. Med. Chem. Lett. 2012, 22,
In a 10 mL reaction vial charge with compound 3 (0.5 mmol,
1 equiv) was added boronic acid 8 (0.75 mmol, 1.5 equiv), Pd(PPh3)4
(0.025 mmol, 5 mol %) and Na2CO3 (1.0 mmol, 2 equiv). Then water/
dioxane (2:1) 2 mL was added and the vial was sealed tightly with
Teflon cap. The mixture was irradiated for 30 min at a preselected
temperature of 110 ꢀC, with maximum irradiation power of 300 W.
After the completion of reaction as monitored by TLC and MS
analysis, the resulting crude mixture was added water (50 mL) and
extracted with ethyl acetate (2ꢁ50 mL). The combined organic layer
was washed with brine (50 mL) and dried over MgSO4. After fil-
tration, solvent was evaporated under reduced pressure and crude
product was subjected to silica gel column chromatography (20%
diethylether in DCM) to afford corresponding compounds 9aed.
ꢀ
ꢀ
2266e2270; (b) Gonzalez, S. M.; Hernandez, A. I.; Varela, C.; Rodrĭguez-Arĭs-
tegui, S.; Alvarez, R. M.; Garcĭa, A. B.; Lorenzo, M.; Rivero, V.; Oyarzabal, J.; Rabal,
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2006,16,1582e1585; (b) Davey, D. D. J. Org. Chem.1987, 52, 4379e4381; (c) Liu, Q;
Batt, D. G.; DeLucca, G. V.; Shi, Q.; Tebben, A. J. U.S. Patent US 2010/0160303 A1,
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340e348; (c) Knochel, P.; Calaza, M. I.; Hupe, E. In Metal Catalysed Cross-
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4.7.1. 7-(4-Methoxyphenyl)-3-methyl-5-p-tolylimidazo[1,2-a]pyr-
azin-8(7H)-one (9a). White solid, mp 263e265 ꢀC, yield 94%, 1H
NMR (300 MHz, CDCl3):
(d, J¼8.67 Hz, 2H), 6.56 (s, 1H), 3.83 (s, 3H), 2.43 (s, 3H), 1.80 (s, 3H).
13C NMR (75 MHz, CDCl3):
159.2, 152.9, 140.0, 138.0, 133.3, 132.2,
d 7.41e7.31 (m, 4H), 7.29e7.24 (m, 2H), 6.98
d
130.7, 129.1, 127.8, 127.5, 127.2, 120.1 (2), 114.5, 55.5, 21.4, 12.3.
HRMS (EI): calcd for C21H19ClN3O2: 345.1477, found: 345.1479.
4. (a) Donets, P. A.; Van Hecke, K.; Van Meervelt, L.; Van der Ecyken, E. V. Org. Lett.
2009, 11, 3618e3621; (b) Peskov, V. A.; Van Hove, S.; Donets, P. A.; Pereshivko,
O. P.; Van Hecke, K.; Van Meervelt, L.; Van der Eycken, E. V. Eur. J. Org. Chem.
2011, 1837e1840.
4.7.2. 7-(4-Methoxyphenyl)-3-methyl-5-phenylimidazo[1,2-a]pyr-
azin-8(7H)-one (9b). White solid, mp>300 ꢀC, yield 75%, 1H NMR
(300 MHz, CDCl3):
(s, 1H), 6.98 (d, J¼8.10 Hz, 2H), 6.60 (s, 1H), 3.83 (s, 3H), 1.79 (s, 3H).
13C NMR (75 MHz, CDCl3):
159.2, 152.9, 138.1, 133.4, 132.2, 130.8,
d
7.56e7.42 (m, 5H), 7.38 (d, J¼8.10 Hz, 2H), 7.28
5. Mehta, V. P.; Modha, S. G.; Ermolat’ev, D.; Van Hecke, K.; Van Meervelt, L.; Van
der Eycken, E. Aust. J. Chem. 2009, 62, 27e41.
6. For a thematic special issue on Coinage Metals in Organic Synthesis see; Chem.
d
Rev. 2008, 108, 2793e3442.
129.8, 128.5, 128.4, 127.6, 127.1, 120.2, 120.0, 114.6, 55.5, 12.3. HRMS
(EI): calcd for C20H17ClN3O2: 331.1321, found: 331.1320.
7. For an early review see: (a) Hoornaert, G. Bull. Soc. Chim. Belg. 1994, 103,
583e589 for a recent review see; (b) Pawar, V. G.; De Borggraeve, W. M. Syn-
thesis 2006, 2799e2814 using microwave irradiation, see; (c) Mehta, V. P.;
Appukkuttan, P.; Van der Eycken, E. Curr. Org. Chem. 2011, 15, 265e283; (d)
Topics in Heterocyclic Chemistry; Van der Eycken, E., Kappe, C. O., Eds.; Spinger:
Berlin/Germany, 2006; Vol. 1, p 267; (e) Kaval, N.; Bisztrav, K.; Dehaen, W.;
Kappe, C. O.; Van der Eycken, E. Mol. Diversity 2003, 7, 125e134; (f) Kaval, N.;
Singh, B. K.; Ermolat’ev, D. S.; Claerhout, S.; Van der Eycken, J.; Van der Eycken,
E. J. Comb. Chem. 2007, 9, 446e453.
4.7.3. 5-(3-Chlorophenyl)-3,7-dimethyl-6-phenylimidazo[1,2-a]pyr-
azin-8(7H)-one (9c). White solid, mp>300 ꢀC, yield 60%, 1H NMR
(300 MHz, CDCl3):
(75 MHz, CDCl3):
d
7.34 (m, 10H), 3.23 (s, 3H), 1.63 (s, 3H). 13C NMR
153.9,137.4,133.9,133.4,133.1,132.1,131.8,130.6,
d
8. (a) Mehta, V. P.; Sharma, A.; Van der Eycken, E. Adv. Synth. Catal. 2008, 350,
2174e2178; (b) Mehta, V. P.; Sharma, A.; Van der Eycken, E. Org. Lett. 2008, 10,
1147e1150; (c) Mehta, V. P.; Modha, S. G.; Van der Eycken, E. J. Org. Chem. 2009,
74, 6870e6873.
130.5, 130.4, 129.3, 129.2, 129.1, 128.7, 128.5, 126.7, 117.3, 32.9, 12.2.
HRMS (EI): calcd for C20H16ClN3O: 349.0982, found: 349.0973.
9. For representative examples of silver-catalyzed intramolecular cyclizations
using alkynes see: (a) Prajapati, R. K.; Kumar, J.; Verma, S. Chem. Commun. 2010,
46, 3312e3314; (b) Patil, N. T.; Singh, V. J. Organomet. Chem. 2011, 696, 419e432.
10. For representative examples of gold-catalyzed intramolecular cyclizations us-
ing alkyne see: (a) Ye, L.; Wang, Y.; Aue, D. H.; Zhang, L. J. Am. Chem. Soc. 2012,
4.7.4. 7-(4-Methoxybenzyl)-3-methyl-5-(thiophen-3-yl)imidazo[1,2-
a]pyrazin-8(7H)-one (9d). Grey solid, mp 190e192 ꢀC, yield 89%, 1H
NMR (300 MHz, CDCl3):
d
7.43e7.37 (m, 2H), 7.30 (d, J¼8.49 Hz, 2H),
7.23 (s, 1H), 7.11 (dd, J¼1.55, 4.65 Hz, 1H), 6.86 (d, J¼8.46 Hz, 2H),

D.D. Vachhani et al. / Tetrahedron 69 (2013) 359e365
365
ꢀ
ꢀ~
€
134, 31e34; (b) Jimenez-Nunez, E.; Echavarren, A. Chem. Commun. 2007,
333e346; (c) Ferrer, C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45,
1105e1109; (d) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2010, 49, 5232e5241; (e)
Rudolph, M.; Hashmi, A. S. K. Chem. Commun. 2011, 47, 6536e6544; (f) Cera, G.;
Crispino, P.; Monari, M.; Bandini, M. Chem. Commun. 2011, 47, 7803e7805.
11. Vachhani, D. D.; Mehta, V. P.; Modha, S. G.; Van Hecke, K.; Van Meervelt, L.; Van
der Eycken, E. V. Adv. Synth. Catal. 2012, 354, 1593e1599.
12. (a) Vekemans, J.; Pollers-Wieers, C.; Hoornaert, G. J. Heterocycl. Chem. 1983, 20,
€
919e923 For recent microwave-assisted synthesis, see; (b) Gising, J.; Ortqvist,
P.; Sandstrom, A.; Larhed, M. Org. Biomol. Chem. 2009, 7, 2809e2815.
13. Azzam, R.; De Borggraeve, W.; Compernolle, F.; Hoornaert, G. J. Tetrahedron Lett.
2004, 45, 1885e1888.
14. The geometry of the double bond was confirmed by 2D NMR (NOESY), for more
details see Supplementary data.
€