Aldehydes umpolung reactions

This is reminiscent of the Umpolung reactions of organic chemistry. As the group CO—CH2OH is transferred from a donor molecule (R —CO—CH2OH) to the aldehyde (R—CHO), the corresponding enzymes are classified among transferases. The use of transketolase will be considered in this Section. 

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). 

Abstract. N-Heterocyclic carbenes (NHC) have become an important class of organocatalysts and class of ligands for transition-metal catalysis. In organocat-alyzed umpolung reactions, thiazolium salt-derived NHC have been used successfully for decades. Even so, during recent years there has been an increased interest in NHC-catalyzed transformations and many new reactions have been developed. This article focuses on the use of NHC in the conjugate umpolung of ,f>-unsaturated aldehydes. 

Thiazolium and triazolium salt-derived NHC, in particular, are well known catalysts for benzoin- and Stetter-type umpolung reactions. In the course of these reactions, the NHC catalyst adds to the electrophilic aldehyde, resulting in the formation of a nucleophilic enamine species. Subsequently, this enamine can react with a series of different electrophiles such as aldehydes (benzoin condensation) or a, )-unsaturalcd substrates (Stetter reaction) (Scheme 4). 

Chan A, Scheldt KA (2005) Conversion of a,fS-unsaturated aldehydes into saturated esters an umpolung reaction catalyzed by nucleophilic carbenes. Org Lett 7 905-908... 

Moreover, the growing group of extended umpolung reactions is attracting considerable attention. This integration of functionalized aldehyde substrates in umpolung reactions (Reynolds et al. 2004 Chow and Bode 2004), and hence their cooperative interaction to yield new, de-functionalized intermediates has already been applied in a remarkable number of stereoselective variations (Scheme 7). 

In general, all extended umpolung reactions deal with aldehyde substrates that bear somehow reducible side chains prone to subsequent interaction at the stage of the common so-called Breslow intermediate (Zeitler 2005). Their subsequent participation leads—depending on the... 

Abstract The possible utilization of room temperature ionic liquids (RTILs), instead of volatile organic compounds (VOCs), in the electrochemical procedures of organic synthesis has been discussed. The synthesis of p-lactams, the activation of carbon dioxide and its utilization as renewable carbon source and the carbon-carbon bond formation reactions via umpolung of aldehydes (benzoin condensation and Stetter reaction) and via Henry reaction have been selected as typical electrochani-cal methodologies. The results, related to procedures performed in RTILs, have been compared with those performed in VOCs. The double role of RTILs, as green solvents and parents of electrogenerated reactive intermediates or catalysts, has been emphasized. 

The actual umpolung reaction that allows a ketene dithioacetal to function as if it had an electrophilic carbon a to a carbonyl is achieved by conjugate addition of nucleophiles to the ketene dithioacetal, followed by hydrolysis. Both sulfide and sulfoxide ketene derivatives can be used. Conjugate addition of an ester enol-ate derived from ferf-butyl acetate (secs. 9.2, 9.4.B, 9.7.A) to the ketene dithioacetal [CH2=C(SOMe)2] gave the stable dithioacetal anion (382). Conversion of the dithioacetal to the bis(sulfoxide) enhanced the ability of that species to function as a Michael acceptor. Subsequent transformation of 382 gave the aldehyde-ester (383).370... 

Reductive umpolung of aldehydes. A three-step reaction sequence accomplishes... 

Umpolung occurs by transmetallation of the 7r-allylpalladium intermediate, formed from the allene 462 and iodobenzene, with hexabutyldistaimane, and the generated the allylstaimane intermediate 463 reacts with aldehyde intramolecularly to yield the cyclopentanols 464 and 465 [175]. A similar umpolung reaction was carried out using indium [176,177]. 

Scheme 7.2 NHC-catal3rzed umpolung of aldehydes via the Breslow intermediate (azo) benzoin reaction and Stetter reaction.

Due to the unique bivalent carbene and diversity of the N-heterocyclic motif, NHCs have been demonstrated to be efficient organocatalysts for various enantioselective reactions. In addition to the traditional thioazolium and imidazolium NHCs, triazolium NHCs have become the most successful organocatalysts. Recently, NHC/Lewis acid cocatalysis and bifunctional NHCs have shown a very promising future. Beyond the classic NHC-catalysed umpolung of aldehydes, the extended umpolung of functionalised aldehydes are extremely successful. A series of NHC-catalysed reactions of ketenes have been developed for the synthesis of various enantioriched heterocycles. Esters, anhydrides, carboxylic acids and even Michael acceptors are useful alternative substrates for NHC-catalysed reactions. With increasing interest and rapid development of NHC catalysis, new structures of the catalysts, new reaction modes, and synthetic applications can be expected in the near future. 

In 2009, You et al. [60] reported an interesting NHC-catalyzed umpolung reaction of aldehydes 49 with 3-(l-arylsulfonylalkyl)indoles 50 as electrophiles. The alkene 51, generated in situ, were believed to be the real intermediate (Scheme 7.40). 

NHC is widely used for the a -d umpolung reactions of aldehydes. In 2004, Burstein and Glorius [6a] and Bode and co-workers [6b] independently reported the... 

NHC-catalysed umpolung reactions of both simple and a, -unsaturated aldehydes have been studied by NMR spectroscopy and X-ray diffraction key intermediates characterized include diamino enols, diamino dienols, azolium enolates, and the first report of an azolimn enol (92). Interconversion of these species has been followed by NMR kinetics, with mechanistic characterization further supported by DPT calculations. 

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. 

The metalation of vinyl ethers, the reaction of a-lithiated vinyl ethers obtained thereby with electrophiles and the subsequent hydrolysis represent a simple and efficient method for carbonyl umpolung. Thus, lithiated methyl vinyl ether 56 and ethyl vinyl ether 54, available by deprotonation with t- or n-butyllithium, readily react with aldehydes, ketones and alkyl halides. When the enol ether moiety of the adducts formed in this way is submitted to an acid hydrolysis, methyl ketones are obtained as shown in equations 72 and 73 . Thus, the lithiated ethers 56 and 54 function as an acetaldehyde d synthon 177. The reactivity of a-metalated vinyl ethers has been reviewed recently . 

Umpolung The reversal of polarity of the carbonyl carbon atom is termed umpolung (German for polarity reversal). Normally the carbonyl carbon atom of an aldehyde (or a ketone) is partially positive i.e., electrophilic and therefore it reacts with nucleophiles. When the aldehyde is converted to a dithiane by reaction with 1,3-propanedithiol and reacted with butyl lithium the same carbon now becomes negatively charged to react with electrophiles. This reversed polarity of the carbonyl carbon is termed umpolung which increases the versatility of the carbonyl group in synthesis. The sulphur atoms stabilize... 

This is another example of umpolung (see 0-95) 1478 the normally electrophilic carbon of the aldehyde is made to behave as a nucleophile. The reaction can be applied to the unsubstituted dithiane (R = H) and one or two alkyl groups can be introduced, so a wide variety of aldehydes and ketones can be made starting with formaldehyde.1504 R may be primary or secondary alkyl or benzylic. Iodides give the best results. The reaction has been used to close rings.1505 A similar synthesis of aldehydes can be performed starting with ethyl ethyl-thiomethyl sulfoxide EtSOCH2SEt.1506... 

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