Ketones from Acid Equivalents

The reaction of Grignard reagents with formic acid has been reinvestigated. Yields of aldehydes are improved if THF is used as solvent [equation (4)], A study of orthoformates in Grignard reactions indicates that yields of aldehyde acetals are considerably higher when the 2-alkoxy-l,3-dioxolan (7) is used in place of triethyl orthoformate.  

Tetrahedron Lett., 1979,4303. 

4RCH=CH2 (RCH2CH2)4AlLi Reagents i, LiAlH4-TiCl4 ii, R COCl-CuCl 

The highly functional cuprate reagent (12) reacts with acid chlorides to give ketones which are capable of further modification by rearrangement.  

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Similarly, with two equivalents of DDQ, A -3-ketones give A -3-ketones in good yield ( 70%), without isolation of the intermediate A -3-ke-tone/ These trienones are also obtainable directly from A -3-alcohols with three equivalents of DDQ in refluxing dioxane (20 hr), and the overall yield ( 50%) compares favorably with less direct methods. The direct formation of A -3-ketones from A -3-ketones with acid catalysis is not successful. Enol derivatives have proven to be useful for the preparation... 

Acid-catalyzed reaction of an aldehyde or ketone with 2 equivalents of a monoalcohol or 1 equivalent of a diol yields an acetal, in which the carbonyl oxygen atom is replaced by two -OK groups from the alcohol. 

OxazoIones are alkylated at position 4 by alkyl halides, allyl halides and electrophilic alkynes, such as methyl propiolate (equation 36). In contrast, 2-phenyloxazolones react with methyl vinyl ketone at both C(4) and C(2) to yield a mixture of Michael adducts (equation 37). If the phenyl substituent is replaced by the bulky 2,4,6-trimethylphenyl group the addition is directed exclusively to C(4) (81CB2580). Alkylation of 5(4//)-oxazolones is a key step in the synthesis of ketones from a-amino acids (Scheme 16). The outcome of this sequence is the union of the electrophilic fragment R3 with the group R2CO the amino acid thus functions as the equivalent of an acyl anion (78AG(E)450). 

The acyliron(0) complex (102) has been isolated and subjected to the same nucleophilic displacement (or equivalently oxidative addition) with excellent correlation (Scheme 39). The same species is also readily available from acid chlorides (i.e. formation of 103), but the overall process has not been widely used in the synthesis of ketones (Scheme 40). The final step of the process, a reductive elimination of acyliron(II) complex (104) or (105), is quite rapid and it has not been possible to isolate and identify the presumed intermediates in this case (Scheme 41). Since the oxidative addition of the acyliron complex with the alkyl halide is extremely mild, the corresponding ketone formed in the reaction is not subject to attack by organometallic reagents and no tertiary tdcohol is formed. 

Carbon-carbon bond formation is a reaction of fundamental importance to the cellular metabolism of all living systems and includes alkylation reactions involving one and five carbon fragments as well as carboxylation reactions. In addition, a very common method of generating carbon-carbon bonds in biology includes the reactions of enolates and their equivalents (such as enamines) with aldehydes, ketones, keto acids, and esters. Reactions in which the enolate derives from an acyl thioester are Claisen condensations, whereas the remainder are classified as aldol reactions. 

B.vii. Acid Dianions. All of the named reactions discussed in Section 9.4 constitute relatively minor variations of the fundamental condensation reaction of aldehydes, ketones, or acid derivatives with another aldehyde, ketone, or acid derivative. The ability to produce kinetic enolates from acid derivatives has made possible another useful modification of the enolate reaction. Carboxylic acids have an acidic proton that is removed by 1 equivalent of base to first give a carboxylate (see 226). Addition of a second equivalent of a powerful base such as a dialkylamide leads to the dianion (227). Subsequent reaction with an electrophilic species, in this case 1-bromobutane, occurred first at the more nucleophilic a-carbon to give hexanoic acid. 2 The carboxylate is usually generated with n-butyllithium and the enolate with LDA, although 2 equivalents of LDA can be used. As discussed in Chapter 8, treatment of a carboxylic acid with an excess of an organo-... 

In Chapter 20 we established that enolates can be formed from acid chlorides, but that they decompose to ketenes. Enolates can be formed from amides with difficulty, but with primary or secondary amides one of the NH protons is likely to be removed instead. For the remainder of this section we shall look at how to make specific enol equivalents of acids, esters, aldehydes, and ketones. 

The fourth item in the table, phenol (hydroxybenzene), is alkylated on oxygen, forming an ether, methoxybenzene (anisol), with the powerful alkylating agent trimethyloxonium tetrafluoroborate [(CH30)3 BFt]. Other alkoxonium tetrafluo-roborates are also commercially available and can be used to the same end with phenols, enols, and alcohols, forming aryl ethers, enol ethers, and dialkyl ethers, respectively. In contrast to dialkyl, diaryl, and aralkyl ethers, which are quite inert and are often used as solvents, enol ethers are capable of acid-catalyzed hydrolysis to produce ketones (or their equivalent enol) and the alcohol from which the enol ether is formed (Scheme 8.47). 

As described above, two new Cu-catalyzed desulfitative transformations have been discovered that can be used for the construction of peptidyl ketones from peptidic thiol esters and boronic acids. Under aerobic reaction conditions, S -acylthiosalicylamides are effective and efficient, although 2 equiv of the boronic acid are mechanistically required (Scheme 23.6). In comparison, 5 -acyl-2-mercaptoaryloximes function as MT mimics and can produce peptidyl ketones under anaerobic reaction conditions from only a single equivalent of boronic acid. The latter reaction is also efficient and general, but in its current design, it is only catalytically effective at elevated temperatures (>90 C). 

Methods for the regeneration of ketones from dithioacetals continue to be developed, including the use of ceric ammonium nitrate (four equivalents are necessary), ° sulphuryl chloride fluoride, trimethyloxonium tetrafluorobor-ate, ° mercuric oxide and tetrafluoroboric acid, and pyridinium hydrobromide perbromide under phase-transfer conditions. ... 

Ethyl stearate added with stirring at 0° under Ng to 2 equivalents of a ca. 1 M soln. of methylsulfingl carbanion (prepn. s. Synth. Meth. 17, 895) in dimethyl sulfoxide-tetrahydrofuran, allowed to warm to room temp, over 30 min., then water added j6-ketosulfoxide (Y > 98%) stirred and refluxed 60-90 min. with Al-amalgam in tetrahydrofuran containing 10% water n-heptadecyl methyl ketone (Y > 98%). F. e. also ketones from -ketosulfones and )6-ketosulfonic acid amides by the same reduction method, s. E. J. Gorey and M. Chaykovsky, Am. Soc. 86, 1639 (1964). 

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