Enamides with electrophiles

Only few general methods allow for the introduction of a substituent at the C-7 position. However, treatment of cyano-enamide 335 with LiTMP followed by reaction with electrophiles has been successfully used to introduce an alkyl chain at G-7. It is worth noting that the amide obtained by acidic hydrolysis of the cyano-enamide group can be further alkylated to form tricyclic hexahydro-oxazolo[3,2- ]pyridin-5-ones 337 (Scheme 92) <1998JOC1619>. 

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). 

The Af-acylenamines 1 (enamides, w-vinylamides) are usually regarded as deactivated enamines1,2. However the influence of acyl group attached to the nitrogen atom increases both the reactivity of enamides in their excited state and of the products of interaction of enamides with cationoid electrophiles, i.e. the Af-acyliminium ions 2. 

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. 

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. 

When the pyrrolo[l,2-c]oxazole 269 was treated with trimethyl orthoformate in the presence of BF3 Et20, in dichloromethane at — 78 °C, a mixture of compounds was obtained from which the expected 5-dimethoxymethyl derivative, 270, was isolated in poor yield (12%) with another dimethoxylated compound 271 (23%). The formation of 271 could be explained by the addition of the formyl cation equivalent at C-7, followed by the protonation at C-6 of the resulting enamide 272 leading to the electrophilic iV-acyliminium ion 273 (Scheme 40). The regioselectivity of this electrophilic addition of trimethylorthoformate to the silyloxypyrrole 269 at C-7, in a non-vinylogous manner, is unusual <1999TL2525>. 

Addition of electrophilic carbenes to enamines usually does not proceed with good efficiency, very likely because of the disturbance by the Lewis basic nitrogen 15). If however the less basic enamide derivatives are used as olefins, high conversions to donor-acceptor cyclopropanes are possible. Thus cyclic carbamate 245, which itself originates from an oxycyclopropane, gives the bicyclic compound 246 almost quantitatively. Its cleavage with aqueous base provides lactone 247 that could be coupled with tryptophyl bromide to afford 248, a direct precursor of the alkaloid eburnamoni-ne 105>. 

Zinc enamides such as 50 are reactive organozinc species, which can undergo addition to unactivated olefins with good to excellent yields. After trapping of the organozinc intermediate 51 with an electrophile and hydrolysis, a variety of functionalized primary, secondary, and tertiary a-alkylated ketones are isolated (Equation (100)).170... 

Acyiiminium ions can also be created by treatment of the easily accessible enamides (63) with protic acids (Scheme 31 see also Section 4.2.2.1). Alternatively, transformation of enamides (63) to (60) can be achieved with C-electrophiles, by simultaneous formation of carbon-carbon bonds (cf. Scheme 37). In contrast, considerably less importance can be attributed to the comparable preparation of (60) from acylimines (64 Scheme 31), by protonation for example, due to their usually pronounced instability. 

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. 

The dihydropyridines produced by the methods described above are multifunctional and can be manipulated, for example the enamide character in these products can be utilised by interaction with an electrophile (iodine in the example) which brings about intramolecular attack and formation of a lactone. ... 

The most studied diazine derivatives are the oxy- and amino-pyrimidines, since uracil, thymine and cytosine are found as bases in DNA and RNA. Carbonyl tautomers are the preferred forms. It is the enamide-Uke character of the double bonds in diazine diones that allows electrophilic substitution - uracil, for example, can be brominated at C-5. One amino-substituent permits electrophilic ring substitution and two amino, or one amino and one oxy, substituents, permit substitution with even weakly electrophilic reactants. 

Numerous alkene derivatives that possess one electron-releasing substituent have been found to react with salt (1). These include enamines, enamides, enecarbamates, enol ethers and enol acetates. Electrophilic substitution of these alkene derivatives occurs readily, yielding iminium salts that have found substantial use in synthesis. ... 

A related reaction involves the use of aryl indole-3-carbinols with enamides. Under the influence of acid catalysts the carbinols generate electrophiles. The adducts hydrolyze to products that are the equivalent of conjugate addition to 1,3-diaryl propenones. These reactions can be done in up to 90% ee with chiral BINOL-phosphoric acid catalysts [293]. 

Inspired by the work of Ishihara, Zhu and Masson demonstrated that a chiral nonracemic calcium bis(phosphate) complex 140c was capable of catalysing an enantioselective electrophilic amination of enamides 144 with azodicarbojylates 145 to give chiral enantioenriched 1,2-hydrazinoimines 146 in excellent yields and enantioselectivities. Subsequent in situ hydrolysis of the imine function led to 2-hydrazinoketones 147 in good yields (73-97%) and enantioselectivities (85-94% ee). By a one-pot reduction, syn-1,2-disubstituted diamines 148 could also be obtained (Scheme 3.45). 

Kitazume et al. examined the first example of Michael additions via the MBH-type reaction that used 3-fluoromethylprop-2-enamide as a chiral auxiliary electrophile towards activated olefins in the DABCO ionic liquid system. The reaction of (45)-3-[( )-4,4,4-trifluorobut-2-enoyl]-4-isopropyl-2-oxazolidinone (297) with activated vinyl moiety proceeded smoothly at 80 °C to give the corresponding adducts 298 in moderate yields, albeit with low diastereoselectivity (Scheme 1.109). 

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