Diversity-oriented synthesis of substituted furo[2,3-b]pyrazines

Article abstract of DOI:10.1071/CH08376

A highly efficient method for the synthesis of diversely substituted furo[2,3-b]pyrazines has been elaborated. The Ag⁺- or iodine-mediated electrophilic cyclization of readily generated 5-chloro-3-substituted ethynyl-1-(4-methoxybenzyl)-pyrazin-2(1H)-ones affords substituted furo[2,3-b]pyrazines, which undergo various palladium catalyzed reactions to generate a library of difficult to attain diversely substituted furo[2,3-b]pyrazines. CSIRO 2009.

Full text of DOI:10.1071/CH08376

RESEARCH FRONT
Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2009, 62, 27–41
Diversity-Oriented Synthesis of Substituted
Furo[2,3-b]pyrazines
Vaibhav P. Mehta,A Sachin G. Modha,A Denis Ermolat’ev,A Kristof Van Hecke,B
Luc Van Meervelt,B and Erik V. Van der EyckenA,C
ALaboratory for Organic and Microwave-Assisted Chemistry (LOMAC), Department of Chemistry,
Katholieke Universiteit Leuven, Celestijnenlaan 200F, 3001, Leuven, Belgium.
BBiomolecular Architecture, Department of Chemistry, Katholieke Universiteit Leuven,
Celestijnenlaan 200F, 3001, Leuven, Belgium.
CCorresponding author. Email: erik.vandereycken@chem.kuleuven.be
A highly efficient method for the synthesis of diversely substituted furo[2,3-b]pyrazines has been elaborated. The Ag+-
or iodine-mediated electrophilic cyclization of readily generated 5-chloro-3-substituted ethynyl-1-(4-methoxybenzyl)-
pyrazin-2(1H)-ones affords substituted furo[2,3-b]pyrazines, which undergo various palladium catalyzed reactions to
generate a library of difficult to attain diversely substituted furo[2,3-b]pyrazines.
Manuscript received: 3 September 2008.
Final version: 25 October 2008.
Introduction
elaborated a novel cyclization protocol for the synthesis of
furo[2,3-b]pyrazines starting from 1-(4-methoxybenzyl)-3,5-
dichloropyrazine-2(1H)-ones by a Ag+-catalyzed cyclization
with concomitant cleavage of the 4-methoxybenzyl (PMB) pro-
tecting group (Scheme 1).[18] We now wish to describe a novel
approach for the synthesis of this interesting framework by
an iodocyclization[19] reaction. We will also comment on the
subsequent palladium-catalyzed cross-coupling reactions for
the decoration of both generated scaffolds to yield densely
substituted furo[2,3-b]pyrazines.
The construction of the furan ring, which is found in many
natural and biologically important compounds,[1–3] is attracting
considerable attention.[4] Heteroannulation processes for the
synthesis of ring-fused furans have been described by the
palladium-catalyzed annulation of alkynes.[5,6] Electrophilic
cyclization of unsaturated compounds has been proven to be
an efficient method for the one-step construction of sub-
stituted furans.[7–10] Different methods have been explored
for the electrophilic halocyclization of α-alkynyl carbonyl
compounds.[7,11] Several syntheses of fused furan moieties like
benzo[b]furans,[12] furopyridines,[13] and furopyrimidines[14]
are reported. The synthesis of furo[2,3-b]pyrazines[15] is
described by the cyclization of chloroketones.[16] However this
method is restricted to the synthesis of 2- or 2,3-disubstituted
furo[2,3-b]pyrazines. Being oxo-analogues of aloisines, which
are known to be selective kinase inhibitors for CDK 1/2/3
and GSK-3 α/β,[17] we were keen to explore the synthesis of
diversely substituted furo[2,3-b]pyrazines. We have previously
Results and Discussion
Analogously to our previously developed route[18] our sequence
starts with a regioselective Sonogashira cross-coupling reaction
at the reactive 3-position of the 3,5-dichloropyrazin-2(1H)-
one 1[20] to generate the 5-chloro-3-substituted ethynyl-
1-(4-methoxybenzyl)-pyrazin-2(1H)-ones 3 (Scheme 2 and
Table 1).[21] These substrates were further evaluated for
the cyclization to 2-chloro or 2-chloro-7-iodo substituted
PMB
N
PMB
N
R1
Cl
O
R1
O
R1
N
N
O
R2
2 mol% AgOTf
R2
Sonogashira
coupling
TFA (5 equiv.)
rt, 5–20 min
N
Cl
N
Cl
Cl
Inactive
Active
Active
R2
PMB ϭ 4-methoxybenzyl
R1
R3
N
N
O
Suzuki or
R2
Buchwald–Hartwig
coupling
Scheme 1. Synthesis of tri-substituted furo[2,3-b]pyrazine.
© CSIRO 2009 10.1071/CH08376
0004-9425/09/010027

RESEARCH FRONT
28
V. P. Mehta et al.
R1
Cl
N
N
O
O
PMB
PMB
N
AgOTf,
R2
TFA, CH2Cl2,
rt, 5–20 min
R1
Cl
N
O
R1
Cl
O
R2
2
4a–e
N
Cl
N
Pd(PPh3)2Cl2, Et3N
R1
N
I2, CH2Cl2,
1
DMF, MW, 80°C, 10 min
3a–k
R2
R2
rt, 5–15 min
Cl
N
I
5a–g
Scheme 2. Ag+- or I2-mediated cyclization to generate 2-chloro and 2-chloro-7-iodo substituted furo[2,3-b]pyrazines. MW, microwave.
Table 1. Synthesis of substituted 2-chloro and 2-chloro-7-iodo furo[2,3-b]pyrazinesA
Entry
4 or 5
Product
Cyclization time
[min]B
Yield of 3
[%]C
Yield of 4
[%]C
Yield of 5
[%]C
O
O
N
O
O
1
4a
5
5
99
92
83
85
96
92
91
79
–
–
–
–
O
Cl
Cl
N
N
N
2
3
4
4b
4c
4d
O
N
N
O
20
20
BiPh
Cl
O
N
N
O
N
Cl
Bn
N
O
Me
5
6
4e
5a
5
5
99
82
91
–
–
Cl
N
N
N
O
76
Cl
I
Me
Me
Cl
N
O
7
5b
7
94
–
86
N
I
(Continued)

RESEARCH FRONT
Diversely Substituted Furo[2,3-b]pyrazines
29
Table 1. (Continued)
Entry
4 or 5
Product
Cyclization time
[min]B
Yield of 3
[%]C
Yield of 4
[%]C
Yield of 5
[%]C
O
F
N
N
O
8
5c
10
99
–
88
Cl
I
N
N
O
Me
9
5d
5e
5
99
88
–
–
91
96
Cl
I
N
N
O
S
10
10
Cl
I
O
N
O
11
11
5f
6
96
84
–
–
96
68
Cl
N
I
Me
Cl
N
O
5g
10
N
I
AThe Sonogashira cross-coupling reaction was run on a 5 mmol scale, using acetylene (1.20 equiv.), Pd(PPh3)2Cl2 (1 mol%), and CuI (3 mol%) in DMF/Et3N
(1:1, 20 mL) under microwave irradiation at a maximum power of 80W and 80◦C ceiling temperature for 10 min. Cyclization reactions was run on a 2 mmol
scale, using AgOTf (2 mol%), TFA (5.0 equiv.) in DCM (12 mL) at room temperature for the stipulated time. The iodocyclization was run on 2 mmol scale
using I2 (2.0 equiv.) in DCM (12 mL) at room temperature for the stipulated time.
BCyclization time as determined by TLC.
CIsolated yields (single runs).
furo[2,3-b]pyrazines4and 5usingAg+ orI2 respectively.Apply-
ing 2 mol% AgOTf in 20% TFA/CH2Cl2 resulted in smooth
formation of the desired compounds 4a–e in 5–20 min at room
temperature. For the iodocyclization, compounds 3e–k were
reacted with 2.0 equiv. of I2 in dichloromethane to afford the
requested compounds 5a–g in 5–15 min at room temperature.
These mild and selective procedures provide mono- and di-
halo-substituted furo[2,3-b]pyrazines, which are susceptible to
various transition-metal catalyzed coupling reactions for the
decoration of the scaffold (Scheme 2 and Table 1).[18]
We were keen to know whether it should be possible to per-
form a regioselective Suzuki–Miyaura cross-coupling on the
7-position of the dihalogenated substrates 5, as a higher reac-
tivity at the site of the iodine could be expected. As a proof of
concept the reaction of 2-chloro-6-cyclopentyl-7-iodofuro[2,3-
b]pyrazine 5a with p-MeO-phenylboronic acid 6a was investi-
gated applying microwave irradiation (Scheme 3, Table 2, entry
1).[22] The reaction proceeded to full conversion in a mere
20 min to afford the mono-substituted compounds 7a and 7ꢀꢀa
as well as the di-substituted compound 7ꢀa. Several attempts
were made to obtain regioselective arylation of the 7-position
(Table 2). Finally the best conditions for mono arylation were
found to be 1.25 equiv. of boronic acid, 1 mol% of Pd(PPh3)4,
2.0 equiv. of K2CO3 in 4 mL of N,N-dimethylformamide (DMF)
at a ceiling temperature of 120◦C using 200W maximum power
during 20 min, which afforded the required compound 7a in 91%
isolated yield with only trace amounts of 7ꢀa and 7ꢀꢀa (Table 2,
entry 4).
Having optimized the conditions, we reacted an array of
differentlysubstituted2-chloro[18] and2-chloro-7-iodofuro[2,3-
b]pyrazines 4a–c,e and 5a–g with various boronic acids 6a–l
that bear electron withdrawing or electron donating groups
(Scheme 4, Table 3). The corresponding arylated products
7b–j and 8a–d were obtained in excellent yields regardless of
the bulkiness of the R1 and R2-substitutents of the boronic acid.
Even when 4-cyano-phenylboronic acid was used the corre-
sponding arylated product was obtained in an excellent 91%
yield after 45 min of microwave irradiation (Table 3, entry 9).

RESEARCH FRONT
30
V. P. Mehta et al.
N
N
N
N
O
N
O
O
Cl
Cl
N
ϩ
I
7a
MeO
O
5a
Conditions
ϩ
7؅a
OMe
OMe
B(OH)2
6a
N
N
ϩ
OMe
I
7؆a
MeO
Scheme 3. Optimization of the conditions for the regioselective Suzuki–Miyaura cross-coupling reaction.
Table 2. Optimization of the conditions for the regioselective Suzuki–Miyaura cross-coupling reactionA
Entry
Boronic acid equiv.
Base (equiv.)
Solvent
Temp. [◦C]
Time [min]
Ratio [%] of
7a/7ꢀa/7ꢀꢀa/5aB
1
2
3
4
5
1.25
1.05
1.25
1.25
1.25
Na2CO3 (2.0)
Na2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
K2CO3 (2.0)
DMF:H2O (1:1)
DMF:H2O (1:1)
Dioxan:H2O (1:1)
DMF
100
90
110
120
110
20
20
20
10
10
70:21:8:0
60:15:0:15
74:20:0:0
95C:4:0:0
85:5:0:10
DMF
AThe Suzuki–Miyaura cross-coupling reaction was run on a 0.3 mmol scale of 5a, using boronic acid 6a (1.05–1.25 equiv.), Pd(PPh3)4 (1 mol%), and base
(2.0 equiv.) in the indicated solvent (4 mL) under microwave irradiation at a maximum power of 200W and stipulated temperature for the indicated time.
BRatios were determined by GC-MS analysis.
CThe isolated yield was 91% (single run).
R1
Cl
N
N
R1
Cl
N
N
O
O
Pd(PPh3)4, K2CO3
DMF
R2
R2
MW, 120°C, 20–30 min
I
R3
7b–j
5a–g
ϩ
R3-B(OH)2
6a–l
R1
N
R1
Cl
N
N
O
O
Pd(PPh3)4, Na2CO3
DMF/H2O (1:1)
R2
R2
MW, 100°C, 10 min
R3
N
8a–d
4a–c,e
Scheme 4. Microwave (MW)-assisted Suzuki–Miyaura cross-coupling of compounds 4 and 5.
The structure of compound 8d was unambiguously assigned by
X-ray analysis (Fig. 1).[23]
it should be possible to perform a regioselective Sonogashira
cross-coupling reaction on the 7-position of the dihalogenated
substrates 5. However, using the same conditions as for the sub-
strates 4a–c, the reaction turned out to be rather sluggish and
resulted in the formation of a complex mixture of compounds.
To our satisfaction we found that when TBAI was omitted from
the reaction mixture, the conversion proceeded well when 5e was
reactedwith3-ethynylthiophene2i (1.05equiv.)uponmicrowave
irradiation for 7 min at a ceiling temperature of 95◦C and a maxi-
mum power of 150 W. The monoalkynylated compound 10a was
obtained in 89% yield next to only traces of the dialkynylated
product (4%) (Scheme 5,Table 4, entry 4). Similarly compounds
10b,c were regioselectively synthesized applying this protocol
(Scheme 5, Table 4, entries 5 and 6).
Having successfully established the protocol for the Suzuki–
Miyaura cross-coupling, we were next interested in checking
whether Sonogashira cross-coupling[24] could be performed
on substrates 4 and 5. Substrate 4a was reacted with acetyl-
ene (1.3 equiv.) in the presence of tetrabutylammonium iodide
(TBAI) (1.2 equiv.) as additive, Pd(PPh3)Cl2 (5 mol%) and CuI
(10 mol%) as catalytic system in DMF/triethylamine (TEA) (1:1,
4 mL) under microwave irradiation at 80W maximum power
and 100◦C ceiling temperature for 15 min.[25] Gratifyingly, we
obtained the desired alkynylated product 9a in an excellent yield
of 85%. Remarkably, if no TBAI was added; only the starting
material was recovered even after 1 h of microwave irradiation.
Analogously compounds 9b,c were synthesized in 92% and 96%
yield (Table 4, entries 2 and 3). We then investigated whether
We then investigated whether the selectively generated 7-
substituted 2-chloro furo[2,3-b]pyrazines 7 could be further

RESEARCH FRONT
Diversely Substituted Furo[2,3-b]pyrazines
31
decorated at their 2-position (Scheme 6).Three different starting
compounds 7b,d,e were subjected to the optimized Suzuki–
Miyaura and Sonogashira conditions for chloro substitution
to result in the formation of the corresponding substituted
furo[2,3-b]pyrazines in good to excellent yields (Table 5).
Finally, we have investigated the Suzuki cross-coupling to
generate symmetrically substituted furo[2,3-b]pyrazines starting
from the 2-chloro-,7-iodo-substituted compound 5g (Scheme 7).
A mixture of this compound together with a large excess of
boronic acid 6o (3.0 equiv.), Pd(PPh3)4 (5 mol%) and K2CO3
(5.0 equiv.) in DMF (4 mL) was irradiated for 25 min at 140◦C
ceiling temperature using 300W maximum power. The desired
disubstituted compound 12a could be isolated in 93% yield.
under an argon atmosphere. After stirring for 45 min, a solu-
tion of 4-methoxybenzylamine (32 mL, 0.25 mol) in methanol
(100 mL)wasaddeddropwisetothereactionmixtureandstirring
was continued for 2 h at 60◦C. NaCN (14.7 g, 0.25 mol) was then
addedandthereactionmixturewasleftstirringovernightat60◦C
(in a fumehood!). The reaction mixture was cooled to room tem-
perature and extracted with dichloromethane (3 × 300 mL). The
organic phases were combined, washed with brine (1 × 200 mL),
andthendriedfor2 hoverNa2SO4 andconcentrated.Theresidue
was dissolved in dry ether (500 mL) and the resulting solution
was cooled to 0◦C. Dry HCl gas was bubbled through the solu-
tion upon vigorous stirring for 20 min and the precipitate was
filtered off and dried. The precipitate was then suspended in a
1 L flask in dry toluene (400 mL) and oxalyl chloride (86 mL,
1 mol, 4.0 equiv.) was added dropwise under an argon atmo-
sphere. After stirring for 45 min, triethylamine hydrochloride
(52 g, 0.38 mol, 1.5 equiv.) was added in small portions, DMF
(2 mL, 25 mmol, 0.1 equiv.) was added and the reaction mix-
ture was kept stirring for 2 days. The reaction mixture was
concentrated and the residue was purified by silica gel column
chromatography (from 10% to 30% EtOAc in petroleum ether)
to afford 3,5-dichloropyrazin-2(1H)-one 1 as a white solid.
Conclusion
In conclusion we have developed a novel procedure for the
generation of difficult to attain diversely substituted furo[2,3-
b]pyrazines starting from 3,5-dichloropyrazin-2(1H)-ones
pyrazinones protected with a p-methoxybenzylether at their N1
position.The key step of this sequence is a mild, one stepAg+- or
iodine-mediated electrophilic cyclization with concomitant
cleavage of the protecting p-methoxybenzylether. The corre-
sponding compounds were evaluated for selective palladium-
catalyzed cross-coupling reactions. The chloro substituent,
inactive in the pyrazinone, becomes sensitive to substitution
in the generated pyrazines. We have also demonstrated that in
the case of the generated 2-chloro,7-iodo furo[2,3-b]pyrazines,
regioselective Suzuki–Miyaura and Sonogoshira cross-coupling
reactions are possible at the 7-position. The application of
microwave irradiation during the different steps of the sequence
has been shown to be highly valuable for speeding up reactions.
3,5-Dichloro-1-(4-methoxybenzyl)pyrazin-
2(1H)-one (1a)
53% yield. δH (300 MHz, CDCl3) 7.29 (d, J 7.2, 2H), 7.18 (s,
1H), 6.91 (d, J 7.2, 2H), 5.04 (s, 2H), 3.81 (s, 3H). δC (75 MHz,
CDCl3) 160. 4, 152.0, 147.4, 130.6, 126.1, 125.5, 124.2, 114.9,
55.5, 53.4. m/z (HR-MS EI) Found 285.0119. C12H10Cl2N2O2
requires 285.0119.
3,5-Dichloro-1-(4-methoxybenzyl)-6-methyl-pyrazin-
2(1H)-one (1b)
Experimental
General Experimental Methods
51% yield. δH (400 MHz, CDCl3) 7.16 (d, J 7.1, 2H), 6.86
(d, J 7.3, 2H), 5.29 (s, 2H), 3.79 (s, 3H), 2.44 (s, 3H). δC
(100 MHz, CDCl3) 159.6, 153.2, 143.7, 136.2, 128.7, 125.9,
123.9, 114.5, 55.4, 49.6, 16.8. DEPT (100 MHz, CDCl3) 128.6,
114.5, 113.8, 55.3, −49.8, 16.9. m/z (HR-MS EI) Found
298.0279. C13H12Cl2N2O2 requires 298.0276.
1H NMR spectra were recorded on a Bruker Avance 300 MHz
instrument using CDCl3 as solvent unless otherwise stated. The
1H and 13C chemical shifts are reported in parts per million
relative to tetramethylsilane using the residual solvent 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 150–250◦C, as required. High-resolution elec-
tron impact (EI) mass spectra were performed with a resolution
of 10000. The low-resolution spectra were obtained with a
HP5989A MS instrument. For TLC, analytical TLC plates (Alu-
gram SIL G/UV254) and 70–230 mesh silica gel (E. M. Merck)
were used.
6-Benzyl-3,5-dichloro-1-(4-methoxybenzyl)pyrazin-
2(1H)-one (1c)
32% yield. δH (300 MHz, CDCl3) 7.40–7.32 (m, 3H), 7.12–
7.07 (m, 4H), 6.88 (d, J 9.6, 2H), 5.10 (s, 2H), 4.15 (s, 2H), 3.80
(s, 3H). δC (75 MHz, CDCl3) 159.7, 153.4, 145.3, 137.4, 133.9,
129.6, 128.2, 127.9, 127.5, 126.3, 125.4, 114.7, 55.5, 49.3, 32.3.
DEPT (75 MHz, CDCl3) 129.9, 128.5, 128.2, 127.8, 115.0, 55.7,
−49.6, −35.6. m/z (HR-MS EI) Found 250.0879. C13H15ClN2O
requires 250.0873; Found 374.0596. C19H16Cl2N2O2 requires
374.0589.
Microwave Irradiation Experiments
A multimode Milestone MicroSYNTH microwave reactor (Lab-
oratory Microwave Systems) was used in the standard configura-
tionasdelivered, includingproprietarysoftware.Allexperiments
were carried out in sealed microwave process vials (15, 50 mL).
Temperature control was performed using both external infrared
and internal fibre optic sensors.After completion of the reaction,
the vial was cooled to 25◦C with air jet cooling before opening.
3,5-Dichloro-1-(4-methoxybenzyl)-6-(4-
methoxyphenyl)pyrazin-2(1H)-one (1d)
76% yield. δH (400 MHz, CDCl3) 7.04 (d, J 7.2, 2H), 6.97
(d, J 7.3, 2H), 6.81 (d, J 7.2, 2H), 6.72 (d, J 7.1, 2H), 5.05 (s,
2H), 3.88 (s, 3H), 3.76 (s, 3H). δC (100 MHz, CDCl3) 161.1,
159.5, 152.9, 145.8 138.6, 130.9, 129.4, 126.9, 124.7, 122.3,
114.5, 113.9, 55.5, 55.3, 50.8. DEPT (100 MHz, CDCl3) 130.9,
129.4, 114.4, 113.8, 55.4, 55.3, −50.7. m/z (HR-MS EI) Found
390.0549. C19H16Cl2N2O3 requires 390.0538.
A Typical Procedure for the Preparation of
1-(4-Methoxybenzyl)-3,5-dichloropyrazin-
2(1H)-ones 1a–d
In a 1 L round-bottomed flask NaHSO3 (26.1 g, 0.25 mol) was
dissolved in 400 mL water and aldehyde was added dropwise

RESEARCH FRONT
32
V. P. Mehta et al.
Table 3. Microwave-assisted Suzuki–Miyaura cross-coupling of compounds 4A and 5B
Entry Compd
Product
Yield Entry Compd
[%]C
Product
Yield
[%]C
N
N
O
MeO
N
O
Cl
t
Bu
1
7b
78
8
7i
89
Cl
N
BnO
t
Bu
Bn
N
N
Me
Cl
N
N
O
O
Me
Cl
2
7c
86
9
7jD
91
OEt
CN
Bn
N
N
O
S
MeO
Cl
N
N
O
3
4
5
7d
7e
7f
87
89
78
10
11
12
8a
8b
8c
85
Et
COCH
3
Me
Me
Me
Cl
N
O
MeO
N
N
O
N
90
OMe
Me
OMe
Me
MeO
MeO
F
N
N
O
N
O
BiPh
Cl
87
N
CF
COOEt
3
Me
Me
Cl
N
N
O
Bn
N
N
O
6
7g
90
13
8d
100
Me
Me
(Continued)

RESEARCH FRONT
Diversely Substituted Furo[2,3-b]pyrazines
33
Table 3. (Continued)
Entry Compd
Product
Yield Entry Compd
[%]C
Product
Yield
[%]C
Bn
Cl
N
N
O
Me
7
7h
79
Br
AReaction conditions for 8a–d: the Suzuki–Miyaura cross-coupling reaction was run on a 0.3 mmol scale of 4a–c,e, using boronic acid (1.50 equiv.),
Pd(PPh3)4 (1 mol%), and Na2CO3 (2.0 equiv.) in DMF/H2O (1:1, 4 mL), under microwave irradiation at a maximum power of 100W and 100◦C ceiling
temperature for 10 min.
BReaction conditions for 7b–j: the Suzuki–Miyaura cross-coupling reaction was run on a 0.3 mmol scale of 5a–g, using boronic acid (1.25 equiv.), Pd(PPh3)4
(1 mol%), and K2CO3 (2 equiv.) in DMF (4 mL) under microwave irradiation at a maximum power of 200W and 120◦C ceiling temperature and 20–30 min.
CIsolated yields (single runs).
D45 min of irradiation was needed.
C22
C21
C23
C16
C17
C20
C15
C28
C9
C3
C29
C4
N1
C14
C10
C1
C18
C12
C5
C27
C59
C30
C8
C26
C19
C2
C25
C7
O1
C6
C11
C13
N2
O2
C58
C37
C31
C24
C36
C60
C32
C52
C35
C57
C51
C50
C33
C41
C40
N4
N3
C34
C53
C38
C55
C56
C43
C54
C39
C49
C46
C42
C48
C44
C47
C45
Fig. 1. X-Ray crystal structure[23] of 8d. Thermal ellipsoids at the 50% probability level.
Sonogashira Coupling Reaction on 1-(4-Methoxybenzyl)-
3,5-dichloropyrazin-2(1H)-ones 1a–d. A Typical Procedure
10% to 30% EtOAc in petroleum ether) to afford compounds
3a–k.
In a 50 mL microwave vial were successively dissolved in
DMF/Et3N (1:1, 20 mL), pyrazinone 1 (5 mmol), acetylene
2 (6.25–7.5 mmol), Pd(PPh3)Cl2 (35 mg, 1 mol%), and CuI
(28 mg, 3 mol%). The reaction tube was sealed and irradiated
in a microwave reactor at a ceiling temperature of 80◦C at
80W maximum power for 10 min. Afterwards the reaction mix-
ture was cooled with an air flow for 15 min, extracted with
dichloromethane (2 × 150 mL), and dried over MgSO4. The
solvent was removed under reduced pressure and the residue
was subjected to silica gel column chromatography (from
1-(4-Methoxybenzyl)-5-chloro-6-(4-methoxyphenyl)-3-
(2-(4-methoxyphenyl)ethynyl)-pyrazin-2(1H)-one (3a)
99% yield. δH (300 MHz, CDCl3) 7.63 (d, J 8.91, 2H), 7.06
(d, J 8.79, 2H), 6.96 (d, J 8.43, 2H), 6.90 (d, J 8.85, 2H), 6.84 (d,
J 8.49, 2H), 6.73 (d, J 8.55, 2H), 5.05 (s, 2H), 3.87 (s, 3H), 3.84
(s, 3H), 3.76 (s, 3H). δC (75 MHz, CDCl3) 160.9, 159.3, 139.6,
138.1, 134.5, 131.0, 129.3, 127.6, 123.0, 114.3, 113.9, 98.9,
85.3, 55.5, 55.4, 55.3, 49.9. m/z (HR-MS EI) Found: 486.1353.
C28H23O4N2Cl requires 486.1346.

RESEARCH FRONT
34
V. P. Mehta et al.
R1
N
N
R1
N
N
O
O
R3
2e,l,m
R2
R2
Pd(PPh3)2Cl2, Et3N
DMF, TBAI
MW, 100°C, 15 min
Cl
9a–c
4a–c
R3
R1
Cl
N
N
R1
Cl
N
N
O
O
R3
2i,e,n
R2
R2
Pd(PPh3)2Cl2, Et3N
DMF
I
MW, 95°C, 7–10 min
5c,e
10a–c
R3
Scheme 5. Microwave (MW)-assisted Sonogashira cross-coupling reactions on substrates 4 and 5.
Table 4. Evaluation of the microwave-assisted Sonogashira cross-coupling reaction
Entry Compd
ProductA
Yield Entry Compd
[%]C
ProductB
Yield
[%]C
MeO
Bn
Cl
N
N
O
S
N
O
OMe
1
9a
85
4
10a
89 (4)
N
S
Bn
Cl
N
N
O
S
MeO
N
N
O
2
9b
92
5
10b
86 (5)
Et
Me
Me
MeO
MeO
F
N
N
O
N
N
O
BiPh
3
9c
96
6
10c
74 (9)
Cl
Hexyl
AReaction conditions for 9a–c: the reaction was run on a 0.3 mmol scale of 4a–c, using acetylene (1.3 equiv.), Pd(PPh3)2Cl2 (5 mol%), CuI (10 mol%),
and tetrabutylammonium iodide (TBAI) (2.0 equiv.), in DMF/Et3N (1:1, 4 mL) under microwave irradiation at a maximum power of 80W at 100◦C ceiling
temperature for 15 min.
BReaction conditions for 10a–c: the reaction was run on a 0.3 mmol scale of 5c,e, using acetylene (1.05 equiv.), Pd(PPh3)2Cl2 (1 mol%), and CuI (3 mol%),
in DMF/Et3N (1:1, 4 mL) under microwave irradiation at a maximum power of 80W and 95◦C ceiling temperature for 7–10 min.
CIsolated yields (single runs); yields in parenthesis indicate dialkynylated product.
1-(4-Methoxybenzyl)-5-chloro-3-(2-(4-ethylphenyl)
ethynyl)-6-(4-methoxyphenyl)pyrazin-2(1H)-one (3b)
8.5, 2H), 6.73 (d, J 8.5, 2H), 5.06 (s, 2H), 3.88 (s, 3H), 3.77
(s, 3H), 2.66 (m, 2H), 1.25 (t, J 15.3, 7.5, 3H). δC (75 MHz,
CDCl3) 161.3, 159.7, 156.2, 146.9, 139.8, 138.8, 133.2, 131.3,
129.6, 128.4, 127.9, 127.7, 123.3, 119.1, 114.7, 114.3, 99.0, 85.9,
92% yield. δH (300 MHz, CDCl3) 7.60 (d, J 8.1, 2H), 7.22
(m, 2H), 7.05 (d, J 8.4, 2H), 6.95 (d, J 8.4, 2H), 6.83 (d, J

RESEARCH FRONT
Diversely Substituted Furo[2,3-b]pyrazines
35
R1
R4
N
N
O
R4-B(OH)2 6f,m,n
R2
Pd(PPh3)4, Na2CO3
DMF/H2O (1:1)
MW, 100°C, 10 min
R1
Cl
N
R3
O
11a–c
R2
ϩ
R1
N
N
O
N
R4
R3
2e
R2
7b,d,e
Pd(PPh3)2Cl2, Et3N
DMF, TBAI,
MW, 100°C, 15 min
R3
11d
R4
Scheme 6. Microwave (MW)-assisted decoration of the 7-substituted 2-chloro furo[2,3-b]pyrazines.
Table 5. Microwave-assisted decoration of the 7-substituted 2-chloro furo[2,3-b]pyrazinesA
Entry
Compd
Product
Yield [%]B
Bn
N
O
S
N
1
11a
87
tBu
COCH3
N
O
N
2
11b
92
OEt
Me
tBu
Me
N
O
N
3
11c
95
F
OMe
O
Bn
N
N
S
4
11d
86
Me
COCH3
AReaction conditions for 11a–c: the reaction was run on a 0.3 mmol scale of 7, using boronic acid (1.5 equiv.), Pd(PPh3)4 (1 mol%),
and Na2CO3 (2 equiv.) in DMF/H2O (1:1, 4 mL) under microwave irradiation using a maximum power of 100W at 100◦C ceiling
temperature for 10 min; reaction condition for 11d: the reaction was run on a 0.3 mmol scale of 7, using acetylene (1.3 equiv.),
Pd(PPh3)2Cl2 (5 mol%), CuI (10 mol%), and TBAI (1.2 equiv.) as additive, in DMF/Et3N (1:1, 4 mL) under microwave irradiation
using a maximum power of 80W and 100◦C ceiling temperature for 15 min.
BIsolated yields (single run).

RESEARCH FRONT
36
V. P. Mehta et al.
Me
N
N
O
Me
Cl
N
O
Pd(PPh3)4,
K2CO3, DMF
4-F-Ph B(OH)2
ϩ
N
6o
MW, 140°C, 25 min
I
F
12a
5g
93% yield
F
Scheme 7. Suzuki cross-coupling to generate symmetrically substituted furo[2,3-b]pyrazines. MW, microwave.
55.8, 55.7, 50.3, 29.4, 15.6. m/z (HR-MS EI) Found: 484.1577.
1-(4-Methoxybenzyl)-5-chloro-3-(2-(3-fluorophenyl)
C29H25O3N2Cl requires 484.1554.
ethynyl)-6-(4-methoxyphenyl)pyrazin-2(1H)-one (3h)
Yellow solid in 99% yield. mp 142–145◦C. δH (300 MHz,
CDCl3) 7.46 (d, J 7.32, 1H), 7.38–7.32 (q, J 5.49, 2.73, 2H),
7.11–7.05 (m, 3H), 6.97 (d, J 8.22, 2H), 6.83 (d, J 9.03, 2H),
6.72 (d, J 9.12, 2H), 5.06 (s, 2H), 3.88 (s, 3H), 3.76 (s, 3H).
δC (75 MHz, CDCl3) 163.9, 161.0, 159.4, 155.84, 139.3, 138.7,
130.9, 130.2, 129.3, 128.6, 127.6, 127.2, 123.5, 122.7, 119.5,
117.3, 114.4, 113.9, 96.1, 86.3, 55.5, 50.0. m/z (HR-MS EI)
Found 474.1154. C27H20O3N2ClF requires 474.1146.
3-(1,1ꢀ-Biphenyl-4-ylethynyl)-5-chloro-1-(4-
methoxybenzyl)-6-(4-methoxyphenyl)pyrazin-
2(1H)-one (3c)
83% yield. δH (300 MHz, CDCl3) 7.75 (d, J 8.2, 2H), 7.61
(m, 5H), 7.43 (m, 3H), 7.07 (d, J 8.7, 2H), 6.97 (d, J 8.8, 2H),
6.84 (d, J 8.6, 2H), 6.73 (d, J 8.5, 2H), 5.07 (s, 2H), 3.88 (s, 3H),
3.77 (s, 3H). δC (75 MHz, CDCl3) 160.9, 159.3, 155.8, 142.5,
140.0, 139.1, 138.6, 133.1, 132.9, 130.9, 129.2, 128.9, 127.9,
127.6, 127.2, 127.1, 122.8, 120.4, 114.3, 113.9, 98.1, 86.5, 55.4,
55.2, 49.9. m/z (HR-MS EI) Found: 532.1549. C33H25O3N2Cl
requires 532.1554.
1-(4-Methoxybenzyl)-6-benzyl-5-chloro-3-(2-(thiophen-
3-yl)ethynyl)pyrazin-2(1H)-one (3i)
88% yield. δH (300 MHz, CDCl3) 7.76 (s, 1H), 7.38–7.30
(m, 5H), 7.14–7.09 (m, 4H), 6.88 (d, J 8.94, 2H), 5.11 (s, 2H),
4.17 (s, 2H), 3.79 (s, 3H). δC (75 MHz, CDCl3) 159.5, 156.2,
138.7, 137.5, 134.3, 132.2, 130.3, 129.5, 128.3, 127.6, 126.5,
125.7, 120.8, 114.6, 93.5, 85.5, 55.4, 48.4, 35.6. m/z (HR-MS
EI) Found 446.0858. C25H19O2N2SCl requires 446.0856.
1-(4-Methoxybenzyl)-5-chloro-6-(4-methoxyphenyl)-
3-(2-(pyridin-4-yl)ethynyl)pyrazin-2-(1H)-one (3d)
85% yield. δH (300 MHz, CDCl3) 8.65 (d, J 5.2, 2H), 7.50 (d,
J 6.0, 2H), 7.07 (d, J 8.4, 2H), 6.97 (d, J 8.7, 2H), 6.83 (d, J 8.6,
2H), 6.74 (d, J 8.4, 2H), 5.08 (s, 2H), 3.89 (s, 3H), 3.77 (s, 3H).
δC (75 MHz, CDCl3) 161.1, 159.4, 155.7, 149.9, 140.2, 130.7,
129.7, 129.3, 128.6, 128.4, 127.8, 126.9, 126.0, 114.4, 113.9,
93.7, 89.0, 55.5, 55.3, 50.1. m/z (HR-MS EI) Found: 457.1208.
C26H20ClN3O3 requires 457.1193.
1-(4-Methoxybenzyl)-3-(2-(4-tert-butylphenyl)ethynyl)-
5-chloro-6-(4-methoxyphenyl)pyrazin-2(1H)-one (3j)
Yellow solid in 96% yield. mp 178–180◦C. δH (300 MHz,
CDCl3) 7.62 (d, J 9.4, 2H), 7.39 (d, J 9.1, 2H), 7.05 (d, J 9.6,
2H), 6.96 (d, J 9.2, 2H), 6.84 (d, J 9.3, 2H), 6.73 (d, J 9.4, 2H),
5.06 (s, 2H), 3.88 (s, 3H), 3.77 (s, 3H), 1.33 (s, 9H). δC (75 MHz,
CDCl3) 160.9, 159.3, 155.9, 153.4, 139.5, 138.4, 132.6, 131.0,
129.5, 129.3, 127.6, 127.4, 125.6, 123.0, 122.3, 118.6, 114.4,
113.9, 98.7, 85.6, 55.5, 55.3, 50.0, 35.1, 31.2. m/z (HR-MS EI)
Found 512.1867. C31H29O3N2Cl requires 512.1867.
1-(4-Methoxybenzyl)-6-benzyl-5-chloro-3-
(2-p-tolylethynyl)pyrazin-2(1H)-one (3e)
99% yield. δH (300 MHz, CDCl3) 7.56 (d, J 8.07, 2H), 7.38–
7.33 (m, 3H), 7.19–7.10 (m, 6H), 6.88 (d, J 8.79, 2H), 5.11
(s, 2H), 4.17 (s, 2H), 3.79 (s, 3H), 2.38 (s, 3H). δC (75 MHz,
CDCl3) 159.5, 156.2, 140.4, 138.9, 137.3, 134.3, 132.6, 129.5,
128.3, 127.7, 126.6, 118.5, 114.6, 98.8, 85.3, 55.4, 48.4, 35.6,
21.8. m/z (HR-MS EI) Found 454.1464. C28H23O2N2Cl requires
454.1448.
1-(4-Methoxybenzyl)-5-chloro-3-(2-
cyclopropylethynyl)-6-methylpyrazin-2(1H)-one (3k)
1-(4-Methoxybenzyl)-5-chloro-3-(2-
cyclopentylethynyl)pyrazin-2(1H)-one (3f)
84% yield. δH (300 MHz, CDCl3) 7.17 (d, J 8.22, 2H), 6.85
(d, J 9.12, 2H), 5.25 (s, 2H), 3.78 (s, 3H), 2.44 (s, 3H), 1.61–
1.57 (s, 1H), 0.97–0.93 (m, 4H). δC (75 MHz, CDCl3) 159.4,
156.2, 137.6, 135.5, 128.6, 126.4, 114.4, 103.7, 55.3, 48.8, 17.1,
9.5. m/z (HR-MS EI) Found: 328.0982. C18H17O2N2Cl requires
328.0979.
Yellow solid in 82% yield. δH (300 MHz, CDCl3) 7.28 (d,
J 9.12, 2H), 7.10 (s, 1H), 6.90 (d, J 9.12, 2H), 4.99 (s, 2H),
3.81 (s, 3H), 2.96–2.91 (m, 1H), 2.24–1.99 (m, 2H), 1.78 (s,
4H), 1.60 (s, 2H). δC (75 MHz, CDCl3) 160.1, 155.0, 141.4,
130.5, 126.4, 125.9, 125.4, 114.7, 106.0, 55.4, 52.5, 33.5, 31.0,
25.4. m/z (HR-MS EI) Found 342.1141. C19H19O2N2Cl requires
342.1135.
A Typical Procedure for the Preparation of
1-(4-Methoxybenzyl)-5-chloro-6-methyl-3-(2-o-
tolylethynyl)pyrazin-2(1H)-one (3g)
Furopyrazines 4a–e
In a 25 mL flask pyrazinone 3 (2 mmol) was dissolved in
dry dichloromethane (12 mL). AgOTf (11 mg, 2 mol%) and
trifluoroacetic acid (0.8 mL, 10 mmol, 5 equiv.) were then added
and the reaction mixture was stirred at room temperature for
5–20 min. After reaction completion the solvent was evaporated
and the residue was subjected to silica gel column chromato-
graphy (from 20% to 50% CH2Cl2 in petroleum ether) to afford
compounds 4a–e.
Orange solid in 94% yield. mp 144–147◦C. δH (300 MHz,
CDCl3) 7.61 (d, J 7.32, 1H), 7.29–7.16 (m, 5H), 6.87 (d, J
8.22, 2H), 5.32 (s, 2H), 3.79 (s, 3H), 2.60 (s, 3H), 2.48 (s,
3H). δC (75 MHz, CDCl3) 159.5, 156.1, 141.7, 137.5, 136.3,
132.9, 129.8, 128.5, 126.8, 126.3, 125.7, 121.5, 114.5, 96.8,
89.4, 55.4, 48.9, 20.8, 17.3. m/z (HR-MS EI) Found 378.1141.
C22H19O2N2Cl requires 378.1135.

RESEARCH FRONT
Diversely Substituted Furo[2,3-b]pyrazines
37
2-Chloro-3,6-bis(4-methoxyphenyl)furo
[2,3-b]pyrazine (4a)
2-Chloro-7-iodo-3-methyl-6-o-tolylfuro
[2,3-b]pyrazine (5b)
Yellow solid in 96% yield. mp 118–119◦C. δH (300 MHz,
CDCl3) 7.88 (d, J 9.1, 2H), 7.83 (d, J 8.2, 2H), 7.04–6.99 (m,
5H), 3.89 (s, 6H). δC (75 MHz, CDCl3) 161.9, 161.7, 160.5,
154.1, 144.5, 143.1, 140.1, 131.4, 129.2, 129.1, 128.9, 127.5,
121.3, 114.7, 114.6, 113.7, 88.9, 55.6, 55.5. m/z (HR-MS EI)
Found 366.0793. C20H15O3N2Cl requires 366.0771.
Yellow solid in 86% yield. mp 158–161◦C. δH (300 MHz,
CDCl3) 7.61 (d, J 7.32, 1H), 7.45 (m, 1H), 7.34 (m, 2H),
2.77 (s, 3H), 2.41 (s, 3H). δC (75 MHz, CDCl3) 160.9, 153.3,
147.3, 145.7, 139.8, 138.4, 131.1, 128.2, 125.8, 64.6, 22.6,
20.6. m/z (HR-MS EI) Found 383.9522. C14H10ON2ICl requires
383.9526.
2-Chloro-6-(3-fluorophenyl)-7-iodo-3-(4-
methoxyphenyl)furo[2,3-b]pyrazine (5c)
2-Chloro-6-(4-ethylphenyl)-3-(4-
methoxyphenyl)furo[2,3-b]pyrazine (4b)
Light yellow solid in 88% yield. mp 210–214◦C. δH
(300 MHz, CDCl3) 8.13 (d, J 8.22, 1H), 8.03 (d, J 10.05,
1H), 7.85 (d, J 8.22, 2H), 7.53 (m, 1H), 7.24 (d, J 2.73,
1H), 7.03 (d, J 8.22, 2H), 3.89 (s, 3H). δC (75 MHz, CDCl3)
160.9, 156.4, 144.5, 131.6, 130.7, 128.4, 123.6, 118.2, 117.1,
114.9, 114.6, 113.8, 55.5. m/z (HR-MS EI) Found 479.9565.
C19H11O2N2IClF requires 479.9538.
92% yield. δH (300 MHz, CDCl3) 7.85 (m, 4H), 7.34 (d, J
8.1, 2H), 7.12 (s, 1H), 7.03 (d, J 8.3, 2H), 3.89 (s, 3H), 2.72
(m, 2H), 1.28 (t, J 7.4, 3H). δC (75 MHz, CDCl3) 162.3, 160.8,
154.4, 147.9, 145.2, 143.5, 140.1, 131.7, 129.4, 129.1, 126.5,
126.1, 114.0, 100.3, 55.8, 29.3, 15.7. m/z (HR-MS EI) Found
364.0975. C21H17O2N2Cl requires 364.0979.
6-(1,1ꢀ-Biphenyl-4-yl)-2-chloro-3-(4-methoxy-
phenyl)furo[2,3-b]pyrazine (4c)
3-Benzyl-2-chloro-7-iodo-6-p-tolylfuro
[2,3-b]pyrazine (5d)
91% yield. δH (300 MHz, CDCl3) 8.03 (d, J 9.00, 2H), 7.86 (d,
J 9.00, 2H), 7.77–7.65 (m, 4H), 7.52–7.47 (m, 3H), 7.21 (s, 1H),
7.05 (d, J 9.00, 2H), 3.90 (s, 3H). δC (75 MHz, CDCl3) 161.3,
160.5, 145.2, 143.5, 139.9, 131.3, 129.0, 128.1, 127.8, 127.1,
126.2, 113.7, 100.6, 55.4. m/z (HR-MS EI) Found 412.0983.
C25H17O2N2Cl requires 412.0979.
Yellow solid in 91% yield. mp 157–159◦C. δH (300 MHz,
CDCl3)8.16(d, J9.15, 2H), 7.37–7.26(m, 7H), 4.40(s, 2H), 2.44
(s, 3H). δC (75 MHz, CDCl3) 158.0, 152.8, 148.5, 145.5, 141.6,
141.2, 137.3, 129.6, 129.4, 128.7, 127.9, 126.9, 125.8, 59.7,
41.2, 21.7. m/z (HR-MS EI) Found 459.9829. C20H14ON2ICl
requires 459.9839.
3-Benzyl-2-chloro-7-iodo-6-(thiophen-3-yl)furo
[2,3-b]pyrazine (5e)
2-Chloro-3-(4-methoxyphenyl)-6-pyridin-4-
ylfuro[2,3-b]pyrazine (4d)
Yellow solid in 96% yield. mp 168–171◦C. δH (300 MHz,
CDCl3) 8.40 (d, J 1.83, 1H), 7.98 (d, J 5.49, 7H), 7.50–
7.48 (m, 1H), 7.37–7.23 (m, 5H), 4.40 (s, 2H). δC (75 MHz,
CDCl3) 155.3, 152.5, 148.5, 145.6, 141.0, 137.2, 130.1, 129.1,
128.7, 127.8, 126.9, 126.2, 59.6, 41.2. m/z (HR-MS EI) Found
451.9242. C17H10ON2SICl requires 451.9247.
79% yield. δH (300 MHz, CDCl3) 8.84 (br, 2H), 7.89 (m,
4H), 7.48 (s, 1H), 7.05 (d, J 8.8, 2H), 3.90 (s, 3H). δC (75 MHz,
CDCl3) 160.9, 157.3, 154.4, 149.4, 147.6, 144.4, 138.0, 136.9,
132.1, 131.5, 128.5, 128.4, 119.5, 113.8, 104.9, 55.4. m/z (HR-
MS EI) Found 337.0621. C18H12O2N3Cl requires 337.0618.
3-Benzyl-2-chloro-6-p-tolylfuro[2,3-b]pyrazine (4e)
6-(4-tert-Butylphenyl)-2-chloro-7-iodo-3-(4-methoxy
phenyl)furo[2,3-b]pyrazine (5f)
White solid in 91% yield. mp 214–216◦C. δH (300 MHz,
CDCl3) 7.80 (d, J 9.0, 2H), 7.38 (d, J 8.3, 2H), 7.33–7.22 (m,
5H), 7.05 (s, 1H), 4.37 (s, 2H), 2.42 (s, 3H). δC (75 MHz, CDCl3)
161.6, 154.0, 146.5, 144.7, 141.3, 140.2, 137.6, 131.4, 129.9,
128.7, 126.9, 125.9, 125.7, 99.8, 42.3, 21.7 m/z (HR-MS EI)
Found 334.0858. C20H15ON2Cl requires 334.0873.
Yellow solid in 96% yield. mp 146–150◦C. δH (300 MHz,
CDCl3) 8.26 (d, J 9.12, 2H), 7.85 (d, J 9.12, 2H), 7.58 (d, J 8.22,
1H), 7.03 (d, J 9.15, 5H), 3.89 (s, 3H), 1.38 (s, 9H). δC (75 MHz,
CDCl3) 160.7, 158.4, 154.8, 152.9, 146.9, 144.1, 141.0, 131.5,
128.7, 127.8, 125.9, 113.8, 59.8, 55.5, 35.2, 31.2. m/z (HR-MS
EI) Found 518.0268. C23H20O2N2ICl requires 518.0258.
A Typical Procedure for the Preparation of
Furopyrazines 5a–g
2-Chloro-6-cyclopropyl-7-iodo-3-methylfuro
[2,3-b]pyrazine (5g)
Yellow solid in 68% yield. mp 82–85◦C. δH (300 MHz,
CDCl3) 2.69 (s, 3H), 2.34–2.25 (m, 1H), 1.31–1.19 (m, 4H). δC
(75 MHz, CDCl3) 164.9, 152.2, 145.1, 140.2, 130.1, 114.3, 60.7,
22.3, 11.0, 9.4. m/z (HR-MS EI) Found 333.9363. C10H8ON2ICl
requires 333.9370.
In a 25 mL flask pyrazinone 3 (2 mmol) was dissolved in dry
dichloromethane (12 mL). I2 (2.0 equiv.) was then added and the
reaction mixture was stirred at room temperature for 5–15 min.
After reaction completion the solvent was evaporated and the
residuewassubjectedtosilicagelcolumnchromatography(from
5% to 10% CH2Cl2 in petroleum ether) to afford compounds
5a–g.
A Typical Procedure for Selective Suzuki–Miyaura
Reaction on Compounds 5a–g
2-Chloro-6-cyclopentyl-7-iodofuro[2,3-b]pyrazine (5a)
In a 15 mL microwave vial were successively dissolved in
DMF (4 mL) furopyrazine 5a–g (0.3 mmol), boronic acid 6a,f–
l (0.375 mmol, 1.25 equiv.), Pd(PPh3)4 (3 mg, 1 mol%), and
K2CO3 (82 mg, 2 equiv.). The reaction tube was sealed and irra-
diated at a ceiling temperature of 120◦C at 100 W maximum
power for 10–30 min. After the reaction the mixture was cooled
White solid in 76% yield. mp 128–131◦C. δH (300 MHz,
CDCl3) 8.17 (s, 1H), 3.56–3.45 (m, 1H), 2.13–2.07 (m, 2H),
1.93 (s, 4H), 1.76 (s, 2H). δC (75 MHz, CDCl3) 169.2, 153.4,
142.2, 136.8, 62.2, 39.5, 31.7, 26.2. m/z (HR-MS EI) Found
347.9547. C11H10ON2ICl requires 347.9526.

RESEARCH FRONT
38
V. P. Mehta et al.
with an air flow for 15 min, extracted with dichloromethane
(2 × 50 mL), and dried over MgSO4. The solvent was removed
under reduced pressure and the residue was subjected to silica
gel chromatography (from 5% to 20% EtOAC in heptane) to
afford compounds 7a–j.
130.6, 129.7, 128.8, 123.6, 117.8, 116.7, 114.9, 113.3, 61.3,
55.5, 14.5. m/z (HR-MS EI) Found 502.1089. C28H20O4N2ClF
requires 502.1096.
2-Chloro-3-methyl-6-o-tolyl-7-p-tolylfuro
[2,3-b]pyrazine (7g)
White solid in 90% yield. mp 97–99◦C. δH (300 MHz,
CDCl3) 7.48–7.39 (m, 4H), 7.36–7.22 (m, 2H), 7.15 (d, J 7.32,
2H), 2.76 (s, 3H), 2.34 (s, 3H), 2.22 (s, 3H). δC (75 MHz, CDCl3)
156.2, 153.7, 145.7, 144.8, 138.1, 137.9, 131.1, 130.4, 129.5,
128.5, 126.8, 126.1, 117.4, 22.7, 21.4, 20.3. m/z (HR-MS EI)
Found 348.1013. C21H17ON2Cl requires 348.1029.
2-Chloro-6-cyclopentyl-7-(4-methoxyphenyl)furo
[2,3-b]pyrazine (7a)
Yellow oil in 91% yield. δH (300 MHz, CDCl3) 8.16 (s, 1H),
7.54 (d, J 9.15, 2H), 7.04 (d, J 9.15, 2H), 3.86 (s, 3H), 3.55–3.50
(m, 1H), 2.05–1.94 (m, 6H), 1.74–1.68 (m, 2H). δC (75 MHz,
CDCl3) 164.8, 159.4, 153.4, 145.1, 140.9, 135.4, 130.4, 121.6,
115.7, 114.5, 55.4, 37.7, 32.4, 26.4. m/z (HR-MS EI) Found
328.0987. C18H17O2N2Cl requires 328.0979.
3-Benzyl-7-(3-bromophenyl)-2-chloro-6-p-tolylfuro
[2,3-b]pyrazine (7h)
7-(4-tert-Butylphenyl)-2-chloro-6-cyclopentylfuro
[2,3-b]pyrazine (7b)
79% yield. δH (300 MHz, CDCl3) 7.73 (s, 1H), 7.62–7.49
(m, 4H), 7.39–7.28 (m, 5H), 7.26–7.18 (m, 3H), 4.40 (s, 2H),
2.39 (s, 3H). m/z (HR-MS EI) Found 488.0303. C26H18ON2BrCl
requires 488.0291.
White solid in 78% yield. mp 97–99◦C. δH (300 MHz,
CDCl3) 8.17 (s, 1H), 7.57–7.50 (m, 4H), 3.59–3.53 (m, 1H),
2.06–1.94 (m, 6H), 1.75–1.71 (m, 2H), 1.36 (s, 9H). δC (75 MHz,
CDCl3) 165.2, 153.5, 151.1, 145.2, 140.9, 135.5, 128.9, 126.4,
126.0, 116.0, 37.8, 34.8, 32.5, 31.4, 26.4. m/z (HR-MS EI) Found
354.1506. C21H23ON2Cl requires 354.1499.
7-(2-(Benzyloxy)phenyl)-6-(4-tert-butylphenyl)-2-
chloro-3-(4-methoxyphenyl)furo[2,3-b]pyrazine (7i)
White solid in 89% yield. mp 61–65◦C. δH (300 MHz,
CDCl3) 7.83 (d, J 9.12, 2H), 7.67 (d, J 8.22, 2H), 7.50–7.35
(m, 4H), 7.17–7.13 (m, 3H), 7.11–7.00 (m, 6H), 4.96 (s, 2H),
3.87 (s, 3H), 1.31 (s, 9H). δC (75 MHz, CDCl3) 207.0, 160.4,
156.9, 156.6, 153.5, 153.3, 145.0, 143.1, 140.1, 136.6, 132.1,
131.3, 130.2, 129.3, 128.2, 127.6, 127.3, 127.0, 126.8, 125.6,
121.4, 119.1, 113.6, 113.0, 55.4, 34.9, 31.1. m/z (HR-MS EI)
Found 574.2027. C36H31O3N2Cl requires 574.2023.
2-Chloro-6-cyclopropyl-7-(4-ethoxyphenyl)-
3-methylfuro[2,3-b]pyrazine (7c)
White solid in 86% yield. mp 82–85◦C. δH (300 MHz,
CDCl3) 7.71 (d, J 8.22, 2H), 7.03 (d, J 9.12, 2H), 4.12–4.05 (q,
2H), 2.68 (s, 3H), 2.35–2.33 (m, 1H), 1.45 (t, J 13.71, 6.39, 3H),
1.29–1.26 (m, 4H). δC (75 MHz, CDCl3) 160.3, 158.6, 152.5,
144.3, 143.6, 138.9, 130.1, 121.9, 115.0, 63.6, 22.4, 14.9, 9.5,
8.9. m/z (HR-MS EI) Found 328.0987. C18H17O2N2Cl requires
328.0979.
4-(3-benzyl-2-chloro-6-p-tolylfuro[2,3-b]pyrazin-
7-yl)benzonitrile (7j)
White solid in 91% yield. mp 158–162◦C. δH (300 MHz,
CDCl3) 7.74 (m, 4H), 7.58 (d, J 8.22, 2H), 7.38 (d, J 7.32,
2H), 7.33–7.21 (m, 5H), 4.46 (s, 2H), 2.41 (s, 3H). δC (75 MHz,
CDCl3) 157.2, 153.4, 148.0, 145.1, 141.6, 138.6, 137.3, 134.8,
132.7, 130.2, 129.8, 129.1, 128.7, 128.0, 126.9, 125.6, 118.7,
114.0, 111.9, 41.3, 21.6. m/z (HR-MS EI) Found 435.1132.
C27H18ON3Cl requires 435.1138.
1-(4-(3-Benzyl-2-chloro-6-(thiophen-3-yl)furo
[2,3-b]pyrazin-7-yl)phenyl)ethanone (7d)
White solid in 87% yield. mp 209–214◦C. δH (300 MHz,
CDCl3) 8.08 (d, J 8.22, 2H), 7.84 (d, J 2.76, 1H), 7.75 (d, J 8.22,
2H), 7.40–7.23 (m, 7H), 4.40 (s, 2H), 2.66 (s, 3H). δC (75 MHz,
CDCl3) 197.7, 153.2, 152.9, 147.7, 145.2, 139.0, 137.4, 137.0,
134.4, 130.1, 129.2, 128.7, 127.0, 126.9 126.0, 114.5, 41.4,
29.8, 26.8. m/z (HR-MS EI) Found 444.0691. C25H17O2N2SCl
requires 444.0699.
A Typical Procedure for the Preparation of
Furopyrazines 8a–d
In a 15 mL microwave vial were successively dissolved in
DMF/H2O (1:1, 4 mL) furopyrazine 4a–c,e (0.3 mmol), boronic
acid 6b–e (0.45 mmol, 1.50 equiv.), Pd(PPh3)4 (3 mg, 1 mol%),
and Na2CO3 (64 mg, 2 equiv.). The reaction tube was sealed and
irradiated at a ceiling temperature of 100◦C at 100 W maximum
power for 10 min. After the reaction the mixture was cooled
with an air flow for 15 min, extracted with dichloromethane
(2 × 50 mL), and dried over MgSO4. The solvent was removed
under reduced pressure and the residue was subjected to silica gel
flash chromatography (from 10% to 50% CH2Cl2 in petroleum
ether) to afford compounds 8a–d.
2-Chloro-7-(4-methoxyphenyl)-3-methyl-
6-o-tolylfuro[2,3-b]pyrazine (7e)
White solid in 89% yield. mp 136–140◦C. δH (300 MHz,
CDCl3) 7.53 (d, J 8.22, 2H), 7.44 (d, J 8.19, 1H), 7.38 (d, J
7.32, 1H), 7.32–7.23 (m, 2H), 6.88 (d, J 9.15, 2H), 3.80 (s, 3H),
2.76 (s, 3H), 2.22 (s, 3H). δC (75 MHz, CDCl3) 159.4, 155.8,
153.7, 145.6, 144.7, 138.1, 131.1, 130.9, 130.4, 129.8, 129.4,
126.1, 122.1, 117.0, 114.3, 55.3, 22.7, 20.3. m/z (HR-MS EI)
Found 364.0984. C21H17O2N2Cl requires 364.0979.
Ethyl 4-(2-Chloro-6-(3-fluorophenyl)-3-(4-
methoxyphenyl)furo[2,3-b]pyrazin-7-yl)benzoate (7f)
6-(4-Ethylphenyl)-3-(4-methoxyphenyl)-2-p-tolylfuro-
[2,3-b]pyrazine (8a)
White solid in 78% yield. mp 163–167◦C. δH (300 MHz,
CDCl3) 8.18 (d, J 7.29, 2H), 7.87 (d, J 9.12, 2H), 7.73 (d, J 8.22,
2H), 7.52–7.45 (m, 2H), 7.39–7.32 (q, 1H), 7.16–7.10 (m, 1H),
7.04 (d, J 9.12, 2H), 4.46–4.39 (q, 2H), 3.89 (s, 3H), 1.45–1.40
(t, J 14.61, 7.29, 3H). δC (75 MHz, CDCl3) 166.3, 164.5, 161.2,
160.8, 154.8, 153.5, 146.8, 144.0, 138.3, 133.8, 131.5, 130.9,
Light yellow solid in 85% yield. mp 172–175◦C. δH
(300 MHz, CDCl3) 7.89 (d, J 8.22, 2H), 7.43 (d, J 9.12, 2H),
7.36–7.33 (m, 4H), 7.20 (s, 1H), 7.14 (d, J 8.22, 2H), 6.83
(d, J 8.22, 2H), 3.81 (s, 3H), 2.76–2.68 (m, 2H), 2.36 (s,
3H), 1.31–1.26 (t, J 14.61, 7.29, 3H). δC (75 MHz, CDCl3)

RESEARCH FRONT
Diversely Substituted Furo[2,3-b]pyrazines
39
160.7, 159.8, 154.4, 150.3, 147.1, 146.0, 139.9, 138.0, 137.0,
131.5, 129.8, 128.7, 126.7, 125.7, 113.7, 100.6, 55.3, 29.0, 21.4,
15.5. m/z (HR-MS EI) Found 420.1821. C28H24O2N2Cl requires
420.1838.
6-(4-Ethylphenyl)-3-(4-methoxyphenyl)-2-(2-p-
tolylethynyl)furo[2,3-b]pyrazine (9b)
Yellow solid in 92% yield. mp 156–159◦C. δH (300 MHz,
CDCl3) 8.17 (d, J 8.22, 2H), 7.89 (d, J 8.22, 2H), 7.43 (d, J 8.22,
2H), 7.35 (d, J 8.22, 2H), 7.16 (d, J 8.22, 2H), 7.05 (d, J 8.22,
2H), 3.91 (s, 3H), 2.77–2.69 (m, 2H), 2.37 (s, 3H), 1.31–1.26
(t, J 15.54, 7.32, 3H). δC (75 MHz, CDCl3) 161.4, 160.6, 149.0,
147.3, 139.9, 133.6, 131.7, 131.1, 129.2, 128.6, 126.2, 125.7,
119.2, 113.4, 100.1, 93.1, 55.4, 28.9, 21.6, 15.3. m/z (HR-MS
EI) Found 444.1841. C30H24O2N2 requires 444.1838.
2-(3,5-Dimethylphenyl)-3,6-bis(4-methoxyphenyl)furo-
[2,3-b]pyrazine (8b)
Yellow solid in 90% yield. mp 72–75◦C. δH (300 MHz,
CDCl3) 7.92 (d, J 9.15, 2H), 7.43 (d, J 9.12, 2H), 7.11 (s, 1H),
7.05–6.96 (m, 5H), 6.82 (d, J 9.12, 2H), 3.89 (s, 3H), 3.81 (s, 3H),
2.26 (s, 6H). δC (75 MHz, CDCl3) 161.4, 160.6, 159.7, 154.4,
150.4, 145.6, 140.0, 137.9, 131.5, 129.8, 129.4, 128.8, 128.0,
127.7, 127.3, 121.9, 114.6, 113.5, 99.6, 55.5, 21.4. m/z (HR-MS
EI) Found 436.1793. C28H24O3N2 requires 436.1787.
6-(Biphenyl-4-yl)-3-(4-methoxyphenyl)-2-
(phenylethynyl)furo[2,3-b]pyrazine (9c)
Yellow solid in 96% yield. mp 191–194◦C. δH (300 MHz,
CDCl3) 8.16 (d, J 9.15, 2H), 8.04 (d, J 8.22, 2H), 7.75 (d, J 9.15,
2H), 7.66 (d, J 7.32, 2H), 7.55–7.46 (m, 4H), 7.42–7.36 (m,
4H), 7.24 (s, 1H), 7.07 (d, J 8.22, 2H), 3.91 (s, 3H). δC (75 MHz,
CDCl3) 160.9, 154.1, 149.5, 143.3, 140.0, 133.7, 131.9, 131.3,
129.7, 129.2, 128.5, 128.1, 127.8, 127.6, 127.1, 126.2, 122.4,
113.6, 101.0, 93.0, 88.4, 55.5. m/z (HR-MS EI) Found 478.1671.
C33H22O2N2 requires 478.1681.
6-(Biphenyl-4-yl)-3-(4-methoxyphenyl)-2-(3-
(trifluoromethyl)phenyl)furo[2,3-b]pyrazine (8c)
Yellow solid in 87% yield. mp 150–153◦C. δH (300 MHz,
CDCl3) 8.06 (d, J 8.22, 2H), 7.84 (s, 1H), 7.76 (d, J 8.22, 2H),
7.67 (d, J 7.32, 2H), 7.60 (d, J 7.29, 2H), 7.51–7.37 (m, 7H),
7.31 (s, 1H), 6.85 (d, J 8.22, 2H), 3.82 (s, 3H). δC (75 MHz,
CDCl3) 160.7, 160.1, 148.7, 146.5, 143.3, 140.6, 140.0, 133.4,
131.6, 130.8, 130.5, 129.1, 128.7, 128.1, 127.2, 126.9, 126.2,
124.9, 113.9, 101.2, 55.4. m/z (HR-MS EI) Found 522.1566.
C32H21O2N2F3 requires 522.1555.
A Typical Procedure for Selective Sonogashira Coupling
Reaction on Dihalo-Substituted Furo[2,3-b]pyrazine 5c,e
In a 15 mL microwave vial were successively dissolved in
DMF/Et3N (1:1, 4 mL) pyrazine 5c,e (0.3 mmol), acetylene
2i,e,n (0.315 mmol, 1.05 equiv.), Pd(PPh3)Cl2 (3.4 mg, 1 mol%),
and CuI (2.0 mg, 3 mol%). The reaction tube was sealed and
irradiated in a microwave reactor at a ceiling temperature of
95◦C at 80W maximum power for 7–10 min. After reaction the
mixture was cooled with an air flow for 15 min, extracted with
dichloromethane (2 × 150 mL), and dried over MgSO4. The sol-
vent was removed under reduced pressure and the residue was
subjected to silica gel column chromatography (from 5% to 10%
EtOAc in heptane) to afford compounds 10a–c.
3-Benzyl-2-(naphthalen-1-yl)-6-p-tolylfuro
[2,3-b]pyrazine (8d)
100% yield. δH (300 MHz, CDCl3) 7.89 (m, 4H), 7.52 (m,
2H), 7.35 (m, 5H), 7.16 (s, 1H), 7.10 (m, 3H), 6.90 (m, 2H),
3.95 (m, 2H), 2.44 (s, 3H). δC (75 MHz, CDCl3) 160.6, 154.6,
150.5, 148.4, 140.0, 136.2, 133.7, 131.9, 129.8, 128.9, 128.4,
128.2, 127.7, 126.6, 126.2, 126.1, 125.3, 100.5, 41.3, 21.6. m/z
(HR-MS EI) Found 426.1735. C30H22ON2 requires 426.1732.
3-Benzyl-2-chloro-6-(thiophen-3-yl)-7-(2-(thiophen-
3-yl)ethynyl)furo[2,3-b]pyrazine (10a)
Sonogashira Coupling Reaction on Substituted
Yellow solid in 89% yield. mp 140–144◦C. δH (300 MHz,
CDCl3) 8.32 (d, J 1.83, 1H), 7.97 (d, J 5.49, 1H), 7.66 (d,
J 4.0, 1H), 7.48–7.45 (m, 2H), 7.35–7.28 (m, 6H), 4.39 (s,
2H). δC (75 MHz, CDCl3) 155.4, 152.6, 148.8, 145.2, 141.3,
137.4, 130.6, 129.2, 128.7, 128.2, 127.8, 126.9, 126.2, 125.8,
125.9, 116.0, 89.0, 77.8, 41.2. m/z (HR-MS EI) Found 432.0145.
C23H13ON2S2Cl requires 432.0158.
2-Chloro-furo[2,3-b]pyrazine 4a–c. A Typical Procedure
In a 15 mL microwave vial were successively dissolved in
DMF/Et3N (1:1, 4 mL) pyrazine 4a–c (0.3 mmol), acetylene
2e,l,m (0.375 mmol, 1.25equiv.), Pd(PPh3)Cl2 (17 mg, 5 mol%),
and CuI (5.7 mg, 10 mol%). The reaction tube was sealed and
irradiated in a microwave reactor at a ceiling temperature of
100◦C at 80W maximum power for 15 min. After the reaction
themixturewascooledwithanairflowfor15 min, extractedwith
dichloromethane (2 × 150 mL), and dried over MgSO4. The sol-
vent was removed under reduced pressure and the residue was
subjected to silica gel column chromatography (from 10% to
30% EtOAc in heptane) to afford compounds 9a–c.
3-Benzyl-2-chloro-6-(thiophen-3-yl)-7-(2-p-
tolylethynyl)furo[2,3-b]pyrazine (10b)
Yellow solid in 86% yield. mp 121–125◦C. δH (300 MHz,
CDCl3) 8.33 (s, 1H), 7.98 (d, J 5.49, 1H), 7.53 (d, J 8.22, 2H),
7.47–7.43 (m, 1H), 7.37–7.19 (m, 7H), 4.39 (s, 2H), 2.39 (s, 3H).
δC (75 MHz, CDCl3) 157.8, 153.0, 147.9, 145.3, 139.4, 138.4,
137.3, 132.0, 130.5, 129.4, 128.7, 126.9, 125.7, 119.5, 98.8, 98.3,
41.3, 21.7. m/z (HR-MS EI) Found 440.0746. C26H17ON2SCl
requires 440.0750.
2-(2-Cyclohexylethynyl)-3,6-bis(4-methoxyphenyl)furo
[2,3-b]pyrazine (9a)
Yellow solid in 85% yield. mp 140–143◦C. δH (300 MHz,
CDCl3) 8.09 (d, J 9.15, 2H), 7.89 (d, J 8.22, 2H), 7.03–6.98
(m, 5H), 3.89 (s, 6H), 2.66–2.62 (m, 1H), 1.88–1.86 (m, 2H),
1.73–1.70 (m, 2H), 1.56–1.52 (m, 6H). δC (75 MHz, CDCl3)
161.4, 160.4, 153.6, 148.3, 139.9, 133.9, 131.1, 129.9, 129.1,
128.7, 127.3, 121.5, 114.5, 114.0, 113.3, 99.1, 79.7, 55.4, 31.9,
29.9, 25.8, 24.9. m/z (HR-MS EI) Found 438.1964. C28H26O3N2
requires 438.1943.
2-Chloro-6-(3-fluorophenyl)-3-(4-methoxyphenyl)-
7-(oct-1-ynyl)furo[2,3-b]pyrazine (10c)
Yellow solid in 74% yield. mp 97–100◦C. δH (300 MHz,
CDCl3) 8.14 (m, 2H), 7.85 (d, J 8.19, 2H), 7.52–7.47 (m, 1H),
7.21–7.15 (m, 1H), 7.03 (d, J 9.15, 2H), 3.89 (s, 3H), 2.66–2.61
(t, J 13.71, 7.32, 2H), 1.79–1.69 (m, 2H), 1.57–1.54 (m, 2H),

RESEARCH FRONT
40
V. P. Mehta et al.
1.37–1.35 (m, 4H), 0.94–0.89 (t, J 13.71, 6.39, 3H). δC (75 MHz,
CDCl3) 164.5, 161.2, 160.8, 158.9, 152.9, 147.0, 144.1, 139.0,
131.5, 130.5, 128.7, 122.2, 117.6, 113.8, 113.2, 102.3, 69.1,
55.5, 31.4, 28.9, 28.4, 22.6, 20.3, 14.1. m/z (HR-MS EI) Found
462.1516. C27H24O2N2ClF requires 462.1510.
in heptane) to afford 1-(4-(3-benzyl-6-(thiophen-3-yl)-2-(2-p-
tolylethynyl)furo[2,3-b]pyrazin-7-yl)phenyl) ethanone (11d) as
a light yellow solid in 86% yield. mp 210–215◦C. δH (300 MHz,
CDCl3) 8.08 (d, J 8.22, 2H), 7.79–7.76 (m, 3H), 7.50–7.44 (m,
4H), 7.33–7.12 (m, 8H), 4.54 (s, 2H), 2.66 (s, 3H), 2.39 (s, 3H).
δC (75 MHz, CDCl3) 197.8, 152.9, 152.4 139.7, 139.3, 138.5,
136.9, 136.1, 134.8, 131.9, 130.3, 129.4, 128.7, 126.9, 126.0,
119.1, 114.7, 94.8, 86.5, 41.9, 26.8, 21.7. m/z (HR-MS EI) Found
524.1551. C34H24O2N2S requires 524.1558.
A Typical Procedure for the Preparation of
Furopyrazines 11a–c
In a 15 mL microwave vial were successively dissolved
in DMF/H2O (1:1, 4 mL) furopyrazine 7b,d,e (0.3 mmol),
boronic acid 6f,m,n (0.45 mmol, 1.50 equiv.), Pd(PPh3)4 (3 mg,
1 mol%), and Na2CO3 (64 mg, 2 equiv.). The reaction tube was
sealed and irradiated at a ceiling temperature of 100◦C at 100
W maximum power for 10 min. After the reaction the mix-
ture was cooled with an air flow for 15 min, extracted with
dichloromethane (2 × 50 mL), and dried over MgSO4. The sol-
vent was removed under reduced pressure and the residue was
subjected to silica gel flash chromatography (from 10% to 30%
CH2Cl2 in petroleum ether) to afford compounds 11a–c.
Disubstituted Suzuki Cross-Coupling. A Typical Procedure
In a 15 mL microwave vial were successively dissolved in DMF
(4 mL) furopyrazine 5g (0.3 mmol), boronic acid 6o (0.9 mmol,
3.0 equiv.), Pd(PPh3)4 (16 mg, 5 mol%), and K2CO3 (166 mg,
5 equiv.). The reaction tube was sealed and irradiated at a ceiling
temperature of 140◦C at 300W maximum power for 25 min.
After the reaction the mixture was cooled with an air flow for
15 min, extracted with dichloromethane (2 × 50 mL), and dried
over MgSO4. The solvent was removed under reduced pressure
and the residue was subjected to silica gel flash chromatography
(from 0% to 5% EtOAc in heptane) to afford 6-cyclopropyl-
2,7-bis(4-fluorophenyl)-3-methylfuro[2,3-b]-pyrazine (12a) as
a white solid in 93% yield. mp 81–84◦C. δH (300 MHz, CDCl3)
7.86–7.81 (m, 2H), 7.58–7.54 (m, 2H), 7.20–7.13 (m, 4H), 2.64
(s, 3H), 2.37–2.32 (m, 1H), 1.35–1.13 (m, 4H). δC (75 MHz,
CDCl3) 164.5, 163.9, 161.2, 160.6, 159.8, 152.8, 149.5, 143.9,
138.6, 135.6, 131.4, 130.7, 126.3, 116.0, 115.5, 115.1, 23.3, 9.5,
8.8. m/z (HR-MS EI) Found 362.1225. C22H16ON2F2 requires
362.1231.
1-(4-(3-Benzyl-2-(4-tert-butylphenyl)-6-(thiophen-3-
yl)furo[2,3-b]pyrazin-7-yl)phenyl)ethanone (11a)
White solid in 87% yield. mp 149–152◦C. δH (300 MHz,
CDCl3) 8.04 (d, J 8.22, 2H), 7.84–7.80 (m, 3H), 7.44–7.43 (m,
4H), 7.31 (s, 2H), 7.24–7.10 (m, 5H), 4.33 (s, 2H), 2.63 (s, 3H),
1.36 (s, 9H). δC (75 MHz, CDCl3) 197.8, 153.5, 152.2, 151.6,
148.0, 139.4, 136.6, 135.3, 130.5, 129.3, 128.9, 126.7, 126.4,
125.4, 115.0, 41.2, 34.8, 31.5, 26.8. m/z (HR-MS EI) Found
542.2029. C35H30O2N2S requires 542.2028.
7-(4-tert-Butylphenyl)-6-cyclopentyl-2-(3-
ethoxyphenyl)furo[2,3-b]pyrazine (11b)
Accessory Publication
General experimental methods and spectroscopic and analytical
data for compounds are available from the journal’s website.
White solid in 92% yield. mp 102–104◦C. δH (300 MHz,
CDCl3) 8.60 (s, 1H), 7.70 (d, J 8.22, 2H), 7.61–7.53 (m, 4H),
7.41–7.36 (t, J 16.44, 8.22, 1H), 6.98 (d, J 9.12, 1H), 4.15–4.08
(m, 2H), 3.67–3.56 (m, 1H), 2.11–1.96 (m, 6H), 1.74–1.72 (m,
2H), 1.47–1.39 (m, 12H). δC (75 MHz, CDCl3) 161.4, 160.6,
149.0, 147.3, 139.9, 133.6, 131.7, 131.1, 129.2, 128.6, 126.2,
125.7, 119.2, 113.4, 100.1, 93.1, 55.4, 28.9, 21.6, 15.3. m/z
(HR-MS EI) Found 440.2461. C29H32O2N2 requires 440.2464.
Acknowledgement
The authors thank the F.W.O. (Fund for Scientific Research – Flanders
(Belgium)) and the Research Fund of the Katholieke Universiteit Leuven
for financial support to the laboratory. D.E. is grateful to the Katholieke
Universiteit Leuven for obtaining a scholarship. V.P.M. is grateful to the
IRO (Interfacultaire Raad voor Ontwikkelingssamenwerking) for obtain-
ing a doctoral scholarship. The authors thank Ir. B. Demarsin for HRMS
measurements.
2-(2-Fluorophenyl)-7-(4-methoxyphenyl)-3-methyl-
6-o-tolylfuro[2,3-b]pyrazine (11c)
95% yield. δH (300 MHz, CDCl3) 7.61 (m, 10H), 6.84 (d, J
8.22, 2H), 3.77 (s, 3H), 2.60 (s, 3H), 2.26 (s, 3H). δC (75 MHz,
CDCl3) 161.7, 159.1, 158.4, 154.9, 154.4, 146.9, 146.1, 138.1,
132.0, 131.0, 130.5, 129.9, 127.6, 126.1, 124.4, 122.7, 117.3,
115.9, 114.2, 55.2, 22.2, 20.3. m/z (HR-MS EI) Found 542.2035.
C27H21O2N2F requires 542.2028.
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