Efficient carbamate synthesis

Details Efficient carbamate synthesis Efficient carbamate synthesis

2000-02-25

2002-06-04

Solola, T. A. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C560S024000, C560S125000

Reexamination Certificate

active

06399808

ABSTRACT:

1. FIELD OF THE INVENTION
The present invention relates to an efficient method for the synthesis of carbamates of the following general formula,
RR′—N—CO
2
—R″
and N-alkylated derivatives thereof, wherein R, R′, and R″ are selected from the group consisting of hydrogen, alkyl of 1-18 carbon atoms, silyl, phenyl, benzyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, allyl, and heterocycles, which are widely used as industrial products, and as intermediates in organic synthesis. In particular, the invention relates to a method providing efficient formation of carbamates from amines, carbon dioxide, and an organic electrophile, in the presence of a cesium base and, optionally, tetrabutylammonium iodide.
2. BACKGROUND OF THE INVENTION
Carbamates are widely used in industry and research, for example as fungicides, pharmaceuticals, cosmetics, and antibacterial preparations; as intermediates and cleavable protective groups in organic synthesis; and as peptidomimetic compounds.
Carbamates are prepared by a variety of methods, in particular by reaction of amines with alkyl chloroformates; by reaction of alcohols with carbamoyl chlorides or isocyanates; via reactions involving metal complexes or acyl transfer agents; and in some cases by the use of the highly toxic, and inconvenient to handle, phosgene reagent. See for example, Greene, T. W. and Wuts, P. G. M., “Protective Groups in Organic Synthesis”; 1991; Wiley and Sons, p. 309-348.
The above methods suffer from certain drawbacks and limitations. Harsh reaction conditions, including elevated temperatures are often required to achieve acceptable yields of carbamate products. Use of harsh conditions complicates synthesis of compounds containing labile functional groups, requiring either additional protection/deprotection steps, or post-synthesis purification, thus lowering yields and increasing costs. Harsh reaction conditions can also promote inversion of chiral centers causing undesirable racemization of products. Furthermore, the reagents required are often toxic, for example isocyanates, or highly toxic, such as phosgene. In addition, activated compounds used in carbamate synthesis, such as acyl transfer agents, may be unstable. The latter problem is compounded when relatively unreactive aromatic amines are used. For each of these reasons, an improved method for the synthesis of carbamates has long been sought.
Carbon monoxide and certain metal catalysts can be used to synthesize carbamates from several starting compounds, including amines. Metals such as palladium, iridium, uranium, and platinum are used as catalysts. Not only are these metals expensive, but frequently a redox-active co-catalyst such as ferrous chloride is advantageous, which complicates purification and is corrosive.
Methods using carbon dioxide in place of the more toxic carbon monoxide for synthesis of carbamates have been reported, (see for example, Yoshida, Y., et al.,
Bull. Chem. Soc
. Japan 1989, 62, 1534; and Aresta, M., et al.,
Tetradedron,
1991, 47, 9489) but such reactions often require harsh reaction conditions such as elevated temperatures.
Therefore, there exists a need for a method that simply and efficiently converts amines to carbamates in substantial yield. Furthermore, a desirable method would require less toxic and/or more stable reagents than are currently used. Preferably such a method could be performed under mild reaction conditions to minimize side reactions, and could provide for conversion of even poorly reactive amines, such as aromatic amines, both in solution and on solid supports.
BRIEF SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide an improved process for the conversion of amines to carbamates which avoids the aforementioned disadvantages and drawbacks.
It is a further object of the present invention to provide a process that obviates harsh reaction conditions, such as, but not limited to, reaction at high temperatures, or the presence of corrosive transition metal compounds.
It is a further object of the present invention to provide a process characterized by a three-component coupling of an amine, carbon dioxide, and an organic electrophile at mild temperatures in the presence of a cesium base.
It is a further object of the present invention to provide a simple and efficient method for the preparation of silylcarbamates.
It is yet a further object of the invention to provide methods for the synthesis of carbamate compounds upon a solid support matrix.
It is yet a further object of the invention to provide simple and efficient methods for selective synthesis of N-alkylated carbamates.
It is still a further object of the invention to provide methods for the synthesis of carbamates that avoid racemization and preserve the enantiomeric purity of the starting materials.
These and other objects of the present invention will become obvious to those skilled in the art upon review of the following disclosure.
Disclosed herein are methods for the conversion of amines that yield substantially carbamates; require reagents of lesser toxicity and higher stability than those agents set forth in the prior art; can be performed under mild reaction conditions to minimize side reactions; and provide for conversion of amines to carbamates both in solution and on solid supports. In a preferred embodiment, cesium carbonate, a source of carbon dioxide, an amine, and an alkyl halide are reacted in an anhydrous solvent. This catalytic process allows for the efficient and inexpensive preparation of various carbamates essential to industrial and research uses. Applications of the developed methodologies disclosed herewith include peptidomimetic synthesis, combinatorial library synthesis, drug design, protection of groups and the like.


REFERENCES:
patent: 4550188 (1985-10-01), Frulla et al.
patent: 5698731 (1997-12-01), Bosetti et al.
Li et al (1997): Bioorganic & Medicinal Chemistry Letters, vol. 7, 2909-2912.*
Chu et al (1999): Tetrahedron Letters, vol. 40, 1847-1850.

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