Exo-methylene compounds

The base catalyzed rearrangement of a monotosylated 1,2-diol on alumina, followed by immediate condensation of the sensitive ketone with methylenetriphenylphosphorane, gave the exo-methylene compound below (G. Btlchi, 1966B). 

Grubbs et al. reported that the ruthenium-catalyzed RCM of a conjugated diene proceeds in such a way that the less hindered olefin moieties participate in the reaction. Consequently, RCM of 115 gives exo-methylene compound 116, and not exo-vinyl compound 117 (Scheme 24) [105]. This regioselectivity is complementary to that observed for enyne metathesis of 118, which gives exclusively 117 (Scheme 24) [106a]. 

The study on 2,7-di-rerf-butylthiepin has recently been extended to explore more simply substituted thiepins 58). The palladium-catalyzed reaction of the diazo compound 107 lacking a 4-methyl substituent gives exclusively the exo-methylene compound 108 whereas the acid-catalyzed reaction of the same precursor 107 resulted in the formation of 2,7-di-/er/-butyl-4-ethoxycarbonylthiepin (109)58). Due to the substantial thermal stability of 109 it is possible to transform the ethoxy-carbonyl group into the hydroxymethyl (110), trimethylsilyloxymethyl (111) and formyl group (112)58). 

Epoxides can also be reductively opened to form a radical. An example of an intramolecular cyclization of such a radical has recently been reported <06TL7755>. Treatment of 40 with Cp2TiCl generates an intermediate alkoxy radical, which then adds to the carbonyl of the formate ester. The product, 41, is formed as a 2 1 mixture of isomers at the anomeric carbon. This reaction is one of the first examples of a radical addition to an ester. The major byproduct of this reaction is the exo-methylene compound, 42, arising from a P-hydrogen elimination. 

The Tebbe reagent [//-chloro-bis(cyclopentadienylXdimethylalumin-ium)-/r-methylenetitanium] in its pure, crystalline (70,71) or crude (72) forms has been employed for the methylenation of aldonolactones. Thus, D-ribono- 1,4-lactone derivatives 71a and 71b reacted with Tebbe s reagent to give (70,71) the exo-methylene compounds 72a and 72b. 

What, then, about the cyclobutylcarbinyl radical Eq. 3.108 shows the treatment of tricyclic cyclobutylmethyl iodide (268) with Bu3SnH in the presence of AIBN in refluxing benzene solution to generate bicyclic exo-methylene compound (269), via 13-cleavage of the cyclobutylcarbinyl radical. This bicyclic exo-methylene (269) is the skeleton of a terpenoide natural product, guaiane alismol [277-280]. 

The array of dienophiles amenable to these hetero Diels-Alder reactions is not limited to enol ethers and enamines since allylsilanes and simple alkenes have also been successfully employed [370, 371]. More recently, it has been shown that methoxy allenes such as 4-41 undergo formation of 6H-l,2-oxazines 4-43 upon cycloaddition to nitrosoalkenes such as 4-34 and subsequent tauto-merisation of the intermediate exo-methylene compound 4-42 (Fig. 4-9) [372, 373]. In these studies, 4-43 proved to be a versatile synthetical intermediate allowing oxidative demethylation or reductive removal of the methoxy group as well as nucleophilic substitutions after the generation of an azapyrylium ion [372 - 374]. Furthermore, ring contraction reactions of these oxazines leading to pyrroles [373] and y-lactames [375] are known. 

Enones like this, with two hydrogen atoms at the end of the double bond, are called exo-methylene compounds they are very reactive, and cannot easily be made or stored. They certainly cannot be made by aldol reactions with formaldehyde alone as we have seen. The solution is to make the Mannich base, store that, and then to alkylate and eliminate only when the enone is needed. We shall see how useful this is in the Michael reaction in Chapter 29. 

The key substrates for conjugate addition are the a, 3-unsaturated carbonyl compounds. When the double bond is inside a chain or ring these compounds are available via a wide variety of routes including the aldol reaction and are generally stable intermediates that can be stored for use at wiU. When the double bond is exo to the ring or chain (exo-methylene compounds), the unhindered nature of the double bond makes them especially susceptible to attack by nucleophiles (and radicals), This reactivity is needed for conjugate additions but the compounds are unstable and polymerize or decompose rather easily,... 

Either the tertiary amine or the quaternary ammonium salt can be stored as a stable equivalent of the exo-methylene compound. In our first example, the Mannich base with dimethylamine is first methylated with methyl iodide and then added to the conjugate addition reaction. Elimination of trimethylamine, which escapes from the refluxing ethanol as a gas, reveals the exo-methylene ketone in which the methylene group is exo to a chain. Fast conjugate addition of the stabilized enolate of diethyl malonate produces the product. 

The products can be hydrodesilylated by reaction with HCl in CH,OH or with CsF or KF in aqueous DMSO or DMF. The former reaction occurs with almost complete shift of the bond to give exo-methylene products. The latter results in endo- and exo-methylene compounds in the ratio —85 15. These reactions provide attractive routes to various terpenes. 

Cycloadducts were not found in the reaction of 24 with singlet oxygen. The major isolated product 25 is the allylic hydroperoxide from bridgehead hydrogen abstraction while the minor component is the exo-methylene compound 26. Both products arise from exclusive anti attack with respect to the bridgehead methyl group. 

VinyltriphenyljAosphonium bromide (98) reacted with a number of dienes to form cyclic phosphon-ium s ts which s ord exo-methylene compounds via a subsequent Wittig reaction (Scheme 27). ... 

The preferred synthetic route to these important intermediates is the Mannich reaction (Chapter 27). The compound is stored as the stable Mannich base and the imstable enone released by elimination of a tertiary amine with mild base. The same conditions are right for this elimination and for conjugate addition. Thus the exo-methylene compounds can be formed in the flask for immediate reaction with the enol(ate) nucleophile. The overall reaction from P-amino carbonyl to 1,5-dicarbonyl appears to be a substitution but the actual mechanism involves elimination and conjugate addition. 

Thus, the treatment of hexamethyl Dewar benzene with acid at ambient temperature causes rearrangement to a phenonium ion (55) 55) while at lower temperature a cation is formed which is converted into an exo-methylene compound on treatment with a base56>. Addition of tetraeyanoethylene to the latter yields an 1,4-addition product (54). 

Asymmetric hydrovinylation of norbornene and norbornadiene leading exclusively to exo-vinyl products 4 and 5 has been reported with allylnickel systems using isopropylbis(men-thyljphosphane as chiral ligand4,5. Optical yields depend highly on temperature, highest enantiomeric excesses (up to 80.6%) are obtained at about — 70 =C. however with only low productivity. Furthermore, the products tend to isomerize to exo-methylene compounds under the reaction conditions. 

Cyclic exo-methylene compounds bearing a chiral acetal function prove to be excellent dieno-philes in the noncatalyzed Diels-Alder reaction. Dioxolanones 8 react with cyclopentadiene (9) and acyclic dienes 12 and 15 to afford adducts with diastereoselectivities as high as 100% 28,29. The major adduct 16 from the addition of 8b to diene 15 has been applied to the synthesis of the top half of kijanolide30. 

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