A Diastereoselective Synthesis of Phosphorylated Dihydro-1H-pyrazoles from Dialkyl Phosphites, Acetylenic Esters, and Hydrazonoyl Chlorides

Abstract

The 1:1 zwitterionic intermediates formed from the reaction of trialkyl phosphites with acetylenic esters were trapped by hydrazonoyl chlorides to yield dialkyl 4-(dialkoxyphosphoryl)-1-phenyl-3-aryl-4,5-dihydro-1H-pyrazole-4,5-dicarboxylates in good yields. This three-component synthesis of phosphorylated dihydro-1H-pyrazoles produces only one diasteromer.

Key words

pyrazoles - trialkyl phosphites - acetylenic esters - hydrazonoyl chlorides - MCR

References and Notes

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17

General Procedure for the Synthesis of Compound 4 To a stirred solution of P(OR)₃ (1 mmol) and hydrazonyl chloride 3 (1 mmol) in CH₂Cl₂ (5 mL) was added acetylenic ester 2 (1 mmol) at r.t. After completion of the reaction (10 h), as indicated by TLC (hexane-EtOAc, 5:1), the solvent was removed under reduced pressure, and the light cream residue was separated by silica gel (Merck 230400 mesh) column chromatography using hexane-EtOAc mixture as eluant to afford the pure products.
Selected Spectroscopic Data Compound 4a: colorless crystals, mp 115-117 ˚C. IR (KBr): 1741 (C=O), 1609, 1599, 1548, 1498, 1459, 1388, 1264 (P=O), 1234, 1172, 1054, 1051, 766, 693, 547 cm^-¹. ^¹H NMR (500.1 MHz, CDCl₃): δ = 1.12 (t, ^³ J = 7.1 Hz, 3 H, Me), 1.20 (t, ^³ J = 7.1 Hz, 3 H, Me), 3.61 (d, ^³ J = 10.9 Hz, 3 H, POMe), 3.97 (d, ^³ J = 10.8 Hz, 3 H, POMe), 4.06-4.11 (m, 1 H, OCH₂), 4.15 (q, ^³ J = 7.1 Hz, 2 H, OCH₂), 4.22-4.28 (m, 1 H, OCH₂), 5.43 (d, ^³ J = 25.4 Hz, 1 H, CH), 6.93 (t, ^³ J = 7.3 Hz, 1 H, CH), 7.11 (d, ^³ J = 8.3 Hz, 2 H, 2 × CH), 7.27-7.33 (m, 3 H, 3 × CH), 7.35-7.37 (m, 2 H, 2 × CH), 8.01 (d, ^³ J = 7.4 Hz, 2 H, 2 × CH). ^³¹P NMR (202 MHz, CDCl₃): δ = 18.5. ^¹³C NMR (125.6 MHz, CDCl₃): δ = 13.5 (Me), 13.8 (Me), 54.2 (d, ^² J = 6.9 Hz, POMe), 55.1 (d, ^² J = 6.0 Hz, POMe), 62.0 (OCH₂), 62.8 (OCH₂), 67.5 (d, ^¹ J = 141.9 Hz, C), 69.8 (d, ^³ J = 4.0 Hz, CH), 113.5 (2 × CH), 120.5 (CH), 127.2 (2 × CH), 128.0 (2 × CH), 128.6 (CH), 129.0 (2 × CH), 131.0 (C), 142.3 (C), 143.2 (C), 166.3 (C=O), 167.3 (d, ^³ J = 17.0 Hz, C=O). MS (EI): m/z = 474 (5) [M⁺], 429 (15), 77 (45), 71 (65), 57 (100), 43 (80). Anal. Calcd for C₂₃H₂₇N₂O₇P (474.44): C, 58.23; H, 5.74; N, 5.90. Found: C, 58.47; H, 5.42; N, 5.71. Compound 4b: yellow oil, yield 0.42 g (88%). IR (KBr): 1744 (C=O), 1596, 1498, 1432, 1383, 1256 (P=O), 1204, 1161, 1042, 1016, 971, 818, 745, 547 cm^-¹. ^¹H NMR (500.1 MHz, CDCl₃): δ = 1.02 (t, ^³ J = 7.0 Hz, 3 H, Me), 1.34 (d, ^³ J = 7.1 Hz, 3 H, Me), 2.35 (s, 3 H, Me), 3.67-3.70 (m, 6 H, 2 OMe), 3.93-4.03 (m, 2 H, POCH₂), 4.31-4.36 (m, 2 H, POCH₂), 5.42 (d, ^³ J = 25.1 Hz, 1 H, CH), 6.90 (t, ^³ J = 7.3 Hz, 1 H, CH), 7.07 (d, ^³ J = 8.0 Hz, 2 H, 2 × CH), 7.15 (d, ^³ J = 8.1 Hz, 2 H, 2 × CH), 7.27-7.30 (m, 2 H, 2 × CH), 7.80 (d, ^³ J = 8.2 Hz, 2 H, 2 × CH). ^³¹P NMR (202 MHz, CDCl₃): δ = 18.6. ^¹³C NMR (125.6 MHz, CDCl₃): δ = 15.8 (d, ^² J = 6.3 Hz, Me), 16.3 (d, ^² J = 5.7 Hz, Me), 21.3 (Me), 52.8 (OMe), 53.3 (OMe), 63.8 (d, ^² J = 6.9 Hz, POCH₂), 64.7 (d, ^² J = 6.2 Hz, POCH₂), 67.6 (d, ^¹ J = 141.4 Hz, C), 69.7 (d, ^² J = 4.0 Hz, CH), 113.1 (2 × CH), 120.2 (CH), 127.1 (2 × CH), 128.1 (C), 128.8 (2 × CH), 129.1 (2 × CH), 138.8 (C), 142.4 (d, ^³ J = 6.4 Hz, C), 143.3 (C), 167.1 (C=O), 168.2 (d, ^³ J = 16.6 Hz, C=O). MS (EI): m/z = 488 (5) [M⁺], 457 (10), 77 (30), 57 (100), 43 (70). Anal. Calcd for C₂₄H₂₉N₂O₇P (488.47): C, 59.01; H, 5.98; N, 5.73. Found: C, 59.45; H, 5.41; N, 5.47.
Compound 4c: yellow oil, yield: 0.43 g (90%). IR (KBr): 1746 (C=O), 1597, 1572, 1497, 1433, 1384, 1256 (P=O), 1162, 1043, 1016, 972, 829, 745 cm^-¹. ^¹H NMR (500.1 MHz, CDCl₃): δ = 1.03 (t, ^³ J = 7.0 Hz, 3 H, Me), 1.35 (t, ^³ J = 7.0 Hz, 3 H, Me), 3.68-3.70 (m, 6 H, 2 OMe), 3.96-4.02 (m,
2 H, POCH₂), 4.32-4.37 (m, 2 H, POCH₂), 5.41-5.43 (m, ^³ J = 25.1 Hz, 1 H, CH), 6.92 (t, ^³ J = 7.2 Hz, 1 H, CH), 7.08 (d, ^³ J = 8.0 Hz, 2 H, 2 × CH), 7.26-7.32 (m, 4 H, 4 × CH), 7.94 (d, ^³ J = 8.6 Hz, 2 H, 2 × CH). ^³¹P NMR (202 MHz, CDCl₃): δ = 18.7. ^¹³C NMR (125.6 MHz, CDCl₃): δ = 15.8 (d, ^² J = 6.1 Hz, Me), 16.3 (Me), 21.2 (d, ^² J = 5.7 Hz, Me), 52.9 (OMe), 53.4 (OMe), 63.8 (d, ^² J = 7.2 Hz, POCH₂), 64.9 (d, ^² J = 6.2 Hz, POCH₂), 67.5 (d, ^¹ J = 140.5 Hz, C), 69.8 (d, ^³ J = 3.6 Hz, CH), 113.3 (2 × CH), 120.7 (CH), 128.2 (2 × CH), 128.4 (2 × CH), 129.1 (2 × CH), 129.5 (C), 134.5 (C), 141.3 (C), 142.9 (C), 166.8 (C=O), 168.1 (d, ^³ J = 16.9 Hz, C=O). MS (EI): m/z = 508 (5) [M⁺], 447 (15), 77 (45), 57 (100), 43 (75). Anal. Calcd for C₂₃H₂₆N₂O₇PCl (508.88): C, 54.28; H, 5.15; N, 5.50. Found: C, 54.71; H, 5.39; N, 5.21.

19

A referee of this paper suggested a mechanistic alternative, involving the 1,3-dipolar cycloaddition of a nitrilimine (formed by extrusion of HCl from the hydrazonoyl chlorides) to the P-substituted fumarate (product of the reaction of HCl, the phosphite, and the acetylenedi-carboxylate). Although we are unable to rule out this possibility, we prefer the mechanism shown in Scheme  [²] .