Nucleophilic enamides

In the oxidative Eschenmoser sulfide contraction (Scheme 11), thioamide 59 is oxidized by benzoyl peroxide to give either a symmetrical disulfide or the O-benzoate of the thiolactam-S-oxide. In any event, the once-nucleophilic thioamide sulfur atom is now forced to adopt the role of electrophile a reactivity umpolung has, in effect, been achieved.13 The nucleophilic enamide 65 attacks the sulfur atom leading to the formation of sulfur-bridged intermediate 66. The action of a phosphine or a phosphite thiophile on the putative episulfide then gives vinylogous amidine 67. 

A possible side reaction in A-acyliminium chemistry is caused by deprotonation, giving rise to the formation of an enamide. Though this tautomerization is in principle reversible in acid media, this is not always the case. The enamide may react as a nucleophile with the /V-acyliminium ion still present, to produce dimers14. 

Interestingly, enamides or imines are produced in the absence of external or internal nucleophiles as shown by the formation of 342, 344, and 346, respectively, obtained from 341 <1998JOC44>, 343 <1998JOC1619>, and 345 <1996SC3471> in good to excellent yields (Scheme 94). 

The nucleophilic addition of amines to cyclic 2,3-allenamides 565 leads to ( )-3-amino-2-enamides 566 [260]. 

In 2007, AntiUa and coworkers described the Brpnsted add-catalyzed desymmetrization of me yo-aziridines giving vicinal diamines [75]. hi recent years, chiral phosphoric acids have been widely recognized as powerful catalysts for the activation of imines. However, prior to this work, electrophiles other than imines or related substrates like enecarbamates or enamides have been omitted. In the presence of VAPOL-derived phosphoric acid catalyst (5)-16 (10 mol%) and azidotrimethylsilane as the nucleophile, aziridines 129 were converted into the corresponding ring-opened prodncts 130 in good yields and enantioselectivities (49-97%, 70-95% ee) (Scheme 53). 

Kobayashi earlier demonstrated the first use of enamides and enecarbamates as nucleophiles in several enantioselective copper-catlayzed reactions [30]. Inspired by this precedent, Terada reported that 0.1mol% of Im effectively... 

Similarly, the 2-cyano-6-oxazolopiperidine 75 (Scheme 16) can be used to provide a variety of substituted piperidines <99TL3731, 99H(51)2065>. Conversion to the enamide 76 provides a means to introduce C-3 alkyl groups by Michael reaction <99TL3699>. Electrochemical bis-bromination and dehydrohalogenation affords the vinyl bromide 77, which can imdergo substitution at the 4-position by the addition of nucleophiles as simple as water <99T8931>. 

The palladium catalyzed intramolecular nucleophilic substitution of allyl alcohol derivatives (Tsuji-Trost reaction) has successfully been extended to the closure of a seven membered ring. The coupling of the allyl alcohol unit and the enamide was the key step in the preparation of the natural product claviciptic acid (5.14.),14... 

The synthesis of 6-substituted pipecolic acid derivatives has been carried out, in most cases with excellent stereoselectivities (> 95 5 transicis) and yields, by U-3CR between six-membered cyclic imines 53, carboxylic acids and the convertible isonitriles 52. Representative examples are reported in Scheme 1.20. On the other hand, when the chirality was present only on the isocyanide no stereoselectivity was observed, as expected [57]. In situ treatment of enamides 54 with an appropriate nucleophile allowed the conversion into the final products. The same trend in stereoselectivity was observed when similar imines were condensed with isocyanoace-tic acid methyl ester and Boc-glycine to give a series of tripeptides [58]. 

Tandem radical additions have also been utilized for the synthesis of nitrogen containing heterocycles. These reactions have the same requirements as those discussed for the oxygen heterocycles. The reductive addition of phenylsulfanyl radicals to the unsaturated amide 153 has been investigated [95JCS(P1)19], The nucleophilic radical adds selectively to the enamide followed by 5-exo-cyclization to give 154 in excellent yield with high trans selectivity. 

Although the nucleophilic reactivity is generally less than that of the enamine, one of the typical reactions of the enecarbamates and enamides is the reaction with electrophiles at the -position (equation 8). Since this review deals with electrochemistry, chemical reactions of enecarbamates and enamides are not included but some of them are summarized elsewhere9. The oxidation potentials of enecarbamates are more positive than those of enamines (EJV vs SCE, 7 = 1.59 V 8 = 1.37 V in CH3CN-0.1N LiC104, 100 mV/s). 

As knowledge of the reactivity of enamides accumulated during the course of a 10-year study on enamides, attention was focused on the cyclizability of enamides also under thermal conditions. It was first thought that electron deficiency in the aromatic ring of enamides caused by the introduction of an electron-withdrawing factor would bring about nucleophilic attack from the enamine portion of the molecule, therefore giving rise to the cyclized product, even under thermal conditions as described in Scheme 23. 

Scheme 9 demonstrates the further synthetic application of the thus obtained N,0-acetals. Substitution of the alkoxy or acyloxy group by nucleophiles like enol ethers, enol esters, enamines, other electron-rich olefins, CH-acidic compounds, electron-rich aromatics, isocyanides, trimethylsilyl cyanide, organometallics, vinyl and allyl silanes, hydroxy functions, or trialkylphosphites either catalyzed by Lewis acids or proton acids leads to the product of the amidoalkylation reaction (path a). In the presence of stereocenters as control elements, diasteroselective amidoalkylation reactions can be performed as shown in a large number of examples. On the other side, as Nyberg showed for the first time [196], elimination with formation of enecarbamates [208] and enamides [196,208,209] followed by reaction with electrophiles or nucleophiles (path b) also is possible. 

Kobayashi and coworkers pioneered the use of enamides or enecarbamates as nucleophiles in enantioselective reactions with either glyoxylates or glyoxylate derived imines catalyzed by chiral copper complexes [65]. The reaction using enamides or enecarbamates as nucleophilic components, namely, the aza ene reaction, with imines provides P amino imines that can be readily transformed into... 

However, these reactions proceed under acid catalysis and assume an initial conversion of the carbonyl compound into cationoid electrophile which then reacts with a covalent nucleophile. The interaction of the carbonyl compounds with amides leads only seldom to the enamides . Usually the a-hydroxyalkyl amides 8 or the bis-amides (amidals) 9 can be isolated under these conditions . The fV-acylenamines can be then obtained by removal of water from 8, or by elimination of amide molecule from 9 ° (equation 5). 

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. 

Controlled oxidation of A-acyl-piperidines and -pyrrolidines can be used to prepare 2-alkoxy derivatives or the equivalent enamides, which are useful general synthetic intermediates. The former are susceptible to nucleophilic substitution under Lewis-acid catalysis, via Mannich-type intermediates, and the latter can undergo electrophilic substitution at C-3 or addition to the double bond. 

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