Thionocarbonates1

(method used for the deoxygenation of alcohols;6 conversion of vicinal diols to alkenes;3 undergo cyclizations,3g radical allylation,6e rearrangements12)

Solubility: sol methanol, ethanol, most organic solvents.

Preparative Methods: see text.

Purification: chromatography or distillation where appropriate.

Definition.

Thionocarbonates are a class of chemical compounds having the general structure shown. There are two further classifications of this general structure: cyclic, where the two carbons are connected directly or via a carbon or heteroatom chain; and acyclic, where the two carbons are not connected. These compounds exhibit a wide range of activity, allowing the chemist to deoxygenate alcohols or to convert vicinal diols to alkenes (Corey-Winter reaction). In addition, thionocarbonates undergo cyclizations, rearrangements, and radical allylations.

Synthesis.

There are a wide variety of methods for preparing thionocarbonates. They are usually catered to fit the specific substrate and can vary widely with regard to pH, solvent, and temperature constraints. Cyclic thionocarbonates can be prepared by one of three general methods:

  • 1)Vicinal diols can be reacted with 1,1-Thiocarbonyldiimidazole (TCDI) in a suitable solvent such as methylene chloride, acetone, or xylene. Temperatures vary from ambient to reflux. In one case, pyridine was added to facilitate formation of the thionocarbonate. Yields vary widely but in general are good.2 This method is especially useful with acid sensitive substrates. Unfortunately, this method is unsatisfactory for large scale preparations due to the high cost of TCDI.3
  • 2)Thiophosgene reacts with diols in the presence of a base such as 4-Dimethylaminopyridine (DMAP) to give thionocarbonates. The solvent is usually dichloromethane but can vary, depending on the substrate. Reaction temperatures vary also (0 °C to room temperature), as do yields (ca. 80%). Care must be taken in handling thiophosgene as it is highly toxic.4
  • 3)Cyclic thionocarbonates have also been prepared by reaction of the diol with a base (n-Butyllithium, Sodium Hydride, etc.) followed by quenching with Carbon Disulfide then Iodomethane. Reaction temperatures and solvents vary according to the substrate. Reported yields are generally poor (<40%).5

    Acyclic thionocarbonates are prepared by reaction of an alcohol with an aryl chlorothioformate (aryl = Ph, 4-FC6H4, C6F5, 2,4,6-Cl3C6H2). Solvents that are used include acetonitrile, methylene chloride, THF, pyridine, and acetone. A base is also added (pyridine, DMAP, n-BuLi). Temperatures vary widely, as do yields (40-100%).6

    Alkene Synthesis.

    The conversion of vicinal diols to alkenes via the thionocarbonates is commonly known as the Corey-Winter reaction.3c As originally reported, cyclic thionocarbonates are treated with a trialkyl phosphite to give the alkene via cis elimination (eq 1). It was originally postulated that the reaction proceeds through a concerted cycloelimination mechanism,3a but evidence has also been presented supporting a carbene intermediate which decomposes to give CO2 and the alkene.7 Yields are generally high (>90% in some cases). A wide variety of substrates have been synthesized using this protocol, but it appears especially useful in the synthesis of highly strained alkenes.

    Other procedures have been identified to effect the elimination of the thionocarbonate to give an alkene. Pentacarbonyliron,8 Bis(1,5-cyclooctadiene)nickel(0),9 and diazaphosphonolides (1)4c have been used in lieu of trialkyl phosphites. This procedure has been utilized by Paquette in the synthesis of cyclobutenes3b,d and (CH)12 hydrocarbons,4d Ireland in the lasolocid A synthesis,3e and Barton in a synthesis of conduritol-B peracetate.4b

    Vedejs and Wu reported manipulation problems with (1). This led to the development of a less direct conversion involving treatment with an alkyl halide (R = Me, i-Pr) followed by reductive elimination when treated with Magnesium Amalgam (eq 2).2

    Alkenes have been introduced into monohydroxy alcohols using acyclic thionocarbonates. Eq 3 shows how a double bond is introduced by refluxing the phenylthioformate in xylene. This provides a key intermediate in the synthesis of pyrrolo[1,4]benzodiazepine antibiotics.6i Similar transformations have been accomplished with different conditions such as thermolysis6h or radical elimination6g of an acyclic thionocarbonate.

    Deoxygenation.

    Thionocarbonates provide a useful avenue for removal of hydroxyl groups from certain substrates. Typically, the thionocarbonate is treated with R3SnH in the presence of a radical initiator (Azobisisobutyronitrile or Dibenzoyl Peroxide). Other hydrogen donors have been utilized including Ph2SiH2 and Tris(trimethylsilyl)silane.10 The reactions are run in refluxing toluene or xylene. Sugars are easily deoxygenated via this protocol6a,b,d,j,k and Martin et al. used this method in the preparation of difluoroalkylphosphonates.11 One interesting observation was made during the deoxygenation of vicinal bromo thionocarbonates. In this case, treatment with Bu3SnH/AIBN/toluene (reflux) gives the alkene (eq 4).6a

    Other Reactions.

    Medium-ring cyclic thionocarbonates undergo [3,3]-sigmatropic rearrangements to give cyclic thiolcarbonates on treatment with base (eq 5) (70-80%).12 A similar rearrangement allows the conversion of an alcohol to a thiol (eq 6).3f

    Radical cyclizations have been observed when thionocarbonates have been treated with Tri-n-butylstannane (eq 7 AIBN/toluene; 60%).3g Allyl groups have been introduced via the Keck procedure (Allyltributylstannane/AIBN/toluene). This is particularly useful in the synthesis of nucleosides (eq 8) (50-74%).6e


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    Brian A. Roden

    Abbott Laboratories, North Chicago, IL, USA



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