Enolate Intramolecular displacement

The canonical formulation of the mechanism of the Favorskii rearrangement involves initial deprotonation of the a-carbon to generate an enolate, intramolecular displacement of the leaving group on the a -carbon by the enolate to generate a cyclopropanone, addition of a nucleophile to the cyclopropanone ketone followed by elimination to generate the more stable of two possible carbanions, and protonation to yield the rearranged carboxylic acid derivative. 

Yosikoshi reported the synthesis of furan derivatives by the reaction of 1,3-diketones with nitroalkenes, in which the Michael addition of the anions of 1,3-diketones and the subsequent intramolecular displacement of the nitro group by enolate oxygen are involved as key steps (Eq. 7.40).42... 

When the enones 1 were treated with the ai-haloalkanols 2 and base, the deformylated cfv-prod-ucts rac-3 were obtained exclusively13. Clearly this reaction is initiated by conjugate addition of the O-nucleophile. The diastereoselective step, however, is the subsequent intramolecular displacement of halide by the intermediate enolate anion. 

Synthesis of Cyclopropanes. Chiral imide enolates which contain y-halide substituents undergo intramolecular displacement to form cyclopropanes. Halogenation of y,5-unsamrated acyl imides occurs at the y-position in 85% yield with modest stereoinduction. The (Z) sodium enolates of these compounds then cyclize through an intramolecular double stereodifferentiating reaction (eq 61). 

Treatment of 88 with /-BuOK afforded the corresponding palladacycles 89 in good overall yield, as a mixture of two diastereosiomers (Equation 13). The stereoselective event involved an intramolecular displacement of the iodide by a potassium ester enolate generated in situ <20030M2961>. 

Here again, the reaction involved an intramolecular displacement of the iodide by an ester enolate (Scheme 10). Preparation of stable azapalladacycle ( )-93 commenced with treatment of sulfonamide 90, accessible via A -alkylation of A -trifluoromethanesulfonyl-2-iodoaniline with palladium(O) (Pd2(DBA)3 DBA = dibenzylideneacetone) and tetramethylethylenediamine (TMEDA) to afford palladium(ll) complex 91. An easy ring closure of complex 91 provided palladacycle ( )-92 in 92% yield via addition of /-BuOK (IM in solution in THE, 1.2equiv) at room temperature. Displacement of tetramethylethylenediamine with triphenyl-phosphine delivered palladacycle ( )-93 in quantitative yield. 

Bicycloannelation. The first step of a new method for this reaction involves conjugate addition of a cyclic dienolate to a nitro olefin followed by an intramolecular displacement with loss of the nitro group. An example is the reaction of the a -enolate of isophorone (1) with 1-nitropropene. When refluxed with HMPT the initial adduct (2), which can be isolated, is converted into the tricyclooctanones 3 and 4 in 6.7% yield.4... 

Similarly, a convenient procedure for the synthesis of diethyl l-methyl-2-nitroethylphosphonate in 71% yield involves the Michael addition of dialkyl trimethylsilyl phosphite to l-nitropropene. ° The Michael addition of 1-lithio-l-chloromethylphosphonamide to tert-butyl p-silylacrylate proceeds at low temperature. The intermediate y-chlorophosphonamide ester undergoes intramolecular displacement by the incipient enolate to give the corresponding cyclopropane in 75% yield. ... 

Bromine reacts at room temperature and in the absence of light with the acylmethylquinone (28.3) to give good-to-exceilent yields of the quinonoid heterocycle—a class of compounds which has been reviewed [2947, 3650], An oxygen enolate ion intramolecularly displaces a fluorine atom in pentafluoro-phenyl compounds with the formation of fused furan ring. 

This classical synthesis rests on an initial aldol condensation at the carbonyl carbon of a 2-halo-carbonyl-component ring closure is achieved via intramolecular displacement of halide by enolate oxygen intermediates supporting this mechanistic sequence have been isolated in some cases. "... 

The thyroid hormone thyroxine, (204), is reported to yield a complex mixture of products when irradiated with u.v. light. However, the synthetic hormone analogue (205) photocyclises in fair yield to the dibenzofuran (206). Intramolecular displacement of ortho halide is also reported to occur in the photocycllsation of (207) to (208), and in (209) to (210), and for the enolate of... 

Intramolecular displacement of benzylic chlorides by nitrile anions was previously demonstrated as an efficient method making substituted pyrrolidines " however, the question of enanti-oselectivity was not addressed. Recent works on the synthesis of substituted cyclopentane showed that intramolecular enolate displacement of benzylic phosphate proceeded in clean inversion. Thus, it was envisioned that an appropriately substituted cyano phosphonate could be used to construct the pyrrolidine ring (Scheme 5.23). This intermediate could potentially be produced by the addition of a fert-butylamine to acrylonitrile. The desired amine could be produced via reaction... 

B.vi. Tbe Darzens Glycidic Ester Condensation. When an a-halo ester is treated with base and the resulting enolate anion condensed with a carbonyl derivative, the product is an alkoxide. This nucleophilic species can displace the halogen intramolecularly to produce an epoxide, which forms the basis of a classical reaction known as the Darzens glycidic ester condensation. 13S Reaction of ethyl a-chloroacetate and sodium ethoxide, in the presence of benzaldehyde. generated the usual alkoxide (221). Intramolecular displacement... 

Delivery of an electrophile to the less hindered face of an enolate also occurs in intramolecular alkylation reactions. When 500 was treated with potassium fert-butoxide, a mixture of (E) and (Z) enolates (501 and 502. respectively) was obtained. Intramolecular displacement of bromide generated a single isomer (503). In this case, the electrophile can approach the enolate from only one face (the bottom or a face). Because of this conformational constraint, both (E) and (Z) enolates lead to the same product. In cyclopentanone and cyclohexanone enolates. an increase in the size of a facial blocking group increases selectivity. When that group was small, the selectivity decreased. 

Cory and Renneboog53 have devised an efficient bicycloannulation for the synthesis of tricyclo[3.2.1.02,7]octane-6-one (66) as shown in equation 63. The method involves three steps (1) the enolate undergoes an initial conjugate addition to phenyl vinyl sulfone, (2) the resulting sulfone-stabilized carbanion undergoes an intramolecular Michael addition to the enone, and (3) the resulting enolate displaces phenylsulfinyl moiety from the tricyclooctanone. The amount of HMPA (3 mol equivalents) is critical for effective cyclization of the enolate. 

An example of this displacement between a pyridine nitrogen atom and an aryl halide is shown in Scheme 21. When 2-pyridyl acetates 138 were C-acylated with 2-halobenzoyl chlorides, the enolized products 139 resulting from the reaction suffered an intramolecular nucleophilic attack of the pyridine nitrogen atom onto the ipso-position to give benzo[c]quinolizinium salts 140 as intermediates. Loss of HC1 gas from 140 afforded benzo[c]quinolizine derivatives 141 <2002JOC2082>. 

The Sonogashira reaction is of considerable value in heterocyclic synthesis. It has been conducted on the pyrazine ring of quinoxaline and the resulting alkynyl- and dialkynyl-quinoxalines were subsequently utilized to synthesize condensed quinoxalines [52-55], Ames et al. prepared unsymmetrical diynes from 2,3-dichloroquinoxalines. Thus, condensation of 2-chloroquinoxaline (93) with an excess of phenylacetylene furnished 2-phenylethynylquinoxaline (94). Displacement of the chloride with the amine also occurred when the condensation was carried out in the presence of diethylamine. Treatment of 94 with a large excess of aqueous dimethylamine led to ketone 95 that exists predominantly in the intramolecularly hydrogen-bonded enol form 96. 

Elimination reactions (Figure 5.7) often result in the formation of carbon-carbon double bonds, isomerizations involve intramolecular shifts of hydrogen atoms to change the position of a double bond, as in the aldose-ketose isomerization involving an enediolate anion intermediate, while rearrangements break and reform carbon-carbon bonds, as illustrated for the side-chain displacement involved in the biosynthesis of the branched chain amino acids valine and isoleucine. Finally, we have reactions that involve generation of resonance-stabilized nucleophilic carbanions (enolate anions), followed by their addition to an electrophilic carbon (such as the carbonyl carbon atoms... 

Diketones usually exist as mixtures of tautomeric keto and enol forms. The enolic form does not show the normal absorption of conjugated ketones. Instead, a broad band appears in the 1640-1580 cm-1 region, many times more intense than normal carbonyl absorption. The intense and displaced absorption results from intramolecular hydrogen bonding, the bonded structure being stabilized by resonance. 

Enolate formation at the less hindered a-position followed by intramolecular tosylate displacement affords Dl. 

---