Ketones, from

Cyclic ketones are readily available and can be functionalized to produce amino and carboxyl groups. The ring can be opened, after functionalization or prior to it, to generate an acyclic amino acid. This section will discuss synthetic strategies based on cyclic ketone precursors. 

Cyclic ketones can be readily converted to lactams, which can then be hydrolyzed to the corresponding amino acid. Although this could formally be included in the lactam section (2.3), it is presented here to illustrate that cyclic ketones are excellent 

Cyclic ketones can be converted directly to a lactam by using a mixture of sodium azide and an acid, which generates hydrazoic acid (HN3) in situ. This 

Another important method for the preparation of amino acids involves direct cleavage of a cyclic ketone. In section 2.1.A, a lactam product (a cyclic amide) was produced from the ketone and then cleaved by hydrolysis, but in this section the ketone moiety is cleaved directly. A cyclic ketone such as cyclopentanone can be oxidatively cleaved with sulfuric acid. When this cleavage was followed by treatment with nitrosyl sulfate, an oximino acid 2.11) was formed. Catalytic hydrogenation of the oximino group gave 4-aminobutanoic acid (2.72). Similar treatment of cycloheptanone gave 6-aminohexanoic acid (2.75) and cyclononanone led to 8-aminooctanoic acid.  

Nitro-ketones, particularly cyclic derivatives, are important sources of amino acids since the nitro group can be reduced to an amino group (see chapter one, section l.l.B). In one example, cyclohexene was treated with nitrogen dioxide (N2O4) and the product was oxidized with chromium trioxide to give 2-nilrocyclo-hcxanone 2.13). When 2.13 was treated with aqueous bicarbonate, cleavage of the 

---

The problem of the synthesis of highly substituted olefins from ketones according to this principle was solved by D.H.R. Barton. The ketones are first connected to azines by hydrazine and secondly treated with hydrogen sulfide to yield 1,3,4-thiadiazolidines. In this heterocycle the substituents of the prospective olefin are too far from each other to produce problems. Mild oxidation of the hydrazine nitrogens produces d -l,3,4-thiadiazolines. The decisive step of carbon-carbon bond formation is achieved in a thermal reaction a nitrogen molecule is cleaved off and the biradical formed recombines immediately since its two reactive centers are hold together by the sulfur atom. The thiirane (episulfide) can be finally desulfurized by phosphines or phosphites, and the desired olefin is formed. With very large substituents the 1,3,4-thiadiazolidines do not form with hydrazine. In such cases, however, direct thiadiazoline formation from thiones and diazo compounds is often possible, or a thermal reaction between alkylideneazinophosphoranes and thiones may be successful (D.H.R. Barton, 1972, 1974, 1975). 

The selective intermolecular addition of two different ketones or aldehydes can sometimes be achieved without protection of the enol, because different carbonyl compounds behave differently. For example, attempts to condense acetaldehyde with benzophenone fail. Only self-condensation of acetaldehyde is observed, because the carbonyl group of benzophenone is not sufficiently electrophilic. With acetone instead of benzophenone only fi-hydroxyketones are formed in good yield, if the aldehyde is slowly added to the basic ketone solution. Aldols are not produced. This result can be generalized in the following way aldehydes have more reactive carbonyl groups than ketones, but enolates from ketones have a more nucleophilic carbon atom than enolates from aldehydes (G. Wittig, 1968). 

The synthesis of spiro compounds from ketones and methoxyethynyl propenyl ketone exemplifies some regioselectivities of the Michael addition. The electrophilic triple bond is attacked first, next comes the 1-propenyl group. The conjugated keto group is usually least reactive. The ethynyl starting material has been obtained from the addition of the methoxyethynyl anion to the carbonyl group of crotonaldehyde (G. Stork, 1962 B, 1964A). 

Another possibility for asymmetric reduction is the use of chiral complex hydrides derived from LiAlH. and chiral alcohols, e.g. N-methylephedrine (I. Jacquet, 1974), or 1,4-bis(dimethylamino)butanediol (D. Seebach, 1974). But stereoselectivities are mostly below 50%. At the present time attempts to form chiral alcohols from ketones are less successful than the asymmetric reduction of C = C double bonds via hydroboration or hydrogenation with Wilkinson type catalysts (G. Zweifel, 1963 H.B. Kagan, 1978 see p. 102f.). 

Enone Formation from Ketones, and Oxidation of Alcohols... 

Carbonylation of enol triflates derived from ketones and aldehydes affords Q,/)-unsaturated esters[332]. Steroidal esters are produced via their aryl and enol triflates[328]. The enol triflate in 477 is more reactive than the aryl tritlate and the carbonylation proceeds stepwise. First, carbonylation of the enol triflate affords the amide 478 and then the ester 479 is obtained in DMSO using dppp[333]. 

Enamines derived from ketones are allylated[79]. The intramolecular asymmetric allylation (chirality transfer) of cyclohexanone via its 5-proline ally ester enamine 120 proceeds to give o-allylcyclohexanone (121) with 98% ee[80,8l]. Low ee was observed in intermolecular allylation. Similarly, the asymmetric allylation of imines and hydrazones of aldehydes and ketones has been carried out[82]. 

Ailyl enol carbonates derived from ketones and aldehydes undergo Pd-cat-alyzed decarboxylation-elimination, and are used for the preparation of a, /3-unsaturated ketones and aldehydes. The reaction is regiospecific. The regio-isomenc enol carbonates 724 and 726, prepared from 723, are converted into two isomeric enones, 725 and 727. selectively. The saturated aldehyde 728 can be converted into the a,/3-unsaturated aldehyde 730 via the enol carbonate 729[459]. 

Aminolhtazoles were synthetized from thiourea by three methods Method A, from a-haloketones or aldehydes designated as (Cl) or (Br) Method B, from ketones and iodine (fj) or bromine (Btj) Method C, from iodomercuriketones. Method D consists in condensing ketones with cyanamid and sulfur. 

Ketal IS an acceptable sub category term for acetals formed from ketones It was dropped from lUPAC nomen clature but continues to be so widely used that it has been reinstated... 

The position of equilibrium is favorable for acetal formation from most aldehydes especially when excess alcohol is present as the reaction solvent For most ketones the position of equilibrium is unfavorable and other methods must be used for the prepara tion of acetals from ketones... 

Carbohydrates are polyhydroxy aldehydes and ketones Those derived from aldehydes are classified as aldoses, those derived from ketones are ketoses... 

A general one-step method for preparation of primary and secondary nitroparaffins from amines by oxidation with y -chloroperbenzoic acid in 1,2-dichloroethane has been reported (68). This method is particularly useful for laboratory quantities of a wide variety of nitroparaffins because a large number of amines are readily available from ketones by oxime reduction and because the reaction is highly specific for nitroparaffins. 

The a-oxygen-substituted hydroperoxides and dialkyl peroxides comprise a great variety as shown in Figure 1. When discussing peroxides derived from ketones and hydrogen peroxide, (1) is often referred to as a ketone peroxide monomer and (2) as a ketone peroxide dimer. 

Table 5. Melting Points of Some Peroxy Compounds from Ketones and Hydrogen Peroxide ...

Hydroxyall l Hydroperoxides. These compounds, represented by (1, X = OH, R = H), may be isolated as discreet compounds only with certain stmctural restrictions, eg, that one or both of R and R are hydrogen, ie, they are derived from aldehydes, or that R or R contain electron-withdrawing substituents, ie, they are derived from ketones bearing a-halogen substituents. Other hydroxyalkyl hydroperoxides may exist in equihbrium mixtures of ketone and hydrogen peroxide. 

Thermal and photochemical decomposition of peroxides (4) and (5) lacking a-hydrogens (those derived from ketones) produces macrocycHc hydrocarbons andlactones (119,152,153). For example, 7,8,15,16,23,24-hexaoxatrispiro [5.2.5.2.5.2] tetracosane (see Table 5) yields cyclopentadecane and oxacycloheptadecan-2-one. 

The unique chemical behavior of KO2 is a result of its dual character as a radical anion and a strong oxidizing agent (68). The reactivity and solubiHty of KO2 is gready enhanced by a crown ether (69). Its usefiilness in furnishing oxygen anions is demonstrated by its appHcations in SN2-type reactions to displace methanesulfonate and bromine groups (70,71), the oxidation of benzyHc methylene compounds to ketones (72), and the syntheses of a-hydroxyketones from ketones (73). 

Analogously, poly(vinyl ketals) can be prepared from ketones, but since poly(vinyl ketals) are not commercially important, they are not discussed here. The acetalization reaction strongly favors formation of the 1,3-dioxane ring, which is a characteristic feature of this class of resins. The first of this family, poly(vinyl ben2al), was prepared in 1924 by the reaction of poly(vinyl alcohol) with ben2aldehyde in concentrated hydrochloric acid (2). Although many members of this class of resins have been made since then, only poly(vinyl formal) [9003-33-2] (PVF) and poly(vinyl butyral) [63148-65-2] (PVB) continue to be made in significant commercial quantities. 

Reactions with carbon nucleophiles, e.g. from ketones (73CR(C)(277)703, 74CR(C)(278)427), are sometimes accompanied by deacylation in situ to give alkyl derivatives, e.g. (106)... 

By similar procedures diazirines were prepared not only from simple aliphatic ketones but also from hydroxyketones and )3-aminoketones (B-67MI50800), and so were a large number of diazirines from steroidal ketones (65JA2665). Permanganate, bromine, chlorine and hypochlorite were used as oxidants. A one-step preparation of diazirines from ketones like 3-nonanone, ammonia and chlorine has been claimed in a patent (66USP3290289). 3,3-Diazirinedicarboxylic acid derivatives like (286) were obtained directly from oxime tosylates by the action of two moles of O-ethoxyamine (81AG(E)200). 

Synthesis of terminal olefine from ketones or esters via a Ti methylene transfer reagent. 

Most important for the synthetic chemist is an index to the synthesis of functional groups, e.g. synthesis of alkenes from ketones, as well as conversion of ketones to alkenes. 

Although lUPAC no longer uses the term ketal, we have retained it to indicate compounds formed from ketones. 

C=N, C=S, C=C, and N N containing substrates. Thus oxa2oles, imidazoles, thiazoles, p rrroles, and 1,2,4-triazoles have been prepared, respectively. Furthermore, p-tolylsulfonylmethyl isocyanide has found use in a one-step conversion of ketones into cyan-idea and in a two-step synthesis of a-hydroxyaldehydes from ketones. ... 

Two classes of charged radicals derived from ketones have been well studied. Ketyls are radical anions formed by one-electron reduction of carbonyl compounds. The formation of the benzophenone radical anion by reduction with sodium metal is an example. This radical anion is deep blue in color and is veiy reactive toward both oxygen and protons. Many detailed studies on the structure and spectral properties of this and related radical anions have been carried out. A common chemical reaction of the ketyl radicals is coupling to form a diamagnetic dianion. This occurs reversibly for simple aromatic ketyls. The dimerization is promoted by protonation of one or both of the ketyls because the electrostatic repulsion is then removed. The coupling process leads to reductive dimerization of carbonyl compounds, a reaction that will be discussed in detail in Section 5.5.3 of Part B. 

The radicals that are formed from the enolate in this process are rapidly destroyed so that only the stable semidione species remains detectable for EPR study. Semidiones can also be generated oxidatively from ketones by reaction with oxygen in the presence of base. The diketone is presumably generated oxidatively and then reduced to the semidione via reduction by the enolate derived from the original ketone. 

A considerable number of examples will be found in the text in which halo-genated and other substituted olefins are produced. Their modes of fonnation do not usually differ in principle from the corresponding unsubstituted case. However, some special methods have been used, for example, the direct preparation of halo olefins from ketones with phosphorous hahdes, or via hydrazones. 

---