An expeditious route toward pyrazine-containing nucleoside analogues

Article abstract of DOI:10.1021/jo102089h

An improved and convenient methodology for the synthesis of asymmetrically substituted pyrazines starting from 3,5-dichloropyrazin-2(1H)-ones has been elaborated. Several nucleoside analogues have been synthesized containing the pyrazine core as the organic base coupled with the sugar via a triazole linkage. The beneficial effect of microwave irradiation throughout the sequence has been demonstrated.

Full text of DOI:10.1021/jo102089h

pubs.acs.org/joc
An Expeditious Route toward Pyrazine-Containing Nucleoside Analogues
Sachin G. Modha,† Jalpa C. Trivedi,†,‡ Vaibhav P. Mehta,†,§ Denis S. Ermolat’ev,† and
Erik V. Van der Eycken*,†
†Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry,
Katholieke Universiteit Leuven, Celestijnenlaan 200F, B-3001, Leuven, Belgium. ‡Present address:
Department of Chemistry, Shoolini University, Bhajol, Solan-173 229, Himachal Pradesh, India.
§Present address: Institut fur Organische and Biomoleculare Chemie, Georg-August-Universita€t Go€ttingen,
Tamannstr. 2, Goettingen 37077, Germany
erik.vandereycken@chem.kuleuven.be
Received October 21, 2010
An improved and convenient methodology for the synthesis of asymmetrically substituted pyrazines
starting from 3,5-dichloropyrazin-2(1H)-ones has been elaborated. Several nucleoside analogues
have been synthesized containing the pyrazine core as the organic base coupled with the sugar via a
triazole linkage. The beneficial effect of microwave irradiation throughout the sequence has been
demonstrated.
Introduction
and synthetic nucleosides, many with interesting biological
activities, have been prepared via a variety of approaches.3
Although pyrimidine-like nucleosides have been studied ex-
tensively, pyrazine-based nucleosides were still missing from
this array until recently.4 Therefore, we reasoned that it might
be worthwhile to investigate the use of substituted pyrazines
as alternative organic bases of the nucleoside.
Tri- and tetrasubstituted pyrazines are present in the core
structure of a number of important natural as well as syn-
thetic heterocyclic compounds, such as, for example, flavor
components in food.5 Especially, pyrazines substituted with
a thioether function are known to possess a nice aroma.
Nucleosides possess a broad spectrum of biological func-
tions, ranging from their primary role as building blocks
in the genetic code to other functions, such as biosynthetic
intermediates, energy donors, metabolic regulators, and
cofactors in enzymatic processes. Many nucleoside ana-
logues have been developed for screening as antiviral agents,
nonradioactive fluorescent labels for DNA, and as anti-
cancer drugs, by variation of the sugar part and/or the hetero-
cyclic base.1 As a result, nucleosides and their analogues have
generated considerable scientific interest in their chemistry
and biology.2 A substantial number of naturally occurring
(1) (a) De Clercq, E.; Holy, A.; Rosenberg, I.; Sakuma, T.; Balzarini, J.;
Maudgal, P. C. Nature 1986, 323, 464. (b) Haines, D. R.; Tseng, C. K.;
Marquez, V. E. J. Med. Chem. 1987, 30, 943. (c) Borcherding, D. R.;
Narayanan, S.; Hasobe, M.; McKee, J. G.; Keller, B. T.; Borchardt, R. T.
J. Med. Chem. 1988, 31, 1729. (d) Naesens, L.; Snoeck, R.; Andrei, G.;
Balzarini, J.; Neyts, J.; De Clercq, E. Antiviral Chem. Chemother. 1997, 8, 1.
(e) Agrofoglio, L. A.; Challand, S. R. Acyclic, Carbocyclic and L-Nucleosides;
Kluwer Academic: Dordrecht, The Netherlands, 1998; pp 174-284. (f) Kim,
H. S.; Barak, D.; Harden, K. T.; Boyer, J. L.; Jacobson, K. A. J. Med. Chem.
2001, 44, 3092.
(3) (a) Ermolat’ev, D. S.; Mehta, V. P.; Van der Eycken, E. V. QSAR
Comb. Sci. 2007, 26, 1266. (b) Robins, M. J.; Yang, H.; Miranda, K.;
Peterson, M. A.; De Clercq, E.; Balzarini, J. J. Med. Chem. 2009, 52, 3018.
(c) De Clercq, E. Nucleosides, Nucleotides Nucleic Acids 2009, 28, 586.
(d) Romeo, G.; Chiacchio, U.; Corsaro, A.; Merino, P. Chem. Rev. 2010,
110, 3337. (e) Lakshman, M. K.; Singh, M. K.; Parrish, D.; Balachandran,
R.; Day, B. W. J. Org. Chem. 2010, 75, 2461.
(4) (a) Benner, S. A. U.S. patent US006140496A, 2000, p 24. (b) Liu, W.;
Wise, D. S.; Townsend, L. B. J. Org. Chem. 2001, 66, 4783. (c) Von Krosigk,
U.; Benner, S. A. Helv. Chim. Acta 2004, 87, 1299.
(2) (a) Suhadolnik, R. J., Ed. Nucleosides as Biological Probes; John Wiley
& Sons: New York, 1979. (b) Townsend, L. B., Ed. Chemistry of Nucleosides
and Nucleotides; Plenum Press: New York, 1988; Vol. 1; 1991; Vol. 2. (c) Chu,
C. K., Baker, D. C., Eds. Nucleosides and Nucleotides as Antitumor and
Antiviral Agents; Plenum Press: New York, 1993. (d) Townsend, L. B., Ed.
Chemistry of Nucleosides and Nucleotides; Plenum Press: New York, 1994;
Vol. 3.
(5) (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.
In Pyrazines in Food: An Update; Furia, T. E., Ed.; Critical Reviews in Food
Sciences and Nutrition; CRC: Boca Raton, FL, 1982; Vol. 16, pp 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.
846 J. Org. Chem. 2011, 76, 846–856
Published on Web 01/07/2011
DOI: 10.1021/jo102089h
r
2011 American Chemical Society

Modha et al.
JOCArticle
FIGURE 1. Examples of pharmacologically active molecules having a pyrazine core.
Moreover, they are versatile synthetic intermediates.6 Many
substituted pyrazines possess important pharmacological
activities, such as antiviral7 (Figure 1, compounds I and II),
ATR kinase inhibitor8 (Figure 1, compound III), anti-
mutagenic,9 vascular endothelial growth factor inhibitory
activity,10 or as epithelial sodium channel blockers.11 Des-
pite their importance, only a limited number of synthetic
methodologies are described for the generation of asymme-
trically multisubstituted pyrazines.12
We have previously explored the application of 3,5-dichlo-
ropyrazin-2(1H)-ones as attractive starting materials for the
synthesis of different heterocyclic compounds.13 We envi-
saged that the pyrazinone framework offers a unique gate-
way for the generation of asymmetrically tri- and tetra-
substituted pyrazines (Scheme 1). The substituent in the
C6-position of the pyrazinone is determined by the aldehyde
used during its construction,14 whereas the substituent at the
C3-position could be easily introduced via reaction of the
imidoyl chloride moiety.15 The pyrazinone can be converted
to the pyrazine-thione by Lawesson’s reagent, followed by
removal of the p-methoxybenzyl group and simultaneous
conversion of the thione to the methyl thioether.16 In the
newly generated pyrazines, the chlorine becomes susceptible
toward the Sonogashira cross-coupling reaction with tri-
methylsilylacetylene. After desilylation, affording the corre-
sponding ethynyl pyrazine,17,3a a Huisgen [3 þ 2] cyclo-
addition could be performed on this terminal acetylene with
a suitable sugar azide.18 Finally, the methyl thioether group
is involved in a Liebeskind-Srogl19 cross-coupling reaction,
giving the asymmetrically substituted pyrazine coupled with
a sugar moiety via a triazole linkage.
Results and Discussion
Pyrazin-2(1H)-ones 1a-c were alkoxylated at the C3-
position using NaH, giving quantitative yields of 2a-c
(Scheme 2). Treatment of 1d with Me4Sn under Stille condi-
tions provided methylated compound 2d in 95% yield. All
C3-substituted pyrazine-2(1H)-ones 2a-d were reacted
with Lawesson’s reagent in toluene at reflux temperature
to afford the corresponding thioamides 3a-d in good
yields (Scheme 2).
(6) Barlin, G. B. The Chemistry of Heterocyclic Compounds; Wiley: New
York, 1982; Vol. 41.
A mixture of compound 3a with 5 equiv of methyl iodide
and 10 mol % of iodine in toluene was refluxed for 12 h,
yielding 72% of the expected methylthioether 4a together
with 20% of p-methoxybenzylthioether 5a as the main by-
product (Table 1, entry 1).16 The formation of 5a might be
explained by the competitive reaction of the in situ formed
p-methoxybenzyliodide. During the scale-up of the reaction,
we noticed that it was rather difficult to separate the desired
methylthioether 4a from the compound 5a due to similar
polarity. Therefore, efforts were made to make this reaction
more selective. However, under microwave irradiation, at a
temperature of 130 °C for 30 min applying further the same
conditions, the amount of byproduct 5a increased (Table 1,
entry 2). The reaction was rather slow in the absence of
iodine, still giving both 4a and 5a, with decreased yield
(7) (a) Walker, J. A.; Liu, W.; Wise, D. S.; Drach, J. C.; Townsend, L. B.
J. Med. Chem. 1998, 41, 1236. (b) De Clercq, E. Med. Res. Rev. 2010, 30, 667.
(8) Jean-Damien, C.; et al. et al. PCT Int. Appl. 2010, WO2010054398A1.
(9) (a) Pettit, G. R.; Inoue, M.; Kamano, Y.; Herald, D. L.; Arm, C.;
Dufresne, C.; Christie, N. D.; Schmidt, J. M.; Doubek, D. L.; Krupa, T. S.
J. Am. Chem. Soc. 1996, 118, 10672. (b) Pettit, G. R.; Inoue, M.; Kamano, Y.;
Herald, D. L.; Arm, C.; Dufresne, C.; Christie, N. D.; Schmidt, J. M.;
Doubek, D. L.; Timothy, S. K. J. Am. Chem. Soc. 1998, 110, 2006. (c) Garg,
N. K.; Stolz, B. M. Tetrahedron Lett. 2005, 46, 2423. (d) Neelamkavil, S.;
Arison, B.; Birzin, E.; Feng, J.-J.; Chen, K.-H.; Lin, A.; Cheng, F. C.; Taylor,
L.; Thornton, E. R.; Smith, A. B.; Hirschmann, R. J. Med. Chem. 2005,
48, 4025.
(10) Kuo, G. H.; DeAngelis, A.; Emanuel, S.; Wang, A.; Zhang, Y.;
Connolly, P. J.; Chen, X.; Gruninger, R. H.; Rugg, C.; Pesquera, A. F.;
Middleton, S. A.; Jolliffe, L.; Murray, W. V. J. Med. Chem. 2005, 48, 4535.
(11) Hirsh, A. J.; Molino, B. F.; Zhang, J.; Astakhova, N.; Geiss, W. B.;
Sargent, B. J.; Swenson, B. D.; Usyatinsky, A.; Wyle, M. J.; Boucher, R. C.;
Smith, R. T.; Zamurs, A.; Johnson, M. R. J. Med. Chem. 2006, 49, 4098.
(12) (a) Ohta, A.; Itoh, R.; Kaneko, Y.; Koike, H.; Yuasa, K. Hetero-
cycles 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.; Sainsbury, M., Ed.; Elsevier: Amsterdam, 2000;
Vol. 4 (Parts I and J), p 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, 71, 5897.
(h) Taber, D. F.; DeMatteo, P. W.; Taluskie, K. V. J. Org. Chem. 2007, 72,
1492. (i) Candelon, N.; Shinkaruk, S.; Bennetau, B.; Bennetau-Pelissero, C.;
Dumartin, M.-L.; Degueil, M.; Babin, P. Tetrahedron 2010, 66, 2463.
(13) Van der Eycken, E., Kappe, C. O., Eds. Topics in Heterocyclic
Chemistry; Springer: Berlin, Germany, 2006; Vol. 1, p 267.
(17) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467. (b) For a recent review, see: Agrofoligo, L. A.; Gillaizeau, I.;
Saito, Y. Chem. Rev. 2003, 103, 1875. (c) Negishi, E. I.; Anastasia, L. Chem.
Rev. 2003, 103, 1979. (d) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107,
874. (e) Douchet, H.; Hierso, J. C. Angew. Chem., Int. Ed. 2007, 46, 834.
(f) Plenio, H. Angew. Chem., Int. Ed. 2008, 47, 6954.
(18) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2002, 40, 2004. (b) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem.
2002, 67, 3057. (c) Kappe, C. O.; Van der Eycken, E. Chem. Soc. Rev. 2010,
39, 1280. (d) Appukkuttan, P.; Mehta, V. P.; Van der Eycken, E. V. Chem.
Soc. Rev. 2010, 39, 1467 and references cited therein.
(19) (a) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260.
(b) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett. 2001, 3, 91. (c) Lengar,
A.; Kappe, C. O. Org. Lett. 2004, 6, 771. (d) Singh, B. K.; Mehta, V. P.;
Parmar, V. S.; Van der Eycken, E. Org. Biomol. Chem. 2007, 5, 2962.
(e) Prokopcova, H.; Kappe, C. O. J. Org. Chem. 2007, 72, 4440.
(f) Prokopcova, H.; Kappe, C. O. Angew. Chem., Int. Ed. 2009, 48, 2276
and references cited therein.
(14) Vekemans, J.; Pollers-Wieers, C.; Hoornaert, G. J. Heterocycl.
Chem. 1983, 20, 919.
(15) Kaval, N.; Bisztray, K.; Dehaen, W.; Kappe, C. O.; Van der Eycken,
E. Mol. Diversity 2003, 7, 125.
(16) Mehta, V. P.; Sharma, A.; Van Hecke, K.; Van Meervelt, L.; Van der
Eycken, E. J. Org. Chem. 2008, 73, 2382.
J. Org. Chem. Vol. 76, No. 3, 2011 847

Modha et al.
JOCArticle
SCHEME 1. Retrosynthetic Analysis for the Generation of Asymmetrically Substituted Pyrazines Coupled with a Sugar Moiety via a
Triazole Linkage
SCHEME 2. Synthesis of Pyrazin-2(1H)-thiones 3a-d
(Table 1, entry 3). This observation was rather interesting
as only salt formation was expected with methyliodide.
Clearly, upon heating,20 the intermediate salt loses p-meth-
oxybenzyl iodide, forming 4a, and the in situ formed
p-methoxybenzyliodide reacts with an other molecule of
starting material 3a to give 5a. As it was impossible to mini-
mize the competition between methyl iodide and in situ
formed p-methoxybenzyl iodide, it was decided to exclude
methyl iodide from the reaction mixture. This should result
in the sole formation of p-methoxybenzylthioether 5a. As a
proof of concept, when 3a was refluxed in toluene with
10 mol % of I2, to our satisfaction, only 5a was formed in
45% yield (Table 1, entry 4). Interestingly, when the solvent
was changed to dichloromethane, the yield increased to
65% (Table 1, entry 5). When the reaction was run at rt with
5, 10, 50, and 80 mol % of I2, respectively, there was not
much change in yields, but a dramatic difference in reaction
time was observed ranging from 40 to 0.15 h (Table 1,
entries 8, 7, 9, and 10). The best condition was obtained
when the reaction was carried out with 10 mol % of I2 in
dichloromethane under microwave irradiation at 80 °C and
a maximum power of 150 W for 15 min, yielding compound
5a in 83% yield (Table 1, entry 6).
A plausible mechanism for the transfer of the p-methoxy-
benzyl group is shown in Scheme 3. Iodine first reacts with
the sulfur atom of thioamide 3a to give intermediate A. This
loses the p-methoxybenzyl group to form the unstable inter-
mediates B and C that directly react with each other to give
the p-methoxybenzylthioethers 5, while iodine goes back in
the catalytic cycle. It is interesting to note that the reaction,
which is rather slow at room temperature, is speeded up
under microwave irradiation. To the best of our knowl-
edge, there is no literature precedent about the transfer of a
(20) Molina, P.; Alajarin, M.; Fresneda, P. M.; Lidon, M. J.; Vilaplana,
M. J. Synthesis 1982, 7, 598.
848 J. Org. Chem. Vol. 76, No. 3, 2011

Modha et al.
JOCArticle
TABLE 1. Optimization Study for Thioether Formationa
entry
reagent (equiv)
catalyst (mol %)
solvent
temp
time (h)
yield (%) 4a:5a
1b
2c
3
MeI (5)
MeI (5)
MeI (5)
I2 (10)
I2 (10)
toluene
toluene
toluene
toluene
DCM
DCM
DCM
DCM
DCM
DCM
reflux
130 °C
reflux
reflux
reflux
80 °C
rt
rt
rt
rt
12
0.5
1
12
6
0.25
24
40
6
72:20
55:30
40:15
0:45
0:65
0:83
0:79
0:73
0:80
0:85
4
I2 (10)
I2 (10)
I2 (10)
I2 (10)
I2 (5)
5
6d
7
8
9
10
I2 (50)
I2 (80)
0.15
aAll the reactions were run on a 0.1 mmol scale of 3a with conventional heating unless otherwise stated. bScale-up reaction with 5 mmol of 3a was also
done with full conversion, but it was not possible to separate 4a from 5a by column chromatography. cThe reaction mixture was irradiated using a
maximum power of 400 W in a multimode microwave apparatus. dThe reaction mixture was irradiated using a maximum power of 150 W in a multimode
microwave apparatus.
SCHEME 3. Plausible Mechanism for the Transfer of the
p-Methoxybenzyl Group
SCHEME 4. Synthesis of p-Methoxybenzylthioether Deriva-
tives 5b-d
Therefore, it seems obvious to substitute first the S-PMB
group and then to check the reactivity of chlorine again. It
was also interesting to know whether the S-PMB group
should be reactive enough under standard Liebiskind-Srogl
conditions. When pyrazine 5a was reacted with boronic acid
8a in the presence of copper(I)-thiophene-2-carboxylate and
Pd(PPh3)4 in THF under conventional heating as well as
under microwave irradiation (Table 3, entries 1-3, 5, and 6),
poor to average yields were obtained. As the reaction was
rather sluggish, it was assumed that reagents were getting
decomposed during the long reaction time at high tempera-
ture. To overcome this difficulty, the reagents were added in
two portions, and to our satisfaction, the reaction was comp-
lete in 1 h under microwave irradiation at 120 °C, yielding 9a
in 84% (Table 3, entry 4).21
p-methoxybenzyl group from nitrogen to sulfur in a
p-methoxybenzyl-protected thioamide.
This optimized protocol was applied to convert the pyr-
azin-2(1H)-thiones 3b-d into the corresponding p-methoxy-
benzylthioethers 5b-d, which were obtained in good yields
(Scheme 4).
This optimized protocol was then applied for the conver-
sion of 5a-d to 9b-j in good to excellent yields (Table 4).
Having successfully established the optimized conditions
for the pyrazine scaffold, we next explored the scope of the
protocol for some other heterocycles bearing an S-PMB
group. All starting compounds with a p-methoxybenzylthio
or benzylthio group were synthesized according to litera-
ture procedures22 from their respective thiol derivative.
In the newly generated pyrazines 5, the chlorine atom that
was present at the C5-position of the starting pyrazinone is
now susceptible for transition-metal-catalyzed cross-coupling
reactions. However, to our surprise, all efforts made to
perform a Sonogashira reaction met with failure (Table 2).
This is in sharp contrast with our previously published
work,16 where the reaction went smoothly when an S-Me
group was present instead of an S-PMB group at the C2-
position of the pyrazine. Probably, the p-methoxyben-
zylthioether renders the chlorine less susceptible toward
nucleophilic substitution by the palladium.
(21) Singh, B. K.; Parmar, V. S.; Van der Eycken, E. Synlett 2008, 19,
3021.
(22) Radi, M.; et al. ChemMedChem 2008, 3, 573.
J. Org. Chem. Vol. 76, No. 3, 2011 849

Modha et al.
JOCArticle
TABLE 2. Attempts for the Sonogashira Cross-Coupling Reaction on Pyrazine 5aa
entry
R
Pd catalyst
Cu source
additive (equiv)
yield of 7 (%)
b
b
b
b
b
b
1
2
3
4
5
6
Me
Me
iso-propyl
iso-propyl
Me
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(OAc)2
CuI
CuI
CuI
CuI
CuI
CuI
TBAIc (1.2)
TBAIc (1.2)
TBAIc (1.2)
Me
Pd(OAc)2
aReactions were run on a 0.1 mmol scale of 5a, applying silyl acetylene (1.5 equiv), Pd catalyst (5 mol %), and a Cu source (10 mol %) using a mixture
of DMF and triethylamine (1:1, 3 mL). The reactions were irradiated for 15 min at a 95 °C ceiling temperature using a maximum power of 75 W in a
multimode microwave apparatus. bThe starting material was recovered. cTBAI = tetrabutylammoniumiodide.
TABLE 3. Optimization Study for the Liebeskind-Srogl Cross-Coupling Reaction on the S-PMB Groupa
entry
boronic acid (equiv)
CuTC equiv
Pd(PPh3)4 mol %
temp °C (MWb/ΔT)
time (h)
ratioc (9a:5a)
1
2
3
5
3
5
1.2
5
10
3
100 (MW)
120 (MW)
100 (MW)
120 (MW)
reflux (ΔT )
reflux (ΔT )
0.8
1.3
40:30
57:25
30:62
84:08
30:65
45:50
3
1.1
2 þ 1
3
2 þ 1
0.8
0.5 þ 0.5
4d
5
1.5 þ 1
5 þ 5
3
5
10
4 þ 4
6d
1.5 þ 1
5 þ 5
aAll reactions were run on a 0.2 mmol scale of 5a in THF in sealed tubes. bA maximum power of 500 W in a multimode microwave apparatus was used.
cRatio determined by GC-MS. dA fresh batch of reagents was added at the stipulated times. CuTC = copper(I)-thiophene-2-carboxylate.
Gratifyingly, applying our optimized protocol, the aryl-
ated products 11a-i were obtained in good to excellent
yields (Scheme 5). However, the Liebeskind-Srogl cross-
coupling reaction did not proceed in the case of isopropyl
boronic acid. Similarly, no reaction occurred when 2-(4-
methoxybenxylthio)-1-methyl-1H-imidazole 10d was used
(Scheme 5).
to literature procedures. The coupling of the azides 13a-d
with the generated pyrazines 12a-d was then investigated. A
mixture of pyrazine 12 with 1.2 equiv of the protected sugar
azide 13, 2 equiv of copper turnings, 5 mol % of CuSO4, and
5 mol % of tris-[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]-
amine ligand (TBTA) in THF/i-PrOH/H2O (3:1:1, 5 mL)
was irradiated at a 90 °C ceiling temperature using a
maximum power of 200 W for 20 min. The Cu(I)-catalyzed
[3 þ 2] dipolar cycloaddition reaction occurred with full
regioselectivity, resulting in the formation of the corre-
sponding 1,4-disubstituted 1,2,3-triazoles 14a-h in good
yields (Table 6, entries 1-8). Reacting pyrazine 12d with
benzyl azide, applying similar conditions, afforded 1,2,3-
triazole compound 14i in good yield (Table 6, entry 9).
Interestingly, when pyrazine 12d was reacted with TMS-
azide, the corresponding desilylated 1,2,3-triazole product
14j was obtained.
As we were able to substitute the S-PMB group of com-
pound 5 by an aryl group in compound 9, we reinvestigated
the reactivity of the chlorine toward the Sonogashira reac-
tion. To our delight, when a mixture of compound 9 with 1.5
equiv of triisopropylsilylacetylene, Pd(PPh3)2Cl2 (5 mol %),
CuI (10 mol %), and TBAI (1.2 equiv) in DMF/TEA (1:1)
was irradiated for 20 min at a ceiling temperature of 80 °C, a
smooth reaction took place. Subsequent desilylation upon
treatment of the crude compound with 1 M tetrabutylam-
monium fluoride (TBAF) in THF at rt yielded the desired
terminal acetylenes 12a-d (Table 5), which were purified by
simple filtration over silica gel.
Conclusion
For the final step, all protected sugar azides23 and the
benzyl azide24 13a-e (Figure 2) were synthesized according
In conclusion, we have developed a new and efficient syn-
thetic procedure for the synthesis of differently substituted
ethynyl pyrazines starting from 1-(4-methoxybenzyl)-3,5-
dichloropyrazin-2(1H)-ones. These newly generated ethynyl
pyrazines can easily be coupled, via a triazole linkage, with
(23) (a) Stimac, A.; Kobe, J. Carbohydr. Res. 2000, 324, 149. (b) Stimac,
A.; Kobe, J. Carbohydr. Res. 2000, 329, 317.
(24) Ankati, H.; Biehl, E. Tetrahedron Lett. 2009, 50, 4677.
850 J. Org. Chem. Vol. 76, No. 3, 2011

Modha et al.
JOCArticle
TABLE 4. Liebeskind-Srogl Cross-Coupling Reaction on Pyrazines 5a
aReactions were run on a 0.5 mmol scale of 5a-d, boronic acids (2 þ 1 equiv), Pd(PPh3)4 (5 þ 5 mol %), and CuTC (1.5 þ 1 equiv), in THF (4 mL). The
mixture was irradiated in a sealed tube at a ceiling temperature of 120 °C and a maximum power of 500 W for 60 min in a multimode microwave
apparatus. The reagents were added in two portions as stipulated; the second portion was added at half the reaction time (i.e., 30 min). CuTC =
copper(I)-thiophene-2-carboxylate.
sugars applying a regioselective microwave-assisted Cu(I)-
catalyzed [3 þ 2] dipolar cycloaddition reaction, resulting in
the formation of a small library of hitherto unknown nucleoside
analogues. The application of microwave irradiation during
different steps of the sequence has been shown to be highly
valuable for speeding up reactions. We have also demon-
strated that our newly optimized Liebeskind-Srogl protocol
is applicable for different heterocycles bearing a benzylthio
ether functionality.
Experimental Section
General. Proton NMR spectra were recorded on a 300 MHz
instrument using CDCl3 and DMSOd6 as solvents unless
1
otherwise stated. The H and 13C chemical shifts are reported
J. Org. Chem. Vol. 76, No. 3, 2011 851

Modha et al.
SCHEME 5. Expanding the Scope of the Newly Developed Liebeskind-Srogl Cross-Coupling Procedure for Some Other Heterocyclesa
JOCArticle
aAll the reactions were run on a 0.5 mmol scale of 10. bOnly starting material was recovered.
in parts per million relative to tetramethylsilane as an internal
standard. For the mass spectrometry, the ion source tempera-
ture was 150-250 °C, as required. High-resolution EI-mass
spectra were performed with a resolution of 10 000. For chro-
matography, analytical TLC plates and 70-230 mesh silica gel
were used. All the solvents and chemicals were purchased and
used as available.
Microwave Irradiation Experiments. All microwave irradia-
tion experiments were carried out in a multimode Milestone
MicroSYNTH microwave reactor (Laboratory Microwave
Systems). This apparatus was used in the standard configuration
as delivered, including proprietary software. Reactions were
carried out in sealed microwave process vials (15, 50 mL), and
the 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 and 2 min and is included in the total reaction time. The
reaction mixture was continuously stirred during the reaction.
After the irradiation, the reaction vessel was rapidly cooled by
air jet cooling to the ambient temperature.
2.14-2.03 (m, 1H), 1.05 (d, J = 6.57 Hz, 6H); 13C NMR (75
MHz, CDCl3) δ 159.4, 153.1, 143.8, 138.9, 128.3, 126.2, 124.7,
114.4, 55.3, 49.2, 37.8, 28.8, 22.4; HRMS (EI) calcd for
C16H18Cl2N2O2 340.0745, found 340.0753.
General Procedure for the Preparation of 2a-c. The general
procedure for the preparation of 2a-c is the same as previously
described by our group. Data for compounds 2a16 and 2b26 are
in accordance with the previously published work.
1-(4-Methoxybenzyl)-5-chloro-3-ethoxy-6-isobutylpyrazin-
2(1H)-one (2c): white solid; mp 86-88 °C; yield 98%; 1H NMR
(300 MHz, CDCl3) δ 7.09 (d, J = 8.67 Hz, 2H), 6.84 (d, J = 8.64
Hz, 2H), 5.25 (s, 2H), 4.39 (q, J = 7.14 Hz, 2H), 3.77 (s, 3H), 2.59
(d, J = 7.35 Hz, 2H), 1.99 (m, 1H), 1.46 (t, J = 6.96 Hz, 3H),
1.01 (d, J = 6.60 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 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; HRMS (EI) calcd for C18H23ClN2O3
350.1397, found 350.1389.
General Procedure for the Preparation of 2d. The general
procedure for the preparation of 2d is the same as previously
described by our group.16
General Procedure for the Preparation of 1a-d. The general
procedure for the preparation of 1a-d is the same as previously
described by our group.25 Data for compounds 1a,b,d are in
accordance with the previously published work.25
1-(4-Methoxybenzyl)-3,5-dichloro-6-isobutylpyrazin-2(1H)-
one (1c): yellow solid; mp 118-120 °C; yield 44%; 1H NMR (300
MHz, CDCl3) δ 7.10 (d, J = 8.49 Hz, 2H), 6.86 (d, J = 8.67 Hz,
2H), 5.30 (s, 2H), 3.78 (s, 3H), 2.70 (d, J = 7.35 Hz, 2H),
1-(4-Methoxybenzyl)-6-benzyl-5-chloro-3-methylpyrazin-
2(1H)-one (2d): white solid; mp 152-154 °C; yield 95%; 1H
NMR (300 MHz, CDCl3) δ 7.38-7.29 (m, 3H), 7.11 (d, J = 6.78
Hz, 2H), 7.05 (d, J = 8.67 Hz, 2H), 6.87 (d, J = 8.85 Hz, 2H),
5.05 (s, 2H), 4.11 (s, 2H), 3.79 (s, 3H), 2.53 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 159.3, 156.4, 155.9, 134.7, 134.6, 129.3,
127.8, 127.5 (ꢀ2), 127.0, 114.4, 55.3, 47.6, 35.2, 20.9; HRMS
(EI) calcd for C20H19ClN2O2 354.1135, found 354.1134.
(25) 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.
(26) Mehta, V. P.; Modha, S. G.; Van der Eycken, E. J. Org. Chem. 2008,
75, 976.
852 J. Org. Chem. Vol. 76, No. 3, 2011

Modha et al.
JOCArticle
TABLE 5. Sonogashira Cross-Coupling Reaction of Pyrazines 9a,e,f,ha
dichloromethane (15 mL) in a 50 mL glass vial. The resulting
solution was irradiated at an 80 °C ceiling temperature for 15
min using a maximum microwave power of 150 W. After com-
pletion of the reaction, the reaction mixture was diluted with
200 mL of ethyl acetate and washed with sodium thiosulfate (5%
in water, 100 mL) to remove iodine, followed by water (100 mL)
and brine (100 mL). The organic layer was dried over magne-
sium sulfat and removed under reduced pressure, and the resi-
due was purified by silica gel column chromatography (from 0 to
10% of ethyl acetate in heptane) to afford compounds 5a-d.
2-(4-Methoxybenzylthio)-5-chloro-3-methoxypyrazine (5a):
light yellow solid; mp 79-81 °C; yield 83%; 1H NMR (300
MHz, CDCl3) δ 7.99 (s, 1H), 7.31 (d, J = 8.46 Hz, 2H), 6.82 (d,
J = 8.46 Hz, 2H), 4.32 (s, 2H), 4.00 (s, 3H), 3.78 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 158.8, 155.1, 144.2, 140.0, 133.8,
130.2, 128.9, 113.9, 55.2, 54.7, 32.8; HRMS (EI) calcd for
C13H13ClN2O2S 296.0386, found 296.0394.
2-(4-Methoxybenzylthio)-5-chloro-3-methoxy-6-methyl-pyra-
1
zine (5b): off-white; mp 73-75 °C; yield 88%; H NMR (300
MHz, CDCl3) δ 7.33 (d, J = 8.67 Hz, 2H), 6.82 (d, J = 8.67 Hz,
2H), 4.32 (s, 2H), 3.96 (s, 3H), 3.78 (s, 3H), 2.53 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 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) calcd for
C14H15ClN2O2S 310.0543, found 310.0558.
2-(4-Methoxybenzylthio)-5-chloro-3-ethoxy-6-isobutyl-pyr-
azine (5c): colorless oil; yield 80%; 1H NMR (300 MHz, CDCl3)
δ 7.32 (d, J = 8.46 Hz, 2H), 6.82 (d, J = 8.46 Hz, 2H), 4.38 (q,
J = 6.96 Hz, 2H), 4.32 (s, 2H), 3.77 (s, 3H), 2.71 (d, J = 7.17 Hz,
2H), 2.23-2.12 (m, 1H), 1.39 (t, J= 7.14 Hz, 3H), 0.96 (d, J=6.57
Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 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;
HRMS (EI) calcd for C18H23ClN2O2S 366.1169, found 366.115.
2-(4-Methoxybenzylthio)-6-benzyl-5-chloro-3-methyl-pyra-
zine (5d): colorless oil; yield 72%; 1H NMR (300 MHz, CDCl3) δ
7.29-7.27 (m, 5H), 7.19 (d, J = 8.49 Hz, 2H), 6.77 (d, J = 8.46
aReactions were run on a 2.0 mmol scale of 9a,e,f,h in a multimode
microwave apparatus. bYields over two steps. TIPSA = triisopropylsi-
lylacetylene, TBAI = tetrabutylammoniumiodide, and TBAF = tetra-
butylammoniumfluoride.
Hz, 2H), 4.29 (s, 2H), 4.24 (s, 2H), 3.77 (s, 3H), 2.39 (s, 3H); 13
C
NMR (75 MHz, CDCl3) δ 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;
HRMS (EI) calcd for C20H19ClN2OS 370.0907, found 370.0888.
General Procedure for the Preparation of 9a-j. 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 irradiated
in a 15 mL sealed tube at a ceiling temperature of 120 °C using a
maximum power of 500 W for 30 min. After 30 min, a second lot
of the above reactants, boronic acid 8 (1 equiv), Pd(PPh3)4
(5 mol %), and CuTC (1 equiv), was added, and again, the reac-
tion was run for 30 min with the same conditions. After com-
pletion of the reaction, the reaction mixture was filtered through
Celite and the filtrate was diluted with ethylacetate (200 mL) and
washed with water (100 mL) and brine (100 mL). The organic
layer was dried over magnesium sulfate and distilled under redu-
ced pressure, and the residue was purified by silica gel column
chromatography (from 0 to 30% of ethyl acetate in heptane) to
afford compounds 9a-j.
General Procedure for the Preparation of 3a-d. The general
procedure for the preparation of 3a-d is the same as previously
described by our group.16 Data for compound 3a are in accor-
dance with the previously published work.16
1-(4-Methoxybenzyl)-5-chloro-3-methoxy-6-methylpyrazine-
2(1H)-thione (3b): yellow solid; mp 127-129 °C; yield 88%; 1H
NMR (300 MHz, CDCl3) δ 7.07 (d, J = 8.67 Hz, 2H), 6.84 (d,
J = 8.76 Hz, 2H), 6.00 (s, 2H), 4.05 (s, 3H), 3.77 (s, 3H), 2.45 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 168.2, 159.2, 159.0, 131.0,
129.9, 127.6, 124.9, 114.4, 56.1, 55.3, 17.0; HRMS (EI) calcd for
C14H15ClN2O2S 310.0543, found 310.0547.
1-(4-Methoxybenzyl)-5-chloro-3-ethoxy-6-isobutylpyrazine-
2(1H)-thione (3c): yellow liquid; 90% yield; 1H NMR (300 MHz,
CDCl3) δ 6.99 (d, J = 8.49 Hz, 2H), 6.84 (d, J = 8.46 Hz, 2H),
5.99 (bs, 2H), 4.46 (q, J = 7.14 Hz, 2H), 3.77 (s, 3H), 2.71 (d, J =
7.14 Hz, 2H), 2.10-1.96 (m, 1H), 1.49 (t, J = 6.99 Hz, 3H), 1.01
(d, J = 6.60 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 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; HRMS (EI) calcd for
C18H23ClN2O2S 366.1169, found 366.1156.
1-(4-Methoxybenzyl)-6-benzyl-5-chloro-3-methylpyrazine-
2(1H)-thione (3d): yellow solid; mp 125-127 °C; yield 73%; 1H
NMR (300 MHz, CDCl3) δ 7.37-7.34 (m, 3H), 7.08 (d, J = 6.6
Hz, 2H), 7.00 (d, J = 8.1 Hz, 2H), 6.88 (d, J = 8.07 Hz, 2H), 5.81
(bs, 2H), 4.20 (s, 2H), 3.79 (s, 3H), 2.79 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 175.9, 163.8, 159.2, 138.4, 134.3, 134.1, 133.4,
132.3, 132.2, 132.1, 131.5 (ꢀ2), 129.4, 128.5, 128.4, 127.7, 127.4,
127.2, 124.9, 114.5, 55.3, 36.0, 26.8; HRMS (EI) calcd for
C20H19ClN2OS 370.0907, found 370.0912.
5-Chloro-3-methoxy-2-(4-methoxyphenyl)pyrazines (9a): light
1
yellow solid; mp 69-71 °C; yield 84%; H NMR (300 MHz,
CDCl3) δ 8.35 (s, 1H), 8.09 (d, J = 8.85 Hz, 2H), 6.98 (d, J =
8.85 Hz, 2H), 4.06 (s, 3H), 3.97 (s, 3H); HRMS (EI) calcd for
C12H11ClN2O2 250.0509, found 250.0514.
5-Chloro-3-methoxy-2-(3,4-dimethoxyphenyl)pyrazines (9b):
1
white solid; mp 118-120 °C; yield 69%; H NMR (300 MHz,
CDCl3) δ 8.20 (s, 1H), 7.74 (d, J = 8.46 Hz, 1H), 7.65 (s, 1H),
6.95 (d, J = 8.46 Hz, 1H), 4.07 (s, 3H), 3.96-3.94 (m, 6H);
13C NMR (75 MHz, CDCl3) δ 156.5, 150.2, 148.7, 142.3, 140.5,
134.5, 127.4, 122.2, 111.8, 110.4, 55.9, 54.5; HRMS (EI) calcd
for C13H13ClN2O3 280.0615, found 280.0578.
General Procedure for the Preparation of 5a-d. Thioamide 3
(5 mmol) and iodine (10 mol %) were successively added to
5-Chloro-2-(3,4-difluorophenyl)-3-methoxypyrazine (9c): white
solid; mp 113-115 °C; yield 75%; 1H NMR (300 MHz, CDCl3)
J. Org. Chem. Vol. 76, No. 3, 2011 853

Modha et al.
JOCArticle
FIGURE 2. Structure of azides 13a-e.
TABLE 6. Synthesis of Triazoles 14a-ja
entry
substrate
azide R4-N3
product
14a
14b
14c
14d
14e
14f
14g
14h
yield (%)
1
2
3
4
5
6
7
8
12a
12b
12b
12b
12c
12c
12d
12d
12d
12d
13a
13b
13c
13d
13a
13b
13a
13b
82
69
56
38
92
71
73
63
78
80
9
13e
TMS-N3
14i
14j (R4 = H)
10b
aAll the reactions were run on a 0.1 mmol scale of 12a-d in a multimode microwave apparatus. bThe protective group (TMS) was cleaved in situ
applying the described reaction conditions.
δ 8.23 (s, 1H), 8.01-7.88 (m, 2H), 7.28-7.19 (m, 1H), 4.09 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 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), 125.3 (ꢀ2), 118.3, 118.0, 117.1, 116.9, 113.9, 54.7; HRMS
(EI) calcd for C11H7ClF2N2O 256.0215, found 256.0227.
5-Chloro-2-(3-(trifluoromethyl)phenyl)-3-methoxypyrazine (9d):
white solid; mp 38-40 °C; yield 80%; 1H NMR (300 MHz,
CDCl3) δ 8.35 (s, 1H), 8.27-8.25 (m, 2H), 7.69 (d, J = 7.53 Hz,
1H), 7.58 (t, J = 7.74 Hz, 1H), 4.10 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 156.9, 144.1, 139.1, 135.5, 135.1, 132.1, 130.9, 130.5,
128.7, 126.0, 125.9 (ꢀ2), 125.8, 122.2, 54.7; HRMS (EI) calcd for
C12H8ClF3N2O 288.0277, found 288.0276.
2-Chloro-6-methoxy-5-(4-methoxyphenyl)-3-methylpyrazine
(9e): white solid; mp 71-73 °C; yield 86%; 1H NMR (300 MHz,
CDCl3) δ 8.03 (d, J = 8.85 Hz, 2H), 6.98 (d, J = 8.85 Hz, 2H), 4.03
(s, 3H), 3.86 (s, 3H), 2.60 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
160.4, 164.9, 142.1, 140.9, 139.7, 130.4, 127.5, 113.6, 55.3, 54.3, 20.7;
HRMS (EI) calcd for C13H13ClN2O2 264.0666, found 264.0663.
2-Chloro-6-methoxy-5-(3,4-dimethoxyphenyl)-3-methylpyr-
azine (9f): light yellow solid; mp 94-96 °C; yield 93%; 1H NMR
(300 MHz, CDCl3) δ 7.72 (d, J = 8.46 Hz, 1H), 7.65 (d, J = 1.14
Hz, 1H), 6.94 (d, J = 8.46 Hz, 1H), 4.03 (s, 3H), 3.96 (s, 3H), 3.93
(s, 3H), 2.61 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 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), 54.4, 20.7; HRMS (EI) calcd for C14H15ClN2O3 294.0771,
found 294.0765.
δ 7.95 (d, J = 8.46 Hz, 2H), 7.48 (d, J = 8.67 Hz, 2H), 4.02 (s,
3H), 2.60 (s, 3H), 1.34 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 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) calcd for C16H19ClN2O 290.1186, found
290.1186.
2-Chloro-6-ethoxy-3-isobutyl-5-(3,4-dimethoxyphenyl)pyrazine
(9h): off-white solid; mp 72-74 °C; yield 79%; 1H NMR (300
MHz, CDCl3) δ 7.82-7.79 (m, 2H), 6.95 (d, J = 8.28 Hz, 1H),
4.47 (q, J = 6.99 Hz, 2H), 3.95-3.94 (m, 6H), 2.80 (d, J = 7.17
Hz, 2H), 2.29-2.20 (m, 1H), 1.47 (t, J = 6.99 Hz, 3H), 1.00 (d,
J = 6.57 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 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; HRMS (EI) calcd for C18H23ClN2O3
350.1397, found 350.1387.
2-Chloro-6-ethoxy-5-(3,4-difluorophenyl)-3-isobutylpyrazine
(9i): white solid; yield 72%; 1H NMR (300 MHz, CDCl3) δ
8.07-7.94 (m, 2H), 7.20 (t, J = 8.46 Hz, 1H), 4.49 (q, J = 7.14
Hz, 2H), 2.79 (d, J = 7.14 Hz, 2H), 2.30-2.16 (m, 1H), 1.47 (t,
J=7.17 Hz, 3H), 0.99 (d, J = 6.60 Hz, 6H); 13C NMR (75 MHz,
CDCl3) δ 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), 132.1, 125.4 (ꢀ2), 125.3
(ꢀ2), 118.2, 118.0, 117.0, 116.8, 63.5, 42.1, 29.7, 28.1, 22.4, 14.4;
HRMS (EI) calcd for C16H17ClF2N2O 326.0997, found 326.1014.
2-Benzyl-3-chloro-6-(3,4-dimethoxyphenyl)-5-methylpyrazine
(9j): colorless oil; yield 80%; 1H NMR (300 MHz, CDCl3)
δ 7.37-7.21 (m, 6H), 7.18-7.14 (m, 2H), 6.96 (d, J = 7.92 Hz,
1H), 4.32 (s, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 2.61 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 151.0, 150.4, 149.7, 149.0, 148.8,
2-(4-tert-Butylphenyl)-5-chloro-3-methoxy-6-methylpyrazine
(9g): colorless liquid; yield 92%; 1H NMR (300 MHz, CDCl3)
854 J. Org. Chem. Vol. 76, No. 3, 2011

Modha et al.
JOCArticle
144.9, 137.5, 130.0, 129.1, 128.4, 126.6, 121.8, 112.4, 110.7, 55.9
(ꢀ2), 40.6, 22.6; HRMS (EI) calcd for C20H19ClN2O2 354.1135,
found 354.1145.
General Procedure for the Preparation of 10a-e. The general
procedures for the synthesis of compounds 10a-d27 and 10e28
are the same as described in the literature starting from their
respective thiols. Data for compounds 10a,29 10b,30 and 10e28
were in accordance with the already published ones in the
literature.
heptane) to afford the desired terminal acetylenes 12a-d in good
yields.
5-Ethynyl-3-methoxy-2-(4-methoxyphenyl)pyrazine (12a): light
yellow solid; yield 78%; 1H NMR (300 MHz, CDCl3) δ 8.35 (s,
1H), 8.10 (d, J = 8.85 Hz, 2H), 6.99 (d, J = 8.88 Hz, 2H), 4.06 (s,
3H), 3.87 (s, 3H), 3.29 (s, 1H); 13C NMR (75 MHz, CDCl3)
δ 160.8, 156.7, 142.7, 139.6, 131.7, 130.8, 127.7, 113.6, 80.5, 79.8,
55.3, 54.0; HRMS (EI) calcd for C14H12N2O2 240.0899, found
240.0897.
2-(4-Methoxybenzylthio)-4,6-dimethylpyrimidine (10c): white
solid; yield 79%; H NMR (300 MHz, CDCl3) δ 7.36 (d, J =
8.64 Hz, 2H), 6.82 (d, J = 8.67 Hz, 2H), 6.68 (s, 1H), 4.36 (s, 2H),
3.78 (s, 3H), 2.40 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 166.9,
158.6, 130.2, 130.1, 115.6, 113.7, 55.2, 34.6, 23.8; HRMS (EI)
calcd for C14H16N2OS 260.0983, found 260.0998.
2-Ethynyl-6-methoxy-5-(4-methoxyphenyl)-3-methylpyrazine
(12b): dark brown solid; mp 128-130 °C; yield 91%; 1H NMR
(300 MHz, CDCl3) δ 8.09 (d, J = 8.85 Hz, 2H), 6.98 (d, J = 8.85
1
Hz, 2H), 4.03 (s, 3H), 3.86 (s, 3H), 3.45 (s, 1H), 2.65 (s, 3H); 13
C
NMR (75 MHz, CDCl3) δ 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) calcd
for C15H14N2O2 254.1055, found 254.1065.
2-(4-Methoxybenzylthio)-1-methyl-1H-imidazole (10d): white
1
solid; yield 54%; H NMR (300 MHz, CDCl3) δ 7.11 (s, 1H),
2-Ethynyl-6-methoxy-5-(3,4-dimethoxyphenyl)-3-methylpyr-
azine (12c): light brown solid; mp 145-147 °C; yield 80%; 1H
NMR (300 MHz, CDCl3) δ 7.79 (dd, J = 1.71, 8.47 Hz, 1H),
7.71 (d, J = 1.50 Hz, 1H), 6.94 (d, J = 8.46 Hz, 1H), 4.04 (s,
3H), 3.96 (s, 3H), 3.94 (s, 3H), 3.46 (s, 1H), 2.66 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 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) calcd for C16H16N2O3 284.1161, found 284.1170.
2-Ethoxy-6-ethynyl-5-isobutyl-3-(3,4-dimethoxyphenyl)pyr-
azine (12d): pink solid; mp 108-110 °C; yield 59%; 1H NMR (300
MHz, CDCl3) δ 7.88-7.86 (m, 2H), 6.95 (d, J = 8.28 Hz, 1H),
4.48 (q, J =6.96 Hz, 2H), 3.95-3.94 (m, 6H), 3.39 (s, 1H), 2.86 (d,
J = 7.14 Hz, 2H), 2.31-2.18 (m, 1H), 1.47 (t, J = 7.14 Hz, 3H),
0.99 (d, J = 6.78 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 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) calcd for
C20H24N2O3 340.1787, found 340.1775.
7.05 (d, J = 8.46 Hz, 2H), 6.86 (s, 1H), 6.78 (d, J = 8.64 Hz, 2H),
4.12 (s, 2H), 3.77 (s, 3H), 3.28 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 158.9, 140.7, 129.9, 129.8, 129.7, 122.3, 113.8, 55.2,
39.5, 33.1; HRMS (EI) calcd for C12H14N2OS 234.0827, found
234.0840.
General Procedure for the Preparation of 11a-i. The general
procedure for the preparation of 11a-i is the same as that
for 9a-j. Data for compounds 11a,31 11b,32 11c,33 11d,34 11e,35
11f,36 11g,37 and 11h38 were in accordance with the published
data.
5-(3,4-Dimethoxyphenyl)-1-phenyl-1H-tetrazole (11i): white
solid; yield 75%; 1H NMR (400 MHz, CDCl3) δ 7.56 (m, 3H),
7.43 (dd, J = 1.52, 7.68 Hz, 2H), 7.15 (d, 2.04 Hz, 1H), 7.07 (dd,
J = 2.0, 8.3 Hz, 1H), 6.83 (d, J = 8.32 Hz, 1H), 3.89 (s, 3H), 3.74
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 151.4, 149.1, 134.9,
130.4, 129.8, 125.6, 122.1, 115.7, 111.6, 111.1, 55.9, 55.8; HRMS
(EI) calcd for C15H14N4O2 282.1117, found 282.1131.
General Procedure for the Preparation of 12a-d. A mixture of
pyrazine 9 (2.0 mmol), triisopropylsilylacetylene (1.5 equiv),
Pd(PPh3)2Cl2 (5 mol %), CuI (10 mol %), and tetrabutylammo-
nium iodide (TBAI, 1.2 equiv) in DMF/TEA (1:1, 4 mL) was
irradiated in a 15 mL sealed tube at a ceiling temperature of
80 °C using a maximum power of 80 W for 20 min. After comp-
letion of the reaction, the reaction mixture was diluted with
dichloromethane (200 mL) and washed with water (100 mL) and
brine (100 mL). The organic layer was dried over magnesium
sulfate, distilled under reduced pressure. The obtained residue
was dissolved in DCM/THF (1.5:1, 5 mL), and TBAF solution
in THF (1M, 2 equiv) was added dropwise. The reaction mixture
was stirred at room temperature for 3-5 min. After completion
of the reaction, solvents were removed under reduced pressure
and the residue was directly subjected to flash column chroma-
tography on short silica gel pads (from 0 to 30% ethyl acetate in
General Procedure for the Preparation of 13a-e. All protected
sugar azides23 13a-d and the benzyl azide24 13e were synthe-
sized according to literature procedures.
General Procedure for the Preparation of 14a-j. A mixture of
pyrazine 12 (0.1 mmol), azide 13 (1.2 equiv), copper turnings
(2 equiv), CuSO4 solution in water (1M, 5 mol %), and tris-
[(1-benzyl-1H-1,2,3-triazol-4-yl)methyl]amine ligand (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 a maxi-
mum power of 200 W for 20 min. After completion of the reaction,
the reaction mixture was diluted with ethyl acetate (100 mL) and
washed with water (100 mL) and brine (100 mL). The organic
layer was dried over magnesium sulfate, distilled under reduced
pressure. The obtained residue was subjected to silica gel column
chromatography (from 0 to 50% ethyl acetate in heptane) to
afford the desired compounds 14a-j.
(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 (14a): white solid; mp 77-79 °C; yield
82%; 1H NMR (300 MHz, CDCl3) δ 8.96 (s, 1H), 8.30 (s, 1H),
8.11 (d, J = 8.49 Hz, 2H), 8.03-7.96 (m, 6H), 7.62-7.34 (m, 9H),
7.00 (d, J = 8.46 Hz, 2H), 6.54 (d, J = 3.03 Hz, 1H), 6.37 (bs, 1H),
6.18 (t, J = 5.25 Hz, 1H), 4.94-4.88 (m, 2H), 4.63 (dd, J = 3.39,
11.97 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 166.1, 165.1 (ꢀ2), 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; MS (ESIþ) calcd for C40H33N5O9 727.7, found 750.3 [M þ
Na]þ, 1478.2 [2M þ Na]þ.
(27) Radi, M.; et al. ChemMedChem 2008, 3, 573.
(28) Pellecchia, M. Patent PCT WO 2008/118626 A2, 2008.
(29) Ko, H. M.; Lee, D. G.; Kim, M. A.; Kim, H. J.; Park, J.; Lah, M. S.;
Lee, E. Tetrahedron 2007, 63, 5797.
(30) Pathak, A. K.; Pathak, V.; Seitz, L. E.; Suling, W. J.; Reynolds, R. C.
J. Med. Chem. 2004, 47, 273.
(31) Boeini, H. Z.; Najafabadi, K. H. Eur. J. Org. Chem. 2009, 4926.
(32) Zhao, D.; Wang, W.; Yang, F.; Lan, J.; Yang, L.; Gao, G.; You, J.
Angew. Chem., Int. Ed. 2009, 48, 3296.
(33) Jaseer, E. A.; Prasad, D. J. C.; Dandapat, A.; Sekar, G. Tetrahedron
Lett. 2010, 51, 5009.
(34) Begouin, J.-M.; Gosmini, C. J. Org. Chem. 2009, 74, 3221.
(35) Mehta, V. P.; Modha, S. G.; Van der Eycken, E. J. Org. Chem. 2009,
74, 6870.
(36) Ghosh, U.; Katzenellenbogen, J. A. J. Heterocycl. Chem. 2002, 39,
1101.
(37) Schmitt, J.-L.; Stadler, A.-M.; Kyritsakas, N.; Lehn, J.-M. Helv.
Chim. Acta 2003, 86, 1598.
(38) Spulak, M.; Lubojacky, R.; Senel, P.; Kunes, J.; Pour, M. J. Org.
Chem. 2010, 75, 241.
((2R,3S,5R)-3-(4-Chlorobenzoyloxy)-5-(4-(6-methoxy-5-(4-
methoxyphenyl)-3-methyl-pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-
tetrahydro-furan-2-yl)methyl-4-chlorobenzoate (14b): yellow solid;
mp 66-67 °C; yield 69%; 1H NMR (300 MHz, CDCl3) δ 8.28 (s,
1H), 8.14 (d, J = 8.67 Hz, 2H), 8.01 (d, J = 8.46 Hz, 2H), 7.85 (d,
J = 8.46 Hz, 2H), 7.47 (d, J = 8.31 Hz, 2H), 7.31 (d, J = 8.49 Hz,
J. Org. Chem. Vol. 76, No. 3, 2011 855

Modha et al.
JOCArticle
2H), 7.00 (d, J = 8.64 Hz, 2H), 6.52 (t, J = 5.85 Hz, 1H), 5.87 (bs,
1H), 4.75-4.69 (m, 2H), 4.54-4.51 (m, 1H), 3.96 (s, 3H), 3.87 (s,
3H), 3.51-3.42 (m, 1H), 2.98-2.89 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ 165.2, 64.9, 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; MS (ESIþ) calcd for
C34H29Cl2N5O7 690.5, found 691.2 [M]þ, 1403.4 [2M þ Na]þ.
(2R,3R,4S,5R,6R)-2-(Acetoxymethyl)-6-(4-(6-methoxy-5-(4-
methoxyphenyl)-3-methyl-pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-
tetrahydro-2H-pyran-3,4,5-triyl Triacetate (14c): white solid;
mp 182-185 °C; yield 56%; 1H NMR (300 MHz, CDCl3) δ
8.34 (s, 1H), 8.14 (d, J = 8.85 Hz, 2H), 7.00 (d, J = 8.85 Hz, 2H),
5.98 (d, J = 9.42 Hz, 1H), 5.58 (t, J = 9.42 Hz, 1H), 5.46 (t, J =
9.42 Hz, 1H), 5.30 (t, J=9.78 Hz, 1H), 4.37-4.31 (m, 1H), 4.18
(d, J = 12.63 Hz, 1H), 4.08-4.04 (m, 4H), 3.87 (s, 3H), 2.96 (s,
3H), 2.09 (s, 6H), 2.04 (s, 3H), 1.91 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 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), 20.2; MS (ESIþ) calcd for
C29H33N5O11 627.5, found 628.8 [M]þ, 1277.8 [2M þ Na]þ.
(2R,3S,4S,5R,6R)-2-(Acetoxymethyl)-6-(4-(6-methoxy-5-(4-
methoxyphenyl)-3-methyl-pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-
tetrahydro-2H-pyran-3,4,5-triyl Triacetate (14d): white solid; mp
81-83 °C; yield 38%; 1H NMR (300 MHz, CDCl3) δ 8.34 (s, 1H),
8.14 (d, J = 8.85 Hz, 2H), 7.00 (d, J = 8.85 Hz, 2H), 5.93 (d, J =
9.21 Hz, 1H), 5.69 (t, J = 9.78 Hz, 1H), 5.59 (bs, 1H), 5.30 (dd,
J = 3.39, 10.33 Hz, 1H), 4.28-4.20 (m, 3H), 4.10 (s, 3H), 3.87 (s,
3H), 2.96 (s, 3H), 2.25 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H), 1.93 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 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 (ESIþ) calcd for C29H33N5O11 627.5, found 628.9 [M]þ,
1277.6 [2M þ Na]þ.
(d, J = 8.46 Hz, 1H), 6.50 (s, 1H), 6.38 (s, 1H), 6.22 (t, J = 4.89
Hz, 1H), 4.96-4.84 (m, 2H), 4.67-4.63 (m, 1H), 4.35 (t, J = 6.57
Hz, 2H), 3.98-3.95 (m, 6H), 3.41-3.21 (m, 2H), 2.33-2.29 (m,
1H), 1.44 (t, J = 6.03 Hz, 3H), 1.01 (d, J = 6.03 Hz, 6H); 13C
NMR (75 MHz, CDCl3) δ 166.1, 165.1, 154.1, 149.8, 148.4 (ꢀ2),
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, 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), 14.5; MS (ESIþ) calcd for C46H45N5O10 827.8, found 828.3
[M]þ, 1677.1 [2M þ Na]þ.
((2R,3S,5R)-3-(4-Chlorobenzoyloxy)-5-(4-(5-(3,4-dimethoxy-
phenyl)-6-ethoxy-3-isobutyl-pyrazin-2-yl)-1H-1,2,3-triazol-1-yl-
)tetrahydro-furan-2-yl)methyl 4-chlorobenzoate (14h): light yel-
low solid; mp 59-61 °C; yield 63%; 1H NMR (300 MHz,
CDCl3) δ 8.26 (s, 1H), 8.00 (d, J = 7.74 Hz, 2H), 7.92-7.86
(m, 4H), 7.45 (d, J = 7.92 Hz, 2H), 7.32 (d, J = 7.92 Hz, 2H),
6.98 (d, J = 8.67 Hz, 1H), 6.51 (t, J=5.64 Hz, 1H), 5.87 (bs, 1H),
4.70-4.67 (m, 2H), 4.57-4.51 (m, 1H), 4.41 (q, 6.39 Hz, 2H),
3.98 (s, 3H), 3.95 (s, 3H), 3.54-3.45 (m, 1H), 3.39-3.21 (m, 2H),
2.95-2.90 (m, 1H), 2.34-2.25 (m, 1H), 1.47 (t, J = 6.96 Hz,
3H), 1.01 (d, J = 6.57 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
165.2, 164.9, 154.2, 149.8, 148.4 (ꢀ2), 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), 14.6, 14.1; MS (ESIþ) calcd
for C39H39Cl2N5O8 776.6, found 777.2 [M]þ, 1575.6 [2M þ Na]þ.
2-(1-Benzyl-1H-1,2,3-triazol-4-yl)-6-ethoxy-3-isobutyl-5-(3,4-
dimethoxyphenyl)pyrazine (14i): yellow solid; mp 137-139 °C;
yield 78%; 1H NMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.91-7.89
(m, 2H), 7.41-7.33 (m, 5H), 6.96 (d, J = 9.03 Hz, 1H), 5.61 (s,
2H), 4.44 (q, J = 7.23 Hz, 2H), 3.96 (s, 3H), 3.94 (s, 3H), 3.32 (d,
J = 6.96 Hz, 2H), 2.33-2.22 (m, 1H), 1.46 (t, J = 6.99 Hz, 3H),
0.99 (d, J = 6.60 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 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) calcd for C27H31N5O3 473.2427, found
473.2420.
(2R,3R,4R,5R)-2-(Benzoyloxymethyl)-5-(4-(5-(3,4-dimetho-
xyphenyl)-6-methoxy-3-methyl-pyrazin-2-yl)-1H-1,2,3-triazol-
1-yl)tetrahydro-furan-3,4-diyl Dibenzoate (14e): white solid; mp
83-85 °C; yield 92%; 1H NMR (300 MHz, CDCl3) δ 8.35 (s, 1H),
8.03-7.96 (m, 6H), 7.82 (d, J = 8.46 Hz, 1H), 7.77 (s, 1H),
7.62-7.55 (m, 2H), 7.50-7.35 (m, 7H), 6.96 (d, J = 8.46 Hz, 1H),
6.54 (d, J = 1.14 Hz, 1H), 6.38 (t, J = 4.14 Hz, 1H), 6.22 (t, J =
5.28 Hz, 1H), 4.96-4.87 (m, 2H), 4.63 (dd, J = 3.96, 12.24 Hz,
1H), 3.99 (s, 3H), 3.95 (s, 3H), 3.90 (s, 3H), 2.97 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 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), 128.5, 128.4 (ꢀ2), 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
(ESIþ) calcd for C42H37N5O10 771.7, found 772.4 [M]þ, 1565.0
[2M þ Na]þ.
2-Ethoxy-5-isobutyl-3-(3,4-dimethoxyphenyl)-6-(1H-1,2,3-
triazol-4-yl)pyrazine (14j): green solid; mp 202-204 °C; yield
1
80%; H NMR (400 MHz, DMSO) δ 15.3 (bs, 1H), 8.38 (bs,
1H), 7.86 (d, J = 1.50 Hz, 1H), 7.82 (dd, J = 1.50, 6.33 Hz, 1H),
7.09 (d, J = 6.42 Hz, 1H), 4.52 (q, J = 5.28 Hz, 2H), 3.83-3.82
(m, 6H), 2.50 (merged in solvent peak, 2H), 2.21-2.13 (m, 1H),
1.44 (t, J = 5.28 Hz, 3H), 0.93 (d, J = 4.92 Hz, 6H); 13C NMR (75
MHz, DMSO) δ 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; HRMS (EI) calcd for
C20H25N5O3 383.1957, found 383.1973.
((2R,3S,5R)-3-(4-Chlorobenzoyloxy)-5-(4-(5-(3,4-dimethoxy-
phenyl)-6-methoxy-3-methyl-pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-
tetra-hydrofuran-2-yl)methyl 4-chlorobenzoate (14f): yellow solid;
mp 99-101 °C; yield 71%; 1H NMR (300 MHz, CDCl3) δ 8.29 (s,
1H), 8.01 (d, J = 8.46 Hz, 2H), 7.86-7.81 (m, 3H), 7.78 (s, 1H),
7.47 (d, J = 8.31 Hz, 2H), 7.31 (d, J = 8.46 Hz, 2H), 6.96 (d, J =
8.46 Hz, 1H), 6.52 (t, J = 5.82 Hz, 1H), 5.87 (bs, 1H), 4.76-4.69
(m, 2H), 4.53 (d, J = 7.53 Hz, 1H), 3.99-3.95 (m, 9H), 3.51-3.43
(m, 1H), 3.02-2.89 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 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 (ESIþ) calcd for C35H31Cl2N5O8 720.5, found
721.7 [M]þ, 1463.2 [2M þ Na]þ.
Acknowledgment. The authors thank the FWO (Fund for
Scientific Research-Flanders (Belgium)) and the Research
Fund of the Katholieke Universiteit Leuven for financial
support to the laboratory. J.C.T. is grateful 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 Ontwikkel-
ingssamenwerking) for obtaining a doctoral scholarship. D.E.
is grateful to the Katholieke Universiteit Leuven for obtaining
a postdoctoral scholarship. The authors thank Ir. B. Demarsin
for HRMS measurements. This paper is dedicated to Prof.
€ €
Ferenc Fulop on the occasion of his 60th birthday.
(2R,3R,4R,5R)-2-(Benzoyloxymethyl)-5-(4-(5-(3,4-dimetho-
xyphenyl)-6-ethoxy-3-isobutyl-pyrazin-2-yl)-1H-1,2,3-triazol-1-yl)-
tetrahydro-furan-3,4-diyl Dibenzoate (14g): light yellow solid; mp
70-72 °C; yield 73%; 1H NMR (300 MHz, CDCl3) δ 8.31 (s, 1H),
8.03-7.92 (m, 8H), 7.59-7.54 (m, 2H), 7.47-7.32 (m, 7H), 6.97
Supporting Information Available: General experimental
procedures, spectroscopic and analytical data, and copies of 1H
and 13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
856 J. Org. Chem. Vol. 76, No. 3, 2011