Cyanide anion ketones

The most general methods for the syntheses of 1,2-difunctional molecules are based on the oxidation of carbon-carbon multiple bonds (p. 117) and the opening of oxiranes by hetero atoms (p. 123fl.). There exist, however, also a few useful reactions in which an a - and a d -synthon or two r -synthons are combined. The classical polar reaction is the addition of cyanide anion to carbonyl groups, which leads to a-hydroxynitriles (cyanohydrins). It is used, for example, in Strecker s synthesis of amino acids and in the homologization of monosaccharides. The ff-hydroxy group of a nitrile can be easily substituted by various nucleophiles, the nitrile can be solvolyzed or reduced. Therefore a large variety of terminal difunctional molecules with one additional carbon atom can be made. Equally versatile are a-methylsulfinyl ketones (H.G. Hauthal, 1971 T. Durst, 1979 O. DeLucchi, 1991), which are available from acid chlorides or esters and the dimsyl anion. Carbanions of these compounds can also be used for the synthesis of 1,4-dicarbonyl compounds (p. 65f.). 

Dinitro ketone 49 with potassium cyanide provided 5,6-dihydrooxazolo [3,2-/7][l,2,4]triazole 51. Its formation is due to the fact that primary attack by the cyanide anion is not directed at the ring C5 atom but rather at the carbonyl group to give the corresponding cyanohydrin 50 and the subsequent intramolecular displacement of the nitro group gives the final product (Scheme 8) (81 KGS 1403). 

Aromatic aldehydes 1 can undergo a condensation reaction to form a-hydroxy ketones 2 (also called benzoins) upon treatment with cyanide anions.This reaction, which is called benzoin condensation, works by that particular procedure with certain aromatic aldehydes and with glyoxals (RCOCHO). 

Breslow and co-workers elucidated the currently accepted mechanism of the benzoin reaction in 1958 using thiamin 8. The mechanism is closely related to Lapworth s mechanism for cyanide anion catalyzed benzoin reaction (Scheme 2) [28, 29], The carbene, formed in situ by deprotonation of the corresponding thiazolium salt, undergoes nucleophilic addition to the aldehyde. A subsequent proton transfer generates a nucleophilic acyl anion equivalent known as the Breslow intermediate IX. Subsequent attack of the acyl anion equivalent into another molecule of aldehyde generates a new carbon - carbon bond XI. A proton transfer forms tetrahedral intermediate XII, allowing for collapse to produce the a-hydroxy ketone accompanied by liberation of the active catalyst. As with the cyanide catalyzed benzoin reaction, the thiazolylidene catalyzed benzoin reaction is reversible [30]. 

As illustrated using arrow pushing, the cyanide anion adds to the unsaturated ketone via a 1,4-addition. 

The second example is the familiar one of cyanohydrin formation from a ketone. The reaction is indeed reversible but in basic solution the cyanide anion is more stable than the oxyanion in the product and the carbonyl group is very stable too. In acidic solution (at pHs less than about 12) the oxyanion will be protonated and the reaction driven over to the right. 

An especially elegant use of superoxide anion, in combination with dioxygen, is as both an EGB and as an epoxidation reagent [52]. In this way the ROJ species, formed from the carbanion R , reacts in situ with an enone, which is converted into the epoxide (Scheme 15). Specifically, the carrier (PhCHoCN), which has been dubbed an auxiliary carbon acid, is deprotonated by the superoxide anion, and the resulting anion reacts with O2. The Ph2C(CN)OJ species thus formed reacts in situ with an enone, which is converted into the epoxide with elimination of cyanide anion from the carrier and concomitant formation of ketone (Scheme 15). Another possible auxiliary carbon acid is MeCH(C02Et)2 and, apart from the example in Scheme 15, 4,4-dimethyl-2-cyclohexen-l-one, 4-methylpent-3-en-2-one, and trans-cha -cone (PhCH=CHCOPh) may be converted [52] into the corresponding epoxides in >80% yield. 

Reaction with HCN to Form Cyanohydrins (Section 16.5D) For aldehydes and most steiicaUy unhindered aliphatic ketones, equilibrium favors formation of the cyanohydrin. For aryl ketones, equilibrium favors starting materials and little cyanohydrin is obtained. The mechanism involves addition of the cyanide anion to the carbonyl carbon followed by protonation of the resulting alkoxide. 

Scheme 9.38. A comparison of the initial results of addition of cyanide anion (CN-) to the P-carbon of an a,P-unsaturated ketone (but-3-en-2-one) and to the carbon of the carbonyl (C=0) of the same ketone.

Some examples of conjugate addition have already been encountered. For example, the Michael addition of cyanide anion (CN ) to 3-buten-2-one (methyl vinyl ketone, CH2CHCOCH3) was illustrated in Equation 9.37. Another Michael addition example was given in Equation 9.38. Additionally, in Equation 9.44, the... 

Ketone is easily available so we start the search for the synthetic equivalent of the illogical anion, and as a matter of fact this is found in the cyanide anion ... 

The Stetter procedure [22, 23] is an excellent route to 1,4-diketones. Here, cyanide anion, or more often a thiazolium ylide, catalyses the addition of an aldehyde to an a,p-unsaturated ketone or a precursor thereof, e.g. a Mannich base. For example, the reaction of pyridine-4-carbaldehyde with Mannich base 11, catalysed by the ylide from 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide 12, produces the 1,4-diketone 13, from which the central thiophene ring of 14 can be constructed (Scheme 12) [24]. Comparable thiazolium yUde catalysis... 

Other approaches to tetrazoles were also recently published. Primary and secondary amines 195 were reacted with isothiocyanates to afford thioureas 196, which underwent mercury(II)-promoted attack of azide anion, to provide 5-aminotetrazoles 197 . A modified Ugi reaction of substituted methylisocyanoacetates 198, ketones, primary amines, and trimethylsilyldiazomethane afforded the one-pot solution phase preparation of fused tetrazole-ketopiperazines 200 via intermediate 199 <00TL8729>. Microwave-assisted preparation of aryl cyanides, prepared from aryl bromides 201, with sodium azide afforded aryl tetrazoles 202 . 

The anions of primary nitramines, like other nucleophiles, can undergo Michael 1,4-addition reactions with a range of a,-unsaturated substrates to form secondary nitramines of varying molecular complexity (Equation 5.18). Kissinger and Schwartz prepared a number of secondary nitramines from the condensation of primary nitramines with a,/3-unsaturated ketones, esters, amides and cyanides. In a standard experiment a solution of the primary nitramine and... 

Stetter expanded Umpolung reactivity to include the addition of acyl anion equivalents to a,P-unsaturated acceptors to afford 1,4-dicarbonyls Eq. 5a [57-60]. Utilizing cyanide or thiazolylidene carbenes as catalysts, Stetter showed that a variety of aromatic and aliphatic aldehydes act as competent nucleophilic coupling partners with a wide range of a,p-unsaturated ketones, esters, and nitriles [61]. The ability to bring two different electrophilic partners... 

Trunethylpentafluorophenylstlane reacts with ketones in the presence of cyanide ion to form the silyl ether derived from the alkoxide created by the addition of the pentafluorophenyl anion to the carbonyl carbon [89] The nucleofugal character of the pentafluorophenyl group is significantly greater than that of the added cyanide ion so that the addition proceeds under nearly neutral conditions (equation 73)... 

Alternatively, the expedient cyanide (or fluoride) ion desilylation of acylsilanes (235), in the presence of a,3-enones or a, 3-unsaturated esters, affords -y-dicarbonyl adducts 182 even bis(trimethylsilyl)ketone (236), a formyl anion equivalent, adds to 2-cyclohexen-l-one to afford 3-formylcyclohexanone in moderate yields.182 ... 

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