Preparation of Secondary and Tertiary Amines

Besides the classical heterocydization and ammonolysis methods some other syntheses have been developed to prepare secondary and tertiary 

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. 

4-Alky]-5-imino-3-methy -A2-l,2,4-thiadiazoIines react exotherm ally at 0°C with dibenzoy] or dimethoxy carbonylacetylenes in tetrahydrofuran to give the 2-alkylaminothiazoles in high yields (1564). The cycio addition reaction of 2-pyridyl isothiocyanates with 1-azirines results in the formation of 2-pyridylaminothiazoles (1565). 

Recently, a new synthesis of 2-aminothiazo es has been proposed it involves the reaction between quaternary salts of 2-aikylthiothiazo es and the appropriate amine (1566). 

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Sulfenimines are versatile building blocks for the preparation of secondary and tertiary amines. Therefore, fluoroalkylated sulfenimines should be promising building blocks for the preparation of N-fluoroalkylamino compounds. In fact, very recently, trifluoromethylated sulfenimines have been easily prepared in... 

As outlined, electrophilic animation of diorganozincs with A-mono- and A,A-disub-stituted O-benzoylhydroxylamines is a general procedure and an easy route for the preparation of secondary and tertiary amines from diorganozincs. 

ALKYLATION AND REDUCTIVE ALKYLATION PROCEDURES FOR THE PREPARATION OF SECONDARY AND TERTIARY AMINES... 

For the preparation of secondary and tertiary amines by monoalkylation of, respectively, primary and secondary amines by alkali halides there are as few satisfactory prescriptions in the literature as there are for the reaction with ammonia. The main difficulties have been mentioned above. 

A method that achieves the same end result as that desired by alkylation of ammonia but which avoids the formation of secondary and tertiary amines as byproducts is the Gabriel synthesis Alkyl halides are converted to primary alkylamines without contam mation by secondary or tertiary amines The key reagent is the potassium salt of phthal imide prepared by the reaction... 

Among compounds other than simple alkyl halides a halo ketones and a halo esters have been employed as substrates m the Gabriel synthesis Alkyl p toluenesul fonate esters have also been used Because phthalimide can undergo only a single alkyl ation the formation of secondary and tertiary amines does not occur and the Gabriel synthesis is a valuable procedure for the laboratory preparation of primary amines... 

For the preparation of secondary and tertiary selenoamides, several methods have been used reaction of lithium alkyneselenolates (obtained using metallic selenium) with amines, aromatic diselenoic acid Se-methyl esters with amines or dihalomethane with elemental selenium, NaH and amines (Scheme 83).258 266... 

Helgen, C. Bochet, C. G. Preparation of secondary and tertiary amides under neutral conditions by photochemical acylation of amines. Synlett 2001, 1968—1970. 

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. 

We have already encountered alkylation of amines as a side reaction in the preparation of primary amines by the ammonolysis of halides (Sec. 22.10), and as a method of synthesis of secondary and tertiary amines (Sec. 22.13). Let us look at one further aspect of this reaction, the formation of quaternary ammonium salts. 

The conversion of a wide variety of P, S, and N organic compounds over H-mordenite and HZSM-5 catalysts has been described. The reaction of nitric oxide and chlorine near to equilibrium over H-mordenite was studied by use of a pressure-jump method. The preparation of aliphatic amines from the reaction of Ci—C3 alcohols and ethers with ammonia over HZSM-5, HZSM-11, and HZSM-21 has been described. The proportion of secondary and tertiary amines decreased as the size of alcohol or ether reactant increased. Chang and Silvestri showed that methanethiol is converted over HZSM-5 to hydrocarbons in a broadly similar way to methanol. However, a higher temperature (755 K) is required and even so 27.2 % total carbon remains unconverted as (CH3)2S. Propane is the major paraffin and the aromatics are largely C9. 

The procedure described above illustrates a general, two-step method for the preparation of secondary or tertiary amines. It can be considered as a reductive N-alkylation of a nitrile or an N-monoalkylation of a primary or secondary amine. The first step in the procedure involves direct addition of an aliphatic amine to a nitrile promoted by a stoichiometric amount of cuprous chloride, as fully described recently.4 This method may be used with a large variety of nitriles and primary or secondary aliphatic amines. The nitrile itself may be used as solvent (acetonitrile, benzonitrile). In the case of a primary amine, substrate stoichiometry must be adapted to obtain selectively either the N-monosubstituted amidine [1 eq amine, 1.2 eq Cu(l)CI in acetonitrile] or the N,N-disubstituted amidine [4 eq amine, 1 eq Cu(l)CI, 1 eq acetonitrile in alcohol or DMSO].4... 

The most important method of preparing primary aliphatic amines is that due to Gabriel, in which the undesirable formation of secondary and tertiary amines is excluded.443 It consists of treatment of potassium phthalimide with an alkyl halide and hydrolysis of the A-alkylphthalimide formed. 

While Frankland was evolving his theory of combining power, the new type theory was making its appearance. The primary amines methylamine and ethylamine had been prepared in 1849 by Charles Adolphe Wurtz (1817-1884), and he recognised that these compounds were related to ammonia. The work was continued by August Wilhelm von Hofmann (1818-1892), who in 1851 prepared primary, secondary and tertiary amines and also quaternary ammonium salts. He classified these as belonging to the ammonia type (Figure 8.5). 

This is clearly a much longer sequence to make a primary amine than simple reaction with ammonia. It does not suffer from problems of polyalkylation, however, and the yield of the amine for the two-step sequence is often higher than the direct reaction with an amine. The fact that this procedime is used more often to make aliphatic primary amines than the reaction of ammonia with an alkyl halide suggests the severity of the problems associated with polyalkylation. The preparation of secondary or tertiary amines often requires the use of the S- 2 reaction with amines, however. Other amine surrogates are known, including the azide ion (Section 11.3.4) and the cyanide ion (Section 11.3.5), but both give primary amines as the end product. 

In 2008, Fujita, Yamaguchi and co-workers reported an efficient solvent-free synthesis of secondary and tertiary amines by [Cp IrCl2]2-catalyzed multialkylation of ammonium salts with primary or secondary alcohols [96]. The authors found that the type of ammonium salts greatly affected the selectivity of the reaction (Scheme 21a). Secondary 5- and 6-membered cyclic amines could also be prepared from ammonium tetrafluoroborate and diols by the same method. 

The azide synthesis is a better method for preparing primary amines than alkylation of ammonia because it avoids the formation of secondary and tertiary amines. This method involves treating an alkyl halide with sodium azide followed by reduction (Mechanism 23.1). 

The Gabriel synthesis is another method for preparing primary amines while avoiding formation of secondary and tertiary amines. The key reagent is potassium phthahmide, which is prepared by treating phthalimide with potassium hydroxide. 

In Chapter 16 (page 218) you learnt how bromoethane undergoes nucleophilic substitution with ammonia to form a mixture of amines. In order to prepare ethylamine (while avoiding the formation of secondary and tertiary amines and ammonium salts) we use excess hot ethanolic ammonia ... 

To prepare a primary amine by alkylation of ammonia, the level of ammonia is kept high to reduce the formation of secondary and tertiary amines. The preparation of -butylamine is a typical example of the procedure. 

Methods for the preparation of primary amines free of secondary and tertiary amines have occupied the efforts of organic chemists since the days of Hofmann. Several of these have at least a formal resemblance to the Hofmann alkylation. 

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