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Synlett 2010(19): 2839-2842  
DOI: 10.1055/s-0030-1259024
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Highly Substituted Symmetrical 1,3-Dienes via Tandem Carbocupration and Organocuprate Oxidation

Sarah J. Avesa, Kurt G. Pikeb, David R. Spring*a
a Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
Fax: +44(1223)336362; e-Mail: spring@ch.cam.ac.uk;
b AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire, SK10 4TF, UK
Further Information

Publication History

Received 2 September 2010
Publication Date:
03 November 2010 (online)

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Abstract

A ‘one-pot’ tandem carbocupration/organocuprate oxidation allows the formation of highly substituted symmetrical 1,3-dienes from alkynyl esters and alkyl organolithium or Grignard reagents with three C-C bonds being formed in one step.

Key words

cuprates - oxidation - carbocupration - 1,3-diene - tandem reaction

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12

Oxidant-derived by-products can easily be removed by an acidic wash during workup or by filtration through a pad of silica gel.

16

General Procedure for Tandem Carbocupration/Oxidation Reaction: A solution of the requisite organometallic reagent (2.10 mmol) was added to a suspension of CuBr˙SMe2 (216 mg, 1.05 mmol) in THF
(4 mL) at -78 ˚C and stirred for 30 min. Alkyne (2.00 mmol) was added dropwise and the reaction was stirred for 3 h at
-78 ˚C. A solution of oxidant 5 (589 mg, 2.00 mmol) in THF (4 mL) was added, the reaction was allowed to stir at -78 ˚C for 30 min and then allowed to warm to r.t. over 1 h. The resulting solution was filtered through a plug of silica, eluting with either PE-Et2O (1:1) or i-hexane-Et2O (1:1) and the solvent was removed in vacuo. The residue was purified by flash column chromatography.
(2 E ,3 E )-Diethyl 2,3-dipentylidenesuccinate (8a): colourless oil; R f 0.25 (PE-EtOAc, 10:1). IR (Neat): 2957, 2932, 2871, 1712 (C=O), 1631 (C=C), 1464, 1363, 1231, 1206 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.01 (t, 2 H, J = 7.6 Hz), 4.16 (q, 4 H, J = 7.1 Hz), 2.02 (app q, 4 H, J = 7.2 Hz), 1.36-1.46 (m, 4 H), 1.26-1.36 (m, 4 H), 1.24 (t, 6 H, J = 7.1 Hz), 0.90 (t, 6 H, J = 7.2 Hz). ¹³C NMR (125 MHz, CDCl3): δ = 166.5 (C), 146.3 (CH), 127.6 (C), 60.5 (CH2), 30.3 (CH2), 29.3 (CH2), 22.4 (CH2), 14.2 (Me), 13.8 (Me). HRMS (ESI): m/z [M + H]+ calcd for C18H31O4: 311.2217; found: 311.2217.
(2 Z ,3 Z )-Dimethyl 2,3-bis(1-phenylpentylidene)succinate (8b): colourless crystals; mp 60-64 ˚C (i-hexane-EtOAc); R f 0.13 (PE-EtOAc, 10:1). IR (CDCl3): 2957, 2871, 1717 (C=O), 1429, 1305, 1219, 1166, 1022 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.28-7.39 (m, 6 H), 7.18-7.23 (m, 4 H), 3.45 (s, 6 H), 2.53 (m, 4 H), 1.18-1.32 (m, 8 H), 0.83 (t, 6 H, J = 6.7 Hz). ¹³C NMR (125 MHz, CDCl3): δ = 168.0 (C), 154.0 (C), 141.2 (C), 128.0 (CH), 127.3 (CH), 127.1 (CH), 126.5 (C), 51.5 (Me), 36.1 (CH2), 29.1 (CH2), 22.9 (CH2), 13.9 (Me). HRMS (ESI): m/z [M + Na]+ calcd for C28H34O4Na: 457.2349; found: 457.2368.
(2 E ,3 E )-Diethyl 2,3-di(hexan-2-ylidene)succinate (8c): colourless oil; R f 0.37 (PE-EtOAc, 10:1). IR (CDCl3): 2957, 2927, 2867, 1709 (C=O), 1613 (C=C), 1459, 1206, 1092, 1039 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 4.11 (q, 4 H, J = 7.1 Hz), 2.13 (s, 6 H), 2.04 (br s, 4 H), 1.32-1.40 (m, 4 H), 1.22-1.29 (m, 4 H), 1.21 (t, 6 H, J = 7.1 Hz), 0.86 (t, 6 H, J = 7.3 Hz). ¹³C NMR (125 MHz, CDCl3): δ = 167.6 (C), 152.7 (C), 125.2 (C), 59.8 (CH2), 37.0 (CH2), 29.1 (CH2), 22.8 (CH2), 19.7 (Me), 14.2 (Me), 13.9 (Me). HRMS (ESI): m/z [M + Na]+ calcd for C20H34O4Na: 361.2349; found: 361.2348.
(2 E ,3 E )-Diethyl 2,3-bis(2-methylpropylidene)succinate (8d): yellow oil; R f 0.28 (PE-EtOAc, 10:1). IR (CDCl3): 2963, 2872, 1712 (C=O), 1231, 1038, 731 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 6.77 (d, 2 H, J = 10.7 Hz), 4.15 (q, 4 H, J = 7.1 Hz), 2.35 (m, 2 H), 1.22 (t, 6 H, J = 7.1 Hz), 0.96 (m, 12 H). ¹³C NMR (125 MHz, CDCl3): δ = 166.6 (C), 151.9 (CH), 125.2 (C), 60.6 (CH2), 29.0 (CH), 21.4 (Me), 14.2 (Me). HRMS (ESI): m/z [M + Na]+ calcd for C16H26O4Na: 305.1723; found: 305.1708.
(2 Z ,3 Z )-Dimethyl 2,3-bis(1-phenylethylidene)succinate (8e): white amorphous solid; R f 0.04 (PE-EtOAc, 10:1). IR (CDCl3): 2950, 1712 (C=O), 1433, 1221, 1199, 1043, 907, 720, 699 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 7.15-7.29 (m, 10 H), 3.37 (s, 6 H), 2.10 (s, 6 H). ¹³C NMR (125 MHz, CDCl3): δ = 167.6 (C), 149.8 (C), 142.5 (C), 128.0 (CH), 127.5 (CH), 127.1 (C), 126.5 (CH), 51.4 (Me), 23.0 (Me). HRMS (ESI): m/z [M + H]+ calcd for C22H23O4: 351.1596; found: 351.1601.
Diethyl 2,3-di(propan-2-ylidene)succinate (8f): colourless oil; R f 0.31 (PE-EtOAc, 10:1). IR (CDCl3): 2982, 2911, 1709 (C=O), 1625 (C=C), 1444, 1220, 1076 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 4.12 (q, 4 H, J = 7.1 Hz), 2.16 (s,
6 H), 1.72 (s, 6 H), 1.22 (t, 6 H, J = 7.1 Hz). ¹³C NMR (125 MHz, CDCl3): δ = 167.4 (C), 149.1 (C), 125.7 (C), 59.9 (CH2), 23.7 (Me), 22.1 (Me), 14.2 (Me). LCMS (ES+): m/z = 255 [M + H]+. Spectroscopic data were consistent with the literature values.¹8