E
B. Hajjaj et al.
Letter
Synlett
evaporated under reduced pressure, and the residue was diluted
with water and extracted with Et2O. The extract was dried and
concentrated to give 7 (2.8 g, 83%) as a yellow powder. 1H NMR
(400 MHz, acetone d6/D2O + 1.5 equiv Na2S2O4): δ = 1.14 (s, 6 H),
Et2O (24.7 mL) bromomaleic anhydride (286.7 μL, 3.1 mmol)
was added. The reaction was left stirring at r.t. for 3 h. The pre-
cipitate was filtered and washed with Et2O yielding a mixture of
11 and 11′ (910.0 mg, 87%) as a yellow solid.
The mixture of 11 and 11′ (910 mg, 2.7 mmol) and NaOAc
(222.2 mg, 2.7 mmol) was dissolved in Ac2O (13.5 mL) and
heated at 60–70 °C for 3 h. The reaction mixture was then con-
centrated, dissolved in CH2Cl2 and filtered. The filtrate was con-
centrated and purified by column chromatography (cyclohex-
ane–EtOAc) to give 3 (853 mg, 64%) as an orange solid; mp 101–
102 °C. 1H NMR (400 MHz, CDCl3 + phenylhydrazine): δ = 1.08
(s, 3 H), 1.25 (s, 3 H), 1.26 (s, 3 H), 1.36 (s, 3 H), 1.82 (dd, J = 12.5,
8.8 Hz, 1 H), 2.93 (dd, J = 12.5, 11.0 Hz, 1 H), 4.47 (dd, J = 11.0,
1.16 (s, 6 H), 4.02 (d, J = 1.7 Hz, 2 H), 5.50 (s, 1 H).22 23
,
ESI-HRMS:
m/z calcd for C9H16NO2Na+: 193.1073; found: 193.1070.
2,5-Dihydro-2,2,5,5-tetramethyl-3-({[(4-methylphenyl)sul-
fonyl]oxy}methyl)-1H-pyrrol-1-yloxy (8)
A solution of 7 (2.5 g, 14.5 mmol) and triethylamine (1.9 mL,
19.3 mmol) in dry CH2Cl2 (40.0 mL) was cooled at –10 °C, and
then TsCl (2.8 g, 14.5 mmol) was added portionwise upon vigor-
ous stirring. The solution was stirred for 3 h at r.t., washed with
water and with a sat. solution of NaHCO3, dried, and concen-
trated under vacuo. The crude was purified by column chroma-
tography (cyclohexane–EtOAc) yielding 8 (3.5 g, 67%) as a
8.8 Hz,
C
1 H), 6.89 (s, 1 H). ESI-HRMS: m/z calcd for
12H16O3N2BrNa+: 338.0237; found: 338.0223.
yellow solid. ESI-HRMS: m/z calcd for
C
16H22O4NNaS+:
Phenoxymaleimide 2 and 4 – General Procedure
347.1162; found: 347.1154.
3-(Aminomethyl)-2,5-dihydro-2,2,5,5-tetramethyl-1H-pyrrol-
1-yloxy (9)
To molten phenol (13.2 mmol), t-BuOK (1.1 mmol) in dry
dioxane (0.8 mL) was added dropwise, and the solution was left
stirring for 10 min at 40 °C. Then a solution of bromomaleimide
1 or 3 (0.8 mmol) in dry dioxane (0.8 mL) was added dropwise,
and the resulting mixture was stirred at 40 °C for 30 min. After
this time, the solvent was evaporated under reduced pressure.
The mixture was purified by column chromatography (cyclo-
hexane–EtOAc) to give the corresponding phenoxymaleimide.
3-[(3-Phenoxy-2,5-dihydro-1H-pyrrole-2,5-dione-1-yl)-
methyl]-2,5-dihydro-2,2,5,5-tetramethyl-1H-pyrrol-1-yloxy (2)
Yield 279 mg (92%); light yellow powder; mp 92–94 °C. 1H NMR
(400 MHz, CDCl3 + phenylhydrazine): δ = 1.32 (s, 6 H), 1.40 (s, 6
H), 4.14 (d, J = 1.4 Hz, 2 H), 5.34 (s, 1 H), 5.48 (s, 1 H), 7.36–7.29
A solution of 8 (1.5 g, 4.6 mmol) in anhydrous MeOH was added
dropwise into NH3 solution (75.0 mL, 7 N in MeOH). The
mixture was stirred for 2 h at r.t., then left to stand overnight.
The solvent was evaporated under reduced pressure. The
residue was treated with a buffer solution (60.0 mL; mixture of
citric acid and Na2HPO4) at pH 5 and extracted with Et2O. The
aqueous layer was saturated with NaOH and extracted with
Et2O. The extract was dried and concentrated yielding 9 (706.0
mg, 80%) as an orange oil. 1H NMR (400 MHz, CDCl3 + phenylhy-
drazine to reduce the nitroxide radical to a diamagnetic N-
hydroxylamine,24 since we found that our product was
degraded by Na2S2O4): δ = 1.24 (s, 6 H), 1.25 (s, 6 H), 3.31 (d, J =
1.8 Hz, 2 H), 5.42 (s, 1 H). ESI-HRMS: m/z calcd for C9H18ON2
170.1414; found: 170.1408.
3-[(3-Bromo-2,5-dihydro-1H-pyrrole-2,5-dione-1-yl)-
methyl]-2,5-dihydro-2,2,5,5-tetramethyl-1H-pyrrol-1-yloxy
(1)
(m,
C
2 H), 7.51–7.43 (m, 3 H). NSI-HRMS: m/z calcd for
19H22O4N2+: 342.1574; found: 342.1570.
+
:
3-(3-Phenoxy-2,5-dihydro-1H-pyrrole-2,5-dione-1-yl)-2,5-
dihydro-2,2,5,5-tetramethyl-1H-pyrrol-1-yloxy (4)
Yield 345 mg (92%); yellow solid; mp 120–122 °C. 1H NMR (400
MHz, CDCl3 + phenylhydrazine): δ = 1.13 (s, 3 H), 1.24 (s, 3 H),
1.27 (s, 3 H), 1.36 (s, 3 H), 1.80 (dd, J = 12.4, 8.7 Hz, 1 H), 2.98
(dd, J = 11.2, 12.4 Hz, 1 H), 4.46 (dd, J = 11.2, 8.7 Hz, 1 H), 5.29 (s,
1 H), 7.37–7.30 (m, 2 H), 7.54–7.43 (m, 3 H). ESI-HRMS: m/z
calcd for C18H21N2O4Na+: 352.1394; found: 352.1371.
(21) Vizcaíno, J. A.; Csordas, A.; del-Toro, N.; Dianes, J. A.; Griss, J.;
Lavidas, I.; Mayer, G.; Perez-Riverol, Y.; Reisinger, F.; Ternent, T.;
Xu, Q. W.; Wang, R.; Hermjakob, H. Nucleic Acids Res. 2016,
44,01 D447.
Bromomaleic anhydride (388.2 μL, 4.2 mmol) was dissolved in
AcOH (7.0 mL). Nitroxyl 9 (707.9 mg, 4.2 mmol) in AcOH (7.0
mL) was added, and the reaction was heated at 80 °C for 3 h. The
solvent was removed under vacuo, and the mixture was puri-
fied by column chromatography (cyclohexane–EtOAc) to give
the bromomaleimides 1 (644.7 mg, 47%) as an orange powder;
1
mp 146–147 °C. H NMR (400 MHz, CDCl3 + phenylhydrazine):
δ = 1.38 (s, 6 H), 1.45 (s, 6 H), 4.17 (d, J = 1.4 Hz, 2 H), 5.40 (s, 1
H), 6.94 (s, 1 H). NSI-HRMS: m/z calcd for C13H17O3N2Br+:
328.0417; found: 328.0417.
3-(3-Bromo-2,5-dihydro-1H-pyrrole-2,5-dione-1-yl)-2,5-
dihydro-2,2,5,5-tetramethyl-1H-pyrrol-1-yloxy (3)
To a stirred solution of amine 10 (489.0 mg, 3.1 mmol) in dry
(22) Hideg, K.; Hankovszky, H. O.; Lex, L.; Kulcsár, G. Synthesis 1980,
911.
(23) Powell, J. H.; Johnson, E. M. II.; Gannett, P. M. Molecules 2000, 5,
1244.
(24) Lee, T. D.; Keana, J. F. W. J. Org. Chem. 1975, 40, 3145.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E