Umpolung products

Under oxidative conditions (anode, aminium salts) in the presence of methanol/base most enol ethers are known to be dimethoxylated, with or without dimerization [235,251-255], thus opening up a way to formal a-Umpolung products 158. 

Fiq. 3.10 Some syntheses making use of umpolung. Products obtained after treatment with HgCI,/H,0 +. ... 

Recently, a further unique domino methodology has been reported by Lu and coworkers (Scheme 2.74) [173]. Herein, a triphenyl phosphine-catalyzed umpolung addition/cyclization of allenes and alkynes containing an electron-withdrawing group 2-316-2-318 followed by reaction with a double nucleophile 2-319 is assumed to account for the production of a broad palette of various heterocycles 2-321 and 2-323 via 2-320 and 2-322, respectively. Dihydrofurans, piperazines, morpholines and diazepanes were obtained during the process. 

The products described in Chart 2 clearly derive from two sites of acetone reactivity that can be identified with the carbonyl and a-carbon centers, as they are revealed by the reversible transfer of a proton from the a-carbon to oxygen. As such, enolization of the carbonyl compound represents a most fundamental change - an umpolung in which the keto acceptor (A) is interconverted to the enol donor (D) (equation 1). 

The attack of the nucleophile on the acceptor-substituted allene usually happens at the central sp-hybridized carbon atom. This holds true also if no nucleophilic addition but a nucleophilic substitution in terms of an SN2 reaction such as 181 — 182 occurs (Scheme 7.30) [245]. The addition of ethanol to the allene 183 is an exception [157]. In this case, the allene not only bears an acceptor but shows also the substructure of a vinyl ether. A change in the regioselectivity of the addition of nucleophilic compounds NuH to allenic esters can be effected by temporary introduction of a triphenylphosphonium group [246]. For instance, the ester 185 yields the phos-phonium salt 186, which may be converted further to the ether 187. Evidently, the triphenylphosphonium group induces an electrophilic character at the terminal carbon atom of 186 and this is used to produce 187, which is formally an abnormal product of the addition of methanol to the allene 185. This method of umpolung is also applicable to nucleophilic addition reactions to allenyl ketones in a modified procedure [246, 247]. 

C2 is electrophilic, and C4 is. .. electrophilic To make a bond between them, C2 must be turned into a nucleophile (umpolung). This must be the purpose of the -CN. Aldehydes are not acidic at the carbonyl C, so the CN cannot simply deprotonate C2. Instead, it must add to C2. Now C2 is a to a nitrile, it is much more acidic, and it can be deprotonated by excess CN to give an enolate, which can add to C4. Finally, deprotonation of 01 and elimination of CN gives the observed product. 

Fn and co-workers describe Umpolung reactivity of Michael acceptors catalyzed by triazolinylidene carbenes (Eq. 33) [168], Nncleophilic addition followed by tantomerization renders the [3 position of the Michael acceptor nncleophilic, which snbseqnently nndergoes alkylation. Compatible leaving gronps inclnde Br, Cl, and OTs. a,P-unsatnrated esters, nitriles, and amides all provide good to excellent yields of cyclized products. 

The lack of reactivity of 3-halo substituents under non-radical nucleophilic substitution conditions allows differential functionalization of pyri-dines by 3-umpolung and 2-nucIeophilic substitution processes. Thus, treatment of 2-fluoro-3-iodopyridine (189) with oxygen or amine nucleophiles affords products 191 which, upon subjection of SRN1 reactions with carbon, phosphorus, and sulfur systems, give 2,3-difunctionalized pyri-dines 192 (Scheme 56) (88JOC2740). 

In Che latter case, the radical ion pair is thought to arise from electron exchange through a triplet exciplex and to constitute "umpolung by electron transfer". If the photoreaction is conducted in acetonitrile, the free cation radical produces dimerization product (60). 

Triphenylphosphine was employed as a nucleophilic catalyst for the umpolung addition of azoles (225) to the electron-deficient allenes (226 R1 = H, R2 = OEt, R3 = H, Et) to afford the addition products (227). This organocatalytic methodology has been extended to addition-cyclization reactions between electron-deficient allenes or alkynes and pyrrole-2-carboxaldehyde in the presence of a catalytic amount of tri-butylphosphine, giving the substituted indolizine-7-carboxylates (228 R2 = OEt, Me R3 = H, Et).265... 

Umpolung offers access to a wide range of products, especially 1,2-diketones and a-hydroxy ketones, products that cannot be obtained using the normal reactivity. 

The anti-Markovnikov photochemical addition of malononitrile onto styrenes in the presence of lithium carbonate and a cyanoarene has been reported. In this case, excited 9-cyanophenanthrene (9-CP) oxidizes an olefin by PET, and the resultant radical cation adds to the malononitrile anion. The resulting radical is then reduced by 9-CP - and protonated to afford the end products [29]. This represents one of the rare examples involving the photoaddition of a carbanion to an olefin, and is explained by the PET-induced Umpolung of the latter, which thus becomes electrophilic. 

Umpolung reactivity is also evident in the addition of an organolithium to a vinyl carbamate 56.34 The product 57 can be quenched with electrophiles at low temperature, but rearranges to 58 by a [l,2]-acyl transfer on warming. 

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. ... 

The use of species 118 for the umpolung of a carbonyl group, the Stetter reaction, was demonstrated for the intramolecular asymmetric conjugate addition of a formyl group to the enoate moiety of 119 to give the cyclization product 120 in high ee and yield (Scheme 15) [64]. 

As many natural products contain y-butyrolactone fragments (Seitz and Reiser 2005) the scope of this conjugate umpolung reaction was investigated in detail. 

Scheme 18). The formation can be explained by the initial conjugate umpolung of the aldehyde and subsequent 1,4-addition to the unsaturated ketone. After proton transfer, an intramolecular aldol-type addition results in the formation of the aforementioned zwitterions. Nucleophilic displacement of the imidazolium moiety by the alkoxide provides the p-laclonc, which exhibits increased strain, since it is annulated to a cyclopentane ring. Consequently, the P-lactone breaks apart and liberates CO2 and the observed cyclopentene products (Scheme 19). 

In conclusion, the conjugate umpolung of a,P-unsaturated aldehydes represents a versatile and powerful method to synthesize different cyclic products such as f)- and y-lactones and cyclopentenes. More valuable applications based on the NHC-catalyzed umpolung are expected to be discovered in due course. 

Metal rf-inline complexes with various transition metals [1-10] and lanthanides [11,12] are well known in the literature. Early transition metal if-imine complexes have attracted attention as a-amino carbanion equivalents. Zirconium rf-imine complexes, or zirconaaziridines (the names describe different resonance structures), are readily accessible and have been applied in organic synthesis in view of the umpolung [13] of their carbons whereas imines readily react with nucleophiles, zirconaaziridines undergo the insertion of electrophilic reagents. Accessible compounds include heterocycles and nitrogen-containing products such as allylic amines, diamines, amino alcohols, amino amides, amino am-idines, and amino acid esters. Asymmetric syntheses of allylic amines and a-amino acid esters have even been carried out. The mechanism of such transformations has implications not only for imine complexes, but also for the related aldehyde and ketone complexes [14-16]. The synthesis and properties of zirconaaziridines and their applications toward organic transformations will be discussed in this chapter. 

Besides the Michael addition of heteroatomic nucleophiles initiating cyclocondensations, acceptor substituted unsaturated systems can also be reacted with carbon nucleophiles stemming from aldehydes in the sense of an umpolung, generally referred to as the Stetter reaction [244-246]. This process is organocatalytic and furnishes in turn 1,4-dicarbonyl compounds, intermediates that are well suited for Paal-Knorr cyclocondensations giving rise to furans or pyrroles. Among numerous heterocycles furans and pyrroles have always been the most prominent ones since they constitute important classes of natural products [247-249], of synthetic... 

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