Protonated enamine tautomer

The optically active Schiff bases containing intramolecular hydrogen bonds are of major interest because of their use as ligands for complexes employed as catalysts in enantioselective reactions or model compounds in studies of enzymatic reactions. In the studies of intramolecularly hydrogen bonded Schiff bases, the NMR spectroscopy is widely used and allows detection of the presence of proton transfer equilibrium and determination of the mole fraction of tautomers [21]. Literature gives a few names of tautomers in equilibrium. The OH-tautomer has been also known as OH-, enol- or imine-form, while NH tautomer as NH-, keto-, enamine-, or proton-transferred form. More detail information concerning the application of NMR spectroscopy for investigation of proton transfer equilibrium in Schiff bases is presented in reviews.42-44... 

Hansen et al.52 measured the deuterium isotope effects for the Schiff base being a derivative of racemic gossypol [7]. The high negative value of deuterium isotope effect observed at carbon C-7 linked with proton donor group (—190 — 240 ppb), solvent and temperature independent, clearly indicated the existence of this compound as enamine-enamine tautomer. 

A way forward might be to form the imine 7.3 [and hence its enamine tautomer 7.4] by reacting the phenylamine 7.2 with cyclohexanone (Scheme 7.18). Then to generate the benzyne anion 7.5 by treating the tautomers with sodamide and sodium fcr/-buloxide in THF. Cydization to the required indole 7.1 occurs through nucleophilic addition to the benzyne, followed by protonation during work-up. 

Protonation on nitrogen gives the secondary enamine the pKa for this process was argued above87,88 to be well in excess of 20. Protonation on carbon produces the imine which is more stable than its enamine tautomer, hence its pKa is larger yet. 

In contrast to phosphaalkynes, nitriles show quite a different chemical reactivity towards lithium trimethylsilylphosphanides. Whereas with benzonitrile and one equivalent of the lithium phenyltrimethylsilyl compound l-[(l,2-dimethoxyethane-0,0 )hthium-trimethyl-silylamido]benzylidenephosphane is formed, l-(l,2-dimethoxyethane-0,0 )lithium bis(trimethylsilyliminobenzoyl)phosphanide has been isolated from a similar reaction with lithium bis(trimethylsilyl)phosphanide in a molar ratio of 2 1. Solvent coordinate lithium is not bound to phosphorus, but to both the nitrogen atoms. Protonation gives the related bis(trimethylsllyliminobenzoyl)phosphane, which exists only as imino-enamine tautomer in the solid as well as in even very polar solvents. 

The mechanism of the alkylation of imines with electrophilic alkenes has been discussed by D Angelo and coworkers S who conclude that reaction occurs via an aza-ene reaction-like transition state 206 involving concerted proton transfer from the nitrogen and carbon-carbon bond formation (Scheme 206). ITiey further propose that the remarkable regiocontrol observed in these reactions originates from this crucial internal proton transfer which would not be possible in a conformation such as 207 of the less substituted enamine tautomer, since the N—H bond would be anti to the enamine double bond. However, although this seems probable, it is by no means proven. Inconsistencies in the argument and the evidence presented cast some doubt on the validity of these conclusions. For example ... 

Enamines. The condensation of a secondary amine and a ketone to make an enamine is a well known reaction which has seen wide use in organic synthesis [176-178]. Imines of a primary amine and a ketone exist in a tautomeric equilibrium between the imine and secondary enamine forms, although in the absence of additional stabilization factors cf. Scheme 5.33), the imine is usually the only detectable tautomer. Nevertheless, the enamine tautomer is very reactive toward electrophiles and Michael additions occur readily [179]. The mechanism of the Michael additions of tertiary and secondary enamines are shown in Scheme 5.34. For tertiary enamines, the Michael addition is accompanied by proton transfer from the a -position to either the a-carbon or a heteroatom in the acceptor, affording the regioisomeric enamine as the initial adduct [180]. The proton transfer and the carbon-carbon bond forming operations may not be strictly concerted, but they are nearly so, since conducting the addition in deuterated methanol led to no deuterium incorporation [180]. 

Side-chain radical halogenation selects a pyrimidine 5-methyl over a pyrimidine 4-methyl the reverse selectivity can be achieved by halogenation in acid solution -presumably an A-protonated, side-chain deprotonated species, i.e. the enamine tautomer, is involved. 

The proton transfer between the imine and enamine tautomers of 2-phenacylquinolines 24 (Scheme 5.18) in solution is slow on the NMR timescale [56]. This enables quantification of the tautomeric forms by examining 5(H-11), i5(C-ll), and 3(N-1) in CDCI3 solution NMR spectra as well as calculation of both the temperature-dependent equilibrium constants fCp and the free energy differences AGj of the tautomers [56]. 

Other classical synthetic approaches to 2-furanamine have failed, including the Curtius method and Beckmann rearrangement of 2-benzoylfuran oxime. However, hydrazinolysis of AT-(2-furyl)phthalimide, obtained from phthalimide and 2,5-dimethoxy-2,5-dihy-drofuran, gives 2-furanamine which was not isolated but detected by GLC-MS and H NMR spectroscopy. The latter reveals the absence of imino tautomers (75AP713). The chemistry of 2-dialkylamino-5-phenylfurans is typical of enamines protonation occurs on carbon to produce iminium salts. They are stable to base but afford 5-phenylfuran-2(3//)-one on hydrolysis with dilute acid. 2-Morpholino-5-phenylfuran couples with diazonium salts and affords Diels-Alder adducts with maleic anhydride and IV-phenylmaleimide (73JCS(P1)2523). 

Similarly, the enamine salt 15 is obtained by lithiation of 14 (equation 5). In both cases the lower steric hindrance leads to higher stability of the enaminic system33 where the double bond is formed on the less substituted carbon. The Af-metalated enamines 11 and 15 are enolate analogs and their contribution to the respective tautomer mixture of the lithium salts of azomethine derivatives will be discussed below. Normant and coworkers34 also reported complete regioselectivity in alkylations of ketimines that are derived from methyl ketones. The base for this lithiation is an active dialkylamide—the product of reaction of metallic lithium with dialkylamine in benzene/HMPA. Under these conditions ( hyperbasic media ), the imine compound of methyl ketones 14 loses a proton from the methyl group and the lithium salt 15 reacts with various electrophiles or is oxidized with iodine to yield, after hydrolysis, 16 and 17, respectively (equation 5). 

There are other types of proton shift tautomers, such as phenol/dienone, nitroso/oxime and imine/enamine, but these are less often encountered. There are also valence tautomers that exhibit fluxional structures, which undergo rapid sigmatropic rearrangements. Molecules that exhibit this type of isomerism are very interesting, but are not often encountered in undergraduate courses. An example of a valence tautomer is illustrated by the Cope system. 

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