, 2003, 13(1), 29–31
7,8-dihydro-2H-pyrido[1,2-a]pyrazine-1,4(3H,6H)-dione 15 and
9-(5-benzyloxy-2-hydroxyphenyl)-2-phenethyl-7,8-dihydro-2H-
pyrido[1,2-a]pyrazine-1,4(3H,6H)-dione 16 (Table 1).‡
The structures of the prepared compounds were confirmed
by NMR spectroscopy.‡ Two signals due to the protons of
hydroxyl groups (d 8.10–8.51 ppm) were the most characteristic
signals in the 1H NMR spectra of compounds 11–14. The
1H NMR spectrum of O-benzyl derivative 16 exhibited proton
signals due to a hydroxyl group (d 8.45 ppm) and an O-benzyl
group (4.96 ppm, OCH2; 7.10–7.50 ppm, Ph).
RO
N
O
COCH2
NH(CH2)nAr
i
3, 4
O
7
8
9
6
N5
6
'
RO
RO
1
'
N
N
O
O
5
'
The structures of pyridopyrazines 11–16 were chemically
supported by the readily occurring oxidation of compounds 11
and 13 to the corresponding quinolyl derivatives: 2-benzyl-9-
(3,6-dioxocyclohexa-1,4-dienyl)-7,8-dihydro-2H-pyrido[1,2-a]-
pyrazine-1,4(3H,6H)-dione 17 and 9-(3,6-dioxocyclohexa-1,4-
dienyl)-2-(3,4-dimethoxyphenethyl)-7,8-dihydro-2H-pyrido-
[1,2-a]pyrazine-1,4-(3H,6H)-dione 18. Signals due to the
4
3
2
'
4
'
1
2
OH
O
3
'
O
O
N
H
(CH2)nAr
(CH2)nAr
11–16
11 R = H, n = 1, Ar = Ph
12 R = H, n = 2, Ar = Ph
13 R = H, n = 2, Ar = 3,4-(OMe)2C6H3
14 R = H, n = 2, Ar = 3-indolyl
15 R = CH2Ph, n = 1, Ar = Ph
16 R = CH2Ph, n = 2, Ar = Ph
1
protons of hydroxyl groups were absent from the H NMR
spectra of compounds 17 and 18 (Table 1).‡
The signals of protons of the quinone moiety of derivative
17 were downfield shifted (∆d = 0.3 ppm) with respect to the
corresponding signals of the hydroquinone moiety of 11. The
13H NMR spectrum of compound 11 exhibited downfield signals
at 145.6, 149.5 (2'-C, 5'-C) and 158.1, 162.2 (1-C, 4-C). The
positions of 1-C and 4-C signals in the spectrum of compound
17 changed insignificantly (157.5 and 161.0), and downfield
signals (184.6 and 187.1) appeared, which can be attributed to
Scheme 2 Reagents and conditions: i, 2 mol of an amine were added to a
solution of 1 mol of compound 3 (or 4) in DMF; the mixture was stirred
(20 °C, 10 h) and diluted with water; compound 11 (or 12–16) was filtered off.
7
‡
The mass spectra of compounds 11–16 do not contain the peaks of
2
8
9
6
N5
'
O
1'
6'
molecular ions; the peak of [M – H2O]+ is a characteristic peak in the
mass spectra of these compounds.
O
3
'
i
4
3
11, 13
4
'
1
For 11: 1H NMR ([2H6]DMSO) d: 1.82 (q, 2H, 7-CH2, J 5.8 Hz), 2.35
(br. s, 2H, 8-CH2), 3.72 (br. s, 2H, 6-CH2), 3.96 (s, 2H, 3-CH2), 4.46
(br. s, 2H, 2-CH2), 6.37 (d, 1H, 6'-H, J 2.8 Hz), 6.43 (q, 1H, 4'-H), 6.55
(d, 1H, 3'-H, J 8.4 Hz), 7.19–7.37 (m, 5H, Ph), 8.21 and 8.51 (2br. s, 1H,
2'-OH, 5'-OH). 13C NMR ([2H6]DMSO) d: 20.7, 30.6, 39.5, 48.2, 49.1
(7-H, 8-H, 6-H, 3-H, 2-NCH2), 113.9, 115.3, 115.8 (3'-C, 4'-C, 6'-C), 127.3,
127.8, 128.5, 128.9 (Ph), 124.9, 129.8, 136.4 (9-C, 1'-C, 9a-C), 145.6,
149.5 (2'-C, 5'-C), 158.1, 162.2 (1-C, 4-C). MS, m/z: 346 [M –H2O]+.
For 12: 1H NMR ([2H6]DMSO) d: 1.81 (q, 2H, 7-CH2, J 5.8 Hz), 2.35
(br. s, 2H, 8-CH2), 2.73 and 3.42 (2t, 2H, 2-CH2CH2, J 7.2 Hz), 3.70
(br. s, 2H, 6-CH2), 4.00 (s, 2H, 3-CH2), 6.34 (d, 1H, 6'-H, J 2.8 Hz),
6.45 (q, 1H, 4'-H), 6.55 (d, 1H, 3'-H, J 8.4 Hz), 7.10–7.40 (m, 5H, Ph),
8.10 and 8.42 (2br. s, 1H, 2'-OH, 5'-OH). MS, m/z: 360 [M –H2O]+.
For 13: 1H NMR ([2H6]DMSO) d: 1.84 (q, 2H, 7-CH2, J 5.8 Hz), 2.36
(br. s, 2H, 8-CH2), 2.70 and 3.43 (2t, 2H, 2-CH2CH2, J 7.2 Hz), 3.74
and 3.75 (s, 3H, 3''-OMe, 4''-OMe), 4.04 (s, 2H, 3-CH2), 6.38 (d, 1H,
6'-H, J 2.8 Hz), 6.48 (q, 1H, 4'-H), 6.59 (d, 1H, 3'-H, J 8.4 Hz), 6.70–
7.00 (m, 3H, Ph), 8.17 and 8.49 (2br. s, 1H, 2'-OH, 5'-OH). MS, m/z:
420 [M –H2O]+.
O
2
5
'
N
O
(CH2)nAr
Scheme 3 Reagents and conditions: i, an aqueous solution of potassium
ferricyanide, potassium carbonate and potassium bicarbonate was added to
a suspension of compound 11 (or 13) in chloroform with stirring; the mix-
ture was stirred (20 °C, 1 h); the organic layer was separated and evaporated;
the residue was ground with diethyl ether; compound 17 (or 18) was
filtered off.
the 3'-C and 6'-C atoms. The signals of aromatic carbon atoms
also exhibited a strong downfield shift (by 15–20 ppm) on
going from compound 11 to 17; this shift is consistent with a
change from the hydroquinone to the quinone structure.
Note that laktone and chromone ring opening under the action
of amine-containing compounds was described in the litera-
ture.3–5 In this work, we found that the intramolecular nucleo-
philic attack of the NH group on the carbonyl carbon results in
lactone ring cleavage and piperazine ring closure. The latter
circumstance is of particular importance because 2,5-dioxo-
piperazines (cyclic dipeptides) belong to one of the most
naturally widespread classes of peptide derivatives.6 A new
approach to the synthesis of these compounds is of interest in
terms of their biological activity.
For 14: 1H NMR ([2H6]DMSO) d: 1.82 (q, 2H, 7-CH2, J 5.8 Hz), 2.33
(br. s, 2H, 8-CH2), 2.86 and 3.49 (2t, 2H, 2-CH2CH2, J 7.2 Hz), 4.03 (s,
2H, 3-CH2), 6.37 (d, 1H, 6'-H, J 2.8 Hz), 6.44 (q, 1H, 4'-H), 6.56 (d, 1H,
3'-H, J 8.4 Hz), 6.90–7.15 (m, 3H, 2''-H, 5''-H, 6''-H), 7.33 and 7.54 (2d,
1H, 4''-H, 7''-H, J 7.4 Hz), 8.10 and 8.42 (2br. s, 1H, 2'-OH, 5'-OH),
10.70 (br. s, 1H, 1''-NH). MS, m/z: 399 [M –H2O]+.
For 15: 1H NMR (CDCl3) d: 1.95 (m, 2H, 7-CH2), 2.47 (t, 2H, 8-CH2,
J 6.2 Hz), 3.40 and 4.35 (2m, 1H, 6-CH2), 3.95 (AB system, 2H, 3-CH2),
4.58 (AB system, 2H, 2-CH2), 5.01 (s, 2H, 5-OCH2), 6.69 (d, 1H, 6'-H,
J 2.8 Hz), 6.84 (q, 1H, 4'-H), 6.96 (d, 1H, 3'-H, J 8.4 Hz), 7.10–7.60 (m,
10H, 2Ph). MS, m/z: 346 [M –H2O]+.
This work was supported by the Russian Foundation for Basic
Research (grant no. 02-03-32119).
For 16: 1H NMR ([2H6]DMSO) d: 1.83 (q, 2H, 7-CH2, J 5.8 Hz), 2.45
(br. s, 2H, 8-CH2), 2.73 and 3.43 (2t, 2H, 2-CH2CH2, J 7.2 Hz), 3.71
(br. s, 2H, 6-CH2), 4.02 (s, 2H, 3-CH2), 4.96 (s, 2H, 5'-OCH2), 6.59–6.80
(m, 3H, 3'-H, 4'-H, 6'-H), 7.10–7.50 (m, 10H, 2Ph), 8.45 (br. s, 1H,
2'-OH). MS, m/z: 450 [M –H2O]+.
References
2 V. M. Lyubchanskaya, L. M. Alekseeva, S. A. Savina, A. S. Shashkov
and V. G. Granik, Izv. Akad. Nauk, Ser. Khim., 2002, 1736 (Russ. Chem.
Bull., Int. Ed., 2002, 51, 1886).
3 T. Posner and R. Hess, Chem. Ber., 1913, 46, 3816.
4 K. Kostka, Rocz. Chem., 1966, 40, 1683.
For 17: 1H NMR ([2H6]DMSO) d: 1.89 (m, 2H, 7-CH2), 2.37 (m, 2H,
8-CH2), 3.77 (m, 2H, 6-CH2), 3.94 (s, 2H, 3-CH2), 4.47 (AB system,
2H, CH2Ph), 6.43 (d, 1H, 2'-H, J 2.2 Hz), 6.72 (q, 1H, 4'-H), 6.83 (d,
1H, 5'-H, J 7.0 Hz), 7.10–7.40 (m, 5H, Ph). 13C NMR (CDCl3), d: 20.2,
30.4, 40.0, 48.8, 49.5 (7-C, 8-C, 6-C, 3-C, 2-NCH2), 128.0, 128.2, 128.3,
129.0, 136.7, 137.3 (2'-C, 4'-C, 5'-C, Ph), 121.8, 134.4, 151.3 (9-C, 9a-C,
1'-H), 157.5, 161.4 (1-C, 4-C), 184.6, 187.1 (3'-C, 6'-C). MS, m/z: 362 [M+·].
For 18: 1H NMR ([2H6]DMSO) d: 1.83 (br. s, 2H, 7-CH2), 2.38 (br. s,
2H, 8-CH2), 2.65 and 3.55 (2br. s, 2H, 2-CH2CH2), 3.71 (br. s, 8H, 6-CH2,
2OMe), 3.95 (s, 2H, 3-CH2), 6.40–7.00 (m, 6H, 2'-H, 4'-H, 5'-H, C6H3).
MS, m/z: 436 [M+·].
6 B. W. Bycroff, in Comprehensive Organic Chemistry, eds. D. Barton and
W. D Ollis, Pergamon Press, Oxford, New York, 1979, vol. 5 (ed. E. Haslam),
pp. 259–266.
Received: 31st October 2002; Com. 02/2006
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