Synthesis of Homoallylic Ethers

1 Silyl-Modified Sakurai Reaction Secondary and tertiary homoallylic ethers are impotant building blocks in the synthesis of biologically active compounds. In 1991, Marko et al. developed an efficient method for the synthesis of those 

SCHEME 12.11 The first described Hosomi-Sakurai reactions. 

The synthetic utility of this method was exemplified by the efficient and stereocontrolled synthesis of the pyran 53, starling by the product 49a, which resrrlts from the use of silyl 

SCHEME 12.12 General mechanism for Hosomi-Sakurai reaction. 

SCHEME 12.13 Multicomponent (aza-)Hosomi-Sakurai reactions synthesis of homoallylic ethers (Eq. 1) and synthesis of homoaUylic amines (Eq. 2). 

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Acyclic acetals are simple protecting groups for aldehydes and ketones, and we have previously reported their synthesis catalyzed by Bi(OTf)3 [104]. Acyclic acetals can also be converted to other useful functional groups. For example, allylation of acyclic acetals to give homoallyl ethers has been well investigated, and we have reported a Bi(OTf)3-catalyzed method for the same [105]. The success of Bi(OTf)3-catalyzed formation and allylation of acyclic acetals prompted us to develop a one-pot method for the synthesis of homoallyl ethers from aldehydes, catalyzed by bismuth triflate. A one-pot process saves steps by eliminating the need for isolation of the intermediate and thus minimizes waste. Three one-pot procedures for the synthesis of homoallyl ethers were developed [106]. 

Yadav JS, Subba Reddy VB, Srihari P (2000) Scandium triflate catalyzed allylation of acetals and gem-diacetates a facile synthesis of homoallyl ethers and acetates. Synlett 673... 

Wieland LC, Zerth HM, Mohan RS (2002) Bismuth triflate catalyzed allylation of acetals a simple and mild method for synthesis of homoallyl ethers. Tetrahedron Lett 43 4597 1600... 

Anzalone PW, Baru AR, Danielson EM, Hayes PD, Nguyen MP, Panico AF, Smith RC, Mohan RS (2005) Bismuth compounds in organic synthesis a one-pot synthesis of homoallyl ethers and homoallyl acetates from aldehydes catalyzed by bismuth triflate. J Org Chem 70 2091-2096... 

Mekhalfia A, Marko IE (1991) The silyl modified Sakurai (SMS) reaction. An efficient and versatile one-pot synthesis of homoallylic ethers. Tetrahedron Lett 32 4779 1782... 

The aUylation of acetals with y-substituted allylsilanes is occasionally highly syn-selective [362]. Panek et al. have succeeded in highly diastereo- and enantioselective synthesis of homoallyl ethers by aUylation using homochiral a,y-disubstituted allylsilanes [334] (Section 10.3.1.3). 

Zerth, H.M., Leonard, N.M., Mohan, R.S. (2003) Synthesis of homoallyl ethers via alkylation of acetals in ionic liquids catalyzed by trimethylsilyl trifluoromethanesulfonate. Org. Lett., 5,55-57. 

Modified Sakurai reaction.3 The original reaction involved the TiCI4-catalyzed addition of allyllrimclhylsilanc to aldehydes and ketones or the acetals and kctals to form homoallylic alcohols or ethers (7,370-371). Marko et al. have extended this reaction to a synthesis of homoallylic ethers by a Lewis acid catalyzed reaction of allyl-trimcthylsilanc with a carbonyl compound and a trimethylsilyl ether. 

Metzger, J.O., andU. Biermann, Ethylaluminium Dichloride Induced Reactions of Acetals with Unsaturated Carhoxyhc Esters Synthesis of Homoallyl Ethers, Liebigs Ann. 1851-1854 (1996). 

In this chapter, only the most recent multicomponent versions of the Hosomi-Sakurai reaction will be covered [68b], in particular those that allowed the synthesis of homoallylic ethers through the combination of an aldehyde (or ketone) with a silyl ether or the corresponding alcohol and an allylsilane (Scheme 12.13, Eq. 1). And also, the synthesis of homoallylic amines where the allylsilane reacts with an imine in situ formed from the carbonyl compound and an amine is known as aza-Sakurai reaetion (Scheme 12.13, Eq. 2). 

A year later, after Maikd s first article about SMS reaction, Tietze et al. published a stereoselective version of the same reaction using trimethylsilyl ether of (lR,2R)-Af-trifluoro-acetylnorpseudoephedrin, which acts as chiral auxiliary [77]. Since then, Tietze s group has been working extensibly in the domino multicomponent allylation reaction (MCAR) for the stereoselective synthesis of homoallylic ethers... 

SCHEME 12.16 Domino multicomponent allylation reaction (MCAR) for the stereoselective synthesis of homoallylic ethers and alcohols, a proposed mechanism. 

The reaction of carbonyls with alcohols or TMS ethers under catalysis by (la) or Mes Sil provides an efficient, rapid access to oxocarbenium ions. The oxocarbenium ions generated in situ have frequently been utilized for the Hosomi-Sakurai allylation (Scheme 9.14) [2, 56]. This tandem acetalization-allylation reaction is quite convenient to the synthesis of homoallyl ethers. 

Suzuki T, Oriyama T (1999) Novel reactions of ethylene acetals with silyl-substituted nucleophiles. A mild and efficient procedure for the synthesis of homoallyl alkyl ethers and unsymmetrical dialkyl ethers. Synth Commun 29 1263-1269... 

A highly selective synthesis of homoallylic alcohols has been reported by Tietze et al.,917 who reacted methyl ketones, the chiral norpseudoephedrine derivative 285, and an allylsilane in the presence of a catalytic amount (0.2 mol%) of triflic acid [Eq. (5.340)]. The transformation was interpreted as an SN2 attack of the allylsilane to the protonated mixed acetal 286. The obtained ethers were then cleaved to the final product, homoallylic alcohols. 

Since the 1980s, chemists have attempted to develop novel Lewis acids and Lewis bases able to catalyze the Sakurai reaction with full diastereo- and enantiocontrol. A review by Denmark and Fu [19] summarizes the most recent advances in this area. Thus, we will not discuss these aspects of the Sakurai reaction but shall focus our attention on the one-pot three-component synthesis of homoallylic alcohols and ethers. 

A wide variety of silyl ethers can be employed, leading to functionalized homo-allylic alcohols or ethers. This three-component coupling reaction, which generates in a single operation a range of homoallylic ethers, does not require the initial and independent synthesis of the acetal (or ketal) derived from 6. 

The [2,3]-Wittig Rearrangement allows the synthesis of homoallylic alcohols by the base-induced rearrangement of allyl ethers at low temperatures. 

An aluminium-catalysed tandem Claisen-ene sequence has been developed for the synthesis of homoallylic alcohols (89) and thence a-methylene-y-butyrolactones (90) in good overall yields. Extensive investigation has revealed that Et2AlSPh catalyses Claisen rearrangement of ft -substituted allyl vinyl ethers (85) into 0,5-aluminium... 

Admixture of alkynylstannanes, aldehydes, trimethylsilyl chloride, and InClj in acetonitrile at room temperature results in the formation of propargyl silyl ethers. In the synthesis of homoallylic alcohols, simple allylic halides can be used to form the tin halides in situ in water. ... 

The allylation of a carbonyl compound, or equivalent thereof (aldehydes, ketones, acetals, ketals, enones, acid chlorides, epoxides, etc.), performed with an allylsilane 39 promoted by a Lewis acid (TiCl, SnCl, BF3-OEt2, AICI3, EtjAlCl, etc.) is known as Hosomi-Sakurai reaction (Scheme 12.11, Eq. 1) [68, 69]. This reaction was first described in 1976, allowing the synthesis of homoallylic alcohols 43 from aldehydes and ketones 40 [70]. A year later, the authors extended the method to ketals 41, which provide homoallylic ethers 44 (Scheme 12.11, Eq. 2) [71], and to a,p-unsaturated ketones 42 (Scheme 12.11, Eq. 3) [72]. 

Finally, Chen s work on the direct allylation of carbonyl compounds using benzyl alcohol in the multicomponent Sakurai reaction catalyzed by selective and green solid acids, such as sihcomolybdic acid (SMA-SiO ) [92] or perchloric acid (HClO -SiOj) [93], both supported on silica gel, should be mentioned. In some cases, the use of preformed acetals as substrates provided better results. These methods allowed the synthesis of a broad number of homoallylic ethers in moderate to high yields in a short reaction time. Significantly, catalyst loading of HClO -SiOj is only 2mol%. 

D. Kataki, P. Phukan, Tetrahedron Lett. 2009, 50, 1958-1960. Iodine-catalyzed one-pot three-component synthesis of homoallyl benzyl ethers from aldehydes. 

Intramolecular Hydrosilation of Allyl and Homoallyl Alcohols. For a detailed description of the intramolecular hydro-silation-oxidation sequence, see 1,1,3,3-tetramethyldisilazane. 1,1,3,3-Tetramethyldisilazane and AA -diethylaminodimethyl-silane are frequently employed for preparation of hydrodimethyl-silyl ethers for the intramolecular hydrosilation of allyl and homoallyl alcohols. Chlorodimethylsilane in combination with a tertiary amine such as triethylamine is another useful reagent for the synthesis of hydrodimethylsilyl ethers, especially for large scale preparations. ... 

Scheme 1). Introduction of a jt bond into the molecular structure of 1 furnishes homoallylic amine 2 and satisfies the structural prerequisite for an aza-Prins transform.4 Thus, disconnection of the bond between C-2 and C-3 affords intermediate 3 as a viable precursor. In the forward sense, a cation ji-type cyclization, or aza-Prins reaction, could achieve the formation of the C2-C3 bond and complete the assembly of the complex pentacyclic skeleton of the target molecule (1). Reduction of the residual n bond in 2, hydro-genolysis of the benzyl ether, and adjustment of the oxidation state at the side-chain terminus would then complete the synthesis of 1. 

Two approaches for the synthesis of allyl(alkyl)- and allyl(aryl)tin halides are thermolysis of halo(alkyl)tin ethers derived from tertiary homoallylic alcohols, and transmetalation of other allylstannanes. For example, dibutyl(-2-propenyl)tin chloride has been prepared by healing dibutyl(di-2-propenyl)stannane with dibutyltin dichloride42, and by thermolysis of mixtures of 2,3-dimethyl-5-hexen-3-ol or 2-methyl-4-penten-2-ol and tetrabutyl-l,3-dichlorodistannox-ane39. Alternatively dibutyltin dichloride and (dibutyl)(dimethoxy)tin were mixed to provide (dibutyl)(methoxy)tin chloride which was heated with 2,2,3-trimethyl-5-hexen-3-ol40. 

Provided that the silanolate elimination proceeds with anti selectivity, it must be concluded, that the intermediate homoallylic alcohol has an anti configuration, and thus the reagent has an ( -configuration. Acidic hydrolysis of the enol ether leads to enones the overall sequence consists of a nucleophilic acroylation. This has also been applied in the total synthesis of the marine diterpene ( )-aplysin-2067. 

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