2,2,2-Trichloroethyl Chloroformate (TrocCl)

Biographical Sketches

Ederson Oliveira dos Reis was born in Rio de Janeiro, Brazil in 1979. He obtained his M.Sc. in organic chemistry from Federal University of Rio de Janeiro in 2005. Earlier, he graduated in pharmacy and in chemistry from Federal University of Rio de Janeiro and Rio de Janeiro State University. Currently he is working towards his Ph.D. in organic chemistry under the supervision of Prof. Débora de Almeida Azevedo and D.Sc. Adriana Farah. His research interests are focused on the synthesis of different quinic acid derivatives such as chlorogenic acids and their lactones.

Introduction

2,2,2-Trichloroethyl chloroformate (TrocCl, CCl₃CH₂OCOCl, bp 171-172 °C,) is a stable chloro­formate which acylates aliphatic and aromatic hydroxyl and amino groups under mild conditions. [1] [2] This reagent is commercially available and has been widely used in ­regio-, chemo-, and stereoselective syntheses. The Troc group shows a sharp and charactereristic proton singlet at δ = 4.68-4.89 ppm, which makes its presence or absence easily detectable by ¹H NMR spectroscopy. [3-5] TrocCl has proved to be an excellent reagent for dealkylation of ­secondary or tertiary amines, with good selectivity, thus producing clean reaction products. [1] [3] Moreover, TrocCl is a suitable substrate for Mitsunobu inversion reactions. [6] Recently, the total synthesis of Aprotoxin A with protection and deprotection of an allyl ester intermediate with TrocCl was described. [7] Several methods of Troc ­removal have been described, leaving a wide variety of other functional groups unaffected. [7,8] [10] The following ­examples highlight the importance and early applicability of this ­reagent in organic chemistry.

Abstracts

(A) Ansari and Craig [3] have described the use of TrocCl to achieve desethylchloroquine (3) in a short, efficient two-step synthesis. In the first step, an internal amide ion from the secondary nitrogen in chloroquine (1) is generated, followed by rapid elimination of an ethyl group. The carbamate 2 thus produced easily undergoes deprotection to the target compound at room temperature with zinc in acetic acid.
(B) TrocCl selectively acylates the aromatic hydroxyl group of ­ferrulic and p-cumaric acids (1). TrocCl is also used to protect the C-1 position of 3,4-isopropylidene-1,5-quinide (2) in the preparation of 3,4-disubstituted lactones 3. It was shown that the use of TrocCl provides for regiospecificity of the esterification and ­impedes any degradation or isomerization. [4] [11]
(C) Hydroxylamines 2 that are doubly N,O-protected with Troc are easily obtained from TrocCl and hydroxylamine (1). According to Knight and Leese, [6] these intermediates allow ready access to enantiopure hydroxylamines 3 starting from the corresponding secondary alcohols.
(D) The synthesis of an important chiral alkaloid, 1-allyl-1,2,3,4-tetrahydro-β-carboline (2), from β-carboline 1 and a chiral auxiliary (R*) was successfully achieved when TrocCl was employed to protect the N-2 position. [8]
(E) Hydroxyalkylbenzimidazoles 1 with various alkyl chain lengths are selectively acylated with TrocCl in the prepation of benzimidazole functional acrylate monomers 2. [9]
(F) TrocCl has recently been used in the synthesis of three novel C-2-C-3 unsaturated pyrrolo[2.1-c][1,4]benzodiazepine analogues containing conjugated acrylyl C-2 substituents. [10] According to the authors, this reagent was chosen for its compatibility with both palladium coupling chemistry and pyrrolobenzodi­azepine N-10-C-11 imine formation.
(G) Direct conversion of azide 1 to carbamate 2 in high yields (92%) can be achievied via a phosphazene route with TrocCl. [12]

References

• 1 Montzka TA. Matiskella JD. Partyka RA. Tetrahedron Lett.  1974,  14:  1325 
• 2 Greene TW. Wuts PGM. In Protective Groups in Organic Synthesis   3rd ed.:  John Wiley & Sons; New York: 1999.  p.281-282 
• 3 Ansari AM. Craig C. Synthesis  1995,  2:  147 
• 4 De Paulis T, Lovinger DM, and Martin PR. inventors; US Patent  2347879. 
• 5 Vesel J. Dzoganová M. Trnka T. Tislerová I. Saman D. Ledvina M. Synthesis  2006,  4:  699 
• 6 Knight DW. Leese MP. Tetrahedron Lett.  2001,  42:  2593 
• 7 Doi T. Numajori Y. Munakata A. Takahashi T. Org. Lett.  2006,  8:  531 
• 8 Itoh T. Matsuya Y. Enomoto Y. Nagata K. Miyazaki M. Ohsawa A. Synlett  1999,  11:  1799 
• 9 Woudenberg RC. Coughlin EB. Tetrahedron Lett.  2005,  46:  6311 
• 10 Chen Z. Gregson SJ. Howard PW. Thurston DE. Bioorg. Med. Chem. Lett.  2004,  14:  1547 
• 11 Huynh-Ba T. inventors; US Patent  5395950. 
• 12 Sugiyana S. Watanabe S. Ishii K. Tetrahedron Lett.  1999,  40:  7489