Secondary amines alkylation

In a variation on this approach, p-chlorobenzaldehyde is rst condensed with 2-aminopyridine. Reduction of the resulting iff base (62) affords the corresponding secondary amine. Alkyl-ion with the usual side chain affords the antihistamine, chlor-ramine (64). ... 

Secondary Amine Alkylated Aldehyde or Ketone Yield of Tertiary Amine (%)... 

Urethanes. Methyl carbamates (1) can be prepared from primary or secondary amines, alkyl halides, and carbon dioxide in a reaction promoted by copper(I) /-butoxide (equation I). The ligand t-butyl isocyanide can be replaced with tri-n-butylphosphine. Copper(I) f-butoxide is more effective than other copper salts. In the case of diethylamine, the intermediates a and b were isolated and b was converted to the methyl carbamate in 86% yield. 

Synthesis of alkylated thiourea from secondary amine Alkylated thiourea can be prepared from secondary amine ... 

The preparation of pure primary amines by the interaction of alkyl halides and ammonia is very difficult, because the primary amine which is formed reacts with unchanged alkyl halide to give the secondary amine the latter... 

The quinaldine is separated from any unreacted aniline and from the alkyl-anilines by treatment with acetic anhydride, basified with sodium carbonate and steam distilled. Only the primary and secondary amines are acetylated the acetylated amines are now much less volatile so that separation from the steam-volatile quinaldine (a tertiary amine) is facile. 

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. 

A special problem arises in the preparation of secondary amines. These compounds are highly nucleophilic, and alkylation of an amine with alkyl halides cannot be expected to stop at any specifle stage. Secondary amides, however, can be monoalkylated and lydrolyzed or be reduced to secondary amines (p. 11 If.). In the elegant synthesis of phenyl- phrine an intermediate -hydroxy isocyanate (from a hydrazide and nitrous acid) cyclizes to pve an oxazolidinone which is monomethylated. Treatment with strong acid cleaves the cyclic irethan. 

Tertiary amines may be obtained from alkaline alkylation of secondary amines (46), but mixtures are obtained (see Section III.l.B) hence heterocyclization and ammonolysis of 2-halothiazoles are to be preferred. 

A second alkylation may follow converting the secondary amine to a tertiary amine Alkylation need not stop there the tertiary amine may itself be alkylated giving a qua ternary ammonium salt... 

Ammonia can act as a nucleophile toward primary and some secondary alkyl halides to give primary alkylamines Yields tend to be modest because the primary amine IS itself a nucleophile and undergoes alkylation Alkylation of ammonia can lead to a mixture containing a primary amine a secondary amine a tertiary amine and a quaternary ammonium salt... 

Alkylation (Section 22 12) Amines act as nucleophiles toward alkyl halides Pri mary amines yield secondary amines secondary amines yield tertiary amines and tertiary amines yield quaternary ammonium salts... 

N Nitroso amine (Section 22 15) A compound of the type R2N—N=0 R may be alkyl or aryl groups which may be the same or different N Nitroso amines are formed by ni trosation of secondary amines... 

Secondary amine (Section 22 1) An amine with any combma tion of two alkyl or aryl substituents and one hydrogen on nitrogen an amine of the type... 

Phosgene reacts with a multitude of nitrogen, oxygen, sulfur, and carbon centers. Reaction with primary alkyl and aryl amines yield carbamoyl chlorides which are readily dehydrohalogenated to isocyanates. Secondary amines also form carbamoyl chlorides. 

Refluxing linoleic acid and a primary or secondary alkyl amine with -toluenesulfonic acid in toluene for 8—18 h also yields the substituted amides (32—34). The reaction of methyl esters with primary or secondary amines to make substituted amides is catalyzed with sodium methoxide. Reactions are rapid at 30°C under anhydrous conditions (35). Acid chlorides can also be used. Ai,A/-dibutyloleamide [5831-80-17 has been prepared from oleoyl chloride and dibutyl amine (36). 

Reductive amination of cyclohexanone using primary and secondary aHphatic amines provides A/-alkylated cyclohexylamines. Dehydration to imine for the primary amines, to endocycHc enamine for the secondary amines is usually performed in situ prior to hydrogenation in batch processing. Alternatively, reduction of the /V-a1ky1ani1ines may be performed, as for /V,/V-dimethy1 cyclohexyl amine from /V, /V- di m e th y1 a n i1 i n e [121 -69-7] (12,13). One-step routes from phenol and the alkylamine (14) have also been practiced. 

In addition to the nitrile and alcohol routes for fatty amine preparation, processes have been described by Unocal and Pennwalt Corporation, using an olefin and secondary amine (14—16) by Texaco Inc., hydrogenation of nitroparaffins (17—20) by Onyx Corporation, reaction of an alkyl haUde with secondary amines (21,22) by Henkel Cie, GmbH, reduction of an ester in the presence of a secondary amine (23) by catalytic hydroammonolysis of carboxyhc acids (24) and by the Hofmann rearrangement (25). 

Alkyl dimethyl and dialkylmethyl tertiary amines are commercially available. These amines are prepared by reductive methylation of primary and secondary amines using formaldehyde and nickel catalysts (1,3,47,48). The asymmetrical tertiary amines are used as reactive intermediates for preparing many commercial products. 

Primary and secondary amines are usually converted to tertiary amines using formaldehyde and hydrogen in the presence of a catalyst (eqs. 5 and 6). This process, known as reductive alkylation (222), is attractive commercially. The desired amines are produced in high yields and without significant by-product formation. Quatemization by reaction of an appropriate alkylating reagent then follows. 

AsH, primary and secondary amines, and lower alcohols, BCl, BBr, and BI react to hberate the corresponding hydrogen hahde. Tertiary alcohols and the boron tnhahdes yield the alkyl hahde and boric acid. The boron tnhahdes hydrolyze readily in water or moist air to produce boric acid and hydrogen hahdes. 

A -Nitroso derivatives, prepared from secondary amines and nitrous acid, are cleaved by reduction (H2/Raney Ni, EtOH, 28°, 3.5 h CuCl/concd. HCl"). Since many V-nitroso compounds are carcinogens, and because some racemization and cyclodehydration of V-nitroso derivatives of V-alkyl amino acids occur during peptide syntheses, V-nitroso derivatives are of limited value as protective groups. 

The manufacture of alkyl cyanoacrylate monomers, 1, involves the Knoevenagel reaction of formaldehyde, 2, with an alkyl cyanoacetate, 3, and a base, such as a secondary amine, as the catalyst, shown in Eq. 1. 

However, as can also be seen in Fig. 11, primary and secondary amines do not perform very effectively as primers, compared to tertiary amines, even though they also contain long alkyl chains. It has been demonstrated that, instead of directly initiating ECA polymerization, primary and secondary amines first form aminocyanopropionate esters, 12, because proton transfer occurs after formation of the initial zwitterionic species, as shown in Eq. 7 [8,9]. 

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