Corey-Seebach reaction

The Corey-Seebach Reaction (or Seebach Umpolung) uses lithiated 1,3-dithianes as nucleophilic acylating agents. 

The Corey-Seebach Reaction allows a reversal of the normal reactivity of acyl carbon atoms, which combine only with nucleophiles. The German term Umpolung is widely used for this inversion of reactivity. 

Scheme 1.3 Conversion of hexanal into dipentyl ketone (corey-seebach reaction)...

In Scheme 1.3, hexanal on reaction with 1,3-propanedithiol gives the 1,3-dithiane derivative 1.8. A strong base such as u-butyllithium abstracts the proton to give the corresponding 2-lithio-1,3-dithiane 1.9, which reacts with 1-bromopentane to give alkylated product 1.10. Treatment of 1.10 with FIgO and BF3 (boron trifluoride) in aqueous THF (tetrahydrofuran) yields the dipentyl ketone (the corey-seebach reaction ). Thus, dithianyllithium (2-lithio-1,3-dithiane) 1.9 is an acyl anion synthetic equivalent. 

The only example of the equivalent of a Corey-Seebach reaction of the lithium derivative of a carbonyl-protected aldehyde involves an acetylenic ketone (equation 6-25).61... 

In 1971 we discovered ( ) that the reaction of conforma-tionally locked 2-dithianyllithium compounds with electrophiles (Corey-Seebach reaction) proceeds with remarkable stereoselectivity, giving virtually exclusively the equatorial substitution products, as exemplified in Scheme 1 (R=H). The preference for the l,3-dithicUiyl-2-carbcUiion to undergo electrophilic siibstitu-tion from the equatorial side amoiints to over 6 kcal/mol ( ), corresponding to a selectivity factor in excess of 10,000. This high preference was subsequently shown to be due to stereo-electronic factors, in accord with theoretical predictions (4, 5, 6). 

The above two-step reaction sequence is of unusual interest from a synthetic perspective. Note that we have converted a typically electrophilic aldehyde (carbonyl) carbon into a nucleophilic carbanion center in the 1,3-dithiane anion. The overall process thus accomplishes a polarity inversion or, to use the more popular German term, umpolung. The 1,3-dithiane anion may now be reacted with a variety of electrophiles, such as alkyl halides, epoxides, and carbonyl compounds, in what is known as the Corey-Seebach reaction ... 

Dithiolanes, however, are rarely used in the Corey-Seebach reaction because anions derived from them undergo fragmentation via a pericyclic pathway, producing ethylene as one of the products. Use arrow pushing to explain this process. 

In an extension of the procedure, thiols react with gem-dihaloalkanes (Table 4.4) to produce thioacetals [ 10,20-23] and the reaction can be employed in the Corey-Seebach synthesis of aldehydes and ketones (see ref. 24 and references cited therein), gem-Dichlorocyclopiopanes having an electron-withdrawing group at the 2-position react with thiols to produce the thioacetals [25]. In the corresponding reaction of the thiols with biomochloromethane exclusive nucleophilic substitution of the bromo group by the thiolate anion occurs to yield the chloromethyl thioethers [13, 14] (Table 4.5). 

If the reaction is carried out on dithioesters, carbanions stabilized by two a-sulfur atoms are formed. Such carbanions are analogous to those obtained by deprotonation of dithioacetals, such as Corey-Seebach... 

Reactions.—, i-Dithianyl Anions. The Corey-Seebach 1,3-dithianyl anion rates as one of the most popular sulphur anions and nucleophilic acylating agents, as demonstrated by its recent use in the syntheses of potential precursors of the macrocyclic antitumour agent maytansine, of cyclopentenones and other unsaturated ketones,of octoses, of lla-hydrox)rprogesterone, of deuteriated aldehydes, of alnusone, of the sex-attractant of the Douglas fir tussock moth, of l,4-diketones, of 3-s-butylglutaraldehyde, of linaloyl... 

This method for the preparation of cyclobutanone via oxaspiropentane is an adaptation of that described by Salaiin and Conia. The previously known large-scale preparations of cyclobutanone consist of the reaction of the hazardous diazomethane with ketene, the oxidative degradation or the ozonization in presence of pjrridine of methylenecyclobutane prepared from pentaerythritol, or the recently reported dithiane method of Corey and Seebach, which has the disadvantage of producing an aqueous solution of the highly water-soluble cyclobutanone. A procedure involving the solvolytic cyclization of 3-butyn-l-yl trifluoro-methanesulfonate is described in Org. Syn., 54, 84 (1974). 

We owe to Corey and Seebach [302] an efficient procedure for the generation of phenylthiomethyllithium (PhSCH2Li), opening the way for practical applications. They found that this reagent was produced in about a 97% yield through reaction of equimolar amounts of n-butyllithium, DABCO and thioanisole in THF at 0°C for 45 min. 

The action of buQ Uithium on thioanisole in THF generates (phenylthio)methyllithium in a low yield of 35%. - Corey and Seebach found that reaction of equimolar amounts of bu Uithium, DABCO and thioanisole in THF at 0 "C produces (phenylthio)methyllithium in ca. 97% yield. Dimethyl sulfide can be metalated with a butyllithium-TMEDA complex at room temperature (equation 1). Treatment of chloromethyl p-tolyl sulfide with magnesium produces the corresponding Grignard reagent a reaction temperature between 10 and 20 C is crucial for its efficient generation (equation 2). ... 

Overall an inversion of polarity of the carbonyl group can thus be achieved this principle was called umpolung by Seebach. We owe to Corey and Seebach the use of the anions of dithiane, which are more stable than those of noncyclic thioacetals. Although this question was reviewed by Seebach and also by Durst in Comprehensive Organic Chemistry ," we will briefly comment on the main reactions of the dithiane group. 

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