Monoalkylation, of an amines

Even with a limited amount of the alkylating agent, the equilibria between protonated product and the neutral starting amine are sufficiently fast that a mixture of products may be obtained. For this reason, when monoalkylation of an amine is desired, the reaction is usually best carried out by reductive amination, a reaction that is discussed in Chapter 5. If complete alkylation to the quaternary salt is desired, use of excess alkylating agent and a base to neutralize the liberated acid normally results in complete reaction. 

Reduction of an amide is the last step in a useful procedure for monoalkylation of an amine. The process begins with acylation of the amine using an acyl chloride or acid anhydride then the amide is reduced with lithium aluminum hydride. For example,... 

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. 

FORSTER - DECKER Amine Synthesis Selective monoalkylation of primary amines via imines An altemativa method is the reaction ol 1 and 2 in the preserve of NaCNBH4 or tnaceloxyborohydride (Borch reduction)/... 

A trifluoromethylsulfonamide can be prepared from a primary amine to allow monoalkylation of that amine. The triflamide is not stable to strong base, which causes elimination to an imine, but when used to protect an indole, it is cleaved with K2CO3 in refluxing methanol. ... 

Monoalkylation of primary amines. A two-step sequence for this reaction involves conversion of the amine to the N-(cyanomethyl)amine (2) by reaction with chloroaceto-nitrile or with formaldehyde and KCN. Reaction of 2 with an organolithium or a Grignard reagent generates an unstable formaldehyde imint (a) that reacts with a second equivalent of the organometallic reagent to form a secondary amine (3). 

Alkynylation. This base (monohydrate) is an excellent catalyst for alkynylation of carbonyl compounds and selective A-monoalkylation of primary amines.- Cesium hydroxide suppresses overalkylation, and therefore is very useful in the exclusive formation of secondary amines from amino acids. 

Secondary Amines. - Monoalkylation of primary amines continues to be an important route to secondary amines, despite the problem of overalkylation. Irradiation of primary amines in alcohols... 

Monoalkylation of primary amines. This reaction can be carried out in three steps. The primary amine (1) is phosphorylated under phase-transfer conditions to give a diethyl ester (2) of an N-alkylphosphoramidic acid (6, 42) this ester can... 

Secondary Amines.- Selective monoalkylation of primary amines is a goal still actively pursued. Modified borohydride reagents applied in reductive alkylations have been particularly successful in achieving this aim. Sodium cyanoborohydride was used in an effi-cient synthesis of alkylated amino-sugars and also in the synthesis of the imino-carbohydrates 1-deoxynojirimycin and 1-deoxymannojirimycin, in which the reductive alkylation occurred in... 

An attractive route to secondary amines has always been the monoalkylation of primary amines. However, over-alkylation has been an inevitable problem with this approach, and new methodologies that avoid this complication are always welcome. One such method is the transition-metal catalysed N -alkyla-tion of amines by alcohols (Scheme 12). An alternative procedure utilizes aminosilanes (Scheme 13), which react readily with primary halides in the presence of sodium methoxide to afford, selectively, the corresponding secondary amines. 

When enamines are treated with alkyl halides, an alkylation occurs that is analogous to the first step of 12-14. Hydrolysis of the imine salt gives a ketone. Since the enamine is normally formed from a ketone (16-12), the net result is alkylation of the ketone at the a position. The method, known as the Stork enamine reaction is an alternative to the ketone alkylation considered at 10-105. The Stork method has the advantage that it generally leads almost exclusively to monoalkylation of the ketone, while 10-105, when applied to ketones, is difficult to stop with the introduction of just one alkyl group. Alkylation usually takes place on the less substituted side of the original ketone. The most commonly used amines are the cyclic amines piperidine, morpholine, and pyrrolidine. 

Monoalkylation of Af-tosylallylamine 10 with dibromoalkane 101 proceeded in 60-90% yield (Eq. 10 see also Scheme 3 and Eq. 2) [17]. The bromoalkyl-amines 102 were converted to nitro compounds 103. In situ transformation of 103 into nitrile oxides led to spontaneous cycloaddition with formation of isox-azolines fused to 5-, 6-, and 7-membered ring heterocycles 104 a-c. Under very high dilution conditions, 103 d was converted to 104 d, an isoxazoline fused to an 8-membered azocine, in low (10%) yield. 

Most studies of micellar systems have been carried out on synthetic surfactants where the polar or ionic head group may be cationic, e.g. an ammonium or pyridinium ion, anionic, e.g. a carboxylate, sulfate or sulfonate ion, non-ionic, e.g. hydroxy-compound, or zwitterionic, e.g. an amine oxide or a carboxylate or sulfonate betaine. Surfactants are often given trivial or trade names, and abbreviations based on either trivial or systematic names are freely used (Fendler and Fendler, 1975). Many commercial surfactants are mixtures so that purity can be a major problem. In addition, some surfactants, e.g. monoalkyl sulfates, decompose slowly in aqueous solution. Some examples of surfactants are given in Table 1, together with values of the critical micelle concentration, cmc. This is the surfactant concentration at the onset of micellization (Mukerjee and Mysels, 1970) and can therefore be taken to be the maximum concentration of monomeric surfactant in a solution (Menger and Portnoy, 1967). Its value is related to the change of free energy on micellization (Fendler and Fendler, 1975 Lindman and Wennerstrom, 1980). 

It has been reported that the ease of A-alkylation of aromatic amines is enhanced by ultrasonics [9], and, predictably, the presence of mesomeric electron-withdrawing substituents at positions ortho or para to the amino function aids the A-alkylation of the aromatic amines [e.g. 10], see also, for example, the phase-transfer catalysed glycosidation of 2-cyanoaniline [11], Generally, the direct /V-monoalkylation of aminoarenes is not particularly satisfactory, but an alternative protocol [12] in which the N-acyl derivatives are alkylated and then hydrolysed leads to enhanced yields (>90%) (see Section 5.2). In a similar manner, a one pot synthesis converts 2-... 

Alkylation of amines usually proceeds more slowly than acylations, and alkylating reagents can usually be thoroughly mixed with an amine before reaction is complete. Diamines or polyamines can therefore be transformed into mixtures of the statistically expected amounts of alkylated derivatives (Scheme 10.17). The use of CsOH as base has been found to be particularly conducive to the formation of monoalkylated products [72]. Some polyamines have also been monoalkylated selectively after complexation with Zn(II) [73],... 

The selectivity of acylations or alkylations of polyamines can also be modulated by protonation [78] or by conversion to cyclic aminals [71, 79, 80]. The latter strategy has, for instance, been used successfully for the preparation of monofunctionalized 1,4,7-triazacyclononanes (Scheme 10.18). In this reaction the first alkylation leads to the formation of an amidinium salt, which is more difficult to alkylate than a tertiary amine. Thus, the use of only one equivalent of alkylating agent leads to a clean monoalkylation. 

Acylation and arylation have not been thoroughly studied. Treatment of the amine (85 R = H) with an acid chloride gives the monoacylated derivative (154). The N-l monoalkylated derivatives of compound (85 R = H) are monoacylated on the exocyclic amino function. Triacylation of... 

Practical syntheses of 5a or N-substituted 3-aminobenz[d]isothiazole-1,1 -dioxides are mostly based on the following procedures (iv) Refluxing saccharin with an excess of a monoalkyl or aryl amine above 130°, presumably via ring opening, by analogy with 75.161,189,248... 

Treatment of a primary amine with an equimolar amount of an alkylating agent and a base generally produces a mixture of an N-monoalkylated amine (1) and an N,N-dialkylated amine (2) (2/). However, the cooperative function of weakly acidic and weakly basic sites on zeolites, together with steric demands by the zeolite cavities, brought about selective N-monoalkylation of... 

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