Radical Cyclization Reactions with a Zirconocene-Olefin Complex as an Efficient Single Electron Transfer Reagent

Abstract

A zirconocene-olefin complex induced reductive radical cyclization of β-haloalkyl allyl acetals in THF. This complex served as a single electron transfer reagent to promote the cyclization. Furthermore, the reaction in DME afforded tetrahydrofuranylmethylzirconium species effectively.

cyclizations - electron transfer - halo acetals - radical reactions - zirconocene-olefin complex

References

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<A NAME="RY21401ST-5">5</A> Recently, we also reported the Cp₂Zr(H)Cl-mediated radical reaction involving homolytic cleavage of the zirconium-hydrogen bond: Fujita K. Nakamura T. Yorimitsu H. Oshima K. J. Am Chem. Soc.  2001,  123:  3137 

<A NAME="RY21401ST-6">6</A> Spectral data for some compounds (1a, 1b, 2a, 2f, 2i, 3f, 3i) were found in the literature, see: Inoue A. Shinokubo H. Oshima K. Org. Lett.  2000,  2:  651.  This EtMgBr-mediated radical cyclization reaction was induced by a single electron transfer from Grignard reagent to alkyl halide

Bromo analogues of 1j and 1k did not provide the cyclized products under the same conditions. Spectral data for these compounds (1j, 2j, 3j, 1k, 2k and 3k) were found in the literature, see:

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<A NAME="RY21401ST-8">8</A>

Formation of mixtures of 2f-2k and their unsaturated analogues (3f-3k) could be explained by disproportionation of tertiary radical or secondary radical resulting from cyclizations of 1f-1k. Namely, we guess that these alkyl radicals do not recombine with the zirconocene-olefin complex.

<A NAME="RY21401ST-9">9</A>

In addition to these results, no product was obtained in the presence of a radical scavenger such as 2,2,6,6-tetramethylpiperidine-N-oxyl.

<A NAME="RY21401ST-10">10</A>

The formation of 9 could be confirmed by quenching the reaction mixture with DCl in place of HCl. However, deuterium was not completely incorporated (54%). Therefore, we do not exclude the path of hydrogen abstraction from THF.

<A NAME="RY21401ST-11">11</A>

Given this pathway, the reactions should proceed with only one equiv of the zirconocene-olefin complex. However, in this case, two equimolar amounts of ”Cp₂Zr(II)" is required in order to obtain reasonable yields of the cyclization products.

<A NAME="RY21401ST-12">12</A>

We assume that the alkyl radical species resulting from cyclizaton of 1e would abstract hydrogen less efficiently from DME than from THF and that most of them recombine with the zirconocene-olefin complex.

<A NAME="RY21401ST-13">13</A>

Typical Experimental Procedure for Cyclization Reaction in DME: Cp₂ZrCl₂ (585 mg, 2.0 mmol) and n-BuLi (1.5 M in hexane, 2.7 mL, 4.0 mmol) were mixed in DME at 0 °C under argon and were stirred for 1 h at 0 °C to form a zirconocene-olefin complex. A solution of bromo acetal 1e (297 mg, 1.0 mmol) in DME (2 mL) was added to the reaction mixture at 0 °C. The temperature was then raised to ambient temperature, and the stirring was continued for 3 h to yield the alkyl zirconium species 10. The mixture was poured into deuterochloric acid (10 mL, 1 M) and stirred for 30 min. The resulting products were extracted with hexane for three times. The combined organic layer was dried over Na₂SO₄ and concentrated in vacuo. Silica gel column purification (hexane:ethyl acetate = 10:1) of the crude oil provided 11 (152 mg, 0.70 mmol) in 70% yield with 94% deuterium incorporation. Spectroscopic data for 11 (mixture of diastereomers, 68:32): IR(neat): 3061, 3026, 2932, 2872, 1736, 1497, 1450, 1250, 1148, 1022, 991, 951, 897, 872, 733, 702 cm^-1; ¹H NMR (CDCl₃): δ = 1.25-2.00 (m, 5 H), 2.52-2.88 (m, 2 H), 3.41 (dt, J = 2.7, 10.4 Hz, 0.32 H), 3.59-3.68 (m, 1 H), 3.72-3.91 (m, 2.36 H), 4.17 (dt, J = 1.2, 8.1 Hz, 0.32 H), 5.03 (d, J = 3.3 Hz, 0.32 H), 5.27 (d, J = 3.9 Hz, 0.68 H), 7.13-7.32 (m, 5 H); ¹³C NMR (CDCl₃), for major isomer: δ = 19.39, 22.98, 32.90 (t, J = 19.4 Hz), 36.47, 42.29, 60.84, 69.75, 101.92, 126.17, 128.48, 128.52, 140.13. For minor isomer: δ = 20.56, 22.28, 38.19 (t, J = 19.1 Hz), 39.25, 43.65, 64.20, 73.47, 102.08, 126.21, 128.35, 128.52, 139.98. Found: C, 76.38; H + D, 8.56%. Calcd for C₁₄H₁₇DO₂: C, 76.68; H + D, 8.73%.

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<A NAME="RY21401ST-15">15</A>

A solid CuCN was used in this system Replacement of a solid CuCN2 LiCl slightly reduced the yield.