Ketones, unsaturated preparative procedure

The procedure described illustrates a general method for the preparation of o ,j3-unsaturated aldehydes and ketones from the enol ethers of 3-dicarbonyl compounds. 

Deuteriums in the enolizable positions of a,/3-unsaturated keto substrates are unaffected during the course of the reduction. This extends the applicability of this procedure to the preparation of y-labeled ketones by subjecting the substrates to hydrogen-deuterium exchange (section ll-C) prior to reduction. This technique has been utilized for the preparation of the y-labeled ketones (156), (157) and (158). " The deuteriums in the a-positions of these ketones are back exchanged (section 11-B) after the reduction. 

Several improved methods for the preparation of known unsaturated azlactones as well as some interesting new compounds of this type have been reported. Crawford and Little observed that the direct use of 2-phenyl-5-oxazolone (1) in the Erlenmeyer reaction gave much improved yields (35-74%) of unsaturated azlactones with aliphatic aldehydes and with ketones such as acetone and cyclohexanone [Eq, (1)], The usual procedure of mixing a carbonyl compound, hippuric acid, acetic anhydride, and sodium (or lead) acetate affords poor yields in the aliphatic series. 

The (Horner-)Wadsworth-Emmons reaction generally is superior to the Wittig reaction, and has found application in many cases for the synthesis of a ,/3-unsaturated esters, a ,/3-unsaturated ketones and other conjugated systems. Yields are often better then with the original Wittig procedure. However the Wadsworth-Emmons method is not suitable for the preparation of alkenes with simple, non-stabilizing alkyl substituents. 

The procedure described here illustrates the preparation of mixed lithium arylhetero(alkyl)cuprate reagents and their reactions with carboxylic acid chlorides,4 These mixed cuprate reagents also react with a,a -dibromoketones,12 primary alkyl halides,4 and a,/3-unsaturated ketones,4 with selective transfer of only the alkyl group. 

The exocyclic a,P-unsaturated ketones la-h used for the preparation of dibromides 2a-h were E isomers synthesized by known procedures (refs. 7,8). Previously we reported the synthesis of some dibromides (2a,d,g) used here as starting materials, by the bromine addition of the appropriate a,P-unsaturated ketones (la,d,g) (ref. 6). In the case of our present study, compounds lb,c,e,f,h were allowed to react with a small excess of bromine in carbon tetrachloride solution at room temperature for approx. 20 min. to afford the dibromides 2b,c,e,f,h (Eqn. 1) (Table 1). 

This procedure illustrates a new three-step reaction sequence for the one-carbon ring expansion of cyclic ketones to the homologous tt,/3-unsaturated ketones. The key step in the sequence is the iron(III) chloride-induced cleavage of the central bond of trimethyl-silyloxycyclopropanes which me obtained by cyclopropanation of trimethylsilyl enol ethers. The procedure for the preparation of 1-trimethylsilyloxycyclohexene from cyclohexanone described in Part A is that of House, Czuba, Gall, and Olmstead. ... 

The synthetic utility of the carbonylation of zirconacycles was further enhanced by the development of a pair of selective procedures producing either ketones or alcohols [30] and has been extensively applied to the synthesis of cyclic ketones and alcohols, most extensively by Negishi [22—27,29—33,65,87,131—134], as detailed below in Section I.4.3.3.4. The preparation of unsaturated aldehydes by carbonylation with CO is not very satisfactory. The use of isonitriles in place of CO, however, has provided a useful alternative [135], and this has been applied to the synthesis of curacin A [125]. Another interesting variation is the cyanation of alkenes [136]. Further developments and a critical comparison with carbonylation using CO will be necessary before the isonitrile reaction can become widely useful. The relevant results are shown in Scheme 1.35. 

This preparation illustrates a general and convenient way of oxidizing secondary alcohols to ketones. The novel feature of the reaction is represented by acetone solvent which affects markedly the properties of the oxidizing agent. The reaction is very rapid (if not instantaneous), and the yields are high, the reagent rarely attacking unsaturated centers. The procedure is applicable to acetylenic carbinols, allyl and other unsaturated alcohols, and saturated carbinols. The main limitation is the low solvent power of acetone. 

The key step in their-approach was asymmetric photoisomerization of the a, 3-unsaturated (Z)-ketone precursor 103b in diethyl ( + )-Lg-tartrate. The bromide 103a obtained by N-bromo-succinimide bromination of the (Z)[8.8] precursor 64b, was converted into the a,P-unsaturated (Z)-ketone 103b by the routine synthetic procedures. Irradiation in a hexane solution with a medium pressure Hg lamp effected the photoisomerization of the (Z)-precursor 103b to afford a 1 5.5 mixture of (Z)-( )[8.8] ketones. After these preliminary experiments, a neat solution of 103 b in diethyl ( + )-Lg-tartrate was irradiated for 3 h. Preparative GLC of the resulting 1 7 mixture of (Z) and ( )[8.8] ketones produced a 38 % yield of ( )[8.8] ketone 104 enriched in the (—)-enantiomer, [a]n4 —13° (hexane). 

Several 1,5-dioxocanes, including the parent compound, have been prepared via the unsaturated intermediate (345), which unfortunately is only formed in very low yield from (344) <70LA(736)75). As well as (345), there is also formed the 16-membered cyclic dimer of this compound in 14% yield. Catalytic hydrogenation of (345) gives 3-methyl-1,5-dioxocane (346), whilst ozonolysis provides the ketone (347), v = 1725 cm-1, which is converted to 1,5-dioxocane (348) by a three-step reduction procedure via the alcohol and the tosylate. 

The preparation of pyrimidines and hydropyrimidines from thioureas is well established.139,217,218 Since the latest review (1962) covering this reaction,218 several reports of the preparation of heterocyclic compounds by previously reported procedures have appeared in the literature. These involve reactions of thioureas with a,/3-unsaturated ketones,219-224 jS-ketoesters,225-228 aliphatic ketones,229-231 j8-dicar-bonyl compounds,232 and ethyl ethoxymethylenecyanoacetate.233 Selenoureas have also been reported to react with /3-ketoesters to give the analogous 2-selenopyrimidines.234,235 Two reports have appeared of the cyclization of l-/3-carboxyethyl-2-thioureas to hexahydro-pyrimidines in low yields in the presence of acetic anhydride 238,237 however, tetrahydrothiazines are the predominant products in these reactions. 

The preparation of the first unsaturated azlactone was reported in 1883 by Plochl/40 who condensed benzaldehyde with hippuric acid in presence of acetic anhydride. This approach was later used by Erlenmeyer/41 who extended the procedure to include other aldehydes and also established the usefulness of azlactones as intermediates in the synthesis of DHAs. The method involves the condensation of an A-acylglydne 4 with aldehydes and ketones in the presence of acetic anhydride and anhydrous sodium acetate (Scheme 2)J41 t5l Other catalysts such as copper(II) acetate/46 lead acetate/47,48 potassium carbonate/49 or potassium hydrogen carbonate 50 have also been used. The reaction proceeds via formation of an azlactone 5, which then condenses with the appropriate aldehyde or ketone to give unsaturated azlactone 6. Reaction of 6 with a nucleophile such as OH, OR, or NHR leads to the corresponding A-acyl-DHA derivatives 7. Reaction with the sodium salt of an amino acid gives a DHA containing dipeptide acid. 51 ... 

Corey states that their experience shows the above procedure for conversion of (26) - (29) is the method of choice for ring expansion of a,/ -unsaturated ketones such as (26) and that this procedure may be generally useful. However, it is recommended that the operationally simpler one-step Johnson homologation procedure9 be tried first to prepare cycloheptenones. 

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