Efficient preparation of tetrasubstituted pyrazines starting from pyrazin-2(1H)-ones

Article abstract of DOI:10.1055/s-0031-1289714

An efficient methodology for the synthesis of tetrasubstituted pyrazines starting from pyrazin-2(1H)-ones has been elaborated. Diversity in the functionalization and the beneficial effect of microwave irradiation throughout the methodology has been demonstrated. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289714

1614
PRACTICAL SYNTHETIC PROCEDURES
Efficient Preparation of Tetrasubstituted Pyrazines Starting from
Pyrazin-2(1H)-ones
Sachin G. Modha,a Jalpa C. Trivedi,a,b Vaibhav P. Mehta,a,c Denis S. Ermolat’ev,a Erik V. Van der Eycken*a
a
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven (KU Leuven),
Celestijnenlaan 200F, 3001 Leuven, Belgium
E-mail: erik.vandereycken@chem.kuleuven.be
b
Present address: Department of Chemistry, Shoolini University, Bhajol, Solan 173 229,
Himachal Pradesh, India
c
Present address: Institut für Organische and Biomoleculare Chemie,
PSP
Georg-August-Universität Göttingen, Tamannstr. 2, 37077 Göttingen, Germany
Received 4 January 2012
No222
Abstract: An efficient methodology for the synthesis of tetrasubstituted pyrazines starting from pyrazin-2(1H)-ones has been elaborated.
Diversity in the functionalization and the beneficial effect of microwave irradiation throughout the methodology has been demonstrated.
Key words: palladium catalysis, copper catalysis, pyrazines, 3,5-dichloropyrazin-2(1H)-ones, microwaves, nucleosides
MeO
MeO
MeO
OMe
Lawesson's
reagent
R1
N
N
S
R1
Cl
N
N
O
R1
Cl
N
N
O
R1
Cl
N
N
S
substitution
at 3-position
I2, CH2Cl2
MW, 80 °C
15 min
toluene
reflux, 6–8 h
R2
R2
R2
Cl
Cl
inactive
active
inactive
R
2 = OMe, OEt, Me
Liebeskind–Srogl
coupling
R1 = H, Me, Bn, i-Bu
MW
1. triisopropylsilylacetylene
Pd(PPh3)2Cl2
CuI, TBAI, DMF–Et3N
MW
R3
R3
R3
R1
N
R1
N
N
R1
N
N
click chemistry
sugar azide
N
N
R2
Cl
R2
R2
2. TBAF, CH2Cl2–THF
r.t., 1–5 min
N
active
N
PS
PS = protected sugar
R3 = OMe, F, CF3, t-Bu
Scheme 1
Even though a number of important, natural as well as oratory on a 40–50-gram scale. Herein we report an effi-
synthetic, heterocyclic compounds possess a tetrasubsti- cient methodology for the synthesis of tetrasubstituted
tuted pyrazine core structure,1 there are only a limited pyrazines starting from these readily available pyrazin-
number of synthetic methodologies described for their 2(1H)-ones.
synthesis.2 We have previously reported 3,5-dichloropy-
Alkoxylation of pyrazin-2(1H)-ones 1a–c at the C3-posi-
tion gave quantitative yields of 2a–c (Scheme 2). When
treated with tetramethylstannane under Stille conditions,
1d gave methylated compound 2d in 95% yield. All C3-
razin-2(1H)-ones as attractive starting materials for the
synthesis of different heterocyclic compounds.3 Recently
we have described a new methodology, starting from
pyrazin-2(1H)-ones, for the synthesis of tetrasubstituted
substituted pyrazine-2(1H)-ones 2a–d were reacted with
pyrazines coupled with a sugar moiety via a triazole link-
Lawesson’s reagent to afford the corresponding thio-
age (Scheme 1).4 Using our optimized conditions5 3,5-
amides 3a–d in good yields (Scheme 2).
dichloropyrazin-2(1H)-ones can be synthesized in the lab-
A mixture of compound 3a, methyl iodide (5 equiv) and
iodine (10 mol%) in toluene was refluxed for 12 hours
SYNTHESIS 2012, 44, 1614–1624
Advanced online publication: 16.02.2012
DOI: 10.1055/s-0031-1289714; Art ID: Z001012SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
2
yielding 72% of the expected methyl thioether 4a together
with 20% of p-methoxybenzyl thioether 5a as the main
byproduct (Table 1, entry 1).6 The formation of 5a might

PRACTICAL SYNTHETIC PROCEDURES
From Pyrazin-2(1H)-ones to Tetrasubstituted Pyrazines
1615
PMB
PMB
PMB
R1
Cl
N
O
R1
Cl
N
O
R1
Cl
N
O
Me4Sn, Pd(PPh3)4
NaH
MeOH or EtOH
0–30 °C, 3 h
toluene, 120 °C, 30 min
N
Cl
N
R2
N
2d, R1 = Bn (95%)
1a, R1 = H
2a, R1 = H, R2 = OMe (98%)
2b, R1 = Me, R2 = OMe (99%)
2c, R1 = i-Bu, R2 = OEt (98%)
1b, R1 = Me
1c, R1 = i-Bu
1d, R1 = Bn
Lawesson's reagent
toluene, reflux, 4 h
PMB = p-methoxybenzyl
PMB
R1
Cl
N
S
N
R2
3a, R1 = H, R2 = OMe (80%)
3b, R1 = Me, R2 = OMe (88%)
3c, R1 = i-Bu, R2 = OEt (90%)
3d, R1 = Bn, R2 = Me (73%)
Scheme 2
be explained by the competitive reaction of the in situ This optimized protocol was applied to convert the pyra-
formed p-methoxybenzyl iodide. During the scale-up of zine-2(1H)-thiones 3b–d into the corresponding p-meth-
the reaction we noticed that it was rather difficult to sepa- oxybenzyl thioethers 5b–d (Scheme 3).
rate the desired methyl thioether 4a from compound 5a
due to their similar polarity. Therefore efforts were made
MeO
to make this reaction more selective. However, under mi-
crowave irradiation at a temperature of 130 °C for 30 min-
OMe
utes under the same conditions, the amount of byproduct
5a increased (entry 2). The reaction was rather slow in the
absence of iodine, still giving both 4a and 5a, but with de-
creased yields (entry 3). This observation was interesting
as only salt formation was expected with methyl iodide.
Clearly upon heating7 the intermediate salt loses p-meth-
oxybenzyl iodide, forming 4a, and the in situ formed p-
methoxybenzyl iodide reacts with another molecule of
starting material 3a to give 5a.
R1
Cl
N
N
S
R1
Cl
N
N
S
I2 (10 mol%)
CH2Cl2, MW
80 °C, 15 min
R2
R2
3b, R1 = Me, R2 = OMe
3c, R1 = i-Bu, R2 = OEt
3d, R1 = Bn, R2 = Me
5b, R1 = Me, R2 = OMe (88%)
5c, R1 = i-Bu, R2 = OEt (80%)
5d, R1 = Bn, R2 = Me (72%)
Scheme 3
As it was impossible to minimize the competition between
methyl iodide and the in situ formed p-methoxybenzyl io-
dide, it was decided to exclude methyl iodide from the re-
action mixture. This should result in the sole formation of
p-methoxybenzyl thioether 5a. As a proof of concept 3a
was refluxed in toluene with iodine (10 mol%). To our
satisfaction only 5a was formed in 45% yield (entry 4). In-
terestingly when the solvent was changed to dichloro-
methane, the yield increased to 65% (entry 5). When the
reaction was run at room temperature with 5, 10, 50, and
80 mol% of iodine, respectively, there was no important
change in yields, but a dramatic difference in reaction
time was observed ranging from 40 hours to 0.15 hours
(entries 7–10). The best results were obtained when the
reaction was carried out with 10 mol% iodine in dichlo-
romethane under microwave irradiation at 80 °C and 150-
W maximum power for 15 minutes yielding compound 5a
in 83% yield (entry 6).
A plausible mechanism for the transfer of the p-methoxy-
benzyl group is shown in Scheme 4. Iodine first reacts
with the sulfur atom of thioamide 3a to give intermediate
A. This loses the p-methoxybenzyl group to form the un-
stable intermediates B and C that directly react with each
other to give the p-methoxybenzyl thioethers 5, while io-
dine goes back into the catalytic cycle. It is interesting to
note that the reaction, which is rather slow at room tem-
perature, is rapid under microwave irradiation.
To our surprise, all efforts to perform a Sonogashira reac-
tion on compound 5, met with failure. This is in sharp con-
trast with our previously published work,6 where the
reaction went smoothly when a methylthio group was
present instead of a p-methoxybenzylthio group at the C2-
position of the pyrazine. Probably the p-methoxybenzyl
thioether renders the chlorine less susceptible to nucleo-
philic substitution by the palladium (Scheme 5).
Hence we considered whether the p-methoxybenzylthio
group would be sufficiently reactive under standard Lie-
beskind–Srogl conditions. When pyrazine 5a was reacted
© Thieme Stuttgart · New York
Synthesis 2012, 44, 1614–1624

1616
S. G. Modha et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 1 Optimization Study for Thioether Formationa
PMB
N
S
N
SMe
OMe
N
S
PMB
+
Cl
N
OMe
Cl
N
Cl
N
OMe
3a
4a
5a
Entry
Reagent (equiv)
Catalyst (mol%)
Solvent
Temp (°C)
Time (h)
Yield (%)
Yield (%)
4a
5a
1b
2c
3
MeI (5)
I2 (10)
I2 (10)
–
toluene
toluene
toluene
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
reflux
130
reflux
reflux
reflux
80
12
0.5
1
72
55
40
0
20
30
15
45
65
83
79
73
80
85
MeI (5)
MeI (5)
4
–
–
–
–
–
–
–
I2 (10)
I2 (10)
I2 (10)
I2 (10)
I2 (5)
12
6
5
0
6d
7
0.25
24
40
6
0
r.t.
0
8
r.t.
0
9
I2 (50)
I2 (80)
r.t.
0
10
r.t.
0.15
0
a All reactions: 3a (0.1 mmol), conventional heating, unless otherwise stated.
b Scale-up of the reaction with 5 mmol of 3a also resulted in full conversion, but it was not possible to separate 4a from 5a by column chroma-
tography.
c The mixture was irradiated using 400 W maximum power in a multimode microwave apparatus.
d The mixture was irradiated using 150 W maximum power in a multimode microwave apparatus.
MeO
OMe
R1
N
S
N
N
S
OMe
Cl
N
R2
Cl
OMe
3
N
N
S
Sonogashira
conditions
5a
OMe
OMe
R1
N
N
S
R3Si
R3Si
I2
7
MeO
Cl
R2
I–
6
5
Scheme 5
R1
N+
N
S
I
Me
O+
I–
R2
with boronic acid 8a in the presence of copper(I)
thiophene-2-carboxylate (CuTC) and Pd(PPh3)4 in tet-
rahydrofuran under conventional heating as well as under
microwave irradiation (Table 2, entries 1–3, 5, and 6)
poor to average yields were obtained. As the reaction was
rather sluggish it was assumed that the reagents decom-
posed during the long reaction time at high temperature.
To overcome this difficulty, the reagents were added in
two portions and, to our satisfaction, the reaction was
complete in one hour under microwave irradiation at 120
°C yielding 9a in 84% (entry 4).8 This optimized protocol
was then applied for the conversion of 5a–d into 9b–j in
good to excellent yields (Table 3).
Cl
A
C
R1
N
S
I
Cl
N
B
R2
Scheme 4
Synthesis 2012, 44, 1614–1624
© Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
From Pyrazin-2(1H)-ones to Tetrasubstituted Pyrazines
1617
Table 2 Optimization Study of the Liebeskind–Srogl Cross-Coupling Reaction on the p-Methoxybenzylthio Groupa
OMe
OMe
B(OH)2
Liebeskind–Srogl
conditions
N
S
N
+
Cl
N
OMe
Cl
N
OMe
5a
9a
OMe
8a
Entry
Boronic acid (equiv) CuTC (equiv)
Pd(PPh3)4 (mol%) Temp (°C) (MWb/DT) Time (h)
Ratioc 9a/5a
1
3
3
5
10
3
100 (MW)
120 (MW)
100 (MW)
120 (MW)
reflux (DT)
reflux (DT)
0.8
40:30
57:25
30:62
84:08
30:65
45:50
2
5
5
1.3
3
1.1
2 + 1
3
1.2
0.8
4d
5
1.5 + 1
3
5 + 5
0.5 + 0.5
5
10
4 + 4
6d
2 + 1
1.5 + 1
5 + 5
a All reactions were run using 5a (0.2 mmol) in THF in a sealed tube.
b A maximum power of 500 W in a multimode microwave apparatus was used.
c Ratio determined by GC-MS.
d A fresh batch of reagents was added at the stipulated time.
Table 3 Liebeskind–Srogl Cross-Coupling on Pyrazines 5a
OMe
B(OH)2
R3
Pd(PPh3)4 (5 + 5 mol%)
R1
N
N
S
R1
N
N
CuTC (1.5 + 1 equiv)
+
THF, MW 500 W
120 °C, 30 + 30 min
R2
5a–d
Cl
R2
R3
2 + 1 equiv
8a–e
Cl
9b–j
Entry
1
Product
Structure
Yield (%)
OMe
OMe
9b
69
N
N
Cl
OMe
F
F
2
9c
9d
9e
75
80
86
N
N
Cl
Cl
OMe
OMe
N
N
3
CF3
OMe
4b
N
N
Cl
Cl
OMe
OMe
OMe
OMe
5b
9f
93
N
N
© Thieme Stuttgart · New York
Synthesis 2012, 44, 1614–1624

1618
S. G. Modha et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 3 Liebeskind–Srogl Cross-Coupling on Pyrazines 5a (continued)
OMe
B(OH)2
R3
Pd(PPh3)4 (5 + 5 mol%)
R1
N
N
S
R1
N
N
CuTC (1.5 + 1 equiv)
+
THF, MW 500 W
120 °C, 30 + 30 min
R2
5a–d
Cl
R2
R3
2 + 1 equiv
8a–e
Cl
9b–j
Entry
6
Product
Structure
Yield (%)
9g
92
N
N
Cl
OMe
OMe
7b
9h
9i
79
N
N
OMe
Cl
Cl
OEt
F
8
72
N
N
F
OEt
OMe
9
9j
80
N
N
OMe
Cl
a Reactions conditions: 5a–d (0.5 mmol), boronic acids (2 + 1 equiv), Pd(PPh3)4 (5 + 5 mol%), CuTC (1.5 + 1 equiv), THF (4 mL), sealed tube,
MW (multimode microwave apparatus, max. 120 °C and 500 W, 60 min; reagents were added in 2 portions as stipulated; the second portion
was added at half reaction time (i.e., 30 min).
b Using 5a–c (5 mmol).
As we were able to substitute the p-methoxybenzylthio SA, 1.5 equiv), Pd(PPh3)2Cl2 (5 mol%), copper(I) iodide
group of compound 5 by an aryl group in compound 9, the (10 mol%), and tetrabutylammonium iodide (1.2 equiv) in
reactivity of the chlorine towards Sonogashira reaction N,N-dimethylformamide–triethylamine (1:1) was irradi-
was reinvestigated (Table 4). To our delight when a mix- ated for 20 minutes at a ceiling temperature of 80 °C, a
ture of compound 9 with triisopropylsilylacetylene (TIP- smooth reaction took place. Subsequent desilylation upon
treatment of the crude compound with 1 M tetrabutylam-
Cl
monium fluoride in tetrahydrofuran at room temperature
yielded the desired terminal acetylenes 10a–d (Table 4),
which were purified by simple filtration over silica gel.
For the final step, the protected sugar azides9 and benzyl
O
O
azide10 11a–e (Figure 1) were all synthesized according to
literature procedures. Then, the coupling of azides 11a–d
with the generated pyrazines 10a–d was investigated. A
mixture of pyrazine 10 with protected sugar azide 11 (1.2
equiv), copper turnings (2 equiv), copper sulfate (5
O
O
O
N3
O
N3
O
O
O
O
O
O
mol%),
tris[(1-benzyl-1H-1,2,3-triazol-4-yl)meth-
Cl
yl]amine ligand (TBTA, 5 mol%) in tetrahydrofuran–iso-
propyl alcohol–water (3:1:1, 5 mL) was irradiated at 90
°C ceiling temperature using 200-W maximum power for
20 minutes (Table 5). The copper(I)-catalyzed [3+2] di-
polar cycloaddition reaction occurred with full regioselec-
tivity, resulting in the formation of the corresponding 1,4-
disubstituted 1,2,3-triazoles 12a–h in good yields (entries
1–8). Reacting pyrazine 10d with benzyl azide 11e apply-
11a
11b
N3
AcO
AcO
AcO
AcO
O
O
N3
N3
AcO
OAc
AcO
OAc
11e
11d
11c
Figure 1 Structure of azides 11a–e
Synthesis 2012, 44, 1614–1624
© Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
From Pyrazin-2(1H)-ones to Tetrasubstituted Pyrazines
1619
Table 4 Sonogashira Cross-Coupling of Pyrazines 9a,e,f,ha
(i) TIPSA (1.5 equiv)
Pd(PPh3)2Cl2 (5 mol%)
CuI (10 mol%)
TBAI (1.2 equiv)
DMF–Et3N (1:1)
MW, 80 W, 80 °C, 20 min
R3
R3
R1
N
R1
Cl
N
R2
N
R2
N
(ii) TBAF (1 M in THF, 2 equiv)
CH2Cl2–THF (1.5:1)
r.t., 3–5 min
10a–d
9a,e,f,h
Entry
Product
Structure
Yieldb (%)
OMe
OMe
N
1
10a
78
91
80
59
N
OMe
OMe
OMe
N
N
2
3
4
10b
10c
10d
OMe
OMe
N
N
OMe
N
N
OMe
OEt
a Using 9a,e,f,h (2.0 mmol) in a multimode microwave apparatus.
b Yields over two steps.
were carried out in sealed microwave process vials (15, 50 mL) and
temperature control was performed using both, external infrared
and internal fiber optic sensors. The ramp time (time required to
reach the expected temperature) was always between 1 to 2 min and
is included in the total reaction time. The reaction mixture was con-
tinuously stirred during reaction. After irradiation, the reaction ves-
sel was rapidly cooled by air jet cooling to ambient temperature.
ing similar conditions afforded 1,2,3-triazole compound
12i in good yield (entry 9). Interestingly when pyrazine
10d was reacted with trimethylsilyl azide, the correspond-
ing desilylated 1,2,3-triazole product 12j was obtained in
80% yield.
In summary, we have developed a new and efficient pro-
tocol for the synthesis of tetrasubstituted pyrazines start-
ing from 3,5-dichloro-1-(4-methoxybenzyl)pyrazin-
2(1H)-ones. A small library of pyrazine-containing nucle-
oside analogues was generated. The application of micro-
wave irradiation during the different steps of the sequence
has been shown to be highly valuable for speeding up re-
actions.
3,5-Dichloro-1-(4-methoxybenzyl)pyrazin-2(1H)-ones 1a–d;
General Procedure
General procedure for the preparation of 1a–d is the same as previ-
ously described by our group.5 Data for compounds 1a,b,d5 and 1d6
are in accordance with previously published work.
3-Alkoxy-5-chloro-1-(4-methoxybenzyl)pyrazin-2(1H)-ones
2a–c; General Procedure
General procedure for the preparation of 2a–c is the same as previ-
ously described by our group.6 Data for the compounds 2a6 and 2b11
are in accordance with the previously published work.
NMR spectra were recorded on a 300 MHz instrument using CDCl3
and DMSO-d6 as solvent unless otherwise stated, relative to TMS as
internal standard. For mass spectrometry, the ion source tempera-
ture was 150–250 °C, as required. For chromatography, analytical
TLC plates and 70–230 mesh silica gel were used. All solvents and
chemicals were purchased and used as available.
5-Chloro-3-ethoxy-6-isobutyl-1-(4-methoxybenzyl)pyrazin-
2(1H)-one (2c)
White solid; yield: 2.8 g (7.92 mmol, 98%); mp 86–88 °C.
1H NMR (300 MHz, CDCl3): d = 7.09 (d, J = 8.67 Hz, 2 H), 6.84 (d,
J = 8.64 Hz, 2 H), 5.25 (s, 2 H), 4.39 (q, J = 7.14 Hz, 2 H), 3.77 (s,
3 H), 2.59 (d, J = 7.35 Hz, 2 H), 1.99 (m, 1 H), 1.46 (t, J = 6.96 Hz,
3 H), 1.01 (d, J = 6.60 Hz, 6 H).
All microwave irradiation experiments were carried out in a multi-
mode Milestone MicroSYNTH microwave reactor (Laboratory
Microwave Systems). This apparatus was used in the standard con-
figuration as delivered, including proprietary software. Reactions
© Thieme Stuttgart · New York
Synthesis 2012, 44, 1614–1624

1620
S. G. Modha et al.
PRACTICAL SYNTHETIC PROCEDURES
Table 5 Synthesis of Triazoles 12a–ja
R3
R3
Cu turnings (2 equiv)
CuSO4 soln (1 M, 5 mol%),
TBTA ligand (5 mol%)
R1
N
R1
N
N
R4N3
(1.2 equiv)
+
N
R2
R2
N
THF–i-PrOH–H2O
(3:1:1, 5 mL)
MW, 200 W, 90 °C, 20 min
N
10a–d
N
11a–e
R4
12a–j
Entry
Substrate
Azide R4N3
11a
Product
12a
Yield (%)
1
2
3
4
5
6
7
8
10a
10b
10b
10b
10c
10c
10d
10d
82
69
56
38
92
71
73
63
11b
12b
12c
11c
11d
12d
12e
11a
11b
12f
11a
12g
11b
12h
9
10d
10d
11e
12i
78
80
10b
TMSN3
12j (R4 = H)
a Using 10a–d (0.1 mmol) in a multimode microwave apparatus.
b The protective group (TMS) was cleaved in situ.
13C NMR (75 MHz, CDCl3): d = 159.1, 152.9, 151.6, 129.5, 128.2,
127.4, 123.2, 114.2, 63.9, 55.2, 47.6, 37.3, 28.9, 22.3, 14.0.
13C NMR (75 MHz, CDCl3): d = 168.2, 159.2, 159.0, 131.0, 129.9,
127.6, 124.9, 114.4, 56.1, 55.3, 17.0.
HRMS (EI): m/z [M] calcd for C18H23ClN2O3: 350.1397; found:
HRMS (EI): m/z [M] calcd for C14H15ClN2O2S: 310.0543; found:
350.1389.
310.0547.
6-Benzyl-5-chloro-1-(4-methoxybenzyl)-3-methylpyrazin-
2(1H)-one (2d)
5-Chloro-3-ethoxy-6-isobutyl-1-(4-methoxybenzyl)pyrazine-
2(1H)-thione (3c)
The preparation of 2d is the same as previously described by our
Yellow liquid; yield: 2.6 g (7.2 mmol, 90%).
group;6 white solid; yield: 2.7 g (7.6 mmol, 95%); mp 152–154 °C.
1H NMR (300 MHz, CDCl3): d = 6.99 (d, J = 8.49 Hz, 2 H), 6.84 (d,
J = 8.46 Hz, 2 H), 5.99 (br s, 2 H), 4.46 (q, J = 7.14 Hz, 2 H), 3.77
(s, 3 H), 2.71 (d, J = 7.14 Hz, 2 H), 2.10–1.96 (m, 1 H), 1.49 (t,
J = 6.99 Hz, 3 H), 1.01 (d, J = 6.60 Hz, 6 H).
1H NMR (300 MHz, CDCl3): d = 7.38–7.29 (m, 3 H), 7.11 (d,
J = 6.78 Hz, 2 H), 7.05 (d, J = 8.67 Hz, 2 H), 6.87 (d, J = 8.85 Hz,
2 H), 5.05 (s, 2 H), 4.11 (s, 2 H), 3.79 (s, 3 H), 2.53 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 159.3, 156.4, 155.9, 134.7, 134.6,
13C NMR (75 MHz, CDCl3): d = 159.1, 158.0, 133.5, 130.2, 130.0,
127.6, 127.2, 125.3, 114.3, 65.0, 55.2, 49.5, 38.1, 29.2, 24.6, 22.3,
15.6, 14.0.
129.3, 127.8, 127.5 (2 C), 127.0, 114.4, 55.3, 47.6, 35.2, 20.9.
HRMS (EI): m/z [M] calcd for C20H19ClN2O2: 354.1135; found:
354.1134.
HRMS (EI): m/z [M] calcd for C18H23ClN2O2S: 366.1169; found:
366.1156.
5-Chloro-1-(4-methoxybenzyl)pyrazine-2(1H)-thiones 3a–d;
General Procedure
General procedure for the preparation of 3a-d is the same as previ-
ously described by our group.6 Data for compounds 3a are in accor-
dance with previously published work.6
6-Benzyl-5-chloro-1-(4-methoxybenzyl)-3-methylpyrazine-
2(1H)-thione (3d)
Yellow solid; yield: 2.16 g (5.84 mmol, 73%); mp 125–127 °C.
1H NMR (300 MHz, CDCl3): d = 7.37–7.34 (m, 3 H), 7.08 (d,
J = 6.6 Hz, 2 H), 7.00 (d, J = 8.1 Hz, 2 H), 6.88 (d, J = 8.07 Hz, 2
H), 5.81 (br s, 2 H), 4.20 (s, 2 H), 3.79 (s, 3 H), 2.79 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 175.9, 163.8, 159.2, 138.4, 134.3,
134.1, 133.4, 132.3, 132.2, 132.1, 131.5 (2 C), 129.4, 128.5, 128.4,
127.7, 127.4, 127.2, 124.9, 114.5, 55.3, 36.0, 26.8.
5-Chloro-3-methoxy-1-(4-methoxybenzyl)-6-methylpyrazine-
2(1H)-thione (3b)
Yellow solid; yield: 2.18 g (7.04 mmol, 88%); mp 127–129 °C.
1H NMR (300 MHz, CDCl3): d = 7.07 (d, J = 8.67 Hz, 2 H), 6.84 (d,
J = 8.76 Hz, 2 H), 6.00 (s, 2 H), 4.05 (s, 3 H), 3.77 (s, 3 H), 2.45 (s,
3 H).
HRMS (EI): m/z [M] calcd for C20H19ClN2OS: 370.0907; found:
370.0912.
Synthesis 2012, 44, 1614–1624
© Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
From Pyrazin-2(1H)-ones to Tetrasubstituted Pyrazines
1621
5-Chloro-2-(4-methoxybenzylthio)pyrazines 5a–d; General
Procedure
CuTC (1 equiv) were added and the reaction was run for a further
30 min under the same conditions. After completion of the reaction,
the mixture was filtered through celite and the filtrate was diluted
with EtOAc (200 mL), and washed with H2O (100 mL) and brine
(100 mL). The organic layer was dried (MgSO4) and the solvent was
removed under reduced pressure and the residue was purified by
column chromatography (silica gel, 0–30% EtOAc–heptane) to af-
ford compounds 9a–j.
Thioamide 3 (5 mmol) and I2 (10 mol%) were successively added
to CH2Cl2 (15 mL) in a 50-mL glass vial. The resulting soln was ir-
radiated at 80 °C ceiling temperature for 15 min using maximum
150-W microwave power. After completion of the reaction, the
mixture was diluted with EtOAc (200 mL) and washed with 5% aq
Na2S2O3 (100 mL) to remove I2, followed by H2O (100 mL) and
brine (100 mL). The organic layer was dried (MgSO4), the solvent
was removed under reduced pressure, and the residue was purified
by column chromatography (silica gel, 0–10% EtOAc–heptane) to
afford compounds 5a–d.
5-Chloro-3-methoxy-2-(4-methoxyphenyl)pyrazine (9a)
The reaction was carried out on a 5-mmol scale; light-yellow solid;
yield: 1.05 g (4.2 mmol, 84%); mp 69–71 °C.
1H NMR (300 MHz, CDCl3): d = 8.35 (s, 1 H), 8.09 (d, J = 8.85 Hz,
2 H), 6.98 (d, J = 8.85 Hz, 2 H), 4.06 (s, 3 H), 3.97 (s, 3 H).
5-Chloro-3-methoxy-2-(4-methoxybenzylthio)pyrazine (5a)
Light-yellow solid; yield: 1.23 g (4.15 mmol, 83%); mp 79–81 °C.
1H NMR (300 MHz, CDCl3): d = 7.99 (s, 1 H), 7.31 (d, J = 8.46 Hz,
2 H), 6.82 (d, J = 8.46 Hz, 2 H), 4.32 (s, 2 H), 4.00 (s, 3 H), 3.78 (s,
3 H).
13C NMR (75 MHz, CDCl3): d = 158.8, 155.1, 144.2, 140.0, 133.8,
130.2, 128.9, 113.9, 55.2, 54.7, 32.8.
HRMS (EI): m/z [M] calcd for C12H11ClN2O2: 250.0509; found:
250.0514.
5-Chloro-2-(3,4-dimethoxyphenyl)-3-methoxypyrazine (9b)
White solid; yield: 96 mg (0.35 mmol, 69%); mp 118–120 °C.
1H NMR (300 MHz, CDCl3): d = 8.20 (s, 1 H), 7.74 (d, J = 8.46 Hz,
1 H), 7.65 (s, 1 H), 6.95 (d, J = 8.46 Hz, 1 H), 4.07 (s, 3 H), 3.96–
3.94 (m, 6 H).
HRMS (EI): m/z [M] calcd for C13H13ClN2O2S: 296.0386; found:
296.0394.
13C NMR (75 MHz, CDCl3): d = 156.5, 150.2, 148.7, 142.3, 140.5,
5-Chloro-3-methoxy-2-(4-methoxybenzylthio)-6-methylpyra-
zine (5b)
Off white; yield: 1.36 g (4.4 mmol, 88%); mp 73–75 °C.
1H NMR (300 MHz, CDCl3): d = 7.33 (d, J = 8.67 Hz, 2 H), 6.82 (d,
J = 8.67 Hz, 2 H), 4.32 (s, 2 H), 3.96 (s, 3 H), 3.78 (s, 3 H), 2.53 (s,
3 H).
134.5, 127.4, 122.2, 111.8, 110.4, 55.9, 54.5.
HRMS (EI): m/z [M] calcd for C13H13ClN2O3: 280.0615; found:
280.0578.
5-Chloro-2-(3,4-difluorophenyl)-3-methoxypyrazine (9c)
White solid; yield: 96 mg (0.37 mmol, 75%); mp 113–115 °C.
1H NMR (300 MHz, CDCl3): d = 8.23 (s, 1 H), 8.01–7.88 (m, 2 H),
7.28–7.19 (m, 1 H), 4.09 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 158.7, 153.5, 142.6, 141.6, 138.4,
130.3, 129.3, 113.8, 55.2, 54.5, 32.8, 20.5.
HRMS (EI): m/z [M] calcd for C14H15ClN2O2S: 310.0543; found:
310.0558.
13C NMR (75 MHz, CDCl3): d = 152.6, 151.7, 151.6, 149.4, 149.3,
148.5, 148.3, 143.7, 138.3, 134.9, 131.7, 131.6, 129.9, 125.4 (2 C),
125.3 (2 C), 118.3, 118.0, 117.1, 116.9, 113.9, 54.7.
5-Chloro-3-ethoxy-6-isobutyl-2-(4-methoxybenzylthio)pyra-
zine (5c)
Colorless oil; yield: 1.46 g (4 mmol, 80%).
HRMS (EI): m/z [M] calcd for C11H7ClF2N2O: 256.0215; found:
256.0227.
1H NMR (300 MHz, CDCl3): d = 7.32 (d, J = 8.46 Hz, 2 H), 6.82 (d,
J = 8.46 Hz, 2 H), 4.38 (q, J = 6.96 Hz, 2 H), 4.32 (s, 2 H), 3.77 (s,
3 H), 2.71 (d, J = 7.17 Hz, 2 H), 2.23–2.12 (m, 1 H), 1.39 (t, J = 7.14
Hz, 3 H), 0.96 (d, J = 6.57 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 158.7, 152.9, 144.3, 142.7, 138.6,
130.2, 129.4, 113.8, 63.4, 55.2, 42.1, 32.7, 28.1, 22.4, 14.2.
5-Chloro-3-methoxy-2-[3-(trifluoromethyl)phenyl]pyrazine
(9d)
White solid; yield: 115 mg (0.4 mmol, 80%); mp 38–40 °C.
1H NMR (300 MHz, CDCl3): d = 8.35 (s, 1 H), 8.27–8.25 (m, 2 H),
7.69 (d, J = 7.53 Hz, 1 H), 7.58 (t, J = 7.74 Hz, 1 H), 4.10 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 156.9, 144.1, 139.1, 135.5, 135.1,
132.1, 130.9, 130.5, 128.7, 126.0, 125.9 (2 C), 125.8, 122.2, 54.7.
HRMS (EI): m/z [M] calcd for C18H23ClN2O2S: 366.1169; found:
366.115.
HRMS (EI): m/z [M] calcd for C12H8ClF3N2O: 288.0277; found:
288.0276.
6-Benzyl-5-chloro-2-(4-methoxybenzylthio)-3-methylpyrazine
(5d)
2-Chloro-6-methoxy-5-(4-methoxyphenyl)-3-methylpyrazine
(9e)
The reaction was carried out on a 5-mmol scale, white solid; yield:
1.14 g (4.3 mmol, 86%); mp 71–73 °C.
1H NMR (300 MHz, CDCl3): d = 8.03 (d, J = 8.85 Hz, 2 H), 6.98 (d,
J = 8.85 Hz, 2 H), 4.03 (s, 3 H), 3.86 (s, 3 H), 2.60 (s, 3 H).
Colorless oil; yield: 1.33 g (3.6 mmol, 72%).
1H NMR (300 MHz, CDCl3): d = 7.29–7.27 (m, 5 H), 7.19 (d,
J = 8.49 Hz, 2 H), 6.77 (d, J = 8.46 Hz, 2 H), 4.29 (s, 2 H), 4.24 (s,
2 H), 3.77 (s, 3 H), 2.39 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 158.7, 152.6, 149.9, 148.6, 142.0,
137.5, 130.1, 129.2, 128.4, 126.6, 113.8, 55.2, 40.3, 33.5, 20.6.
13C NMR (75 MHz, CDCl3): d = 160.4, 164.9, 142.1, 140.9, 139.7,
130.4, 127.5, 113.6, 55.3, 54.3, 20.7.
HRMS (EI): m/z [M] calcd for C20H19ClN2OS: 370.0907; found:
370.0888.
HRMS (EI): m/z [M] calcd for C13H13ClN2O2: 264.0666; found:
264.0663.
2-Aryl-5-chloropyrazines 9a–j; General Procedure
A mixture of pyrazine 5 (0.5 mmol), boronic acid 8 (2 equiv),
Pd(PPh3)4 (5 mol%), and CuTC (1.5 equiv) in THF (4 mL) was ir-
radiated in a 15-mL sealed tube at a ceiling temperature of 120 °C
using 500-W maximum power for 30 min. After 30 min more of the
above reactants, boronic acid 8 (1 equiv), Pd(PPh3)4 (5 mol%), and
2-Chloro-5-(3,4-dimethoxyphenyl)-6-methoxy-3-methylpyra-
zine (9f)
The reaction was carried out on a 5-mmol scale; light-yellow solid;
yield: 1.37 g (4.65 mmol, 93%); mp 94–96 °C.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 1614–1624

1622
S. G. Modha et al.
PRACTICAL SYNTHETIC PROCEDURES
1H NMR (300 MHz, CDCl3): d = 7.72 (d, J = 8.46 Hz, 1 H), 7.65 (d,
J = 1.14 Hz, 1 H), 6.94 (d, J = 8.46 Hz, 1 H), 4.03 (s, 3 H), 3.96 (s,
3 H), 3.93 (s, 3 H), 2.61 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 154.9, 150.0, 148.7, 142.1, 139.4,
129.6, 127.6, 122.2, 113.8, 111.9, 110.5, 55.9 (2 C), 54.4, 20.7.
tube at a ceiling temperature of 80 °C using 80-W maximum power
for 20 min. After completion of the reaction, the mixture was dilut-
ed with CH2Cl2 (200 mL) and washed with H2O (100 mL) and brine
(100 mL). The organic layer was dried (MgSO4) and distilled under
reduced pressure. The obtained residue was dissolved in CH2Cl2–
THF (1.5:1, 5 mL) and 1 M TBAF in THF (2 equiv) was added
dropwise. The mixture was stirred at r.t. for 3–5 min. After comple-
tion of the reaction, the solvents were removed under reduced pres-
sure and the residue was directly subjected to flash column
chromatography (short silica gel pad, 0–30% EtOAc–heptane) to
afford the desired terminal acetylenes 10a–d in good yields.
HRMS (EI): m/z [M] calcd for C14H15ClN2O3: 294.0771; found:
294.0765.
2-(4-tert-Butylphenyl)-5-chloro-3-methoxy-6-methylpyrazine
(9g)
Colorless liquid; yield: 133 mg (0.46 mmol, 92%).
1H NMR (300 MHz, CDCl3): d = 7.95 (d, J = 8.46 Hz, 2 H), 7.48 (d,
J = 8.67 Hz, 2 H), 4.02 (s, 3 H), 2.60 (s, 3 H), 1.34 (s, 9 H).
5-Ethynyl-3-methoxy-2-(4-methoxyphenyl)pyrazine (10a)
Light-yellow solid; yield: 374 mg (1.56 mmol, 78%).
1H NMR (300 MHz, CDCl3): d = 8.35 (s, 1 H), 8.10 (d, J = 8.85 Hz,
2 H), 6.99 (d, J = 8.88 Hz, 2 H), 4.06 (s, 3 H), 3.87 (s, 3 H), 3.29 (s,
1 H).
13C NMR (75 MHz, CDCl3): d = 160.8, 156.7, 142.7, 139.6, 131.7,
130.8, 127.7, 113.6, 80.5, 79.8, 55.3, 54.0.
13C NMR (75 MHz, CDCl3): d = 155.1, 152.4, 142.3, 141.4, 140.0,
132.1, 128.6, 125.2, 54.3, 34.7, 31.2, 20.7.
HRMS (EI): m/z [M] calcd for C16H19ClN2O: 290.1186; found:
290.1186.
2-Chloro-5-(3,4-dimethoxyphenyl)-6-ethoxy-3-isobutylpyra-
zine (9h)
The reaction was carried out on a 5-mmol scale; off-white solid;
yield: 1.39 g (3.95 mmol, 79%); mp 72–74 °C.
HRMS (EI): m/z [M] calcd for C14H12N2O2: 240.0899; found:
240.0897.
2-Ethynyl-6-methoxy-5-(4-methoxyphenyl)-3-methylpyrazine
1H NMR (300 MHz, CDCl3): d = 7.82–7.79 (m, 2 H), 6.95 (d,
J = 8.28 Hz, 1 H), 4.47 (q, J = 6.99 Hz, 2 H), 3.95–3.94 (m, 6 H),
2.80 (d, J = 7.17 Hz, 2 H), 2.29–2.20 (m, 1 H), 1.47 (t, J = 6.99 Hz,
3 H), 1.00 (d, J = 6.57 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 154.2, 149.9, 148.4, 144.7, 141.0,
138.9, 128.0, 122.2, 112.0, 110.6, 63.1, 55.9, 55.7, 42.1, 28.1, 22.4,
14.4.
(10b)
Dark-brown solid; yield: 462 mg (1.82 mmol, 91%); mp 128–130
°C.
1H NMR (300 MHz, CDCl3): d = 8.09 (d, J = 8.85 Hz, 2 H), 6.98 (d,
J = 8.85 Hz, 2 H), 4.03 (s, 3 H), 3.86 (s, 3 H), 3.45 (s, 1 H), 2.65 (s,
3 H).
13C NMR (75 MHz, CDCl3): d = 160.7, 155.1, 147.7, 141.5, 130.8,
130.0, 127.9, 113.6, 82.1, 80.9, 55.3, 53.9, 20.9.
HRMS (EI): m/z [M] calcd for C18H23ClN2O3: 350.1397; found:
350.1387.
HRMS (EI): m/z [M] calcd for C15H14N2O2: 254.1055; found:
254.1065.
2-Chloro-5-(3,4-difluorophenyl)-6-ethoxy-3-isobutylpyrazine
(9i)
5-(3,4-Dimethoxyphenyl)-2-ethynyl-6-methoxy-3-methylpyra-
zine (10c)
White solid; yield: 117 mg (0.36 mmol, 72%).
1H NMR (300 MHz, CDCl3): d = 8.07–7.94 (m, 2 H), 7.20 (t,
J = 8.46 Hz, 1 H), 4.49 (q, J = 7.14 Hz, 2 H), 2.79 (d, J = 7.14 Hz,
2 H), 2.30–2.16 (m, 1 H), 1.47 (t, J = 7.17 Hz, 3 H), 0.99 (d, J = 6.60
Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 154.3, 152.6, 152.4, 151.7, 151.5,
149.2, 149.1, 148.4, 148.3, 145.2, 142.5, 136.8, 132.3 (2 C), 132.1,
125.4 (2 C), 125.3 (2 C), 118.2, 118.0, 117.0, 116.8, 63.5, 42.1,
29.7, 28.1, 22.4, 14.4.
Light-brown solid; yield: 454 mg (1.6 mmol, 80%); mp 145–147
°C.
1H NMR (300 MHz, CDCl3): d = 7.79 (dd, J = 1.71, 8.47 Hz, 1 H),
7.71 (d, J = 1.50 Hz, 1 H), 6.94 (d, J = 8.46 Hz, 1 H), 4.04 (s, 3 H),
3.96 (s, 3 H), 3.94 (s, 3 H), 3.46 (s, 1 H), 2.66 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 155.2, 150.3, 148.6, 147.7, 141.2,
130.1, 128.0, 122.6, 112.1, 110.5, 82.2, 80.8, 55.9, 53.9, 20.9.
HRMS (EI): m/z [M] calcd for C16H16N2O3: 284.1161; found:
284.1170.
HRMS (EI): m/z [M] calcd for C16H17ClF2N2O: 326.0997; found:
326.1014.
3-(3,4-Dimethoxyphenyl)-2-ethoxy-6-ethynyl-5-isobutylpyra-
zine (10d)
Pink solid; yield: 401 mg (1.18 mmol, 59%); mp 108–110 °C.
1H NMR (300 MHz, CDCl3): d = 7.88–7.86 (m, 2 H), 6.95 (d,
J = 8.28 Hz, 1 H), 4.48 (q, J = 6.96 Hz, 2 H), 3.95–3.94 (m, 6 H),
3.39 (s, 1 H), 2.86 (d, J = 7.14 Hz, 2 H), 2.31–2.18 (m, 1 H), 1.47
(t, J = 7.14 Hz, 3 H), 0.99 (d, J = 6.78 Hz, 6 H).
2-Benzyl-3-chloro-6-(3,4-dimethoxyphenyl)-5-methylpyrazine
(9j)
Colorless oil; yield: 111 mg (0.4 mmol, 80%).
1H NMR (300 MHz, CDCl3): d = 7.37–7.21 (m, 5 H), 7.18–7.14 (m,
2 H), 6.96 (d, J = 7.92 Hz, 1 H), 4.32 (s, 2 H), 3.94 (s, 3 H), 3.91 (s,
3 H), 2.61 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 151.0, 150.4, 149.7, 149.0, 148.8,
144.9, 137.5, 130.0, 129.1, 128.4, 126.6, 121.8, 112.4, 110.7, 55.9
(2 C), 40.6, 22.6.
13C NMR (75 MHz, CDCl3): d = 154.7, 150.5, 150.2, 148.4, 140.7,
130.2, 128.4, 122.7, 112.3, 110.5, 81.5, 81.0, 62.5, 55.9, 55.7, 42.7,
28.8, 22.4, 14.5.
HRMS (EI): m/z [M] calcd for C20H19ClN2O2: 354.1135; found:
354.1145.
HRMS (EI): m/z [M] calcd for C20H24N2O3: 340.1787; found:
340.1775.
2-Aryl-5-ethynylpyrazines 10a–d; General Procedure
Azides 11a–e; General Procedure
All protected sugar azides9 11a–d and benzyl azide10 11e were syn-
thesized according to literature procedures.
A mixture of pyrazine 9 (2.0 mmol), triisopropylsilylacetylene (1.5
equiv), Pd(PPh3)2Cl2 (5 mol%), CuI (10 mol%), and TBAI (1.2
equiv) in DMF–Et3N (1:1, 4 mL) was irradiated in a 15-mL sealed
Synthesis 2012, 44, 1614–1624
© Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
From Pyrazin-2(1H)-ones to Tetrasubstituted Pyrazines
1623
4-(5-Arylpyrazin-2-yl)-1,2,3-triazoles 12a–j; General Proce-
dure
(2R,3S,4S,5R,6R)-2-(Acetoxymethyl)-6-{4-[6-methoxy-5-(4-
methoxyphenyl)-3-methylpyrazin-2-yl]-1H-1,2,3-triazol-1-
yl}tetrahydro-2H-pyran-3,4,5-triyl Triacetate (12d)
White solid; yield: 48 mg (0.08 mmol, 38%); mp 81–83 °C.
1H NMR (300 MHz, CDCl3): d = 8.34 (s, 1 H), 8.14 (d, J = 8.85 Hz,
2 H), 7.00 (d, J = 8.85 Hz, 2 H), 5.93 (d, J = 9.21 Hz, 1 H), 5.69 (t,
J = 9.78 Hz, 1 H), 5.59 (br s, 1 H), 5.30 (dd, J = 3.39, 10.33 Hz, 1
H), 4.28–4.20 (m, 3 H), 4.10 (s, 3 H), 3.87 (s, 3 H), 2.96 (s, 3 H),
2.25 (s, 3 H), 2.06 (s, 3 H), 2.02 (s, 3 H), 1.93 (s, 3 H).
A mixture of pyrazine 10 (0.1 mmol), azide 11 (1.2 equiv), Cu turn-
ings (2 equiv), aq 1 M CuSO4 (5 mol%), and TBTA (5 mol%) in
THF–i-PrOH–H2O (3:1:1, 5 mL) was irradiated in a 15-mL sealed
tube at a ceiling temperature of 90 °C using 200 W maximum power
for 20 min. After completion of the reaction, the mixture was dilut-
ed with EtOAc (100 mL), and washed with H2O (100 mL) and brine
(100 mL). The organic layer was dried (MgSO4) and the solvent was
removed under reduced pressure. The obtained residue was subject-
ed to column chromatography (silica gel, 0–50% EtOAc–heptane)
to afford desired compounds 12a–j.
13C NMR (75 MHz, CDCl3): d = 170.3, 170.0, 169.8, 169.2, 160.4,
154.9, 148.4, 142.4, 140.4, 136.2, 130.6, 128.2, 122.3, 113.6, 86.3,
74.2, 70.8, 67.8, 66.8, 61.2, 55.3, 53.6, 22.4, 20.7, 20.6, 20.5, 20.3.
MS (ESI+): m/z [M] calcd for C29H33N5O11: 627.5; found: 628.9
(2R,3R,4R,5R)-2-(Benzoyloxymethyl)-5-{4-[6-methoxy-5-(4-
methoxyphenyl)pyrazin-2-yl]-1H-1,2,3-triazol-1-yl}tetrahydro-
furan-3,4-diyl Dibenzoate (12a)
[M]+, 1277.6 [2 M + Na]+.
White solid; yield: 119 mg (0.16 mmol, 82%); mp 77–79 °C.
(2R,3R,4R,5R)-2-(Benzoyloxymethyl)-5-{4-[5-(3,4-dimethoxy-
phenyl)-6-methoxy-3-methylpyrazin-2-yl]-1H-1,2,3-triazol-1-
yl}tetrahydrofuran-3,4-diyl Dibenzoate (12e)
1H NMR (300 MHz, CDCl3): d = 8.96 (s, 1 H), 8.30 (s, 1 H), 8.11
(d, J = 8.49 Hz, 2 H), 8.03–7.96 (m, 6 H), 7.62–7.34 (m, 9 H), 7.00
(d, J = 8.46 Hz, 2 H), 6.54 (d, J = 3.03 Hz, 1 H), 6.37 (br s, 1 H),
6.18 (t, J = 5.25 Hz, 1 H), 4.94–4.88 (m, 2 H), 4.63 (dd, J = 3.39,
11.97 Hz, 1 H), 3.90 (s, 3 H), 3.88 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 166.1, 165.1 (2 C), 160.5, 156.8,
146.7, 141.9, 138.9, 133.9, 133.7, 133.3, 132.8, 130.6, 129.9, 129.8,
129.6, 129.1, 128.6, 128.5, 128.4, 128.2, 121.5, 113.6, 90.5, 81.4,
75.3, 71.5, 63.5, 55.3, 53.4.
White solid; yield: 151 mg (0.19 mmol, 98%); mp 83–85 °C.
1H NMR (300 MHz, CDCl3): d = 8.35 (s, 1 H), 8.03–7.96 (m, 6 H),
7.82 (d, J = 8.46 Hz, 1 H), 7.77 (s, 1 H), 7.62–7.55 (m, 2 H), 7.50–
7.35 (m, 7 H), 6.96 (d, J = 8.46 Hz, 1 H), 6.54 (d, J = 1.14 Hz, 1 H),
6.38 (t, J = 4.14 Hz, 1 H), 6.22 (t, J = 5.28 Hz, 1 H), 4.96–4.87 (m,
2 H), 4.63 (dd, J = 3.96, 12.24 Hz, 1 H), 3.99 (s, 3 H), 3.95 (s, 3 H),
3.90 (s, 3 H), 2.97 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 166.1, 165.1, 154.7, 150.0, 148.7,
148.3, 142.2, 139.9, 136.2, 13.9, 133.7, 133.3, 129.9, 129.8, 129.6,
129.1, 128.6 (2 C), 128.5, 128.4 (2 C), 123.3, 122.4, 112.0, 110.5,
90.4, 81.3, 75.4, 71.5, 63.5, 55.9, 53.4, 35.4, 31.8, 26.4, 22.6, 22.5,
14.1.
MS (ESI+): m/z [M] calcd for C40H33N5O9: 727.7; found: 750.3 [M
+ Na]+, 1478.2 [2 M + Na]+.
[(2R,3S,5R)-3-(4-Chlorobenzoyloxy)-5-{4-[6-methoxy-5-(4-
methoxyphenyl)-3-methylpyrazin-2-yl]-1H-1,2,3-triazol-1-
yl}tetrahydrofuran-2-yl]methyl 4-Chlorobenzoate (12b)
Yellow solid; yield: 95 mg (0.14 mmol, 69%); mp 66–67 °C.
MS (ESI+): m/z [M] calcd for C42H37N5O10: 771.7; found: 772.4
[M]+, 1565.0 [2 M + Na]+.
1H NMR (300 MHz, CDCl3): d = 8.28 (s, 1 H), 8.14 (d, J = 8.67 Hz,
2 H), 8.01 (d, J = 8.46 Hz, 2 H), 7.85 (d, J = 8.46 Hz, 2 H), 7.47 (d,
J = 8.31 Hz, 2 H), 7.31 (d, J = 8.49 Hz, 2 H), 7.00 (d, J = 8.64 Hz,
2 H), 6.52 (t, J = 5.85 Hz, 1 H), 5.87 (br s, 1 H), 4.75–4.69 (m, 2 H),
4.54–4.51 (m, 1 H), 3.96 (s, 3 H), 3.87 (s, 3 H), 3.51–3.42 (m, 1 H),
2.98–2.89 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 165.2, 164.9, 160.4, 154.7, 148.3,
142.2, 140.2, 139.8, 136.2, 131.1, 130.9, 130.6, 128.9, 128.2, 127.6,
127.4, 123.2, 113.6, 88.7, 83.5, 74.8, 63.9, 55.3, 53.3, 37.8, 22.4.
[(2R,3S,5R)-3-(4-Chlorobenzoyloxy)-5-{4-[5-(3,4-dimethoxy-
phenyl)-6-methoxy-3-methylpyrazin-2-yl]-1H-1,2,3-triazol-1-
yl}tetrahydrofuran-2-yl]methyl 4-Chlorobenzoate (12f)
Yellow solid; yield: 102 mg (0.14 mmol, 71%); mp 99–101 °C.
1H NMR (300 MHz, CDCl3): d = 8.29 (s, 1 H), 8.01 (d, J = 8.46 Hz,
2 H), 7.86–7.81 (m, 3 H), 7.78 (s, 1 H), 7.47 (d, J = 8.31 Hz, 2 H),
7.31 (d, J = 8.46 Hz, 2 H), 6.96 (d, J = 8.46 Hz, 1 H), 6.52 (t,
J = 5.82 Hz, 1 H), 5.87 (br s, 1 H), 4.76–4.69 (m, 2 H), 4.53 (d,
J = 7.53 Hz, 1 H), 3.99–3.95 (m, 9 H), 3.51–3.43 (m, 1 H), 3.02–
2.89 (m, 4 H).
13C NMR (75 MHz, CDCl3): d = 165.1, 164.9, 154.7, 150.0, 148.7,
148.2, 142.2, 140.3, 139.9, 139.8, 136.3, 131.1, 130.9, 128.9, 128.7,
128.4, 127.6, 127.4, 123.2, 122.4, 112.0, 110.5, 88.7, 83.5, 74.8,
63.9, 55.9, 53.4, 37.8, 35.4, 31.8, 26.4, 26.3, 22.6, 22.4, 14.1.
MS (ESI+): m/z [M] calcd for C34H29Cl2N5O7: 690.5; found: 691.2
[M]+, 1403.4 [2 M + Na]+.
(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-{4-[6-methoxy-5-(4-
methoxyphenyl)-3-methylpyrazin-2-yl]-1H-1,2,3-triazol-1-
yl}tetrahydro-2H-pyran-3,4,5-triyl Triacetate (12c)
MS (ESI+): m/z [M] calcd for C35H31Cl2N5O8: 720.5; found: 721.7
White solid; yield: 70 mg (0.11 mmol, 56%); mp 182–185 °C.
[M]+, 1463.2 [2 M + Na]+.
1H NMR (300 MHz, CDCl3): d = 8.34 (s, 1 H), 8.14 (d, J = 8.85 Hz,
2 H), 7.00 (d, J = 8.85 Hz, 2 H), 5.98 (d, J = 9.42 Hz, 1 H), 5.58 (t,
J = 9.42 Hz, 1 H), 5.46 (t, J = 9.42 Hz, 1 H), 5.30 (t, J = 9.78 Hz, 1
H), 4.37–4.31 (m, 1 H), 4.18 (d, J = 12.63 Hz, 1 H), 4.08–4.04 (m,
4 H), 3.87 (s, 3 H), 2.96 (s, 3 H), 2.09 (s, 6 H), 2.04 (s, 3 H), 1.91 (s,
3 H).
(2R,3R,4R,5R)-2-(Benzoyloxymethyl)-5-{4-[5-(3,4-dimethoxy-
phenyl)-6-ethoxy-3-isobutylpyrazin-2-yl]-1H-1,2,3-triazol-1-
yl}tetrahydrofuran-3,4-diyl Dibenzoate (12g)
Light-yellow solid; yield: 121 mg (0.15 mmol, 73%); mp 70–72 °C.
1H NMR (300 MHz, CDCl3): d = 8.31 (s, 1 H), 8.03–7.92 (m, 8 H),
7.59–7.54 (m, 2 H), 7.47–7.32 (m, 7 H), 6.97 (d, J = 8.46 Hz, 1 H),
6.50 (s, 1 H), 6.38 (s, 1 H), 6.22 (t, J = 4.89 Hz, 1 H), 4.96–4.84 (m,
2 H), 4.67–4.63 (m, 1 H), 4.35 (t, J = 6.57 Hz, 2 H), 3.98–3.95 (m,
6 H), 3.41–3.21 (m, 2 H), 2.33–2.29 (m, 1 H), 1.44 (t, J = 6.03 Hz,
3 H), 1.01 (d, J = 6.03 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 170.5, 169.9, 169.4, 169.0, 160.4,
154.9, 148.5, 142.3, 140.5, 136.0, 130.6, 128.2, 122.3, 113.6, 85.8,
75.2, 70.3, 67.7, 61.6, 55.3, 53.5, 22.4, 20.7, 20.5 (2 C), 20.2.
MS (ESI+): m/z [M] calcd for C29H33N5O11: 627.5; found: 628.8
[M]+, 1277.8 [2 M + Na]+.
13C NMR (75 MHz, CDCl3): d = 166.1, 165.1, 154.1, 149.8, 148.4
(2 C), 145.3, 139.3, 136.2, 133.9, 133.7, 133.3, 129.9, 129.7, 129.1,
128.8, 128.6, 128.5, 128.4, 123.6, 122.4, 112.2, 110.6, 90.4, 81.1,
© Thieme Stuttgart · New York
Synthesis 2012, 44, 1614–1624

1624
S. G. Modha et al.
PRACTICAL SYNTHETIC PROCEDURES
Acknowledgement
75.4, 71.5, 63.6, 62.0, 55.9, 55.7, 42.4, 35.4, 30.9, 28.5, 26.4, 22.6,
22.5 (2 C), 14.5.
The authors thank the F.W.O. [Fund for Scientific Research – Flan-
ders (Belgium)] and the Research Fund of the University of Leuven
(KU Leuven) for financial support to the laboratory. J.C.T. is grate-
ful to EMECW15 (Erasmus Mundus External Cooperation Window
Lot 15 India) for obtaining a postdoctoral scholarship. V.P.M. is
grateful to the IRO (Interfacultaire Raad voor Ontwikkelingssamen-
werking) for obtaining a doctoral scholarship. D.E. is grateful to the
FWO for obtaining a postdoctoral scholarship. The authors thank Ir.
B. Demarsin for HRMS measurements.
MS (ESI+): m/z [M] calcd for C46H45N5O10: 827.8; found: 828.3
[M]+, 1677.1 [2 M + Na]+.
[(2R,3S,5R)-3-(4-Chlorobenzoyloxy)-5-{4-[5-(3,4-dimethoxy-
phenyl)-6-ethoxy-3-isobutylpyrazin-2-yl]-1H-1,2,3-triazol-1-
yl}tetrahydrofuran-2-yl]methyl 4-Chlorobenzoate (12h)
Light-yellow solid; yield: 98 mg (0.13 mmol, 63%); mp 59–61 °C.
1H NMR (300 MHz, CDCl3): d = 8.26 (s, 1 H), 8.00 (d, J = 7.74 Hz,
2 H), 7.92–7.86 (m, 4 H), 7.45 (d, J = 7.92 Hz, 2 H), 7.32 (d,
J = 7.92 Hz, 2 H), 6.98 (d, J = 8.67 Hz, 1 H), 6.51 (t, J = 5.64 Hz, 1
H), 5.87 (br s, 1 H), 4.70–4.67 (m, 2 H), 4.57–4.51 (m, 1 H), 4.41
(q, 6.39 Hz, 2 H), 3.98 (s, 3 H), 3.95 (s, 3 H), 3.54–3.45 (m, 1 H),
3.39–3.21 (m, 2 H), 2.95–2.90 (m, 1 H), 2.34–2.25 (m, 1 H), 1.47 (t,
J = 6.96 Hz, 3 H), 1.01 (d, J = 6.57 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 165.2, 164.9, 154.2, 149.8, 148.4
(2 C), 145.2, 140.2, 139.8, 138.3, 136.3, 131.1, 128.9, 128.8, 127.7,
127.5, 123.5, 122.4, 112.2, 110.6, 88.7, 83.5, 74.9, 64.0, 62.0, 55.9,
55.7, 42.4, 37.6, 35.4, 31.8, 30.9, 28.5, 26.4, 22.6, 22.5 (2 C), 14.6,
14.1.
References
(1) (a) Koehler, P. E.; Odell, G. V. J. Agric. Food Chem. 1970,
18, 895. (b) Maga, J. A.; Sizer, C. E. J. Agric. Food Chem.
1973, 21, 22. (c) Mega, J. A. Pyrazines in Food. An Update,
In Critical Reviews in Food Sciences and Nutrition, Vol. 16;
Furia, T. E., Ed.; CRC: Boca Raton FL, 1982, 1–48.
(d) Leunissen, M.; Davidson, V. J.; Kakuda, Y. J. Agric.
Food Chem. 1996, 44, 2694. (e) Wailzer, B.; Klocker, J.;
Buchbauer, G.; Ecker, G.; Wolschann, P. J. Med. Chem.
2001, 44, 2805. (f) Barlin, G. B. The Chemistry of
Heterocyclic Compounds, Vol. 41; Wiley: New York, 1982.
(g) Walker, J. A.; Liu, W.; Wise, D. S.; Drach, J. C.;
Townsend, L. B. J. Med. Chem. 1998, 41, 1236.
MS (ESI+): m/z [M] calcd for C39H39Cl2N5O8: 776.6; found: 777.2
[M]+, 1575.6 [2 M + Na]+.
2-(1-Benzyl-1H-1,2,3-triazol-4-yl)-5-(3,4-dimethoxyphenyl)-6-
ethoxy-3-isobutylpyrazine (12i)
(h) De Clercq, E. Med. Res. Rev. 2010, 30, 667.
(2) (a) Ohta, A.; Itoh, R.; Kaneko, Y.; Koike, H.; Yuasa, K.
Heterocycles 1989, 29, 939. (b) Buchi, G.; Galindo, J.
J. Org. Chem. 1991, 56, 2605. (c) Heathcock, C. H.; Smith,
S. C. J. Org. Chem. 1994, 59, 6828. (d) Drogemuller, M.;
Flessner, T.; Jautelat, R.; Scholz, U.; Winterfeldt, E. Eur. J.
Org. Chem. 1998, 2811. (e) McCullough, K. J. In Rodd’s
Chemistry of Carbon Compounds, 2nd ed., Vol. 4, Parts I-J;
Sainsbury, M., Ed.; Elsevier: Amsterdam, 2000, 99.
(f) Elmaaty, T. A.; Castle, L. W. Org. Lett. 2005, 7, 5529.
(g) Aparicio, D.; Attanasi, O. A.; Filippone, P.; Ignacio, R.;
Lillini, S.; Mantellini, F.; Palacios, F.; de los Santos, J. M.
J. Org. Chem. 2006, 61, 5897. (h) Taber, D. F.; DeMatteo,
P. W.; Taluskie, K. V. J. Org. Chem. 2007, 62, 1492.
(i) Candelon, N.; Shinkaruk, S.; Bennetau, B.; Bennetau-
Pelissero, C.; Dumartin, M.-L.; Degueil, M.; Babin, P.
Tetrahedron 2010, 66, 2463.
(3) Topics in Heterocyclic Chemistry, Vol. 1; Van der Eycken,
E.; Kappe, C. O., Eds.; Springer: Berlin, 2006, 267.
(4) Modha, S. G.; Trivedy, J. C.; Mehta, V. P.; Ermolat’ev, D.
S.; Van der Eycken, E. V. J. Org. Chem. 2011, 76, 846.
(5) Mehta, V. P.; Modha, S. G.; Ermolate’ev, D.; Van Hecke,
K.; Van Meervelt, L.; Van der Eycken, E. V. Aust. J. Chem.
2009, 62, 27.
Yellow solid; yield: 74 mg (0.16 mmol, 78%); mp 137–139 °C.
1H NMR (300 MHz, CDCl3): d = 7.98 (s, 1 H), 7.91–7.89 (m, 2 H),
7.41–7.33 (m, 5 H), 6.96 (d, J = 9.03 Hz, 1 H), 5.61 (s, 2 H), 4.44
(q, J = 7.23 Hz, 2 H), 3.96 (s, 3 H), 3.94 (s, 3 H), 3.32 (d, J = 6.96
Hz, 2 H), 2.33–2.22 (m, 1 H), 1.46 (t, J = 6.99 Hz, 3 H), 0.99 (d,
J = 6.60 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 154.2, 149.8, 148.4, 148.3, 145.3,
139.0, 136.8, 134.7, 129.1, 128.8, 128.7, 128.0, 124.0, 122.3, 112.2,
110.6, 62.0, 55.9, 55.7, 54.1, 42.5, 28.5, 22.5, 14.5.
HRMS (EI): m/z [M] calcd for C27H31N5O3: 473.2427; found:
473.2420.
3-(3,4-Dimethoxyphenyl)-2-ethoxy-5-isobutyl-6-(1H-1,2,3-tria-
zol-4-yl)pyrazine (12j)
Green solid; yield: 61 mg (0.16 mmol, 80%); mp 202–204 °C.
1H NMR (400 MHz, DMSO): d = 15.3 (br s, 1 H), 8.38 (br s, 1 H),
7.86 (d, J = 1.50 Hz, 1 H), 7.82 (dd, J = 1.50, 6.33 Hz, 1 H), 7.09 (d,
J = 6.42 Hz, 1 H), 4.52 (q, J = 5.28 Hz, 2 H), 3.83–3.82 (m, 6 H),
2.50 (merged in solvent peak, 2 H), 2.21–2.13 (m, 1 H), 1.44 (t,
J = 5.28 Hz, 3 H), 0.93 (d, J = 4.92 Hz, 6 H).
13C NMR (75 MHz, DMSO): d = 153.8, 149.7, 148.0, 127.8, 121.9,
112.1, 111.2, 61.9, 55.4, 55.2, 54.8, 41.9, 27.8, 22.2, 14.3.
(6) Mehta, V. P.; Sharma, A.; Van Hecke, K.; Van Meervelt, L.;
Van der Eycken, E. J. Org. Chem. 2008, 73, 2382.
(7) Molina, P.; Alajarin, M.; Fresneda, P. M.; Lidon, M. J.;
Vilaplana, M. J. Synthesis 1982, 598.
HRMS (EI): m/z [M] calcd for C20H25N5O3: 383.1957; found:
383.1973.
(8) Singh, B. K.; Parmar, V. S.; Van der Eycken, E. Synlett
2008, 3021.
(9) (a) Stimac, A.; Kobe, J. Carbohydr. Res. 2000, 324, 149.
(b) Stimac, A.; Kobe, J. Carbohydr. Res. 2000, 329, 317.
(10) Ankati, H.; Biehl, E. Tetrahedron Lett. 2009, 50, 4677.
(11) Mehta, V. P.; Modha, S. G.; Van der Eycken, E. J. Org.
Chem. 2008, 73, 976.
Synthesis 2012, 44, 1614–1624
© Thieme Stuttgart · New York