t-Butyl Chloroformate

[24608-52-4]  · C5H9ClO2  · t-Butyl Chloroformate  · (MW 136.58)

(reagent for the protection of amino groups, including amino acids2)

Alternate Name: Boc-Cl.

Physical Data: bp 3-4 °C/0.9-1.7 mmHg.1

Solubility: sol ether, toluene, and most organic aprotic solvents.

Form Supplied in: not commercially available; should be prepared from t-butanol2 or potassium t-butoxide1,3 and phosgene shortly before use.

Handling, Storage, and Precautions: unstable at rt. t-Butyl chloroformate should be kept as a solution in anhydrous solvent at low temperature (deep freezer) and for a period of time not exceeding a few days. Decomposition leads to high pressure in the storage vessel. May contain some residual phosgene. Reacts with DMSO or DMF.

Protection of Amino Groups.

t-Butyl chloroformate (Boc-Cl), first prepared by Choppin and Rogers in 1948,1 has been used, despite the reagent's instability, for the t-butyloxycarbonyl (Boc) protection of amino compounds and especially of amino acids. Boc protection has gained considerable importance because of the resistance of the protecting group to strong base hydrolysis and catalytic hydrogenation, as well as the ease of deprotection under mildly acidic conditions. Boc protection has become a fundamental tool of modern peptide synthesis and particularly of the Merrifield strategy for solid-phase peptide synthesis. Most amino acids have been protected with Boc-Cl using slightly modified Schotten-Baumann conditions (eq 1).2

Reaction of pyridine compounds with Boc-Cl and Sodium Borohydride in methanol at -65 °C afforded the corresponding N-t-butyloxycarbonyldihydropyridine derivatives in good yield (eq 2).4

The main drawback of the reagent remains its very low stability and the difficulties encountered in its preparation. Various preparative procedures are currently available in the literature.5 It is also necessary to determine the reagent concentration in solution accurately, which can be done by reacting an aliquot with a selected amino compound before use. These liabilities notwithstanding, t-butyl chloroformate can be a cheap and valuable reagent for Boc protection and in some cases it is the best reagent available. This is, for instance, the case in the synthesis of Boc-protected N-carboxy anhydrides, which are used as building blocks in peptide synthesis (eq 3).6 Di-t-butyl Dicarbonate required much longer reaction times in this case. These Boc-UNCAs (urethane-protected N-carboxy anhydrides) are, in fact, best prepared from the reaction of Boc-Cl with Leuchs anhydride in the presence of N-methylmorpholine or any nonnucleophilic organic base.

Preparation of Other Reagents for Boc Protection.

Because of its low stability, t-butyl chloroformate has mainly been used as a source of various other reagents that are easier to handle under ordinary conditions. t-Butyl Azidoformate, the most widely employed reagent before the discovery of Di-t-butyl Dicarbonate, is conveniently obtained from Boc-Cl through the formation of t-butyl carbazate (eq 4).7

t-Butyl azidoformate is also obtained more directly from Boc-Cl and hydrazoic acid (eq 5).8

Various active carbonates, which are primarily used for the preparation of stable reagents for the introduction of the Boc protection, have been prepared from Boc-Cl.9

Exchange reactions utilizing hydrogen fluoride10 and various salts such as sodium11 and silver fluoride do not lead to the more stable t-butyl fluoroformate, which has to be prepared instead from carbonyl chlorofluoride or fluorophosgene.12

t-Butyl Carbonates and Carbamates.

Because Boc-Cl is potentially the cheapest reagent for the synthesis of t-butyl carbonates, e.g. (1) and (2), or carbamates, it has been claimed in numerous patents and may have growing utility in industrial processes, such as for the production of carbonates as components in thermal recording materials.13

1. Choppin, A. R.; Rogers, J. W. JACS 1948, 70, 2967.
2. Sakakibara, S.; Shin, M.; Fujino, Y.; Shimonishi, Y.; Inouye, S.; Inukai, N. BCS 1969, 42, 809.
3. Howard, J. C. JOC 1981, 46, 1720.
4. Dagnino, L.; Li-Kwong-Ken, M. C.; Wynn, H.; Wolowyk, M. W.; Triggle, C. R.; Knaus, E. E. JMC 1987, 30, 640.
5. Ger. Patent 2 108 782 (CA 1967, 76, 24 715).
6. Fuller, W. D.; Cohen, M. P.; Shabankareh, M.; Blair, R. B.; Goodman, M.; Naider, F. JACS 1990, 112, 7414.
7. Ovchinnikov, Y. A.; Kiryushkin, A. A.; Miroshnikov, A. I. E 1965, 21, 418.
8. Yajima, H.; Kawatani, H. CPB 1968, 16, 183.
9. Rzeszotarska, B.; Wiejak, S.; Pawelczak, K. OPP 1973, 5, 71.
10. Olah, G. A.; Kuhn, S. J. JOC 1961, 26, 237.
11. Olah, G. A.; Kuhn, S. J. CB 1956, 89, 862.
12. Schnabel, E.; Herzog, H.; Hoffmann, P.; Klauke, E.; Ugi, I. AG(E) 1968, 7, 380.
13. Jpn. Patent 04 213 368 (CA 1993, 118, 14 048).

G. Sennyey

SNPE, Vert-le-Petit, France

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