Preparation of Tertiary Amines

Rhenium sulfide was the most active and hydrogenated excess ketone to the corresponding alcohols. The platinum metal sulfides were found to be more active than the base metal sulfides and highly selective for the formation of (V-alkylarylamines. They usually produce a pure product with little or no side reactions, require no excess above the stoichiometric amount of ketone, and are active at relatively low pressures of hydrogen. An example with (V-phenyl-p-phcnylencdiaminc is shown in eq. 6.15.37 Platinum metal sulfides may also be used for the reductive alkylation of aliphatic amines and their nitroalkane precursors with aliphatic ketones. 

The reductive alkylation with aldehydes to prepare Al-n-alkylarylamines generally leads to a mixture of /V,/V-dialkyl- and A-alkylarylamines, and the yields of alkylated amines are often poor with aldehydes other than formaldehyde (see eq. 6.12). 

The preparation of tertiary amines by reductive alkylation of ammonia appears to find only limited application. Triethylamine and tripropylamine were prepared by hydrogenation of acetaldehyde and propionaldehyde, respectively, in the presence of ammonia over platinum catalyst.38 A high yield (84.1% by GC) of trinonylamine was 

The reductive alkylation of a primary amine to give tertiary amine is often successful with formaldehyde over nickel catalyst. Thus aralkylamines ArCH(CH3)CH2NH2 and ArCH2CH(CH3)NH2 were converted to /V,/V-dimclhyl derivatives in 51-85% yields with formaldehyde and hydrogen over Raney Ni in ethanol in the presence of sodium acetate (eq. 6.16).35 

Triethylamine was obtained in a yield of 16% by alkylating ethylamine drop by drop with acetaldehyde in a 1 2 molar ratio in a colloidal platinum solution at room temperature and 0.1 MPa H2.12 Benzyldiethylamine was prepared in a 31% yield from ethylamine, benzaldehyde, and acetaldehyde in a 1 1 1 molar mixture over a colloidal platinum in H20-AcOH-EtOH at room temperature and 0.3 MPa H2. The yield of the tertiary amine, however, was improved to more than 50% by alkylating ethylbenzy-lamine with acetaldehyde. 

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For the preparation of tertiary amines, the conditions must not be too vigorous, otherwise the tertiary amine may react further to form the quaternary methyl methosulphate. 

Amines are powerful nucleophiles which react under neutral or slightly basic conditions with several electron-accepting carbon reagents. The reaction of alkyl halides with amines is useful for the preparation of tertiary amines or quaternary ammonium salts. The conversion of primary amines into secondary amines is usually not feasible since the secondary amine tends towards further alkylation. 

Reductive amination has been successfully applied to the preparation of tertiary amines from carbonyl compounds and secondary amines even though a neutral mine is not possible m this case... 

For a review of the preparation of tertiary amines by reductive alkylation, see Spialter, L. ... 

Hydrolysis of the amides provides a unique method for preparation of tertiary amines. 

Elguero and Espada29S have used this dealkylation reaction with quaternary salts of heterocyclic compounds. Another application is the preparation of tertiary amines functionalized in the <5 position.296 In these reactions, the ammonium salt 196 is both the catalyst and the reagent. 

The preparation of tertiary amines with the aid of insoluble supports has mostly been performed by 3-elimination of support-bound quaternary ammonium salts or by N-alkylation of secondary amines with support-bound alkylating agents (Figure 3.28). 

Tertiary amines. A new preparation of tertiary amines involves alkylation of 1,1 -dimethylhydrazine2 (9,184-185 and earlier volumes) followed by deamination of the resulting hydrazinium salt with nitrous acid in 4 A HC1. 

In an opposite manner to bases such as 1 and 2 in terms of reactivity, polymer-supported tosyl chloride equivalent 14 is able to capture alcohols as polymer-bound sulfonates 15, which are released as secondary amines, sulfides and alkylated imidazoles with primary amines, thiols and imidazoles as nucleophiles in a substitution process (Scheme 6) [24]. This technique has further been extended for the preparation of tertiary amines [25] and esters [26]. Excess of amine was scavenged by polymer-supported isocyanate 16 [27, 28] while excess of carboxylic acid was removed by treatment with aminomethylated polystyrene 17. 

Scheme 7. Preparation of tertiary amines assisted by polymer-bound benzotriazoles.

C - N bond formation is one of the most important transformations in organic synthesis. Amines are widely used as intermediates to prepare solvents, fine chemicals, agrochemicals, pharmaceuticals and catalysts for polymerization. The nucleophilic attack of alkyl halides by primary and secondary amines is useful for the preparation of tertiary amines but the reaction requires a longer reaction time and gives rise to a mixture of secondary and tertiary amines. 

Alcohols and aldehydes are also suitable materials for the creation of an alkyl amine. In addition to the aforementioned formation of alkyl chloride as an intermediate, alcohols can be directly converted to amines under hydrogenation conditions in the presence of ammonia while aldehydes are prereacted to form imine followed by hydrogenation [13]. Selectivity of the primary amine with these techniques is difficult and this process is more typically utilized for the preparation of tertiary amines where the reaction can be driven to completion. In certain cases, alcohols and aldehydes provide structural elements which are not attainable from natural sources. An example is the formation of a hydrogenated tallow 2-ethyl hexyl amine. The amine is prepared as shown below in eqn 6.1.8 using a hydrogenated tallow amine reacted with 2-ethyl hexanal [14, 15] ... 

Malz, Jr. and Greenfield studied the preparation of tertiary amines by reductive alkylation of aliphatic secondary amines with ketones, using platinum metals and their sulfides as catalysts.40 Excellent yields of tertiary amines were obtained with unhindered ketones, such as cyclohexanone and acetone, and relatively unhindered secondary amines. In this study, 5% Pd-C and various transition metal sulfides were compared in the reductive alkylation of dibutylamine with cyclohexanone. By using the reaction conditions suitable to each catalyst, excellent yields of tertiary amines were obtained, as shown in Table 6.5. Approximately 5-15% of the excess cyclohex-... 

The photoreduction of aromatic ketones by polymeric systems having tertiary amine end groups provides an ele nt way for the preparation of block copolymers with high efficiency [138]. The method consists of the synthesis of the bifimctional azo-derivative 4,4 -azobis (iV,i -dimethylaminoethyl-4-cyano pentanoate) (ADCP), successively used as fiee radical thermal initiator for the preparation of tertiary amine-terminated poly(styrene). 

Several methods are available for the preparation of tertiary amines from fatty acids. One of the oldest is the classical Leuckart reaction (32), which uses formaldehyde and formic acid for the reductive alkylation of a secondary amine. 

Fatty alcohols are also available raw materials in the commercial preparation of tertiary amines. The fatty alcohol may be converted directly to an alkyl halide by... 

The reaction between alkyl hahdes and ammonia or primary amines is not usually a feasible method for the preparation of primary or secondary amines, since they are stronger bases than ammonia and preferentially attack the substrate. However, the reaction is very useful for the preparation of tertiary amines and quaternary ammonium salts. If ammonia is the nucleophile, the three or four alkyl groups on the nitrogen of the product must be identical. If a primary, secondary, or tertiary amine is used, then different alkyl groups can be placed on the same nitrogen atom. The conversion of tertiary amines to quaternary salts is called the Menshutkin reaction It is sometimes possible to use this method for the preparation of a primary amine by the use of a large excess of ammonia or a secondary amine by the use of a large excess of primary amine. The use of ammonia in methanol with microwave irradiation has also been effective. Microwave irradiation has also been used in reactions of aniline with allyl iodides. A base other than the amine... 

Figure 15.14 Preparation of tertiary amines with the REM linker, based on the Hofmann elimination reaction.

Preparation of Tertiary Amines from Alkenes and Secondary Amines. A useful preparation of tertiary amines from alkenes can be achieved when a secondary ozonide is treated with a secondary amine (eq 50) 7 The reaction is quite versatile and provides tertiary amines when the reaction is carried out at reflux after addition of the amine. When the reaction medium was kept at room temperature, isolation of the enamine was observed, making this a clean, four-step, one-pot preparation of morpholino enatnines and tertiary amines for use in s)uithesis. Overall, the reaction performed best with morpholine some problems were encountered with methylenecyclohexane and piperidine, as it seems the enamine intermediate is difficult to form in such a hindered system. 

This reaction has been extended to resin for the preparation of tertiary amine library. ... 

The preparation of tertiary amine-functionalized polydienes is less problematic than the situation for primary amine-functionalized polymers. 3-Dimethylaminopropyllithium can be prepared by lithiation of the corresponding alkyl chloride in hexane at 20 ° C, followed by replacement of the solvent by benzene. Using this initiator for butadiene polymerization in hexane at room temperature, a-dimethylaminopolybuta-dienes with high (76-86%) 1,4-microstructure were produced. It was noted that the amount of vinyl microstructure in the resulting polybutadienes increased with the amount of diamine impurity formed by Wurtz coupling during the synthesis of the initiator. 

Craig JC, Purushothaman KK (1970) An improved preparation of tertiary amine N-oxides. J Org Chem 35 1721-1722... 

The preparation of tertiary amines from alkyl halides and a secondary amine, or a primary amine in which both TV-hydre en atoms are to be replaced by identical alkyl groups, can be carried out with favourable yields in many cases, as evidenced by preparations of diethyl-n-hexadecylamine (from diethylamine) and of dimethyl-n-docosylamine (from dimethylamine) . Alkyl sulphonates have similarly been used, and the reaction extended to the preparation of cyclic tertiary amines from primary amines and appropriate terminal di-sulphonates (reaction 38) . Satisfactory conditions have been reported... 

Tertiary Amines.—A new method for the preparation of tertiary amines (and secondary amines) from primary amines has distinct advantages over more conventional methods. Thus, with secondary amines such as piperidine or morpholine, N-benzyl-2,4,6-triphenylpyridinium perchlorate (13) gives the corresponding tertiary amines. Complications arising from quaternization are not observed, and this is attributed to unfavourable steric interactions in the transition state. 

Scheme 6.46. Chemoselective preparation of tertiary amines, (a) Utilization of a REM resin to synthesize multiply substituted tertiary amines. R and R = Me, (CH2)2Ph, tetrahydroisoquinoline, ethyl Isonipecotate, ethyl nipecotate R = allyl, 4-NO2-C6H4. (b) Selective quaternizatlon of diamines to yield tertiary amines. R = CHPh2, CONHPh R = Me, allyl.

S. Lober, P. Gmeiner, Click chemistry on solid support synthesis of a new REM resin and application for the preparation of tertiary amines. Tetrahedron, 2004, 60, 8699-8702. 

A convenient method for the preparation of tertiary amines bearing a t-alkyl group has been described treatment of the trichloromethyl amine (50), readily obtained from a tetra-alkylthiuram disulphide, with an excess of Grignard reagent gives the product as shown in Scheme 121. 

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