An Enantioselective Organocatalytic Route to Chiral 3,6-Dihydropyridazines from Aldehydes

Alexander J. Oelke; Sirirat Kumarn; Deborah A. Longbottom; Steven V. Ley

doi:10.1055/s-2006-951486

LETTER

An Enantioselective Organocatalytic Route to Chiral 3,6-Dihydropyridazines from Aldehydes

Alexander J. Oelke, Sirirat Kumarn, Deborah A. Longbottom, Steven V. Ley*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
Fax: +44(1223)336442; e-Mail: svl1000@cam.ac.uk;

Abstract

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Abstract

Here we describe a highly enantioselective organocatalytic synthesis of chiral 3,6-dihydropyridazines from achiral starting materials which proceeds with good yield via a one-pot procedure.

Key words

asymmetric catalysis - heterocycles - ring closure - tandem reactions - Wittig reaction

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References

References and Notes

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General Procedure: The catalyst was added to a stirred solution of the azodicarboxylate (1.0 mmol) and the alde-hyde (1.2 mmol) in CH₂Cl₂ (3 mL) at r.t. After the amination was complete (indicated by the disappearing yellow colour of the azodicarboxylate), the solution was cooled to 0 °C, diluted with THF (3 mL) and the phosphonium salt (1.5 equiv) and NaH (2.5 equiv) were added. The reaction was quenched with sat. aq NH₄Cl solution (5 mL) and extracted with Et₂O (5 mL). After back-extracting of the aqueous layer with CH₂Cl₂ (2 × 5 mL), the combined organic layers were washed with water and brine and dried over MgSO₄. Evaporation of the solvent gave the crude product, which was purified by flash column chromatography (PE-EtOAc = 9:1).

Analytical data for selected compounds: (3 R )-3-Allyl-3,6-dihydropyridazine-1,2-dicarboxylic Acid Diethyl Ester ( 1c): ¹H NMR (400 MHz, CDCl₃): δ = 5.67-5.98 (m, 3 H, CHC=CHC, HC=CH₂), 5.01-5.16 (m, 2 H, C=CH₂), 4.45-4.70 (m, 1 H, NCH), 4.39 (br d, J = 17.2 Hz, 1 H, NCH _aH_b), 4.08-4.32 (m, 4 H, 2 × CO₂CH _a H _bCH₃), 3.60-3.93 (m, 1 H, NCH_a H _b), 2.32-2.55 (m, 1 H, CH _aH_bCH=CH₂), 2.16-2.30 (m, 1 H, CH_a H _bCH=CH₂), 1.17-1.32 (m, 6 H, 2 × CH₂CH ₃). ¹³C NMR (100 MHz, CDCl₃): δ = 155.9 (2 × CO₂CH₂CH₃), 134.9 (HC=CH₂), 128.0, 123.4 (CHC=CHC), 117.5 (HC=CH₂), 62.7, 62.4 (CO₂ CH₂CH₃), 54.9 (NCH), 42.9 (NCH₂), 37.8 (CH₂CHCH₂), 14.9 (2 × CH₂ CH₃). IR (film): 2981, 2935, 2853, 1703, 1643, 1466, 1410, 1378, 1339, 1306, 1273, 1211, 1173, 1120, 1063, 1023, 916, 869, 755, 735, 709 cm^-1. HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₃H₂₁N₂O₄: 269.1501; found: 269.1495.

(3 R )-3-Isopropyl-3,6-dihydropyridazine-1,2-dicarboxylic Acid Di- tert -butyl Ester ( 1f): ¹H NMR (400 MHz, CDCl₃): δ = 5.67-5.90 (m, 2 H, CHC=CHC), 4.00-4.34 (m, 2 H, NCH, NCH _aH_b), 3.56-3.78 (m, 1 H, NCH_a H _b), 1.70-1.85 [m, 1 H, CH(CH₃)₂], 1. 42-1.51 [m, 18 H, 2 × OC(CH₃)₃], 1.02-1.10 [m, 3 H, CH(CH ₃)_a], 0.95-1.00 [m, 3 H, CH(CH ₃)_b]. ¹³C NMR (100 MHz, CDCl₃): δ = 156.5, 154.5 [CO₂C(CH₃)₃], 127.3, 123.0 (CHC=CHC), 80.9, 80.5 [CO₂ C(CH₃)₃], 60.2 (NCH), 41.8 (NCH₂), 32.1 [CH(CH₃)_a], 28.3 [CO₂C(CH₃)₃], 20.2, 19.1 [CH(CH₃)_b]. IR (film): 2978, 1704, 1477, 1452, 1410, 1391, 1367, 1344, 1298, 1255, 1218, 1170, 1121, 1059, 959, 929, 869, 770, 752, 720 cm^-1. HRMS (ESI+): m/z [M + Na]⁺ calcd for C₁₇H₃₀N₂O₄Na: 349.2103; found: 349.2112.

(3 R )-3-Isopropyl-3,6-dihydropyridazine-1,2-dicarboxylic Acid Dibenzyl Ester ( 1g): ¹H NMR (400 MHz, CDCl₃): δ = 7.50-7.15 (s, 10 H, 2 × C₆H₅), 5.82-5.97 (m, 1 H, CHC=CHC), 5.62-5.82 (m, 1 H, CHC=CHC), 4.97-5.30 (m, 4 H, 2 × CH ₂Ph), 4.05-4.45 (m, 2 H, NCH, NCH _aH_b), 3.63-4.00 (m, 1 H, NCH_a H _b), 1.65-1.90 [m, 1 H, CH(CH₃)₂], 0.84-1.18 [m, 6 H, CH(CH ₃)₂]. ¹³C NMR (100 MHz, CDCl₃): δ = 155.3 (2 × CO₂Bn), 136.2, 136.0, 128.5, 128.4, 128.1 (C_aryl), 127.7, 122.7 (CHC=CHC), 67.9, 67.8 (CO₂ CH₂Ph), 61.0 (NCH), 42.8 (NCH₂), 32.2 [CH(CH₃)₂], 20.2, 19.0 [CH(CH₃)₂]. IR (film): 3035, 2960, 1705, 1498, 1446, 1403, 1357, 1338, 1315, 1285, 1210, 1137, 1110, 1054, 1029, 971, 859, 792, 750, 734, 695 cm^-1. HRMS (ESI+): m/z [M + Na]⁺ calcd for C₂₃H₂₆N₂O₄Na: 417.1790; found: 417.1776.