A Palladium-Catalyzed Sequence of Allylic Alkylation and Hiyama Cross-Coupling: Convenient Synthesis of 4-(α-Styryl) γ-Lactones

Abstract

Unsaturated malonyl esters underwent Pd-catalyzed ­intramolecular allylic alkylation to give 4-vinyl-substituted γ-lactones. In contrast to the previously studied cyclization of malon­amides, this reaction could only be achieved with a substrate incorporating a judiciously positioned silicon moiety, which directs the ionization toward the desired η³-allyl-palladium complex. The resulting 4-[dimethyl(2-thienyl)silylvinyl]lactone could be subsequently engaged into Hiyama couplings to give the corresponding 4-(α-styryl) γ-lactones.

Key words

palladium - allylic alkylations - Hiyama cross-coupling - lactones - ring closure

References and Notes

• 1 Giambastiani G. Pacini B. Porcelloni M. Poli G. J. Org. Chem.  1998,  63:  804 
• 2 See for example: Sibi MP. Liu P. Ji J. Hajra S. Chen J.-X. J. Org. Chem.  2002,  67:  1738 
• Esters are known to prefer the s-trans conformation which does not possess the correct geometry for cyclization. See:
• 3a Deslongchamps P. Stereoelectronic Effects in Organic Chemistry   Pergamon Press; Oxford: 1984. 
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• 3c For a radical cyclization concerning an ester precursor, see for example: Yorimitsu H. Nakamura T. Shinokubo H. Oshima K. Omoto K. Fujimoto H. J. Am. Chem. Soc.  2000,  122:  11041 
• 4 Norrby P.-O. Mader MM. Vitale M. Prestat G. Poli G. Organometallics  2003,  22:  1849 
• 5 Experiments corresponding to entries 1, 2 and 3 can also be found in ref. 4. Formation of the lactone 4 (incorrectly assigned as the lactone 5 in ref. 4) may derive from addition of the malonyl carbon acid to the distal terminus of the η³-allyl-palladium complex, followed by lactonization via carboxylate addition to a newly generated η³-allyl complex. In this case, the Pd-catalyzed cleavage of the malonyl moiety from the substrate might take place either before or after the C-C bond formation. See also: Silvestri MA. He C. Khoram A. Lepore SD. Tetrahedron Lett.  2006,  47:  1625 
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• 7a

  Inspection of molecular models of the silylated substrates 6 suggests that the allylic C-O bond vicinal to silicon is likely to be forced by the bulky Et₃Si group to be almost orthogonal to the C=C, whereas the distal allylic C-O bond is not expected to suffer such a restriction. Since the oxidative addition of Pd(0) to allylic acetates is known to be operative only if the substrate can adopt an orthogonal C=C/C-O disposition (ref. 7b) it appears that the silylated substrates 6 might be intrinsically biased to expel the vicinal rather than the distal allylic leaving group.

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8

Substrates 6a-c were easily prepared in a few steps starting from butyn-1,4-diol.

9

Although the yields are only moderate, ¹H NMR of the crude products as well as TLC analysis indicate complete disappearance of the starting material and the absence of other possible regio- or stereoisomers of 7. Partial decomposition of the starting material as polymeric material is thus likely.

10

To a solution of silylated compound 6c (115 mg, 0.284 mmol, 1 equiv) in DMF (1.5 mL) NaH (60% dispersion in mineral oil; 11.4 mg, 0.290 mmol, 1.0 equiv) was added at 0 °C under argon atmosphere and the resulting mixture was allowed to warm at r.t. in 30 min. In a separate flask, 1,2-(diphenylphosphino)ethane (2.2 mg, 5.6 µmol, 0.02 equiv) was added to a solution of Pd(OAc)₂ (0.6 mg, 2.7 µmol, 0.01 equiv) in DMF (300 µL) under argon atmosphere and the resulting mixture was stirred until it became white. The former solution was then added to the latter, and the resulting mixture was heated at 60 °C for 1 h. Then, sat. NH₄Cl (10 mL) and Et₂O (5 mL) were added and the aqueous layer was extracted with Et₂O (2 × 5 mL). The collected organic layers were washed with sat. NaHCO₃ (5 mL) and brine (2 × 5 mL), dried, and the solvent was removed under reduced pressure. Flash column chromatography (cyclohexane-EtOAc, 85:15) of the resulting crude product afforded 7 (50 mg, 62% yield) as a colorless oil. ¹H NMR (400 MHz, CDCl₃,): δ = 0.62 (m, 6 H), 0.90 (t, ³ J = 7.8 Hz, 9 H), 3.60 (d, ³ J = 9.6 Hz, 1 H), 3.67 (m, 1 H), 3.78 (s, 3 H), 3.93 (t, ² J = 8.6 Hz, ³ J = 8.6 Hz, 1 H), 3.93 (dd, ³ J = 8.6 Hz, ³ J = 7.5 Hz, 1 H), 5.56 (s, 1 H), 5.89 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 2.8, 7.2, 44.7, 51.7, 53.1, 72.7, 127.8, 145.0, 167.9, 171.8. HRMS (DCI⁺): m/z calcd for C₁₄H₂₅O₄Si: 285.1522; found: 285.1523.

15

General Procedure.
A 1.0 M THF solution of nBu₄NF (2.4 equiv) was added at r.t. and under argon atmosphere to a 0.1 M THF solution of vinylsilyl-lactone 9 (1.2 equiv). After 10 min stirring, the aryl halide (1 equiv) and Pd_{2 (}dba)₃ (0.025 equiv) were added in this order. The resulting mixture was then stirred overnight. After treatment with sat. NH₄Cl, the aqueous layer was extracted with CH₂Cl₂ and the resulting organic layer was washed with brine and dried. Removal of the solvent under reduced pressure gave the crude products 10a-g, which were purified via flash chromatography.

16

Hiyama couplings involving 1,2-disubstituted vinylsilanes do not show the same trend. See for example ref. 12.