Olefinic amides, reduction

This section contains dehydrogenations to form olefins and unsaturated ketones, esters, and amides. It also includes the conversion of aromatic rings to olefins. Reduction of aryls to dienes is found in Section 377 (Olefin-Olefin). Hydrogenation of aryls to alkanes and dehydrogenations to form aryls are included in Section 74 (Alkyls, Methylenes, and Aryls from Olefins). 

Since a synthetic route to heterocyclic calcitriol derivatives was still lacking, explorative research had to be carried out. The vitamin D aldehyde 1 was prepared according to the Leo protocol [192] followed by a photosensitized isomerization of the triene unit in seven steps (Scheme 10.2). Wittig-Horner olefination selectively yielded the E-double bond configuration of the Weinreb amide 2. Reduction with diisobutylaluminum hydride gave the unsaturated aldehyde 3 without any evidence for overreduction. This aldehyde could serve as a valuable intermediate for further elaboration of the side-chain [194],... 

The alkylation of enamines with nitroolefins, which gives intermediates for reductive cyclization (6S2), also provided an example of a stable cycliza-tion product derived from attack of the intermediate imonium function by the nitro anion (683). A previously claimed tetrasubstituted enamine, which was obtained from addition of a vinylsulfone to morpholinocyclohexene (314), was shown to be the corresponding cyclobutane (684). Perfluoro-olefins also gave alkylation products with enamines (685). Reactions of enamines with diazodicarboxylate (683,686) have been used diagnostically for 6-substituted cyclohexenamines. In a reaction of 2-penten-4-one with a substituted vinylogous amide, stereochemical direction was seen to depend on solvent polarity (687). 

First, solvent molecules, referred to as S in the catalyst precursor, are displaced by the olefinic substrate to form a chelated Rh complex in which the olefinic bond and the amide carbonyl oxygen interact with the Rh(I) center (rate constant k ). Hydrogen then oxidatively adds to the metal, forming the Rh(III) dihydride intermediate (rate constant kj). This is the rate-limiting step under normal conditions. One hydride on the metal is then transferred to the coordinated olefinic bond to form a five-membered chelated alkyl-Rh(III) intermediate (rate constant k3). Finally, reductive elimination of the product from the complex (rate constant k4) completes the catalytic cycle. 

The actual synthesis (Scheme 21) started with the stereoselective alkylation of Myers hydroxy-amide 131 [40] followed by reductive removal of the auxiliary to give 132 in high yield and enantioselectivity. Wittig olefination furnished enoate 133, which was then elaborated into the (E)-l-acetoxy-diene 129 using... 

Reduction of amides without hydride reagents Asymmetric hydrogenation of un functionalized olefins/enamines/imines... 

The cis-fagaramide (J) was synthesized as outlined below. The required acetylenic acid (c) was prepared from piperonal (a) by the Corey s procedure.Treatment of piperonal with carbon tetrabromide, triphenylphosphine and zinc gave the bromo olefin (b) as an oil in 71% yield. The bromo olefin (b) was treated with 2 equivalents of n-butyl lithium followed by quenching with dry ice to give acetylenic acid (c) in 54% yield. Treatment of (c) with excess thionyl chloride without solvent at 50 followed by addition of isobutyl amine in benzene gave the acetylenic amide (d) as a viscous oil in 96% yield. Partial reduction of (d) gave cis-fagarmide (7 ) in 89% yield. 

Olefination of the Aldehyde 178 using a stabilized Wittig reagent followed by protecting group chemistry at the lower branch and reduction of the a,p-unsaturated ester afforded the allylic alcohol 179 (Scheme 29). The allylic alcohol 179 was then converted into an allylic chloride and the hydroxyl function at the lower branch was deprotected and subsequently oxidized to provide the corresponding aldehyde 161 [42]. The aldehyde 161 was treated with trimethylsilyl cyanide to afford the cyanohydrin that was transformed into the cyano acetal 180. The decisive intramolecular alkylation was realized by treatment of the cyano acetal 180 with sodium bis(trimethylsi-lyl)amide. Subsequent treatment of the alkylated cyano acetal 182 with acid (to 183) and base afforded the bicyclo[9.3.0]tetradecane 184. 

The Wittig reaction efficiently olefinates aldehydes and ketones, but not esters or amides. Several early-transition-metal approaches have been taken to this problem. Recently, Takeshi Takeda of the Tokyo University of Agriculture and Technology reported (Tetrahedron Lett. 44 5571,2003) that the titanocene reagent can effect the condensation of an amide 10 with a thioacetal 11 to give the enamine 12. On hydrolysis, 12 is converted into the ketone 13. When the reaction is intramolecular, reduction proceeds all the way, to give the pyrrolidine IS. 

On the pages which follow, general methods are illustrated for the synthesis of a wide variety of classes of organic compounds including acyl isocyanates (from amides and oxalyl chloride p. 16), epoxides (from reductive coupling of aromatic aldehydes by hexamethylphosphorous triamide p. 31), a-fluoro acids (from 1-alkenes p. 37), 0-lactams (from olefins and chlorosulfonyl isocyanate p. 51), 1 y3,5-triketones (from dianions of 1,3-diketones and esters p. 57), sulfinate esters (from disulfides, alcohols, and lead tetraacetate p. 62), carboxylic acids (from carbonylation of alcohols or olefins via carbonium-ion intermediates p. 72), sulfoxides (from sulfides and sodium periodate p. 78), carbazoles... 

Stereoselective l.4-reduction oi the 1.3-butadiene system to olefin 57 lakes place tinder the conditions of the Birch reduction. Intramolecular protonation of the intermediate carbanion at the 18-position to give 57 occurs with high selectivity syn to the hydroxymethy-iene group Conversion into phosphoric acid derivative 58 and cleavage of the phosphoric acid amide group under (he conditions of the Bcnkeser reduction provides compound 5921 Fluonde ion causes the release of free p-amyrin (1) in a final step I Li, NH3(iyTllF (1/1.75), -78 C 93%. 

Cyclopropane compounds containing the olefin isostere replacement for the amide bond were prepared using Julia olefination chemistry. Aldehydes 39 and 40 were obtained by LAAIH4 reduction of the chiral w-butyl esters of 32 and 33, respectively, followed by swera oxidation of the corresponding alcohols (Figure 22). Condensation of the (S)-N-BOC-cyclohexylalanine sulfone 41 with aldehyde 39 gave after treatment with 2% Na(Hg) and deprotection, the trans and cis olefin-amines... 

The first successful catalytic animation of an olefin by transition-metal-catalysed N—H activation was reported for an Ir(I) catalyst and the substrates aniline and norbornene 365498. The reaction involves initial N—FI oxidative addition and olefin insertion 365 - 366, followed by C—FI reductive elimination, yielding the animation product 367. Labelling studies indicated an overall. vyw-addition of N—FI across the exo-face of the norbornene double bond498. In a related study, the animation of non-activated olefins was catalysed by lithium amides and rhodium complexes499. The results suggest different mechanisms, probably with /5-arninoethyl-metal species as intermediates. 

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