Imines, acylation alkylation

Lithiation of compound 560 with s-BuLi-TMEDA in THF at —78 °C following an inverse addition protocol provided the anion 561. It reacts with primary alkyl iodides and triflates, silyl chlorides, diphenyl disulfide, epoxides, aldehydes, ketones, imines, acyl chlorides, isocyanates and sulfonyl fluorides to yield the expected compounds 562 (Scheme 152). The transmetallation of compound 561 with ZnBr2 allowed the palladium-catalyzed cross-coupling reaction with aryl and vinyl bromides837. When the reaction was quenched with 1,2-dibromotetrafluoroethane, the corresponding bromide 562 (X = Br) is obtained838. 

The photochemical ,Z-isomerization of imines carrying alkyl, aryl, or acyl substituents at the nitrogen of their CN group, on the other hand, was reported much later. This was due to the fact that the energy... 

Pyridin-4-one, 1 -hydroxy-2,6-dimethyl-hydrogen-deuterium exchange reactions, 2, 196 Pyridin-4-one, 1-methyl-hydrogen-deuterium exchange, 2, 287 pK 2, 150 Pyridin-2-one imine tautomerism, 2, 158 Pyridin-2-one imine, 1-methyl-quaternization, 4, 503 Pyridin-4-one imine tautomerism, 2, 158 Pyridinone methides, 2, 331 tautomerism, 2, 158 Pyridinones acylation, 2, 352 alkylation, 2, 349 aromaticity, 2, 148 association... 

A surpnsing feature of the reactions of hexafluoroacetone, trifluoropyruvates, and their acyl imines is the C-hydroxyalkylation or C-amidoalkylaOon of activated aromatic hydrocarbons or heterocycles even in the presence of unprotected ammo or hydroxyl functions directly attached to the aromatic core Normally, aromatic amines first react reversibly to give N-alkylated products that rearrange thermally to yield C-alkylated products. With aromatic heterocycles, the reaction usually takes place at the site of the maximum n electron density [55] (equaUon 5). 

Experimental evidence, obtained in protonation (3,6), acylation (1,4), and alkylation (1,4,7-9) reactions, always indicates a concurrence between electrophilic attack on the nitrogen atom and the -carbon atom in the enamine. Concerning the nucleophilic reactivity of the j3-carbon atom in enamines, Opitz and Griesinger (10) observed, in a study of salt formation, the following series of reactivities of the amine and carbonyl components pyrrolidine and hexamethylene imine s> piperidine > morpholine > cthyl-butylamine cyclopentanone s> cycloheptanone cyclooctanone > cyclohexanone monosubstituted acetaldehyde > disubstituted acetaldehyde. 

Asymmetric addition to ketimine in a reagent controlled manner has seldom been reported, even by 2008. When we investigated the potential for tbis asymmetric addition around 1992, there were no known examples. In 1990, Tomioka et al., reported the first asymmetric addition of alkyl lithium to N-p-methoxyphenyl aldo-imines in the presence ofa chiral (3-amino ether with 40-64% ee [8] (Scheme 1.11). In 1992, Katritzky reported the asymmetric addition of Et2Zn to in situ prepared N-acyl imine in the presence of a chiral (3-amino alcohol with 21-70% ee [15] (Scheme 1.12). In the same year, Soai et al., reported the asymmetric addition of dialkylzinc to diphenylphosphinoyl imines in the presence of chiral (3-amino alcohols with 85-87% ee [16] (Scheme 1.13). These three reports were, to the best of... 

Carbon monoxide rapidly inserts into the carbon—zirconium bond of alkyl- and alkenyl-zirconocene chlorides at low temperature with retention of configuration at carbon to give acylzirconocene chlorides 17 (Scheme 3.5). Acylzirconocene chlorides have found utility in synthesis, as described elsewhere in this volume [17]. Lewis acid catalyzed additions to enones, aldehydes, and imines, yielding a-keto allylic alcohols, a-hydroxy ketones, and a-amino ketones, respectively [18], and palladium-catalyzed addition to alkyl/aryl halides and a,[5-ynones [19] are examples. The acyl complex 18 formed by the insertion of carbon monoxide into dialkyl, alkylaryl, or diaryl zirconocenes may rearrange to a r 2-ketone complex 19 either thermally (particularly when R1 = R2 = Ph) or on addition of a Lewis acid [5,20,21]. The rearrangement proceeds through the less stable... 

To form the stereocenter at C-3 a direct reduction-alkynylation sequence was applied, that provided the diastereomeric homopropargylic alcohols 83 in a ratio of syn anti=76l2A, The major isomer syn-S3 was isolated in 55% yield. The key step of the synthesis was an intramolecular imidotitanium-al-kyne [2+2] cycloaddition/acyl cyanide condensation. With this sequence the pyrrolidine ring was formed and all the carbon atoms of the alkyl side chain were established in acrylonitrile 84. The reduction of the imine double bond proceeded stereoselectively and the nitrile group was removed reductively en route to the target compound. 

The acyl-Pictet-Spengler reaction is also catalyzed by chiral thiourea derivative 6 to provide M-acetyl p-carbolines in high enantioselectivities. Notably, thiourea derivatives can activate not only electronically distinct imine derivatives such as N-alkyl and N-Boc imines but also a weakly Lewis basic N-acyhminium ion with high enantioselectivity using a chiral hydrogen bond donor (Scheme 12.4). 

Taking advantage of the acyl silane and imine methodologies, Scheidt and co-workers illustrated the use of acyl silanes 61 and iV-diarylphosphinoylimines 62 to form a-amino ketones 63 (Eq. 4) [55], Utilizing thiazolium pre-catalyst 64, a variety of acyl silanes, both alkyl and aryl, can be coupled efficiently. The reaction conditions are tolerant of various aryl substitutions, providing high yields. 

Exploiting the Lewis basic phosphoryl oxygen of Im, Terada reported the direct alkylation of a-diazoesters with N-acyl imines to afford P-amino-a-diazoesters in high yields and ee s (Scheme 5.12) [23]. Earlier, Johnston had observed that catalytic TfOH promoted aziridine formation (Aza-Darzens reaction) between diazoacetates and N-benzyl imines [24]. The authors propose that aziridine formation is circumvented through C—H bond cleavage by the phosphoryl oxygen of 1 (Intermediate A). However, as noted by the authors, the low nucleophilicity of N-acyl imines might also be considered as the cause of this selective transformation. 

Aryl and acyl isothiocyanates were also found to react with alkyl azides, but yield thiatriazoline-5-imines only as elusive intermediates which are transformed in situ into a series of bisadducts after loss of nitrogen. Interestingly, L abbe et al. have found that picryl isothiocyanate is an exception to this and reacts smoothly with alkyl azides to yield 4-alkyl-5-picrylimino-l,2,3,4-thiatriazolines (177) which are stable below 100°C <90JHC1059>. Kinetic experiments indicate that the reaction between picryl isothiocyanate and alkyl azides most likely is concerted as no significant solvent effect was observed. 

The 1,2,4-diazaarsoles are colorless oils or crystals. The unsubstituted compound is deprotonated by butyllithium and subsequently alkylated or acylated at N-1 <86TL2957>. The 1-acyl derivatives (9) (R = Me, Ph) readily undergo a regiospecific cycloaddition of nitrones, nitrile oxides and diazoacetic esters (Scheme 1). The cycloaddition of diphenyl nitrile imine is more general in respect to the 1-substituent (R = H, Me, Ph, COMe). The cycloreversion of the adduct (10) at higher temperatures provides an in situ access to the 1,3-diphenyl diazaarsole (11) which immediately enters another cycloaddition (Scheme 2) <86TL2957>. 

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