Synthesis of 1,2,3,4-tetrahydropyrido- [2,3-b]pyrazine-2,3-dione derivatives with a chiral substituent at the nitrogen atom

Article abstract of DOI:10.1007/s10593-009-0249-z

The sequence of steps including nucleophilic substitution of the chlorine atom in 2-chloro-3-nitropyridine by esters of optically active phenylalanine, reduction of the nitro group, acylation with ethyl oxalyl chloride, and intramolecular cyclization, leads to the synthesis of derivatives of 1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-2,3-dione with a chiral substituent at the nitrogen atom. It was established that, depending on the conditions of carrying out the cyclization, the parallel formation of derivatives of imidazo[4,5-b]pyridine is possible. Conditions were found for selectively carrying out the cyclization under with only structures of pyrazines or imidazole condensed with pyridine were formed.

Full text of DOI:10.1007/s10593-009-0249-z

Chemistry of Heterocyclic Compounds, Vol. 45, No. 2, 2009
SYNTHESIS OF 1,2,3,4-TETRAHYDROPYRIDO-
[2,3-b]PYRAZINE-2,3-DIONE DERIVATIVES WITH
A CHIRAL SUBSTITUENT AT THE NITROGEN ATOM*
A. V. Kurkin1, K. V. Bukhryakov1, and M. A. Yurovskaya1**
The sequence of steps including nucleophilic substitution of the chlorine atom in 2-chloro-
3-nitropyridine by esters of optically active phenylalanine, reduction of the nitro group, acylation with
ethyl oxalyl chloride, and intramolecular cyclization, leads to the synthesis of derivatives of 1,2,3,4-
tetrahydropyrido[2,3-b]pyrazine-2,3-dione with a chiral substituent at the nitrogen atom. It was
established that, depending on the conditions of carrying out the cyclization, the parallel formation of
derivatives of imidazo[4,5-b]pyridine is possible. Conditions were found for selectively carrying out the
cyclization under with only structures of pyrazines or imidazole condensed with pyridine were formed.
Keywords: tert-butyl ester of imidazo-[4,5-b]pyridine-2-carboxylic acid, 2-chloro-3-nitropyridine,
1,2,3,4-tetrahydropyrido[2,3-b]pyrazine-2,3-diones, chiral substituent at the nitrogen atom, esters of
optically active phenylalanine, nucleophilic substitution.
Derivatives of 1,2,3,4-tetrahydro-2,3-dioxoquinoxalines, based on their affinity towards the AMPA
receptor, are used as medicinal agents suitable for the treatment of illnesses caused by the hyperactivity of
exciting amino acids such as glutamic or aspartic for example [1]. Such illnesses include Parkinson’s disease,
Alzheimer’s disease, Huntington’s chorea, etc. Particular attention has been paid recently to derivatives of
1,4-dihydropyrido[2,3-b]pyrazines, since replacement of the benzene fragment in the quinoxaline molecule by
pyridine significantly strengthens the biological action of such preparations due to the high affinity to the
benzodiazepine receptors as well. Consequently such compounds may be used for the prophylaxis of post-
ischemic cell death, the death of cells after trauma of the brain, on insult, hypoxia, anoxia, and hypoglycemia,
and also epilepsy, and muscular spasms [2]. In addition the clearly marked tendency in contemporary medical
practice to use chiral enantiomerically pure compounds as drug substances must be considered.
In this connection the aim of our investigation was the development of methods of synthesis of
derivatives of 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinediones with a chiral substituent at the nitrogen atom. As a
source of chirality we used enantiomerically pure esters of phenylalanine 1a-c. To obtain the desired derivatives
of 1,2,3,4-tetrahydropyrido[2,3-b]pyrazines 7 we proposed the following synthetic route.
_______
* Dedicated to Academician J. Stradins in connection with his 75th jubilee.
** To whom correspondence should be addressed, e-mail: kurkin@direction.chem.msu.ru.
1M. V. Lomonosov Moscow State University, Moscow 119992, Russia .
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 237-243, February, 2009. Original
article submitted November 26, 2008.
188
0009-3122/09/4502-0188©2009 Springer Science+Business Media, Inc.

Nucleophilic substitution of the chlorine atom in 2-chloro-3-nitropyridine with esters of L-phenyl-
alanine 1a-c on heating in DMF in the presence of triethylamine leads to the formation of esters of N-(3-nitro-
2-pyridyl)-L-phenylalanine 2a-c in moderate yield. Initial experiments on the catalytic hydrogenation of ethyl
ester 2a showed that it is accompanied by spontaneous cyclization into 3-benzyl-1,2,3,4-tetrahydropyrido-
[2,3-b]pyrazin-2-one (5) in quantitative yield. Based on literature data [3] we proposed that the use of the benzyl
(2b) or tert-butyl (2c) esters may prevent the spontaneous cyclization on reduction of the nitro group. However,
according to data of chromato-mass spectrometry (LCMS) on hydrogenation of the benzyl ester 2b a complex
mixture is formed containing, together with compound 5, acid 6 (~30%) the product of debenzylation of the
initial ester, consequently the most convenient subject for further investigation proved to be the tert-butyl ester
3c. The L-phenylalanine tert-butyl ester (2c) necessary for obtaining ester 3c was synthesized by us by a
modification of the procedure of [4] from L-phenylalanine and isobutene in an autoclave in the presence of
sulfuric acid.
4
NO2
3
NO2
NH
NH2
NH
5
6
NH2
2
1
H2
N
Cl
OR
N
N
Pd/C
Et3N, DMF
OR
OR
Ph
O
1a–c
Ph
O
Ph
O
2a–c
3a–c
Cl
O
3b
3a
3c
O
OEt
H
NH2
NH
N
O
OEt
O
N
O
N
N
H
NH
NH
Ph
CO2H
6
5
Ph
N
OBu- t
Ph
O
4
2, 3 a R = Et, b R = Bn, c R = t-Bu
There are two electrophilic centers in the polyfunctional compound 4 resulting on acylation with monoethyl
oxalyl chloride, an ester and an amide carbonyl group. Attack by the amino group in position 2 at the ester group of
the oxalyl fragment must lead to the desired piperazine derivative 7, while on reaction involving the amide carbonyl
the imidazole compound 8 must be formed.
The formation of piperazinones under conditions of acid catalyzed cyclization was reported in [5]. Our
attempts to use this procedure and carry out the cyclization of compound 4 in the presence of HCl in butanol led
to the parallel formation of both compounds, with the preferential formation of imidazoles 8a,b (70%) (the
process is accompanied by transesterification with the formation of the butyl ester 8b). An analogous picture
was also observed on using a basic catalyst. On carrying out cyclization in the presence of
diisopropylethylamine in butanol the preferential formation (60%) of compounds 8a,b was also observed.
189

H
N
O
N
N
O
O
DMF
t
OBu-
Cl
OEt
Ph
O
O
PhMe
4
3c
7
8a
(i-Pr)2NEt
BuOH
BuOH/HCl
OR
O
N
7 +
7 + 8a + 8b
6 : 1 : 9
N
N
OBu-
t
Ph
8a
2 : 1 : 4
O
+
8b
8 a R = Et, b R = Bu
Peaks were observed in the mass spectra of compounds 7 and 8 corresponding to the molecular ions of
the proposed structures, and this was confirmed by the character of their fragmentation. The mass spectral
decomposition of piperazine structure 7 is linked mainly with the fragmentation of the N-alkyl substituent, and
one of the most intense peaks in the spectrum is that of the ion with m/z 163, having the structure of the
unsubstituted pyridopyrazinone.
H
N
.
+
O
N
N
O
O
Me
Me
Me
Ph
O
7
M+ 367
H
N
O
O
+
H
N
–C4H8
– OCMe3
O
N
N
N
N
O
+
–CO2CMe3
O
OH
Ph
m/z 294
Ph
m/z 311
O
H
N
H
N
+
O
O
O
O
+
N
– 103
N
N
N
H
m/z 163
Ph
m/z 266
190

The fragmentation of the molecular ion of compound 8a is also linked with the primary decomposition
of the N-alkyl substituent, but the peak of the 2-ethoxycarbonylimidazo[4,5-b]pyridine ion (m/z 192, I 100%) is
the maximum in the mass spectrum.
O
N
N
OEt
O
N
Me
Me
Me
O
Ph
8a M+ 395
O
N
N
–C4H8
–OC4H9
OEt
O
N
m/z 322
–PhC2H4
–CO2C4H9
O
N
OH
m/z 399
Ph
+
N
OEt
N
H
O
N
+
m/z 192
–PhCH2
N
OEt
N
–C2H4
O
N
+
O
N
+
N
Ph
N
OH
N
OEt
N
m/z 294
CO2H
Ph
m/z 266
m/z 248
It turned out that the direction of thermal cyclization depends to a very high degree on the solvent used
in the reaction. We successfully chose conditions in which each process may selectively be carried out
separately. In reality carrying out the cyclization in a nonpolar solvent (toluene) leads selectively to the
formation of imidazole 8a, while the use of a polar aprotic solvent (DMF) enables the desired piperazine
structure 7 to be obtained exclusively
It should be noted that all the stages of the proposed synthetic route proceed without affecting the
asymmetric center, which enabled us to obtain enantiomerically pure (ee 100%) pyridopiperazinedione 7 with a
chiral substituent at the nitrogen atom.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker DPX (400 MHz) instrument in CDCl3 (if no other
solvent is indicated), internal standard was TMS, and 13C NMR spectra on a Bruker AMX 400 (100 MHz)
instrument. Chromato-mass spectral investigations of reaction mixtures and isolated compounds were carried out
using a Shimadzu Analytical HPLC SCL10Avp liquid chromatograph and a PE SCIX API 150 mass
spectrometer (electrospray, positive ionization).
A check on the progress of reactions and the purity of the compounds obtained was carried out by TLC
on Sorbfil plates (sorbent was STKh-1VE silica gel) in the system hexane−ethyl acetate, 10:1, or by liquid
chromatography with the mass spectral detector.
191

Commercial 2-chloro-3-nitropyridine and L-phenylalanine ethyl ester hydrochloride (Aldrich) were
used, L-phenylalanine benzyl ester was obtained by the procedure of [6].
L-Phenylalanine tert-Butyl Ester. L-Phenylalanine (5 g, 0.03 mol) was suspended in dioxane (100 ml)
in a 250 ml autoclave and conc. H2SO4 (3.3 g, 33 mmol) was added. The obtained solution was cooled to -15oC,
liquid isobutene (50 ml) was added to the resulting solid mass, and the mixture was stirred in the sealed
autoclave at 50oC for 12 h. The contents of the autoclave, cooled to ~20oC were poured into a cooled (~0oC)
mixture of ether (100 ml) and 1 N NaOH solution (300 ml), extracted with ether (3×100 ml), the extract dried
with sodium sulfate, evaporated, and the tert-butyl ester (2 g, 30%) was obtained as a colorless liquid. 1H NMR
spectrum, δ, ppm (J, Hz): 1.43 (9H, s, 3CH3); 2.84 (1H, dd, J = 13.5, J = 6.2, CH2Ph); 3.03 (1H, dd, J = 13.5,
J = 6.2, CH2Ph); 3.61 (1H, m, NH2CHCO); 7.23 (3H, m, H Ph); 7.30 (2H, m, H Ph).
N-(3-Nitropyrid-2-yl)-L-phenylalanine Esters 2a-c (General Method). 2-Chloro-3-nitropyridine
(11.1 g, 0.07 mol) was added to a solution of phenylalanine ester hydrochloride (0.07 mol) in DMF (100 ml),
and triethylamine (14.85 g, 0.147 mol) was poured in. The reaction mixture was stirred at 100oC for 10 h (check
by TLC, hexane−ethyl acetate, 10:1), poured into water, and extracted with ethyl acetate (3×100 ml). The extract
was dried over sodium sulfate, and evaporated. The residue was chromatographed on a column of silica gel in
hexane−ethyl acetate, 10:1.
N-(3-Nitropyrid-2-yl)-L-phenylalanine Ethyl Ester (2a). Yield 50%; mp 66-68oC. 1H NMR spectrum,
δ, ppm (J, Hz): 1.24 (3H, t, J = 7.1, CH3); 3.22 (1H, dd, J = 13.8, J = 7.4, CH2Ph); 3.33 (1H, dd, J = 13.8,
J = 7.4, CH2Ph); 4.20 (2H, q, J = 7.2, CH2CH3); 5.13 (1H, m, NHCHCO); 6.70 (1H, m, NH); 7.26 (3H, m,
H Ph); 7.35 (2H, m, H Ph); 8.36 (1H, dd, J = 4.5, J = 1.8, H-5); 8.41 (1H, dd, J = 8.4, J = 1.8, H-6); 8.45 (1H,
m, H-4). Found, %: C 60.99; H 5.32; N 13.37. C16H17N3O4. Calculated, %: C 60.94; H 5.43; N 13.33.
1
N-(3-Nitropyrid-2-yl)-L-phenylalanine Benzyl Ester (2b). Yield 45%; mp 120-122oC. H NMR
spectrum, δ, ppm, (J, Hz): 3.22 (1H, dd, J = 13.8, J = 7.4, CH2Ph); 3.33 (1H, dd, J = 13.8, J = 7.4, CH2Ph); 5.17
(3H, m, NHCHCO, CH2Ph); 6.68 (1H, m, NH); 7.20 (2H, d, J = 6.6, H Ph); 7.27 (5H, m, H Ph); 7.35 (3H, m,
H Ph); 8.29 (1H, dd, J = 4.5, J = 1.4, H-5); 8.40 (1H, dd, J = 8.3, J = 1.4, H-6); 8.43 (1H, m, H-4). Found, %:
C 67.04; H 4.97; N 11.31. C21H19N3O4. Calculated, %: C 66.83; H 5.07; N 11.13.
1
N-(3-Nitropyrid-2-yl)-L-phenylalanine tert-Butyl Ester (2c). Yield 70%; mp 137-139oC. H NMR
spectrum, δ, ppm (J, Hz): 1.41 (9H, s, 3CH3); 3.25 (2H, m, CH2Ph); 5.04 (1H, m, NHCHCO); 6.70 (1H, m,
NH); 7.28 (5H, m, H Ph); 8.37 (1H, d, J = 4.5, H-5); 8.41 (1H, d, J = 8.3, H-6); 8.48 (1H, m, H-4). Found, %:
C 63.11; H 6.12; N 12.21. C18H21N3O4. Calculated, %: C 62.96; H 6.16; N 12.24.
(3S)-3-Benzyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-2-one (5). 10 % Pd/C (5 wt.%) was added to a
solution of compound 2a (0.95 g, 3 mmol) in methanol (50 ml), the mixture was purged with argon, and then
with hydrogen. The mixture was hydrogenated in an atmosphere of hydrogen at room temperature (check by
TLC). The reaction mixture was filtered, the filtrate was heated to 50oC, and the methanol evaporated. The
1
residue was washed with ether and compound 5 (0.70 g, 95%) was obtained having mp 265-267oC. H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 2.97 (2H, m, CH2Ph); 4.30 (1H, d, J = 1.3, NHCHCO); 6.43 (1H, dd,
J = 7.5, J = 5.1, H-5); 6.68 (1H, s, NH); 6.75 (1H, dd, J = 7.5, J = 1.1, H-6); 7.20 (5H, m, H Ph); 7.54 (1H, dd,
J = 5.1, J = 1.1, H-4); 10.28 (1H, s, NHCO). Found, %: C 70.25; H 5.42; N 17.61. C14H13N3O. Calculated, %:
C 70.28; H 5.48; N 17.56.
(2S)-2-(1,4-Dihydro-2,3-dioxopyrido[2,3-b]pyrazin-4-yl)-3-phenylpropionic Acid tert-Butyl Ester
(7). 10% Pd/C was added to a solution of compound 2c (1.00 g, 3 mmol) in ether (50 ml), the mixture was
purged with argon and then with hydrogen. The mixture was hydrogenated in an atmosphere of hydrogen at
room temperature (check by TLC). The reaction mixture was filtered. Triethylamine (0.48 g, 4.8 mmol) was
added to the filtrate containing compound 3c, the solution was cooled to 0oC, ethyl oxalyl chloride (0.57 g,
4.2 mmol) was added dropwise, giving a white precipitate. The mixture was stirred at room temperature for 1 h.
The solid was filtered off, and the filtrate evaporated. Compound 4 was obtained as a yellow oily liquid.
1H NMR spectrum, δ, ppm (J, Hz): 1.37 (9H, s, 3CH3); 1.41 (3H, t, J = 7.1, CH3); 3.16 (2H, m, CH2Ph); 4.39
192

(2H, q, J = 7.1, CH2CH3); 4.88 (2H, m, NHCHCO); 6.70 (1H, m, H-5); 7.21 (3H, m, H Ph); 7.26 (2H, m, H Ph);
7.71 (1H, dd, J = 7.7, J = 1.5, H-6); 8.03 (1H, dd, J = 5.1, J = 1.4, H-4). 13C NMR spectrum, δ, ppm: 13.5, 27.5,
37.9, 55.3, 63.3, 66.6, 113.6, 117.4, 126.3, 127.9, 129.1, 131.4, 136.5, 145.3, 150.5, 154.7, 160.0, 171.7.
A solution of the obtained compound 4 (without further purification) in DMF (20 ml) was stirred at
120oC (check by TLC), then poured into water, and extracted with ethyl acetate (3×50 ml). The extract was
dried over sodium sulfate, and evaporated. The residue was chromatographed on a column of silica gel in ethyl
acetate. Piperazine 7 (0.6 g, 50%) was obtained having mp 212-214oC. 1H NMR spectrum, δ, ppm (J, Hz): 1.41
(9H, s, C(CH3)3); 3.63 (2H, m, CH2Ph); 6.28 (1H, m, NCHCO); 7.05 (5H, m, H Ph); 7.12 (1H, m, H-5); 7.65
(1H, d, J = 7.5, H-6); 8.21 (1H, d, J = 4.6, H-4); 11.78 (1H, s, NH). Mass spectrum, m/z (Irel, %): 368 [M + 1]+
(0.4), 311 (1.0), 294 (7.2), 266 (14.4), 163 (72.0), 57 (100). Found, %: C 65.41; H 5.81; N 11.48. C20H21N3O4.
Calculated, %: C 65.38; H 5.76; N 11.44.
3-[(1S)-1-Benzyl-tert-butoxycarbonylmethyl]-3H-imidazo[4,5-b]pyridine-2-carboxylic Acid Ethyl
Ester (8a). A solution of compound 4 obtained as indicated in the previous procedure was evaporated. Toluene
(30 ml) was added to the obtained yellow oily liquid, the mixture boiled for 10 h (check by TLC), and the
toluene distilled off in vacuum. The residue was chromatographed on a column of silica gel in the system
hexane−ethyl acetate, 10:1. Imidazole 8a (0.6 g, 55%) was obtained as a yellow oily liquid. 1H NMR spectrum,
δ, ppm (J, Hz): 1.40 (12H, m, 3CCH3, CH2CH3); 3.73 (2H, m, CH2Ph); 4.41 (2H, m, CH2CH3); 6.36 (1H, dd,
J = 10.4, J = 5.5, NCHCO); 6.85 (2H, dd, J = 6.6, J = 2.7, H Ph); 7.01 (3H, m, H Ph); 7.25 (1H, dd, J = 8.2,
J = 4.6, H-5); 8.10 (1H, dd, J = 8.2, J = 1.5, H-6); 8.43 (1H, dd, J = 4.6, J = 1.3, H-4). Mass spectrum, m/z (Irel,
%): 396 [M + 1]+ (0.2) , 339 (0.2), 294 (16.6), 266 (4.2), 248 (10.4), 192 (73.9), 57 (100). Found, %: C 66.86;
H 6.40; N 10.67. C22H25N3O4. Calculated, %: C 66.82; H 6.37; N 10.63.
Cyclization of N-[3-(Ethoxyoxalylamino)pyrid-2-yl]-L-phenylalanine tert-Butyl Ester (4).
A. In the presence of hydrochloric acid. Hydrochloric acid (2 drops) was added to a solution of
compound 4 in butanol (10 ml), and the mixture boiled for 10 h (check by chromato-mass spectrometry). A
mixture of compounds 7, 8a, and 8b in a ratio of 2:1:4 was obtained.
B. In the presence of diisopropylethylamine. Diisopropylethylamine (2 drops) was added to a solution of
compound 4 in butanol (10 ml) and the mixture boiled for 10 h (check by chromato-mass spectrometry). A
mixture of compounds 7, 8a, and 8b in a ratio of 6:1:9 was obtained.
3-[(1S)-1-Benzyl-2-tert-butoxycarbonylmethyl]-3H-imidazo[4,5-b]pyridine-2-carboxylic Acid Butyl
Ester (8b) was isolated chromatographically on a column of silica gel in the system hexane−CH2Cl2−MeOH,
1
1:4:(from 0 to 25). H NMR spectrum, δ, ppm (J, Hz): 0.95 (3H, t, J = 7.1, CH2CH2CH2CH3); 1.37 (11H, m,
3CCH3, CH2CH2CH2CH3); 1.76 (2H, m, CH2CH2CH2CH3); 3.74 (2H, m, CH2Ph); 4.34 (2H, m,
CH2CH2CH2CH3); 6.36 (1H, dd, J = 10.4, J = 5.5, NCHCO); 6.84 (2H, m, H Ph); 7.00 (3H, m, H Ph); 7.23 (1H,
dd, J = 8.2, J = 4.6, H-5); 8.09 (1H, dd, J = 8.2, J = 1.5, H-6); 8.43 (1H, dd, J = 4.6, J = 1.3, H-4). Mass
spectrum, m/z (Irel, %): 424 [M + 1]+ (80.9), 368 (100), 312 (4.2), 268 (6.8), 220 (4.7), 120 (1.1).
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