Novel syntheses of 3-anilino-pyrazin-2(1H)-ones and 3-anilino-quinoxalin-2-(1H)-ones via microwave-mediated Smiles rearrangement

Article abstract of DOI:10.1016/j.tetlet.2008.01.056

In this Letter, we report a novel approach to the preparation of 3-anilino-pyrazin-2(1H)-ones and 3-anilino-quinoxalin-2(1H)-ones from the corresponding 3-halo pyrazin-2-amines and 3-haloquinoxalin-2-amines, using a microwave-mediated Smiles rearrangement

Full text of DOI:10.1016/j.tetlet.2008.01.056

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1832–1835
Novel syntheses of 3-anilino-pyrazin-2(1H)-ones and
3-anilino-quinoxalin-2-(1H)-ones via microwave-mediated
Smiles rearrangement
F. Christopher Bi *, Gary E. Aspnes, Angel Guzman-Perez, Daniel P. Walker
Pfizer Global Research and Development, Groton, CT 06340, United States
Received 22 June 2007; revised 8 January 2008; accepted 10 January 2008
Available online 15 January 2008
Abstract
In this Letter, we report a novel approach to the preparation of 3-anilino-pyrazin-2(1H)-ones and 3-anilino-quinoxalin-2(1H)-ones
from the corresponding 3-halo pyrazin-2-amines and 3-haloquinoxalin-2-amines, using a microwave-mediated Smiles rearrangement.
Ó 2008 Elsevier Ltd. All rights reserved.
Amino-pyrazinones and amino-quinoxalinones are fre-
quently encountered in the chemical literature as versatile
scaffolds for medicinally relevant molecules (Fig. 1), such
as anti-apoptotic protease inhibitors (1),1 anti-diabetic
glycogen phosphorylase inhibitors (2),2 antithrombotics
(3),3 and antiviral HIV-reverse transcriptase inhibitors
(4).4 In this Letter, we disclose a novel and facile
method to prepare 3-anilino-pyrazin-2(1H)-ones and
N
O
O
O
H
H
H
O
N
N
N+
N
N
O
S
N
N
N
H
N
O
CO2H
F
N
H
1
2
NH2
Cl
N
O
CN
OH
N
O
N
N
H
N
O
O
N
H
O
N
H
NH2
CN
NH
3
4
Fig. 1. Biologically active amino-pyrazinones and amino-quinoxalinones.
*
Corresponding author. Tel.: +1 858 622 7956.
E-mail address: Feng.C.Bi@Pfizer.com (F. Christopher Bi).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.056

F. Christopher Bi et al. / Tetrahedron Letters 49 (2008) 1832–1835
1833
3-anilino-quinoxalin-2(1H)-ones, based on a microwave-
mediated Smiles rearrangement.
the known rate acceleration effect of ortho or para electron-
withdrawing groups on the Smiles rearrangement.5
To greatly shorten the reaction time and thus make this
transformation a more practical means to obtain 3-anilino-
pyrazinones and 3-anilino-quinoxalinones, microwave-
mediated conditions were chosen to replace the original
thermal conditions. As summarized in Table 1, reactions
proceeded smoothly with both aminoquinoxaline (5b)
and aminopyrazine templates (5c and 5d) to provide the
rearrangement products in good yield and high purity after
a simple work-up.7 The structure of the rearrangement
product 9 was confirmed by a single crystal X-ray analysis
(Fig. 2).8 As anticipated,9 nucleophilic displacement took
place exclusively at the 3-position of the 3,5-dihalo substi-
tuted 2-aminopyrazine templates (Table 1, entries 3 and 4).
Subsequent rearrangement yielded 3-anilino-5-halo-pyr-
azin-2(1H)-ones containing multiple functional handles
for medicinal chemistry exploration. Although reactions
were originally run for 30 min, it was later found that
5–10 min was sufficient for reactions to go to completion
(Table 1, entry 2).
In the course of work on a medicinal chemistry pro-
gram, we were interested in C(3)-phenoxy substituted
2-amino-5-trifluoromethylpyrazines such as 8 as novel
chemical structures (Scheme 1). At the onset of this work,
introduction of the C(3)-phenoxy group of 8 was envi-
sioned to take place via SNAr displacement of the corres-
ponding aryl bromide. However, to our surprise, the
reaction of bromide 5a with phenol 6a in the presence of
a base gave rise to a small quantity of the desired adduct
(8) along with an unexpected product, which based on
spectral data was assigned as 3-anilino-pyrazine 2(1H)-
one (7). Pyrazinone 7 is presumably generated by a Smiles
rearrangement5 of the desired product 8 via complex A.
The facile equilibrium between the 2-hydroxypyrazine
and pyrazin-2-one tautomers of 7 at ambient temperature
complicated the structural assignment, because the
C(5)–H of 7 appears as a very broad signal in the 1H
NMR spectrum in DMSO-d6 solution.6
Encouraged by this result, we next examined the reac-
tions of the readily available 3-halopyrazin-amines and
3-haloquinoxalin-amines with 4-methylsulfonylphenol
(6a). Phenol 6a was selected for the initial study due to
To further explore the scope of this rearrangement, a set
of substituted phenols possessing different electronic prop-
erties was identified to react with 2-amino-3-chloroquinox-
HO
H
SO2Me
F3C
N
Br
F3C
N
N
O
F3C
H
N
O
SO2Me
6a
+
K2CO3, DMF, 100 oC
N
NH2
NH2
SO2Me
5
N
H
N
5a
8
7
F3C
N
N
O
SO2Me
N
H
A
Scheme 1. Initial result.
Table 1
Reactions of halide 5 with 4-methylsulfonylphenol
HO
H
SO2Me
R1
R2
N
X
R1
R2
N
O
SO2Me
6a
K2CO3, 200 oC, μW,
N
NH2
N
N
H
NMP
5b-d
9-11
Entry
Compound
R1, R2
X
Reaction T (min)
Product
Yield (%)
1
2
3
4
5b
5b
5c
5d
CH@CH–CH@CH
CH@CH–CH@CH
Cl, H
Cl
Cl
Cl
Br
30
5
30
30
9
9
86
79
76
74
10
11
Br, H

1834
F. Christopher Bi et al. / Tetrahedron Letters 49 (2008) 1832–1835
Fig. 2. ORTEP plots of 9 and 13f.
aline 5b. As illustrated in Table 2, rearrangement reactions
took place readily with phenols containing a range of elec-
tron-withdrawing groups at the ortho- or para-positions
(entries 1–4). In this case, typical reaction times were less
than 10 min. Under identical reaction conditions, more
electron-rich phenols, such as para-fluoro substituted,
para-chloro substituted, and unsubstituted phenols, pre-
dominantly gave rise to normal SNAr products (entries
5–7, T = 10 min).10 However, products 13e–g could be
converted to the rearrangement products 12e–g in reason-
able yield upon isolation and prolonged reaction times
(Table 3).11
In summary, we have developed a novel approach
to provide access to 3-anilino-pyrazin-2(1H)-ones and
3-anilino-quinoxalin-2(1H)-ones from the corresponding
3-halopyrazin-2-amines and 3-haloquinoxalin-2-amines,
Table 2
Reactions of halide 5b with substituted phenols (ND: Not detected by 1H NMR)
HO
R3
H
N
Cl
N
O
N
O
6a-g
R3
+
R3
K2CO3, 200 oC, μW,
N
NH2
N
N
H
N
NH2
NMP
5b
13a-g
12a-g
Entry
Compound
R3
Reaction T (min)
12a–g % yield
13a–g % yield
1
2
3
4
5
6
7
6a
6b
6c
6d
6e
6f
p-SO2Me
o-SO2Me
p-CN
p-Ac
p-Cl
p-F
5
10
10
10
10
10
10
79
75
77
79
Trace
ND
ND
Trace
ND
ND
ND
76
63
37
6g
p-H
Table 3
Smiles rearrangement
H
N
O
N
O
R3
R3
K2CO3, 200 oC, μW,
NMP
N
N
H
N
NH2
13e-g
12e-g
Entry
Compound
Reaction T (min)
12e–g % yield
1
2
3
13e
13f
13g
30
90
90
90
58
53

F. Christopher Bi et al. / Tetrahedron Letters 49 (2008) 1832–1835
1835
the corresponding 3-(4-methylsulfonylphenylamino) compounds
15b–d. Removal of the PMB protecting group with TES/TFA in
dichloromethane yielded the equivalent products 9, 10, and 11.
based on a microwave-mediated Smiles rearrangement. A
selection of readily available 3-halopyrazin-2-amines and
PMB
H
N
R1
R2
N
N
OPMB
NH2
R1
R2
O
SO2Me
R1
R2
N
X
R1
R2
N
N
O
SO2Me
a
b
c
N
N
H
N
NH2
N
H
14b-d
9-11
5b-d
15b-d
o
(a) PMBOH, t-BuOK, dioxane, Δ; (b) NaH, 4-fluorophenyl methyl sulfone, DMF, 80 C; (c) Et3SiH, TFA, CH2Cl2.
7. Representative procedure: A 2–5 mL microwave vial equipped with a
stir-bar was charged with 2-amino-3-chloroquinoxaline (5b) (180 mg,
1.0 mmol), 4-methylsulfonylphenol (6a) (207 mg, 1.2 mmol) and
potassium carbonate (691 mg, 5.0 mmol). 1-Methyl-2-pyrrolidinone
(NMP, 3.5 mL) was added, and the vessel was subsequently sealed
and heated to 200 °C in the microwave reactor (Biotage Initiator) for
30 min. The reaction mixture was cooled to rt, diluted with 20 mL of
water, and acidified to pH 2 with 1 N HCl. The resulting precipitate
was collected via a medium-pore frit funnel, and washed sequentially
with water (20 mL) and MeOH (2 mL). The residue was dried in
vacuo to give 3-(4-(methylsulfonyl)phenylamino)quinoxalin-2(1H)-
one (9) as a yellow solid (270 mg, 86%). 1H NMR (400 MHz, DMSO-
d6) d 12.57 (s, 1H), 9.91 (s, 1H), 8.42 (d, 2H, J = 8.9), 7.86 (d, 2H,
J = 8.9), 7.56 (d, 1H, J = 7.5), 7.21–7.30 (m, 3H), 3.17 (s, 3H). 13C
NMR (100 MHz, DMSO-d6) d 152.03, 147.85, 144.86, 134.26, 132.36,
129.57, 128.54, 126.53, 126.41, 124.27, 120.10, 115.83, 44.57. IR (neat)
3293, 1680, 1599, 1574, 1554, 1539, 1287, 1135, 1088, 795, 772, 752,
716, 606, 579, 535 cmÀ1. HRMS: Calcd for C15H14N3O3S (MH+):
316.0750, found: 316.0747.
3-haloquinoxalin-amines, and phenols with a range of
electronic properties and substitution patterns can be
employed successfully in this rearrangement reaction. To
the best of our knowledge, this constitutes the first pub-
lished account of a Smiles rearrangement of amino-aryloxy
substituted pyrazines and quinoxalines.
Acknowledgments
We would like to thank Mr. Robert M. Oliver for the
preparation of substrates 5b and 5c. We thank Dr. Antonio
DiPasquale of UCSD for solving the X-ray structure of 9
and Dr. Jon Bordner of Pfizer for solving the X-ray struc-
ture of 13f.
References and notes
8. The data collection for 9 was carried out at the University of
California—San Diego X-ray facility using direct methods (SIR-97)
and refined with SHELXL-97: C15H13N3O3S; Fw = 315.34; yellow
needle, monoclinic; space group C2/c; unit cell dimensions: a =
1. Han, Y.; Giroux, A.; Colucci, J.; Bayly, C. I.; Mckay, D. J.; Roy, S.;
Xanthoudakis, S.; Vailancourt, J.; Rasper, D. M.; Tam, J.; Tawa, P.;
Nicholson, D. W.; Zamboni, R. J. Bioorg. Med. Chem. Lett. 2005, 15,
1173–1180.
2. Dudash, J., Jr.; Zhang, Y.; Moore, J. B.; Look, R.; Liang, Y.;
Beavers, M. P.; Conway, B. R.; Rybczynski, P. J.; Demarest, K. T.
Bioorg. Med. Chem. Lett. 2005, 15, 4790–4793.
3. Parlow, J. J.; Case, B. L.; Dice, T. A.; Fenton, R. L.; Hayes, M. J.;
Jones, D. E.; Neumann, W. L.; Wood, R. S.; Lachance, R. M.;
Girard, T. J.; Nicholson, N. S.; Clare, M.; Stegeman, R. A.; Stevens,
A. M.; Stallings, W. C.; Kurumbail, R. G.; South, M. S. J. Med.
Chem. 2003, 46, 4050–4062.
4. Heeres, J.; de Jonge, M. R.; Koymans, L. M. H.; Daeyaert, F. F. D.;
Vinkers, M.; Van Aken, K. J. A.; Arnold, E.; Das, K.; Kilonda, A.;
Hoornaert, G.; Compernolle, F.; Cegla, M.; Azzam, R. A.; Andries,
˚
˚
˚
22.8162(10) A, a = 90°; b = 5.4818(3) A, b = 101.342(2)°; c =
3
˚
22.7237(10) A, c = 90°; volume = 2786.6(2) A ; Z = 8; Dcalcd
=
1.503 Mg/m3; absorption coefficient = 2.227 mmÀ1; F(000) = 1312;
GOF on F2 = 1.132; final R indices [I > 2r(I)]: R1 = 0.0407, wR2 =
0.1154; R1 = 0.0463, wR2 = 0.1188 for all data.
9. (a) Jiang, B.; Yang, C.-G.; Xiong, W.-N.; Wang, J. Bioorg. Med.
Chem. Lett. 2001, 9, 1149–1154; (b) Camerino, B.; Palamidessi, G.
Gazz. Chim. Ital. 1960, 90, 1807.
10. Normal SNAr products were isolated as HCl salts with unexpected
low aqueous solubility. Salt formation was confirmed by 1H NMR of
the corresponding p-TsOH salt of 13f. Structural assignment of
normal SNAr products was confirmed by a single crystal X-ray
structure of compound 13f. The data for 13f were collected on a
Bruker APEX diffractometer at Pfizer Groton Laboratories, and all
crystallographic calculations were facilitated by the SHELXTL system:
´
K.; de Bethune, M.-P.; Azijn, H.; Pauwels, R.; Lewi, P. J.; Janssen, P.
A. J. J. Med. Chem. 2005, 48, 1910–1918.
5. For a review on Smiles rearrangement, see: (a) Truce, W. E.; Kreider,
E. M.; Brand, W. W. Org. React. 1970, 18, 99–215. For more recent
literature examples, see: (b) Xiang, J.; Zheng, L.; Chen, F.; Dang, Q.;
Bai, X. Org. Lett. 2007, 9, 765–767; (c) El Kaim, L.; Gizolme, M.;
Grimaud, L.; Oble, J. Org. Lett. 2006, 8, 4019–4021.
6. The C(5)–H signal became sharper when running the 1H NMR at
elevated temperature. Structure of similar Smiles rearrangement
products 9, 10, and 11 was confirmed through preparation via an
independent chemical route: Reaction of appropriate starting material
5b–d with p-methoxybenzylalcohol (PMB-OH) in the presence of
potassium tert-butoxide in hot dioxane gave the 2-PMB ethers 14b–d.
Deprotonation of these amines with sodium hydride followed by an
addition to 4-fluorophenyl methyl sulfone in DMF at 80 °C yielded
+
À
ꢀ
C14H11N3OF Cl ÁH2O; Fw = 309.72; triclinic; space group P1; unit
˚
˚
cell dimensions: a = 5.3954(2) A, a = 81.067(2)°; b = 8.8496(2) A,
˚
b = 88.690(2)°;
c = 15.1200(5) A,
c = 87.780(2)°;
volume =
712.54(4) A ; Z = 2; Dcalcd = 1.444 Mg/m3; absorption coefficient =
2.563 mmÀ1; F(000) = 320; GOF on F2 = 1.027; final R indices
[I > 2r(I)]: R1 = 0.0448, wR2 = 0.1289.
3
˚
11. Isolation of the normal SNAr product of the less reactive 4-
fluorophenol followed by subsequent re-subjection of it to prolonged
heating provided better yield than the one-pot procedure. Reaction of
the corresponding normal SNAr product of the more electron-rich 4-
methoxyphenol failed to give any desired rearrangement product,
even at higher temperature (T = 250 °C) and prolonged reaction time.