Seebach dithiane reaction

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). 

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

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. 

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. 

Review. Seebach and Corey have published a general paper on the preparation and metalation of 1,3-dithianes and examples of the reaction of 2-lithio-l,3-dithianes with electrophilic reagents (alkyl halides, carbonyl compounds, acids, and oxides). The value of these sulfur-stabilized anionic reagents is that they are equivalent to acyl anions (a), in which the normal polarity of the carbonyl group is reversed (reversible umpolung). 

Seebach D, Beck AK. (1971) Organic Syntheses 51 76. In this procedure 1,3-dithiane is lithiated with BuLi in THF-hexane at — 10 to — 20 C. The initial concentration of 1,3-dithiane is about four times as low as that of HjQSCHj), the reaction time for the lithiation of 1,3-dithiane is 2h... 

In Seebach s reviews [1,2] several examples of successful alkylation reactions with lithiated S,S-acetals (mainly 1,3-dithianes) are mentioned. These data and our experimental results gave rise to the following summary of the reactivities of lithiated S,S-acetals in alkylations and the result ... 

Seebach D, Corey EJ (1975) J Org Chem 40 231. A general procedure for the alkylation of 2-lithiated 1,3-dithianes is given. In our opinion the reaction times mentioned in this paper can be shortened considerably compare Seebach D, Beck AK (1971) Org Syntheses 51 76... 

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 ... 

Lithio-l,3-dithianes add to the carbonyl group of aldehydes and ketones to provide mercaptal derivatives of a-hydroxy aldehydes or ketones (equation 55). The yields are normally quite high. Reaction with a,j8-unsaturated ketones has been observed to give only 1,2-addition however, Seebach and Lietz have reported 1,4-addition to occur in reactions with a,]8-unsaturated nitro derivatives (equation 56). In the case... 

Finally, Seebach has used the cyclic urea (69), DMPU, as a co-solvent in double lithiations, oxirane ring-opening, Wittig reactions, Michael additions of lithiated dithianes to cycloalkenones, and the selective generation of enolates." The interesting point here is that DMPU exhibits the same solvent effect as the carcinogen HMPA and might therefore be a safe substitute. 

Meyers, A. I. Heterocycles in Organic Synthesis Wiley-Interscience, 1974 (332 pages). DegITnnocenti, A. Pollicino, S. Capperucci, A. Synthesis and Stereoselective Functionalization of Silylated Heterocycles as a New Class of Formyl Anion Equivalents Chemical Communications 2006, 4881—4893. Yus, M. Najera, C. Foubelo, F. The Role of 1,3-Dithianes in Natural Product Synthesis Tetrahedron 2003, 59, 6147-6212. Albright, J. D. Reactions of Acyl Anion Equivalents Derived from Cyanohydrins, Protected Cyanohydrins and a-Dialkylaminonitriles Tetrahedron 1983, 39, 3207-3233. Seebach, D. Corey, E. J. Generation and Synthetic Applications of 2-Lithio-l,3-dithianes /. Orpi. Chem. 1975, 40, 231-237. 

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