Acyl anion equivalents, reactions with

Allylalion of the alkoxymalonitrile 231 followed by hydrolysis affords acyl cyanide, which is converted into the amide 232. Hence the reagent 231 can be used as an acyl anion equivalent[144]. Methoxy(phenylthio)acetonitrile is allylated with allylic carbonates or vinyloxiranes. After allylation. they are converted into esters or lactones. The intramolecular version using 233 has been applied to the synthesis of the macrolide 234[37]. The /i,7-unsaturated nitrile 235 is prepared by the reaction of allylic carbonate with trimethylsilyl cyanide[145]. 

The (V-methyldihydrodithiazine 125 has also been used as an effective formyl anion equivalent for reaction with alkyl halides, aldehydes, and ketones (77JOC393). In this case there is exclusive alkylation between the two sulfur atoms, and hydrolysis to give the aldehyde products is considerably easier than for dithianes. However, attempts to achieve a second alkylation at C2 were unsuccessful, thus ruling out the use of this system as an acyl anion equivalent for synthesis of ketones. Despite this limitation, the compound has found some use in synthesis (82TL4995). 

The simplest and most direct manner to generate acyl anion equivalents is through reaction of an NHC with an aldehyde, generating an enamine species 8, commonly referred to as a Breslow intermediate . Subsequent reaction with an electrophile, classically using aldehydes or enones, generates the benzoin and Stetter products 10 and 11 respectively (Scheme 12.1). 

Acylzirconocene chlorides 78, which are easily available through the hydrozirco-nation of alkenes or alkynes with Cp2Zr(H)Cl and subsequent CO insertion, can be used as acyl anion equivalents Cu(I)-catalyzed reactions with propargyl compounds 77 afford allenyl ketones 79 (Scheme 3.40) [86]. The use of an excess of 77 (2 equiv. to 78) is important for the selective preparation of 79, which prevents an undesirable side reaction of the allenic products 79 with 78. 

An example where the presence of a counterion makes a difference between the gas phase and solution phase pathways involves the intriguing carbanion produced on deprotonation of 1,3-dithiane at C-2. In solution, this species, almost invariably produced by reaction of the dithiane with butyllithium, is widely used as an acyl anion equivalent in synthetic chemistry. Its importance for the present work is that this is a configurationally stable lithiated species in solution the carbanion stays sp -hybridized, and the lithium prefers the equatorial position, even to the extent of driving a terr-butyl group on the same acidic C-2 carbanion to the axial position in the lithiocarbon species. The carbanion is thought to be stabilized primarily by orbital overlap with the C-S antibonding orbitals, as opposed to more conventional polar and 7t-resonance stabilization. ... 

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]. 

Suzuki and co-workers achieve aromatic substitution of fluoroarenes with a variety of aldehydes in good yields [91, 92], Imidazolilydene carbene formed from 143 catalyzes the reaction between 4-methoxybenzaldehyde 22a and 4-fluoroni-trobezene 141 to provide ketone 142 in 77% yield (Scheme 20). Replacement of the nitro group with cyano or benzoyl results in low yields of the corresponding ketones. The authors propose formation of the acyl anion equivalent and subsequent addition to the aromatic ring by a Stetter-like process forming XXVIII, followed by loss of fluoride anion to form XXIX. 

The first natural product synthesis that utilized the Stetter reaction was reported by Stetter and Kuhhnann in 1975 as an approach to aT-jasmone and dihydrojas-mone (Scheme 21) [93]. Thiazolium pre-catalyst 74 was effective in catalyti-cally generating the acyl anion equivalent with aldehydes 144 and 145, then adding to 3-buten-2-one 146 in good yield. Cyclization followed by dehydration gives cii-jasmone and dihydrojasmone in 62 and 69% yield, respectively, over two steps. Similarly, Galopin coupled 3-buten-2-one and isovaleraldehyde in the synthesis of ( )-rran5-sabinene hydrate [94]. 

Desilylation of acylsilanes. Two groups have reported that KF in combination with l8-crown-6, DMSO, or HMPT2 converts acylsilanes into acyl anion equivalents. The reaction can be used to obtain aldehydes, ketones, and hydroxy ketones in moderate to good yield. 

Dithioacetals (see also dithianes and dithiolanes) alkylation of 98 as acyl anion equivalents 75 carbanions of 87,97-102 cleavage of 14-18,98,102 desulfurization of 78 metal-catalysed coupling 127 reaction with Grignard reagents 127 reductive lithiation of 89 synthesis of 12-19,97-102 Dithioacids synthesis of 40... 

The synthetic utility of a-phosphorus- and a-thio-stabilized carbanions is the subject of numerous reviews.21 Notable are additions of phosphonium ylides (237),183 sulfonium ylides (238),l84 ° oxosulfo-nium ylides (239)184 " and sulfoximine ylides (240)184,1 to electron-deficient alkenes which afford nucleophilic cyclopropanation products. In contrast, with a-(phenylthio)-stabilized carbanions, which are not acyl anion equivalents, either nucleophilic cyclopropanation or retention of the hetero substituent occurs, depending on the acceptor and reaction conditions used. For example, carbanion (241) adds to 1,1-... 

Several aromatic and heterocyclic acyl trimethylsilanes have been used as acyl anion equivalents by treatment with fluoride ion (Scheme 81, path a)23 133 154b160191192. Provided that the acyl substituent is electron-withdrawing, and that there are no aryl substituents on the silicon atom, acyl anions can be trapped by various electrophiles in moderate to good yields indeed, acyl anions and pentacoordinate silicon anionic species have both been detected in gas-phase reactions of acyl silanes with fluoride ion193. 

Alkylation reactions in the 2-position are restricted to 1,3-dithiepins and related compounds. The anions behave as an acyl anion equivalent, and treatment with an electrophile affords 2-alkylated products. 

The acyl anion (R-C=0) is not stable as such, but when an aldehyde is converted into a 1,3-dithiane by reaction with propane-1,3-dithiol and then treated with base, it forms an acyl anion equivalent, and hence is susceptible to attack by electrophilic reagents (see Section 5.9). Two extensive compilations of formyl and acyl anion synthons together with references to their reactions... 

The reaction of aldehydes or ketones with ethane-1,2-dithiol or propane-1,3-dithiol to form 1,3-dithiolanes or 1,3-dithianes is an important reaction, as these compounds under suitable conditions are acyl anion equivalents (see Section 5.9, p. 626). These cyclic dithioacetals have been less used as protective groups, though when required are formed in high yield in the presence of boron trifluoride-etherate.138... 

In both reactions cyanide has usually been employed as catalyst [231, 232], Under these conditions, the acyl anion equivalent is represented by the tautomeric form XIX of the cyanohydrin anion which results from addition of cyanide to an aldehyde (Scheme 6.104). In nature, this type of Umpolung is performed enzymatically, with the aid of the cofactor thiamine pyrophosphate 226 (vitamin Bl, Scheme 6.105) [232, 233]. 

Nitro compounds can be alkylated and are good at conjugate addition (chapter 21) so the products of these reactions can be used to make aldehydes, ketones and amines. A simple synthesis of octanal5 shows that these methods can work very well indeed. Alkylation of nitromethane with bromoheptane gives the nitro-compound 11. Formation of the anion 12 and oxidation with KMnC>4 gives octanal in 89% yield. This chemistry gives us the disconnection to an alkyl halide and a carbonyl anion. The anion 12 is an acyl anion equivalent and we shall need these in the next chapter. 

Cyanide (one carbon) and acetylene (two carbons) are limited and other acyl anion equivalents are more versatile. Dithians are thioacetals of aldehydes that can be deprotonated between the two sulfur atoms by strong bases such as BuLi. Reaction with a second aldehyde gives 27 and hydrolysis of the thioacetal by acid, usually catalysed by Cu(II) or Hg(II), gives the a-hydroxyketone 4. The disconnection is that shown on diagram 4 and the lithium derivative 26 acts as the acyl anion 2. Unlike previous methods, R1 does not have to be H or Me. 

Three approaches leading to 8 were considered (Figure 3.6.9) Following the biosynthetic pathway directly, polymer-supported thiamine 9 was constructed (path A) and could lead via crossed acyloin couplings to the target structure. Polymer-supported hydrazones 10 were reported to add directly to aldehydes in a non-catalyzed Umpolung reaction (path B) with results reported in due course. Finally, phosphine ylides 11 were investigated as polymer-supported acyl anion equivalents (path C). 

Pathway C seemed to be especially attractive, because it should enable addition of acyl anion equivalents to a large number of readily accessible activated carboxylic acids (Figure 3.6.10). Thus diversity in all relevant positions should be readily attainable. High-loaded triphenyl phosphine resin 12 (1.6 mmol g-1) was alkylated with bromoacetonitrile under the action of microwave irradiation yielding phos-phonium salt 13 quantitatively. 13 was converted into stable ylide 14 by treatment with tertiary amine. Carboxylic acids were activated in the presence of N-(3-dimethylaminopropyl)-N -ethylcarbodiimide hydrochloride (EDC) and reacted with 14 yielding acyl cyanophosphoranes 15. The reaction was monitored by ATR-IR coupling yields could be determined by spectrophotometric Fmoc-determination and were 90% for Fmoc-phenylalanine as reference amino acid. 

The carbanion derived from diethyl l-(trimethylsiloxy)-l-phenylmethanephosphonate 291 served as an acyl anion equivalent. Its reaction with carbonyl compounds afforded the silylated benzoin derivatives 292 (equation 182)443. This reaction was useful for the synthesis of 2-phenylbenzo[h]furans without laborious isolation of the intermediate benzoin. 

Difluoro-l-(tosyloxy)vinyllithium 586 has been employed as an acyl anion equivalent of the type 587. This anion was prepared by treatment of 2,2,2-trifluoroethyl tosylate with two equiv of LDA at —78 °C860 (Scheme 159). The reaction of intermediate 586 with carbonyl compounds, followed by acid hydrolysis, gave compounds 588 which, after basic treatment with sodium hydroxide, afforded ct-keto acids 589. The reaction of the intermediate 586 with boranes provided the corresponding borates, which have been used in the synthesis of fluorinated molecules861. 

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