A Novel Access to γ-Alkylidenebutenolides: Sequential Stille Couplings of Dibromomethylenebutenolides

Abstract

γ-(Dibromomethylene)butenolide (2) and β-bromo-γ-(bromomethylene)butenolide (Z-5), both of which obtained from dibromolevulinic acid (6) in a single step, underwent Pd-catalyzed couplings with phenyl- or styryltributylstannane giving mono­bromobutenolides with excellent stereo- and regiocontrol. A second Stille coupling or the reduction with Zn dust led to bromine-free γ-alkylidenebutenolides as single stereoisomers.

catalysis - palladium - regioselective C,C coupling - ­stereoselective C,C coupling - unsaturated lactone

References

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20

5-(Dibromomethylene)-2(5 H )-furanone ( 2): 3,5-Dibromolevulinic acid (6; 4.77 g, 17.4 mmol), oleum (18 mL, 65% SO₃), and concentrated H₂SO₄ (9 mL) were stirred at 50-60 °C for 6 min. The solution was poured on ice and extracted with CH₂Cl₂ (3 × 30 mL). The combined organic extracts were dried (Na₂SO₄) and evaporated under reduced pressure. After flash chromatography on silica gel [22] (cyclohexane:EtOAc 15:1Æ5:1) compound 2 (1.22 g, 28%) was obtained as a slightly yellow solid (mp 132-134 °C). ¹H NMR (300 MHz, CDCl₃): δ = 6.41 (d, J _3,4 = 5.6 Hz, 3-H), 7.67 (d, J _4,3 = 5.6 Hz, 4-H).

21

( Z )-4-Bromo-5(bromomethylene)-2(5 H )-furanone ( Z- 5): 3,5-Dibromolevulinic acid (6; 912 mg, 3.33 mmol) and concentrated H₂SO₄ (20 mL) were stirred at r.t. for 20 min and at 85 °C for 30 min. The solution was poured on ice and extracted with CH₂Cl₂ (3 × 30 mL). The combined organic extracts were dried (Na₂SO₄) and evaporated under reduced pressure. After flash chromatography on silica gel [22] (cyclohexane:EtOAc 15:1Æ5:1) compound Z-5 (346 mg, 41%) was obtained as a slightly yellow solid (mp 96-97 °C). ¹H NMR (300 MHz, CDCl₃): δ = 6.41 (s, 1′-H), 6.50 (s, 3-H).

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26

The stereochemical problem was clarified by the (albeit small) NOE observed at 2′-H (δ = 7.28 ppm in CDCl₃) while irradiating 4-H (δ = 8.02 ppm) of the isomer labeled E-7. The regiochemistry problem was solved by the occurrence of two vicinal C_sp2 -H/C_sp2 -H couplings (J = 11.7 Hz, 15.8 Hz) for the olefinic protons of the isomer designated Z-13 as contrasting with only one such coupling (J = 16.1 Hz) in the isomer designated Z-17. The same answer came from the occurrence of one olefinic ¹H NMR singlet in Z-13 (δ = 6.21 ppm) as opposed to two such singlets in Z-17 (δ = 6.28 and 6.31 ppm).

27

The differentiation of compound Z-9 from stereoisomer E-9 followed from irradiating 4-H (δ = 7.87 ppm in CDCl₃) and the resulting increase of absorption by 2′-H (δ = 7.07 ppm). Butenolide Z-14 was distinguished from the isomeric structure iso-14 by the occurrence of two olefinic 3-bond H,H couplings (J _{1 ′ ,2 ′} = 11.4 Hz, J _{3 ′ ,2 ′} = 15.8 Hz) rather than one. Monocoupling product Z-16 was differentiated from regioisomer iso-16 by an NOE experiment: irradiation of ortho-H (δ = 7.78-7.83 ppm in CDCl₃) enhanced only the absorption by 1′-H (δ = 6.36 ppm) and not by 1′-H and 3-H as expected for iso-16.

28

( Z )-4-Bromo-5-( trans -3-phenyl-2-propenylidene)-2(5 H )-furanone ( Z -14): ¹H NMR (300 MHz, CDCl₃): δ = 6.30 (d, J _{1 ′ ,2 ′} = 11.4 Hz, 1′-H), 6.37 (s, 3-H), 6.93 (d, J _{3 ′ ,2 ′} = 15.8 Hz, 3′-H), 7.25-7.41 (m, 2′-H, 2 × meta-H, para-H), 7.50-7.53 (m, 2 × ortho-H). ¹³C NMR (125.7 MHz, CDCl₃): δ = 114.51 (C-1′), 119.11 (C-3), 121.01 (C-2′), 127.40 (2 × C _ortho ), 128.92 (2 × C _meta ), 129.41 (C _para ), 136.11 and 136.19 (C-4, C _ipso ), 140.13 (C-3′), 147.23 (C-5), 166.64 (C-2). Anal. Calcd for C₁₃H₉BrO₂ (276.5): C, 56.34; H, 3.27. Found: C, 56.36; H, 3.19.

29

( Z )-5-(1-Bromo-1-phenylmethylene)-2(5 H )-furanone ( Z -11): ¹H NMR (300 MHz, CDCl₃): δ = 6.31 (d, J _3,4 = 5.6 Hz, 3-H), 7.41-7.49 (m, C₆H₅ and 4-H). ¹³C NMR (75.4 MHz, CDCl₃): δ = 110.88 (C-1′), 120.80 (C-3), 128.75 and 130.11 (2 × C _ortho , 2 × C _meta ), 130.23 (C _para ), 135.39 (C _ipso ), 140.88 (C-4), 149.10 (C-5), 168.46 (C-2). Anal. Calcd for C₁₁H₇BrO₂ (250.5): C, 52.62; H, 2.81. Found: C, 52.66; H, 2.70.

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31

While we debrominated 1,1-dibromoolefin 2 using Pd(PPh₃)₄ and HSnBu₃ (ÆZ-10, Scheme [4] ) the same reagents [30] or variations thereof [Pd(PPh₃)₄/HSiEt₃ or HSi(SiMe₃)₃ or NH₄HCO₂; Pd(dba)₂ or NiCl₂(PPh₃)₂/HSnBu₃] failed to reduce 1,3-dibromodiene Z-5 due to inertness (15 was not formed, Scheme [5] ).

Method, albeit without sonication:

32a Villa MJ. Lete E. Badia D. Dominguez E. J. Chem. Res., Synop.  1987,  418 

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33

The C^{1 ′} = C^γ configuration of debromination product E-8 followed from the NOE’s induced by irradiating, in CDCl₃ solution, 4-H (δ = 7.84 ppm): The absorption of 1′-H (δ = 6.50 ppm) remained unaltered while the absorption of 2′-H (δ = 7.02 ppm) increased. In Z-8 an analogous assignment was impossible because the resonances of 4-H and 2′-H overlapped. The C^{1 ′} = C^γ configurations of the debromination products E-12 and Z-12 were established by the absence(presence) of an NOE at 1′-H (δ = 6.81 ppm and δ = 6.03 ppm, respectively, in CDCl₃) when irradiating 4-H (δ = 7.82 ppm and δ = 7.49 ppm, respectively).

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Alternative ways to alkylidenebutenolides of this substitution pattern:

37a Negishi E.-i. Kotora M. Synthesis  1997,  121 

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37c Rousset S. Thibonnet J. Abarbri M. Duchêne A. Parrain J.-L. Synlett  2000,  260 

38a

Sorg, A. Dissertation (in progress)

38b Brückner R. Siegel K. Sorg A. In Strategies and Tactics in Natural Product Synthesis   Vol. 5:  Harmata M. Elsevier/Academic Press; Orlando: p.in press