2,5-Bis-(sulfonyl)pyrazines as unprecedented building blocks and their SNAr reactions

Article abstract of DOI:10.1016/j.tetlet.2013.01.106

Previously unknown 2,5-bis-sulfonylpyrazines are prepared and their SNAr reactions are investigated. When 2 equiv of thiols are employed, the corresponding bis-thiopyrazines are obtained exclusively. However, phenols or alkoxides gave rise to only the corresponding mono-substituted aryloxy- or alkoxy-sulfonylpyrazines in excellent yields. A carbon nucleophile prepared by treating malonate with NaH also produced the corresponding mono- sulfonylpyrazines. Aliphatic amines and anilines only provided the mono-anilino-sulfonylpyrazines in poor to moderate yields.

Full text of DOI:10.1016/j.tetlet.2013.01.106

Tetrahedron Letters 54 (2013) 1938–1942
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
2,5-Bis-(sulfonyl)pyrazines as unprecedented building blocks and their
SNAr reactions
Jie Jack Li a, Wei Meng b, Shung Wu b, Yong-Jin Wu c, Jason Guernon c, Martin P. Allen a, Michael M. Miller a,
,
⇑
Peter T. Cheng b, Bang-chi Chen a
a Medicinal Chemistry, Bristol-Myers Squibb Company, Route 206 & Province Line Road, Princeton, NJ 08543, United States
b Medicinal Chemistry, Bristol-Myers Squibb Company, 311 Pennington-Rocky Hill Road, Pennington, NJ 08534, United States
c Medicinal Chemistry, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Previously unknown 2,5-bis-sulfonylpyrazines are prepared and their SNAr reactions are investigated.
When 2 equiv of thiols are employed, the corresponding bis-thiopyrazines are obtained exclusively. How-
ever, phenols or alkoxides gave rise to only the corresponding mono-substituted aryloxy- or alkoxy-sul-
fonylpyrazines in excellent yields. A carbon nucleophile prepared by treating malonate with NaH also
produced the corresponding mono-sulfonylpyrazines. Aliphatic amines and anilines only provided the
mono-anilino-sulfonylpyrazines in poor to moderate yields.
Received 27 December 2012
Revised 22 January 2013
Accepted 24 January 2013
Available online 4 February 2013
Keywords:
Pyrazine
Ó 2013 Elsevier Ltd. All rights reserved.
SNAr reactions
Bis-(sulfonyl)pyrazines
Pyrazines are not common in nature. However, the importance
of pyrazine as the bioisostere for either benzene or pyridine rings
has been manifested by eszopiclone (Fig. 1, 1, Lunesta)1 as a synap-
of sodium methanethiolate in DMF overnight.3 Oxidation of disul-
fides 8a to bis-sulfones 9a was initially accomplished by using
6 equiv of OxoneÒ in i-PrOH/H2O (5:1) at room temperature in
nearly quantitative yields.7 However, the reaction was heteroge-
neous and the workup was cumbersome because of large amounts
of OxoneÒ used. An alternative oxidation employing hydrogen per-
oxide in acetic acid is homogeneous and operationally more
convenient.8
With bis-sulfone 9a in hand, we explored its ability to undergo
SNAr reactions with a wide variety of nucleophiles. As shown in
Scheme 2, when 4-fluorophenol was employed, the SNAr reaction
halted after 1 equiv of the nucleophile was added to the pyrazine
ring. After the phenyl–pyrazinyl ether 10 is formed, the pyrazine
ring is deactivated because of the strong electron-donating nature
tic c-aminobutyric acid (GABA) receptor modulator for the treat-
ment of insomnia. Another pyrazine-containing drug is
bortezomib (2, Velcade), an intravenously administered first-in-
class proteasome inhibitor for the treatment of patients with
multiple myeloma (MM) who had received at least two prior
therapies.2
Sulfonylpyrazines, on the other hand, have emerged as impor-
tant moieties in pharmaceutical agents. Conspicuously, (methyl-
sulfonyl)pyrazine
3
is
a
cell proliferation inhibitor3 and
sulfonylpyrazine 4 is a prostacyclin (PGI2) receptor agonist, poten-
tially used for the treatment of various vascular diseases (Fig. 2).4
In addition, (methylsulfonyl)pyrazine 5 is an adenosine antago-
nist,5 and sulfonylpyrazine 6 was investigated as an insecticide,
acaricide, or nematicide.6
During our drug discovery programs, we have developed a no-
vel methodology for preparing 2,5-bis-sulfonylpyrazines from
commercially available 2,5-bis-bromopyrazine (7). Surprisingly,
neither 2,5-bis-alkylsulfonylpyrazines nor 2,5-bis-arylsulfonyl-
pyrazines were previously known in the literature.
O
N
N
Cl
N
N
O
OH
B
H
N
O
N
N
O
N
H
OH
Me
N
O
We prepared 2,5-bis-(sulfonyl)pyrazines
9
from readily
commercially available 2,5-bis-bromopyrazine (7). As shown in
Scheme 1, disulfide 8a was obtained by refluxing 7 with 10 equiv
Me
, bortezomib (Velcade)
N
Me
2
1
, eszopiclone (Lunesta)
⇑
Corresponding author. Tel.: +1 609 252 3238.
E-mail address: michael.miller@bms.com (M.M. Miller).
Figure 1. Pyrazine-containing drugs on the market.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.01.106

J. J. Li et al. / Tetrahedron Letters 54 (2013) 1938–1942
1939
Me
N
N
S
N
Br
2.5 equiv NaStBu
Me
N
tBu
tBu
Me
N
H
N
S
N
8b
Br
N
7
Ph
Ph
N
N
MeCN
N
N
µW (100 oC, 30 min), 96%
O
O
N
S
O
S
O
CO2H
O2
Me
O
N
S
tBu
6 equiv of Oxone
4
, prostacyclin receptor agonist
3
, cell proliferation in hibitor
tBu
S
N
iPrOH/H2O (3:5)
rt, 4 d, 94%
O2
9b
O
O
N
N
O
S
Scheme 4. Two-step preparation of 2,5-bis-t-butylsulfonylpyrazine 9b.
H2N
N
N
N
Me
Me
O
S
N
O
O
S
Me
O
Me
O
Me
Me
N
Br
Me
Me
N
S
Me
SH
5
, adenosine antagonist
6
, insecticide
Br
N
7
S
N
8c
Me
Me
K2CO3, MeCN, reflux
overnight, 97%
Figure 2. Sulfonylpyrazine-containing compounds in medicinal chemistry.
O2
S
N
30% H2O2 (6 equiv), HOAc
75 oC, overnight, 84%
N
N
S
N
Br
10 equiv NaSMe
Me
S
N
Me
DMF, reflux
O2
S
Br
N
7
overnight, 83%
9c
8a
O2
Scheme 5. Two-step preparation of 2,5-bis(tolylsulfonyl)pyrazine 9c.
N
N
S
Me
30% H2O2 (6 equiv), HOAc
75 oC, overnight, 90%
3). In the same vein, the SNAr reaction of 9a with 2.5 equiv of ethyl
2-mercaptoacetate, perhaps not surprisingly, afforded the double
SNAr reaction product, bis-sulfide 13. Again, employing only
1 equiv of ethyl 2-mercaptoacetate, the mono-substitution product
14 was produced in 69% yield, along with concurrent formation of
29% of 13.10 Unfortunately, the yields for the SNAr reactions of the
nitrogen nucleophiles were poor to moderate. When the aliphatic
amine tert-butyl piperazine-1-carboxylate was used, only 37% of
the mono-substituted pyrazine 15 was isolated. The bis-substitu-
tion product was not isolated presumably because of its extremely
low solubility. When a bis-Boc-guanidine was employed as the
nucelophile, the mono-substituted product 16 was isolated. Our
methodology was also found to have additional limitations in ali-
phatic alcohols. No reaction was observed when aliphatic alcohols
were used as nucleophiles. However, when sodium ethoxide was
used, 2-ethoxy-5-(methylsulfonyl)pyrazine (17) was isolated in
84% yield. In addition, when the SNAr reaction of 9a with a carbon
nucleophile was initially carried out using diethyl malonate trea-
ted with 1 equiv of NaOEt, a mixture of 2-ethoxy-5-(methylsulfo-
nyl)pyrazine (17) and diethyl 2-(5-(methylsulfonyl)pyrazin-2-
yl)malonate (18) was afforded in 55% and 33% yields, respectively
(Scheme 3). This is a reflection of the fact that NaOEt is more nucle-
ophilic than sodium malonate. Although when sodium malonate
was derived by the treatment of diethyl malonate with 1 equiv of
NaH, 2-(5-(methylsulfonyl)-pyrazin-2-yl)malonate (18) was iso-
lated as the sole product in 86% yield. This was the case even when
2 equiv of the nucleophile was employed.11
Me
S
O2
9a
Scheme 1. Two-step preparation of 2,5-bis-(methysulfonyl)pyrazine 9a.
2.5 equiv
N
N
O
HO
F
Me
9a
F
S
O2
K2CO3, MeCN
reflux, 2 h, 90%
10
2.5 equiv
F
N
S
HS
F
9a
S
N
11
F
K2CO3, MeCN
reflux, 2 h, quant.
Scheme 2. SNAr reactions of 9a with phenol and thiophenol.
CO2Et
CO2Et
CO2Et
O
N
Et
N
CO2Et
Me
N
S
Me
N
9a
O2
S
NaOEt, THF, reflux, 2 h
O2
Meanwhile, 2,5-bis-t-butylsulfonylpyrazine (9b) was prepared
in a similar fashion to that described for 9a (Scheme 4). Double
SNAr displacement of 2,5-bis-bromopyrazine (7) with 2.5 equiv of
sodium t-butanethiolate upon microwave irradiation (MeCN,
30 min, 100 °C) provided disulfide 8b. Oxidation of disulfide 8b
to bis-sulfone 9b was accomplished by using 6 equiv of OxoneÒ
in i-PrOH/H2O at room temperature over 4 days. The prolonged
reaction time may be a reflection of the steric hindrance that the
t-butyl group exerted.
17, 55%
18, 33%
Scheme 3. SNAr reactions of 9a with sodium ethoxide and malonate.
of the oxygen atom. Therefore, even though an excess amount of 4-
fluorophenol (2.5 equiv) was used, the mono-SNAr product was the
sole product produced, giving rise to 10 in 90% isolated yield.9 In
contrast, when 2.5 equiv of 4-fluorothiophenol was used as the
nucleophile, bis-sulfide 11 was isolated exclusively. Interestingly,
employing only 1 equiv of 4-fluorothiophenol, the mono-substitu-
tion product 12 was produced as the sole product (Table 1, entry
The SNAr reactions of bis-sulfones 9b with a wide variety of
nucleophiles have been explored. Compared to 9a, a similar trend
of reactivity for 9b was observed. As shown in Table 2, sulfur

1940
J. J. Li et al. / Tetrahedron Letters 54 (2013) 1938–1942
Table 1
SNAr reactions of 2,5-bis-(methylsulfonyl)pyrazine 9a
Entry
1
Bis-sulfone
Nucleophile
Product
Yield (%)
90
N
N
O
F
HO
9a
Me
F
S
F
O2
10
N
S
F
HS
2
3
4
5
9a
9a
9a
9a
100a
89b
88a
69c
S
N
F
11
N
N
S
F
HS
Me
S
F
O2
12
N
EtO2C
SH
SH
S
CO2Et
EtO2C
S
N
N
13
EtO2C
HN
S
CO2Et
Me
S
N
O2
14
Boc
N
N
Boc
N
N
N
6
9a
37
Me
S
O2
15
O
NH
O
H
N
N
N
Boc
tBuO
N
N
OtBu
7
8
9a
9a
34
H
H
Me
Me
HN
S
N
N
Boc
O2
16
O
Et
NaOEt
84d
S
N
O2
17
CO2Et
CO2Et
CO2Et
CO2Et
Na
N
N
9
9a
86e
Me
S
O2
18
a
b
c
2.5 equiv of the nucleophile were used.
1.0 equiv of the nucleophile was used.
1.0 equiv of the nucleophile was used and a mixture of 14/13 was isolated in 7:3 ratio.
Refluxed in THF for 3 h with 2.2 equiv of NaOEt.
Refluxed in THF overnight with 2.2 equiv of the nucleophile generated by treating malonate with NaH.
d
e
Table 2
SNAr reactions of 2,5-bis-t-butylsulfonylpyrazines (9b)
Entry
1
Bis-sulfone
Nucleophile
Product
Yield (%)
72
N
O
F
HO
tBu
tBu
9b
S
N
N
F
O2
19
O
N
HO
N
2
3
4
9b
9b
9b
96
79
S
N
N
O2
20
S
Br
F
HS
HS
tBu
F
S
N
Br
O2
21
N
S
58a
S
N
F
11

J. J. Li et al. / Tetrahedron Letters 54 (2013) 1938–1942
1941
Table 2 (continued)
Entry
Bis-sulfone
Nucleophile
Product
Yield (%)
Me
N
HN
Me
N
N
N
5
6
9b
23
81
tBu
tBu
N
S
O2
22
Me
HN
Me
N
N
N
N
N
N
N
9b
S
O2
23
Me
HN
Me
N
N
N
7
9b
9b
65
tBu
tBu
S
O2
24
CO2Et
CO2Et
CO2Et
Na
N
N
CO2Et
8
86b
S
O2
25
a
2.2 equiv of the nucleophile were used.
Refluxed overnight in THF with 2.2 equiv of the nucleophile generated by treating malonate with NaH.
b
Table 3
SNAr reactions of 2,5-bis-arylsulfonylpyrazines (9c)
Entry
1
Bis-sulfone
Nucleophile
Product
Yield (%)
93
Me
Me
N
O
O
N
HO
N
9c
S
N
N
O2
26
27
N
HO
N
2
3
9c
9c
67
99
S
N
O2
Me
HO
Me
Me
Me
N
N
O
S
O2
28
29
H
N
H2N
N
N
N
4
5
9c
9c
30
34
N
S
O2
Me
N
HN
Me
N
Me
Me
N
N
N
S
O2
30
31
CO2Et
CO2Et
CO2Et
Na
N
N
CO2Et
6
9c
89a
S
O2
a
Refluxed overnight in THF with 2.2 equiv of the nucleophile generated by treating malonate with NaH.
nucleophile is the most reactive toward the replacement of t-butyl-
sulfone, followed by phenolic oxygen, selected heterocyclic ring
nitrogen, and amine nitrogen. When 1 equiv of 4-bromothiol was
used (entry 3), mono-SNAr product 21 was the sole product gener-
ated in good yields. On the other hand, when 2.2 equiv of a 4-flu-
orobenzenethiol nucleophile were used, the bis-sulfide product
11 was isolated exclusively under the reaction conditions. In con-
trast, when 2.5 equiv of 4-fluorophenol were employed (entry 1),
only mono-SNAr product 19 was produced due to the deactivation
of the pyrazine ring as discussed above. Amine nitrogen showed
limited reactivity toward this type of reaction. While 9b was trea-
ted with N-methylpyridin-4-amine (entry 5), the desired mono-

1942
J. J. Li et al. / Tetrahedron Letters 54 (2013) 1938–1942
SNAr product 22 was produced in 23% yield, we were unable to per-
form the similar transformation with aliphatic amines. Heterocy-
clic ring nitrogen can also be used as nucleophiles for this
reaction. Both 2-methylimidazole (entry 6) and 2-methyl-1H-
benzo[d]imidazole (entry 7) react readily with 9b to provide only
the mono-SNAr products 23 and 24 in good to excellent yields.
When sodium malonate (entry 8) was prepared by the treatment
of diethyl malonate with 1 equiv of NaH, 2-(5-(t-butylsulfonyl)pyr-
azin-2-yl)malonate (25) was isolated as the major product in 86%
yield even when 2 equiv of nucleophile was employed.
zine (9a), 2,5-bis(t-butylsulfonyl)-pyrazine (9b), and 2,5-bis(toly-
lsulfonyl)pyrazine (9c). The respective SNAr reactions of these
have been explored with a variety of nucleophiles. When 2 equiv
of thiols or thiophenols were employed as the nucleophiles, bis-
thiopyrazines were obtained exclusively. However, phenols or alk-
oxides only gave rise to the corresponding mono-substituted aryl-
oxy- or alkoxy-sulfonylpyrazines in excellent yields because the
pyrazine is deactivated by the oxygen atom. A carbon nucleophile
prepared by treating malonate with NaH also produced the corre-
sponding mono-sulfonylpyrazines even though 2 equiv of the
nucleophile was used. Finally, the SNAr reaction of aliphatic amines
and anilines with 2,5-bis-(sulfonyl)pyrazines provided the mono-
anilino-sulfonylpyrazines in poor to moderate yields.
We further investigated the arylsulfonyl-pyrazines using 2,5-
bis-(tolylsulfonyl)-pyrazine (9c) as an example. As shown in
Scheme 5, double SNAr displacement of 2,5-bis-bromopyrazine
(7) gave di-sulfide 8c. Same oxidation procedure using hydrogen
peroxide in glacial acetic acid produced bis-sulfone 9c. We also at-
tempted to prepare 9c in one step by treating 2,5-bisbromopyr-
azine (7) with 2 equiv of sodium sulfinate with no success.12
With substrate 9c in hand, its SNAr reactions with several differ-
ent nucleophiles were explored. Reaction of 2,5-ditosylsulfonyl-
pyrazine (9c) with pyridin-3-ol under typical conditions afforded
2-(pyridin-3-yloxy)-5-tosylsulfonylpyrazine (26) in excellent yield
(Table 3, entry 1), while a much lower yield of 2-(pyridin-2-yloxy)-
5-tosylsulfonylpyrazine (27) was obtained with pyridin-2-ol (entry
2). The lower yield resulted from the formation of 2,5-bis(pyridin-
2-yloxy)pyrazine (structure not shown) as a major side product. In
addition to pyridinols, we also evaluated o-cresol, a relatively ste-
rically hindered phenol. This phenol (entry 3) underwent smooth
mono-SNAr substitution to furnish 2-(o-tolyloxy)-5-tosylsulfonyl-
pyrazine (28) in nearly quantitative yield. This methodology has
also been extended to aminopyridines with limited success. In gen-
eral, multiple substitution products from aminopyridines were ob-
served in the crude reaction mixture as shown by LC–MS analysis,
thus resulting in poor yields. For example, both pyridin-4-amine
(entry 4) and N-methylpyridin-4-amine (entry 5) furnished the de-
sired mono-substituted products 29 and 30 in roughly 30% yield.
When pyridin-2-amine was utilized, only a trace amount of the de-
sired mono-substituted product was formed. As aminopyridines
are common building blocks for medicinal chemistry research, fu-
ture work will be directed toward improving the efficiency of the
reactions with 2,5-ditosylsulfonylpyrazine involving aminopyri-
dines. When sodium malonate was prepared by the treatment of
diethyl malonate with 1 equiv of NaH (entry 6), 2-(5-(tolylsulfo-
nyl)pyrazin-2-yl)malonate (31) was isolated as the predominant
product in 89% yield even when 2 equiv of nucleophile was
employed.
Supplementary data
Supplementary data (full experimental detail, as well as charac-
terization of all compounds) associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2013.01.106.
References and notes
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9. Typical experimental procedure: To a suspension of 2,5-bis(methylsulfonyl)-
pyrazine (9a, 500 mg, 2.12 mmol) in acetonitrile (5 mL) was added para-
fluorophenol (593 mg, 5.29 mmol, 2.5 equiv) and K2CO3 (877 mg, 6.35 mmol,
3 equiv) The resulting suspension was refluxed for 2 h and cooled to rt. The
suspension was filtered, the solvent was removed in vacuo and the residue was
purified using a column eluting with 30–50% EtOAc in hexanes to give the
desired product 10 as a white and highly crystalline solid (512 mg, 90%).
Rf = 0.51 (1:1 hexanes/EtOAc); 1H NMR (300 MHz, CDCl3) d: 8.69 (s, 1H), 8.44 (s,
1H), 7.09 (m, 4H), 3.15 (s, 3H); 19F NMR (282 MHz, CDCl3) d: 116.2; 13C NMR
(75 MHz, CDCl3) d: 165.6, 164.0 (d), 148.6, 141.4 (d), 137.7 (d), 121.7 (d), 117.4
(d); MS (ESI+) m/z 269.11 (M+1).
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In summary, we have prepared the previously unknown 2,5-
bis-(sulfonyl)-pyrazines including 2,5-bis-(methysulfonyl)-pyra-