Reactivity inversion

Although all these strategies imply, in some respect, a reactivity inversion of some of the starting reagents or synthons, the term "reactivity inversion" (or Umpolung as proposed by Seebach in 1979) [1] is commonly used in the context of the strategy known as "illogical disconnections" [2]. 

In using the "reactivity inversion" strategy, three different approaches may be considered the simple, the reversible and the use of "inversion operators". 

Simple reactivity inversion" implies using an umpoled synthon whose origin has, in principle, nothing in common with the synthon with "unnatural" polarity. An example of this type of reactivity inversion is found in one of the possible synthesis of cw-jasmone (3) in which the nitroethane (4) is used as an equivalent of an "acetyl anion" and reacts with an a,P-unsaturated ketone to give the corresponding 1,4-bifunctional system which can then be transformed by a Nef-type reaction into the dissonant 1,4-dicarbonyl system [5]. An intramolecular aldol condensation finally affords the target molecule (Scheme 5.3). 

Chemists were using cyanide ion for the synthesis of 1,2-D systems even before the concept of "reactivity inversion" was formally established. Thus, in the classical benzoin condensation, the cyanide-induced coupling of two aromatic aldehydes takes place according to the following mechanism [7] (Scheme 5.6) ... 

A classical application of cyclopropane rings in "reactivity inversion", in which a previously negatively polarised y-carbon atom (see 29) to a carbonyl group is inverted by formation of a cyclopropane ring (30) and is then intramolecularly attacked by a nucleophilic aromatic ring, is found in the synthesis of hydrophenanthrene system 11 (Scheme 5.19) developed by Stork in 1969 [21]. 

As we have seen in Chapter 2 (Scheme 2.3, equation 3), the doubly deprotonated nitroalkanes are nitroalkenes with reactivity inversion which violate the Lapworth model of alternating polarities and react with electrophiles at the ipso- and a-positions ... 

On the other hand, doubly deprotonated nitroalkenes are reagents with a double reactivity inversion (Scheme 5.30) provided they are used to prepare normal 0-, A-derivatives [1]. For instance, the 1-nitrobutadiene dianion 43 reacts with electrophiles to give a mixture of a- and y-isomers, 44a and 44b. Addition of the dianion 43 to 2-cyclohexenone gives only the y-adduct 45 which was transfomed into the 1,7-ketoaldehyde 46 by a Nef-type reaction with TiCl3 [38]. As shown in Scheme 5.30, although the resulting product is a "consonant system" (1,7-C), the... 

HP-3 FGI, in order to introduce a C=0 group, modify a double bond or to proceed to a "reactivity inversion" operation Umpolung) in dissonant bifunctional relationships (see below iii-a). 

A word of caution must be finally given concerning the assumed general validity of the postulate that the looser the ionic association, the hi er their propagating potential. A few exceptions to this rule have been reported in anionic polymerisation and unusually high reactivity of ion pairs in certain specific situations has been discussed by Szwarc To our knowledge, no such reactivity inversion has been published concerning cationic systems. 

---