Aldehydes, reaction with dithiane anions

The dithiane anion 1.9 also reacts with acyl halides, ketones and aldehydes to give the corresponding dioxygenated compounds. Schemes 1.4 and 1.5 show the reaction of dithiane anions 1.11 and 1.12 with ketones. The most common example of umpolung reactivity of a carbonyl group is the benzoin condensation (Scheme 1.6). 

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). 

Halo-1,3-dithiane trans-l,3-dioxides (80 X = Cl, Br) act as diastereoselective carbonyl anion equivalents in reactions with aldehydes.117 The scope of the reaction has been explored by varying the temperature, the aldehyde, and the metal used as counterion. Similarly, metal 1,3-dithianides (81 M = Li, Cu1) can be added diastereoselec-tively to chiral aldehydes subsequent hydrolysis yields an a-hydroxyaldehydc.118... 

The scope and limitations of the metal anions of 2-halo-l,3-dithiane trans-1,3-dioxide as diastereoselective carbonyl anion equivalents has been explored with regard to reaction with aldehydes.79 Reactions of metallated trans-, 3-dithiolanc 1,3-dioxide (five-membered ring) with aldehydes under kinetic and thermodynamic control have also been studied and contrasted with those of the metallated monooxide, parent sulfide, and 1,3-dithiane 1,3-dioxide (six-membered ring).80... 

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... 

Dicyanopyridazine may react with pyrrole and indole systems as a heterocyclic azadiene in IEDDA Diels-Alder reactions. However, in acetic acid as solvent reaction occurs by substitution of CN at the 4-position and intermediates such as (10) may be isolated.50 Reaction of dichloropyrazines with a dithiane anion in THF may result in a tele-substitution process, as shown in Scheme 5, in which initial nucleophilic attack occurs at an unsubstituted ring position. Deprotection of the substituted product yields the corresponding aldehydes.51... 

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. 

Protection of 194 as a p-methoxybenzylether and subsequent epoxydation led to the trans-epoxide 195, which was transformed into the unsaturated aldehyde 196 by a three-reaction sequence, including regioselective oxirane opening with a 1,3-dithiane anion, hydrolysis of the dithioacetal formed, and dehydration. Chlorite promoted aldehyde oxidation, methyl ester formation, and removal of the hydroxyl protections delivered methyl (+)-shikimate 197 in a remarkable 12% yield from 193. 

Aggarwal has discovered that the anion derived from 1,3-dithiane dioxide undergoes rapid reaction with a range of aldehydes leading to the formation of diastereoisomeric mixtures in good yield (Scheme 20).76b... 

Some of the problems associated with the synthesis of a-dicarbonyl starting materials have been alleviated by the use of propane-1,3-dithiol, which reacts with aldehydes to give cyclic thioacetals. With butyllithium the resulting stable dithiane anions (134) can be transformed into a-diketones or a-hydroxy ketones (Scheme 73). A further approach to such compounds is found in the reaction of a-ketonitrate esters with sodium acetate (Scheme 73), while aryl a-diketones are also available from a-ketoanils (prepared from the cyanide-ion-catalyzed transformation of aromatic aldimines) (70AHC(12)103). 

Helerolytic fragmentation of 1. -Mianyl tosylates. Marshall and Belletirc have shown (hat a 1,3-dithiane anion can participate in a heterolytic fragmentation reaction. Thus condensation of the aldehyde (1) with 1,3-propanedi thiol gives the 1,3-dithiane (2),... 

Dropwise addition of butyllithium to a solution of ( )-l,3-dithiane 5,5 -dioxide (110) in pyridine-THF (1.5 1) generates an anion (111), which reacts with an aldehyde to give an adduct (112) as a 1 1 diastereomeric mixture. The reaction is extremely rapid at -78 °C, but the kinetic selectivity is moderate. In the reaction with benzaldehyde or pivalaldehyde, equilibration is attained at 0 C to give predominantly a single diastereomer in good yield (Scheme 31). ... 

In dithioacetals the proton geminal to the sulfur atoms can be abstracted at low temperature with bases such as Bu"Li. Lithium ion complexing bases such as DABCO, HMPA and TMEDA enhance the process. The resulting anion is a masked acyl carbanion, which enables an assortment of synthetic sequences to be realized via reaction with electrophiles. Thus, a dithioacetal derived from an aldehyde can be further functionalized at the aldehyde carbon with an alkyl halide, followed by thioacetal cleavage to produce a ketone. Dithiane carbanions allow the assemblage of polyfunctional systems in ways complementary to traditional synthetic routes. For instance, the p-hydtoxy ketone systems, conventionally obtained by an aldol process, can now be constructed from different sets of carbon groups. ... 

The regio- and diastereo-selective reaction of the anion generated from 2-(l-propen-l-yl)-l,3-dithiane with an aldehyde is applicable to the synthesis of rraru-p,y-disubstituted y-lactones, inciting the natural products ( )-eldnolide and ( )-rram-quercus lactone. ... 

Although chlorohydrins are obtained in good yield and with high diastereoselectivity by the reaction of the anion derived from 2-chloro-1,3-dithiane 1,3-dioxide with aromatic aldehydes, subsequent ring closure to the epoxide is prevented by a competing retro-aldol reaction <97JCS(P1)11>. 

The above two-step reaction sequence is of unusual interest from a synthetic perspective. Note that we have converted a typically electrophilic aldehyde (carbonyl) carbon into a nucleophilic carbanion center in the 1,3-dithiane anion. The overall process thus accomplishes a polarity inversion or, to use the more popular German term, umpolung. The 1,3-dithiane anion may now be reacted with a variety of electrophiles, such as alkyl halides, epoxides, and carbonyl compounds, in what is known as the Corey-Seebach reaction ... 

To make a 1,3-dithiane anion, an aldehyde is first converted to a thioacetal by reaction with 1,3-propanedithiol and a Lewis add, such as BF3 (the formaldehyde derivative, called 1,3-dithiane, is commercially available). The resulting thioacetal is then deprotonated with a strong base, such as n-butyllithium. 

Reaction of a 1,3-dithiane anion nucleophile with a ketone or aldehyde electrophile, followed by a mercury-assisted hydrolysis, affords an a-hydroxy ketone. 

Anionic Additions to Aldehydes. The /dCa of trans-, >-dithiolane 1,3-dioxide has been determined by Bordwell and disclosed by Aggarwal to be 19.1, a surprisingly low value compared to Trans-1,3-dithiane 1,3-dioxide (24.9). While the deprotonation of 1,3-dithiolane and 1,3-dithiolane 1-oxide leads to unstable carbanions that cleave, the anion of Trans-1,3-dithiolane 1,3-dioxide has shown sufBcient stability to undergo addition reactions with aldehydes. Moreover, because of the Cj-symmetry incorporated into a five-membered ring, its potential to serve as a chiral acyl anion equivalent has been tested. 

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