2-tert-Butyl-1,3-bis-(2,2-dimethyl[1,3]dioxolan-4-ylmethyl)isourea

[159390-24-6]  · C17H32N2O5  · (MW 344.45)

(reagent for mild, efficient formation of tert-butyl esters)

Alternate Name: BDDC, 2-tert-butyl-isourea.

Physical Data: viscous oil.

Solubility: soluble in most organic solvents.

Form Supplied in: not commercially available; pale yellow oil; easily made from commercially available 1,3-bis(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)carbodiimide (BDDC).1

Purification: made and used immediately.

Handling, Storage, and Precautions: material should be stored under a dry atmosphere of Ar or N2 at 0 °C. Many carbodiimides and their derivatives are strong sensitizers and, therefore, this reagent should be considered as such. Avoid all skin contact, and use proper PPE. This reagent should only be used in a well-ventilated fume hood. It is incompatible with strong acids, and aqueous systems. It is flammable; avoid fire or sparks. Decomposes upon prolonged storage at room temperature and exposure to air and moisture.

Preparative Methods: the title reagent is easily synthesized in the laboratory from commercially available 1,3-bis(2,2-dimethyl-1,3-dioxolan-4-ylmethyl)carbodiimide (BDDC).1 BDDC reacts with tert-butyl alcohol with or without the use of CuCl to form BDDC-2-tert-butyl-isourea (1).1 Unlike isourea formation from other carbodiimides,2 such as EDC, DIC and DCC, the reaction with BDDC is quantitative and clean.

The reactive isourea can be stored for short periods below 0 °C under an inert atmosphere. It needs no purification, and residual CuCl catalyst has no effect on the esterification reactions. Excess tert-butanol is easily removed under reduced pressure.

Esterifications

Many methods are known for forming tert-butyl esters of carboxylic acids.3 Strongly acidic or basic methods dominate these methods. One essentially neutral method employs BDDC-2-tert-butyl isourea (2).4 BDDC-2-tert-butyl isourea is generally effective at esterifying carboxylic acids and protected amino acids in a variety of solvents.

Carboxylic acids are cleanly converted to the corresponding tert-butyl esters without the use of harshly acidic or basic reagents. This is desirable when sensitive functional groups are present in the molecule and racemization must be avoided. The isourea reacts electrophilically with the carboxylic acid which serves as the nucleophile, so a-racemization of protected amino acids cannot occur.

Ester Purification

BDDC, its corresponding isoureas, and by-products are designed to be easily removed from reaction mixtures with a dilute acid wash (3). Simply washing the reaction mixture with dilute acid (typically 0.1 to 1.0 M) removes the urea by-product as well as any unreacted isourea. Washing with dilute base removes any unreacted carboxylic acid. The resulting product is often analytically pure and ready for further reaction without any other work-up.

Related Reagents.

DCC, dicyclohexylcarbodiimide; DIC, diisopropylcarbodiimide; EDC, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride; Vilsmeier reagent; tert-butyl bromide; tert-butanol; isobutylene.


1. Gibson, F.; Park, M.; Rapoport, H., J. Org. Chem. 1994, 59, 7503.
2. (a) Williams, A.; Ibrahim, I., Chem. Rev. 1981, 81, 589. (b) Mikolajczyk, M.; Kielbasinski, P., Tetrahedron 1981, 37, 233. (c) Kurzar, F.; Douraghi-Zadeh, D., Chem. Rev. 1967, 67, 107.
3. Greene, T.; Wuts, P., In Protective Groups in Organic Synthesis; 3rd edn, Chichester: Wiley Interscience, 1999, pp 372-428.
4. Mathias, L., Synthesis 1979, 561.

Frank Gibson

Bristol-Myers Squibb, New Brunswick, New Jersey, USA



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