Isobutyl Chloroformate

[543-27-1]  · C5H9ClO2  · Isobutyl Chloroformate  · (MW 136.59)

(used for making mixed anhydrides which serve as active intermediates for peptide synthesis;1-3 used to block the 5-hydroxy function of deoxyribosides in oligonucleotide synthesis;4 condensing reagent5)

Physical Data: bp 128.8 °C; d 1.04 g cm-3.

Solubility: miscible with benzene, chloroform, ether.

Form Supplied in: clear colorless liquid.

Handling, Storage, and Precautions: gradually decomposed by water and alcohol; highly toxic; vapor irritates eyes and mucous membranes; stable on storage.6,7 Use in a fume hood.

Peptide Reagent.1,3

Protected amino acids, such as the N-benzyloxycarbonyl (Cbz) derivatives, are brought into solution in toluene or THF by addition of enough Triethylamine to form the salt, and isobutyl chloroformate is added at 0 °C to produce the mixed anhydride. A solution of an amino acid ester (or peptide ester) to be N-acylated is added in an inert solvent and the mixture is allowed to come to rt. Evolution of carbon dioxide begins immediately (eq 1). The isobutyl chloroformate is preferred to lower esters for preparation of peptides of moderate or high molecular weight;6,7 ethyl chloroformate is preferred for synthesis of dipeptides.

Boc-Gly-Gly-OEt and Boc-Gly-Gly-Gly-OEt have been successfully synthesized in reasonable yields (77% and 88%, respectively) via mixed anhydride derivatives from isobutyl chloroformate.8 Previously it was reported9 that considerable quantities of diacylated side products are formed in mixed anhydride syntheses with glycine when ethyl chloroformate is used.

5-Hydroxy Function Blocking Agent for Deoxyribosides.

The reagent has been used to block the 5-hydroxy function of deoxyribosides in oligonucleotide synthesis (eq 2).4 The reagent shows good selectivity for the 5-hydroxy group, as is evident in the high yield of (2). The blocking group is removed smoothly by alkaline hydrolysis to give (4).

N-Protection.10

In the synthesis of enantiomerically pure symmetric vicinal diamines involving chirality transfer from a single chiral source, 1,2-diphenylethane-1,2-diamine, hydrolysis of the bisacetamides to the corresponding vicinal diamines was attempted using a number of amide hydrolysis procedures. However, the various base- and acid-catalyzed procedures did not result in a clean hydrolysis of the acetamide groups. This was achieved by converting amines into biscarbamate derivatives, followed by treatment with 30% HBr in acetic acid (eq 3).

Cyclodehydration.5

In the synthesis of 1,4-dihydropyran[3,4-b]indolones, the reagent was used along with triethylamine for cyclodehydration of hydroxymethylindoleacetic acid to produce the lactone (eq 4).

Regioselective Arylation.11

Arylation in the 4-position in pyridines results from 1:1 adduct formation between an aryltriisopropoxytitanium reagent and an N-isobutyloxycarbonylpyridinium salt, and after successive 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone dehydrogenation and cleavage of the 1-substituent (eq 5).

Isobutyl Sulfonate.12

With Silver(I) p-Toluenesulfonate, alkyl chloroformate forms sulfonic carbonic anhydride which when heated liberates carbon dioxide, producing alkyl sulfonate. In order to find out the mechanism of the decomposition of the mixed anhydride, reaction of isobutyl chloroformate and silver p-toluenesulfonate was investigated. If the free alkyl cation, i.e. isobutyl carbonium ion, is formed, the rearrangement to s-butyl and t-butyl carbonium ion would be expected, finally resulting in the formation of s-butyl p-toluenesulfonate. t-Butyl p-toluenesulfonate is unstable and is not expected to survive under the reaction conditions. In fact, decomposition gave a mixture of isobutyl p-toluenesulfonate and s-butyl p-toluenesulfonate in a 0.8:1 mol ratio, with a quantity of isobutene and free p-toluenesulfonic acid. Isobutene was considered to be derived from the t-butyl cation.


1. Boissonnas, R. A. HCA 1951, 34, 874; HCA 1952, 35, 2229 and 2237.
2. Vaughan, J. R. JACS 1951, 73, 3547; JACS 1952, 74, 676 and 6137; JACS 1953, 75, 5556; JACS 1954, 76, 2474.
3. Wieland, T.; Bernhard, H. LA 1951, 572, 190.
4. Ogilvie, K. K.; Letsinger, R. L. JOC 1967, 32, 2365.
5. Fray, E. B.; Moody, C. J.; Shah, P. T 1993, 49, 439.
6. Vaughan, J. R.; Osato, R. L. JACS 1952, 74, 676.
7. Anderson, G. W.; Zimmerman, J. E.; Callahan, F. M. JACS 1966, 88, 1336. ibid 1967, 89, 5012.
8. Hoffmann, J. A.; Tilak, M. A. OPP 1975, 7, 215.
9. Kopple, K. D.; Renick, K. J. JOC 1974, 39, 660.
10. Nantz, M. H.; Lee, D. A.; Bender, D. M.; Roohi, A. H. JOC 1992, 57, 6653.
11. Gundersen, L.; Rise, F.; Undheim, K. T 1992, 48, 5647.
12. Yamamoto, A.; Kobayashi, M. BCJ 1966, 39, 1283.

Tapan Ray

Sandoz Pharmaceuticals, East Hanover, NJ, USA



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