A convenient synthesis of novel 2,8-disubstituted pyrido[3,4-b]pyrazines possessing biological activity

Article abstract of DOI:10.1055/s-0031-1289613

A regioselective synthetic route to 2,8-disubstituted pyrido[3,4-b] pyrazines, by initial condensation reaction between suitable diaminopyridines and α-keto aldehydes equivalents, has been developed. Focusing on the functionalization on C-8, 2-aryl-8-bromo- and 8-amino-2-arylpyrido[3,4-b] pyrazines have been synthesized. Anilines, amides, and ureas have been introduced at the 8-position from key intermediates. 2,8-Disubstituted pyrido[3,4-b]pyrazines thus prepared were found to be of biological interest. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0031-1289613

PAPER
69
A Convenient Synthesis of Novel 2,8-Disubstituted Pyrido[3,4-b]pyrazines
Possessing Biological Activity
Synthesis of
N
ovel 2, 8
a
-Disubstitu
u
d
4-
b
]pyrazines Antoine,a Matthias Gerlach,b Eckhard Günther,b Tilmann Schuster,b Michael Czech,b Irene Seipelt,b
Pascal Marchand*a
a
Université de Nantes, Nantes Atlantique Universités, Laboratoire de Chimie Thérapeutique, Cibles et Médicaments des Infections,
de l’Immunité et du Cancer, IICiMed UPRES EA 1155, UFR de Sciences Pharmaceutiques et Biologiques, 1 rue Gaston Veil,
44035 Nantes, France
Fax +33(2)40412876; E-mail: pascal.marchand@univ-nantes.fr
Æterna Zentaris GmbH, Weismuellerstr. 50, 60314 Frankfurt/Main, Germany
b
Received 22 September 2011; revised 24 October 2011
In this paper, we present a regioselective synthetic route
to 2,8-disubstituted pyrido[3,4-b]pyrazines obtained by
initial condensation reaction between suitable diaminopy-
ridines and a-keto aldehyde equivalents (Scheme 1).
Abstract: A regioselective synthetic route to 2,8-disubstituted py-
rido[3,4-b]pyrazines, by initial condensation reaction between suit-
able diaminopyridines and a-keto aldehydes equivalents, has been
developed. Focusing on the functionalization on C-8, 2-aryl-8-bro-
mo- and 8-amino-2-arylpyrido[3,4-b]pyrazines have been synthe-
sized. Anilines, amides, and ureas have been introduced at the 8-
position from key intermediates. 2,8-Disubstituted pyrido[3,4-
b]pyrazines thus prepared were found to be of biological interest.
R3
R1
R1
N
N
R2
N
N
R2
NH2
NH2
R2 = aryl
R1 = Br, NH2
N
N
N
Key words: pyrido[3,4-b]pyrazines, pyridines, thioacetals, phe-
nylglyoxals, regioselectivity, condensation
R3 = ureas, amides, anilines
Scheme 1 Structures of synthesized 2,8-disubstituted pyrido[3,4-
b]pyrazines
In recent years, some pyrido[2,3-b]pyrazines and pyri-
do[3,4-b]pyrazines have been described in the literature as
compounds with promising biological properties. In par-
ticular, 2,3,8-trisubstituted pyrido[2,3-b]pyrazines have
been used for the treatment of malignant tumors and other
diseases associated to pathological cell proliferations.1
Other compounds bearing a pyridopyrazine scaffold have
been described as vasculostatic agents (by inhibition of
Src-family kinases: c-Src and Yes) and as inhibitors of
FtsZ polymerization.2 In addition, pyrido[3,4-b]pyrazine
derivatives exhibited tubulin polymerization inhibition in
the micromolar range.3
Our synthetic strategy was to functionalize directly 2- and
8-positions of the pyrido[3,4-b]pyrazine scaffold by ring-
closing reaction. We envisioned to prepare our key inter-
mediates, 2-aryl-8-bromo- and then 8-amino-2-arylpyri-
do[3,4-b]pyrazines by an initial condensation reaction
between 3,4-diamino-5-bromopyridine and an a-dioxo
partner.
b-Oxosulfoxides or corresponding hemithioacetals were
first used as 1,2-diketone equivalents.6,10 The reaction was
carried out in the past with 3,4-diaminopyridine and 2-
aryl-2-oxoethyl methyl sulfoxides in a mixture of benzene
and acetic acid to give selectively 2-arylpyrido[3,4-
b]pyrazines.6 This synthetic approach was applied to pre-
pare 2-aryl-8-bromopyrido[3,4-b]pyrazines by reaction
with 3,4-diamino-5-bromopyridine (3), which was ob-
tained in three steps from commercially available 4-ami-
nopyridine as previously described.4
As part of our continuing efforts to identify new chemical
classes of kinase inhibitors, we previously developed an
efficient synthetic approach for the preparation of 2,3,8-
trisubstituted pyrido[3,4-b]pyrazines,4 but unfortunately
they did not exhibit any kinase inhibitory activity (data
not shown).
A literature survey revealed that no example of 2,8-disub-
stituted pyrido[3,4-b]pyrazines targeting kinase pathway
was described. To our knowledge, only a few papers have
reported on the preparation of 2- or 2,8-disubstituted pyri-
do[3,4-b]pyrazines.5–9 Thus, it was decided to synthesize
new compounds with a pyrido[3,4-b]pyrazine scaffold
bearing only one aryl group, in position 2, and an urea, an
amide or an aniline in position 8, expecting to better inter-
act with the target protein.
b-Oxosulfoxides were synthesized by a modified Corey
and Chaykovsky method,11–13 using sodium hydride in
dimethyl sulfoxide in the presence of a suitable ethyl ben-
zoate 1a,b, as depicted in Scheme 2. The corresponding
hemithioacetals 2a,b were prepared by acidic hydrolysis
of b-oxosulfoxides 1a¢,b¢ via a Pummerer rearrange-
ment.12,13 Reaction of 2-phenyl-2-oxoethyl methyl sulfox-
ide (1a¢) with 3,4-diamino-5-bromopyridine (3) in
benzene containing few drops of acetic acid (method M1¢)
produced a mixture of two regioisomers, 8-bromo-2-phe-
nylpyrido[3,4-b]pyrazine (6aa) and 8-bromo-3-phenylpy-
rido[3,4-b]pyrazine (6ab) in 55% yield (NMR ratio: 7:3).
SYNTHESIS 2012, 44, 69–82
x
x.
x
x
.
2
0
1
1
Advanced online publication: 18.11.2011
DOI: 10.1055/s-0031-1289613; Art ID: T91311SS
© Georg Thieme Verlag Stuttgart · New York

70
M. Antoine et al.
PAPER
The mixture was unfortunately inseparable by column The synthesis of our target compounds by the reaction be-
chromatography.
tween 3,4-diamino-5-bromopyridine (3) and various sub-
stituted phenylglyoxals was next examined. Interestingly,
phenylglyoxals could be obtained easily in one step by
oxidation of the corresponding acetophenones; and many
acetophenones with a large variety of substituents are
commercially available. Phenylglyoxal monohydrates
5a–e were prepared by oxidation of corresponding ace-
tophenones 4a–e using selenium dioxide in 1,4-dioxane–
water mixture in good yields as depicted in Scheme 2.14–16
In order to try to develop a regioselective access route to
2-aryl-8-bromopyrido[3,4-b]pyrazines, the reaction of
3,4-diamino-5-bromopyridine (3) with hemithioacetals
2a,b that behave as 1,2-diketones was next explored. This
reaction was carried out in refluxing acetic acid, in the
presence of sodium acetate (method 1, Scheme 2), to af-
ford regioselectively 2-aryl-8-bromopyrido[3,4-b]pyra-
zines 6aa–6ba in moderate yields (52–55%).
NH2
NH2
Br
O
O
S
N
3
COOEt
a
Me
c
R1
R1
method 1' (M1')
1a R1 = H
1a' R1 = H (60%)
1b R1 = OMe
1b' R1 = OMe (70%)
NH2
NH2
b
inseparable mixture of 6aa
and 6ab (NMR ratio: 7:3)
Br
O
N
3
SMe
OH
2a R1 = H (70%)
d
R1
method 1 (M1)
2b R1 = OMe (75%)
NH2
Br
NH2
Br
R2
O
O
N
N
3
R1
R2
R1
OH
OH
R2
e
Br
+
N
R2
R1
N
N
f
N
R1
method 2 (M2)
N
4a R1 = R2 = H
5a R1 = R2 = H (78%)
6aa R1 = R2 = H (M1, 52%, M2, 84%, M3, 75%) 6ab R1 = R2 = H (M1, < 1%, M2–M3, 0%)
4b R1 = OMe, R2 = H
4c R1 = R2 = OMe
5b R1 = OMe, R2 = H (60%)
5c R1 = R2 = OMe (64%)
6ba R1 = OMe, R2 = H (M1, 55%, M2, 92%)
6ca R1 = R2 = OMe (M2, 72%)
6bb R1 = OMe, R2 = H (M1, < 1%, M2, 0%)
6cb R1 = R2 = OMe (M2, 0%)
4d R1 = 1-piperidinyl, R2 = H 5d R1 = 1-piperidinyl, R2 = H (60%) 6da R1 = 1-piperidinyl, R2 = H (M2, 62%)
6db R1 = 1-piperidinyl, R2 = H (M2, 16%)
6eb R1 = OH, R2 = H (M2, 0%)
4e R1 = OH, R2 = H
5e R1 = OH, R2 = H (85%)
6ea R1 = OH, R2 = H (M2, 85%)
R2
R1
N
N
NH2
NH2
N
8aa R1 = R2 = H (83%)
O
N
7
8ba R1 = OMe, R2 = H (40%)
g
R2
OH
OH
+
method 3
(M3 for 8aa)
f
N
R1
5a R1 = R2 = H
N
R2
R1
5b R1 = OMe, R2 = H
N
8ab R1 = R2 = H (0%)
8bb R1 = OMe, R2 = H (35%)
Scheme 2 Preparation of 2-aryl-8-bromopyrido[3,4-b]pyrazines 6aa–ea. Reagents and conditions: (a) NaH, DMSO, 0 °C to r.t.; (b) DMSO,
H2O, HCl, r.t.; (c) benzene, AcOH, reflux; (d) NaOAc, AcOH, reflux; (e) SeO2, 1,4-dioxane, reflux, then H2O, reflux; (f) 1,4-dioxane, reflux;
(g) Br2, AcOH, r.t.
Synthesis 2012, 44, 69–82
© Thieme Stuttgart · New York

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Synthesis of Novel 2,8-Disubstituted Pyrido[3,4-b]pyrazines
71
Reaction of 3,4-diamino-5-bromopyridine (3) with phe- using tris(dibenzylideneacetone)dipalladium [Pd2(dba)3],
nylglyoxals 5a–e in refluxing 1,4-dioxane led to the 2,2¢-bis(diphenylphosphino)-1,1¢-binaphthyl (BINAP),
desired regioisomers, 2-aryl-8-bromopyrido[3,4-b]pyra- and t-BuONa in toluene to give benzophenone imines 9a–
zines 6aa–ea in very good yields (method 2, Scheme 2), d in good yields as outlined in Scheme 3. The reaction
except with 4-(piperidin-1-yl)phenylglyoxal (5d), which failed for the hydroxy derivative 9e, probably because of
afforded a mixture of two regioisomers, 8-bromo-2-[4- its poor solubility (starting material was recovered). Sub-
(piperidin-1-yl)phenyl]pyrido[3,4-b]pyrazine (6da) and sequent reaction with hydroxylamine hydrochloride in
8-bromo-3-[4-(piperidin-1-yl)phenyl]pyrido[3,4-b]pyrazine
methanol in the presence of sodium acetate led to the de-
(6db) in 62% and 16% yield, respectively. In this last sired 8-amino-2-arylpyrido[3,4-b]pyrazines 10a–d in
case, the two compounds were easily separated by column good yields (method 4, Scheme 3). In a second strategy,
chromatography unlike the phenyl analogues 6aa and 8-amino-2-arylpyrido[3,4-b]pyrazines 10a and 10e were
6ab.
synthesized by the reaction of 3,4,5-triaminopyridine
(11), prepared in two steps from 4-aminopyridine,4 with
the corresponding phenylglyoxal monohydrates in meth-
anol in the presence of sodium carbonate in moderate to
good yields (method 5, Scheme 3).
The regioselective formation of 2-substituted pyrido[3,4-
b]pyrazines is obvious since the more nucleophilic 3-ami-
no group of compound 3 attacks the more electrophilic
formyl function of phenylglyoxals 5a–e before the cy-
clization step.
From our key intermediates, 2-aryl-8-bromopyrido[3,4-
b]pyrazines 6aa–ea and 8-amino-2-arylpyrido[3,4-
b]pyrazines 10a–e, various chains (ureas, amides,
anilines, Table 1) were introduced in position 8 in order to
obtain broad functionality for an evaluation of kinase ac-
tivity for example. Ureas 12a–k were prepared from 2-
aryl-8-aminopyrido[3,4-b]pyrazines 10a,b using suitable
isocyanates, by reaction with sodium hydride in dimethyl-
formamide for aryl isocyanates, or in pyridine for alkyl
isocyanates as depicted in Scheme 3. Unfortunately, ureas
were not obtained using these conditions from 8-amino-2-
(4-hydroxyphenyl)pyrido[3,4-b]pyrazine (10e); in these
cases no reaction was observed and the starting material
was recovered. Amides 13a–c were synthesized by reac-
tion between 2-aryl-8-aminopyrido[3,4-b]pyrazines
10a,b and various acid chlorides in refluxing acetonitrile
with acceptable yields. Anilines 14a–q were prepared by
a Buchwald palladium-catalyzed reaction between 2-aryl-
8-bromopyrido[3,4-b]pyrazines 6aa–ea and various
anilines. Nevertheless, the desired product was not ob-
tained from 8-bromo-2-(4-hydroxyphenyl)pyrido[3,4-
In addition, reaction of phenylglyoxal (5a) with commer-
cially available 3,4-diaminopyridine (7) under the same
conditions yielded exclusively the previously described6
2-phenylpyrido[3,4-b]pyrazine (8aa), which could be
brominated using bromine in acetic acid to give 8-bromo-
2-phenylpyrido[3,4-b]pyrazine (6aa) in 75% yield (meth-
od 3, Scheme 2). Nevertheless, this synthetic route ap-
plied to substituted 4-methoxyphenylglyoxal (5b) gave
unfortunately a mixture of two inseparable regioisomers
8ba and 8bb. In addition, it would be expected that elec-
tron-donating methoxy group would induce the formation
of by-products, in particular by bromination on phenyl
ring in the second step.
Preparation of 2-aryl-8-aminopyrido[3,4-b]pyrazines was
accomplished using the same method as previously
described for the synthesis of 2,3,8-trisubstituted
pyrido[3,4-b]pyrazines.4 8-Bromo-2-arylpyrido[3,4-b]pyr-
azines 6aa–da were converted to the corresponding
benzophenone imine derivatives via a Buchwald reaction
g
R2
Ph
R2
R2
R2
R1
R1
R1
R1
d or e or f
Br
Ph
N
NHR3
NH2
a
b
N
N
N
N
N
N
N
N
method 4 (M4)
N
N
N
N
12a–k ureas (R3 = CONHR4)
13a–c amides (R3 = COR4)
14a–q anilines (R3 = R4)
6aa R1 = R2 = H
9a R1 = R2 = H (70%)
10a R1 = R2 = H (M4, quant., M5, 54%)
10b R1 = OMe, R2 = H (M4, 96%)
10c R1 = R2 = OMe (M4, 89%)
6ba R1 = OMe, R2 = H
6ca R1 = R2 = OMe
9b R1 = OMe, R2 = H (62%)
9c R1 = R2 = OMe (88%)
6da R1 = 1-piperidinyl, R2 = H
6ea R1 = OH, R2 = H
9d R1 = 1-piperidinyl, R2 = H (62%)
9e R1 = OH, R2 = H (failure)
10d R1 = 1-piperidinyl, R2 = H (M4, 54%)
10e R1 = OH, R2 = H (M5, 88%)
O
NH2
R2
OH
OH
H2N
NH2
c
+
method 5 (M5)
R1
5a R1 = R2 = H
5e R1 = OH, R2 = H
N
11
Scheme 3 Functionalization of 2-aryl-8-bromopyrido[3,4-b]pyrazines 6aa–ea. Reagents and conditions: (a) benzophenone imine, Pd2(dba)3,
BINAP, t-BuONa, toluene, 110 °C; (b) NH2OH·HCl, NaOAc, MeOH, 75 °C; (c) Na2CO3, MeOH, H2O, reflux; (d) 1) NaH, DMF, r.t., 2)
R4NCO, r.t.; (e) R4NCO, pyridine, reflux; (f) R4COCl, MeCN, reflux; (g) RNH2, Pd2(dba)3, BINAP, t-BuONa, toluene, 110 °C.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 69–82

72
M. Antoine et al.
PAPER
b]pyrazine (6ea) as previously observed for the prepara- kinases.17 Compounds were examined for their ability to
tion of ureas.
inhibit activation of mitogen-activated protein (MAP)
kinase pathway (cRaf-Erk, Erk). An assessment of other
kinases, which include receptor tyrosine kinases (KDR,
In an initial screening, 12a–k, 13a–c and 14a–q were test-
ed for inhibition of a panel of 8 cancer-related protein
Table 1 2,8-Disubstituted Pyrido[3,4-b]pyrazines 12a–k, 13a–c and 14a–q
Product
12a
12b
12c
12d
12e
12f
R1
R2
H
R3
R4
Yield (%)a,b
53
H
CONHR4
CONHR4
CONHR4
CONHR4
CONHR4
CONHR4
CONHR4
CONHR4
CONHR4
CONHR4
CONHR4
COR4
COR4
COR4
R4
Et
H
H
allyl
51
H
H
Ph
57
H
H
2-ClC6H4
58
H
H
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
3,5-(MeO)2C6H3
Ph
62
H
H
67
12g
12h
12i
H
H
66
H
H
62
OMe
H
55
12j
OMe
H
3-MeOC6H4
4-MeOC6H4
Me
64
12k
13a
13b
13c
14a
14b
14c
14d
14e
14f
OMe
H
67
H
H
66
H
H
Ph
71
H
H
4-MeOC6H4
3-BrC6H4
62
H
H
63
H
H
R4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
3-(ethynyl)C6H4
4-(piperidin-1-yl)C6H4
4-(morpholin-4-yl)C6H4
4-HOC6H4
52
H
H
R4
70
H
H
R4
67
H
H
R4
56
H
H
R4
55
14g
14h
14i
H
H
R4
56
H
H
R4
21
OMe
H
R4
3-BrC6H4
58
14j
OMe
H
R4
4-(piperidin-1-yl)C6H4
4-(morpholin-4-yl)C6H4
2,5-(MeO)2C6H3
3-MeOC6H4
4-(piperidin-1-yl)C6H4
4-(morpholin-4-yl)C6H4
Ph
68
14k
14l
OMe
H
R4
67
OMe
H
R4
72
14m
14n
14o
14p
14q
OMe
OMe
OMe
OMe
H
R4
77
OMe
R4
65
OMe
R4
65
piperidin-1-yl
piperidin-1-yl
R4
59
H
R4
3-MeOC6H4
54
a Reaction conditions: R4NCO, pyridine, reflux (for 12a–b); NaH, DMF, r.t., 30 min, then R4NCO, r.t. (for 12c–k); R4COCl, MeCN, reflux (for
13a–c); R4NH2, Pd2(dba)3, BINAP, t-BuONa, toluene, 110 °C (for 14a–q).
b Isolated yields.
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Synthesis of Novel 2,8-Disubstituted Pyrido[3,4-b]pyrazines
73
ic Elemental Analyzer Flash EA 1112 and were found within
0.4% of the theoretical values.
TrkA), nonreceptor tyrosine kinases (c-Abl, Yes), and
serine/threonine kinases (HIPK1, Pim1) was also per-
formed.
2-Phenyl-2-oxoethyl Methyl Sulfoxide (1a¢); Typical Procedure
A solution of NaH at 60% in mineral oil (2.00 g, 50.0 mmol) in
DMSO (30 mL) was heated at 70 °C for 1 h. The resulting solution
was cooled in an ice bath and ethyl benzoate (1a; 3.6 mL, 25.0
mmol) was added dropwise noting that the temperature did not in-
crease after each addition. The reaction mixture was stirred at r.t.
overnight and then quenched with H2O (40 mL). Concd HCl was
added to reach pH 1 and the aqueous layer was extracted with
CH2Cl2 (2 × 30 mL). The combined organic phases were dried
(Na2SO4) and the solvent was removed under reduced pressure to
give 1a¢ (2.73 g, 60%) as a yellow powder; mp 84–85 °C (Lit.11 mp
86–86.5 °C, Lit.12 mp 85–86 °C).
While ureas 12a–k and amides 13a–c failed to exhibit sig-
nificant kinase inhibition, results revealed that some de-
rivatives from 8-arylamino series 14a–q inhibit kinases in
micromolar concentration range. Most active compounds
were 14b, 14f, 14k, and 14l (IC50 values from 1.4 to 5.3
mM) bearing phenyl or 4-methoxyphenyl in position 2 of
pyrido[3,4-b]pyrazine ring and 2-methoxyaniline, 4-(pip-
eridin-1-yl)aniline, 4-(morpholin-4-yl)aniline, and 2,5-
dimethoxyaniline in position 8, respectively. These com-
pounds did not exhibit any selectivity towards the panel of
kinases. Compared to 14f (IC50 values from 2.0 to 2.6 IR (KBr): 3399, 1695, 1680, 1108, 960 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.09–7.96 (m, 1 H), 7.78–7.51
(m, 3 H), 4.72 (d, J = 14.9 Hz, 1 H), 4.63 (d, J = 14.9 Hz, 1 H), 2.74
(s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 193.7 (C), 136.3 (C), 134.2
(CH), 129.0 (CH), 128.9 (CH), 62.0 (CH2), 38.8 (CH3).
mM), introduction of an oxygen atom in the piperidine
ring (morpholine analogue 14g) was deleterious for the
activity. Shifting the position of methoxy group on 8-
anilino substituent from ortho (14b) to meta (14c) or para
(14d) led to loss of activity. Demethylated analogues 10f
of 14h remained inactive.
MS (ESI): m/z (%) = 183 [(M + H), 100].
Compound 14f was the only derivative that showed a be-
Anal. Calcd for C9H10O2S: C, 59.32; H, 5.53. Found: C, 59.41; H,
ginning of activity on MAP kinase pathway (IC50 = 2 mM 5.51.
for cRaf-Erk and Erk) and surprisingly, 4-methoxy ana-
2-(4-Methoxyphenyl)-2-oxoethyl Methyl Sulfoxide (1b¢)
logue 14j was inactive. In contrast, 4-(morpholin-4-
yl)aniline derivative 14k (IC50 values from 2.5 to 5.3 mM)
was more active than its unsubstituted counterpart 14g.
We attempted to invert the substituents in positions 2
and 8 of N-(4-piperidin-1-ylphenyl)-2-phenylpyrido[3,4-
b]pyrazin-8-amine (14f), but this chemical modification
produced only inactive compound 14p.
Compound 1b¢ was obtained as a white powder; yield: 3.71 g
(70%); mp 98–99 °C (Lit.11 mp 96 °C and 104–105 °C, Lit.12 mp
101–102 °C).
IR (KBr): 3429, 1684, 1599, 1265, 1168, 1102 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.04 (d, J = 8.8 Hz, 2 H), 7.12
(d, J = 8.8 Hz, 2 H), 4.63 (d, J = 14.6 Hz, 1 H), 4.56 (d, J = 14.6 Hz,
1 H), 3.90 (s, 3 H), 2.72 (s, 3 H).
In summary, many 2,8-disubstituted pyrido[3,4-b]pyra-
zines, with promising biological activity have been pre-
pared easily from our key intermediates, 2-aryl-8-
bromopyrido[3,4-b]pyrazines and 8-amino-2-arylpyri-
do[3,4-b]pyrazines. This synthetic approach enabled se-
lective introduction of a large variety of aryl groups in
position 2 of the scaffold and also introduction of various
chains in position 8 at the end of synthesis due to the pres-
ence of bromine atom and amine function.
13C NMR (100 MHz, DMSO-d6): d = 191.7 (C), 164.0 (C), 131.4
(CH), 129.3 (CH), 114.2 (CH), 61.7 (CH2), 55.8 (CH3), 38.8 (CH3).
MS (ESI): m/z (%) = 213 [(M + H), 100].
Anal. Calcd for C10H12O3S: C, 56.58; H, 5.70. Found: C, 56.64; H,
5.67.
2-Hydroxy-2-(methylsulfanyl)-1-phenylethanone (2a); Typical
Procedure
A solution of 1a¢ (1.00 g, 5.5 mmol) and concd HCl (2.1 mL) in a
mixture of H2O (16 mL) and DMSO (2.1 mL) was stirred at r.t. for
24 h. The reaction mixture was quenched with aq NaHCO3 (30 mL)
and extracted with CH2Cl2 (2 × 20 mL). The combined organic ex-
tracts were dried (Na2SO4) and the solvent was removed under re-
duced pressure to give the desired compound 2a (700 mg, 70%) as
a beige powder; mp 104–105 °C (Lit.12 mp 106–107 °C).
Our continued efforts to synthesize novel pyrido[3,4-
b]pyrazines with substituents in position 8 will be de-
scribed in future publications, in particular 3,8-disubsti-
tuted pyrido[3,4-b]pyrazine analogues of biological
interest.
IR (KBr): 3387, 1674, 1259, 1093, 1071 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.06 (d, J = 7.3 Hz, 2 H), 7.67
(t, J = 7.3 Hz, 1 H), 7.58–7.51 (m, 2 H), 6.51 (d, J = 8.1 Hz, 1 H),
6.40 (d, J = 8.1 Hz, 1 H), 1.98 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 192.8 (C), 167.3 (C), 133.3
(CH), 128.5 (CH), 128.4 (CH), 75.0 (CH), 10.2 (CH3).
All reactions were carried out under argon. All reactions were mon-
itored by TLC analysis using Merck silica gel 60F-254 thin-layer
plates. Column chromatography was carried out on silica gel Merck
60 (70–230 mesh ASTM). Melting points were determined on a
Electrothermal IA 9000 melting point apparatus and are uncorrect-
ed. IR spectra were recorded on a Paragon 1000 PC PerkinElmer
spectrometer. 1H and 13C NMR spectra were performed in DMSO-
d6 using a Bruker Avance 400 MHz spectrometer. Chemical shifts
are reported as d values relative to TMS as internal standard and
coupling constants (J) are given in hertz (Hz). Standard abbrevia-
tions are used to describe peak patterns. Mass spectra were recorded
using an electrospray ionization method with Waters ZQ 2000 spec-
trometer. Elemental analyses were performed on a Thermo Scientif-
MS (ESI): m/z (%) = 183 [(M + H), 100].
Anal. Calcd for C9H10O2S: C, 59.32; H, 5.53. Found: C, 59.28; H,
5.54.
2-Hydroxy-1-(4-methoxyphenyl)-2-(methylsulfanyl)ethanone
(2b)
Compound 2b was obtained as a beige powder; yield: 875 mg
(75%); mp 91–93 °C (Lit.12 mp 92–94 °C).
© Thieme Stuttgart · New York
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74
M. Antoine et al.
PAPER
IR (KBr): 3387, 1668, 1599, 1262, 1168, 1068, 969 cm–1.
13C NMR (100 MHz, DMSO-d6): d = 192.2 (C), 154.4 (C), 129.7
(CH), 126.3 (C), 114.2 (CH), 90.7 (CH), 52.4 (CH2), 25.9 (CH2),
25.5 (CH2).
1H NMR (400 MHz, DMSO-d6): d = 8.05 (d, J = 8.9 Hz, 2 H), 7.07
(d, J = 8.9 Hz, 2 H), 6.36 (d, J = 8.5 Hz, 1 H), 6.33 (d, J = 8.5 Hz, 1
H), 3.88 (s, 3 H), 1.98 (s, 3 H).
MS (ESI): m/z (%) = 236 [(M + H), 100].
13C NMR (100 MHz, DMSO-d6): d = 193.3 (C), 164.9 (C), 132.5
(CH), 127.9 (C), 115.4 (CH), 76.5 (CH), 57.1 (CH3), 12.0 (CH3).
Anal. Calcd for C13H17NO3: C, 66.36; H, 7.28; N, 5.95. Found: C,
66.45; H, 7.19; N, 5.93.
MS (ESI): m/z (%) = 213 [(M + H), 100].
2,2-Dihydroxy-1-(4-hydroxyphenyl)ethanone (5e)
Yellow powder; yield: 5.71 g (85%); mp 64–65 °C; Rf = 0.52
(CH2Cl2–EtOH, 9:1).
Anal. Calcd for C10H12O3S: C, 56.58; H, 5.70. Found: C, 56.61; H,
5.68.
1H NMR (400 MHz, DMSO-d6): d = 10.44 (br s, 1 H), 7.98 (d,
J = 8.9 Hz, 2 H), 6.88 (d, J = 8.9 Hz, 2 H), 6.58 (d, J = 7.5 Hz, 2 H),
5.66 (t, J = 7.1 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 192.5 (C), 162.9 (C), 130.2
(CH), 129.4 (C), 115.8 (CH), 90.4 (CH).
2,2-Dihydroxy-1-phenylethanone (5a); Typical Procedure
To a solution of SeO2 (9.23 g, 83.2 mmol) in a mixture of 1,4-diox-
ane (42 mL) and H2O (2 mL) was added acetophenone (4a; 10.00 g,
83.2 mmol). The reaction mixture was heated at reflux for 2 h and
after cooling to r.t., filtered on Celite. The solvent was removed un-
der reduced pressure, the residue was dissolved in H2O (200 mL),
and heated at reflux for 5 h. The resulting solution was cooled in an
ice bath to give a white precipitate, which was collected by filtration
and air-dried to give 5a (9.87 g, 78%) as a beige powder; mp 74–
76 °C (Lit.15 mp 70–74 °C); Rf = 0.69 (CH2Cl2–EtOH, 9:1).
1H NMR (400 MHz, DMSO-d6): d = 8.10 (dd, J = 8.2, 1.2 Hz, 2 H),
7.69–7.65 (m, 1 H), 7.56 (d, J = 8.2 Hz, 2 H), 6.80 (d, J = 7.2 Hz, 2
H), 5.73 (t, J = 7.2 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 196.1 (C), 133.6 (C), 133.2
(CH), 129.3 (CH), 128.4 (CH), 89.1 (CH).
MS (ESI): m/z (%) = 169 [(M + H), 100].
Anal. Calcd for C8H8O4: C, 57.14; H, 4.80. Found: C, 56.99; H,
4.84.
8-Bromo-2-phenylpyrido[3,4-b]pyrazine (6aa); Typical Proce-
dures
Method 1¢ (b-Oxosulfoxide, AcOH, Benzene): A mixture of 3,4-di-
amino-5-bromopyridine (3; 111 mg, 0.6 mmol) and 2-phenyl-2-
oxoethyl methyl sulfoxide (1a¢; 108 mg, 0.6 mmol) in benzene (5
mL) containing few drops of AcOH was refluxed for 8 h. After re-
moval of the solvent, the residue was made basic by addition of am-
monia and the aqueous layer was extracted with CH2Cl2 (2 × 20
mL). The combined organic layers were dried (Na2SO4), filtered,
and the solvent was removed under reduced pressure to give 6aa ad-
mixed with 8-bromo-3-phenylpyrido[3,4-b]pyrazine (6ab) (7:3
NMR ratio in 55% yield).
MS (ESI): m/z (%) = 153 [(M + H), 100].
Anal. Calcd for C8H8O3: C, 63.15; H, 5.30. Found: C, 63.03; H,
5.33.
2,2-Dihydroxy-1-(4-methoxyphenyl)ethanone (5b)
White powder; yield: 4.37 g (60%); mp 112–114 °C (Lit.15 mp 110–
114 °C); Rf = 0.66 (CH2Cl2–EtOH, 9:1).
1H NMR (400 MHz, DMSO-d6): d = 8.09 (d, J = 7.5 Hz, 2 H), 7.08
(d, J = 7.5 Hz, 2 H), 6.67 (d, J = 7.3 Hz, 2 H), 5.68 (t, J = 7.3 Hz, 1
H), 3.88 (s, 3 H).
Method 1 (Hemithioacetal, NaOAc, AcOH): To a solution of 3,4-di-
amino-5-bromopyridine (3; 200 mg, 1.1 mmol) in glacial AcOH (6
mL) was added successively NaOAc (194 mg, 1.1 mmol) and 2-hy-
droxy-2-(methylsulfanyl)-1-phenylethanone (2a; 194 mg, 1.1
mmol). The reaction mixture was stirred at r.t. for 30 minutes, then
heated at reflux for 4 h (methylmercaptan formed was trapped in a
solution of NaOH). The solution was cooled in an ice bath, the pre-
cipitate was collected by filtration and washed with i-Pr2O (5 mL)
to afford 6aa (164 mg, 52%) as a beige powder.
13C NMR (100 MHz, DMSO-d6): d = 192.0 (C), 163.4 (C), 131.8
(CH), 126.1 (C), 114.1 (CH), 90.6 (CH), 55.5 (CH3).
MS (ESI): m/z (%) = 183 [(M + H), 100].
Anal. Calcd for C9H10O4: C, 59.34; H, 5.53. Found: C, 59.48; H,
5.48.
Method 2 (Phenylglyoxal Monohydrate, 1,4-Dioxane): A mixture of
3,4-diamino-5-bromopyridine (3; 200 mg, 1.1 mmol) and 2,2-dihy-
droxy-1-phenylethanone (5a; 167 mg, 1.1 mmol) in 1,4-dioxane (10
mL) was heated at reflux for 6 h. The reaction mixture was cooled
to r.t., and poured into H2O (10 mL). The aqueous layer was extract-
ed with CH2Cl2 (2 × 20 mL), the combined organic layers were
dried (Na2SO4) and the solvent was removed under reduced pres-
sure. The residue was triturated with i-Pr2O (5 mL) and then filtered
to give 6aa (264 mg, 84%) as a beige powder.
2,2-Dihydroxy-1-(3,4-dimethoxyphenyl)ethanone (5c)
Red oil; yield: 5.43 g (64%); Rf = 0.67 (CH2Cl2–EtOH, 9:1).
1H NMR (400 MHz, DMSO-d6): d = 7.81 (dd, J = 8.6, 2.0 Hz, 1 H),
7.58 (d, J = 1.9 Hz, 1 H), 7.10 (d, J = 8.6 Hz, 1 H), 5.72 (br s, 1 H),
3.88 (s, 3 H), 3.84 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 192.5 (C), 154.2 (C), 149.7
(C), 130.1 (C), 122.1 (CH), 115.2 (CH), 114.0 (CH), 90.8 (CH),
56.5 (CH3), 56.3 (CH3).
Method 3 (Br2, KOAc, AcOH): A mixture of 2-phenylpyrido[3,4-
b]pyrazine (8aa; 400 mg, 1.9 mmol) and KOAc (190 mg, 1.9 mmol)
in glacial AcOH (10 mL) was stirred at r.t. for 1 h and then Br2 (100
mL, 1.9 mmol) was added dropwise. The resulting mixture was
stirred at r.t. for 5 h. The reaction was quenched with H2O (10 mL)
and the aqueous layer was extracted with CH2Cl2 (2 × 20 mL). The
combined organic layers were dried (Na2SO4) and the solvent was
removed under reduced pressure. The crude product was purified by
column chromatography on silica gel, eluting with CH2Cl2 to give
6aa (408 mg, 75%) as a beige powder; mp 142–143 °C; Rf = 0.66
(CH2Cl2–EtOH, 9:1).
MS (ESI): m/z (%) = 213 [(M + H), 100].
Anal. Calcd for C10H12O5: C, 56.60; H, 5.70. Found: C, 56.67; H,
5.69.
2,2-Dihydroxy-1-[4-(piperidin-1-yl)phenyl]ethanone (5d)
Red oil; yield: 5.64 g (60%); Rf = 0.66 (CH2Cl2–EtOH, 9:1).
1H NMR (400 MHz, DMSO-d6): d = 7.98–7.91 (m, 2 H), 7.04–6.92
(m, 2 H), 5.96 (br s, 2 H), 5.66 (br s, 1 H), 3.45–3.41, 1.63–1.60 (m,
10 H).
IR (KBr): 3411, 1557, 1307, 1183, 972, 770, 686 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.87 (s, 1 H), 9.51 (s, 1 H), 9.16
(s, 1 H), 8.52–8.50 (m, 2 H), 7.73–7.70 (m, 3 H).
Synthesis 2012, 44, 69–82
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Synthesis of Novel 2,8-Disubstituted Pyrido[3,4-b]pyrazines
75
13C NMR (100 MHz, DMSO-d6): d = 154.5 (C), 152.2 (CH), 147.9
(CH), 145.8 (CH), 141.1 (C), 136.4 (C), 134.0 (C), 131.0 (CH),
128.5 (CH), 127.4 (CH), 118.9 (C).
1H NMR (400 MHz, DMSO-d6): d = 9.85 (s, 1 H), 9.40 (s, 1 H), 9.00
(s, 1 H), 8.31 (d, J = 8.9 Hz, 2 H), 7.15 (d, J = 8.9 Hz, 2 H), 3.45–
3.43, 1.66–1.64 (m, 10 H).
MS (ESI): m/z (%) = 286 [(M + H), 100], 288 [(M + H) + 2, 100].
13C NMR (100 MHz, DMSO-d6): d = 152.9 (C), 149.6 (C), 148.9
(CH), 148.1 (CH), 144.7 (CH), 141.8 (C), 139.3 (C), 128.4 (CH),
122.7 (C), 121.0 (C), 114.8 (CH), 52.4 (CH2), 25.9 (CH2), 25.5
(CH2).
Anal. Calcd for C13H8BrN3: C, 54.57; H, 2.82; N, 14.69. Found: C,
54.59; H, 2.85; N, 14.67.
8-Bromo-2-(4-methoxyphenyl)pyrido[3,4-b]pyrazine (6ba)
Beige powder; yield: 191 mg (55%, method 1); yield: 320 mg (92%,
method 2); mp 168–169 °C; Rf = 0.68 (CH2Cl2–EtOH, 9:1).
IR (KBr): 3044, 1551, 1312, 975 cm–1.
MS (ESI): m/z (%) = 369 [(M + H), 100], 371 [(M + H) + 2, 100].
Anal. Calcd for C18H17BrN4: C, 58.55; H, 4.64; N, 15.17. Found: C,
58.64; H, 4.66; N, 15.12.
8-Bromo-2-(4-hydroxyphenyl)pyrido[3,4-b]pyrazine (6ea)
Brown powder; yield: 282 mg (85%, method 2); mp 221–223 °C;
Rf = 0.69 (CH2Cl2–EtOH, 9:1).
IR (KBr): 3363, 1557, 1533, 1307, 1280, 1246, 1168, 1114 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.77 (s, 1 H), 9.43 (s, 1 H), 9.10
(s, 1 H), 8.43 (d, J = 8.9 Hz, 2 H), 7.07 (d, J = 8.9 Hz, 2 H).
1H NMR (400 MHz, DMSO-d6): d = 9.81 (s, 1 H), 9.44 (s, 1 H), 9.11
(s, 1 H), 8.52 (d, J = 9.2 Hz, 2 H), 7.25 (d, J = 9.2 Hz, 2 H), 3.93 (s,
3 H).
13C NMR (100 MHz, DMSO-d6): d = 162.1 (C), 154.5 (C), 152.4
(CH), 148.2 (CH), 145.9 (CH), 141.7 (C), 136.5 (C), 129.7 (CH),
126.7 (C), 119.1 (C), 114.5 (CH), 55.1 (CH3).
MS (ESI): m/z (%) = 316 [(M + H), 100], 318 [(M + H) + 2, 100].
13C NMR (100 MHz, DMSO-d6): d = 161.5 (C), 155.2 (C), 152.6
(CH), 148.6 (CH), 146.2 (CH), 142.1 (C), 136.8 (C), 130.3 (CH),
125.5 (C), 119.4 (C), 116.2 (CH).
Anal. Calcd for C14H10BrN3O: C, 53.19; H, 3.19; N, 13.29. Found:
C, 53.16; H, 3.17; N, 13.31.
MS (ESI): m/z (%) = 302 [(M + H), 100], 304 [(M + H) + 2, 100].
8-Bromo-2-(3,4-dimethoxyphenyl)pyrido[3,4-b]pyrazine (6ca)
Yellow powder; yield: 274 mg (72%, method 2); mp 172–173 °C;
Rf = 0.59 (CH2Cl2–EtOH, 9:1).
Anal. Calcd for C13H8BrN3O: C, 51.68; H, 2.67; N, 13.91. Found:
C, 51.75; H, 2.69; N, 13.88.
IR (KBr): 3047, 1554, 1309, 982 cm–1.
2-Phenylpyrido[3,4-b]pyrazine (8aa)
Compound 8aa was obtained by the reaction of 3,4-diaminopyri-
dine (7) with 2,2-dihydroxy-1-phenylethanone (5a) following the
procedure described for 6aa; white powder; yield: 189 mg (83%,
method 2); mp 123–124 °C (Lit.6 mp 125–126 °C); Rf = 0.52
(CH2Cl2–EtOH, 9:1).
1H NMR (400 MHz, DMSO-d6): d = 9.86 (s, 1 H), 9.44 (s, 1 H), 9.11
(s, 1 H), 8.18 (dd, J = 8.5, 1.8 Hz, 1 H), 8.09 (d, J = 1.8 Hz, 1 H),
7.27 (d, J = 8.5 Hz, 1 H), 3.97 (s, 3 H), 3.93 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 155.0 (C), 152.8 (CH), 152.4
(C), 149.3 (C), 148.6 (CH), 146.4 (CH), 142.0 (C), 137.0 (C), 127.2
(C), 122.2 (CH), 119.5 (C), 112.0 (CH), 110.8 (CH), 55.8 (CH3),
55.7 (CH3).
IR (KBr): 3417, 1557, 1542, 1439, 1394, 1313, 1232, 957, 680
cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.78 (s, 1 H), 9.54 (d, J = 0.6
Hz, 1 H), 8.89 (d, J = 5.8 Hz, 1 H), 8.46–8.41 (m, 2 H), 8.08 (dd,
J = 5.8, 0.6 Hz, 1 H), 7.69–7.66 (m, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 155.3 (C), 153.3 (CH), 147.0
(CH), 146.1 (CH), 144.3 (C), 135.2 (C), 131.5 (CH), 129.2 (CH),
128.2 (CH), 121.9 (CH).
MS (ESI): m/z (%) = 346 [(M + H), 100], 348 [(M + H) + 2, 100].
Anal. Calcd for C15H12BrN3O2: C, 52.04; H, 3.49; N, 12.14. Found:
C, 51.91; H, 3.51; N, 12.15.
8-Bromo-2-[4-(piperidin-1-yl)phenyl]pyrido[3,4-b]pyrazine
(6da)
Red powder; yield: 252 mg (62%, method 2); mp 176–178 °C;
Rf = 0.48 (CH2Cl2–EtOH, 9:1).
MS (ESI): m/z (%) = 208 [(M + H), 100].
Anal. Calcd for C13H9N3: C, 75.35; H, 4.38; N, 20.28. Found: C,
75.11; H, 4.41; N, 20.48.
IR (KBr): 2929, 1608, 1551, 1521, 1349, 1244, 1199, 1180, 1120,
972, 818 cm–1.
N-(2-Phenylpyrido[3,4-b]pyrazin-8-yl)benzophenone Imine
(9a); Typical Procedure
1H NMR (400 MHz, DMSO-d6): d = 9.73 (s, 1 H), 9.35 (s, 1 H), 9.04
(s, 1 H), 8.40 (d, J = 8.9 Hz, 2 H), 7.17 (d, J = 8.9 Hz, 2 H), 3.45–
3.43, 1.66–1.64 (m, 10 H).
13C NMR (100 MHz, DMSO-d6): d = 155.0 (C), 153.3 (C), 152.4
(CH), 148.5 (CH), 146.2 (CH), 142.4 (C), 136.6 (C), 129.8 (CH),
122.6 (C), 119.2 (C), 114.1 (CH), 47.8 (CH2), 24.9 (CH2), 24.0
(CH2).
To a solution of 8-bromo-2-phenylpyrido[3,4-b]pyrazine (6aa; 944
mg, 3.3 mmol) in toluene (40 mL) under argon was added succes-
sively benzophenone imine (667 mL, 4.0 mmol), Pd2(dba)3 (10 mg,
2.5·10–5 mol), BINAP (4 mg, 8.3·10–6 mol), and t-BuONa (446 mg,
4.6 mmol). The reaction mixture was heated at 100 °C for 12 h,
cooled to r.t., and then EtOAc (60 mL) was added. The mixture was
washed with H2O (40 mL) and extracted with EtOAc (2 × 30 mL).
The combined organic layers were dried (Na2SO4) and the solvents
were removed under reduced pressure. The crude product was puri-
fied by column chromatography on silica gel eluting with CH2Cl2–
EtOH mixtures (from 10:0 to 9:1) to give the title compound 9a
(893 mg, 70%) as a yellow powder; mp 179–180 °C; Rf = 0.63
(CH2Cl2–EtOH, 9:1).
MS (ESI): m/z (%) = 369 [(M + H), 100], 371 [(M + H) + 2, 100].
Anal. Calcd for C18H17BrN4: C, 58.55; H, 4.64; N, 15.17. Found: C,
58.61; H, 4.67; N, 15.11.
8-Bromo-3-[4-(piperidin-1-yl)phenyl]pyrido[3,4-b]pyrazine
(6db)
Red powder; yield: 65 mg (16%, method 2); mp 201–203 °C;
Rf = 0.66 (CH2Cl2–EtOH, 9:1).
IR (KBr): 3026, 1563, 1512, 1425, 1293, 1255, 1134, 1010, 954
cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.69 (s, 1 H), 9.10 (s, 1 H), 8.33
(s, 1 H), 7.90–7.20 (m, 15 H).
IR (KBr): 2926, 1550, 1523, 1342, 1237, 1100, 952 cm–1.
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76
M. Antoine et al.
PAPER
13C NMR (100 MHz, DMSO-d6): d = 171.3 (C), 153.7 (C), 147.9
(CH), 145.7 (CH), 143.5 (C), 137.4 (CH), 136.2 (C), 136.1 (C),
135.5 (C), 132.2 (CH), 131.8 (CH), 131.5 (CH), 129.5 (CH), 129.2
(CH), 128.9 (CH), 128.3 (CH), 128.2 (CH), 128.1 (CH), 128.0
(CH).
Anal. Calcd for C31H27N5: C, 79.29; H, 5.80; N, 14.91. Found: C,
79.34; H, 5.81; N, 14.85.
8-Amino-2-phenylpyrido[3,4-b]pyrazine (10a); Typical Proce-
dure
Method 4: To a solution of N-(2-phenylpyrido[3,4-b]pyrazin-8-
yl)benzophenone imine (9a; 155 mg, 0.4 mmol) in MeOH (5 mL)
was added NaOAc (85 mg, 1.04 mmol) and hydroxylamine hydro-
chloride (54 mg, 0.8 mmol). The reaction mixture was stirred at
75 °C for 48 h and then cooled to r.t. The solution was poured into
aq NaOH (5%, 5 mL) and extracted with CH2Cl2 (2 × 20 mL). The
combined organic layers were dried (Na2SO4) and the solvent re-
moved under reduced pressure to give 10a (88.9 mg, ~100%) as a
brown powder.
MS (ESI): m/z (%) = 387 [(M + H), 100].
Anal. Calcd for C26H18N4: C, 80.81; H, 4.69; N, 14.50. Found: C,
80.89; H, 4.68; N, 14.43.
N-[2-(4-Methoxyphenyl)pyrido[3,4-b]pyrazin-8-yl]benzophe-
none Imine (9b)
Yellow powder; yield: 851 mg (62%); mp 77–78 °C; Rf = 0.62
(CH2Cl2–EtOH, 9:1).
IR (KBr): 3021, 1553, 1532, 1434, 1285, 1245, 1152, 1023, 972
cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.65 (s, 1 H), 9.04 (s, 1 H), 8.33
(d, J = 8.9 Hz, 2 H), 8.31 (s, 1 H), 7.84–7.17 (m, 12 H), 3.88 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 171.0 (C), 161.9 (C), 152.9
(C), 147.4 (CH), 145.0 (CH), 143.0 (C), 138.0 (C), 137.1 (CH),
135.8 (C), 135.5 (C), 131.5 (CH), 129.4 (CH), 129.1 (CH), 128.8
(C), 128.5 (CH), 128.0 (CH), 127.8 (CH), 127.5 (C), 114.7 (CH),
55.4 (CH3).
Method 5: To a solution of 3,4,5-triaminopyridine (11; 500 mg, 3.2
mmol) in H2O (6 mL) was added NaHCO3 (338 mg, 3.2 mmol) and
a solution of 2,2-dihydroxy-1-phenylethanone (5a; 485 mg, 3.2
mmol) in 1,4-dioxane (3 mL). The reaction mixture was refluxed
for 6 h. After cooling to r.t., CH2Cl2 (10 mL) was added. The aque-
ous layer was extracted with CH2Cl2 (2 × 15 mL) and the combined
organic extracts were dried (Na2SO4). The solvent was removed un-
der reduced pressure to yield the title compound 10a (384 mg, 54%)
as a brown powder; mp 172–173 °C; Rf = 0.39 (CH2Cl2–EtOH,
9:1).
MS (ESI): m/z (%) = 417 [(M + H), 100].
IR (KBr): 3415, 1608, 1518, 1447, 1312, 1265, 1122, 1017 cm–1.
Anal. Calcd for C27H20N4O: C, 77.87; H, 4.84; N, 13.45. Found: C,
77.78; H, 4.87; N, 13.49.
1H NMR (400 MHz, DMSO-d6): d = 9.70 (s, 1 H), 8.64 (s, 1 H),
8.58–8.53 (m, 2 H), 8.21 (s, 1 H), 7.66–7.63 (m, 3 H), 6.41 (br s, 2
H).
N-[2-(3,4-Dimethoxyphenyl)pyrido[3,4-b]pyrazin-8-yl]ben-
zophenone Imine (9c)
Yellow powder; yield: 1.30 g (88%); mp 81–83 °C; Rf = 0.64
13C NMR (100 MHz, DMSO-d6): d = 151.0 (C), 145.0 (CH), 140.6
(C), 138.0 (CH), 136.1 (C), 135.4 (C), 133.1 (CH), 132.7 (C), 130.8
(CH), 129.4 (CH), 129.0 (CH), 128.6 (CH), 127.8 (CH), 127.7
(CH).
(CH2Cl2–EtOH, 9:1).
IR (KBr): 3411, 1557, 1518, 1454, 1283, 1265, 1238, 1144, 1018,
978 cm–1.
MS (ESI): m/z (%) = 223 [(M + H), 100].
1H NMR (400 MHz, DMSO-d6): d = 9.67 (s, 1 H), 9.04 (s, 1 H), 8.45
(s, 1 H), 8.02 (dd, J = 8.6, 2.1 Hz, 1 H), 7.94 (d, J = 2.1 Hz, 1 H),
7.87–7.17 (m, 11 H), 3.88 (s, 3 H), 3.67 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 152.6 (C), 151.8 (C), 149.1
(C), 147.2 (CH), 144.9 (CH), 143.1 (C), 138.2 (C), 137.5 (CH),
136.3 (C), 135.6 (C), 135.1 (C), 132.7 (CH), 131.5 (CH), 129.6
(CH), 129.2 (CH), 128.9 (CH), 128.5 (CH), 128.2 (CH), 127.8
(CH), 127.5 (C), 121.3 (C), 111.9 (CH), 110.0 (CH), 55.7 (CH3),
55.0 (CH3).
Anal. Calcd for C13H10N4: C, 70.26; H, 4.54; N, 25.21. Found: C,
70.12; H, 4.59; N, 25.29.
8-Amino-2-(4-methoxyphenyl)pyrido[3,4-b]pyrazine (10b)
Orange powder; yield: 96.8 mg (96%, method 4); mp 178–179 °C;
Rf = 0.36 (CH2Cl2–EtOH, 9:1).
IR (KBr): 3425, 1619, 1528, 1443, 1322, 1275, 1131, 1019 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.64 (s, 1 H), 8.60 (s, 1 H), 8.53
(d, J = 8.9 Hz, 2 H), 8.18 (s, 1 H), 7.17 (d, J = 8.9 Hz, 2 H), 6.34 (br
s, 2 H), 3.92 (s, 3 H).
MS (ESI): m/z (%) = 447 [(M + H), 100].
13C NMR (100 MHz, DMSO-d6): d = 161.6 (C), 150.8 (C), 144.7
(CH), 140.4 (C), 138.1 (CH), 135.7 (C), 132.8 (C), 129.4 (CH),
129.3 (CH), 127.9 (C), 114.4 (CH), 55.4 (CH3).
Anal. Calcd for C28H22N4O2: C, 75.32; H, 4.97; N, 12.55. Found: C,
75.41; H, 4.96; N, 12.52.
N-{2-[4-(Piperidin-1-yl)phenyl]pyrido[3,4-b]pyrazin-8-yl}ben-
zophenone Imine (9d)
Yellow powder; yield: 960 mg (62%); mp 87–88 °C; Rf = 0.67
(CH2Cl2–EtOH, 9:1).
MS (ESI): m/z (%) = 253 [(M + H), 100].
Anal. Calcd for C14H12N4O: C, 66.65; H, 4.79; N, 22.21. Found: C,
66.72; H, 4.76; N, 22.23.
IR (KBr): 3417, 2922, 1602, 1560, 1527, 1436, 1234, 1183, 1123,
698 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.56 (s, 1 H), 8.95 (s, 1 H), 8.25
(s, 1 H), 8.20 (d, J = 8.9 Hz, 2 H), 7.83–7.18 (m, 10 H), 7.08 (d,
J = 8.9 Hz, 2 H), 3.45–3.43, 1.66–1.64 (m, 10 H).
8-Amino-2-(3,4-dimethoxyphenyl)pyrido[3,4-b]pyrazine (10c)
Yellow powder; yield: 100 mg (89%, method 4); mp 182–184 °C;
Rf = 0.44 (CH2Cl2–EtOH, 9:1).
IR (KBr): 3435, 1611, 1539, 1518, 1454, 1334, 1286, 1265, 1132,
1015 cm–1.
13C NMR (100 MHz, DMSO-d6): d = 170.8 (C), 153.1 (C), 152.8
(C), 147.2 (CH), 144.9 (CH), 142.9 (C), 138.2 (C), 137.0 (CH),
136.2 (C), 136.1 (C), 135.3 (C), 131.5 (CH), 129.1 (CH), 129.0
(CH), 128.8 (CH), 128.6 (CH), 128.0 (CH), 127.8 (CH), 123.2 (C),
114.3 (CH), 47.8 (CH2), 24.8 (CH2), 24.0 (CH2).
1H NMR (400 MHz, DMSO-d6): d = 9.68 (s, 1 H), 8.60 (s, 1 H), 8.18
(s, 1 H), 8.14–8.11 (m, 2 H), 7.17 (d, J = 8.9 Hz, 1 H), 6.39 (br s, 2
H), 3.99 (s, 3 H), 3.91 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 151.5 (C), 151.0 (C), 149.3
(C), 145.0 (CH), 140.5 (C), 138.1 (CH), 135.8 (C), 132.8 (C), 129.4
(CH), 128.1 (C), 121.2 (CH), 111.7 (CH), 110.7 (CH), 55.9 (CH3),
55.7 (CH3).
MS (ESI): m/z (%) = 470 [(M + H), 100].
Synthesis 2012, 44, 69–82
© Thieme Stuttgart · New York

PAPER
Synthesis of Novel 2,8-Disubstituted Pyrido[3,4-b]pyrazines
77
MS (ESI): m/z (%) = 283 [(M + H), 100].
1H NMR (400 MHz, DMSO-d6): d = 9.83 (s, 1 H), 9.66 (s, 1 H), 9.16
(s, 1 H), 9.08 (br s, 1 H), 8.66–8.62 (m, 2 H), 7.83 (t, J = 5.8 Hz, 1
H), 7.73–7.69 (m, 3 H), 6.04–5.93 (m, 1 H), 5.35–5.16 (m, 2 H),
3.92–3.87 (m, 2 H).
Anal. Calcd for C15H14N4O2: C, 63.82; H, 5.00; N, 19.85. Found: C,
63.89; H, 4.98; N, 19.82.
8-Amino-2-[4-(piperidin-1-yl)phenyl]pyrido[3,4-b]pyrazine
(10d)
Orange powder; yield: 65.9 mg (54%, method 4); mp 187–189 °C;
Rf = 0.38 (CH2Cl2–EtOH, 9:1).
13C NMR (100 MHz, DMSO-d6): d = 154.6 (C), 152.7 (C), 145.8
(CH), 144.3 (CH), 136.0 (CH), 135.7 (C), 135.2 (C), 134.0 (C),
133.9 (CH), 132.1 (C), 131.7 (CH), 129.3 (CH), 128.5 (CH), 115.5
(CH2), 41.7 (CH2).
IR (KBr): 3423, 1602, 1533, 1241, 1189, 1120 cm–1.
MS (ESI): m/z (%) = 306 [(M + H), 100].
1H NMR (400 MHz, DMSO-d6): d = 9.58 (s, 1 H), 8.56 (s, 1 H), 8.39
(d, J = 9.0 Hz, 2 H), 8.14 (s, 1 H), 7.10 (d, J = 9.0 Hz, 2 H), 6.23 (br
s, 2 H), 3.38–3.36, 1.64–1.63 (m, 10 H).
Anal. Calcd for C17H15N5O: C, 66.87; H, 4.95; N, 22.94. Found: C,
66.94; H, 4.99; N, 22.87.
N-Phenyl-N¢-(2-phenylpyrido[3,4-b]pyrazin-8-yl)urea (12c);
Typical Procedure
13C NMR (100 MHz, DMSO-d6): d = 152.8 (C), 151.2 (C), 144.7
(CH), 140.2 (C), 138.2 (CH), 135.5 (C), 133.1 (C), 129.3 (CH),
129.0 (CH), 124.0 (C), 114.4 (CH), 48.1 (CH2), 24.9 (CH2), 24.0
(CH2).
To a solution of 8-amino-2-phenylpyrido[3,4-b]pyrazine (10a; 200
mg, 0.9 mmol) in DMF (10 mL) was added portionwise NaH (60%
in mineral oil, 43 mg, 1.1 mmol). The reaction mixture was stirred
at r.t. for 30 min and phenyl isocyanate (98 mL, 0.9 mmol) was add-
ed. The reaction mixture was stirred for 3 h at r.t. and then quenched
with H2O (10 mL). The aqueous layer was extracted with CH2Cl2
(2 × 20 mL), the combined organic extracts were dried (Na2SO4),
and the solvent was removed under reduced pressure to give 12c
(175 mg, 57%) as an orange powder; mp 214–215 °C; Rf = 0.62
(CH2Cl2–EtOH, 9:1).
MS (ESI): m/z (%) = 306 [(M + H), 100].
Anal. Calcd for C18H19N5: C, 70.80; H, 6.27; N, 22.93. Found: C,
70.87; H, 6.26; N, 22.87.
8-Amino-2-(4-hydroxyphenyl)pyrido[3,4-b]pyrazine (10e)
Orange powder; yield: 670 mg (88%, method 5); mp >250 °C;
Rf = 0.31 (CH2Cl2–EtOH, 9:1).
IR (KBr): 3405, 3299, 1525, 1452, 1312, 1264, 1121, 1022 cm–1.
IR (KBr): 3263, 1669, 1542, 1513, 1409, 1312, 1211 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 10.01 (br s, 1 H), 9.85 (s, 1 H),
9.71 (s, 1 H), 9.41 (br s, 1 H), 9.15 (s, 1 H), 8.66–8.62 (m, 2 H),
7.76–7.71 (m, 3 H), 7.62 (dd, J = 8.6, 1.2 Hz, 2 H), 7.39 (m, 2 H),
7.10 (t, J = 7.5 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 152.8 (C), 151.9 (C), 145.8
(CH), 144.8 (CH), 139.2 (C), 135.4 (C), 135.0 (C), 134.1 (C), 134.0
(CH), 131.5 (CH), 131.3 (C), 129.2 (CH), 128.9 (CH), 128.3 (CH),
122.3 (CH), 118.4 (CH).
1H NMR (400 MHz, DMSO-d6): d = 9.87 (s, 1 H), 8.89 (s, 1 H), 8.58
(d, J = 8.9 Hz, 2 H), 8.05 (s, 1 H), 7.05 (d, J = 8.9 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 158.5 (C), 152.9 (C), 145.3
(C), 145.1 (C), 144.2 (CH), 139.0 (CH), 137.6 (CH), 136.0 (C),
128.9 (CH), 125.7 (C), 116.4 (CH).
MS (ESI): m/z (%) = 239 [(M + H), 100].
Anal. Calcd for C13H10N4O: C, 65.54; H, 4.23; N, 23.52. Found: C,
65.43; H, 4.27; N, 23.56.
MS (ESI): m/z (%) = 342 [(M + H), 100].
Anal. Calcd for C20H15N5O: C, 70.37; H, 4.43; N, 20.52. Found: C,
70.45; H, 4.42; N, 20.47.
N-Ethyl-N¢-(2-phenylpyrido[3,4-b]pyrazin-8-yl)urea (12a);
Typical Procedure
To a solution of 8-amino-2-phenylpyrido[3,4-b]pyrazine (10a; 200
mg, 0.9 mmol) in pyridine (8 mL) was added ethyl isocyanate (71
mL, 0.9 mmol) and the reaction mixture was heated at reflux over-
night. Pyridine was removed under reduced pressure and the crude
product was purified by column chromatography on silica gel elut-
ing with CH2Cl2–EtOH mixtures (from 10:0 to 9:1) to yield 12a
(140 mg, 53%) as a yellow powder; mp 176–177 °C; Rf = 0.62
(CH2Cl2–EtOH, 9:1).
N-(3-Chlorophenyl)-N¢-(2-phenylpyrido[3,4-b]pyrazin-8-
yl)urea (12d)
Yellow powder; yield: 198 mg (58%); mp 245–246 °C; Rf = 0.65
(CH2Cl2–EtOH, 9:1).
IR (KBr): 3275, 1667, 1542, 1534, 1412, 1314, 1211 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 10.21 (br s, 1 H), 9.85 (s, 1 H),
9.69 (s, 1 H), 9.44 (br s, 1 H), 9.17 (s, 1 H), 8.64–8.62 (m, 2 H), 7.88
(s, 1 H), 7.74–7.71 (m, 3 H), 7.40–7.39 (m, 2 H), 7.13–7.12 (m, 1
H).
13C NMR (100 MHz, DMSO-d6): d = 152.8 (C), 151.8 (C), 145.9
(CH), 145.1 (CH), 140.7 (C), 135.4 (C), 134.9 (C), 134.2 (CH),
133.3 (C), 131.5 (CH), 131.0 (C), 130.5 (CH), 129.2 (CH), 128.3
(CH), 122.0 (CH), 117.7 (CH), 116.7 (CH).
IR (KBr): 3211, 2983, 1663, 1564, 1244 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.92–9.84 (m, 3 H), 9.24 (s, 1
H), 8.97 (m, 1 H), 8.60–8.58 (m, 2 H), 7.72–7.69 (m, 3 H), 3.63–
3.57 (m, 2 H), 1.23 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 153.1 (C), 146.9 (CH), 145.7
(CH), 138.9 (CH), 136.4 (C), 135.7 (C), 135.0 (C), 131.6 (CH),
131.1 (C), 129.2 (CH), 128.3 (CH), 115.7 (CH), 30.6 (CH2), 13.9
(CH3).
MS (ESI): m/z (%) = 377 [(M + H), 100], 379 [(M + H) + 2, 40].
Anal. Calcd for C20H14ClN5O: C, 63.92; H, 3.75; N, 18.64. Found:
C, 64.02; H, 3.73; N, 18.62.
MS (ESI): m/z (%) = 294 [(M + H), 100].
Anal. Calcd for C16H15N5O: C, 65.52; H, 5.15; N, 23.88. Found: C,
65.41; H, 5.11; N, 23.93.
N-(2-Methoxyphenyl)-N¢-(2-phenylpyrido[3,4-b]pyrazin-8-
yl)urea (12e)
Orange powder; yield: 207 mg (62%); mp 87–89 °C; Rf = 0.60
(CH2Cl2–EtOH, 9:1).
IR (KBr): 3285, 1672, 1545, 1521, 1403, 1322, 1204 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.94 (br s, 1 H), 9.85 (s, 1 H),
9.69 (s, 1 H), 9.48 (br s, 1 H), 9.15 (s, 1 H), 8.68–8.63 (m, 2 H), 8.12
(d, J = 8.2 Hz, 1 H), 7.74–7.71 (m, 3 H), 3.95 (s, 3 H).
N-Allyl-N¢-(2-phenylpyrido[3,4-b]pyrazin-8-yl)urea (12b)
Yellow powder; yield: 140 mg (51%); mp 215–217 °C; Rf = 0.62
(CH2Cl2–EtOH, 9:1).
IR (KBr): 3308, 1638, 1560, 1548, 1403, 1234 cm–1.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 69–82

78
M. Antoine et al.
PAPER
13C NMR (100 MHz, DMSO-d6): d = 153.0 (C), 152.3 (C), 148.9
(C), 145.8 (CH), 144.6 (CH), 135.6 (C), 135.0 (C), 134.7 (C), 134.5
(CH), 131.8 (C), 131.5 (CH), 129.1 (CH), 128.5 (CH), 127.8 (C),
123.0 (CH), 120.5 (CH), 120.4 (CH), 111.0 (CH), 55.7 (CH3).
N-[2-(4-Methoxyphenyl)pyrido[3,4-b]pyrazin-8-yl]-N¢-phenyl-
urea (12i)
Yellow powder; yield: 184 mg (55%); mp 236–237 °C; Rf = 0.60
(CH2Cl2–EtOH, 9:1).
MS (ESI): m/z (%) = 372 [(M + H), 100].
IR (KBr): 3375, 1671, 1608, 1527, 1506, 1297, 1250, 1171, 1017,
833 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 10.00 (br s, 1 H), 9.83 (s, 1 H),
967 (s, 1 H), 9.39 (br s, 1 H), 9.11 (s, 1 H), 8.68–8.64 (m, 2 H), 7.62
(d, J = 7.5 Hz, 2 H), 7.43–7.36 (m, 2 H), 7.28 (d, J = 7.5 Hz, 2 H),
7.15–7.09 (m, 1 H), 3.96 (s, 3 H).
Anal. Calcd for C21H17N5O2: C, 67.91; H, 4.61; N, 18.86. Found: C,
68.02; H, 4.59; N, 18.84.
N-(3-Methoxyphenyl)-N¢-(2-phenylpyrido[3,4-b]pyrazin-8-
yl)urea (12f)
Orange powder; yield: 224 mg (67%); mp 195–196 °C; Rf = 0.60
(CH2Cl2–EtOH, 9:1).
IR (KBr): 3282, 1669, 1537, 1520, 1409, 1325, 1213 cm–1.
13C NMR (100 MHz, DMSO-d6): d = 162.4 (C), 152.7 (C), 152.2
(C), 145.8 (CH), 145.0 (CH), 139.5 (C), 135.4 (C), 134.5 (C), 134.3
(CH), 131.4 (C), 130.4 (CH), 129.1 (CH), 127.6 (C), 122.6 (CH),
118.6 (CH), 114.9 (CH), 55.7 (CH3).
1H NMR (400 MHz, DMSO-d6): d = 10.02 (br s, 1 H), 9.85 (s, 1 H),
9.70 (s, 1 H), 9.40 (br s, 1 H), 9.15 (s, 1 H), 8.66–8.62 (m, 2 H),
7.76–7.71 (m, 3 H), 7.32–7.25 (m, 2 H), 7.11 (dd, J = 8.1, 1.1 Hz, 1
H), 6.66 (dd, J = 7.8, 1.6 Hz, 1 H), 3.81 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 159.7 (C), 152.8 (C), 151.9
(C), 145.9 (CH), 144.9 (CH), 140.4 (C), 135.5 (C), 135.0 (C), 134.2
(C), 134.1 (CH), 131.5 (CH), 131.3 (C), 129.7 (CH), 129.2 (CH),
128.4 (CH), 110.7 (CH), 107.9 (CH), 104.2 (CH), 55.0 (CH3).
MS (ESI): m/z (%) = 372 [(M + H), 100].
Anal. Calcd for C21H17N5O2: C, 67.91; H, 4.61; N, 18.86. Found: C,
68.01; H, 4.58; N, 18.84.
N-(3-Methoxyphenyl)-N¢-[2-(4-methoxyphenyl)pyrido[3,4-
b]pyrazin-8-yl]urea (12j)
Yellow powder; yield: 231 mg (64%); mp 195–196 °C; Rf = 0.62
(CH2Cl2–EtOH, 9:1).
IR (KBr): 3272, 1666, 1541, 1519, 1411, 1332, 1213 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 10.01 (br s, 1 H), 9.83 (s, 1 H),
9.67 (s, 1 H), 9.38 (br s, 1 H), 9.11 (s, 1 H), 8.65 (d, J = 9.1 Hz, 2
H), 7.34–7.25 (m, 4 H), 7.12 (dd, J = 9.1, 1.8 Hz, 1 H), 6.66 (dd,
J = 8.2, 1.8 Hz, 1 H), 3.96 (s, 3 H), 3.82 (s, 3 H).
MS (ESI): m/z (%) = 372 [(M + H), 100].
Anal. Calcd for C21H17N5O2: C, 67.91; H, 4.61; N, 18.86. Found: C,
68.00; H, 4.62; N, 18.82.
N-(4-Methoxyphenyl)-N¢-(2-phenylpyrido[3,4-b]pyrazin-8-
yl)urea (12g)
Orange powder; yield: 220 mg (66%); mp 207–208 °C; Rf = 0.62
(CH2Cl2–EtOH, 9:1).
IR (KBr): 3398, 1702, 1545, 1505, 1241, 991 cm–1.
13C NMR (100 MHz, DMSO-d6): d = 162.4 (C), 160.0 (C), 152.7
(C), 152.2 (C), 145.8 (CH), 145.1 (CH), 140.7 (C), 135.4 (C), 134.5
(C), 134.4 (CH), 131.4 (C), 130.4 (CH), 130.0 (CH), 127.6 (C),
115.0 (CH), 111.0 (CH), 108.2 (CH), 104.4 (CH), 55.8 (CH3), 55.2
(CH3).
1H NMR (400 MHz, DMSO-d6): d = 10.09 (br s, 1 H), 9.94 (s, 1 H),
9.68 (s, 1 H), 9.56 (br s, 1 H), 9.29 (s, 1 H), 8.71–8.69 (m, 2 H),
7.75–7.72 (m, 3 H), 7.53 (d, J = 8.9 Hz, 2 H), 6.98 (d, J = 8.9 Hz, 2
H), 3.79 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 154.8 (C), 152.7 (C), 152.2
(C), 145.8 (CH), 144.6 (CH), 135.5 (C), 135.0 (C), 134.2 (C), 134.0
(CH), 132.3 (C), 131.6 (C), 131.5 (CH), 129.2 (CH), 128.4 (CH),
120.4 (CH), 114.1 (CH), 55.2 (CH3).
MS (ESI): m/z (%) = 402 [(M + H), 100].
Anal. Calcd for C22H19N5O3: C, 65.83; H, 4.77; N, 17.45. Found: C,
65.78; H, 4.78; N, 17.47.
N-(4-Methoxyphenyl)-N¢-[2-(4-methoxyphenyl)pyrido[3,4-
b]pyrazin-8-yl]urea (12k)
Yellow powder; yield: 242 mg (67%); mp 231–323 °C; Rf = 0.62
(CH2Cl2–EtOH, 9:1).
IR (KBr): 3274, 1660, 1536, 1524, 1405, 1326, 1204 cm–1.
MS (ESI): m/z (%) = 372 [(M + H), 100].
Anal. Calcd for C21H17N5O2: C, 67.91; H, 4.61; N, 18.86. Found: C,
67.87; H, 4.64; N, 18.84.
1H NMR (400 MHz, DMSO-d6): d = 9.81 (br s, 2 H), 9.66 (s, 1 H),
9.29 (br s, 1 H), 9.09 (s, 1 H), 8.64 (d, J = 9.1 Hz, 2 H), 7.52 (d,
J = 8.9 Hz, 2 H), 7.28 (d, J = 8.9 Hz, 2 H), 6.98 (d, J = 9.1 Hz, 2 H),
3.95 (s, 3 H), 3.79 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 162.4 (C), 155.1 (C), 152.6
(C), 152.4 (C), 145.8 (CH), 144.8 (CH), 135.4 (C), 134.4 (C), 134.2
(CH), 132.4 (C), 131.6 (C), 130.4 (CH), 127.6 (C), 120.7 (CH),
114.9 (CH), 114.4 (CH), 55.8 (CH3), 55.4 (CH3).
N-(3,5-Dimethoxyphenyl)-N¢-(2-phenylpyrido[3,4-b]pyrazin-8-
yl)urea (12h)
Orange powder; yield: 224 mg (62%); mp 134–136 °C; Rf = 0.63
(CH2Cl2–EtOH, 9:1).
IR (KBr): 3314, 1629, 1548, 1527, 1409, 1219, 1201, 1147 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 10.00 (br s, 1 H), 9.86 (s, 1 H),
9.70 (s, 1 H), 9.39 (br s, 1 H), 9.16 (s, 1 H), 8.65–8.61 (m, 2 H),
7.75–7.71 (m, 3 H), 6.82 (d, J = 2.2 Hz, 2 H), 6.25 (t, J = 2.2 Hz, 1
H), 3.80 (s, 6 H).
13C NMR (100 MHz, DMSO-d6): d = 160.7 (C), 152.9 (C), 151.8
(C), 145.9 (CH), 145.0 (CH), 141.0 (C), 135.5 (C), 135.0 (C), 134.2
(C), 134.1 (CH), 131.5 (CH), 131.3 (C), 129.2 (CH), 129.1 (CH),
128.3 (CH), 127.8 (CH), 55.1 (CH3).
MS (ESI): m/z (%) = 402 [(M + H), 100].
Anal. Calcd for C22H19N5O3: C, 65.83; H, 4.77; N, 17.45. Found: C,
65.91; H, 4.79; N, 17.39.
N-(2-Phenylpyrido[3,4-b]pyrazin-8-yl)acetamide(13a); Typical
Procedure
To a solution of 8-amino-2-phenylpyrido[3,4-b]pyrazine (10a; 200
mg, 0.9 mmol) in MeCN (10 mL) was added acetyl chloride (78 mL,
1.1 mmol) and the reaction mixture was heated at reflux for 6 h. The
resulting solution was filtered off and the solvent was removed un-
der reduced pressure. The residue was purified by column chroma-
tography on silica gel eluting with CH2Cl2–EtOH mixtures (from
MS (ESI): m/z (%) = 402 [(M + H), 100].
Anal. Calcd for C22H19N5O3: C, 65.83; H, 4.77; N, 17.45. Found: C,
65.78; H, 4.76; N, 17.44.
Synthesis 2012, 44, 69–82
© Thieme Stuttgart · New York

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Synthesis of Novel 2,8-Disubstituted Pyrido[3,4-b]pyrazines
79
10:0 to 9:1) to give 13a (157 mg, 66%) as a beige powder; mp 210–
211 °C; Rf = 0.58 (CH2Cl2–EtOH, 9:1).
Anal. Calcd for C19H13BrN4: C, 60.49; H, 3.47; N, 14.85. Found: C,
60.54; H, 3.44; N, 14.94.
IR (KBr): 3346, 2995, 1656, 1519, 1415, 1335, 1222 cm–1.
N-(2-Methoxyphenyl)-2-phenylpyrido[3,4-b]pyrazin-8-amine
(14b)
Red powder; yield: 85.3 mg (52%); mp 156–158 °C; Rf = 0.53
(CH2Cl2–EtOH, 9:1).
1H NMR (400 MHz, DMSO-d6): d = 10.21 (br s, 1 H), 9.85 (s, 1 H),
9.65 (s, 1 H), 9.25 (s, 1 H), 8.69–8.64 (m, 2 H), 7.72–7.68 (m, 3 H),
2.39 (s, 3 H).
13C NMR spectrum could not be obtained due to poor solubility.
IR (KBr): 3332, 1599, 1548, 1539, 1493, 1457, 1406, 1238, 1027,
731, 686 cm–1.
MS (ESI): m/z (%) = 265 [(M + H), 100].
1H NMR (400 MHz, DMSO-d6): d = 9.81 (s, 1 H), 8.89 (s, 1 H),
8.58–8.53 (m, 3 H), 8.43 (s, 1 H), 7.72–7.61 (m, 4 H), 7.20–7.08 (m,
3 H), 3.94 (s, 3 H).
Anal. Calcd for C15H12N4O: C, 68.17; H, 4.58; N, 21.20. Found: C,
68.34; H, 4.56; N, 21.16.
13C NMR (100 MHz, DMSO-d6): d = 160.3 (C), 152.5 (C), 145.4
(CH), 142.6 (C), 141.8 (CH), 136.7 (C), 135.5 (C), 135.2 (C), 134.4
(C), 131.2 (CH), 130.5 (CH), 129.2 (CH), 129.0 (CH), 128.5 (CH),
112.1 (CH), 108.4 (CH), 106.2 (CH), 55.2 (CH3).
N-(2-Phenylpyrido[3,4-b]pyrazin-8-yl)benzamide (13b)
Yellow powder; yield: 208 mg (71%); mp 243–244 °C; Rf = 0.56
(CH2Cl2–EtOH, 9:1).
IR (KBr): 3387, 1662, 1521, 1406, 1328, 1300, 1247, 708 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 10.69 (br s, 1 H), 9.92 (s, 1 H),
9.64 (s, 1 H), 9.47 (s, 1 H), 8.61–8.56 (m, 2 H), 8.19–8.15 (m, 2 H),
7.73–7.68 (m, 6 H).
MS (ESI): m/z (%) = 329 [(M + H), 100].
Anal. Calcd for C20H16N4O: C, 73.15; H, 4.91; N, 17.06. Found: C,
73.11; H, 4.90; N, 17.09.
13C NMR spectrum could not be obtained due to poor solubility.
N-(3-Methoxyphenyl)-2-phenylpyrido[3,4-b]pyrazin-8-amine
(14c)
MS (ESI): m/z (%) = 327 [(M + H), 100].
Anal. Calcd for C20H14N4O: C, 73.61; H, 4.32; N, 17.17. Found: C,
73.68; H, 4.33; N, 17.14.
Orange powder; yield: 114 mg (70%); mp 111–113 °C; Rf = 0.35
(CH2Cl2–EtOH, 9:1).
IR (KBr): 3362, 1596, 1548, 1529, 1491, 1280, 1162, 765, 686
cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.81 (br s, 1 H), 8.92 (s, 1 H),
8.77 (s, 1 H), 8.69 (s, 1 H), 8.69–8.63 (m, 2 H), 7.68–7.65 (m, 3 H),
7.34 (t, J = 8.1 Hz, 1 H), 7.14–7.09 (m, 2 H), 6.70 (d, J = 8.1 Hz, 2
H).
13C NMR (100 MHz, DMSO-d6): d = 160.2 (C), 152.0 (C), 145.6
(CH), 142.4 (C), 141.8 (CH), 136.2 (C), 135.8 (C), 135.2 (C), 134.6
(C), 131.2 (CH), 130.0 (CH), 129.5 (CH), 129.1 (CH), 128.2 (CH),
112.5 (CH), 108.3 (CH), 106.3 (CH), 55.1 (CH3).
4-Methoxy-N-(2-phenylpyrido[3,4-b]pyrazin-8-yl)benzamide
(13c)
Yellow powder; yield: 199 mg (62%); mp 214–215 °C; Rf = 0.56
(CH2Cl2–EtOH, 9:1).
IR (KBr): 3369, 1524, 1506, 1436, 1406, 1247, 1177, 1020 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 10.43 (br s, 1 H), 9.86 (s, 1 H),
9.62 (s, 1 H), 9.34 (s, 1 H), 8.57–8.53 (m, 2 H), 8.15 (d, J = 8.8 Hz,
2 H), 7.72–7.69 (m, 3 H), 7.20 (d, J = 8.8 Hz, 2 H), 3.93 (s, 3 H).
13C NMR spectrum could not be obtained due to poor solubility.
MS (ESI): m/z (%) = 357 [(M + H), 100].
MS(ESI): m/z (%) = 329 [(M + H), 100].
Anal. Calcd for C21H16N4O2: C, 70.77; H, 4.53; N, 15.72. Found: C,
70.79; H, 4.54; N, 15.68.
Anal. Calcd for C20H16N4O: C, 73.15; H, 4.91; N, 17.06. Found: C,
73.32; H, 4.89; N, 17.02.
N-(3-Bromophenyl)-2-phenylpyrido[3,4-b]pyrazin-8-amine
(14a); Typical Procedure
N-(4-Methoxyphenyl)-2-phenylpyrido[3,4-b]pyrazin-8-amine
(14d)
To a solution of 8-bromo-2-phenylpyrido[3,4-b]pyrazine (6aa; 150
mg, 0.5 mmol) in toluene (8 mL) under argon was added successive-
ly 3-bromoaniline (68 mL, 0.6 mmol), Pd2(dba)3 (2 mg, 3.9·10–6 mol),
BINAP (1 mg, 1.3·10–6 mol) and t-BuONa (71 mg, 0.7 mmol). The
resulting mixture was stirred at 100 °C for 4 h and then allowed to
cool to r.t. EtOAc (15 mL) was added, the combined organic layers
were washed with H2O (3 × 15 mL), collected, dried (Na2SO4) and
the solvent was removed under reduced pressure. The crude product
was purified by column chromatography on silica gel eluting with
CH2Cl2–EtOH mixtures (from 10:0 to 9:1) to afford 14a (119 mg,
63%) as an orange powder; mp 194–196 °C; Rf = 0.61 (CH2Cl2–
EtOH, 9:1).
Red powder; yield: 110 mg (67%); mp 128–130 °C; Rf = 0.52
(CH2Cl2–EtOH, 9:1).
IR (KBr): 3356, 1591, 1551, 1519, 1482, 1273, 1164, 769, 693
cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.79 (s, 1 H), 8.80 (s, 1 H),
8.66–8.63 (m, 3 H), 8.34 (s, 1 H), 7.66–7.64 (m, 3 H), 7.45 (d,
J = 8.5 Hz, 2 H), 7.05 (d, J = 8.5 Hz, 2 H), 3.83 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 155.8 (C), 151.6 (C), 145.4
(CH), 140.1 (CH), 137.6 (C), 136.1 (C), 135.3 (C), 133.8 (C), 133.4
(C), 131.1 (CH), 129.0 (CH), 128.2 (CH), 127.2 (CH), 124.4 (CH),
114.6 (CH), 55.2 (CH3).
IR (KBr): 3329, 1592, 1544, 1518, 1486, 1413, 1224, 1017 cm–1.
MS (ESI): m/z (%) = 329 [(M + H), 100].
1H NMR (400 MHz, DMSO-d6): d = 9.82 (s, 1 H), 8.99 (s, 1 H), 8.94
(br s, 1 H), 8.73 (s, 1 H), 8.62–8.60 (m, 2 H), 7.69–7.65 (m, 4 H),
7.53–7.51 (m, 1 H), 7.36 (t, J = 8.1 Hz, 1 H), 7.26–7.23 (m, 1 H).
Anal. Calcd for C20H16N4O: C, 73.15; H, 4.91; N, 17.06. Found: C,
73.19; H, 4.89; N, 17.04.
13C NMR (100 MHz, DMSO-d6): d = 152.5 (C), 145.9 (CH), 143.7
(C), 143.2 (CH), 136.4 (C), 135.4 (C), 135.3 (C), 135.2 (C), 131.5
(CH), 131.3 (CH), 130.9 (CH), 129.3 (CH), 128.5 (CH), 124.8
(CH), 122.6 (CH), 122.3 (C), 118.4 (CH).
N-(3-Ethynylphenyl)-2-phenylpyrido[3,4-b]pyrazin-8-amine
(14e)
Orange powder; yield: 90.1 mg (56%); mp 190–191 °C; Rf = 0.61
(CH2Cl2–EtOH, 9:1).
IR (KBr): 3351, 2216, 1592, 1539, 1524, 1461, 1272, 1152 cm–1.
MS (ESI): m/z (%) = 377 [(M + H), 100], 379 [(M + H) + 2, 100].
© Thieme Stuttgart · New York
Synthesis 2012, 44, 69–82

80
M. Antoine et al.
PAPER
1H NMR (400 MHz, DMSO-d6): d = 9.82 (s, 1 H), 8.96 (s, 1 H), 8.87
(br s, 1 H), 8.69–8.61 (m, 3 H), 7.68–7.65 (m, 3 H), 7.61–7.58 (m,
2 H), 7.46–7.39 (m, 1 H), 7.19 (d, J = 7.6 Hz, 1 H), 4.25 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 152.4 (C), 145.8 (CH), 142.7
(CH), 142.0 (C), 136.4 (C), 135.6 (C), 135.4 (C), 135.1 (C), 131.5
(CH), 130.2 (CH), 129.9 (CH), 129.3 (CH), 128.5 (CH), 125.8
(CH), 123.4 (CH), 122.8 (C), 120.7 (CH), 83.6 (C), 80.9 (CH).
N-(3-Bromophenyl)-2-(4-methoxyphenyl)pyrido[3,4-b]pyrazin-
8-amine (14i)
Orange powder; yield: 118 mg (58%); mp 159–161 °C; Rf = 0.61
(CH2Cl2–EtOH, 9:1).
IR (KBr): 3319, 1583, 1534, 1525, 1472, 1422, 1213, 1019 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.77 (s, 1 H), 8.95 (s, 1 H), 8.88
(br s, 1 H), 8.71–8.60 (m, 3 H), 7.67 (s, 1 H), 7.54–7.50 (m, 1 H),
7.39–7.32 (m, 1 H), 7.25–7.18 (m, 3 H), 3.92 (s, 3 H).
MS (ESI): m/z (%) = 323 [(M + H), 100].
Anal. Calcd for C21H14N4: C, 78.24; H, 4.38; N, 17.38. Found: C,
78.29; H, 4.37; N, 17.34.
13C NMR (100 MHz, DMSO-d6): d = 162.2 (C), 152.2 (C), 145.6
(CH), 143.8 (C), 143.2 (CH), 136.0 (C), 135.4 (C), 134.9 (C), 131.2
(CH), 130.9 (CH), 130.3 (CH), 127.8 (C), 124.6 (CH), 122.4 (CH),
122.3 (C), 118.1 (CH), 114.7 (CH), 55.7 (CH3).
2-Phenyl-N-[4-(piperidin-1-yl)phenyl]pyrido[3,4-b]pyrazin-8-
amine (14f)
Red powder; yield: 105 mg (55%); mp 189–191 °C; Rf = 0.47
(CH2Cl2–EtOH, 9:1).
MS (ESI): m/z (%) = 407 [(M + H), 100], 409 [(M + H) + 2, 100].
Anal. Calcd for C20H15BrN4O: C, 58.98; H, 3.71; N, 13.76. Found:
C, 58.98; H, 3.73; N, 13.73.
IR (KBr): 3393, 1542, 1515, 1442, 1328, 1238, 1183, 1093, 918,
777, 686 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.78 (s, 1 H), 8.77 (s, 1 H),
8.68–8.65 (m, 2 H), 8.58 (br s, 1 H), 8.34 (s, 1 H), 7.67–7.64 (m, 3
H), 7.36 (d, J = 9.0 Hz, 2 H), 7.05 (d, J = 9.0 Hz, 2 H), 3.17–3.15,
1.69–1.50 (m, 10 H).
13C NMR (100 MHz, DMSO-d6): d = 151.5 (C), 148.5 (C), 145.3
(CH), 139.7 (CH), 137.7 (C), 136.1 (C), 135.3 (C), 133.7 (C), 131.7
(C), 131.1 (CH), 129.0 (CH), 128.2 (CH), 127.2 (CH), 123.8 (CH),
118.1 (CH), 116.8 (CH), 114.7 (CH), 52.0 (CH2), 50.0 (CH2), 25.8
(CH2), 25.4 (CH2), 23.9 (CH2).
2-(4-Methoxyphenyl)-N-[4-(piperidin-1-yl)phenyl]pyrido[3,4-
b]pyrazin-8-amine (14j)
Red powder; yield: 140 mg (68%); mp 185–187 °C; Rf = 0.45
(CH2Cl2–EtOH, 9:1).
IR (KBr): 3368, 1578, 1521, 1279, 1247, 1177, 1023, 831 cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.73 (s, 1 H), 8.72 (s, 1 H), 8.64
(d, J = 8.6 Hz, 2 H), 8.51 (br s, 1 H), 8.31 (s, 1 H), 7.34 (d, J = 8.7
Hz, 2 H), 7.18 (d, J = 7.9 Hz, 2 H), 7.04 (d, J = 8.1 Hz, 2 H), 3.92
(s, 3 H), 3.16–3.14, 1.68–1.57 (m, 10 H).
13C NMR (100 MHz, DMSO-d6): d = 161.8 (C), 151.3 (C), 148.4
(C), 145.1 (CH), 139.7 (CH), 137.4 (C), 135.7 (C), 133.8 (C), 131.8
(C), 129.9 (CH), 127.7 (C), 127.1 (CH), 123.7 (CH), 116.8 (CH),
114.5 (CH), 55.4 (CH3), 50.0 (CH2), 30.7 (CH2), 25.3 (CH2), 23.8
(CH2).
MS (ESI): m/z (%) = 382 [(M + H), 100].
Anal. Calcd for C24H23N5: C, 75.56; H, 6.08; N, 18.36. Found: C,
75.61; H, 6.07; N, 18.32.
N-[4-(Morpholin-4-yl)phenyl]-2-phenylpyrido[3,4-b]pyrazin-8-
amine (14g)
Red powder; yield: 107 mg (56%); mp 187–189 °C; Rf = 0.48
MS (ESI): m/z (%) = 412 [(M + H), 100].
Anal. Calcd for C25H25N5O: C, 72.97; H, 6.12; N, 17.02. Found: C,
72.92; H, 6.13; N, 17.03.
(CH2Cl2–EtOH, 9:1).
IR (KBr): 3417, 1539, 1515, 1442, 1325, 1231, 1126, 922 cm–1.
2-(4-Methoxyphenyl)-N-[4-(morpholin-4-yl)phenyl]pyrido[3,4-
b]pyrazin-8-amine (14k)
Red powder; yield: 138 mg (67%); mp 204–206 °C; Rf = 0.56
(CH2Cl2–EtOH, 9:1).
1H NMR (400 MHz, DMSO-d6): d = 9.78 (s, 1 H), 8.78 (s, 1 H),
8.68–8.64 (m, 2 H), 8.61 (br s, 1 H), 8.36 (s, 1 H), 7.67–7.64 (m, 3
H), 7.40 (d, J = 8.8 Hz, 2 H), 7.06 (d, J = 8.8 Hz, 2 H), 3.82–3.78
(m, 4 H), 3.17–3.13 (m, 4 H).
13C NMR (100 MHz, DMSO-d6): d = 151.5 (C), 147.7 (C), 145.4
(CH), 139.9 (CH), 137.5 (C), 136.1 (C), 135.3 (C), 133.7 (C), 132.4
(C), 131.1 (CH), 129.0 (CH), 128.2 (CH), 127.2 (CH), 123.7 (CH),
116.0 (CH), 66.1 (CH2), 48.8 (CH2).
IR (KBr): 3368, 1603, 1542, 1518, 1436, 1252, 1117, 1024, 925
cm–1.
1H NMR (400 MHz, DMSO-d6): d = 9.73 (s, 1 H), 8.74 (s, 1 H), 8.64
(d, J = 8.9 Hz, 2 H), 8.54 (br s, 1 H), 8.33 (s, 1 H), 7.39 (d, J = 8.5
Hz, 2 H), 7.18 (d, J = 9.0 Hz, 2 H), 7.06 (d, J = 8.5 Hz, 2 H), 3.92
(s, 3 H), 3.82–3.78, 3.17–3.13 (m, 8 H).
MS (ESI): m/z (%) = 384 [(M + H), 100].
Anal. Calcd for C23H21N5O: C, 72.04; H, 5.52; N, 18.26. Found: C,
71.98; H, 5.55; N, 18.31.
13C NMR (100 MHz, DMSO-d6): d = 161.8 (C), 151.3 (C), 147.6
(C), 145.0 (CH), 139.9 (CH), 137.3 (C), 135.7 (C), 133.8 (C), 132.5
(C), 129.9 (CH), 127.7 (C), 127.2 (CH), 123.6 (CH), 116.0 (CH),
114.4 (CH), 66.1 (CH2), 55.4 (CH3), 48.9 (CH2).
N-(4-Hydroxyphenyl)-2-phenylpyrido[3,4-b]pyrazin-8-amine
(14h)
MS(ESI): m/z (%) = 414 [(M + H), 100].
Red powder; yield: 33.0 mg (21%); mp 252–254 °C; Rf = 0.53
(CH2Cl2–EtOH, 9:1).
IR (KBr): 3387, 1518, 1279, 1243, 1093, 1023, 828, 767 cm–1.
Anal. Calcd for C24H23N5O2: C, 69.72; H, 5.61; N, 16.94. Found: C,
69.75; H, 5.60; N, 16.92.
1H NMR (400 MHz, DMSO-d6): d = 9.79 (s, 1 H), 9.42 (br s, 1 H),
8.76 (s, 1 H), 8.68–8.66 (m, 2 H), 8.56 (br s, 1 H), 8.26 (s, 1 H),
7.67–7.64 (m, 3 H), 7.32 (d, J = 8.8 Hz, 2 H), 6.88 (d, J = 8.8 Hz, 2
H).
N-(2,5-Dimethoxyphenyl)-2-(4-methoxyphenyl)pyrido[3,4-
b]pyrazin-8-amine (14l)
Red powder; yield: 140 mg (72%); mp 158–159 °C; Rf = 0.52
(CH2Cl2–EtOH, 9:1).
13C NMR spectrum could not be obtained due to poor solubility.
IR (KBr): 3411, 1608, 1557, 1529, 1210, 1177, 1020, 794 cm–1.
MS (ESI): m/z (%) = 315 [(M + H), 100].
1H NMR (250 MHz, DMSO-d6): d = 9.77 (s, 1 H), 8.88 (s, 1 H),
8.55–8.47 (m, 4 H), 7.23 (d, J = 8.2 Hz, 2 H), 7.17 (d, J = 2.8 Hz, 1
H), 7.11 (d, J = 9.2 Hz, 1 H), 6.70 (dd, J = 9.0, 2.8 Hz, 1 H), 3.93 (s,
3 H), 3.90 (s, 3 H), 3.80 (s, 3 H).
Anal. Calcd for C19H14N4O: C, 72.60; H, 4.49; N, 17.82. Found: C,
72.69; H, 4.49; N, 17.71.
Synthesis 2012, 44, 69–82
© Thieme Stuttgart · New York

PAPER
Synthesis of Novel 2,8-Disubstituted Pyrido[3,4-b]pyrazines
MS (ESI): m/z (%) = 444 [(M + H), 100].
81
13C NMR (100 MHz, DMSO-d6): d = 162.0 (C), 153.5 (C), 151.6
(C), 145.3 (CH), 144.8 (C), 141.5 (CH), 135.6 (C), 134.6 (C), 134.1
(C), 130.3 (C), 129.6 (CH), 128.5 (CH), 127.5 (C), 114.7 (CH),
112.4 (CH), 107.1 (CH), 106.2 (CH), 56.3 (CH3), 55.5 (CH3), 55.4
(CH3).
Anal. Calcd for C25H25N5O3: C, 67.70; H, 5.68; N, 15.79. Found: C,
67.63; H, 5.69; N, 15.82.
N-Phenyl-2-[4-(piperidin-1-yl)phenyl]pyrido[3,4-b]pyrazin-8-
amine (14p)
MS (ESI): m/z (%) = 389 [(M + H), 100].
Red powder; yield: 112 mg (59%); mp 132–134 °C; Rf = 0.48
(CH2Cl2–EtOH, 9:1).
IR (KBr): 3441, 1605, 1517, 1497, 1238, 1198, 1126 cm–1.
Anal. Calcd for C22H20N4O3: C, 68.03; H, 5.19; N, 14.42. Found: C,
67.99; H, 5.21; N, 14.45.
2-(3,4-Dimethoxyphenyl)-N-(3-methoxyphenyl)pyrido[3,4-
b]pyrazin-8-amine (14m)
Red powder; yield: 149 mg (77%); mp 156–158 °C; Rf = 0.59
1H NMR (250 MHz, DMSO-d6): d = 9.66 (s, 1 H), 8.80 (br s, 1 H),
8.61 (s, 1 H), 8.58 (s, 1 H), 8.48 (d, J = 8.9 Hz, 2 H), 7.52–7.39 (m,
5 H), 7.10 (d, J = 8.9 Hz, 2 H), 3.37–3.36, 1.66–1.65 (m, 10 H).
13C NMR (100 MHz, DMSO-d6): d = 152.9 (C), 152.3 (C), 145.2
(CH), 140.9 (C), 140.9 (CH), 135.8 (C), 135.3 (C), 135.0 (C), 129.5
(CH), 129.4 (CH), 128.9 (CH), 128.0 (CH), 123.1 (C), 122.8 (CH),
120.5 (CH), 114.7 (CH), 114.2 (CH), 47.9 (CH2), 24.7 (CH2), 23.8
(CH2).
(CH2Cl2–EtOH, 9:1).
IR (KBr): 3350, 1602, 1529, 1515, 1457, 1403, 1286, 1253, 1211,
1168, 1153, 1014 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 9.78 (s, 1 H), 8.89 (s, 1 H), 8.72
(br s, 1 H), 8.65 (s, 1 H), 8.21 (dd, J = 8.5, 1.5 Hz, 1 H), 8.13 (d,
J = 1.5 Hz, 1 H), 7.32 (t, J = 8.1 Hz, 1 H), 7.20 (d, J = 8.5 Hz, 1 H),
7.10–7.04 (m, 2 H), 6.67 (dd, J = 8.1, 2.1 Hz, 1 H), 3.96 (s, 3 H),
3.92 (s, 3 H), 3.80 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 160.2 (C), 152.0 (C), 145.6
(CH), 142.4 (C), 141.8 (CH), 136.2 (C), 135.8 (C), 135.2 (C), 134.6
(C), 131.2 (CH), 130.0 (CH), 129.5 (CH), 129.1 (CH), 128.2 (CH),
112.5 (CH), 108.3 (CH), 106.3 (CH), 55.1 (CH3).
MS(ESI): m/z (%) = 382 [(M + H), 100].
Anal. Calcd for C24H23N5: C, 75.56; H, 6.08; N, 18.36. Found: C,
75.54; H, 6.09; N, 18.37.
N-(3-Methoxyphenyl)-2-[4-(piperidin-1-yl)phenyl]pyrido[3,4-
b]pyrazin-8-amine (14q)
Red powder; yield: 111 mg (54%); mp 129–131 °C; Rf = 0.56
(CH2Cl2–EtOH, 9:1).
MS (ESI): m/z (%) = 389 [(M + H), 100].
Anal. Calcd for C22H20N4O3: C, 68.03; H, 5.19; N, 14.42. Found: C,
68.04; H, 5.20; N, 14.43.
IR (KBr): 3411, 1605, 1545, 1524, 1494, 1352, 1241, 1192, 1165,
1123, 818 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 9.68 (s, 1 H), 8.82 (s, 1 H), 8.64
(s, 1 H), 8.61 (br s, 1 H), 8.49 (d, J = 8.9 Hz, 2 H), 7.32 (t, J = 7.9
Hz, 1 H), 7.14–7.08 (m, 4 H), 6.68–6.66 (m, 1 H), 3.82 (s, 3 H),
3.44–3.42, 1.66–1.64 (m, 10 H).
13C NMR (100 MHz, DMSO-d6): d = 160.2 (C), 152.9 (C), 152.0
(C), 145.1 (CH), 142.7 (C), 141.8 (CH), 135.5 (C), 135.2 (C), 135.0
(C), 129.9 (CH), 129.6 (CH), 129.6 (CH), 123.5 (C), 114.2 (CH),
112.0 (CH), 108.0 (CH), 105.8 (CH), 55.0 (CH3), 48.0 (CH2), 24.9
(CH2), 23.9 (CH2).
2-(3,4-Dimethoxyphenyl)-N-[4-(piperidin-1-yl)phenyl]pyri-
do[3,4-b]pyrazin-8-amine (14n)
Red powder; yield: 143 mg (65%); mp 202–204 °C; Rf = 0.54
(CH2Cl2–EtOH, 9:1).
IR (KBr): 3393, 1542, 1517, 1457, 1282, 1262, 1225, 1156, 1117,
1020, 925 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 9.76 (s, 1 H), 8.74 (s, 1 H), 8.50
(br s, 1 H), 8.29 (s, 1 H), 8.29–8.17 (m, 2 H), 7.35 (d, J = 8.6 Hz, 2
H), 7.19 (d, J = 8.2 Hz, 1 H), 7.05 (d, J = 8.6 Hz, 2 H), 3.98 (s, 3 H),
3.92 (s, 3 H), 3.18–3.16, 1.70–1.68 (m, 10 H).
13C NMR (100 MHz, DMSO-d6): d = 152.9 (C), 150.3 (C), 149.8
(C), 146.9 (C), 144.7 (CH), 143.6 (C), 139.6 (C), 139.0 (CH), 137.6
(CH), 136.0 (C), 132.6 (C), 126.4 (C), 120.8 (CH), 117.9 (CH),
117.5 (CH), 115.8 (CH), 115.4 (CH), 115.1 (CH), 112.3 (CH), 56.1
(CH3), 55.8 (CH3), 52.4 (CH2), 26.0 (CH2), 25.5 (CH2).
MS (ESI): m/z (%) = 412 [(M + H), 100].
Anal. Calcd for C25H25N5O: C, 72.97; H, 6.12; N, 17.02. Found: C,
73.02; H, 6.11; N, 16.99.
References
(1) Claus, E.; Seipelt, I.; Günther, E.; Polymeropoulos, E.;
Czech, M.; Schuster, T. PCT Int. Appl. WO 2007/054556,
2007; Chem. Abstr. 2007, 146, 521825.
(2) White, L. E.; Reynolds, R. C.; Suling, W. PCT Int. Appl.
WO 2004/005472, 2004; Chem. Abstr. 2004, 140, 105238.
(3) Barbier, P.; Peyrot, V.; Sarrazin, M.; Rener, G. A.; Briand,
C. Biochemistry 1995, 34, 16821.
MS (ESI): m/z (%) = 442 [(M + H), 100].
Anal. Calcd for C26H27N5O2: C, 70.73; H, 6.16; N, 15.86. Found: C,
70.69; H, 6.14; N, 15.89.
2-(3,4-Dimethoxyphenyl)-N-[4-(morpholin-1-yl)phenyl]pyri-
do[3,4-b]pyrazin-8-amine (14o)
Red powder; yield: 144 mg (65%); mp 205–207 °C; Rf = 0.52
(CH2Cl2–EtOH, 9:1).
(4) Antoine, M.; Czech, M.; Gerlach, M.; Günther, E.; Schuster,
T.; Marchand, P. Synthesis 2011, 794.
(5) For a review on the preparation of pyridopyrazines, see:
Sako, M. In Science of Synthesis: Houben-Weyl Methods of
Molecular Transformations, Vol. 16; Yamamoto, Y., Ed.;
Georg Thieme Verlag: Stuttgart, 2004, 1269.
(6) Kano, S.; Yuasa, Y. J. Heterocycl. Chem. 1983, 20, 769.
(7) Herbich, J.; Kapturkiewicz, A.; Nowacki, J.; Goliński, J.;
Dabrowski, Z. Phys. Chem. Chem. Phys. 2001, 3, 2438.
(8) Temple, C. Jr.; Laseter, A. G.; Rose, J. D.; Montgomery, J.
A. J. Heterocycl. Chem. 1970, 7, 1195.
IR (KBr): 3382, 1539, 1522, 1463, 1272, 1234, 1163, 1112, 1022,
921 cm–1.
1H NMR (250 MHz, DMSO-d6): d = 9.77 (s, 1 H), 8.75 (s, 1 H), 8.53
(br s, 1 H), 8.31 (s, 1 H), 8.24–8.17 (m, 2 H), 7.39 (d, J = 9.1 Hz, 2
H), 7.20 (d, J = 8.2 Hz, 1 H), 7.06 (d, J = 8.9 Hz, 2 H), 3.98 (s, 3 H),
3.92 (s, 3 H), 3.80–3.78, 3.16–3.14 (m, 8 H).
13C NMR (100 MHz, DMSO-d6): d = 151.7 (C), 151.4 (C), 149.3
(C), 147.7 (C), 145.3 (CH), 140.0 (CH), 137.4 (C), 135.8 (C), 133.8
(C), 132.6 (C), 127.9 (C), 127.5 (CH), 123.8 (CH), 121.8 (CH),
116.0 (CH), 111.7 (CH), 111.2 (CH), 66.1 (CH2), 56.0 (CH3), 55.7
(CH3), 48.9 (CH2).
(9) Mederski, W. W. K. R.; Kux, D.; Knoth, M.; Schwarzkopf-
Hofmann, M. J. Heterocycles 2003, 60, 925.
© Thieme Stuttgart · New York
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M. Antoine et al.
PAPER
(17) Kinase Inhibition Assay: Recombinant kinases were
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purchased from Millipore or ProQinase. AlphaScreen Bead
Kits from Perkin-Elmer were used to quantify the kinase
activity. For the assessment of IC50 values, compounds were
tested at 10 final concentrations between 3.16 nM and 100
mM. Kinase, 10 mM ATP, kinase substrate, and the test
compound were incubated for 1 h on a 384-well Optiplate in
a final volume of 15 ml. The kinase reaction was stopped by
adding 10 ml ALPHA-Beadmix. The read out was done on
the next morning using an Envision reader (PerkinElmer).
IC50 values were calculated using Graph Pad Prism software.
(16) Young, R. M.; Davies-Coleman, M. T. Tetrahedron Lett.
2011, 52, 4036.
Synthesis 2012, 44, 69–82
© Thieme Stuttgart · New York