Vol. 2, No. 7
Eckert's Cartridges for Safe Phosgenations

Introduction / Applications / Phosgene and Substitutes / Instructions for Use / References

Applications of Phosgene in Modern Synthesis
Transformations Using Phosgene
Phosgene is a small bifunctional molecule of high synthetic value. It is used mainly to create four types of functional groups: carbonyls, chloro substituents, chlorocarbonyls, and dehydration products. Additional manipulation allows access to various functional groups important for the preparation of many pharmaceuticals as well as the raw materials used to produce polyurethanes and polycarbonates.1

Some of the functional groups that can be obtained include (Scheme 1):
  • Chloroformates
  • Isocyanates
  • Alkyl and acyl chlorides
  • Cyanides and isocyanides
  • Carbodiimides
  • Carbamoyl chlorides
  • Carbamates
  • Carbonates
  • Ureas
  • N-carboxylic anhydrides
An interesting silver ion mediated lactam formation between a carbamoyl chloride and an enecarbamate was reported in 1996.2 The starting substrate, a useful intermediate in the stereocontrolled total synthesis of (±)-gelsemine, was prepared with phosgene (Scheme 2).
A macrocyclic receptor for the chiral recognition of hydroxycarboxylates (such as those derived from lactic or mandelic acids) has been synthesized from a readily available known bischromenylurea and a spirobifluorene linker.3 The diisocyanato intermediate is achieved in 89% yield by carbonylation of the corresponding diamine with phosgene (Scheme 3).
Phosgene has also been used as a chloroformylating agent in the synthesis of hydroquinolines (Scheme 4). The subsequent intramolecular reactions proceed under mild conditions and provide hydroquinolines stereospecifically by a suprafacial (cis) cycloaddition.4
Taxol® is a powerful anticancer drug with versatile and widespread medical applications. In Taxol chemistry, cyclocarbonates are useful tools in protecting and functionalizing the Taxol rings. During the first total synthesis of Taxol®, a sequence of reactions (Scheme 5) were performed with phosgene to form both a carbonate and a cyclocarbonate (yields were 75% and 97%, respectively).5 The cyclocarbonylation of the triol occurred regioselectively and yielded the six-membered ring.
Phosgene can also be used to afford an intermediate protecting group. Cyclocarbonylation of the 1,2-diol of 10-TES baccatin III with phosgene yields 95% of 10-TES baccatin III-1,2-carbonate.6 When the intermediate is reacted with a variety of nucleophiles (R-Li), the cyclic carbonate can be opened with precise control of regiochemistry to afford new C-2 analogues of Taxol in high yield (Scheme 6).7
A simple stereospecific synthesis of the important vitamin (+)-biotin has been reported by E. J. Corey.8 The importance of (+)-biotin in human and animal nutrition is constantly increasing the demand for the synthetic vitamin. In the first step of the synthesis, a diisocyanate is prepared in 91% yield from L-cysteine dimethyl ester by treatment with a slow stream of phosgene (Scheme 7).
Taxol is a registered trademark of Bristol-Meyers Squibb Co.