Dithianes as acyl anion equivalents

C-C BOND-FORMING REACTIONS 4.2.1 Use of sulfides, dithioacetals and orthotrithioesters 4.2.1.1 1,3-Dithianes as acyl anion equivalents... 

Dithianes as acyl anion equivalents useful for synthesis of carbonyl compounds. 

FIGURE 20.7 Use of dithianes as acyl anion equivalents (umpolung). 

The most important use of 1,3-dithianes (792) stems from their ability to function as acyl anion equivalents (794 Scheme 184). Metallation of this heterocycle followed by alkylation of the anion and cleavage of the dithiane group produces a carbonyl compound. Since such aspects of dithiane chemistry have been extensively documented (69S17 75JOC231), only a few of the more current applications of these heterocycles are highlighted. We again note here that the application of heterocycles to the synthesis of carbonyl compounds has been the sole subject of an extensive review (77H(6)73l). 

The widespread use of compounds derived from the 1,3-dithiane carbanion or its homologues as acyl anion equivalents (for applications see Section 4.2.1.1) followed the pioneering works of Corey and Seebach on nucleophilic acylation (for reviews, see [43] and [44]). 

Diethyl-3,5-octadiene 174 Dithiane oxides alkylation of 84 carbanions of 84 Dithianes alkylation of 76,79 as acyl anion equivalents 75 carbanions of 76,79 cleavage of 14-18.76,79 desulfurization of 78 oxidation of 23... 

Dithioacetals (see also dithianes and dithiolanes) alkylation of 98 as acyl anion equivalents 75 carbanions of 87,97-102 cleavage of 14-18,98,102 desulfurization of 78 metal-catalysed coupling 127 reaction with Grignard reagents 127 reductive lithiation of 89 synthesis of 12-19,97-102 Dithioacids synthesis of 40... 

Most of the chemistry associated with this series of heterocycles is a consequence of the acetal moiety. For example, all three saturated systems undergo acetal hydrolysis, the dioxanes being the most acid-sensitive. The chemistry of 1,3-dithianes and 1,3-oxathianes is further dominated by the acidity of the C-2 protons, leading to the use of the derived carbanions as acyl anion equivalents, particularly in the case of 1,3-dithiane derivatives. Oxidation at sulfur is also a common process. 

The commonly encountered C-2 anions derived from 1,3-dithiane and 1,3-oxathiane and their derivatives can be generated by treatment with any of a wide range of bases, but typically n-butyllithium (for 1,3-dithianes) or yec-butyllithium (sometimes necessary for 1,3-oxathianes). There are many instances where the deprotonated heterocycles have been used in synthesis, usually as acyl anion equivalents <8977643, b-95MI 608-05>. Use of 1,3-dithiane derivatives is by far the most common, and the derived anions react with with a very wide variety of electrophiles <69AG(E)639, 8977643), whether or not the dithiane system is initially substituted at C-2. For example, 2-lithio-... 

Over the last two decades, 1,3-dithianes have become ubiquitous as acyl anion equivalents in organic synthesis, with thioacetal chemistry having already been well established [107]. It is therefore somewhat surprising to find that 2-acyl-l,3-dithianes, which may easily be prepared in excellent yield from dithiane 2-anions, have received relatively little attention [108]. The development of 2-acyl-l,3-... 

Formally, the resulting ketone 5 arises from alkylation of an acyl anion with an alkyl halide. Therefore, 2-lithio-l,3-dithianes can be regarded as acyl anion equivalents ... 

The (V-methyldihydrodithiazine 125 has also been used as an effective formyl anion equivalent for reaction with alkyl halides, aldehydes, and ketones (77JOC393). In this case there is exclusive alkylation between the two sulfur atoms, and hydrolysis to give the aldehyde products is considerably easier than for dithianes. However, attempts to achieve a second alkylation at C2 were unsuccessful, thus ruling out the use of this system as an acyl anion equivalent for synthesis of ketones. Despite this limitation, the compound has found some use in synthesis (82TL4995). 

In Step C a dithiane anion was used as a nucleophilic acyl anion equivalent to introduce the C(10)-C(13) isobutyl group. 

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 l,3-dithiane-l,3-dioxides can also be prepared by sodium periodate oxidation of the 1,3-dithiane, and the irons isomer was thus obtained in a 58% recrystallized yield [81]. Chiral molecules of this type (C2 symmetry ) are particularly suitable for use as chiral acyl anion equivalents [11,82]. 

The acyl anion (R-C=0) is not stable as such, but when an aldehyde is converted into a 1,3-dithiane by reaction with propane-1,3-dithiol and then treated with base, it forms an acyl anion equivalent, and hence is susceptible to attack by electrophilic reagents (see Section 5.9). Two extensive compilations of formyl and acyl anion synthons together with references to their reactions... 

The reaction of aldehydes or ketones with ethane-1,2-dithiol or propane-1,3-dithiol to form 1,3-dithiolanes or 1,3-dithianes is an important reaction, as these compounds under suitable conditions are acyl anion equivalents (see Section 5.9, p. 626). These cyclic dithioacetals have been less used as protective groups, though when required are formed in high yield in the presence of boron trifluoride-etherate.138... 

Cyanide (one carbon) and acetylene (two carbons) are limited and other acyl anion equivalents are more versatile. Dithians are thioacetals of aldehydes that can be deprotonated between the two sulfur atoms by strong bases such as BuLi. Reaction with a second aldehyde gives 27 and hydrolysis of the thioacetal by acid, usually catalysed by Cu(II) or Hg(II), gives the a-hydroxyketone 4. The disconnection is that shown on diagram 4 and the lithium derivative 26 acts as the acyl anion 2. Unlike previous methods, R1 does not have to be H or Me. 

You might also have considered the addition of an acyl anion equivalent, such as the lithium derivative of the dithian 74 to ArCHO (chapter 23). There are obviously many other methods but these are the most likely. 

The dithiane functions here as an acyl anion equivalent. For more on this read Chapter 46. 

Hie anions of 68 and 79 are then useful acyl anion equivalents, but in natural product syntheses they are far less popular than reagents containing two sulphur atoms54, particularly dithians55. The chemistry of dithians, e. g. 86 and 87 has been well explored and they have been used in the synthesis of many natural products . The synthesis56 of the Douglas-Fir tussock moth sex pheromone 88 is an example of the way a dithian 86 acts as an acyl anion equivalent in ketone syntheses. 

The synthesis of a drug using a dithian as an acyl anion equivalent Dithioacetal monoxides Protected Cyanohydrins of Aldehydes... 

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