Alkoxyallene

The palladium(0)-catalyzed hydrostannylation of alkoxyallenes also provides a useful synthesis of 3-alkoxyallylstannanes11... 

As shown in Eq. 9.34, 3-alkoxy-2-propyn-l-yl carbonates were shown to react with 1 to afford titanated alkoxyallenes, which, in turn, react regiospecifically with aldehydes to provide the corresponding y-addition products [66]. 

As mentioned above, the reactivity of alkoxyallenes is governed by the influence of the ether function, which leads to the expected attack of electrophiles at the central carbon C-2 of the cumulene. However, the alkoxy group also activates the terminal double bond by its hyperconjugative electron-withdrawing effect and makes C-3 accessible for reactions with nucleophiles (Scheme 8.3). This feature is of particular importance for cyclizations leading to a variety of heterocyclic products. The relatively high CH-acidity at C-l of alkoxyallenes allows smooth lithiation and subsequent reaction with a variety of electrophiles. In certain cases, deprotonation at C-3 can also be achieved. 

The substitutions at C-l can be classified as processes with umpolung of reactivity since a negatively charged carbon directly connected to oxygen is involved. A variety of synthons with umpolung of reactivity are therefore derived from simple alkoxyallenes as summarized in Scheme 8.4. The rich and often very surprising chemistry of these unique, but easily available, building blocks is still under development and it is expected that even more new synthons derived from alkoxyallenes will be detected in the future. 

An exceptional approach to phosphorus-substituted alkoxyallenes via isomerization of alkynes was introduced by Beletskaya s group. The treatment of 1-alkoxy-l-propynes 23 with l-halo-2,2-bis(trimethylsilyl)phosphaethen 24 furnished alkoxyallenes 25 (Scheme 8.9) [31]. 

So far, the formation of cyclic alkoxyallenes bearing an exocydic or endocyclic allenyl unit has been less developed. Several examples with this structural feature are described as unstable compounds or highly reactive intermediates [32-35]. However, in the 1990s, Lavoisier-Gallo and Rodriguez demonstrated a useful one-pot protocol for the synthesis of 2-vinylidenedihydrofurans such as 29 involving a tandem C-O cycloalkylation of stabilized carbanion intermediates 28 as crucial step (Scheme 8.10) [36, 37]. 

Two convenient methods have been developed for the preparation of trifluoro-methyl-substituted alkoxyallenes. Reductive elimination of allylic acetates 30 with samarium diiodide leads to 31 (Scheme 8.11) [38], whereas reaction of Wittig cumu-lene 32 with phenyl trifluoromethyl ketone (33) and thermolysis of the intermediate 34 provides 35 (Scheme 8.12) [39]. 

Deprotonation of Alkoxyallenes and Reaction with Electrophiles -Ring-Closing Reactions... 

Due to the synthetic versatility of donor-substituted allenes, it is of great importance to modify these compounds by substitution reactions at C-l. The CH-acidity at the a-carbon of alkoxyallenes allows their smooth lithiation [12, 42] which conveniently... 

The addition of carbonyl compounds towards lithiated 1-siloxy-substituted allenes does not proceed in the manner described above for alkoxyallenes. Tius and co-work-ers found that treatment of 1-siloxy-substituted allene 67 with tert-butyllithium and subsequent addition of aldehydes or ketones led to the formation of ,/i-unsaturated acyl silanes 70 (Scheme 8.19) [66]. This simple and convenient method starts with the usual lithiation of allene 67 at C-l but is followed by a migration of the silyl group from oxygen to C-l, thus forming the lithium enolate 69, which finally adds to the carbonyl species. Transmetalation of the lithiated intermediate 69 to the corresponding zinc enolate provided better access to acylsilanes derived from enolizable aldehydes. For reactions of 69 with ketones, transmetalation to a magnesium species seems to afford optimal results. 

An alternative formation of titanated alkoxyallenes could be achieved by reaction of 3-alkoxy-2-propyn-l-yl carbonates 78 with (r/2-propene)titanium diisopropoxylate (79). Successive addition of 80 to benzaldehyde afforded the corresponding addition products 81 in high yield (Scheme 8.22) [70]. The results demonstrate that titanium species 75 and 80 can serve as easily available ester homoenolate equivalents. Notably, conversion of lithiated alkoxyallenes to the magnesium species by treatment with MgBr2 followed by addition to chiral carbonyl compounds resulted in a mixture of a- and y-products [71]. 

In analogy with a-hydroxy-substituted alkoxyallene adducts, the corresponding allenylamines, e.g. 109 in Scheme 8.30 and 85 in Eq. 8.20, can be cyclized to dihydropyrrole derivatives either under basic conditions [43, 74, 75] or by treatment with catalytic amounts of AgN03 in acetone or acetonitrile [43, 73, 74],... 

The substrate-controlled diastereoselective addition of lithiated alkoxyallenes to chiral nitrones such as 123, 125 and 126 (Scheme 8.32) furnish allenylhydroxyl-amines as unstable products, which immediately cydize to give enantiopure mono-orbicyclic 1,2-oxazines (Eqs 8.25 and 8.26) [72, 76]. Starting with (R)-glyceraldehyde-derived nitrone 123, cydization products 124 were formed with excellent syn selectivity in tetrahydrofuran as solvent, whereas precomplexation of nitrone 123 with... 

Additions of lithiated alkoxyallenes to alkyl-substituted isocyanates and isothiocyanates as electrophiles were recently disclosed by Nedolya and co-workers [87-91]. A short route to N-[2(5H)-furanylidene]amines 133 consists in the addition of lithiated methoxyallene 42 to alkyl isocyanates 132 and silver acetate-mediated cydi-zation of the intermediate (Scheme 8.33) [87]. 

These authors also demonstrated that the outcome of analogous additions of lithiated alkoxyallenes 120 to isothiocyanates is highly dependent on the nature of the alkyl group in the isothiocyanates as depicted in Schemes 8.34and 8.35 [88, 91]. Whereas methyl isothiocyanate 134 leads to pyrrole derivative 135, the correspond-... 

Cycloadditions and cyclization reactions are among the most important synthetic applications of donor-substituted allenes, since they result in the formation of a variety of carbocyclic and heterocyclic compounds. Early investigations of Diels-Alder reactions with alkoxyallenes demonstrated that harsh reaction conditions, e.g. high pressure, high temperature or Lewis acid promotion, are often required to afford the corresponding heterocycles in only poor to moderate yield [12b, 92-94]. Although a,/3-unsaturated carbonyl compounds have not been used extensively as heterodienes, considerable success has been achieved with activated enone 146 (Eq. 8.27) or with the electron-deficient tosylimine 148 (Eq. 8.28). Both dienes reacted under... 

In the [4 + 2] cycloadditions discussed so far, the enol ether double bond of alkoxyallenes is exclusively attacked by the heterodienes, resulting in products bearing the alkoxy group at C-6of the heterocycles. This regioselective behavior is expected for [4+2] cycloadditions with inverse electron demand considering the HOMO coefficients of methoxyallene 145 [100]. In contrast, all known intramolecular Diels-Alder reactions of allenyl ether intermediates occur at the terminal C=C bond [101], most probably because of geometric restrictions. 

The few reported [2 + 2] cycloadditions of alkoxyallenes illustrated in Eqs 8.29 and 8.30 are probably of less synthetic importance. Cyclobutene derivative 162 could be prepared in good yield by cycloaddition of tetramethoxyallene 39 and acetylenedicar-boxylate 161 [105], whereas the reaction of 1,1-diethoxyallene 163 and phenylisocya-nate (164) gave the expected /3-lactam 165 [106]. Another example for a [2 + 2] cycloaddition is the dimerization of 39 described by Saalfrank et al. [107]. 

An interesting possibility for the construction of a tetracyclic system 174 with two cyclobutane rings arises by addition of lithiated alkoxyallenes 120 to 173 followed by two consecutive electrocydic reactions. Products such as 174 are useful precursors for benz[a]anthracene-7,12-diones (Scheme 8.43) [110]. 

Tius and co-workers investigated a number of cationic cyclopentannelations of allenyl ethers [113] and found that 1-lithio-l-alkoxyallenes 180 react with a,/3-unsatu-rated carbonyl compounds 181 leading to highly functionalized cyclopentenones 182 (Scheme 8.44). The primary products are a-allenyl ketones 183, which form pentadienyl cations 184 by protonation. The latter undergo a thermally allowed 4jt-conrotatory ring closure to intermediates 185, which with elimination of R1 finally lead to the expected products 182 (Scheme 8.45). 

Saalfrank, Hoffmann and co-workers performed a number of reactions with tetra-alkoxyallenes such as 196 (Scheme 8.47) [1, 41, 105, 114—116] and demonstrated that this class of donor-substituted allenes can serve as a 1,3-dianion equivalent of malonic acid. Treatment of 196 with cyclopropyldicarboxylic acid dichloride 197 produces 2,4-dioxo-3,4-dihydro-2H-pyran 198 through release of two molecules of ethyl chloride [115]. Similarily, the reaction of this allene 196 with oxalyl chloride gives 3-chloromalonic acid anhydride derivative 199. This intermediate is a reactive dieno-phile which accepts 2,3-dimethyl-l,3-butadiene in a subsequent [4+2] cycloaddition to afford cycloadduct 200 in good yield [116]. 

Van Boom and co-workers published an expeditious route to chiral oxepines with monosaccharide derivatives as precursors. The synthesis was accomplished by treatment of 210 with alkoxyallenes 8 under Rutjes s optimized reaction conditions (Scheme 8.50) [121]. 

Considerable attention has been devoted to the preparation and chemistry of a,/3-unsaturated carbonyl compounds, which are valuable intermediates in organic synthesis [125]. Acid-promoted hydrolysis of alkoxyallenes has therefore frequently been employed to prepare a variety of functionalized a,/8-unsaturated carbonyl compounds [12b, 41, 44, 60, 126]. A recent example is illustrated in Scheme 8.54with C-l-silylated alkoxyallene 218 as a convenient starting material for the synthesis of bicyclo[5.4.0]undec-4-en-2-one 221. Sequential deprotonation and silylation at the terminal C=C bond efficiently transformed 218 into a 1,3-disilylated allene which was converted into the acryloylsilane 219 under acidic conditions. A [3 + 4] annula-tion of intermediate 219 with lithium dienolate 220 furnished bicydic compound 221 in good yield [127]. 

Capperucd and co-workers investigated the dimerization of a,/i-un saturated thioacylsilanes 224, which are generated in situ from 1-silylated alkoxyallenes 222 using bis(trimethylsilyl) sulfide and cobalt(II) chloride hexahydrate as reagents. The resulting 1,2-thiins 223 are isolated as major products in 29-65% yield [128] (Scheme 8.55). 

As an example of the use of a polymer-bound reagent 228, the transformation of alkoxyallenes 8 into vinyl halides 229 is depicted in Scheme 8.57 [131]. 

Alkoxyallenes have also been subjected to oxidative reaction conditions [46, 62, 74, 132-134]. Ozonolysis of the already mentioned a-hydroxy-substituted methoxyal-lenes 230 provided a syn-anti mixture of a-hydroxy esters 231 (Scheme 8.58) [62]. 

Alkoxyallenes turned out to be excellent starting materials also for the synthesis of highly functionalized 1,3-dienes, two examples being depicted in Schemes 8.61 and 8.62. As described by Kantlehner et al., 1,3-dienes such as 238 were obtained from methoxyallene derivative 50 by condensation with CH-acidic compounds 237 [135]. Hoppe and co-workers explored the stereochemical course of the allene Claisen rearrangement under Johnson s conditions, e.g. the reaction of 239 with trimethyl orthoacetate, which furnished intermediate 240 followed by rearrangement to the isomeric dienes 241a,b [136],... 

Alkoxyallenes react with diazomethane at the terminal C=C bond to give 4-methy-lenepyrazoline 87, whereas the reaction with diphenyldiazomethane affords 3-methy-lenepyrazoline 88 [85],... 

The following reactions of propargyl 3-vinyl-2-cyclohexenyl ethers 160 also involved initial isomerization to an alkoxyallene. The terminal allenic C=C double bond participated in an intramolecular [4+ 2]-cycloaddition [133],... 

Allenyl ethers 202, which are easily accessible by the methods described in Chapter 1, consequently lead to cyclic ethers 203. The alkoxyallenes were much more reactive than the alkylallenes from the previous example. Thus the amount of catalyst could be reduced to 0.1mol% and 820 turnovers were reached. Five- to seven-membered rings were isolated (Scheme 15.65) [131],... 

As the integrity of chiral alcohols are retained in the phase-transfer catalysed O-alkylation, the procedure is valuable for the synthesis of chiral ethers under mild conditions as, for example, in the preparation of alkoxyallenes via the initial formation of chiral propargyl ethers [8]. It has been proposed that a combination of 18-crown-6 and tetra-n-butylammonium iodide provide the best conditions for the O-benzylation of diethyl tartrate with 99% retention of optical purity [9]. 

Reaction of lithium alkoxyallenes (e.g. 176, equation 114) with nitrones such as 175 proceeded through two sequential additions and provided good yield of six-membered... 

Methylenetetrahydropyrans are formed regioselectively in good yields from the Ru-catalysed reaction of prop-2-yn-l-ols with allyl alcohol <99JOC3524>, whilst 2-vinyltetrahydropyrans result from a Pd-catalysed intramolecular hydrocarbonation of alkoxyallenes <99TL1747>. Various hepta-5,6-dien-l-ols 13 undergo a Ru-catalysed... 

In addition to the examples of diene cyclisations described above there are reports of alkoxyallenes as precursors of five- to seven-membered oxygen heterocycles <99TL1747>. Of interest here is the cyclisation of 45 to 46 in 88% yield in the presence of Pd(0 Ac)2-dppb complex. The same reagent system has also been used in the regioselective lactonisation of steroids where the aromatic ring of estrone is fused to a seven-membered lactone <99TL1171>. 

Diastereoselective cleavage of propynyl acetals of enantiomeric pure diols with organocopper(I) reagents leads to alkoxyallenes with high diastereomeric purity, in which the chiral auxiliary is included... 

The resulting alkoxyallenes are very prone to racemization under the conditions of the reaction, as well as after isolation. Therefore, contact time with the organometallic reagents should be minimized and the product stored over potassium carbonate. Esterification of the free hydroxy group gives compounds of increased stability107,... 

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