Aldehydes acyl anions

Terminal alkyne anions are popular reagents for the acyl anion synthons (RCHjCO"). If this nucleophile is added to aldehydes or ketones, the triple bond remains. This can be con verted to an alkynemercury(II) complex with mercuric salts and is hydrated with water or acids to form ketones (M.M.T. Khan, 1974). The more substituted carbon atom of the al-kynes is converted preferentially into a carbonyl group. Highly substituted a-hydroxyketones are available by this method (J.A. Katzenellenbogen, 1973). Acetylene itself can react with two molecules of an aldehyde or a ketone (V. jager, 1977). Hydration then leads to 1,4-dihydroxy-2-butanones. The 1,4-diols tend to condense to tetrahydrofuran derivatives in the presence of acids. 

An interesting application of the Paal thiophene synthesis was documented for the synthesis of a polystyrene-oligothiophene-polystyrene copolymer. In the Stetter reaction of aldehyde 13 and P-dimethylaminoketone 14, in situ generation of the a,p-unsaturated ketone preceded nucleophilic 1,4-conjugate addition by the acyl anion... 

The 2-substituted 1,3-benzodithioles 57 are readily lithiated and react as acyl anions with various electrophiles, including alkyl halides, aldehydes, ketones. 

The methylenebis(boronic acid) 122 may be deprotonated and alkylated at the central position and may thus behave as an acyl anion equivalent. Monoalkylation of 122 followed by hydrolysis gives aldehydes in good yield, and a second alkylation led to a ketone in one case (77JA3196). 

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). 

A number of lyases are known which, unlike the aldolases, require thiamine pyrophosphate as a cofactor in the transfer of acyl anion equivalents, but mechanistically act via enolate-type additions. The commercially available transketolase (EC 2.2.1.1) stems from the pentose phosphate pathway where it catalyzes the transfer of a hydroxyacetyl fragment from a ketose phosphate to an aldehyde phosphate. For synthetic purposes, the donor component can be replaced by hydroxypyruvate, which forms the reactive intermediate by an irreversible, spontaneous decarboxylation. 

Generation of Acyl Anion Equivalents (d Synthons) from Aldehydes... 

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). 

In 1976, Stetter extended the synthetic utility of the Breslow intermediate (1) as an acyl anion equivalent by showing that aldehydes could be coupled with Michael acceptors to generate 1,4-dicarbonyl compounds [55]. 

The thiazolium-catalyzed addition of an aldehyde-derived acyl anion with a Michael acceptor (Stetter reaction) is a well-known synthetic tool leading to the synthesis of highly funtionalized products. Recent developments in this area include the direct nucleophilic addition of acyl anions to nitroalkenes using silyl-protected thiazolium carbinols <06JA4932>. In the presence of a fluoride anion, carbinol 186 is not cleaved to an aldehyde... 

When the aldehydes 92 and 95 are treated with oxygen and t-butoxide the emission spectrum of the chemiluminescence matches the fluorescence of a mixture of the acridone and the 9-carboxylate the latter being formed via an acyl anion. 

Several anionic metal carbonyl hydrides stoichiometrically convert acyl chlorides to aldehydes. The anionic vanadium complex [Cp(CO)3VH] reacts quickly with acyl chlorides, converting them to aldehydes [44]. Although no further reduction of the aldehyde to alcohol was observed, the aldehydes reacted further under the reaction conditions in some cases, so a general procedure for isolation of the aldehydes was not developed. 

Transfer of the acyl group from the acylzirconocene chloride to aluminum (transmetala-tion) by treatment with aluminum chloride has been reported to give an acylaluminum species in situ, and the possibility of the acylaluminum acting as an acyl anion donor has been suggested (Scheme 5.5) [7]. However, the acyl anion chemistry through this trans-metalation procedure appears to be limited since only protonolysis to the aldehyde proceeds in good yield, which could be achieved by direct hydrolysis of the acylzirconocene chloride. 

Synthetic routes to a-ketol through the reactions of an unmasked acyl anion with carbonyl compounds are not numerous. The first practical application of an acylzirconocene chloride as an unmasked acyl anion donor was reported in the reaction with aldehydes in 1998 (Scheme 5.12 and Table 5.1) [19]. 

The benzoin reaction dates back to 1832 when Wohler and Liebig reported that cyanide catalyzes the formation of benzoin 6 from benzaldehyde 5, a seminal example in which the normal mode of polarity of a functional group was reversed (Eq. 1) [26], This reversal of polarity, subsequently termed Umpolung [27], effectively changes an electrophilic aldehyde into a nucleophilic acyl anion equivalent. 

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]. 

Miiller and co-workers have developed an enantioselective enzymatic crossbenzoin reaction (Table 2) [43, 44], This is the first example of an enantioselective cross-benzoin reaction and takes advantage of the donor-acceptor concept. This transformation is catalyzed by thiamin diphosphate (ThDP) 23 in the presence of benzaldehyde lyase (BAL) or benzoylformate decarboxylase (BFD). Under these enzymatic reaction conditions the donor aldehyde 24 is the one that forms the acyl anion equivalent and subsequently attacks the acceptor aldehyde 25 to provide a variety of a-hydroxyketones 26 in good yield and excellent enantiomeric excesses without contamination of the other cross-benzoin products 27. The authors chose 2-chlorobenzaldehyde 25 as the acceptor because of its inability to form a homodimer under enzymatic reaction conditions. 

The proposed mechanism is as follows initial cyanation of the acyl silane followed by a [1,2]-Brook rearrangement yields acyl anion equivalent XIV (Scheme 4). Subsequent attack by the acyl anion equivalent XV to the aldehyde leads to... 

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... 

In a related process, Johnson and co-workers have developed an asymmetric metallophosphite-catalyzed intermolecular Stetter-hke reaction employing acyl silanes [81, 82], Acyl silanes are effective aldehyde surrogates which are capable of forming an acyl anion equivalent after a [l,2]-Brook rearrangement. The authors have taken advantage of this concept to induce the catalytic enantioselective synthesis of 1,4-dicarbonyls 118 in 89-97% ee and good chemical yields for a,p-unsaturated amides (Table 11). Enantioselectivities may be enhanced by recrystallization. 

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]. 

Homoenolates generated catalytically with NHCs can also be employed for C-C and C-N bond formation. Bode and Glorias have independently accomplished the diastereoselective synthesis of y-butyrolactones by annulation of enals and aldehydes [121, 122]. Bode and co-workers envisioned that increasing the steric bulk of the acyl anion equivalent would allow reactivity at the homoenolate position. While trying to suppress the competing benzoin and enal dimerization the authors comment on the steric importance of the catalyst. Thiazolium pre-catalyst 173 proved unsuccessful at inducing annulation. A-mesityl substituted imidazolium salt 200 was found to provide up to 87% yield and moderate diastereoselectivities (Scheme 34). 

The proposed catalytic cycle is shown in Scheme 35 and begins with the imida-zolylidene carbene adding to the enal. Proton transfer provides acyl anion equivalent XLVII, which may be drawn as its homoenolate resonance form XLVIII. Addition of the homoenolate to aldehyde followed by tautomerization affords L the precursor for lactonization and regeneration of the carbene. 

In this transformation, manganese(IV) oxide oxidizes allylic or benzylic alcohols to aldehydes followed by nucleophilic attack of the in situ formed triazolinyli-dene carbene (Scheme 41). The authors suggest the formation of an acyl anion equivalent LX is slow in MeOH compared to oxidation to allow for an activated carboxylate LXII. 

In an attempt to use an acyl anion equivalent to open an aziridine, Wu and co-workers isolated an unexpected ring opened product 316 (Eq. 31) [158], The authors found that the presence of oxygen was the determining factor between benzoin formation and ester formation. No desired ketones were ever formed. Various aromatic substituted aldehydes were treated under standard reaction conditions to afford esters in good yields. 4-Methoxybenzaldehyde provided product in only 40% yield, presumably due to the ease of aldehyde oxidation. 

The authors proposed mechanism involves initial attack of an in sitn formed carbene onto the aldehyde to produce tetrahedral intermediate LXXIII (Scheme 47). Proton transfer wonld produce an acyl anion eqnivalent, bnt is inconsistent with product formation. Instead S 2 displacement to produce ring opened intermediate LXXIV is proposed, followed by proton transfer. At this point, molecular oxygen apparently becomes involved to oxidize nncleophilic alkene LXXV. The active catalyst is then regenerated and observed prodnct is formed. 

She and co-workers took advantage of the acyl anion equivalent formed from the addition of an NHC to an aldehyde to catalyze the formation of benzopyranones via an intramolecular S 2 displacement (Scheme 50) [167], Various aromatic aldehydes provide alkylation products in moderate yields when the leaving group is either tosylate or iodide. No reaction was observed when phenyl or methyl was placed alpha to the leaving group. 

In 2008, the same group employed chiral dicarboxylic acid (R)-5 (5 mol%, R = 4- Bu-2,6-Me2-CgHj) as the catalyst in the asymmetric addition of aldehyde N,N-dialkylhydrazones 81 to aromatic iV-Boc-imines 11 in the presence of 4 A molecular sieves to provide a-amino hydrazones 176, valuable precursors of a-amino ketones, in good yields with excellent enantioselectivities (35-89%, 84-99% ee) (Scheme 74) [93], Aldehyde hydrazones are known as a class of acyl anion equivalents due to their aza-enamine structure. Their application in the field of asymmetric catalysis has been limited to the use of formaldehyde hydrazones (Scheme 30). Remarkably, the dicarboxylic acid-catalyzed method applied not only to formaldehyde hydrazone 81a (R = H) but also allowed for the use of various aryl-aldehyde hydrazones 81b (R = Ar) under shghtly modified conditions. Prior to this... 

Converting furfuraldehyde into its 1,3-dithian-2-y] derivative by reacting it with propane-1,3-dithiol could also be the basis of a route to furoin. Once deprotonated. this forms an acyl anion equivalent that could be reacted with a second equivalent of the aldehyde and then protonated and deprotected to yield furoin ... 

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