Enolates cyclic

The Michael reaction is of central importance here. This reaction is a vinylogous aldol addition, and most facts, which have been discussed in section 1.10, also apply here the reaction is catalyzed by acids and by bases, and it may be made regioselective by the choice of appropriate enol derivatives. Stereoselectivity is also observed in reactions with cyclic educts. An important difference to the aldol addition is, that the Michael addition is usually less prone to sterical hindrance. This is evidenced by the two examples given below, in which cyclic 1,3-diketones add to o, -unsaturated carbonyl compounds (K. Hiroi, 1975 H, Smith, 1964). 

The addition of large enolate synthons to cyclohexenone derivatives via Michael addition leads to equatorial substitution. If the cyclohexenone conformation is fixed, e.g. as in decalones or steroids, the addition is highly stereoselective. This is also the case with the S-addition to conjugated dienones (Y. Abe, 1956). Large substituents at C-4 of cyclic a -synthons direct incoming carbanions to the /rans-position at C-3 (A.R. Battersby, 1960). The thermodynamically most stable products are formed in these cases, because the addition of 1,3-dioxo compounds to activated double bonds is essentially reversible. 

The oxidation of the cyclic enol ether 93 in MeOH affords the methyl ester 95 by hydrolysis of the ketene acetal 94 formed initially by regioselective attack of the methoxy group at the anomeric carbon, rather than the a-alkoxy ketone[35]. Similarly, the double bond of the furan part in khellin (96) is converted ino the ester 98 via the ketene acetal 97[l23],... 

The isoflavone 406 is prepared by the indirect a-phenylation of a ketone by reaction of phenylmercury(II) chloride with the enol acetate 405, prepared from 4-chromanone[371]. A simple synthesis of pterocarpin (409) has been achieved based on the oxypalladation of the oriho-mercurated phenol derivative 408 with the cyclic alkene 407[372,373]. 

The decarboxylation of allyl /3-keto carboxylates generates 7r-allylpalladium enolates. Aldol condensation and Michael addition are typical reactions for metal enolates. Actually Pd enolates undergo intramolecular aldol condensation and Michael addition. When an aldehyde group is present in the allyl fi-keto ester 738, intramolecular aldol condensation takes place yielding the cyclic aldol 739 as a main product[463]. At the same time, the diketone 740 is formed as a minor product by /3-eIimination. This is Pd-catalyzed aldol condensation under neutral conditions. The reaction proceeds even in the presence of water, showing that the Pd enolate is not decomposed with water. The spiro-aldol 742 is obtained from 741. Allyl acetates with other EWGs such as allyl malonate, cyanoacetate 743, and sulfonylacetate undergo similar aldol-type cycliza-tions[464]. 

Addition of a hydroxy group to alkynes to form enol ethers is possible with Pd(II). Enol ether formation and its hydrolysis mean the hydration of alkynes to ketones. The 5-hydroxyalkyne 249 was converted into the cyclic enol ether 250[124], Stereoselective enol ether formation was applied to the synthesis of prostacyclin[131]. Treatment of the 4-alkynol 251 with a stoichiometric amount of PdCl2, followed by hydrogenolysis with formic acid, gives the cyclic enol ether 253. Alkoxypalladation to give 252 is trans addition, because the Z E ratio of the alkene 253 was 33 1. 

The cyclic enol ether 255 from the functionalized 3-alkynoI 254 was converted into the furans 256 by the reaction of allyl chloride, and 257 by elimination of MeOH[132], The alkynes 258 and 260, which have two hydroxy groups at suitable positions, are converted into the cyclic acetals 259 and 261. Carcogran and frontalin have been prepared by this reaction[124]. 

Cyclic 1,2-diketones demonstrate enolic tautomerism, with solvent polarity affecting tautomeric equilibrium ... 

The formation of g-alkyl-a,g-unsaturated esters by reaction of lithium dialkylcuprates or Grignard reagents in the presence of copper(I) iodide, with g-phenylthio-, > g-acetoxy-g-chloro-, and g-phosphoryloxy-a,g-unsaturated esters has been reported. The principal advantage of the enol phosphate method is the ease and efficiency with which these compounds may be prepared from g-keto esters. A wide variety of cyclic and acyclic g-alkyl-a,g-unsaturated esters has been synthesized from the corresponding g-keto esters. However, the method is limited to primary dialkylcuprates. Acyclic g-keto esters afford (Zl-enol phosphates which undergo stereoselective substitution with lithium dialkylcuprates with predominant retention of stereochemistry (usually > 85-98i )). It is essential that the cuprate coupling reaction of the acyclic enol phosphates be carried out at lower temperatures (-47 to -9a°C) to achieve high stereoselectivity. When combined with they-... 

The fundamental mechanistic concept by which the stereochemical course of the aldol addition under conditions of kinetic control has been analyzed involves a cyclic transition state in which both the carbonyl and enolate oxygens are coordinated to a Lewis... 

There has been little study of the stereoselectivity of the reaction under acidic conditions. In the absence of a coordinating Lewis acid, there is no preference for a cyclic transition state. When regioisomeric enols are possible, acid-catalyzed reactions tend to proceed through the more substituted of the enols. This reflects the predominance of this enol. (See Section 7.2.)... 

Three possible mechanisms for the Serini reaction were originally suggested. These proceed via (a) a A -enol acetate, (b) a A -epoxide, or (c) a cyclic orthoester ... 

Parham and co-workers have studied the addition of dichloro- and dibro-mocarbene to cyclic enol ethers and the transformations of the resulting dihalocyclopropanes. ... 

The addition (150-157) of Grignard reagents, alkoxides, hydroxide, sulfides, cyanide, and enolate anions to pyridinium and isoquinolinium salts again provides a variety of cyclic enamines of potential synthetic use. 

Alkylation of enamines with epoxides or acetoxybromoalkanes provided intermediates for cyclic enol ethers (668) and branched chain sugars were obtained by enamine alkylation (669). Sodium enolates of vinylogous amides underwent carbon and nitrogen methylation (570), while vicinal endiamines formed bis-quaternary amonium salts (647). Reactions of enamines with a cyclopropenyl cation gave alkylated imonium products (57/), and 2-benzylidene-3-methylbenzothiazoline was shown to undergo enamine alkylation and acylation (572). A cyclic enamine was alkylated with methylbromoacetate and the product reduced with sodium borohydride to the key intermediate in a synthesis of the quebrachamine skeleton (57i). 

Thus the reactions of cyclic or acyclic enamines with acrylic esters or acrylonitrile can be directed to the exclusive formation of monoalkylated ketones (3,294-301). The corresponding enolate anion alkylations lead preferentially to di- or higher-alkylation products. However, by proper choice of reaction conditions, enamines can also be used for the preferential formation of higher alkylation products, if these are desired. Such reactions are valuable in the a substitution of aldehydes, which undergo self-condensation in base-catalyzed reactions (117,118). Monoalkylation products are favored in nonhydroxylic solvents such as benzene or dioxane, whereas dialkylation products can be obtained in hydroxylic solvents such as methanol. The difference in products can be ascribed to the differing fates of an initially formed zwitterionic intermediate. Collapse to a cyclobutane takes place in a nonprotonic solvent, whereas protonation on the newly introduced substitutent and deprotonation of the imonium salt, in alcohol, leads to a new enamine available for further substitution. 

Imines with an electron-withdrawing group at the nitrogen atom are excellent acceptors for the acetate (1) or the carbonate (13) [36]. Thus, N-tosylimines (84) gave very good yields of pyrrolidines (85) under typical conditions. The strained cyclic imine (86) and a,/ -unsaturated imine (87) both participated smoothly in the cydoadditions. The hindered nitrimine (88) also reacts well with (1) (but not with 13) to produce the pyrrolidine (89) with a 17 1 diastereoselectivity. However, the unhindered nitrimines from cyclohexanone and 2-nonanone failed to react presumably due to enolization (Scheme 2.24). 

The chiral BOX-copper(ll) complexes, (S)-21a and (l )-21b (X=OTf, SbFg), were found by Evans et al. to catalyze the enantioselective cycloaddition reactions of the a,/ -unsaturated acyl phosphonates 49 with ethyl vinyl ether 46a and the cyclic enol ethers 50 giving the cycloaddition products 51 and 52, respectively, in very high yields and ee as outlined in Scheme 4.33 [38b]. It is notable that the acyclic and cyclic enol ethers react highly stereoselectively and that the same enantiomer is formed using (S)-21a and (J )-21b as the catalyst. It is, furthermore, of practical importance that the cycloaddition reaction can proceed in the presence of only 0.2 mol% (J )-21a (X=SbF6) with minimal reduction in the yield of the cycloaddition product and no loss of enantioselectivity (93% ee). 

Alkyl aryl ethers and enol ethers are also accessible by the Mitsunobu method. Cyclic ethers can be obtained by an intramolecular variant, which is especially suitable for the synthesis of three- to seven-membered rings ... 

The reaction of a cyclic ketone—e.g. cyclohexanone 1—with methyl vinyl ketone 2 resulting in a ring closure to yield a bicyclic a ,/3-unsaturated ketone 4, is called the Robinson annulation This reaction has found wide application in the synthesis of terpenes, and especially of steroids. Mechanistically the Robinson annulation consists of two consecutive reactions, a Michael addition followed by an Aldol reaction. Initially, upon treatment with a base, the cyclic ketone 1 is deprotonated to give an enolate, which undergoes a conjugate addition to the methyl vinyl ketone, i.e. a Michael addition, to give a 1,5-diketone 3 ... 

Several methods for the carbethoxylation of cyclic ketones via their enolates have been described. The methods differ primarily in the nature of the acylating agent employed. Thus, diethyl oxalate, diethyl carbonate, and ethyl diethoxyphosphinyl... 

Cyclic and acyclic silyl enol ethers can be nitrated with tetranitromethane to give ct-nitro ketones in 64-96% yield fEqs. 2.42 and 2.43. " The mechanism involves the electron transfer from the silyl enol ether to tetranitromethane. A fast homolydc conphng of the resultant cadon radical of silyl enol ether with NO leads tn ct-nitro ketones. Tetranitromethane is a neutral reagent it is commercially available or readdy prepared. " ... 

High-pressnre promoted cycloadditions of nitroalkenes and enol ethers eliminate the nse of Lewis acids fEq 8 106 "Thus, even sterically hmdered nitroalkenes react with 2,3-thhydro-furan to give the exo cyclic nitronates stereoselecdvely without using Lewis acids... 

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