Umpolung activation

The attempted formation of (127) by NHC-catalysed annulation of chromene-3-carboxaldehydes (128) was unsuccessful since this umpolung activation proved to favour a rearrangement process giving 3-methyl coumarins (129) in moderate to good yield (Scheme Ib). " ... 

Canesi and coworkers [73] recently reported an elegant oxidative dearomatizing formal cycloaddition process between sulfonamides 105 and naphthalene to afford highly fused tetracyclic compounds 106 (Scheme 25). The reaction is postulated to occur via an intramolecular nucleophilic addition of the A -moiety to Wheland intermediate 107 generated during the oxidative umpolung activation. The above reaction with slightly modified conditions was successfully applied to the synthesis of dihydrobenzo[A,d]furan derivatives [73]. 

Acyloins (a-hydroxy ketones) are formed enzymatically by a mechanism similar to the classical benzoin condensation. The enzymes that can catalyze reactions of this type arc thiamine dependent. In this sense, the cofactor thiamine pyrophosphate may be regarded as a natural- equivalent of the cyanide catalyst needed for the umpolung step in benzoin condensations. Thus, a suitable carbonyl compound (a -synthon) reacts with thiamine pyrophosphate to form an enzyme-substrate complex that subsequently cleaves to the corresponding a-carbanion (d1-synthon). The latter adds to a carbonyl group resulting in an a-hydroxy ketone after elimination of thiamine pyrophosphate. Stereoselectivity of the addition step (i.e., addition to the Stand Re-face of the carbonyl group, respectively) is achieved by adjustment of a preferred active center conformation. A detailed discussion of the mechanisms involved in thiamine-dependent enzymes, as well as a comparison of the structural similarities, is found in references 1 -4. 

Fermenting baker s yeast also catalyzes the 1,4-addition of a formal trifluoroethanol-d1-synthon to a,/i-unsaturated aldehydes, to give optically active l,l,l-trifluoro-2-hydroxy-5-alka-nones52. Presumably, the mechanism involves oxidation of the alcohol to the corresponding aldehyde followed by an umpolung step with thiamine pyrophosphate and Michael addition to the a,/i-unsaturated aldehyde. For example, l,l,l-trifluoro-2-hydroxy-5-hexanone (yield 26%, ee 93%) is thus obtained from trifluoroethanol and l-bnten-3-one. 

Hetero-substituted allyl compounds obtained by electrophilic attack in the 1-position can be reduced to give the heteroalkyl compounds carrying the new substituent on the a-carbon atom ( ). In this case, the double bond was used as an activating substituent only, to achieve easier deprotonation and higher nucleophilicity. In both cases the synthetically important umpolung of reactivity was achieved20. 

Such additions of nucleophiles to non-activated double bonds mediated by hypervalent iodine compounds are also possible in other cases (Section 3.5). This umpolung of reactivity is due to the formation of an adduct with hypervalent iodine which renders this intermediate highly electrophilic. In this way 6-propionylflavo-nols gave 1,2-dimethoxy-adducts in methanol-perchloric acid [10] ... 

Therefore acceptor cyclopropanes 1 will be ring opened by nucleophiles N to provide products like 2 (homo Michael addition) as depicted in Eq. 1. On the other hand, electrophiles E+ cleave donor activated cyclopropanes 3 affording adducts 4 or 5 which demonstrates that the cyclopropane serves as a homoenolate equivalent in this sequence (Eq. 2). Seebach consequently classified these methods as umpolung with the cyclopropane trick 4. ... 

Redistribution of electron density in CT complexes results in a modification of the chemical properties of coordinated arenes, and this effect is widely used in organometallic catalysis [2]. To demonstrate the relationship between charge transfer in arene complexes and their reactivity, we focus our attention on carbon-hydrogen bond activation, nucleophilic/ electrophilic umpolung, and the donor/acceptor properties of arenes in a wide variety of organometallic reactions. 

Charge-Transfer Activation of Coordinated Arenes 452 Carbon-Hydrogen Bond Activation 453 Nucleophilic/ Electrophilic Umpolung 455... 

The second major class of non-umpolung nucleophilic carbene catalysis comprises reactions by initial NHC-activation of various silicon compounds. Their proposed common pathway is thought to lead to a hypervalent silicon complex4 and thus provide carbene-catalyzed activation of the corresponding nucleophiles such as TMSCN, TMSCF3 etc. (Kano et al. 2006 Song et al. 2005 2006). It is not only certain carbon-silicon bonds that can be effectively activated, but a comparable activation of Si-O bonds, e.g. of trimethylsily enol ethers etc., allows for mild, NHC-promoted Mukaiyama aldol reactions (Scheme 6 Song et al. 2007). 

Finally, there are also some special NHC-mediated transformations that do not completely fit into the classification, such as triazolylidene-catalyzed hydroacylations (Chan and Scheldt 2006). Aldehydes can serve as hydride donors for activated ketones partly following a standard 1,2-addition of the NHC to the aldehyde, but instead of the usual carbonyl umpolung a hydride ( H-umpolung ) transfer is initiated. A related Cannizzaro-type transformation has been described for indazole-derived carbene catalysts (Schmidt et al. 2007). 

G3P) and D-sedoheptulose 7-P as illustrated in Scheme 5.53. In addition D-erythrose 4-phosphate can function as the ketol acceptor thus producing D-fructose-6-P and G3P (Scheme 5.53). The enzyme relies on two cofactors for activity — thiamin pyrophosphate (TPP) and Mg2+—and utilizes the nucleophilic catalysis mechanism outlined in (Scheme 5.54).83 When TPP is used as a cofactor for nucleophilic catalysis, an activated aldehyde intermediate is formed. This intermediate functions as a nucleophile, and thus TK employs a strategy that is similar to the umpolung strategy exploited in synthetic organic chemistry. 

Hamachi, R. Eboshi, J. Watanabe, S. Shinkai, Guest-Induced Umpolung on a Protein Sirnface A Strategy for Regulation of Enzymatic Activity , J. Am. Chem. Soc., 122,4530 (2000)... 

Single electron oxidation of the non-activated carbonyl group, e.g. in aliphatic or aromatic aldehydes, ketones and carboxylic acid derivatives, is, on the other hand, much less feasible and only a handful of methods and synthetic applications are known. Useful methods for synthetic applications are chemical modifications to lower the oxidation potentials by peripheral donor substitution and a-silylation, or redox umpolung via oxidation of the corresponding carbonyl enols or enol ethers. 

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. 

Compared with well-established electrophilic it-allylpalladium chemisty, the catalytic asymmetric reaction via umpolung of jt-allylpalladium has received very limited exploration [93]. Zhou and co-workers investigated the Pd-catalyzed asymmetric umpolung allylation reactions of aldehydes [22a, 94], activated ketones [95], and imines [96] by using chiral spiro ligands (5)-18e, (S)-17c, and (5)-17a, respectively. One representative example is that of the Pd/(5)-18e-catalyzed umpolung allylation of aldehydes with allylic alcohols and their derivatives, which provided synthetically useful homoallylic alcohols from readily available allylic alcohols, with high yields and excellent enantioselectivities (Scheme 33). 

Nucleophiles, e.g. secondary amines, react with 4 in the presence of activated manganese dioxide to give 7 from which a 5-substituted o-phenylenediamine 8 can be obtained by reduction with sodium di-thionite. The conversion of o-phenylenediamine into 4 can be regarded as an umpolung , since the former reacts only with electrophiles [123]. 

H -OH) with the product of umpolung (H -Z) or reagent produces molecular hydrogen. To confirm the activity of hexacoordinated dihydrophosphate, a proton of water was exchanged with hydrogen on the phosphorus and next the hydride reduction and reductive deuteriation of selected carbonyl compounds was accomplished. ... 

Besides that, electrochemical methods can be used to activate aromatic substrates by means of redox-umpolung procedure, which makes possible to cOTivert imreactive arenes, azoles, phenols, and other aromatic compounds, bearing electron-donating groups, into the intermediate radical cation species, which are able to react with nucleophiles (Scheme 61) [47, 187]. 

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