Pyrido[3,4-b]pyrazines. A new application of 2-chloro-3,4-diaminopyridine

Article abstract of DOI:10.3987/com-02-9666

5-Chloropyrido[3,4-b]pyrazines were prepared from 1,2-dicarbonyl compounds and 2-chloro-3,4-diaminopyridine. Condensation of unsymmetrical glyoxals provided a mixture of two regiosiomers with 2-substituted pyrido[3,4-b]-pyrazines as the major product. The regiochemistry was unambiguously assigned by 2D-NMR experiments. C-C- and C-N coupling reactions of 5-chloro or 5-oxo intermediates afforded the corresponding C-5 or N-6 substituted derivatives.

Full text of DOI:10.3987/com-02-9666

HETEROCYCLES, Vol. 60, No. 4, 2003
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HETEROCYCLES, Vol. 60, No. 4, 2003, pp. 925 - 932
Received, 5th November, 2002, Accepted, 27th January, 2003, Published online, 4th February, 2003
PYRIDO[3,4-b]PYRAZINES.
A NEW APPLICATION OF 2-CHLORO-3,4-DIAMINOPYRIDINE
Werner W. K. R. Mederski,§, Dieter Kux,§ Markus Knoth,± and Markus J.
*
Schwarzkopf-Hofmann±
Merck KGaA, Preclinical Pharmaceutical Research§ and Central Services
±
*
Analysis , 64271 Darmstadt, Germany E-mail: mederski@merck.de
Abstract - 5-Chloropyrido[3,4-b]pyrazines were prepared from 1,2-dicarbonyl
compounds and 2-chloro-3,4-diaminopyridine. Condensation of unsymmetrical
glyoxals provided a mixture of two regiosiomers with 2-substituted pyrido[3,4-b]-
pyrazines as the major product. The regiochemistry was unambiguously assigned
by 2D-NMR experiments. C-C- and C-N coupling reactions of 5-chloro or 5-oxo
intermediates afforded the corresponding C-5 or N-6 substituted derivatives.
One of the current aims in medicinal chemistry is the search for unique and patentable scaffolds. These
scaffolds equipped with appropriate side chains and functional groups should give rise to new
pharmacological active molecules.
In this respect 2-chloro-3,4-diaminopyridine (CDAP) (1) served as a starting point for the synthesis of
the scaffold imidazo[4,5-c]pyridin-5-one (2) (Figure 1). Some of these 2,3,5-trisubstituted derivatives
led to potent angiotensin AT1-antagonists1 and others to mixed AT1-/AT2-antagonists2 as well. In order
to find new bicyclic heterocycles from CDAP pyrido[3,4-b]pyrazines of the common structure (3) were
envisaged (Figure 1).
2 N
N
N
3
5
H2N
H2N
N
N
or
N
N
N
2
Cl
O
6
N
2 Imidazo[4,5-c]pyridine
1
N
3
O
3 Pyrido[3,4-b]pyrazine
Figure. 1
A literature survey revealed only one compound 2-chloropyrido[3,4-b]pyrazine (5a) mentioned as an
intermediate in a patent application3 and the use of CDAP to form a tetracyclic compound.4 In general

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HETEROCYCLES, Vol. 60, No. 4, 2003
2,3-disubstituted pyrido[2,3-b]pyrazines and pyrido[3,4-b]pyrazines have been synthesized by
condensing the appropriate ortho substituted diaminopyridine with 1,2-dicarbonyl derivatives such as
4.5,6 Condensation of cyclic diketo derivatives with diaminopyridines, however, led to isomeric mixtures
of tetrameric heterocycles.7,8
In this paper the synthesis of 5-chloropyrido[3,4-b]pyrazines and subsequent functionalization reactions
to C-5 or N-6 substituted derivatives together with the structural characterization of regioisomers by
NMR spectroscopy is described.
In order to evaluate the reactivity of CDAP to form the 5-chloropyrido[3,4-b]pyrazines the commercial
available 1,2-dicarbonyls such as glyoxal, diacetyl, benzil, methyl- and phenyl glyoxal were chosen.
Pyrido[3,4-b]pyrazines (5a – 5f) were prepared in moderate to good yields by condensing the respective
diketo compound with CDAP in refluxing ethanol (Scheme 1). In these cases diacetyl was the least
5a R = R1 = H
5b R = R1 = Me
5c R = R1 = Ph
5d R = Me, R1 = H
5e R = H, R1 = Me
5f R = Ph, R1 = H
R
N
N
O
H2N
H2N
EtOH, reflux
20 h
R1
+
N
R
N
R1
O
Cl
Cl
4
1
Scheme 1
reactive compound which led to 5b in only 60% yield. However, methyl glyoxal converted CDAP to the
corresponding regioisomers (5d) and (5e). The major isomer (5d) is thought to arise from attack by the
more nucleophilic 3-amino group on the more electrophilic formyl function. The 2- and 3-methyl
derivatives (5d) and (5e) were separated by chromatography and characterized by NMR spectroscopy.
1
The H NMR spectral data, chemical shifts and coupling constants of both molecules (5d) and (5e) are
depicted in Table 1.
Table 1:
Compound (5d)
Chemical shift (ppm)
Coupling
Coupling constant (Hz)
H1
H2
H3
H4
8.59
7.95
9.07
2.80
3J(1,2)
5.7
5.7
-
3J(1,2)
-
-
-
Compound (5e)
H1
H2
H3
H4
8.57
8.01
9.16
2.81
3J(1,2)
5.7
5.7
-
3J(1,2)
-
-
-
1
The H NMR spectra, the intensities of the signals, their chemical shifts and coupling constants, were
very similar and it was therefore impossible to determine to which C-atom of the pyrazine ring the
methyl substituent was attached.
In general for molecules of this type it proved advantageous to record HMBC spectra (Hetero-Multi-
1
Bond-Correlation). With standard H-13C-HMBC it was impossible to verify one of the two structures.

HETEROCYCLES, Vol. 60, No. 4, 2003
927
1
The problem could, however, be solved in an elegant and unambiguous fashion by observing H-15N-
HMBC spectra. The results of these investigations are shown in Figure 2.
5d
3
1
2
4
(ppm)
304
b
2
a
4
N
1
a
312
320
328
N
3
N
c
Cl
b
c
(ppm)
8.0
6.0
4.0
2.0
5e
4
2
3
1
(ppm)
304
b
2
N
1
3
a
c
312
320
328
N
a
4
N
c
Cl
b
(ppm)
8.0
6.0
4.0
2.0
Figure. 2
The assignment of the protons and nitrogens and for that reason the position of the methyl group was
now straightforward from the interpretation of the cross signals. In both molecules proton 1 has just one
coupling partner within nitrogen a. Proton 2 couples with nitrogen a and nitrogen b (indicated by an
arrow). So it is easily shown that nitrogen b and nitrogen c switch their places in the spectra. The cross
peak from the methyl group (4) into nitrogen b and the signal proton 3/nitrogen c in the upper spectrum

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HETEROCYCLES, Vol. 60, No. 4, 2003
confirm unambiguously the assignment to structure (5d), while the corresponding signals of the lower
spectrum fit into structure (5e).
Treatment of CDAP with phenyl glyoxal gave rise to 2-phenyl derivative (5f) after recrystallization of
the crude isomeric mixture9 from ethanol in 79% yield. The structure of 5f was assigned on the basis of
the spectroscopic results of the methyl analogue, the mechanism, the reaction outcome (5f as the main
product) and similar literature results with 3,4-diaminopyridine as the corresponding nucleophile.10
With the key intermediates (5a – 5f) in hand, we focused our attention on the chloro atom in 5-position
of the pyrido[3,4-b]pyrazine scaffold. At the outset of these studies C- and N-arylations at the chloro
position were envisaged (Scheme 2).
Pd2(dba)3, dppf
Zn, Zn(CN)2, DMA
Me
N
Me
N
N
N
N
N
5d
Cl
6
N
Ph
N
Ph
N
PhCH2NH2
N
N
N
N
N
7
5f
Cl
Cl
HN
Ph
Ph
N
N
Ph
Ph
N
HCO2H, H2O
NH
N
8
O
5c
4OMe-C6H4B(OH)2, Cu(OAc)2
MS 4A, pyridine, DCM
4OMe-C6H4CH2Cl,
K2CO3, DMF
Ph
Ph
N
OMe
Ph
N
N
N
N
N
Ph
O
10
9
OMe
O
Scheme 2
To extand the scope of a recently published Pd-catalyzed cyanation reaction11 2-methyl isomer (5d) was
converted with Zn(CN)2 as the cyanide source in the presence of catalytic amounts of Zn powder,
Pd2(dba)3 and dppf to 5-cyano derivative (6) in 59% yield. An amination reaction without using any
catalysts was investigated with the primary benzylamine. The coupling of benzylamine with compound
(5f) gave the required adduct (7) in excellent yields. In order to get access to the N-6 nitrogen atom in
the pyrido[3,4-b]pyrazine moiety chloro derivative (5c) was hydrolized in aqueous formic acid to
provide 5-oxo derivative (8) in 91% yield. Parts of the structure of compound (8) can be regarded as a 2-

HETEROCYCLES, Vol. 60, No. 4, 2003
929
pyridone. In general those compounds can react as ambident nucleophiles to give mixtures of N/O-
products. However, when compound (8) was alkylated with 4-methoxybenzyl chloride and potassium
carbonate in dimethylformamide exclusive formation of 9 occurred in high yield. Next, a recent
developed method to N-arylate pyridone systems was applied.12 4-Methoxyphenylboronic acid
underwent coupling with cupric acetate and compound (8) to the 4-methoxy derivative (10). In both
reactions no traces of O-alkylation or O-arylation products were found, respectively.
In summary, it has been shown that condensation of CDAP with different 1,2-dicarbonyls provided the
corresponding 5-chloropyrido[3,4-b]pyrazines in good yields. With unsymmetrical glyoxals the 2-
substituted adducts were obtained as major products. In one case this was confirmed by NMR
experiments. Subsequent C-C- and C-N coupling reactions afforded the appropriate C-5 or N-6
substituted derivatives in good yields.
Therefore, the 5-chloropyrido[3,4-b]pyrazine scaffold can be of use as an intermediate in the design of
new drug candidates.
EXPERIMENTAL
Melting points were determined with a HWS Labortechnik SGV 500 Plus melting point apparatus and
are uncorrected. IR, NMR and MS spectra are in agreement with the structures cited and were recorded
on a Bruker 85 IFS 48 IR spectrophotometer, a Bruker Avance 250, AMX 300, Avance 400 or Avance
DRX 500 (TMS as internal standard), and a Micromass (Manchester, England) VG 70-70E (electron-
impact: EI) or 70-250SE (fast atom bombardement: FAB) at 70eV, respectively. HRMS spectra were
recorded on a Autospec M from Micromass. Microanalyses were obtained with a Perkin-Elmer 240B
CHN analyzer. TLC was carried out on precoated silica gel 60 F254 plates with a layer thickness of 0.25
mm from Merck KGaA (Darmstadt, Germany). Visualization was performed with UV and I2. Yields
were not optimized. The preparative chromatography was performed on Merck KGaA silica gel 60
(230-400 mesh) and all solvents were of Merck extra-pure grade. The 15N-HMBC spectra were
measured on a Bruker Avance 400 MHz spectrometer with about 50 mg of compound (5d) and (5e),
each dissolved in 0.7 mL of DMSO-d6 (99.95% D, Merck KGaA, Darmstadt). The spectra were
obtained with a standard HMBC pulse programme (inv4gplplrnd) with z-gradients (relevant parameters:
SW(1H)= 4006 Hz, SW(15N)= 4056 Hz, AQ= 0.13s, TD= 1024pts., RD= 1.5s, NS= 96, number of
FID´s= 256, J(H,N)= 8 Hz). Data were multiplied with a pure sinebell window in both directions and
zero-filled to give a 2K ∗ 512 Matrix after Fourier-transformation. The internal standard in 1H direction
was TMS, in 15N direction was made a standard calibration with NH3(l) as reference set to zero.
5-Chloropyrido[3,4-b]pyrazine (5a): To 30 mL of ethanol was added 2.12 mL (13.93 mmol) of
glyoxal (30% in water) and 2.0 g (13.93 mmol) of 2-chloro-3,4-diaminopyridine (1a). The mixture was
refluxed for 20 h. On cooling the crude precipitated product was filtered off, washed with 20 mL of
ethanol and dried. The resulting product was purified by recrystallization from ethanol to yield 1.88 g
1
(81.5 %) of 5a: mp 141-143°C. MS (EI): m/z = 165 (M+, 100%), 167 (35%). H NMR (DMSO-d6) δ

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HETEROCYCLES, Vol. 60, No. 4, 2003
9.26 (d, J = 1.8 Hz, 1H), 9.19 (d, J = 1.8 Hz, 1H), 8.65 (d, J = 5.7 Hz, 1H), 8.07 (d, J = 5.7 Hz, 1H).
HRMS calcd for (M+) m/z 165.0094, found m/z 165.0095. Anal. Calcd for C7H4N3Cl: C, 50.78; H, 2.43;
N, 25.38. Found: C, 50.40; H, 2.50; N, 25.70.
5-Chloro-2,3-dimethylpyrido[3,4-b]pyrazine (5b): This compound was prepared from CDAP and
diacetyl (4 R, R’ = Me) by the method described above with a yield of 60% after recrystallization from
ethanol: mp 121-123°C. MS (EI): m/z = 193 (M+, 100%), 195 (35%). 1H NMR (DMSO-d6) δ 8.50 (d, J
= 5.6 Hz, 1H), 7.90 (d, J = 5.6 Hz, 1H), 2.76 (s, 6H). HRMS calcd for (M+) m/z 193.0407, found m/z
193.0407. Anal. Calcd for C9H8N3Cl: C, 55.83; H, 4.16; N, 21.70. Found: C, 55.70; H, 4.10; N, 22.00.
5-Chloro-2,3-diphenylpyrido[3,4-b]pyrazine (5c): This compound was prepared from CDAP and
benzil (4 R, R’ = Ph) by the method described above with a yield of 91% after recrystallization from
ethanol: mp 146-148°C. MS (EI): m/z = 317 (M+,100 %), 319 (33%). 1H NMR (DMSO-d6) δ 8.64 (d, J
= 5.7 Hz, 1H), 8.08 (d, J = 5.7 Hz, 1H), 7.60-7.34 (m, 10H). HRMS calcd for (M+) m/z 317.0720, found
m/z 317.0728. Anal. Calcd for C19H12N3Cl: C, 71.81; H, 3.81; N, 13.22. Found: C, 71.95; H, 3.60; N,
13.44.
5-Chloro-2-methylpyrido[3,4-b]pyrazine (5d) and 5-Chloro-3-methylpyrido[3,4-b]pyrazine (5e):
These compounds were prepared from CDAP and methyl glyoxal (4 R = H, R’ = Me) by the method
described above and provided after chromatography on silica gel with dichloromethane/ tert-butyl
methyl ether = 95/5 82% of 5d and 12% of 5e. 5d: mp >280°C (from ethanol). MS (EI): m/z = 179 (M+,
100%), 181 (33%). HRMS calcd for (M+) m/z 179.0250, found m/z 179.0248. Anal. Calcd for
C8H6N3Cl: C, 53.50; H, 3.37; N, 23.40. Found: C, 53.50; H, 3.40; N, 23.00. 5e: mp 145-147°C. MS (ei):
m/z = 179 (M+, 100%), 181 (35%). HRMS calcd for (M+) m/z 179.0250, found m/z 179.0250. Anal.
Calcd for C8H6N3Cl: C, 53.50; H, 3.37; N, 23.40. Found: C, 53.40; H, 3.50; N, 23.30.
5-Chloro-2-phenylpyrido[3,4-b]pyrazine (5f): This compound was prepared from CDAP and phenyl
glyoxal monohydrate (4 R = H, R’ = Ph) by the method described above with a yield of 79% after
recrystallization of the crude isomeric mixture from ethanol: mp 189-190°C. MS (EI): m/z = 241 (M+,
1
100%), 243 (35%). H NMR (DMSO-d6) δ 9.80 (s, 1H), 8.64 (d, J = 5.7 Hz, 1H), 8.46-8.36 (m, 2H),
8.07 (d, J = 5.7 Hz, 1H), 7.71-7.62 (m, 3H). HRMS calcd for (M+) m/z 241.0402, found m/z 241.0404.
Anal. Calcd for C13H8N3Cl: C, 64.61; H, 3.34; N, 17.39. Found: C, 64.20; H, 3.50; N, 17.10.
2-Methylpyrido[3,4-b]pyrazine-5-carbonitrile (6): To 250 mg (1.376 mmol) of 5-chloro-2-
methylpyrido[3,4-b]pyrazine (5d), 25 mg (2 mol %) of tris(dibenzylidenacetone)palladium(0), 30.0 mg
(4 mol %) of 1,1’-bis(diphenylphosphino)ferrocene, 10.5 mg (12 mol %) of zinc dust and 97.0 mg
(0.827 mmol) of zinc cyanide was added 10.0 mL of N,N-dimethylacetamide under a nitrogen
atmosphere. The mixture was heated at 120°C for 24 h. It was cooled to rt, diluted with ethyl acetate,
and then washed with 2N ammonium hydroxide solution and brine. After drying over sodium sulfate,

HETEROCYCLES, Vol. 60, No. 4, 2003
931
the ethyl acetate solution was evaporated under reduced pressure. The residue was chromatographed on
silca gel using ethyl acetate / hexane (60:40) to provide 160 mg (59%) of 6: mp >170°C (decomp, from
1
ethanol). IR (KBr) 2235 cm-1. MS (FAB): m/z = 171 (M+H+, 100%). H NMR (DMSO-d6) δ 9.16 (s,
1H), 8.96 (d, J = 5.7 Hz, 1H), 8.28 (d, J = 5.7 Hz, 1H), 2.83 (s, 3H). HRMS calcd for (M+) m/z
170.0592, found m/z 170.0595. Anal. Calcd for C9H6N4: C, 63.52; H, 3.55; N, 32.92. Found: C, 63.46;
H, 3.49; N, 32.71.
Benzyl-(2-phenylpyrido[3,4-b]pyrazin-5-yl)amine (7): To 20 mL of benzylamine was added 1.06 g
(4.355 mmol) of 5-chloro-2-phenylpyrido[3,4-b]pyrazine (5f). The mixture was stirred at 130°C for 4 h.
After cooling, it was partitioned between brine and ethyl acetate. The organic extract was washed with
10% hydrochloric acid. The precipitated solid was collected and dried. The resulting product was
purified by recrystallization from ethanol to yield 1.345 g (99%) of 7: mp 250-252°C. MS (FAB): m/z =
313 (M+H+,100 %). 1H NMR (DMSO-d6) δ 10.32 (br s, 1H), 9.61 (s, 1H), 8.40 (dd, J = 2.3 und J = 3.7
Hz, 2H), 7.95 (d, J = 7.0 Hz, 1H), 7.70-7.62 (m, 3H), 7.51 (dd, J = 7.3 und J = 1.4 Hz, 2H), 7.41-7.28
(m, 3H), 7.25 (d, J = 7.0 Hz, 1H), 4.99 (d, J = 6.6 Hz, 2H). HRMS calcd for (M+) m/z 312.1375, found
m/z 312.1374. Anal. Calcd for C20H16N4: C, 76.90; H, 5.16; N, 17.94. Found: C, 76.95; H, 5.03; N,
17.64.
2,3-Diphenyl-6H-pyrido[3,4-b]pyrazin-5-one (8): To 15 mL of formic acid and 5 ml of water was
added 1.0 g (3.147 mmol) of 5-chloro-2,3-diphenylpyrido[3,4-b]pyrazine (5c). The mixture was stirred
at 80°C for 12 h. On cooling the crude precipitated product was filtered off, washed with 20 mL water
and dried. The resulting product was purified by recrystallization from ethanol to yield 857 mg (91%) of
8: mp > 300°C. IR (KBr) 1665 cm-1. MS (EI): m/z = 299 (M+, 100%). 1H NMR (DMSO-d6) δ 7.57 (d, J
= 7.3 Hz, 1H), 7.52-7.29 (m, 10H), 6.71 (d, J = 7.3 Hz, 1H). HRMS calcd for (M+) m/z 299.1059, found
m/z 299.1058. Anal. Calcd for C19H13N3O: C, 76.24; H, 4.38; N, 14.04. Found: C, 75.91; H, 4.50; N,
14.09.
6-(4-Methoxybenzyl)-2,3-diphenyl-6H-pyrido[3,4-b]pyrazin-5-one (9): To 50 mL of dimethylform-
amide was added 370 mg (1.236 mmol) of 2,3-diphenyl-6H-pyrido[3,4-b]pyrazin-5-one (8). This
mixture was treated with 205 mg (1.483 mmol) of potassium carbonate and 0.2 mL (1.483 mmol) of 4-
methoxybenzyl chloride. The reaction mixture was allowed to stir at rt over night. On diluting with
water the crude precipitated product was filtered off, washed with 50 mL water and dried. The resulting
product was purified by recrystallization from ethanol to yield 492 mg (91%) of 9: mp 285-287°C. IR
(KBr) 1660 cm-1. MS (FAB): m/z = 420 (M+H+, 35%). 1H NMR (DMSO-d6) δ 7.98 (d, J = 7.6 Hz, 1H),
7.52-7.30 (m, 12H), 6.91 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 7.6 Hz, 1H), 5.21 (s, 2H), 3.73 (s, 3H). HRMS
calcd for (M+) m/z 419.1633, found m/z 419.1625. Anal. Calcd for C27H21N3O2: C, 77.31; H, 5.05; N,
10.02. Found: C,77.61 ; H, 5.14; N, 10.30.

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HETEROCYCLES, Vol. 60, No. 4, 2003
6-(4-Methoxyphenyl)-2,3-diphenyl-6H-pyrido[3,4-b]pyrazin-5-one (10): A mixture of 750 mg (2.5
mmol) of 2,3-diphenyl-6H-pyrido[3,4-b]pyrazin-5-one (8) , 1.14 g (7.5 mmol) of 4-methoxyphenyl-
boronic acid, 253 mg (5.5 mmol) of anhydrous cupric acetate, 1.5 g of activated 4 Å molecular sieve and
1.0 mL (12.4 mmol) of pyridine, in dichloromethane (40 mL) was treated at rt for 48 h. The reaction
mixture was poured into water and extracted with dichloromethane. The organic phase was washed with
saturated sodium bicarbonate solution and 10% hydrochloric acid in succession, and then dried and
evaporated. The resulting product was purified by recrystallization from ethanol to yield 793 mg (78%)
1
of 10: mp 155-156°C. IR (KBr) 1679 cm-1. MS (EI): m/z = 405 (M+, 100%). H NMR (DMSO-d6) δ
7.81 (d, J = 7.6, 1H), 7.52-7.34 (m, 12H), 7.11 (d, J = 8.9, 2H), 6.84 (d, J = 7.6, 1H), 3.84 (s, 3H).
HRMS calcd for (M+) m/z 405.1477, found m/z 405.1474. Anal. Calcd for C26H19N3O2: C, 77.02; H,
4.72; N, 10.36. Found: C, 76.80; H, 4.60; N, 9.90.
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