Alkene metathesis amide

Ethers, esters, amides and imidazolidines containing an epithio group are said to be effective in enhancing the antiwear and extreme pressure peiformance of lubricants. Other uses of thiiranes are as follows fuel gas odorant (2-methylthiirane), improvement of antistatic and wetting properties of fibers and films [poly(ethyleneglycol) ethers of 2-hydroxymethyl thiirane], inhibition of alkene metathesis (2-methylthiirane), stabilizers for poly(thiirane) (halogen adducts of thiiranes), enhancement of respiration of tobacco leaves (thiirane), tobacco additives to reduce nicotine and to reduce phenol levels in smoke [2-(methoxymethyl)thiirane], stabilizers for trichloroethylene and 1,1,1-trichloroethane (2-methylthiirane, 2-hydroxymethylthiirane) and stabilizers for organic compounds (0,0-dialkyldithiophosphate esters of 2-mercaptomethylthiirane). The product of the reaction of aniline with thiirane is reported to be useful in the flotation of zinc sulfide. 

Applications of the cross-metathesis reaction in more diverse areas of organic chemistry are beginning to appear in the literature. For example, the use of alkene metathesis in solution-phase combinatorial synthesis was recently reported by Boger and co-workers [45]. They assembled a chemical library of 600 compounds 27 (including cisttrans isomers) in which the final reaction was the metathesis of a mixture of 24 oo-alkene carboxamides 26 (prepared from six ami-nodiacetamides, with differing amide groups, each functionalised with four to-alkene carboxylic acids) (Eq.27). 

The enantiomerically-pure intermediate 1 was prepared from the dioxolanone 4, available in three steps from L-malic acid. Lewis acid-mediated homologation converted 4, a 4 1 mixture of diastereomers, into 5 as a single diastereomer. After establishment of the alkenyl iodide, it necessary to maintain the lactone in its open form. A solution was found in the formation of the Weinreb amide. The final stereogenic center was established by Brown allylation of the derived aldehyde. The alkene metathesis to form 1 was carried out with the commercially-available Schrock Mo catalyst. The authors did not comment on the relative efficacy of alternative alkene metathesis catalysts. 

With the advances in pro-catalyst design that have been witnessed over the last decade or so, the transition-metal-catalysed alkene metathesis reaction has now become a practical procedure that can be utilised by the chemist at the bench. Undeniably, this has added a new dimension to the repertoire of synthetic organic chemistry as it facilitates disconnections that, pre-metathesis, simply would not have been considered. Take, for example, a macro-cyclic amide where the normal disconnection would be at the amide. Now, with the ready reduction of alkenes to alkanes, a ring-closing diene metathesis (RCM), followed by hydrogenation, becomes an alternative disconnection. And, when one considers that any of the C—C linkages could be established in such a manner, the power of the RCM disconnection becomes obvious. 

The cross metathesis of acrylic amides [71] and the self metathesis of two-electron-deficient alkenes [72] is possible using the precatalyst 56d. The performance of the three second-generation catalysts 56c,d (Table 3) and 71a (Scheme 16) in a domino RCM/CM of enynes and acrylates was recently compared by Grimaud et al. [73]. Enyne metathesis of 81 in the presence of methyl acrylate gives the desired product 82 only with phosphine-free 71a as a pre-... 

These alkylation processes become particularly attractive when used in conjunction with powerful catalytic ring-dosing metathesis protocols [11]. The requisite starting materials can be readily prepared catalytically and in high yields. The examples shown in Scheme 6.3 demonstrate that synthesis of the heterocyclic alkene and subsequent alkylation can be carried out in a single vessel to afford unsaturated alcohols and amides in good yields and with >99% ee (GLC analysis) [12],... 

A solid-phase synthesis of furo[3,2-3]pyran derivatives utilizing highly functionalized sugar templates has been reported <2003JOC9406>. After incorporation of alkenes within the sugar template, such as compound 95, the solid support is introduced via formation of the acid amide. This immobilized system then allows a ruthenium-catalyzed ring-closing metathesis that leads to the formation of the fused oxacycles. 

The N-heterocyclic alkenes derived from ring-closing metathesis are useful substrates for further transformation. In a synthesis directed toward the insecticidal cripowellin 12, Dieter Enders of RWTH Aachen has shown (Angew. Chem. Int. Ed. 2005,44, 3766) that the tertiary amide 8 cyclizes efficiently to the nine-membered alkene 9. The vision was that an intramolecular Heck cyclization could then deliver the cripowellin skeleton. Indeed, the Heck did proceed, and, depending on conditions, could be directed toward either 10 or 11. Unfortunately, the conformation of 9 is such that the cyclization proceeded cleanly across the undesired face. Nevertheless, both 10 and 11 appear to be valuable intermediates for further transformation. 

Metathesis reactions may be intramolecular and ring-closing diene metathesis (RCM, implicated in Scheme 1.13, see Chapter 12) allows disconnections in retro-synthetic analysis otherwise of little use. The normal disconnection of the macrocyclic amide in Scheme 1.13 would be at the amide but, because of the ready reduction of alkenes to alkanes, the alternative disconnection now becomes a viable option. And since any of the C—C linkages could be formed by RCM, such a disconnection allows far greater synthetic flexibility than the conventional disconnection at the functional group. 

The complex ZrCl[N(C6H3Me2)(adamantyl)]3, containing bulky amido ligands was prepared via a metathesis reaction involving the Li amide and ZrCl4(THF)256 Similarly, the species ZrCl(NHSiBu 3)3 was prepared.57 The complexes MX2[N(SiMe3)(C6H3 Pr 2)]2 (M = Zr, Hf X = F, Cl) were also prepared and found to yield low activities for alkene polymerization catalysis upon activation 58,59... 

Recently, ionic liquids with amino acids as anions were synthesized by neutralization between [C2mim][OH] and amino acids [88], Tetrabutylphosphonium amino acids [P(C4)4][AA] were synthesized by the reaction of tetrabutylphosphonium hydroxide [P(C4)4][OH] with amino acids, including glycine, L-alanine, l-/1-alanine, L-serine and L-lysine [89], The esters or amide derivatives of bromoacetic acid were either commercially available or formed in one step via the reaction of bromoacetyl bromide with the appropriate alcohol or amine [90-92], An advantage of this route is that a wide range of ester and amide side chains can be prepared easily. For ionic liquids with anions other than bromide, a metathesis reaction was employed to introduce the counter ion of choice. Additionally, functionalized ionic liquids with electrophilic alkene-type appendages were synthesized. 

Cross-metathesis of conjugated electron-deficient alkenes such as a,ft-unsatur-ated esters, ketones, aldehydes, and amides often give high cross-product/dimer ratios due to the slow rate of dimerization of these substrates (Eq. 171). When this occurs, the cross-product is dominant even when the reactions are performed with a 1 1 stoichiometry of the reactants.330 When one of the alkene partners homodimerizes slowly, such as happens with electron-deficient and sterically hindered alkenes, the reaction is driven to the cross-product. With respect to the stereochemistry of the reaction, the E-isomer is obtained with electron-deficient alkenes (Eq. 171), and the E/Z ratio may also vary depending on the types of substituents present on the reactants. 

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