Synthesis of 6,7-ethylenedioxyquinoxalines and pyrido[2,3-b]pyrazines as intermediates in the preparation of antineoplastic agents

Article abstract of DOI:10.1016/S0040-4020(02)00500-8

A convenient procedure for the synthesis of quinoxalines and pyridopyrazines has been developed from aryldiamines. The condensation of aminocarbamates such as 12 with ethyl 2,3-dibromopropionate provide the quinoxaline 14 directly, in a one-step operation. The methodology reported herein represents an alternative to condensation of o-phenylenediamines with α-dicarbonyl compounds for the quinoxalines formation. The same procedure was applied to the 2,3-diaminopyridine to obtain the corresponding pyridopyrazines.

Full text of DOI:10.1016/S0040-4020(02)00500-8

TETRAHEDRON
Pergamon
Tetrahedron 58 32002) 5241±5250
Synthesis of 6,7-ethylenedioxyquinoxalines and pyrido[2,3-b]-
pyrazines as intermediates in the preparation of
antineoplastic agents
M. Mateu, A. S. Capilla, Y. Harrak and M. D. Pujolp
 Á Á
Laboratori de Quõmica Farmaceutica, Facultat de Farmacia, Universitat de Barcelona, Av. Diagonal 643, 08028 Barcelona, Spain
Received 27 August 2001; revised 4 January 2002; accepted 10 May 2002
AbstractÐA convenient procedure for the synthesis of quinoxalines and pyridopyrazines has been developed from aryldiamines. The
condensation of aminocarbamates such as 12 with ethyl 2,3-dibromopropionate provide the quinoxaline 14 directly, in a one-step operation.
The methodology reported herein represents an alternative to condensation of o-phenylenediamines with a-dicarbonyl compounds for the
quinoxalines formation. The same procedure was applied to the 2,3-diaminopyridine to obtain the corresponding pyridopyrazines. q 2002
Elsevier Science Ltd. All rights reserved.
1. Introduction
condensation of o-phenylenediamines with a-dicarbonyl
compounds is the most studied to date, but the alkylation
of 1,2-diamines with 1,2-dihalogenated 3a,b-dibromo-
propionaldehyde or tribromoacetone) compounds followed
by oxidation is also well known.8±14 Our investigations on
the preparation of the title compounds involved an oxidative
condensation of o-diaminated compounds with ethyl-2,3-
dibromopropionate in DMF.
Some time ago, we started a research program to synthesize
a new class of compounds related to known antineoplastic
agents such as ellipticine1 or podophyllotoxin.2 The
compounds studied exhibited the 1,4-benzodioxine ring
system 3A) as part of their structure and this, along with
the search for further information in SAR studies, led us
to synthesize 6,7-ethylenedioxyquinoxalines 3B) and
pyrido[2,3-b]pyrazines 3C) in order to introduce these
nuclei into the synthesis of new anticancer agents.
The synthesis of quinoxaline 14 is shown in Scheme 2. The
commercial 3available from Aldrich Chemical Co.)
6-amino-2,3-dihydro-1,4-benzodioxine 31) was converted
to N-alkylated compounds 2 and 3 using 3CH3)2SO4 or
benzyl bromide, respectively, according to standard pro-
cedure15 3Scheme 1). The acylated compounds 4 and 5
were prepared from 1 by treatment with acetic anhydride
or ethyl chloroformate, respectively, in good yields. For the
nitration of compounds 2±5 we employed a mild, general
and ef®cient procedure using a mixture of HNO3/AcOH
31:2) and operating at below 58C.16 Thus, the N-acyl
derivatives 8 and 9 were obtained in 88 and 95% yield,
respectively, whereas the nitration of N-alkyl derivatives
Quinoxaline derivatives have attracted interest as biologi-
cally active materials. They also ®nd considerable applica-
tion as angiotensin II receptor antagonists,3 NMDA
antagonists,4 anti-in¯ammatory,5 antidepressant-tranquiliz-
ing agents,6 and antitumor drugs 3Fig. 1).6,7
2. Chemistry
Of the routes available for the synthesis of quinoxalines, the
Figure 1. 1,4-Benzodioxines, ethylenedioxyquinoxalines and pyrido[2,3-b]pyrazines.
Keywords: quinoxalines; o-phenylenediamines; polycyclic systems; pyridopyrazines.
Corresponding author. Fax: 193-40359416; e-mail: mdpujol@farmacia.far.ub.es
p
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020302)00500-8

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M. Mateu et al. / Tetrahedron 58 .2002) 5241±5250
Scheme 1. 3i) 3CH3CO)2O or ClCOOCH2CH3 33). 3ii) HNO3±CH3COOH 31:2) ,58C. 3iii) Fe/AcOH; 3iv) H2/Pd±C/CH3OH or Zn/HCl 3see Table 1).
such as 3 proceeded with a lower yield 354%), possibly due
to oxidation at the benzylic position. Similarly, 6-amino-7-
nitro-2,3-dihydro-1,4-benzodioxine 36) was obtained in
54% yield by reacting 1 directly with the oxidative
mixture. The reduction of the nitro group was the next
key step in the preparation of these quinoxalines. It should
be mentioned that reduction of the nitroamine 6 by hydro-
genation using Pd±C,17 with hydrides as LiAlH4,
BH3´3CH3)2S or LiB3C2H5)3H18 or with metals as Zn/HCl
or Sn/HCl,19 was unsuccessful. All attempts led to aniline 1
by hydride ipso-substitution of the nitro group20 3see
Table 1).
Reduction of the nitro-N-benzyl derivative 37) by treatment
with Zn in acidic media gave the diamine 10 and degrada-
tion products 3entry c, Table 1), whereas the reduction using
Table 1. Conditions used for the reduction of nitro-compounds 6±9
Entry
Starting material
Conditions
Compound
Yield 3%)
a
a
90
b
c
d
e
f
Fe/AcOH 90±1008C/22 h
Zn/HCl re¯ux/20 h
75
36
80
39
87
88
H2/Pd±C/MeOH rt/12 h
LiAlH4/THF re¯ux/24 h
H2/Pd±C/MeOH rt/12 h
Fe/HCl re¯ux/4 h
g
a
LiAlH4/THF, re¯ux, 24 h or H2/Pd±C/MeOH, rt 24 h or Ni±Ra/Zn, AcOH±MeOH, 608C, 24 h or SnCl2/HCl, CH2Cl2, 308C, 24 h or Zn/NH4Cl, MeOH,
re¯ux, 1h.

M. Mateu et al. / Tetrahedron 58 .2002) 5241±5250
5243
Fe/AcOH afforded the nitroamine 6 by debenzylation in
75% yield 3entry b).
effective procedure of reduction because the reduced
compound obtained was easily puri®ed.
The N-acetyl nitro compound 38) was converted to the
corresponding N-acetyl amino 11 in a good yield 3entry d,
Table 1) by hydrogenation using Pd±C in the methanol.
However, when LiAlH4 was used as a reducing agent, the
diamine 13 was obtained in low yield 3entry e) since reduc-
tion of the nitro group and acetyl group was produced simul-
taneously. The puri®cation of the resulting diamine 13 was
laborious because of poor solubility in organic solvents.
The quinoxaline 14 was prepared by condensation of the
amino-carbamate 12 with ethyl 2,3-dibromopropionate in
the presence of NaH in DMF in 61% yield 3Scheme 2). It
seemed likely that under the conditions employed 3NaH/
DMF/908C/18 h) elimination of hydrogen bromide from
ethyl 2,3-dibromopropionate to give the a-bromoole®nic
ester would occur more rapidly than nucleophilic displace-
ment of bromide ion by the formed anion.21 Under these
conditions, elimination of the ethoxy carbonyl group
occurred rapidly, and the corresponding tricyclic
N-protected intermediate was not detected. Since the
o-carbamate anilines oxidize readily in air, the condensa-
tions were carried out under argon atmosphere, but the
work-up was carried out with exposure to air. It is thus
Reduction of the nitrocarbamate 9 with Fe in the presence of
HCl in methanol afforded the aminocarbamate 12 in 88%
yield 3entry g). We attempted also the reduction of 9 by
catalyzed hydrogenation 3entry f). This reduction proceeds
with a good yield and we considered the last method as an
Scheme 2. 3i) BrCH2CHBrCOOCH2CH3/NaH/DMF, 908C, 18 h; 3ii) KOH; 3iii) LDA/THF/CH3CHO/2788C; 3iv) ZnCl2/THF rt; 3v) SOCl2/CH3CH2NH2 /
CH2Cl2.

5244
M. Mateu et al. / Tetrahedron 58 .2002) 5241±5250
Scheme 3. 3i) BrCH2±CHBr±COOCH2CH3/K2CO3/DMF/1108C/24 h.
Scheme 4. 3i) BrCH2±CHBr±COOCH2CH3/K2CO3/DMF; 3ii) DDQ/CH2Cl2.
probable that the oxidation to quinoxaline occurs during this
time.22,23 In the next step, hydrolysis of the ester 14 using
KOH 8% gave the corresponding acid 18 in an excellent
yield 3Scheme 2). The intermediate 6,7-diaminobenzo-
dioxane 16 was prepared by hydrolysis of the carbamate
12 in 89% yield, but condensation of 16 with ethyl 2,3-
dibromopropionate in basic media 3K2CO3 or NaH) was
unsuccessful. In the latter case, the poor solubility in organic
solvents and facile oxidation of unsubstituted diamines may
account for the failure. On the other hand, the same condi-
tions applied to the monoalkylated diamine 13 gave the
N-ethyl quinoxaline 15 in poor yield 320%) 3Scheme 3).
In the last reaction, the N-ethyl group impedes the aromati-
zation of the heterocyclic system, although the oxidation of
C-7 and C-8 was observed.
The carboxylic acid 18 treated with LDA at 2788C
followed by the addition of acetaldehyde gave the desired
hydroxy-acid 19.
The analogous conditions applied to the carboxamide 20,
prepared from the carboxylic acid 18 by a conventional
procedure,24 afforded only traces of the corresponding
hydroxy-amide 21 and this route was abandoned. The
Figure 2. HMBC spectrum of 23 3500 MHz, CDCl3). The horizontal axis of the spectrum corresponds to the 13C spectrum and the vertical axis refers to the 1H
spectrum.

M. Mateu et al. / Tetrahedron 58 .2002) 5241±5250
5245
hydroxy-acid 19 was readily dehydrated to the corre-
sponding lactone 22 in THF with ZnCl2. The last intra-
molecular cyclization gave the lactone in low yield. This
step proved to be of relatively tedious elaboration, both in
basic and acidic 3APTS/Toluene or ZnCl2/CH2Cl2) protocols.
Concentration of the mixture under vacuum afforded an
oil, and the residue was puri®ed by a chromatography
column on silica gel eluting with hexane/ethyl acetate to
afford 2 370% yield) as an oil. IR 3NaCl) n 3cm21) 3050,
1
1664, 1260, 1110. H NMR 3CDCl3, 200 MHz) d 3ppm)
2.85 3s, 3H, CH3); 3.42 3bs, 1H, NH); 4.19 3m, 4H, CH2±
O±); 6.20 3s, 1H, Ar); 6.38 3m, 1H, Ar); 6.60 3m, 1H, Ar).
13C NMR 3CDCl3, 50.3 MHz) d 3ppm) 29.8 3CH3, CH3±N);
64.3 3CH2, CH2±O); 102.4 3CH, C5H); 107.1 3CH, C8H);
117.3 3CH, C7H); 137.2 3C, C6); 142.1 3C, C4a); 142.3 3C,
C8a).
Scheme 4 depicts the synthesis of related compounds
pyridopyrazine 23 and the tetrahydropyrazines 24 and 25.
Treatment of 2,3-diaminopyridine, commercially available,
with the ethyl 2,3-dibromopropionate gave the pyrazine 23
as the major compound, and also a mixture of position
isomers 24 and 25. The small quantity of the isomer 24
obtained was converted into the aromatic heterocycle 23
by treatment with DDQ. By contrast, isomer 25 led to
none of the corresponding aromatic system 26. These results
can be rationalized in terms of the spontaneous oxidation of
the tetrahydro intermediate 24 that led to the direct forma-
tion of the 2-substituted isomer 23. The results are also
consistent with the fact that the intermediate 25 was the
most dif®cult to obtain 3Scheme 4).
3.1.2. N-/2,3-Dihydro-1,4-benzodioxin-6-yl) benzylamine
/3). To a solution of 1 31g, 6.61mmol) in toluene was added
benzaldehyde 30.84 g, 7.9 mmol), and APTS 3catalytic,
amount). The resulting mixture was stirred at 1208C for
24 h. Then the reaction was cooled to room temperature
and the product extracted with ether 360 mL). The organic
solution was washed with aqueous sodium bicarbonate,
dried over Na2SO4, and concentrated under vacuum to
obtain the crude of reaction as an oil. After, the residue
was dissolved in methanol 320 mL) and the NaBH4 30.3 g,
7.9 mmol) was added in several portions. The resulting
mixture was stirred at room temperature for 2 h. The solvent
was removed under vacuum and the residue was poured into
ice-water 320 mL). The product was extracted with CH2Cl2
33£20 mL), dried over Na2SO4, and concentrated under
vacuum. The residue was chromatographed on silica gel
eluting with hexane/ethyl acetate to afford 3 382% yield)
With this condensation, it is possible, in principle, to obtain
two regioisomeric pyrido-pyrazine compounds. In order to
identify the main isomer formed, we performed 2D NMR-
experiments 3HMQC and HMBC) and the results con®rm
the proposed structure for 23 3Fig. 2).
The carbon at 136.7 ppm is assignable as the C-8a and this
carbon shows a cross peak with the 7-H. Whereas 3-H gives
a cross peak to a carbon signal at 140.0 ppm corresponding
to C-4a, and also 6-H shows a correlation peak to C-4a.
1
as an oil. IR 3NaCl) n 3cm21) 3100, 1590, 1240, 1090. H
NMR 3CDCl3, 200 MHz) d 3ppm) 3.92 3m, 2H, CH2±O±);
3.98 3m, 2H, CH2±O±); 4.24 3s, 2H, CH2±Ar); 6.38 3m, 2H,
Ar); 6.60 3s, 1H, Ar); 7.38 3m, 5H, Ar). 13C NMR 3CDCl3,
50.3 MHz) d 3ppm) 48.2 3CH2, CH2±N); 70.5 3CH2, CH2±
O); 104.2 3CH, C5H); 112.0 3CH, C8H); 113.8 3CH, C7H);
125.8 3CH, C40H); 128.7 3CH, C20H, C60H); 129.0 3CH,
C30H, C50H); 130.2 3C, C10); 138.2 3C, C6); 140.1 and
141.8 3C, C4a and C8a). Analysis calculated for
C15H15NO2: C, 74.67; H, 6.27; N, 5.80%. Found: C,
74.28; H, 5.81; N, 5.42%.
3. Experimental
3.1. General
Melting points were determined on an MFB 595010 M
Gallenkamp melting point apparatus and are uncorrected.
1
The H and 13C NMR spectra were recorded on a Varian
Gemini 200 or Varian Gemini 300 spectrometer or on a
Varian VXR-500 spectrometer with tetramethylsilane as
internal standard and using CDCl3 as solvent or CD3OD.
Chemical shifts were expressed in ppm down®eld from
internal TMS or residual signal of deuterated solvent 3d).
IR spectra were recorded on a FTIR Perkin Elmer 1600
spectrophotometer. Mass spectra were recorded on a
Hewlett-Packard spectrometer 5988-A 370 eV). The
chromatography was carried out on SiO2 3silica gel 60,
SDS, 60±200 mm). Microanalyses were determined on a
3.1.3. N-/2,3-Dihydro-1,4-benzodioxin-6-yl) acetamide
/4). A mixture of 1 32.61g, 17.26 mmol) and acetic anhy-
dride 350 mL) was stirred at 1408C for 8 h. The resulting
reaction mixture was poured onto ice and extracted with
CH2Cl2 3100 mL). The organic phase was dried, ®ltered
and concentrated under vacuum to gave a brown solid
which was puri®ed by silica gel chromatography, using as
eluent hexane/ethyl acetate 6:4 to give the white solid 4 in
87% yield 32.9 g). Mp: 129±1308C 3hexane/ethyl acetate).
IR 3KBr) n 3cm21) 3312, 1664, 1258, 1067. 1H NMR
3CDCl3, 300 MHz) d 3ppm) 2.14 3s, 3H, CH3); 4.25 3m,
4H, C2H2 and C3H2); 6.79 3d, Jˆ8.5 Hz, 1H, C8H); 6.86
3dd, Jˆ8.5 Hz, J0ˆ2.3 Hz, 1H, C7H); 7.08 3ba, 1H, NH);
7.12 3d, Jˆ2.3 Hz, 1H, C5H). 13C NMR 3CDCl3, 50.3 MHz)
d 3ppm) 22.9 3CH3, ±CH3); 63.8 3CH2, CH2±O); 63.9 3CH2,
CH2±O); 109.4 3CH, C5H); 113.3 3CH, C7H); 116.5 3CH,
C8H); 131.5 3C, C6); 139.8 3C, C8a); 142.8 3C, C4a); 169.5
3C, CO). Analysis calculated for C10H11NO3: C, 62.17; H,
5.74; N, 7.25%. Found: C, 62.52; H, 5.31; N, 6.80%.
Â
Á
Carlo Erba 1106 Analyzer by Serveis Cientõ®co-Tecnics,
Universitat de Barcelona, and analytical values obtained
were within ^0.4% of the calculated values. All reagents
were of commercial quality or were puri®ed before use and
the organic solvents were of analytical grade or puri®ed by
standard procedures.
3.1.1. N-/2,3-Dihydro-1,4-benzodioxin-6-yl) methyl-
amine /2). To a solution of N-32,3-dihydro-1,4-benzo-
dioxin-6-yl)amine
1 31g, 6.61mmol) in anhydrous
acetone was added anhydrous K2CO3 32.74 g, 19.8 mmol).
After 0.5 h of stirring, 3CH3)2SO4 34.2, 33 mmol) was added
and the mixture was stirred for 4 h at room temperature.
3.1.4. 6-Ethoxycarbonylamino-2,3-dihydro-1,4-benzo-
dioxine /5). To
a solution of ethyl chloroformate

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M. Mateu et al. / Tetrahedron 58 .2002) 5241±5250
1
2923, 1513, 1230, 1066. H NMR 3CDCl3, 200 MHz) d
30.47 mL, 4.96 mmol) in dry CH2Cl2 35 mL) was cooled to
08C and then a solution of 6-amino-2,3-dihydro-1,4-benzo-
dioxine 3500 mg, 3.30 mmol) and K2CO3 3252 mg,
6.61mmol) in dry CH 2Cl2 315 mL) was added dropwise,
the reaction mixture was stirred at room temperature for
1h. Then, water 325 mL) was added and extracted with
CH2Cl2 33£15 mL). The extracts were dried 3Na2SO4),
®ltered off and evaporated under vacuum giving 603 mg
of carbamate as a white solid 381% yield). Mp: 124±
1258C 3hexane/ethyl acetate). IR 3KBr) n 3cm21) 3329,
2985, 1699, 1543, 1228, 1064. 1H NMR 3CDCl3,
200 MHz) d 3ppm) 1.29 3t, Jˆ7.2 Hz, 3H, OCH2CH3);
4.18 3q, Jˆ7.2 Hz, 2H, OCH2CH3); 4.22 3m, 4H, C2H2
and C3H2); 6.57 3bs, 1H, NH); 6.78 and 6.78 3s, 2H, C5H
and C7H); 6.98 3bs, 1H, C8H). 13C NMR 3CDCl3,
50.3 MHz) d 3ppm) 14.5 3CH3, OCH2CH3); 61.1 3CH2,
3ppm) 4.27 3m, 4H, C2H2 and C3H2); 4.45 3d, Jˆ4.4 Hz,
2H, CH2±N); 6.20 3CH, 1H, C5H); 7.33 3CH, 5H, Ar); 7.76
3CH, 1H, C8H); 8.40 3s, 1H, NH). 13C NMR 3CDCl3,
50.3 MHz) d 3ppm) 47.3 3CH2, CH2±N); 63.8 and 65.3
3CH2, C2H2 and C3H2); 100.1 3CH, C5H); 114.1 3CH,
C8H); 127.0 3CH, C20H and C60H); 127.6 3CH, C40H);
128.8 3CH, C30H and C50H); 131.8 3C, C8a); 134.6 3C,
C6); 137.4 3C, C7); 142.6 3C, C4a); 152.0 3C, C10). Analysis
calculated for C15H14N2O4: C, 62.93; H, 4.93; N, 9.78%.
Found: C, 63.02; H, 4.51; N, 9.39%.
3.1.7. 6-Acetamido-7-nitro-2,3-dihydro-1,4-benzodiox-
ine /8). Using the same procedure as 6, the nitro-derivative
8 as a yellow solid 32.17 g, 88% yield) was obtained from
the N-acetyl-2,3-dihydro-1,4-benzodioxin-6-amina 34) 32 g,
10.4 mmol). Mp: 165±1678C 3hexane/ethyl acetate). IR
3KBr) n 3cm21) 3312, 1664, 1520, 1230, 1110. MS 3EI)
OCH2CH3); 64.1and 64.3 3CH , C2 and C3); 108.5 3CH,
2
C5); 112.4 3CH, C7); 117.0 3CH, C8); 131.6 3C, C6); 139.5
3C, C8a); 143.4 3C, C4a); 153.7 3C, CO). Analysis calcu-
lated for C11H12N2O6: C, 49.26; H, 4.51; N, 10.44%. Found:
C, 49.68; H, 4.4.32; N, 10.09%.
1
m/z 3%): 238 359); 196 3100); 94 349). H NMR 3CDCl3,
200 MHz) d 3ppm) 2.30 3s, 3H, CH3); 4.35 3m, 4H, CH2±
O); 6.76 3s, 1H, C5H); 7.78 3s, 1H, C8H); 8.31 3s, 1H, NH).
13C NMR 3CDCl3, 50.3 MHz) d 3ppm) 26.6 3CH3, ±CH3);
64.2 3CH2, CH2±O); 115.8 3CH, C5H); 119.8 3CH, C8H);
139.1 3C, C6); 144.2 3C, C8a); 148.6 3C, C7); 150.2 3C,
C4a); 172.3 3C, CO). Analysis calculated for C10H10N2O5:
C, 50.43; H, 4.23; N, 11.76%. Found: C, 50.08; H, 4.74; N,
12.09%.
3.1.5. 6-Amino-7-nitro-2,3-dihydro-1,4-benzodioxine /6).
Method A: To aniline 1 3500 mg, 3.3 mmol) was added at
08C dropwise a solution of HNO3 35 mL) in acetic acid
340 mL). The mixture was stirred for 3 h at room tempera-
ture. After the mixture was poured into ice-water, and pH
value was adjusted to 8±9 by the addition of NaOH 50%,
then extracted with CH2Cl2. The organic layer was sepa-
rated, dried over Na2SO4, and concentrated to give the
nitro 6 as a yellow solid 3352 mg, 54% yield). Mp: 150±
1528C 3ethyl acetate). 1H NMR 3CDCl3, 200 MHz) d 3ppm)
4.34 3m, 4H, C2H2 and C3H2); 6.94 3s, 1H, C5H); 7.79 3s,
1H, C8H). 13C NMR 3CDCl3, 50.3 MHz) d 3ppm) 64.0 and
64.6 3CH2, CH2±O); 113.2 3CH, C5H); 117.4 3CH, C8H);
136.2 3C, C6); 142.0 3C, C8a); 143.5 3C, C7); 149.3 3C,
C4a). Analysis calculated for C8H8N2O4: C, 48.98; H,
4.11; N, 14.28%. Found: C, 48.60; H, 4.28; N, 13.98%.
3.1.8. 6-Ethoxycarbonylamino-7-nitro-2,3-dihydro-1,4-
benzodioxine /9). A solution of the carbamate 6 3460 mg,
2.06 mmol) in acetic acid 33 mL) was cooled to 2108C.
Then nitric acid 60% 31.5 mL) was added dropwise and
the mixture was stirred for 20 min at the same temperature.
Then a solution of NaOH 30% was added until basic pH and
extracted with ether 33£15 mL). The combined organic
layer was dried 3Na2SO4), ®ltered off and the solvent evapo-
rated under vacuum giving 538 mg of nitro 9 as a yellow
solid 395% yield). Mp: 145±1468C 3hexane/ethyl acetate).
IR 3KBr) n 3cm21) 3333, 2978, 1747, 1519, 1257. 1H NMR
3CDCl3, 200 MHz) d 3ppm) 1.33 3t, Jˆ7.2 Hz, 3H,
OCH2CH3); 4.23 3q, Jˆ7.2 Hz, 2H, OCH2CH3); 4.34 3m,
4H, C2H2 and C3H2); 7.79 3s, 1H, C5H); 8.08 3s, 1H,
C8H); 9.90 3s, 1H, NH). 13C NMR 3CDCl3, 50.3 MHz)
d3ppm) 14.4 3CH3, OCH2CH3); 61.7 3CH2, OCH2CH3);
63.9 and 65.0 3CH2, C2 and C3); 107.9 3CH, C5); 114.1
3CH, C8); 129.3 3C, C6); 131.1 3C, C7); 139.5 3C, C8a);
150.5 3C, C4a); 153.0 3C, CO). Analysis calculated for
C11H12N2O6: C, 49.26; H, 4.51; N, 10.44%. Found: C,
48.87; H, 4.30; N, 10.78%.
Method B: A solution of 7 3100 mg, 0.35 mmol) in acetic
acid 310 mL) was added Fe 339 mg, 0.70 mmol) and the
resulting mixture was stirred at 90±1008C for 22 h. The
mixture was then ®ltered and extracted with ether
33£20 mL). The organic phase was separated and dried
over Na2SO4, and the solvent was removed by rotary
evaporation. The resulting residue was puri®ed by column
chromatography 3hexane/ethyl acetate 70:30) giving the
debenzylated coumpond 6 in 75% yield.
3.1.6.
6-Benzylamino-7-nitro-2,3-dihydro-1,4-benzo-
dioxine /7). A mixture of 7-bromo-6-nitro-2,3-dihydro-
1,4-benzodioxin 3500 mg, 1.92 mmol) and benzylamine
34 mL, 38.1mmol) was stirred at 170 8C for 2 h. A solution
of HCl 5N was added until acidic pH and extracted with
ether 33£15 mL).
3.1.9. 6-Amino-7-benzylamino-2,3-dihydro-1,4-benzo-
dioxine /10). To a solution of 6-benzylamino-7-nitro-2,3-
dihydro-1,4-benzodioxine 3100 mg, 0.34 mmol) in
a
mixture of ethanol/water 34:1) was added Zn 3113 mg,
1.74 mmol) and HCl concentrated 30.5 mL). The mixture
reaction was re¯uxed for 20 h. The Zn was ®ltered off and
the solvent was removed under vacuum. A solution of
NaOH 2N was added until basic pH and the mixture was
extracted with ethyl acetate 33£15 mL). The combined
organic solution was dried 3Na2SO4) and ®ltered off and
the solvent evaporated under vacuum. The residue was puri-
®ed by column chromatography 3on silica gel hexane/ethyl
acetate/metanol in a ratio 6:3:1) to give the 6-amino-7-
The combined organic phase was dried 3Na2SO4), ®ltered
off and the solvent removed under vacuum. The residue was
puri®ed by column chromatography 3on silica gel hexane/
ethyl acetate in a ratio 9:1) giving 184 mg of starting
product, 3hexane/ethyl acetate in a ratio 7:3) give the
6-benzylamino-7-nitro-2,3-dihydro-1,4-benzodioxine as a
red oil 3300 mg, 54% yield). IR 3NaCl) n 3cm21) 3383,

M. Mateu et al. / Tetrahedron 58 .2002) 5241±5250
5247
benzylamino-2,3-dihydro-1,4-benzodioxine as an oil
332 mg, 36% yield). IR 3NaCl) n 3cm21) 3383, 2874,
1470, 1183. H NMR 3CDCl3, 200 MHz) d 3ppm) 4.25 3s,
dried 3Na2SO4), ®ltered off and the solvent removed, the
resulting residue was puri®ed by column chromatography
3on silica gel hexane/ethyl acetate in a ratio 6:4) giving
38 mg of 12 as a brown solid 388% yield).
1
4H, C2H2 and C3H2); 5.20 3s, 2H, CH2±N); 6.67 3s, 1H,
C5H); 7.20 3s, 1H, C8H); 7.29 3m, 5H, Ar). 13C NMR
3CDCl3, 50.3 MHz) d 3ppm) 47.2 3CH2, CH2±N); 64.1
and 64.4 3CH2, C2H2 and C3H2); 96.9 3CH, C5H); 106.1
3CH, C8H); 126.2 3CH, C20H and C60H); 127.8 3CH, C40H);
128.9 3CH, C30H and C50H); 135.8 3C, C6); 136.8 3C, C7);
140.3 and 140.7 3C, C4a and C8a); 151.4 3C, C10). Analysis
calculated for C15H16N2O2: C, 70.29; H, 6.29; N, 10.93%.
Found: C, 70.73; H, 6.01; N, 10.57%.
3.1.12. 6-Amino-7-ethylamino-2,3-dihydro-1,4-benzo-
dioxine /13). A solution of 8 31.39 g, 5.8 mmol) in THF
330 mL) was cooled to 08C and treated with LiAlH4
31.09 g, 28.72 mmol) dropwise over 10 min. The cooling
bath was removed and the reaction mixture heated at re¯ux
for 24 h. The reaction mixture was cooled to 08C and
quenched with water. After, the reaction was allowed to
reach room temperature and was diluted with ethyl acetate.
Anhydrous sodium sulfate was added directly to the mixture
with constant stirring for 10 min. The reaction was then
®ltered and the solvent evaporated. The obtained residue
was puri®ed by column chromatography 3silicagel-Et3N,
100% ethyl acetate) and the ethylamine 13 was obtained
3.1.10.
6-Acetamido-7-amino-2,3-dihydro-1,4-benzo-
dioxine /11). The nitro 8 3100 mg, 0.42 mmol) in absolute
methanol 325 mL) was shaken with 10% palladium on char-
coal 310 mg) in the presence of hydrogen at atmospheric
pressure for 18 h. After the resultant mixture was ®ltered
off and the solution was evaporated to reduced pressure. The
residue was diluted with ethyl acetate and washed with
water, dried over Na2SO4. The resulting oil obtained was
puri®ed by silica gel column chromatography 3ethyl acetate/
hexane 10:90) to give 11 as an oil 370 mg, 80% yield). IR
as a colorless oil 3436 mg, 39% yield). IR 3KBr) n 3cm21
)
3332, 2964, 1520, 1190, 1067. 1H NMR 3CDCl3, 200 MHz)
d 3ppm) 1.27 3t, Jˆ7 Hz, 3H, CH3); 3.05 3q, Jˆ7 Hz, 2H,
CH2±N); 3.10 3m, 1H, NH); 4.18 3q, 4H, C2H2 and C3H2);
6.22 3s, 1H, C5H); 6.30 3s, 1H, C8H). 13C NMR 3CDCl3,
50.3 MHz) d 3ppm) 15.0 3CH3, ±CH3); 39.3 3CH2, CH2±N);
64.6 3CH2, C2 and C3); 101.6 3CH, C8); 105.9 3CH, C5);
128.3 3C, C7); 132.8 3C, C6); 135.2 3C, C8a); 137.0 3C,
C4a). Analysis calculated for C10H14N2O2: C, 61.84; H,
7.27; N, 14.42%. Found: C, 62.29; H, 6.93; N, 14.30%.
1
3NaCl) n 3cm21) 3307, 1682, 1558, 1260, 1108. H NMR
3CDCl3, 200 MHz) d 3ppm) 2.22 3s, 3H, CH3); 4.38 3m, 4H,
CH2±O); 6.24 3s, 1H, H-8); 6.42 3s, 1H, H-5). 13C NMR
3CDCl3, 50.3 MHz) d 3ppm) 26.8 3CH3, CH3±); 64.2 and
64.4 3CH2, CH2±O±); 95.9 3CH, C5H); 107.2 3CH, C8H);
132.1 3C, C6); 136.1 3C, C7); 140.8 and 141.0 3C, C4a and
C8a); 170.1 3C, CO). Analysis calculated for C10H12N2O3:
C, 57.69; H, 5.81; N, 13.45%. Found: C, 57.91; H, 5.39; N,
13.73%.
3.1.13. Ethyl-/2,3-dihydro-1,4-dioxino[2,3-g]quinoxalin-
7-yl)carboxylate /14). To a suspension of NaH 60%
392 mg, 2.3 mmol) in dry DMF 31mL) a solution of carba-
mate 12 3250 mg, 1.05 mmol) in dry DMF 32 mL) was
added, the reaction mixture was stirred at room temperature
for 30 min. Then a solution of ethyl dibromopropionate
30.3 mL, 2.09 mmol) in dry DMF was added dropwise.
After the addition was completed, the mixture was stirred
under argon at 908C for 18 h. Then the residue was hydro-
lyzed with water 315 mL), and the product extracted with
ether 33£15 mL). The organic extracts were dried over
Na2SO4, ®ltered, and after removal of the solvent, the resi-
due was puri®ed by column chromatography 3on silica gel
hexane/ethyl acetate in a ratio 5:5) to give 66 mg of 14 as a
brown solid 361% yield). Mp: 129±1398C 3hexane/ethyl
acetate). IR 3KBr) n 3cm21) 2981, 1715, 1495, 1225,
3.1.11. 7-Amino-6-ethoxycarbonylamino-2,3-dihydro-
1,4-benzodioxine /12). Method A: Pd±C 35 mg, 10%) was
added to a solution of the nitro-carbamate 9 350 mg,
0.18 mmol) in ethyl acetate 320 mL). The reaction mixture
was strongly stirred at room temperature under atmosphere
of hydrogen for 12 h. The catalyst was ®ltered and the
®ltrate was evaporated to dryness at reduced pressure. The
resulting residue was puri®ed by column chromatography
3on silica gel hexane/ethyl acetate in a ratio 6:4) to afforded
47 mg of product 12 as a brown solid 337 mg, 87% yield).
Mp: 103±1048C 3hexane/ethyl acetate). IR 3KBr) n 3cm21
)
3367, 3200, 2976, 1719, 1697, 1498, 1191, 1066. 1H NMR
3CDCl3, 200 MHz) d 3ppm) 1.29 3t, Jˆ7.2 Hz, 3H,
OCH2CH3); 3.43 3bs, 2H, NH2); 4.14 3q, Jˆ7.2 Hz, 2H,
OCH2CH3); 4.18 3m, 4H, C2H2 and C3H2); 6.30 3s, 1H,
C5H); 6.40 3bs, 1H, NH); 7.81 3s, 1H, C8H). 13C NMR
3CDCl3, 50.3 MHz) d 3ppm) 14.5 3CH3, OCH2CH3); 61.3
3CH2, OCH2CH3); 64.0 and 64.5 3CH2, C2 and C3); 105.7
3CH, C8H); 114.0 3CH, C5H); 117.9 3C, C6); 134.7 3C,
C4a); 136.3 3C, C7); 142.8 3C, C8a); 154.8 3C, CO). Analy-
sis calculated for C11H14N2O4: C, 55.27; H, 5.95; N,
11.81%. Found: C, 54.90; H, 5.53; N, 11.98%.
1
1061. MS 3EI): m/z 3intensity) 260 3M, 20); 239 365). H
NMR 3CDCl3, 200 MHz) d 3ppm) 1.50 3t, Jˆ7 Hz, 3H,
OCH2CH3); 4.513s, 4H, C2H
and C3H2); 4.55 3q,
2
Jˆ7 Hz, 2H, OCH2CH3), 7.56 3s, 1H, C10H); 7.70 3s, 1H,
C5H); 9.35 3s, 1H, C8H). 13C NMR 3CDCl3, 50.3 MHz) d
3ppm) 14.3 3CH3, OCH2CH3); 62.2 3CH2, OCH2CH3); 64.1
and 64.3 3CH2, C2 and C3); 113.0 3CH, C10); 114.2 3CH,
C5); 138.1 3C, C7); 140.5 and 140.6 3C, C4a and C10a);
143.2 3CH, C8); 147.8 3C, C9a); 149.1 3C, C5a); 164.0 3C,
CO). Analysis calculated for C13H12N2O4: C, 59.99; H, 4.65;
N, 10.76%. Found: C, 60.32; H, 4.30; N, 10.32%.
Method B: To a solution of the nitro-carbamate derivative 9
350 mg, 0.18 mmol) in ethanol 315 mL), Fe 350 mg,
0.90 mmol) and concentrated HCl 31mL) were added, and
the resulting suspension was re¯uxed for 4 h. The solvent
was removed under vacuum and a solution of NaOH 2N was
added dropwise until pH basic, followed by extraction with
ethyl acetate 33£15 mL). The combined organic layers were
3.1.14. Ethyl 6-ethyl-2,3,6,9-tetrahydro-1,4-dioxino[2,3-
g]quinoxalin-8-carboxylate /15). To a mixture of the
diamine 13 3100 mg, 0.52 mmol) dry K2CO3 3176 mg,
1.27 mmol), KI 3catalyst amount) in DMF 325 mL) was
added ethyl 2,3-dibromopropionate 30.09 mL) in twice
separated by 1h. The resulting solution was heated at

5248
M. Mateu et al. / Tetrahedron 58 .2002) 5241±5250
110^108C for 24 h. The crude of reaction was extracted
several times with ether and a crude product obtained was
puri®ed by column chromatography 3hexane/ethyl acetate)
giving compound 15 as an oil 330 mg, 20% yield). IR 3KBr)
n 3cm21) 3310, 1731, 1255, 1102. MS 3EI) m/z 3%): 290
322); 261352); 94 3100). 1H NMR 3CDCl3, 200 MHz) d
3ppm) 1.29 3m, 6H, CH3); 3.65 3m, 2H, CH2±N); 4.00 3m,
2H, CH2±O); 4.25 3m, 4H, CH2±O); 6.40 3d, Jˆ1Hz, 1H,
Ar); 7.12 3d, J<1 Hz, 1H, Ar); 7.34 3s, 1H, H-7); 8.12 3s,
1H, NH). 13C NMR 3CDCl3, 50.3 MHz) d 3ppm) 13.6 3CH3,
CH3); 13.8 3CH3, CH3); 36.2 3CH2, CH2±N); 62.3 3CH2,
CH2±O); 64.8 3CH2, CH2±O); 108.2 and 108.6 3CH, C5H
and C10H); 130.8 3CH, C8H); 134.2 3C, C7); 140.3 and
141.3 3C, C5a and C9a); 146.8 and 147.5 3C, C4a and
C10a), 169.5 3C, CO). Analysis calculated for
C15H18N2O4: C, 62.06; H, 6.25; N, 9.65%. Found: C,
61.88; H, 6.49; N, 9.60%.
THF/n-heptane) 30.28 mL, 0.56 mmol) dropwise over
10 min. The reaction mixture was stirred at this temperature
for 3 h. Then acetaldehyde 332 mg, 0.51mmol) in dry THF
was added and the mixture was allowed to reach room
temperature over 8 h. The reaction was quenched by the
addition of NH4Cl 32 mL) and then diluted with ether acidi-
®ed with HCl 2N and extracted. The organic layer was
separated and dried 3Na2SO4), and the solvent was evapo-
rated to dryness. The crude was puri®ed by column chro-
matography 3silica gel, hexane/ethyl acetate 3:7) to afford
27 mg of starting material, 3ethyl acetate/methanol 9:1) give
the alkylated compound 19 as an oil 332 mg, 44% yield).
MS 3EI) m/z 3%): 276 314); 258 341); 187 3100). IR 3KBr) n
1
3cm21) 3490, 1732, 1490, 1260, 1110. H NMR 3CD3OD,
200 MHz) d 3ppm) 1.67 3d, Jˆ6.6 Hz, 3H, ±CH3); 4.43 3s,
4H, C2H2 and C3H2); 5.62 3q, Jˆ6.6 Hz, 1H, CH±OH);
7.43 3s, 1H, C5H); 7.47 3s, 1H, C10H); 9.28 3s, 1H, OH).
13C NMR 3CDCl31CD3OD, 50.3 MHz) d 3ppm) 19.7
3CH3); 64.8 and 64.9 3CH2, CH2±O); 74.6 3CH, CH±O);
113.1 3CH); 113.8 3CH); 136.2 3C, C-7); 140.2 and 141.4
3C, C-5a, C-9a); 143.5 3CH, C-8); 147.2 and 148.3 3C, C-4a,
C-10a); 168.2 3C, CO). Analysis calculated for C13H12N2O5:
C, 56.52%; H, 4.38%; N, 10.14%. Found: C, 56.91%; H,
4.63%; N, 10.45%.
3.1.15. 6,7-Diamino-2,3-dihydro-1,4-benzodioxine /16).
A solution of the amino-carbamate 12 340 mg, 0.17 mmol)
in ethanol 32 mL) a solution of KOH 2N 35 mL) was added.
The mixture was heated at re¯ux for 4 h. The solvent was
removed under vacuum, then resulting mixture was
extracted with ethyl acetate 33£10 mL), the combined
organic solution was dried 3Na2SO4), ®ltered off and evapo-
rated to dryness giving 20 mg as a brown solid of 6,7-
diamino-2,3-dihydro-1,4-benzodioxine 389% yield). Mp:
75±768C 3hexane/ethyl acetate). IR 3KBr) n 3cm21) 3336,
3.1.18. N-Ethyl-2,3-dihydro-1,4-dioxino[2,3-g]quinoxa-
lin-2-carboxamide /20). A solution of the carboxylic acid
18 3100 mg, 0.43 mmol) in toluene was cooled at 08C and
SOCl2 30.1mL, 1.37 mmol) was slowly added. The result-
ing mixture was heated at 1208C for 4 h. After, the mixture
was cooling to room temperature and the toluene was
removed under vacuum.
1
2870, 1517, 1192, 1063. H NMR 3CDCl3, 200 MHz) d
3ppm) 3.19 3bs, 4H, NH2); 4.19 3s, 4H, C2H2 and C3H2);
6.27 3s, 2H, C5H and C8H). 13C NMR 3CDCl3, 50.3 MHz) d
3ppm) 64.5 3CH2, C2 and C3); 105.8 3CH, C5 and C8);
128.9 3C, C6 and C7); 136.7 3C, C4a and C8a). Analysis
calculated for C8H10N2O2: C, 57.82; H, 6.07; N, 16.86%.
Found: C, 57.49; H, 6.33; N, 16.42%.
The crude of reaction was directly treated with ethylamine
358.16 mg, 1.29 mmol) in CH2Cl2 315 mL), stirring at room
temperature for 4 h.
3.1.16. /2,3-Dihydro-1,4-dioxino[2,3-g]quinoxalin-7-yl)-
carboxylic acid /18). A solution of the ester 14 380 mg,
0.30 mmol) and potassium hydroxide 3112 mg, 2 mmol) in
methanol 35 mL) and water 35 mL) was stirred at room
temperature for 4 h. The solvent was removed under
vacuum and the residue was poured onto crushed ice, acidi-
®ed with HCl 2N until pH 6, and extracted with CH2Cl2. The
combined extracts were dried 3Na2SO4) and concentrated to
give the acid as a solid product. Chromatography 3silica gel,
ethyl acetate/methanol 9:1) gave the carboxylic acid 18 as a
white solid 365 mg, 93% yield). Mp: 241±2428C 3ethyl
acetate/hexane). IR 3KBr) n 3cm21) 3428, 1734, 1500,
1234. MS 3EI): m/z 3intensity) 232 3M, 38), 231380), 187
Finally, water 315 mL) was added to the crude of reaction
and the obtained mixture and was extracted with CH2Cl2.
The combined organic layers were dried, ®ltered off, and the
solvent removed giving the amide 20. Puri®cation by
column chromatography 3SiO2, hexane/ethyl acetate) gave
the desired amide as an oil 399 mg, 0.38 mmol, 89% yield).
IR 3KBr) n 3cm21) 3387, 1674, 1494, 1223, 1060. 1H NMR
3CDCl3, 200 MHz) d 3ppm) 1.33 3t, Jˆ7.2 Hz, 3H, CH3);
3.58 3q, Jˆ7.2 Hz, 2H, CH2±N); 4.45 3s, 4H, CH2±O); 7.49
3s, 1H, Ar); 7.56 3s, 1H, Ar); 7.95 3bs, 1H, NH); 9.47 31s,
1H, H-8). 13C NMR 3CDCl3, 50.3 MHz) d 3ppm) 14.9
3CH3); 34.3 3CH2, CH2±N); 64.2 and 64.3 3CH2, C-2,
C-3); 113.3 and 113.8 3CH, C-5, C-10); 136.8 3C, C-7);
140,6 and 141.8 3C, C-5a, C-9a); 141.9 3C, C-8); 147.7
and 148.4 3C, C-10a, C-4a); 163.4 3C, CO). Analysis calcu-
lated for C12H13N3O3: C, 58.29%; H, 5.30%; N, 16.99%.
Found: C, 58.72%; H, 5.08%; N, 16.59%.
1
376). H NMR 3CD3OD, 200 MHz) d 3ppm) 4.813s, 4H,
C2H2 and C3H3); 7.28 3s, 1H, C5H); 7.48 3s, 1H, C10H);
9.12 3s, 1H, C8H). 13C NMR 3DMSO, 50.3 MHz) d 3ppm)
64.2 3CH2, CH2±O); 64.4 3CH2, CH2±O); 112.3 3CH);
113.2 3CH); 138.1 3C, C-7); 140.0 and 141.2 3C, C-5a,
C-9a); 143.1 3CH, C-8); 147.8 and 149.1 3C, C-4a,
C-10a); 165.9 3C, CvO). Analysis calculated for
C11H8N2O4: C, 56.89%; H, 3.47%; N, 12.06%. Found: C,
56.42%; H, 3.32%; N, 12.28%.
3.1.19. N-Ethyl-8-/1-/1-hydroxyethyl))-/2,3-dihydro-1,4-
benzodioxino[2,3-g]quinoxalin-7-yl) carboxamide /21).
The compound 21 was prepared from the carboxamide 20
following the same procedure described above for 19 from
18. Under these conditions only was detected trace of 21.
3.1.17. 8-/1-/1-Hydroxyethyl))-/2,3-dihydro-1,4-benzo-
dioxino[2,3-g]quinoxalin-7-yl)carboxylic acid /19). A
solution of compound 18 360 mg, 0.25 mmol) in dry THF
32 mL) was cooled to 2788C and treated with LDA 32 M in
3.1.20. 3-Methyl-6,7-ethylenedioxi-1-oxofuro [3,4-b]
quinoxaline /22). A solution of the hydroxyacid 19

M. Mateu et al. / Tetrahedron 58 .2002) 5241±5250
5249
3100 mg, 0.36 mmol) in dry THF 36 mL) was added ZnCl2,
anhydrous, powder 399.999%) 358.9 mg, 0.43 mmol). The
reaction mixture was stirred at room temperature for 24 h.
Then the mixture was ®ltered and the corresponding residue
was washed with a solution of NaOH 1N. The residue was
puri®ed by column chromatography 3silica gel, hexane/
ethyl acetate 8:2) and the desired lactone was obtained as
a colourless oil 362 mg, 66%). IR 3NaCl) n 3cm21) 1762,
1204. MS 3EI): m/z 3intensity) 258 3M, 20). 1H NMR
3CDCl31CD3OD, 200 MHz) d 3ppm) 1.60 3d, Jˆ6.2 Hz,
3H, CH3); 4.42 3s, 4H, CH2±O); 5.42 3q, Jˆ6.2 Hz, 1H,
CH±O); 7.45 3s, 1H, Ar); 7.47 3s, 1H, Ar). Analysis calcu-
lated for C13H10N2O4: C, 60.47%; H, 3.90%; N, 10.85%.
Found: C, 60.05%; H, 3.68%; N, 10.56%.
115.1 3CH, C8H); 118.9 3CH, C7H); 127.0 3C, C8a);
136.2 3CH, C6); 140.9 3C, C4a); 169.8 3C, CO). Analysis
calculated for C10H13N3O2 1/2H2O: C, 55.55%; H, 6.53%;
N, 19.43%. Found: C, 55.89%; H, 6.32%; N, 19.07%.
Acknowledgements
The ®nancial support from the Generalitat de Catalunya
Â
3SGR1999-00080) and the Ministerio de Educacion y
Cultura 3SPAIN) 3CICYT QUI-1999-0512) are gratefully
acknowledged.
3.1.21. Ethyl pyrido[2,3-b]pyrazin-2-carboxylate /23)
and ethyl 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-
References
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2,3-Diaminopyridine
3500 mg,
1. 3a) Bozzo, C.; Pujol, M. D. Tetrahedron 1999, 55, 11843±
11852. 3b) Bozzo, C.; Pujol, M. D. Synlett 2000, 550±552.
2. 3a) Capilla, A. S.; Pujol, M. D. Synth. Commun. 1996, 26,
4.58 mmol), anhydrous potassium carbonate 33.17 g,
22.94 mmol), and DMF 310 mL) were combined at room
temperature. After, ethyl 2,3-dibromopropionate 32.4 g,
9.2 mmol) was added in twice for an hour. The reaction
mixture was placed in an oil bath and heated to 608C for
24 h. Upon cooling to room temperature the solvent was
removed under vacuum and the resulting residue was
poured into water an extracted with ether. The organic
phase was dried over Na2SO4 and the solvent was evapo-
rated to dryness. The crude of reaction was puri®ed by
column chromatography 3ethyl acetate/hexane 30:70). The
compounds 24 336 mg, 2.5%) and 25 3170 mg, 10% yield)
were obtained. The compound 24 330 mg, 0.15 mmol)
dissolved in CH2Cl2 310 mL), was treated with DDQ
340 mg, 0.18 mmol). The reaction mixture was stirred at
re¯ux temperature for 4 h. Then, the organic phase was
treated with HCl 2N until acid pH, and extracted with
CH2Cl2. After NaOH 2N was added and extracted with
CH2Cl2 33£10 mL) the last organic phase was dried and
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1729±1738. 3b) Capilla, A. S.; Sanchez, I.; Caignard, D. H.;
Renard, P.; Pujol, M. D. Eur. J. Med. Chem. 2001, 36, 389±
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Miller, A. V. J. Med. Chem. 1993, 36, 2335±2342.
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8. Waller, C. W.; Hutchings, B. L.; Mowat, J. H.; Stokstad,
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1
concentrated to give the crude product. The H NMR of
the crude of reaction is the same obtained by the compound
23. Eluting with ethyl acetate 50:50 the pyrazine 23 was
obtained as a yellow oil 3367 mg, 20% yield). Compound
23: IR 3KBr) n 3cm21) 3356, 1727, 1558, 1198, 1024. MS
9. Cosulich, D. B.; Smith, J. M. J. Am. Chem. Soc. 1948, 70,
1922±1926.
3EI): m/z 3intensity) 205 3M12, 100); 159 382); 78 335). H
1
NMR 3CDCl3, 500 MHz) d 3ppm) 1.39 3t, Jˆ7 Hz, 3H,
±CH3); 4.43 3q, Jˆ7 Hz, 2H, CH2±O); 6.30 3dd, J1ˆ8 Hz,
J2ˆ1Hz, 1H, C8H); 6.64 3t, Jˆ8 Hz, 1H, C7H); 7.54 3dd,
J1ˆ8 Hz, J2ˆ1 Hz, 1H, C6H); 8.10 3s, 1H, C3H). 13C NMR
3CDCl3, 50.3 MHz) d 3ppm) 14.5 3CH3, CH3); 61.0 3CH2,
CH2±O); 102.5 3CH, C8H); 115.1 3CH, C7H); 115.6 3CH,
C6H); 118.0 3CH, C3H); 135.2 3C, C2); 136.7 3C, C8a);
140.0 3C, C4a); 163.3 3C, CO). Analysis calculated for
C10H9N3O2: C, 59.11%; H, 4.46%; N, 20.68%. Found: C,
58.80%; H, 4.82%; N, 20.79%. Compound 25: IR 3KBr) n
3cm21) 3356, 1721, 1557, 1100. MS 3EI): m/z 3intensity) 207
3M1, 10); 205 378) 159 395); 133 3100); 104 342); 78 365).
1H NMR 3CDCl3, 200 MHz) d 3ppm) 1.86 3t, Jˆ7 Hz, 3H,
-CH3); 3.84 3d, Jˆ6.2 Hz, 1H, C2H); 3.94 3d, Jˆ3.4 Hz, 1H,
C2H); 4.15 3q, Jˆ7.2 Hz, 2H, CH2±O); 4.23 3d, Jˆ6.2 Hz,
1H, C3H); 4.39 3bs, 1H, NH); 6.62 3dd, J1ˆ4.8 Hz,
J2ˆ7.6 Hz, 1H, C7H); 6.83 3dd, J1ˆ7.6 Hz, J2ˆ1.4 Hz,
1H, C8H); 7.57 3dd, J1ˆ4.8 Hz, J2ˆ1.4 Hz, 1H, C6H). 13C
NMR 3CDCl3, 50.3 MHz) d 3ppm) 13.1 3CH3, CH3); 46.8
3CH2, CH2±N); 51.6 3CH, CH±N); 59.9 3CH2, CH2±O);
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