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B. Metten et al.
PAPER
HR–MS (EI): m/z calcd for C24H36BNO9: 493.2483; found:
493.2488.
2-Methoxycarbonylmethoxy-N,N-bis(methoxycarbonylmeth-
yl)-4-(1H-phenathro[9,10-d]-imidazol-2yl)aniline (11)
A solution of 6a (177 mg, 0.50 mmol), 9,10-phenanthrenequinone
(10, 104 mg, 0.50 mmol) and ammoniumacetate (385 mg, 5.00
mmol) in glacial AcOH was charged in a 10 mL glass tube which
was then tightly sealed with an aluminum/Teflon crimp and heated
at 180 °C by irradiation at 250 W for 2 min in a CEM-Discover
mono-mode microwave apparatus. The cooled solid mixture was
poured in crushed ice and then neutralized with an aq NH3 solution
(10%). The precipitate was filtered and purified by column chroma-
tography on silica gel (eluent: CH2Cl2 to CH2Cl2–EtOAc, 90:10).
Compound 11 (95 mg, 35%) was obtained as a white-yellow pow-
der; mp 199–200 °C.
1H NMR (300 MHz, CDCl3): d = 3.66 (s, 6 H, OCH3), 3.77 (s, 3 H,
OCH3), 4.29 (s, 4 H, NCH2), 4.93 (s, 2 H, OCH2), 6.95 (s, J = 8.1
Hz, 1 H, C6H3), 7.63 (t, J = 7.3 Hz, 2 H), 7.75 (t, J = 7.3 Hz, 2 H),
7.77 (s, 1 H, C6H3), 7.83 (d, J = 8.8 Hz, 1 H, C6H3), 8.54 (d, J = 8.1
Hz, 2 H), 8.85 (d, J = 8.1 Hz, 2 H), 13.38 (br s, 1 H, NH).
4-Formyl-2-ethoxycarbonylmethoxy-N,N-bis(ethoxycarbonyl-
methyl)aniline (6b)
To a solution of 3b (1.47 g, 4.00 mmol), pyridine (388 mg, 0.40 mL,
5.00 mmol) in DMF (3.76 g, 4,0 mL, 50.0 mmol) was added POCl3
(4.94 g, 3.00 mL, 32.0 mmol) in a dropwise manner at 0 °C over 5–
10 min. The reaction was heated for 1–2 h at 65 °C until completion.
The reaction was monitored by the disappearance of the starting
material on silica TLC plate. After completion of the reaction, the
reaction mixture was poured into ice-water . After extraction with
EtOAc the organic layer was washed with brine and dried over
MgSO4. After removal of the solvent under reduced pressure, the
residue was purified by column chromatography on silica gel (elu-
ent: CH2Cl2–EtOAc, 9:1). This afforded 6b (1.33 g, 61%) as white
crystals; mp 59–60 °C.
1H NMR (300 MHz, CDCl3): d = 1.25–1.31 (m, 9 H, OCH3), 4.21–
4.27 (m, 10 H, NCH2, OCH2), 4.65 (s, 2 H, OCH2), 6.80 (d, J = 8.1
Hz, 1 H, C6H3), 7.27 (d, J = 1.8 Hz, 1 H, C6H3), 7.44 (dd, J = 8.1,
1.8 Hz, 1 H, C6H3,), 9.76 (s, 1 H, CHO).
13C NMR (75 MHz, CDCl3): d = 190.3, 170.7, 168.0, 148.7, 145.3,
129.8, 127.3, 117.2, 111.6, 65.6, 61.4, 61.0, 54.0, 14.2, 14.1.
13C NMR (75 MHz, CDCl3): d = 171.9, 168.7, 154.6, 150.4, 146.1,
143.4, 140.4, 138.8, 129.4, 129.3, 128.0, 125.1, 120.8, 120.4, 120.3,
119.1, 117.6, 115.8, 114.0, 108.2, 65.5, 60.7.
LR–MS (CI): m/z = 542 [MH+].
HR–MS (EI): m/z calcd for C30H27N3O7: 541.1849; found:
541.1838.
LR–MS (CI): m/z = 396 [MH+].
HR–MS (EI): m/z calcd for C19H25NO8: 395.1580; found: 395.1574.
2-Ethoxycarbonylmethoxy-N,N-bis(ethoxycarbonylmeth-
yl)benzene-1,4-diamine (12b)
4-Formyl-2-methoxycarbonylmethoxy-N,N-bis(methoxycarbo-
nylmethyl)aniline (6a)
Compound 6a was prepared in the same way as 6b giving 6a (4.24
To a solution of 3 (6.85 g, 18.6 mmol) in AcOH (60 mL) was added
fuming HNO3 (1.40 g, 1.00 mL, 22.3 mmol) dissolved in AcOH (10
mL) in a dropwise manner at 0 °C over 5–10 min. The reaction was
monitored by the disappearance of the starting material on a silica
TLC plate. After completion, the reaction mixture was poured on to
ice-water. After extraction with CH2Cl2, the organic layer was dried
over MgSO4 and filtered. After removing of the solvent under re-
duced pressure, the residue was purified by column chromatogra-
phy on silica gel (eluent: CH2Cl2). Compound 13b (3.94 g, 51%)
was obtained as yellow crystals; mp 76–78 °C.
1H NMR (300 MHz, CDCl3): d = 1.25–1.30 (m, 9 H, OCH3), 4.21–
4.27 (m, 10 H, OCH2, NCH2), 4.66 (s, 2 H, OCH2), 6.71 (d, J = 8.8
Hz, 1 H, C6H3), 7.61 (d, J = 2.6 Hz, 1 H, C6H3), 7.83 (dd, J = 8.8 Hz,
J = 2.6 Hz, 1 H, C6H3).
g, 60%) as white crystals; mp 94 °C.
1H NMR (300 MHz, CDCl3): d = 3.78 (s, 6 H, OCH3), 3.80 (s, 3 H,
OCH3), 4.29 (s, 4 H, NCH2), 4.67 (s, 2 H, OCH2), 6.80 (d, J = 8.8
Hz, 1 H, C6H3), 7.27 (d, J = 1.5 Hz, 1 H, C6H3), 7.43 (dd, J = 8.8,
1.5 Hz, 1 H, C6H3).
13C NMR (75 MHz, CDCl3): d = 190.7, 171.5, 168.5, 148.9, 145.5,
130.3, 127.8 (CH), 117.5 (CH), 111.9, 65.8, 54.2, 52.6, 52.4.
LR–MS (CI): m/z = 354 [MH+].
HR–MS (EI): m/z calcd for C16H19NO8: 353.1111; found: 353.1111.
4-(3,5-Dimethyl-1,7-diphenyl-1,7-dihydrodipyrazolo[3,4-b:4,3-
e]-2-ethoxycarbonylmethoxy-N,N-bis(ethoxycarbonylmeth-
yl)aniline (9)
13C NMR (75 MHz, CDCl3): d = 170.9, 168.0, 147.8, 145.8, 141.1,
119.4, 116.8, 109.1, 66.2, 62.0, 61.9, 61.6, 60.9, 54.5, 14.5, 14.4.
Compound 6b (99 mg, 0.25 mmol) and 5-amino-1-phenyl-3-meth-
ylpyrazole (8, 108 mg, 0.75 mmol) were heated in a long tube under
Ar to 120–160 °C for 1 h and 2 min at 200 °C. After cooling, EtOH
(8 mL) was added and the mixture was heated at reflux temperature
for 20 min. The solvent was evaporated and the obtained residue
was purified by column chromatography on silica gel (eluent:
CH2Cl2 to CH2Cl2–EtOAc, 80:20) to give 9 (30 mg, 17%) as yellow
glass film; mp 141 °C.
1H NMR (300 MHz, CDCl3): d = 1.20–1.30 (m, 9 H, OCH3), 2.10
(s, 6 H, pyrazole-CH3), 4.21–4.42 (m, 10 H, OCH2, NCH2), 4.67 (s,
2 H, OCH2), 6.87 (s, 1 H, C6H3), 6.99–7.05 (m, 2 H, C6H3), 7.31 (t,
J = 8.1 Hz, 2 H, C6H5), 7.52 (t, J = 8.1 Hz, 4 H, C6H5), 7.52 (d, J =
8.1 Hz, 4 H, C6H5).
LR–MS (CI): m/z = 413 [MH+].
HR–MS (EI): m/z calcd for C18H24N2O9: 412.1482; found:
412.1493.
To a solution of the nitrated APTRA derivative 13b (1.65 g, 4.00
mmol) in Et2O (100 mL) was added Pd/C (5%, 200 mg) and the sus-
pension was left under H2 at atmospheric pressure. After stirring
overnight the mixture was filtered through a layer Celite. The resi-
due, after evaporation of the solvent, was purified by flash column
chromatography on silica gel (eluent: EtOAc), giving 12b (968 mg,
63%) as an oil that turned brown after long-time exposure to air.
1H NMR (300 MHz, CDCl3): d = 1.21–1.29 (m, 9 H, OCH3), 3.49
(br s, 2 H, NH2), 4.10–4.17 (m, 8 H, NCH2, OCH2), 4.25 (q, 2 H,
OCH2), 4.67 (s, 2 H, OCH2), 6.22 (d, J = 2.6 Hz, 1 H, C6H3), 6.28
(dd, J = 8.4, 2.6 Hz, 1 H, C6H3), 6.88 (d, J = 8.4, 2.6 Hz, 1 H, C6H3).
13C NMR (75 MHz, CDCl3): d = 171.6, 168.7, 150.9, 149.2, 144.9,
141.4, 140.8, 129.3, 127.9, 125.5, 123.4, 120.6, 119.2, 115.1, 114.0,
66.3, 61.7, 61.3, 54.2, 15.3, 14.6, 14.5.
13C NMR (75 MHz, CDCl3): d = 171.3, 169.2, 151.6, 142.6, 131.4,
122.8, 109.1, 103.4, 66.4, 61.4, 60.4, 54.1, 14.2, 14.1.
LR–MS (CI): m/z = 705 [MH+].
HR–MS (EI): m/z calcd for C39H40N6O7: 704.2958; found:
LR–MS (CI): m/z = 383 [MH+].
704.2971.
Compound 12a was prepared in the same way as 12b giving 13a
(6.20 g, 84%) after nitration (pure on TLC, no additional purifica-
Synthesis 2005, No. 11, 1838–1844 © Thieme Stuttgart · New York