Enol carbonates alkylation

The preparation of the sodium derivative of the phenol may be avoided by heating the enol and alkyl halide in the presence of potassium carbonate and acetone, for example ... 

Carboxylic acids can be directly alkylated by conversion to dianions with two equivalents of LDA. The dianions are alkylated at the a-carbon, as would be expected, because the enolate carbon is a more strongly nucleophilic than the carboxylate anion.76... 

C-alkylation is predicted to occur via attack on the enolate carbon perpendicular to the C — C — O plane for maximum overlap of the re-system. Such a transition state 5 can be easily achieved when the ring to be formed is six-membered. In the five-membered ring closure there is less strain in a nucleophilic substitution involving the lone-pair orbital on oxygen. 

In a similar manner to that described for bicyclic lactams (Section 1.1.1.3.3.4.1.5.I.). alkylation reactions of tricyclic lactams, which contain a fused benzene ring adjacent to the carbon undergoing alkylation, have been exploited14. The first alkylation of the benzo-annulated bicyclic lactam 1 gives a mixture of diastereomers, which is then further alkylated. In the second alkylation step, the counterion on the alkoxide, which is formed prior to enolate formation, proved to be crucial for the diastereoselectivity of the subsequent alkylation reaction. The best diastcrcoselectivity was obtained when either dichlorobis(ij5-cyclopentadienyl)zirconium or triisopropoxytitanium chloride was added to the preformed alkoxide, followed by enolization and alkylation. Using this method the second alkylation step gives a satisfactory diastereoselectivity. Hydride reduction of the purified major diastereomer 2, followed by acid treatment of the product, furnishes chiral naphthalenones 414. 

Quenching this reaction with deuteriomethanol gave 2-methylcycloheptanone having deuterium at the 2-position (199 E = D) in 75% yield with 95% deuterium incorporation. Aldehydes and benzoyl chloride gave the desired products in 60-70% yields. Alkylation of the enolate intermediate (198) was successfully carried out with alkyl halides in the presence of HMPA in good yields. The reaction with ethyl chloroformate and chlorotri-ethylsilane gave enol carbonate (200) and sUyl enol ether (201) in 74 and 75% yield, respectively. 

Enol carbonates and carbamates. Olofson and Cuomo have extended the regio-ipccilic alkylation of ketones (6, 44) to a regiospeeific preparation of enol carbonates and carbamates. The enol carbonates are prepared by reaction of silyl... 

Baldwin concluded that the remarkable difference between these two cycliza-tions results from stereoelectronic control of the alkylation of the amhi-dent nucleophile, i.e. the enolate ion. For such an ion, carbon alkylation requires approach of the electrophile perpendicular to the plane of the enolate, whereas oxygen alkylation requires approach in the plane of the enolate. Consequently, in the five-membered ring case, the C-alkylation process 196A 198 (which can be considered as a 5-Endo-trigonal process) is sterically difficult, but not the 0-alkylation process 196B 197 (a 5-Exo-tetrahedral process). 

Palladium-catalysed asymmetric a-allyl alkylation of acyclic ketones has been reported allyl enol carbonates of a wide range of ketones undergo allyl transfer in high yields and ees at room temperature.197... 

A regio- and enantio-selective palladium-catalysed allylic alkylation of ketones has been reported, using allyl enol carbonate chemistry in which a CO2 unit tethers the allylating agent to the nucleophile.198... 

Platinacyclobutane complex 118 undergoes equilibrium heterolytic scission of the exocyclic carbon-carbon bond to form a cationic allyl complex and the organic enolate ion (Equation 35) <1993OM3019>. Similar dissociative ionization was previously reported for rearrangements of iridium and rhodium metallacyclobutane complexes formed by nucleophilic alkylation < 1990JA6420>. This carbon-carbon bond activation is generally associated with reversible central carbon alkylation of Jt-allyl complexes (Section 2.12.9.3.3), but the homolytic equivalent has recently been... 

Lewis acids can be used to induce the rearrangement of iridacyclobutane complexes formed by central carbon alkylation of cationic 7i-allyl precurors with organic enolates (Section 2.12.9.3.3). The reaction, which presumably proceeds by Lewis acid coordination to the remote carbonyl functionality and release of the boron enolate, cleanly provides the thermodynamically more stable terminal carbon adducts (Equation 40) <1990JA6420>. 

Equation 76) <1993OM3019>, which react as ester and ketone enolate equivalents, respectively. The latter reaction requires the use of fluoride ion activation (tetrabutylammonium fluoride, TBAF) to actuate the addition. Central carbon alkylation is less common for allylpalladium reactions despite this, nucleophilic alkylation of TMEDA-stabilized 1,3-diphenylallyl palladium complexes proceeds selectively to the central carbon (Equation 77) <1995AGE100>. 

Despite the synthetic possibilities suggested by this early study, the chemistry of the alkynyliodonium salts lay dormant until the mid-1980s. In 1986, Ochiai and his coworkers published an important communication which shaped much of the later thinking on the reactions of alkynyliodonium ions with nucleophiles28. When / -dicarbonyl enolates are treated with alkynyliodonium tetrafluoroborates containing a long (> three carbons) alkyl chain, derivatives of cyclopentene are produced. This is illustrated in equation 41 for the... 

As with the aza-enolate of Figure 10.31, the aza-enolate D in Figure 10.32 contains a polar, covalent N—Li bond that is twisted out of the plane of the enolate. And again as with Figure 10.31, the lithium of this N—Li bond directs the added alkyl halide from, the side of the lithium to the enolate carbon. The kethydrazone E is formed with high diastereoselectivity and, after chromatographic separation, it is obtained in 100% stereochemically pure form. 

Muzart and coworkers have reported a new catalytic enantioselective protonation of prochiral enolic species generated by palladium-induced cleavage of p-ketoesters or enol carbonates of a-alkylated 1-indanones and 1-tetralones [21 ]. Among the various (S)-p-aminocycloalkanols examined, 17 and 18 were effective chiral catalysts for the asymmetric reaction and (J )-enriched a-alkylated 1-indanones and 1-tetralones were obtained with up to 72% ee. In some cases, the reaction temperature affected the ee. 

The end result is that the larger of the two groups is on the inside There are other ways to do this too. If we alkylate the enolate of a bicyclic lactone, the alkyl group (black) goes on the outside as expected. But wha t will happen if we repeat the alkylation with a different alkyl group The new enolate will be flat and the stereochemistry at the enolate carbon will be lost. When the new alkyl halide comes in, it will approach from the outside (green) and push the alkyl group already there into the inside. 

Various substitutions of hydrogen at positions 3 and 4 in -lactams can be performed with electrophilic reagents. The 3-position is activated by the carbonyl group. Alkylation at the 3-position is readily executed via the enolate with alkyl halides, aldehydes, ketones, carbon dioxide, etc. A carboxyl group at C(4) as in 79 does not interfere, the dilithium salt being alkylated at C(3) with excellent stereocontrol, giving the /ra j-disubstituted lactams 80. Hydrolysis leads to -alkyl aspartic acids 81. 

Enol carbonates react with alkylating agents in the presence of a palladium catalyst. The decarboxylative alkylation of allyl enol carbonates to the corresponding aUylcyclohexanone derivatives is known as the Tsuji alkylation. An asymmetric version of this reaction has been reported. The same reaction can be done using enolate anion and aUylic acetates with a palladium catalyst. ... 

As an alternative to using dialkyl carbonates [(R0)2C=0] for a-acylation of ketones, the reaction of ketone enolates with alkyl cyanoformates (NC-CO2R, Mander s reagent) provides P-keto esters in good yields. Reaction of lithium enolates with acyl halides or anhydrides, however, usually leads to mixtures of O- and C-acylated... 

The copper-mediated 1,4-addition of alkyl groups to a,P-unsaturated ketones affords regiochemically pure enolate anions (see also Section 7.5) which may be trapped at oxygen with silyl halides, acyl halides, or dialkylcarbonates to provide silyl enol ethers, enol acetates, or enol carbonates, respectively. These can be unmasked at a later stage by reaction with MeLi to regenerate the enolate for further elaboration. ... 

We reasoned that the /-butyl group is still too small for an efficient chiral induction therefore, the optically pure 0-TBDPS lactaldehyde was chosen for the formation of the N,O-acetal. But only amides 39 and 41 are now non-racemic 39 exhibits a satisfactory chiral induction on allylation, because the enolate carbon is shielded by the adjacent axial bulky substituent. In 41, both sidechains at C-2 and C-4 are equatorial and the stereocontrol drops significantly.The use of a chiral aldehyde for acetal formation even allows the use of the achiral O-aminobenzylalcohol (43) as a template. Acetals 44 and 45 are formed and separated due to the allylic 1,3-strain of the amide moiety both derivatives have axial sidechains (as detectable in the crystal structure of alkylation product 46d) (Fig. 2) and the chiral induction is similarly high in both cases. The chiral auxiliary is removed with lithium aluminium hydride without any racemization of the newly created stereocenter (6). 

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