Acyl anions, synthetic equivalents dithiane

Additional examples of the use of a dithiane to generate an acyl anion synthetic equivalent are provided by tire following equations ... 

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. 

An example where the presence of a counterion makes a difference between the gas phase and solution phase pathways involves the intriguing carbanion produced on deprotonation of 1,3-dithiane at C-2. In solution, this species, almost invariably produced by reaction of the dithiane with butyllithium, is widely used as an acyl anion equivalent in synthetic chemistry. Its importance for the present work is that this is a configurationally stable lithiated species in solution the carbanion stays sp -hybridized, and the lithium prefers the equatorial position, even to the extent of driving a terr-butyl group on the same acidic C-2 carbanion to the axial position in the lithiocarbon species. The carbanion is thought to be stabilized primarily by orbital overlap with the C-S antibonding orbitals, as opposed to more conventional polar and 7t-resonance stabilization. ... 

The nucleophile obtained by deprotonation of a dithiane serves as the synthetic equivalent of an acyl anion, a species that is too unstable to be prepared directly. 

The ketone 4 is formally produced by alkylation of an acyl anion with an alkyl halide. For this reason, 2-lithio-l,3-dithianes are also regarded as synthetic acyl anion equivalents ... 

One method that achieves the required umpoiung is using a 1,3-dithiane anion as a synthetic equivalent of the acyl anion (the Henry-Nef strategy using a nitroalkane anion offers an analogous approach, but it will not be discussed here). While the acyl anion is unstable and cannot be prepared, the 1,3-dithiane anion is stable due to the inductive withdrawal of electron density by the two sulfur atoms. The 1,3-dithiane anion can be used as a nucleophile and then converted to a carbonyl by hydrolysis. 

Dithiane Anion is the Synthetic Equivalent of an Acyl Anion... 

Disconnection of the TM at the newly formed C-C bond gives an illogical synthon (an acyl anion, for which a 1,3-dithiane anion is the synthetic equivalent). An alternate, stepwise approach to the retrosynthesis involves first doing a functional group interconversion, followed by a logical disconnection. Either... 

Related Reagents. Several other chiral acyl anion equivalents have been published. Conqtarison with 1,3-disulfur derived compounds is reported below. Benzaldehyde has been taken as the reference electrophile. The equivalents are of two kinds mono-and dioxides. Generally, monoxides are slightly less efficient (85 15 ds) or much more difficult to prepare and thus of scarce synthetic interest (100 0 ds). Furthermore, they lead to additional problems because they lack C -sjunmetry. Dioxides are either cyclic or acyclic. Acyclic bis(sulfoxides) work also slightly less efficiently with benzaldehyde (90 10 to 95 5 ds), but slightly better with aliphatic aldehydes. The two reported cyclic dioxides (trans-l,3-dithiane 1,3-dioxide and trans-1,3-dithiolane 1,3-dioxide) are comparable and work equally well (>98 2 ds). Yet, there are some differences trans-1,3-dithiolane 1,3-dioxide proceeds under kinetic control, while trans-1,3-dithiane 1,3-dioxide is best under thermodjuiamic conditions. The latter also offers the advantage to be available in enantioenriched form. 

In summary, the title compound, readily available from diethyl oxalate, is a synthetically useful synthon in various C-C bondforming reactions, requiring only catalytic amounts of mild Lewis acids such as zinc chloride. Mtematives to such an acyl anion equivalent include dithiane derivatives of glyoxylic acid esters, which have not been tested as widely and which require some synthetic effort in the final deprotection step. ... 

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. 

The a-ethylthiosulfoxides can be converted to the corresponding carbonyl compounds by hydrolysis catalyzed by mercuric ion. In both the dithiane and alkylthiomethylsulfoxide systems, an umpolung is achieved on the basis of the carbanion-stabilizing ability of the sulfur substituents. Scheme 13.2 summarizes some examples of synthetic sequences which employ acyl anion equivalents. 

Trost has published additional applications of a-lithiocyclopropyl phenyl sulphide, including an approach to spiro-sesquiterpenes, involving geminal alkylation, which utilizes a process that is formally the reversal of dithian-carbonyl addition(also see related studies by Marshall Synthetic applications of the highly nucleophilic methoxy-phenylthio-methyl-lithium PhSCH(Li)OMe and of the acyl anion equivalent methylthioacetic acid dianion RSCHCLOCOgLi (R = Me or Ph ) have also been described, as have synthetic procedures based on anions of a-alkylthio- or a-phenylthio-ketones and methylthiomethyl dithiocarbamates. ... 

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