A Novel Synthesis of Spiro-2,5-dihydro-1,2-λ⁵-oxaphospholes Using a Three-Component Reaction

Abstract

The zwitterionic intermediate generated from dialkyl acetylenedicarboxylate and triphenylphosphine on reaction with N-substituted isatins leads to new highly functionalized spiro-2,5-dihydro-1,2-oxaphospholes.

Key words

1,2-oxaphospholes - isatin - isopropylacetylenedicarboxylate - triphenylphosphine

References and Notes

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23

Compounds 1-methylisatin (3a), 5-bromo-1-methylisatin (3b), 1-ethylisatin (3c), 5-bromo-1-ethylisatin (3d), 1-benzylisatin (3e) and 1-benzyl-5-bromoisatin (3f) were prepared from alkyl benzensolfonates and the potassium isatin or potassium 5-bromoisatin by known methods.²⁹ Melting points were measured on an Electrothermal 9100 apparatus and are uncorrected. Elemental analyses for C, H and N were performed using a Heraeus CHN-O-Rapid analyzer. IR spectra were measured on a Perkin-Elmer 783 infrared spectrophotometer. ¹H, ¹³C and ³¹P NMR spectra were measured using a Bruker DRX-250 Avance spectrometer at 500, 125.7 and 202.5 MHz, respectively. Mass spectra were recorded on a Shimadzu GCMS-QP5050 mass spectrometer operating at an ionization potential of 70 eV.
Preparation of 1-(morpholinomethyl)isatin (3g): A slurry consisting of the isatin (5 mmol), THF (5 mL) and formalin (2 mL, 37%) was made. To this morpholine (5 mmol) was added dropwise, with cooling and stirring. The reaction mixture was allowed to stir at r.t. for 1 h and then it was warmed on a steam bath for 15 min. At the end of the period the contents were cooled and the product obtained was recrystallized from EtOAc-hexane. Mp 203-205 °C; IR (KBr): 1760, 1720 cm^-1; ¹H NMR (500 MHz, DMSO-d ₆): δ = 2.54 (t, J = 4.0 Hz, 4 H, -CH₂NCH₂-), 3.52 (t, J = 4.0 Hz, 4 H, -CH₂OCH₂-), 4.39 (s, 2 H, NCH₂N), 7.12 (t, J = 7.5 Hz, 1 H, CH_arom), 7.26 (d, J = 7.9 Hz, 1 H, CH_arom), 7.54 (d, J = 7.8 Hz, 1 H, CH_arom), 7.64 (t, J = 7.8 Hz, 1 H, CH_arom); ¹³C NMR (125 MHz, DMSO-d ₆): δ = 50.40 (-CH₂NCH₂-), 61.75 (NCH₂N), 65.98 (-CH₂OCH₂-), 111.94 (CH_arom), 117.52 (C_arom), 123.21 (CH_arom), 124.16 (CH_arom), 137.91 (CH_arom), 151.36 (C_arom), 158.90 (N-C=O), 183.10 (C=O); MS (EI, 70 eV): m/z (%) = 246 (2) [M⁺], 147 (2) [M⁺ - 99], 100 (100) [CH₂N(CH₂CH₂)₂].

24

General procedure for the synthesis of diisopropyl-2′,2′,2′-triphenyl-2-oxospiro[1-methylindole-3,5′-(2′,5′-dihydro-1′,2′-λ ⁵ -oxaphosphole)]-3′,4′-dicarboxylate (4a): To a magnetically stirred solution of N-methylisatin (2 mmol) and PPh₃ (2 mmol) in CH₂Cl₂ (3 mL) was added dropwise, DIAD (2 mmol) at r.t. over 10 min. After 5 h the crude reaction mixture was diluted with CH₂Cl₂ and passed through a short plug of silica gel. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to give a white powder; mp 177-178 °C; IR (KBr): 1720 (N-C=O) 1735, 1740 (2 CO₂ i-Pr), 1660 (C=C), 1610 (C=C_arom), 1430, 1107, 1009 (P-Ph), 1010 (P-O) cm^-1; ¹H NMR (500 MHz, CDCl₃): δ = 0.72 (d, J = 6.2 Hz, 3 H, CHMe ₂), 1.05 (d, J = 6.2Hz, 3 H, CHMe ₂), 1.09 (d, J = 6.0 Hz, 3 H, CHMe ₂), 1.10 (d, J = 6.0 Hz, 3 H, CHMe ₂), 3.11 (s, 3 H, N-Me), 4.53 (sept, J = 6.2 Hz, 1 H, OCHMe₂), 4.83 (sept, J = 6.2 Hz, 1 H, OCHMe₂), 6.14 (d, J = 7.3 Hz, 1 H, CH_arom), 6.68 (t, J = 7.5 Hz, 1 H, CH_arom), 6.70 (d, J = 7.7 Hz, 1 H, CH_arom), 7.15 (t, J = 7.6 Hz, 1 H, CH_arom), 7.30 (m, 9 H, CH_para and CH_meta of PPh₃), 7.70 (m, 6 H, CH_ortho of PPh₃); ¹³C NMR (125 MHz, CDCl₃): δ = 21.32 (Me), 21.47 (Me), 21.87 (Me), 21.90 (Me), 26.84 (N-Me), 69.57 (OCHMe₂), 70.07 (OCHMe₂), 79.09 (d, ² J _CP = 3.3 Hz, P-O-C_spiro), 108.30 (C_3a), 122.95 (C4), 124.37 (C5), 127.93 (d, ³ J _CP = 12.8 Hz, C_meta of PPh₃), 128.85 (C₇), 129.18 (C₆), 129.87 (C_para of PPh₃), 132.24 (d, ² J _CP = 9.9 Hz, C_ortho of PPh₃), 144.02 (d, ¹ J _CP = 103.1 Hz, C_ipso of PPh₃) 147.05 (d, ² J _CP = 30.1 Hz, C=C-P), 147.51 (d, ¹ J _CP = 50.9 Hz, C=C-P), 160.83 (d, ² J _CP = 25 Hz, CO₂ i-Pr), 166.93 (d, ³ J _CP = 19.2 Hz, CO₂ i-Pr), 174.53 (N-C=O); ³¹P NMR (202 MHz, CDCl₃); δ = -46.86; MS (EI, 70 eV): m/z (%) = 621 (5) [M⁺], 606 (1) [M⁺ - 15], 578 (1) [M⁺ - i-Pr], 562 (2) [M⁺ - Oi-Pr]_, 544 (55) [M⁺ - C₆H₅], 447 (14) [M⁺ + 1 - 2CO₂ i-Pr], 277 (100) [Ph₃PO - H], 262 (40) [Ph₃P], 183 (52) [C₁₂H₈P], 152 (15) [C₁₂H₈], 108 (20) [C₆H₅P], 77 (30) [Ph]; Anal. Calcd for C₃₇ H₃₆ NO₆P: C, 71.49; H, 5.84; N, 2.25. Found: C, 71.00; H, 5.80; N, 2.30.