Allenes, substituted, electrophilic additions

The electrophilic addition of alkyl-substituted allenes may afford terminal attack and center attack products, depending on the structures of allenes and electrophiles (Scheme 10.1). 

As in the case of addition reactions of carbon nucleophiles to activated dienes (Section HA), organocopper compounds are the reagents of choice for regio- and stereoselective Michael additions to acceptor-substituted enynes. Substrates bearing an acceptor-substituted triple bond besides one or more conjugated double bonds react with organocuprates under 1,4-addition exclusively (equation 51)138-140 1,6-addition reactions which would provide allenes after electrophilic capture were not observed (cf. Section IV). 

Allenes can also act as the -participant in electrophilic heteroatom cyclizations. Reviews of electrophilic additions to allenes discuss early examples of this type of cyclization.ld le-202 Numerous examples of cyclizations of a-functionalized allenes, including carboxylic acids, phosphonates, sulfinates and alcohols, to form five-membered heterocycles (equation 84) are cited in these reviews. The silver nitrate-mediated conversion of ot-allenic alcohols to 2,5-dihydrofurans203 has recently been applied to trimethylsilyl-substituted systems.204... 

Propargylic Anion Equivalent. (TMS)allene reacts with electrophiles at the C-3 position in an Se2 process analogous to electrophilic substitution reactions of allyl- andpropargylsilanes. For example, upon treatment with trimethylsilyl chlorosulfonate or sulfur trioxide-1,4-dioxane, (TMS)allene yields silyl esters of sulfonic acids (eq 3). (TMS)allene undergoes conjugate addition with a, 8-unsaturated acyl cyanides to yield 5,e-acetylenic acyl cyanides. ... 

Trimethylchlorosilane, dimethyldisulfide, butyl bromide, butyl iodide, paraform, acetic and pivalic aldehydes, benzaldehyde, acetone, and cyclohexanone are used as electrophilic reagents relative to N-allenylpyrrole metalated with butyUithium. The conditions of the second stage of the reaction, electrophilic substitution, or addition (for aldehydes and ketones) depend upon the electrophile anployed. In all the cases, a-allenic derivatives are formed as a rule (Table 2.20). 

Introduction of a double bond between the triple bond and the leaving group leads to enyne electrophiles 45, which would give access to vinylallenes 46 if the attack of the nucleophile takes place at the triple bond in an SN2" (1,5) substitution reaction (Scheme 2.16). In addition to the regioselectivity, two types of stereoselectivity also have to be considered in this transformation, i.e. the configuration of the olefinic double bond of the vinylallene and the (relative or absolute) configuration of the allenic chirality axis. 

Allene is a versatile functionality because it is useful as either a nucleophile or an electrophile and also as a substrate for cycloaddition reactions. This multi-reactivity makes an allene an excellent candidate for a synthetic manipulations. In addition to these abilities, the orthogonality of 1,3-substitution on the cumulated double bonds of allenes enables the molecule to exist in two enantiomeric configurations and reactions using either antipode can result in the transfer of chirality to the respective products. Therefore, the development of synthetic methodology for chiral allenes is one of the most valuable subjects for the synthetic organic chemist. This chapter serves as an introduction to recent progress in the enantioselective syntheses of allenes. Several of the earlier examples are presented in excellent previous reviews [ ] ... 

A variety of optically active 4,4-disubstituted allenecarboxylates 245 were provided by HWE reaction of intermediate disubstituted ketene acetates 244 with homochiral HWE reagents 246 developed by Tanaka and co-workers (Scheme 4.63) [99]. a,a-Di-substituted phenyl or 2,6-di-tert-butyl-4-methylphenyl (BHT) acetates 243 were used for the formation of 245 [100]. Addition of ZnCl2 to a solution of the lithiated phos-phonate may cause binding of the rigidly chelated phosphonate anion by Zn2+, where the axially chiral binaphthyl group dictates the orientation of the approach to the electrophile from the less hindered si phase of the reagent. Similarly, the aryl phosphorus methylphosphonium salt 248 was converted to a titanium ylide, which was condensed with aromatic aldehydes to provide allenes 249 with poor ee (Scheme 4.64) [101]. 

Hence the positional selectivity is different from that of the furan additions to 417 (Scheme 6.90). Assuming diradical intermediates for these reactions [9], the different types of products are not caused by the nature of the allene double bonds of 417 and 450 but by the properties of the allyl radical subunits in the six-membered rings of the intermediates. Also N-tert-butoxycarbonylpyrrole intercepted 450 in a [4 + 2]-cycloaddition and brought about 455 in 29% yield. Pyrrole itself and N-methylpyr-role furnished their substituted derivatives of type 456 in 69 and 79% yield [155, 171b]. Possibly, these processes are electrophilic aromatic substitutions with 450 acting as electrophile, as has been suggested for the conversion of 417 into 442 by pyrrole (Scheme 6.90). 

Not only electrophilic 1,4-addition, as shown above, but also radical 1,4-addition to conjugated enynes such as selenosulfonation is known to yield acceptor-substituted allenes [118]. Finally, monotitanation of conjugated diynes followed by treatment with benzaldehyde and aqueous workup leads to an ester of penta-2,3,4-tri-enoic acid, which is formally also a product of 1,4-addition [147]. 

The attack of the nucleophile on the acceptor-substituted allene usually happens at the central sp-hybridized carbon atom. This holds true also if no nucleophilic addition but a nucleophilic substitution in terms of an SN2 reaction such as 181 — 182 occurs (Scheme 7.30) [245]. The addition of ethanol to the allene 183 is an exception [157]. In this case, the allene not only bears an acceptor but shows also the substructure of a vinyl ether. A change in the regioselectivity of the addition of nucleophilic compounds NuH to allenic esters can be effected by temporary introduction of a triphenylphosphonium group [246]. For instance, the ester 185 yields the phos-phonium salt 186, which may be converted further to the ether 187. Evidently, the triphenylphosphonium group induces an electrophilic character at the terminal carbon atom of 186 and this is used to produce 187, which is formally an abnormal product of the addition of methanol to the allene 185. This method of umpolung is also applicable to nucleophilic addition reactions to allenyl ketones in a modified procedure [246, 247]. 

In contrast to the rich chemistry of alkoxy- and aryloxyallenes, synthetic applications of nitrogen-substituted allenes are much less developed. Lithiation at the C-l position followed by addition of electrophiles can also be applied to nitrogen-containing allenes [10]. Some representative examples with dimethyl sulfide and carbonyl compounds are depicted in Scheme 8.73 [147, 157]. a-Hydroxy-substituted (benzotriazo-le) allenes 272 are accessible in a one-pot procedure described by Katritzky and Verin, who generated allenyl anion 271 and trapped it with carbonyl compounds to furnish products 272 [147]. The subsequent cyclization of 272 leading to dihydro-furan derivative 273 was achieved under similar conditions to those already mentioned for oxygen-substituted allenes. 

The examples illustrated in the almost 100 schemes in this chapter demonstrate how versatile donor-substituted allenes can be in synthetic processes. The major applications concern addition reactions and cycloadditions to the allenic double bonds, which furnish products with valuable functional groups. Of particular interest are metalations - usually at C-l of the allene unit - followed by reactions with electrophiles that deliver compounds which can often be used for cyclization reactions. A variety of highly substituted and functionalized heterocycles arises from these flexible methods, which cannot be obtained by other reactions. Many of these transformations proceed with good regioselectivity and excellent stereoselection. 

Reaction of the transient zinc intermediates with various electrophiles yielded the acetylenic substitution products and only minor amounts of allenes (Table 9.49). Reactions with aldehydes were non-selective, affording mixtures of stereo- and regioisomeric adducts. However, prior addition of ZnCl2 resulted in the formation of the homopropargylic alcohol adducts with high preference for the anti adduct, as would be expected for an allenylzinc chloride intermediate (Table 9.50). 

According to results from laser flash photolysis, the p-(methoxyphenyl) sulfanyl radical adds exclusively to the central atom in of 2,4-dimethylpenta-2,3-diene (If) with a rate constant of 1.1 x 10s M-1 s-1 (23 1 °C) (Scheme 11.6) [45], A correlation between the measured rate constants for addition of para-substituted arylsulfanyl radicals to allene If was feasible using Brown and Okomoto s o+ constant [46], The p+ value of 1.83, which was obtained from this analysis, was interpreted in terms of a polar transition state for C-S bond formation with the sulfanyl radical being the electrophilic part [45]. This observation is in agreement with an increase in relative rate constant for phenylsulfanyl radical addition to 1-substituted allene in the series of methoxyallene lg, via dimethylallene Id, to phenylsulfanylallene lh, to ester-substituted 1,2-diene li (Table 11.2). 

As previously mentioned, allenes can only be obtained by 1,6-addition to acceptor-substituted enynes when the intermediate allenyl enolate reacts regioselectively with an electrophile at C-2 (or at the enolate oxygen atom to give an allenyl ketene acetal see Scheme 4.2). The regioselectivity of the simplest trapping reaction, the protonation, depends on the steric and electronic properties of the substrate, as well as the proton source. Whereas the allenyl enolates obtained from alkynyl enones 22 always provide conjugated dienones 23 by protonation at G-4 (possibly... 

Secondary and tertiary dialkylcuprates, lithium dialkenyl-, and even diphenyl-cuprates, add in very good yields to the reactive propionaldehyde diethyl acetal. The syn addition products may be trapped with a variety of electrophiles such as alkyl, alkenyl, alkynyl and aryl halides. The method has been used for the synthesis of several natural products. Substituted alkynic acetals also react with lithium dialkylcuprates in ether to furnish stable dialkenylcuprates of type (128) which do not eliminate to the corresponding alkoxy allenes (129) if the temperature is maintained below -20 C.164-179... 

Similar to the addition reactions of acceptor-substituted dienes (Scheme 16), the outcome of the transformation depends on the regioselectivity of the nucleophilic attack of the organocopper reagent (1,4- vs. 1,6-addition) and of the electrophilic capture of the enolate formed. The allenyl enolate obtained by 1,6-addition can afford either a conjugated diene or an allene upon reaction with a soft electrophile, and thus opens up the possibility to create axial chirality. The first copper-mediated addition reactions to Michael acceptors of this type, for example, 3-alkynyl-2-cyclopentenone 75,... 

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