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Synlett 2006(16): 2548-2552  
DOI: 10.1055/s-2006-951486
LETTER
© Georg Thieme Verlag Stuttgart · New York

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;
Further Information

Publication History

Received 13 July 2006
Publication Date:
22 September 2006 (online)

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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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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).

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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 aHb), 4.08-4.32 (m, 4 H, 2 × CO2CH a H bCH3), 3.60-3.93 (m, 1 H, NCHa H b), 2.32-2.55 (m, 1 H, CH aHbCH=CH2), 2.16-2.30 (m, 1 H, CHa 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.

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(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 aHb), 3.56-3.78 (m, 1 H, NCHa 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.

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(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 × C6H 5 ), 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 aHb), 3.63-4.00 (m, 1 H, NCHa 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 (Caryl), 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.