Palladium-catalyzed cross-coupling reactions of 7-bromo-2,3-diphenyl- pyrido[2,3-b]pyrazine

Article abstract of DOI:10.1055/s-2005-861871

First examples of palladium-catalyzed cross-coupling reactions, such as Suzuki, Sonogashira, Heck and Buchwald-Hartwig reactions, are reported in the pyrido[2,3-b]pyrazine series. This methodology circumvents problems found in uncatalyzed nucleophilic sub

Full text of DOI:10.1055/s-2005-861871

PAPER
1345
Palladium-Catalyzed Cross-Coupling Reactions of 7-Bromo-2,3-diphenyl-
pyrido[2,3-b]pyrazine
C
L
ross-Coupling
u
Reactions
o
n
f
7-Bromo-2
x
i
a
,3-
b
]pyrazi
nn e g Yin, Jürgen Liebscher*
Institut für Chemie, Humboldt-Universität Berlin, Brook-Taylor-Straße 2, 12489 Berlin, Germany
Fax +49(30)20937552; E-mail: liebscher@chemie.hu-berlin.de
Received 13 December 2004; revised 17 January 2005
OH
Abstract: First examples of palladium-catalyzed cross-coupling re-
O
N
actions, such as Suzuki, Sonogashira, Heck and Buchwald–Hartwig
reactions, are reported in the pyrido[2,3-b]pyrazine series. This
methodology circumvents problems found in uncatalyzed nucleo-
philic substitution used so far to introduce substituents into the py-
rido[2,3-b]pyrazine ring.
N
N
H
CO2H
CO2H
HN
H2N
N
N
Folic acid
Key words: palladium catalysis, cross-coupling, pyrido[2,3-
b]pyrazine, heterocycles, synthesis
O
N
NH
N
R
N
O
Annulated pyrazines, such as quinoxaline and pteridine
derivatives are very important nitrogen-containing hetero-
cycles found in biological systems and widely used as
Flavine
1
8
1
,2
N
N
N
N
pharmaceuticals. Folic acid (vitamin B-9), a well-
N
N
7
6
2
3
known pteridine derivative, is essential to the body for
N
N
N
3
the formation of new cells; it is a key vitamin in cellular
5
4
function and repair. Flavines also represent pteridine
derivatives and are involved in the formation of red blood
Quinoxaline
Pteridine
Pyrido[2,3-b]pyrazine
4
Figure 1 Pyrido[2,3-b]pyrazine and analogous bicyclic hetero-
cycles
cells, in respiration, antibody production, in human
growth regulation and reproduction. Furthermore, qui-
noxaline derivatives have found application as materials
for light emitting diodes and organic semiconductors.5
Pyrido[2,3-b]pyrazines (also named 5-azaquinoxalines)
are analogues of pteridines and quinoxalines (Figure 1),
,6
side chain, mostly aminoalkyl, aminoalkynyl or amino-
alkylheteroatom chains. So far, pyrazolopyrimidines and
pyrazolotriazines were chosen as core heterocycles for
7
and as such have potential pharmaceutical activities and
8
11
this application.
other applications.
In order to achieve deeper insight into the effect of the
central heterocycle of such assemblies onto the enzyme
inhibiting properties we approached the synthesis of anal-
ogous systems with pyrido[2,3-b]pyrazine as the core
ring. Our strategy was to start with diarylpyrido[2,3-
b]pyrazines and to introduce the functionalized side chain
In the last few decades, many new synthetic transforma-
tions have been developed that use palladium catalysis,
such as carbon–carbon and carbon–heteroatom coupling
reactions (e.g., Buchwald–Hartwig, Heck, Suzuki–
Miyaura, Kumada, Negishi, Nozaki–Hiyama, Sonoga-
9
shira, Stille, and Tsuji–Trost reaction). Palladium-cata-
lyzed cross-coupling reactions gain increasing popularity by palladium-catalyzed cross-coupling. 2,3-Diaryl-7-bro-
amongst pharmaceutical chemists as they often tolerate a mosubstituted pyrido[2,3-b]pyrazine derivatives can be
wide-range of functional groups and therefore can be used easily prepared by the condensation of 2,3-diaminopy-
for the synthesis of complex molecules. Application of ridines with appropriate 1,2-dicarbonyl compounds.12
palladium catalysis in the syntheses of heterocycles has Several nucleophilic substitutions of 7-bromo-2,3-diphe-
increased exponentially. Several review articles summa- nylpyrido[2,3-b]pyrazine (1) have been reported. These
reactions, however, provide low yields, give mixtures of
regioisomeric products due to elimination/addition mech-
anism and often addition competes with substitution. For
example Kumari13 reported the nucleophilic substitution
of 7-bromo-2,3-diphenylpyrido[2,3-b]pyrazine (1) with
secondary amines yielding mixtures of regioisomeric 7-
and 8-aminosubstituted products. Vinot et al. investigat-
ed uncatalyzed cross-coupling reactions of 7-bromo-2,3-
diphenylpyrido[2,3-b]pyrazine (1) with organomagne-
sium reagents. While 1 reacted with phenylmagnesium
rize the development of palladium chemistry in this
field.
1
0
Aiming at the development of new phosphatase inhibitors,
we focused our interest on heterocycles which are substi-
tuted by two aryl groups and a terminally functionalized
14
SYNTHESIS 2005, No. 8, pp 1345–1349
x
x
.
x
x
.2
0
0
5
Advanced online publication: 17.03.2005
DOI: 10.1055/s-2005-861871; Art ID: T15004SS
Georg Thieme Verlag Stuttgart · New York
©

1
346
L. Yin, J. Liebscher
PAPER
bromide by nucleophilic substitution affording 2,3,7- The starting material 1 was obtained in 73% yield from 5-
triphenylpyrido[2,3-b]pyrazine in 28% yield, nucleo- bromo-2,3-diaminopyridine and benzil by refluxing in
philic addition took place with ethylmagnesium bromide ethanol in the presence of catalytic amounts of hydrochlo-
providing 6-ethyl-4,6-dihydro-2,3-diphenylpyrido[2,3- ric acid. The product could be successfully submitted to
1
5
b]pyrazine in 55% yield. Armoand reported the reduc- Sonogashira coupling with N,N-dimethylpropargylamine
tion of pyrido[2,3-b]pyrazine derivatives with sodium and homopropargyl alcohol using Pd(PPh ) Cl (5 mol%)/
3
2
2
borohydride which gave the corresponding 5,6-dihydro CuI (10 mol%) as catalyst. In this way w-dimethylamino
compounds. Considering these problems, palladium-cata- or w-hydroxyalkynyl groups, respectively, could be intro-
lyzed cross coupling can be expected to be an advanta- duced into 1 affording the coupling products 2 in high
geous alternative to introduce functionalized side chains yields. Methyl acrylate, acrylonitrile and N-allylphthalim-
and other substituents into the 7-bromo-2,3-diphenylpyri- ide were used as alkenes in Heck coupling of 7-bromo-
do[2,3-b]pyrazines without facing the problems found in 2,3-phenylpyrido[2,3-b]pyrazine (1) in the presence of
uncatalyzed nucleophilic substitution. To the best of our Pd(OAc) (10 mol%), tri(o-tolyl)phosphine (10 mol%)
2
knowledge, there is no report about the cross-coupling re- and triethylamine in acetonitrile at elevated temperature.
action of pyrido[2,3-b]pyrazine derivatives so far.
While satisfactory yields of the 7-alkenyl-2,3-phenylpyri-
do[2,3-b]pyrazines 3 were obtained with the electron poor
alkenes, N-allylphthalimide provided only 33% of the cor-
responding coupling product 3c. In a Buchwald–Hartwig
reaction 3-dimethylaminopropylamine and 4-methylpip-
erazine afforded 2,3-phenylpyrido[2,3-b]pyrazines 4,
where the aminoalkyl substituents are attached to the het-
erocyclic ring via a nitrogen bridge atom. Pd (dba) (2
In order to synthesize diarylpyrido[2,3-b]pyrazines with
terminally functionalized side chains we submitted 7-bro-
mo-2,3-diphenylpyrido[2,3-b]pyrazine (1) to a series of
palladium-catalyzed cross-coupling reactions, such as Su-
zuki, Sonogashira, and Heck coupling as well as Buch-
wald–Hartwig amination (Scheme 1).
2
3
mol%) in the presence of racemic BINAP (6 mol%) and
sodium tert-butoxide turned out to be a useful catalytic
system in these cases. In order to demonstrate the versatil-
ity of 7-bromo-2,3-phenylpyrido[2,3-b]pyrazine (1) in
palladium-catalyzed cross-couplings we finally investi-
gated Suzuki coupling with areneboronic acids. The de-
Br
N
N
Ph
Ph
Br
NH2
NH2
benzil, ethanol
HCl, reflux
73%
N
N
1
R
R
N
Ph
Ph
sired products 5 could be obtained using Pd(PPh ) (5
(
2 equiv)
3 4
mol%) as catalyst in the presence of potassium carbonate
(Scheme 1).
Pd(PPh3)2Cl2 (5 mol%)/
CuI (10 mol%)
N
N
In summary, 7-bromo-2,3-diphenylpyrido[2,3-b]pyrazine
(1) turned out to be a versatile starting material for palla-
dium-catalyzed cross-coupling reactions, such as Sono-
gashira, Heck, Buchwald–Hartwig and Suzuki coupling.
Using this methodology the problems faced in uncata-
lyzed cross-coupling and substitution reactions of 1 could
be circumvented. A number of new compounds could be
synthesized consisting of a central heterocyclic core sub-
stituted by two aryl substituents and a terminally function-
alized side chain. First investigations of inhibition of
certain phosphatases showed promising results.
TEA, DMF, 100 °C, 24 h
2a, R = CH2OH, 98%
2
b, R = NMe2, 76%
R'
N
Ph
R'
(3 equiv)
N
N
Ph
Pd(OAc) (10 mol%)/
P(o-tolyl)3 (10 mol%)
3
a, R = CO2Me, 96%
3b, R =CN, 65%
c, R = CH2NPhth, 33%
TEA, MeCN, 100 °C, 20 h
3
1
1
2
1
2
R R N
N
N
Ph
Ph
R R NH (2 equiv)
All cross-coupling reactions were carried out under argon in oven-
dried glassware. Solvents were dried and deoxygenated by standard
procedures. Starting materials were purchased from Aldrich, Lan-
caster, Acros, and Merck. TLC analysis was performed on Merck
Pd2(dba)3 (2 mol%)/
BINAP (6 mol%), t-BuONa
N
1
2
4
a, R R N =
-methylpiperazin-1-yl, 68%
toluene, 110 °C, 24 h
4
1
2
silica gel 60F254 plate or Merck Al O 60F neutral (Typ E) plates
and visualized with UV illumination. Column chromatography was
conducted with Merck silica gel 60 (400–639 mesh) or Merck neu-
2 3 254
4
b, R R N =
Me2N(CH2)3NH, 73%
tral Al O gel (90 standard). Melting points were determined on a
ArB(OH)2 (1.4 equiv)
2
3
1
Ar
N
N
Ph
Ph
Boetius hot-stage apparatus and are reported uncorrected. H NMR
Pd(PPh3)4 (5 mol%), K2CO3
toluene, 100 °C, 16 h
13
and C NMR spectra were recorded at 300 and 75.5 MHz, respec-
tively, on a Bruker AC-300 in CDCl with TMS as internal stan-
3
N
dard.
5
5
a, Ar = Ph, 96%
b, Ar = 4-AcC6H4, 50%
7-Bromo-2,3-diphenylpyrido[2,3-b]pyrazine (1)
A 100 mL flask was charged with 2,3-diamino-5-bromopyridine
Scheme 1
(
965 mg, 5.0 mmol), benzil (1.26 g, 6.0 mmol), EtOH (30 mL) and
7% HCl (3 drops). The mixture was refluxed for 12 h. The EtOH
3
Synthesis 2005, No. 8, 1345–1349 © Thieme Stuttgart · New York

PAPER
Cross-Coupling Reactions of 7-Bromo-2,3-diphenylpyrido[2,3-b]pyrazine
1347
was evaporated and the residue was dissolved in CH Cl (60 mL).
3-(2,3-Diphenylpyrido[2,3-b]pyrazin-7-yl)acrylic Acid Methyl
2
2
The solution was washed with H O (2 × 30 mL) and dried (MgSO ).
Ester (3a)
2
4
The solvent was evaporated, and the residue was purified by column
chromatography on silica gel, eluting with cyclohexane–EtOAc
The crude product was purified by flash column chromatography on
silica gel; eluent: cyclohexane–EtOAc (5:1 → 1:1); yellow solid;
yield: 176 mg (96%); mp 197–198 °C.
(
4:1). After evaporation of the solvent, the product was obtained as
1
3
a yellow solid (1.33 g, 73%); mp 149–150 °C (Lit. mp 154–
1
H NMR (CDCl ): d = 3.88 (s, 3 H, CH ), 6.77 (d, 1 H, J = 16.2
3
3
1
55 °C).
Hz, =CH), 7.34–7.65 (m, 10 H, Ph-H), 7.91 (d, 1 H, J = 16.2
Hz, =CH), 8.58 (d, 1 H, J6,8 = 2.6 Hz, H-8), 9.32 (d, 1 H, J6,8 = 2.6
Hz, H-6).
1
H NMR (CDCl ): d = 7.27–7.63 (m, 10 H, Ph-H), 8.67 (d, 1 H,
3
J6,8 = 2.6 Hz, H-8), 9.15 (d, 1 H, J = 2.6 Hz, H-6).
6,8
1
3
13
C NMR (CDCl ): d = 120.9 [C(C-7)], 128.2 (CH), 128.5 (CH),
C NMR (CDCl ): d = 52.1 (CH ), 122.0 [CH(=CH)], 128.2 (CH),
3
3
3
1
(
(
29.6 (CH), 129.7 (CH), 129.8 (CH), 130.2 (CH), 136.4 (C), 137.8
C), 138.1 (C), 139.4 [CH(C-8)], 148.3 (C), 155.1 [CH(C-6)], 155.5
C), 156.5 (C).
128.5 (CH), 129.5 (CH), 129.7 (CH), 129.8 (CH), 130.3 (CH),
131.6 (C), 135.7 (C), 136.4 [CH(=CH)], 137.8 (C), 138.3 (C), 140.0
[CH(C-8)], 150.3 (C), 153.1 [CH(C-6)], 155.6 (C), 156.8 (C), 166.5
(C=O).
Anal. Calcd for C H BrN (362.22): C, 63.00; H, 3.34; Br, 22.06;
19
12
3
N, 11.60. Found: C, 62.83; H, 3.45; Br, 22.29; N, 11.63.
Anal. Calcd for C H N O (367.40): C, 75.19; H, 4.66; N, 11.44.
2
3
17
3
2
Found: C, 75.19; H, 4.85; N, 11.28.
7
-Alkynyl-2,3-diphenylpyrido[2,3-b]pyrazines 2; General Pro-
cedure
3-(2,3-Diphenylpyrido[2,3-b]pyrazin-7-yl)acrylonitrile (3b)
The crude product was purified by flash column chromatography on
silica gel; eluent: cyclohexane–EtOAc (3:1 → 1:1); yellow solid;
yield: 109 mg (65%); mp 188–199 °C.
A 25 mL Schlenk flask was charged with 7-bromo-2,3-diphenylpy-
rido[2,3-b]pyrazine (1; 181 mg, 0.5 mmol), Pd(PPh ) Cl (18 mg,
0
3
2
2
.025 mmol), CuI (10 mg, 0.05 mmol), anhyd Et N (5 mL), anhyd
3
DMF (5 mL) and alkyne (1.0 mmol). Argon was passed three times
and the mixture was heated at 100 °C for 24 h, the solvent was evap-
orated in vacuum, and the residue was purified by column chroma-
tography.
1
H NMR (CDCl ): d = 6.23 (d, 1 H, J = 17.0 Hz, =CH), 7.60 (d, 1
3
H, J = 17.0 Hz, =CH), 7.32–7.66 (m, 10 H, Ph-H), 8.53 (d, 1 H,
J6,8 = 2.3 Hz, H-8), 9.32 (d, 1 H, J6,8 = 2.3 Hz, H-6).
1
3
C NMR (CDCl ): d = 100.8 [CH(=CH)], 117.1 (C), 128.3 (CH),
3
1
(
1
28.5 (CH), 129.7 (CH), 130.0 (CH), 130.3 (CH), 130.5 (C), 135.3
4
-(2,3-Diphenylpyrido[2,3-b]pyrazin-7-yl)but-3-yn-1-ol (2a)
C), 136.0 [CH(=CH)], 137.6 (C), 138.0 (C),145.8 [CH(C-8)],
50.6 (C), 151.9 [CH(C-6)], 155.9 (C), 157.4 (C).
The residue was purified by column chromatography on silica gel;
eluent: EtOAc; yellow solid; yield: 172 mg (98%); mp 165–167 °C.
1
Anal. Calcd for C H N (334.37): C, 79.02; H, 4.22; N, 16.76.
22 14 4
Found: C, 79.14; H, 4.35; N, 16.67.
H NMR (CDCl ): d = 2.06 (br, 1 H, OH), 2.79 (t, 2 H, J = 6.4 Hz,
3
CH ), 3.90 (t, 2 H, J = 6.4 Hz, CH ), 7.29–7.61 (m, 10 H, Ph-H),
2
2
8
.44 (d, 1 H, J6,8 = 3.0 Hz, H-8), 9.09 (d, 1 H, J6,8 = 3.0 Hz, H-6).
2
-[3-(2,3-Diphenylpyrido[2,3-b]pyrazin-7-yl)allyl]isoindole-1,3-
1
3
C NMR (CDCl ): d = 24.0 (CH ), 60.8 (CH ), 78.6 (C), 93.4 (C),
3
2
2
dione (3c)
1
1
1
28.2 (CH), 128.4 (CH), 129.4 (CH), 129.6 (CH), 129.8 (CH),
30.2 (CH), 135.3 (C), 137.8 (C), 138.3 (C), 139.5 [CH(C-8)],
48.5 (C), 155.3 (C), 156.1 (C), 156.2 [CH(C-6)].
The crude product was purified by flash column chromatography on
silica gel; eluent: cyclohexane–EtOAc (3:1 → 1:1); light yellow
solid; yield: 78 mg (33%); mp 89–91 °C.
Anal. Calcd For C H N O (351.40): C, 78.61; H, 4.88; N, 11.96.
Found: C, 78.90; H, 5.12; N, 11.65.
1
23
17
3
H NMR (CDCl ): d = 4.57 (dd, 2 H, J = 6.3, 1.1 Hz, CH ), 6.63 (dt,
3
2
1
H, J = 16.0, 6.3 Hz, =CH), 6.87 (d, 1 H, J = 16.0 Hz), 7.31–7.63
(
m, 10 H, Ph-H), 7.75 (dd, 2 H, J = 5.7, 3.0 Hz, Ph-H), 7.90 (dd, 2
H, J = 5.7, 3.0 Hz, Ph-H), 8.37 (d, 1 H, J6,8 = 2.3 Hz, H-8), 9.19 (d,
H, J6,8 = 2.3 Hz, H-6).
[
3-(2,3-Diphenylpyrido[2,3-b]pyrazin-7-yl)prop-2-ynyl]di-
methylamine (2b)
The residue was purified by column chromatography on silica gel;
eluent: EtOAc–MeOH (4:1); light yellow solid; yield: 133 mg
(
1
1
3
C NMR (CDCl ): d = 39.5 (CH ), 123.5 [CH(=CH)], 128.0 (CH),
3
2
1
1
1
28.1 (CH), 128.4 (CH), 129.1 (CH), 129.3 (CH), 129.4 (CH),
29.8 (CH), 130.3 (CH), 132.0 (C), 133.6 (C), 133.9 [CH(=CH)],
34.2 [CH(C-8)], 135.9 (C), 138.0 (C), 138.5 (C), 149.3 (C), 152.9
76%); mp 101–103 °C.
1
H NMR (CDCl ): d = 2.32 (s, 6 H, 2 CH ), 3.47 (s, 2 H, CH ), 7.20–
3
3
2
7
.53 (m, 10 H, Ph-H), 8.40 (d, 1 H, J6,8 = 2.3 Hz, H-8), 8.40 (d, 1 H,
CH(C-6), 155.0 (C), 155.7 (C), 167.9 (C).
J6,8 = 2.3 Hz, H-6).
1
Anal Calcd for C H N O (468.50): C, 76.91; H, 4.30; N, 11.96.
Found: C, 76.70; H, 4.48; N, 11.83.
3
30 20
4
C NMR (CDCl ): d = 44.3 (CH ), 48.6 (CH ), 81.7 (C), 91.0 (C),
3
3
2
1
(
1
21.7 (C), 128.1 (CH), 128.4 (CH), 129.4 (CH), 129.5 (CH), 129.8
CH), 129.8 (CH), 130.2 (CH), 135.3 (C), 137.9 (C) 138.3 (C),
39.6 [CH(C-8)], 148.6 (C), 155.2 (C), 156.1 [CH(C-6)].
7
-Substituted Amino 2,3-Diphenylpyrido[2,3-b]pyrazines 4;
General Procedure
Anal. Calcd for C H N (364.44): C, 79.10; H, 5.53; N, 15.73.
Found: C, 78.94; H, 5.69; N, 15.46.
A 25 mL Schlenk flask was charged with 7-bromo-2,3-diphenylpy-
rido[2,3-b]pyrazine (1; 181 mg, 0.5 mmol), Pd (dba) (10 mg, 0.01
2
4
20
4
2
3
mmol), BINAP (19 mg, 0.03 mmol), t-BuONa (68 mg, 0.7 mmol),
the appropriate substituted amine (1.0 mmol) and anhyd toluene (5
mL). Argon was passed inside and the mixture was heated to 110 °C
7
-Alkenyl-2,3-diphenylpyrido[2,3-b]pyrazines 3; General Pro-
cedure
A 25 mL Schlenk flask was charged with 7-bromo-2,3-diphenylpy-
for 24 h. After cooling, H O (50 mL) was added, and the mixture
2
rido[2,3-b]pyrazine (1; 181 mg, 0.5 mmol), Pd(OAc) (11 mg,
was extracted with EtOAc (3 × 40 mL). The combined extracts
2
0
.05mol), P(o-tolyl) (15 mg, 0.05 mmol), Et N (200 mg, 2.0
were washed with H O (2 × 40 mL) and dried (MgSO ). After evap-
3
3
2
4
mmol), and MeCN (10 mL). Argon was passed inside and the ap-
propriate alkene (1.5 mmol) was added with a syringe. The mixture
was heated at 100 °C bath temperature for 20 h, the solvent was
evaporated and the residue was purified by column chromatography
on silica gel.
oration of the solvent, the residue was purified by column chroma-
tography.
Synthesis 2005, No. 8, 1345–1349 © Thieme Stuttgart · New York

1
348
L. Yin, J. Liebscher
PAPER
7
-(4-Methylpiperazin-1-yl)-2,3-diphenylpyrido[2,3-b]pyrazine
1-[4-(2,3-Diphenylpyrido[2,3-b]pyrazin-7-yl)phenyl]ethanone
(5b)
(
4a)
The crude product was purified by flash column chromatography on
silica gel; eluent: CH Cl –MeOH (10:1); brown solid; yield: 122
mg (68%); mp 164–166 °C.
The crude product was purified by flash column chromatography on
silica gel; eluent: cyclohexane–EtOAc (4:1 → 1:1); yellow solid;
yield: 101 mg (50%); mp 273–274 °C.
2
2
1
1
H NMR (CDCl ): d = 2.28 (s, 3 H, CH ), 2.55 (t, 4 H, J = 4.9 Hz,
H NMR (CDCl ): d = 2.66 (s, 3 H, CH ), 7.32–7.65 (m, 10 H, Ph-
3
3
3
3
2
7
6
CH ), 3.38 (t, 4 H, J = 4.9 Hz, 2 CH ), 7.20–7.51 (m, 2 H, Ph-H),
H), 7.88 (d, 2 H, J = 10.3 Hz, Ph-H), 8.13 (d, 2 H, J = 10.3 Hz, Ph-
H), 8.69 (d, 1 H, J6,8 = 2.6 Hz, H-8), 9.43 (d, 1 H, J6,8 = 2.6 Hz, H-6).
2
2
.47–7.51 (m, 11 H, Ph-H and H-8), 8.94 (d, 1 H, J6,8 = 3.0 Hz, H-
).
13
C NMR (CDCl ): d = 26.8 (CH ), 127.7 (CH), 128.2 (CH), 128.5
3
3
1
3
C NMR (CDCl ): d = 46.1 (CH ), 48.1 (CH ), 54.5 (CH ), 116.1
(CH), 129.4 (CH), 129.5 (CH), 129.6 (CH), 129.8 (CH), 130.3
(CH), 135.2 [CH(C-8)], 135. 8 (C), 136.8 (C), 137.0 (C), 137.9 (C),
138.4 (C), 140.9 (C), 149.4 (C), 153.1 [CH(C-6)], 155.4 (C), 156.4
(C), 197.5 (C=O).
3
3
2
2
[
(
[
CH(C-8)], 128.0 (CH), 128.3 (CH), 128.7 (CH), 128.9 (CH), 129.7
CH), 130.1 (CH), 137.3 (C), 139.0 (C), 139.0 (C), 144.3 (C), 147.3
CH(H-6)], 147.8 (C), 152.2 (C), 154.5 (C).
+
Anal. Calcd for C H N (381.47): C, 75.56; H, 6.08; N, 18.36.
HRMS (EI): m/z calcd for C H N O (M ): 401.15285; found:
2
4
23
5
27 19
3
Found: C, 75.44; H, 6.32; N, 18.07.
401.15281.
Anal. Calcd for C H N O (401.46): C, 80.78; H, 4.77; N, 10.47.
Found: C, 81.01; H, 4.92; N, 10.24.
2
7
19
3
N¢-(2,3-Diphenylpyrido[2,3-b]pyrazin-7-yl)-N,N-dimethylpro-
pane-1,3-diamine (4b)
The crude product was purified by flash column chromatography on
standard neutral Al O ; eluent: EtOAc–MeOH (10:1); brown solid;
yield: 140 mg (73%); mp 150–152 °C.
2
3
Acknowledgment
We gratefully acknowledge the financial support from Deutsche
Forschungsgemeinschaft, Fonds der Chemischen Industrie and El-
bion AG.
1
H NMR (CDCl ): d = 1.83 (m, 2 H, CH ), 2.25 (s, 6 H, 2 CH ), 2.43
3
2
3
(
(
t, 2 H, J = 5.7 Hz, CH ), 3.30 (m, 2 H, CH ), 6.42 (s, 1 H, NH), 7.20
2
2
d, 1 H, J6,8 = 3.0 Hz, H-8), 7.27–7.57 (m, 10 H, Ph-H), 8.68 (d, 1
H, J6,8 = 3.0 Hz, H-6).
1
3
C NMR (CDCl ): d = 25.4 (CH ), 43.3 (CH ), 45.5 (CH ), 58.5 References
3
2
2
3
(
1
(
CH ), 108.4 [CH(C-8)], 127.9 (CH), 128.2 (CH), 128.3 (CH),
28.7 (CH), 129.8 (CH), 130.1 (CH), 138.5 (C), 138.8 (C), 139.3
C), 143.6 (C), 145.9 (C), 147.9 [CH(C-6)], 150.0 (C), 154.0 (C).
2
(
1) (a) Auberson, Y. P.; Bischoff, S.; Moretti, R.; Schmutz, M.;
Veenstra, S. J. Bioorg. Med. Chem. Lett. 1998, 8, 65.
(b) Kim, K.; Qian, L.; Dickinson, K. E. J.; Delaney, C. L.;
Anal. Calcd for C H N (383.49): C, 75.17; H, 6.57; N, 18.26.
Found: C, 75.21; H, 6.72; N, 17.99.
Bird, J. E.; Waldron, T. L.; Moreland, S. Bioorg. Med.
Chem. Lett. 1993, 3, 2667. (c) Acklin, P.; Allgester, H.;
Auberson, Y. P.; Bischoff, S.; Ofner, S.; Sauer, D.; Schmutz,
M. Bioorg. Med. Chem. Lett. 1998, 8, 493. (d) Gazit, A.;
App, H.; McMahon, G.; Chen, J.; Levitzki, A.; Bohmer, F.
D. J. Med. Chem. 1996, 39, 2170. (e) Sehlstedt, U.; Aich,
P.; Bergman, J.; Vallberg, H.; Norden, B.; Graslund, A. J.
Mol. Biol. 1998, 278, 31. (f) Sheardown, M. J.; Nielsen, E.
O.; Hansen, A. J.; Jacobsen, P.; Honoré, T. Science 1990,
247, 571.
2
4
25
5
7
-Aryl-2,3-diphenylpyrido[2,3-b]pyrazines 5; General Proce-
dure
A 25 mL Schlenk flask was charged with 7-bromo-2,3-diphenylpy-
rido[2,3-b]pyrazine (1; 181 mg, 0.5 mmol), K CO (97 mg, 0.7
2
3
mmol), arylbronic acid (0.7 mmol), Pd(PPh3)4 (29 mg, 0.025
mmol), and anhyd toluene (10 mL). Argon was passed through the
mixture three times and the mixture was heated at 100 °C for 16 h.
The solvent was evaporated under vacuum, the residue was dis-
solved in CH Cl (50 mL) and was washed with H O (2 × 30 mL).
(2) (a) Reynolds, R. C.; Johnson, C. A.; Piper, J. R.; Sirotnak, F.
M. Eur. J. Med. Chem. 2001, 36, 237. (b) Rabow, A. A.;
Shoemaker, R. H.; Sausville, E. A.; Covell, D. G. J. Med.
Chem. 2002, 45, 818. (c) Froehlich, L. G.; Kotsonis, P.;
Hermann, T.; Schmidt, W.; Harald, H. H. W. J. Med. Chem.
1999, 42, 4108.
2
2
2
The organic layer was dried (MgSO ) and the solvent evaporated.
The residue was purified by column chromatography.
4
2
,3,7-Triphenylpyrido[2,3-b]pyrazine (5a)
The crude product was purified by flash column chromatography on
(3) (a) Birnbacher, R.; Messerschmidt, A. M.; Pollak, A. P.
Curr. Opin. Urol. 2002, 12, 461. (b) Hart, B. P.; Haile, W.
H.; Licato, N. J.; Bolanowska, W. E.; McGuire, J. J. J. Med.
Chem. 1996, 39, 56. (c) Cravo, M. L.; Pinto, A. G.; Chaves,
P. Clin. Nutr. 1998, 17, 45. (d) McNulty, H.; Cuskelly, G.
J.; Ward, M. Am. J. Clin. Nutr. 2000, 71, 1308S.
silica gel; eluent: cyclohexane–EtOAc (6:1 → 2:1); light yellow
solid; yield: 172 mg (96%); mp 172–173 °C. (Lit. mp 282–
2
1
1
4
84 °C !).
H NMR (CDCl ): d = 7.31–7.82 (m, 15 H, Ph-H), 8.67 (d, 1 H,
3
J6,8 = 2.6 Hz, H-8), 9.45 (d, 1 H, J6,8 = 2.6 Hz, H-6).
1
(
4) (a) Benohr, H. C.; Dreher, R.; Neunhoffer, J.; Waller, H. D.
Verh. Dtsch. Ges. Inn. Med. 1973, 79, 464. (b) Starlinger,
H. Hoppe-Seylers Z. Physiol. Chem. 1977, 358, 491.
5) (a) Dailey, S.; Feast, J. W.; Peace, R. J.; Sage, I. C.; Till, S.;
Wood, E. L. J. Mater. Chem. 2001, 11, 2238. (b) O’Brien,
D.; Weaver, M. S.; Lidzey, D. G.; Bradley, D. D. Appl. Phys.
Lett. 1996, 69, 881.
3
C NMR (CDCl ): d = 127.6 (CH), 128.2 (2 CH), 128.5 (CH),
3
1
1
(
29.0 (CH), 129.3 (CH), 129.4 (CH), 129.8 (CH), 130.3 (CH),
34.5 [CH(C-8)], 136.0 (C), 136.5 (C), 138.1 (C), 138.6 (C), 149.1
C), 153.6 [CH(C-6)], 155.1 (C), 155.9 (C).
(
+
HRMS (EI): m/z calcd for C H N (M ): 359.14225; found:
3
2
5
17
3
59.14226.
(
6) (a) Yamamoto, T.; Sugiyama, K.; Kushida, T.; Inoue, T.;
Kanbara, T. J. Am. Chem. Soc. 1996, 118, 3930.
Anal. Calcd for C H N (359.42): C, 83.54; H, 4.77; N, 11.69.
Found: C, 83.69; H, 4.83; N, 11.48.
2
5
17
3
(b) Nurulla, I.; Yamaguchi, I.; Yamamoto, T. Polym. Bull.
2
2
000, 44, 231. (c) Mao, L.; Sakurai, H.; Hirao, T. Synthesis
004, 2535.
Synthesis 2005, No. 8, 1345–1349 © Thieme Stuttgart · New York

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(
(
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27.
8) (a) Abbott, L. C.; Arnold, C. J.; Ye, T. Q. J. Phys. Chem. A
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1
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(
b) Tsuji, J. Palladium Reagents and Catalysts: Innovations
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(
Palladium-Catalyzed Organic Reactions; Academic Press:
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Synthesis 2005, No. 8, 1345–1349 © Thieme Stuttgart · New York