Carbon nucleophiles enamides

Nachtsheim and co-workers utilized phenolic benzamido-acrylates of type 124 to construct carbo-spirocycles 125 [88]. They relied on the use of BTI in propionitrile at 90°C to activate the phenols toward the anticipated dearomative spirocyclization, hoping that the carbon-based enamide nucleophilic unit would be the major actor of this intramolecular event. However, the yields of the desired products hardly passed beyond 50%, notably because an unexpected competitive oxo-spirocyclization took place to furnish the 8-spirolactone 126 (Fig. 31). The yield of 126 could even be optimized up to 70% by performing the reaction with the isopropyl ester 124c (i.e., R=i-Pr) in TFE at 0°C in the presence of TFA (2 equiv.). These conditions completely shut down the formation of the corresponding spirolactam 125 [88]. The use of other X -iodane reagents, such as DIB and Koser s HTIB reagent, was also attempted, but BTI turned out to be by far the best reagent for this oxo-spirocyclization. 

We will examine two very different approaches to perhydrohistrionicotoxin. The first one revolves around the chemistry of 27-acyliminium ions, a field largely developed by the Speckamp group in the Netherlands. In Chapter 8 we saw that iminium ions (the nitrogen analogs of oxocarbenium ions) are excellent electrophiles (Mannich reaction). N-Acyliminium ions are even more electrophilic than iminium ions. They react with both heteroatom and carbon nucleophiles as expected. An early use of an N-acyliminium ion in synthesis is the cyclization of enamide 16 to 18 in an electrophilic aromatic substitution reaction. This reaction was an early step in Stork s approach to lycopodine. The reaction presumably proceeds through N-acyliminium ion 17, generated by protonation of the enamide. 

An alternative means for effecting reaction at a side-chain depends on a prior electrophilic addition to the nitrogen this acidifies further the side-chain hydrogens, then deprotonation generates an enamine or an enamide, each being nucleophilic at the side-chain carbon the condensation of 4-picoline with benzal-dehyde using acetic anhydride illustrates this. 

Intramolecular reactions of species (69) with simple alkenes have been of great importance in the field of /V-acyliminium chemistry. In Section 4.4.2.2, the mechanistic principles of IV-acyliminium cycliza-tions using these ir-nucleophiles have already been treated. If the carbon-carbon double bond tethered to the nitrogen atom does not have an electronic bias, a considerable preference exists for the formation of a six-membered ring by way of a chair-like transition state. Some recent applications of this reaction type are the preparation of bicyclic imidazolidin-2-ones (equation 57) and a cyclization reaction proceeding via a tertiary iV-acyliminium intermediate generated by protonation of an enamide (equation 58). A third example (equation 59) leads to a bicyclic system that apparently prefers proton loss instead of formation of a tertiary formate. ... 

The facility with which the phosphorus-carbon bond in acylphosphonic derivatives is cleaved by the action of the more basic nucleophiles has already been commented upon. Those nucleophiles include alkoxides and amines, but it may be noted that thiols undergo normal addition to the carbonyl group. With regard to the latter, diethyl acetylphosphonate yields the monothioacetals 256 the derivatives may not be stable thermally but their decomposition occurs with cleavage of the phosphorus-carbon bond Reactions between the same substrate and simple carboxamides in the presence of an acid catalyst under dry conditions furnish the acylated enamides 257 ". ... 

In a beautiful synthesis of (+ )-vindorosine (64b) (Scheme 22), c and E rings are made in a one-step process which depends on the fact that indoles, even / -substituted indoles, react more rapidly with electrophiles at the jS-position than at the a-position. In the present context the elegant step which makes use of this concept is the formation of (74), together with some (76), from (73). The electrophilic species is generated by interaction of the enamide at the future C-20 with an acid. The success of this step depends on the possibility of trapping a rapidly formed 3,3-disubstituted-3H-indolium salt intermediate, (75) in the present case, by an intramolecular nucleophilic addition to the indole a-carbon here the nucleophile is the enol of the methyl ketone. 

Acidic hydrolysis of the reactive enamide led to the corresponding carboxylic acids 14 whereas alcoholysis gave esters 16 and aminolysis amides 15. The mechanism of the hydrolysis was shown to proceed via miinchnone derivatives 20 which, instead of being opened with a nucleophile, reacted as a 1,3-dipole in [3+2] cycloaddition reactions with propiolic esters or acetylene dicarboxylic esters to give after elimination of carbon dioxide protected pyrroles 19 (Scheme 3.2.4)... 

In 2009, Chen and co-workers [136] developed an enantioselective allylic substimtion of BH carbonate using indole as nucleophile in a IV-alkylation fashion, where (DHQD)2PHAL (74) was found efficiently promoted the asymmetric A-alkylation in good yields and enantioselectivities (Scheme 9.39). Subsequently, the same group showed that cyclic imides and enamides are good nucleophiles to... 

In 2008, Sorimachi and Terada reported a relay catalysis using a rhodium hydride complex/Brpnsted acid (129) binary system (Scheme 5.88) [89]. The sequential transformation involves a three-step relayed catalysis, where (1) isomerization of allylamide 130 to enamide A is catalyzed by RhClH(CO)(PPh3)j (2) subsequent isomerization of A to imine B is relayed by 129 and (3) the catalytic sequence is terminated by a carbon-carbon bond forming the reaction of B with a nucleophilic component 131 under 129. This approach enables the generation of reactive imines B from readily available allylamides 130 in a one-pot reaction via tandem isomerization. 

As an extension of their methodology, Armstrong and coworkers have synthesized 2-acetamido-2-deoxyhexose via the use of tethered internal nucleophiles. Thus, theU-4CR of aldehyde 9k, derived from D-arabinose, p-methoxybenzylamine (6i), acetic acid (10b), and Im, provided enamide 127 in a high yield as a 3.4 1 mixture of inseparable diastereomers at the a-carbon. In the presence of mild acidic conditions (HCI generated from AcCl), cleavage of the isopropylidene PG and protonation of the enamide followed by miinchnone 128 formation takes place. Internal nucleophilic attack by the secondary alcohol (attack by the primary alcohol is unfavorable as it forms a seven-membered ring) forms the expected six-membered 2-acetamido-2-deoxy-D-mannono-5-lactone 129 (Scheme 7.38) [56]. 

Nucleophilicity parameters N and % for electrophile-nucleophile combination based on the Mayr equation log k=+E) were reported for fluorides in protic solvents, enamines derived from imidazolidinones, trimethylsilyl enol ethers with perfluori-nated substituents at the a-carbon, O-methylated Breslow intermediates, anions of nucleobases and their subunits, enamides, symmetrical and unsymmetrical hydrazines, and heteroarylboron compounds. Of note, replacement of CH3 with CF3 and C6H5 with CgF5 in the trimethylsilyl enol ethers reduces the nucleophilicity by 8 and 4.5 orders of magnitude, respectively. Hydrazines have very similar nucle-ophilicities to alkyl amines in other words, there is no evidence of an a-effect. With NH2NMC2, there is a fast reversible reaction corresponding to addition of the tertiary amine, followed by a slow irreversible reaction for addition at the primary amine, with a 3000-fold difference in nucleophilicity between the two sites. ... 

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