Umpolung

Umpolung.—The proposition to convert available nucleophilic centres into electrophilic centres, and vice versa, would in principle double the number of reactions available to synthetic chemists. For instance, two papers have been noted from Seebach on the reversal of various carbonyl reactions, while the anionic equivalent of the Friedel-Crafts reaction has been provided by Whitlock and co-workers. 

Multi-phase Systems.—Interest in the attachment of reagents to polymeric or other insoluble supports has continued, with a view to easing reaction processes. Reagents have included borohydride (Amberlite resin), permanganate and cyanide (inorganic support), metallocenes as hydrogenation catalysts (20% divinylben-zene-styrene copolymer), and chelated transition metals (modified 2% divinyl-benzene-styrene copolymer). New supports have been silica (for the Nef reaction  

Chapter in Annual Reports in Organic Synthesis , 1976, Vol. 7, ed. R. B. Miller and L. G. Wade, 

Seebach and M. Kolb, Annalen, 1977, 811 D. Seebach, R. Burstinghaus, B. Grobel, and M. Kolb, 

Leznoff has published further on the solid-phase synthesis of insect sex attrac-tants. The advantages and uses of enzymes attached to solid supports have been reviewed. Aspects of triphase catalysis (organic layer-water-polymer) have been discussed by Regen, while advances in phase-transfer catalysis have been reviewed. A crown ether NAD(P)H mimic has been described,bringing synthetic chemists nearer to the objective of artificial enzyme systems. 

Reagents with carbonyl type groupings exhibit a or (if n. S-unsaturated) a properties. In the presence of acidic or basic catalysts they may react as enol type electron donors (d or d reagents). This reactivity pattern is considered as normal . It allows, for example, syntheses of 1,3- and 1,5-difunctionaI systems via aldol type (a -H d or Michael type (a + d additions. 

We are used to seeing a certain kind of reactivity associated with a given functional group. In some cases, it is possible to reverse the reactivity, in effect making an electrophilic center in to a nucleophilic one and vice versa. This section will explore reactions that allow this reversal. 

Definition of Umpolung. Under normal conditions, a carbonyl group is polarized as shown in 333. The carbonyl carbon is electrophilic and the a-carbon nucleophilic, as in an enolate anion (277). It would be very attractive from a synthetic viewpoint if the polarity of a carbonyl could be reversed, as in 334. 

In 334, the acyl carbon would be nucleophilic. To attain this reversal, it is necessary to change the carbonyl into another functional group such that the carbon becomes nucleophilic. If this transformation can be accomplished, the carbonyl must be easily regenerated when the desired reactions have been carried out. Seebach termed this process umpolung. l There is umpolung (reversal of reactivity) whenever one observes 

Watanabe, and M. Sato, Tetrahedron Lett., 1980, 21, 2869. 

Reagents i, Me3SiCN-Znl2 ii, DiBAL iii, MejSiLi iv, LiNPr H3O  

Dimethyl diazomethylphosphonate allows the generation of a variety of aldehydic enol ethers and enamines from aliphatic ketones with this single reagent [equation (5)]. Of particular interest is the direct synthesis of allyl vinyl ethers via the Wittig reaction.  

JV-Methylanilinomethyldiphenylphosphine oxide has advantages in yield over its morpholino counterpart in the conversion of enolizable ketones into their 

Substituted bis(phenylthio)carbanions (11) are alkylated by alkyl iodides in THF only when the substituent is aromatic (11 R = Ph). However, the alkyl d reagents (11 R = alkyl) can be alkylated in good yield if hexane-TMEDA is used as solvent.  

In a method which may only be applicable to the preparation of benzylic carbonyl compounds, Grignard reagents (stereospecifically) transform methyl-sulphinyl derivatives (7) into the anion [equation (6)]. Other than protonation, no further transformations of the arylacetaldehyde derivatives were described. 

Reagents i, CH2N2 ii. NaH.Mel iii, LiAIH, iv, NaH, cinnamyl bromide, v, base vi, RX vii, HC104,H20,Et20 

Reagents i, Bu Li ii, RCHO iii. PhCOCl iv. 25 °C v, NaOAc.AciO vi. CaCO,HgCh,MeCN,H 0 

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After the umpolung of an aldehyde group by conversion to a l,3 dithian-2-ide anion (p. 17) it can be combined with a carbonyl group (D. Seebach, 1969, 1979 B.-T. GrO-bel, 1977 B). Analogous reagents are tosylmethyl isocyanide (TosMIC), which can be applied in the nucleophilic formylation of ketones (O.H. Oldenziel, 1974), and dichloromethyl lithium (G. KObrich, 1969 P. Blumbergs, 1972 H. Taguchi, 1973),... 

Allylic metal compounds useful for further transformations can be prepared by Pd-catalyzed reactions of allylic compounds with bimetallic reagents. By this transformation, umpolung of nucleophilic 7r-allylpalladium complexes to electrophilic allylmetal species can be accomplished. Transfer of an allyl moiety from Pd to Sn is a typical umpolung. 

In fact, the polarity of the Ge-H bond can readily be reversed (umpolung) by an appropriate choice of constituents, e.g. ... 

In the oxidative Eschenmoser sulfide contraction (Scheme 11), thioamide 59 is oxidized by benzoyl peroxide to give either a symmetrical disulfide or the O-benzoate of the thiolactam-S-oxide. In any event, the once-nucleophilic thioamide sulfur atom is now forced to adopt the role of electrophile a reactivity umpolung has, in effect, been achieved.13 The nucleophilic enamide 65 attacks the sulfur atom leading to the formation of sulfur-bridged intermediate 66. The action of a phosphine or a phosphite thiophile on the putative episulfide then gives vinylogous amidine 67. 

Scheme 2.67 lndium(i)-mediated umpolung and addition to aldehydes. 

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. 

The second concept is to switch the reactivity of the complex by addition or substruction of one or two electrons to or from the complex applies the Umpolung principle. The effect of redox change is dramatic increase in the rate is often of the order of 109 for a given reaction [15-18]. These properties are summarized in the following Scheme I ... 

Ye and co-workers have shown that NHC 67 can catalyse the aza-Morita-Bay-lis-Hillman reaction of enones 66 and N-tosyl imines 63, presumably via initial NHC conjugate addition to the enone to generate an azolium enolate 68 [18]. A related conjugate addition approach has been exploited by Fu and co-workers, with tautomerisation of the initial enolate 72 derived from NHC conjugate addition to 70 giving 73, with subsequent cyclisation resulting in the umpolung of Michael acceptors (Scheme 12.13) [19]. 

Sulfur compounds are useful as nucleophilic acyl equivalents. The most common reagents of this type are 1,3-dithianes, which on lithiation provide a nucleophilic acyl equivalent. In dithianes an umpolung is achieved on the basis of the carbanion-stabilizing ability of the sulfur substituents. The lithio derivative is a reactive nucleophile toward alkyl halides and carbonyl compounds. 11... 

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