Efficient synthesis of secondary amines by selective...

Details Efficient synthesis of secondary amines by selective... Efficient synthesis of secondary amines by selective...

2000-02-25

2002-07-23

Barts, Samuel (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S386000, C564S404000, C564S445000, C564S459000, C564S481000, C560S155000

Reexamination Certificate

active

06423871

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to the N-alkylation of organic nitrogen compounds containing a primary amine group and, in particular, to such N-alkylation performed by reacting an alkyl amine with an organic electrophile in the presence of a base catalyst under conditions such that substantially mono-N-alkylation of the alkyl amine occurs, resulting in a high yield of secondary amine.
BACKGROUND OF THE INVENTION
Secondary amines are widely used in the synthesis of numerous products including surfactants, textiles, agricultural products and medicines. Thus, an efficient means for the synthesis of secondary amines has long been sought. However, all the known direct alkylation methods give mainly over-alkylation products such as tertiary amines and quaternary ammonium salts instead of the desired secondary amines. See for example, M. S. Gibson, “The Chemistry of the Amino Group” (S. Patai, ed.), Interscience, 1968, p.45, and Mitsunobu, “Comprehensive Organic Chemistry”, (H. D. Barton, ed.), Pergamon Press, 1979, 7:65.
The general scheme for production of secondary (2), tertiary (3) and quaternary (4) amines by successive N-alkylation reactions of primary amine (1) with an organic electrophile R′—X is as follows:
Because secondary amines are more nucleophilic than their corresponding primary amines, further alkylation to form tertiary (3) or quaternary (4) amines is thermodynamically favorable and difficult to suppress. Even with a limited amount of alkylating agent, the equilibriation of protonated dialkyl product (2′) with the neutral primary amine (1) is sufficiently fast that a mixture of all alkylation products is obtained.
The resulting complex product mixture usually provides a low yield of secondary amine, and purification can be difficult. To avoid problems associated with overalkylation, reductive alkylation methods have been widely employed, wherein amines are reacted with aldehydes and the imine intermediates are reduced by sodium cyanoborohydride or a similar reductant to produce secondary amines, as described in: Szardenings et al.
J. Org. Chem
. (1996) 61:6720, and Klyuev & Khidekel,
Russian Chemical Rev
. (1980) 1:49. Depending on the choice of substrate, these methods typically give overalkylation products. In addition, aldehydes are usually unstable and expensive, limiting reactant availability, and reducing agents are both expensive and difficult to handle.
High temperatures are often required to achieve base-catalyzed direct N-alkylation. To minimize the need for harsh reaction conditions, activated reactants are frequently used. For example, U.S. Pat. No. 4,209,463 to Maender et al. discloses the use of activated formyl derivatives of aryl amines in the formation of nitrodiarylamines; U.S. Pat. No. 4,417,048 to Soula et al. describes N-alkylation of compounds bearing a labile hydrogen, and Fukuyama et al.,
Tetrahedron Lett
. (1995) 36:6373 describes the use of 2,4-dinitrobenzenesulfonamides as activated N-alkylating agents.
Various additives that promote N-alkylation are known. These include phase-transfer catalysts, as described in Masse,
Synthesis
(1977) p.342; tertiary amine sequestering agents, as described in U.S. Pat. No. 4,417,048 to Soula et al.; and alkali cation exchange zeolites or molecular sieves, that improved selectivity of N-alkylation of aniline, as disclosed by Onaka et al., in
Chem. Lett
. (1982) 1783, and
J. Chem. Soc. Chem. Commun
. (1985) 1202. While these additives are effective in promoting certain specific N-alkylation reactions, there remains a need for reliable, efficient and generally-applicable N-alkylation procedures effective for a wide range of reactants, as required, for example, in the construction of peptidomimetic libraries, as discussed in Reichwein & Liskamp,
Tetrahedron Lett
. (1998) 39:1243.
Indirect methods of N-alkylation can provide substantially mono-N-alkylated products through the use of protecting groups that prevent further N-alkylation. See Fukuyarna et al.,
Tetrahedron Lett
. (1995) 36:6373, and Croce et al.,
J. Chem. Res
. (S) (1988) 347. These methods are of particular importance in the field of pharmaceuticals, see Sharm & Moniot “Isoquinoline Alkaloid Research” (1972), Plenum Press; solid phase synthesis, as described in Reichwein & Liskamp,
Tetrahedron Lett
. (1998) 39:1243 and Heinonen & Lonnberg,
Tetrahedron Lett
. (1997) 38:8569, and in the synthesis of peptidomimetic compounds such as N-alkylated peptides. After N-alkylation, the protecting group is removed to yield the secondary amine product. While the benefit of substantially mono-N-alkylation is achieved, and racemization of chiral centers is suppressed, additional synthetic steps and expense are required as compared to direct N-alkylation methods.
Therefore, there exists in this field a need for methods of simple, efficient N-alkylation of primary amines that yield substantially secondary amines, require only mildly reactive alkylating agents, such as alkyl bromides, which are generally more readily available than corresponding activated compounds, and can be performed under mild reaction conditions to minimize side reactions.
BRIEF SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide an improved process for mono-N-alkylation of primary alkyl amines 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, suppresses over-alkylation, and avoids the use of protecting groups.
It is a further object of the present invention to provide a process characterized by reaction of an organic electrophile with a primary amine in the presence of a cesium base at mild temperatures.
It is a further object of the present invention to provide a process broadly comprising providing a cesium base catalyst, preferably CsOH or Cs
2
CO
3
, in an anhydrous solvent, and optionally including a molecular sieve for the removal of water and/or a halide-exchange promoting agent such as tetrabutyl ammonium iodide (TBAI).
It is a further object of the present invention to provide a process whereby unprotected primary amines are smoothly N-monoalkylated using more than one equivalent of alkylating agent in the presence of cesium hydroxide in DMF, giving rise to respectable yields and selectivity through an N-alkylation protocol that is direct, efficient and utilizes mild reaction conditions, and which can be exploited for other synthetic purposes.
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 is an efficient synthetic protocol for secondary alkyl amines, which can be generated by cesium hydroxide promoted N-alkylation of various primary alkyl amines with alkyl halides. Unlike the known methods, these protocols produce either mainly or exclusively secondary alkyl amines in high yields. All kinds of aliphatic amines are compatible with this technology and a variety of alkyl halides are readily incorporated to furnish dialkylamines efficiently. In a preferred embodiment, cesium hydroxide is used as a base in a catalytic amount when reactive halides such as benzyl bromide are employed. This catalytic process allows for the efficient and inexpensive preparation of various secondary amines essential to industrial and practical applications. The developed methodologies disclosed herewith are also believed to make significant contributions to the material sciences by providing new types of secondary amines in an economical fashion.
Thus a process providing a secondary amine of the general formula, R—NH—R′, is disclosed wherein an organic electrophile, R—X, is reacted with a primary amine R′—NH
2
in an anhydrous solvent containing a cesium base in an amount sufficient to preferentially promote mono-N-alkylation of said primary amine by said organic electrophile, to provide a secondary amine. R and R′ each comprise the same or a different hydrocarbon having one or more ca

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