N-Alkylation of primary

N-Alkylation of primary aromatic amines increases their nucleophilic character, making them couple much more readily, the introduction of the azo group occurring in the 4-position. Thus, in contrast to aniline, N-methylaniline couples readily and N,N-dimethyl-aniline very readily with simple diazonium salts. Diphenylamine also couples in the 4-position, but less readily than N-methylaniline. 

A possible mechanism for the N-alkylation of primary amines is shown in Scheme 5.21. The first step of the reaction involves the oxidation of an alcohol to a carbonyl intermediate, accompanied by the generation of an iridium hydride. 

Table 5.10 N-Alkylation of primary amines with various primary and secondary alcohols catalyzed by [Cp lrCl2]2 (1)- ...

Reductive N-Alkylation of Primary Amides with Carbonyl Compounds... 

Scheme 10.11 Cobalt carbonyl catalyzed reductive N-alkylation of primary amides (partially reproduced from Ref [62]).

Nearly all such quinoxalinones have been made either by primary synthesis (see Chapter 1) or by N-alkylation of tautomeric quinoxalinones (see Section 4.1.2.2). However, several recently used minor routes are illustrated by the following examples. 

Secondary amines synthesized by catalytic reductive alkylation of primary amines are used in a variety of fine and specialty chemical indnstries. For example, derivatives of cyclohexylamine are used as corrosion inhibitors, N-(l,3-dimethylbntyl)-N -phenyl-p-phenylenediamine (6-PPD) is nsed as an anti-oxidant in rabber indnstiy, several dialkylated diamines are used in the coatings indnstiy, while they are nsed in the pharmacentical industry as pharmacophores (1-7). Harold Greenfield and co-workers have examined the ability of platinum group metals (PGM), base metals, and their snlfides to catalyze rednctive alkylation of primary and secotrdary amines (8-11). They found that different catalysts are optimal for the... 

The addition of C-centered radicals to the C=N bond giving rise to radicals B (Scheme 3.98) can be used for organization of radical C-alkylation of primary nitro compounds containing the sulfo group at the a-position (315). 

The simplicity of the two-phase modification of the Gabriel synthesis of primary amines, via the N-alkylation of potassium phthalimide, makes the procedure considerably more convenient than the traditional method, which normally requires the use of anhydrous dipolar aprolic solvents. The reaction can be conducted under solid liquid conditions using potassium hydroxide in toluene [25], or with preformed potassium phthalimide [26, 27] (cf ref. 28). As is normal for acylation reactions, relatively mild conditions are required for the preparation of the A-ethoxycarbonyl derivative [29], whereas a reaction temperature of 100°C is generally used for N-alkylation (Table 5.16). The reaction time for the soliddiquid two-phase system can be reduced dramatically with retention of the high yields, when the reaction mixture is subjected to microwave irradiation [30]. 

The alkylation of primary nitramines with alkyl halides is of little preparative value for the synthesis of secondary nitramines. Such reactions often result in a mixture of N- and 0-alkylated products. The product distribution appears to be very dependent on the nature of the cation of the nitramine used, with silver salts ° favouring 0-alkylation and alkali metal salts usually giving A-alkylation as the predominant product. However, this is not always the case. 

A. Zwierzak, ACS Symp. Ser. 171,169-172 (1981) N-Alkylation of Organophosphorus Amides. A New, Convenient Route to Primary and Secondary Amines". 

When the reagent is the thiocyanate ion, S-alkylation is an important side reaction (0-42), but the cyanate ion practically always gives exclusive N-alkylation.422 Primary alkyl halides have been converted to isocyanates by treatment with sodium nitrocyanamide NaNCNNOi and m-chloroperbenzoic acid, followed by heating of the initially produced RN(N02)CN.956 When alkyl halides are treated with NCO" in the presence of ethanol, carbamates can be prepared directly (see 6-8).957 Acyl halides give the corresponding acyl isocyanates and isothiocyanates.958 For the formation of isocyanides, see 0-101. 

Barco et al.127 and Bocchi et al.128 have described independently N-alkylation of indole in very good yield when primary halides or sulfates are used. With allyl halides,128 however, alkylation occurs to a large extent at position 3. 

Sulfonamides of primary amines are readily deprotonated (pAia 9-11) and can thus be N-alkylated or N-arylated. Because of their high nucleophilicity and low basicity, deprotonated sulfonamides also react smoothly with less reactive electrophiles, such as n-alkyl bromides [136] (Table 8.9). Sulfonamides can also be N-alkylated with aliphatic alcohols under Mitsunobu conditions. Suitable solvents for the N-alkylation of sulfonamides on polystyrene by Mitsunobu reaction are DCM, toluene, and THF. 

Secondary amines can be prepared by conversion of primary amines into sulfonamides, followed by N-alkylation and hydrolysis. Because sulfonamides are often difficult to hydrolyze, the N-alkylation of trifluoroacetamides has been investigated. Tri-... 

This method is suitable for the mono-N-alkylation of other primary aromatic amines. Trimethyl and triethyl orthoformate are commercially available, and other alkyl orthoformates can be obtained readily from them by transesterification.2 The following have been prepared in a similar manner by the submitters.3... 

Most such pyrazinones have been made by primary synthesis (Chapters 1 and 2) or N-alkylation of tautomeric pyrazinones (Section 5.1.2.2). The minor route by rearrangement of alkoxypyrazines (H 184) appears to be unpresented in recent literature, but there are examples of the hydrolysis of nontautomeric iminopyrazines to corresponding pyrazinones. Thus 3-imino-4-methyl-3, 4-dihy-dro-2-pyrazinamine hydriodide (191, R = H) (i.e., 2,3-diamino-l-methyl-pyrazinium iodide) underwent hydrolysis in 2 M sodium hydroxide during 1 h at 100°C to afford 3-amino-1 -methyl-2(l//)-pyrazinonc (192, R = H) ( 40%) without any evidence of Dimroth rearrangement to 3-methylamino-2-pyrazinamine 1008 l-methyl-3-methylamino-2(l//)-pyrazinimine (191, R = Me) likewise gave 1-methyl-3-methylamino-2(l//)-pyrazinone (192, R = Me) ( 50%) 1008 and other examples have been reported.598... 

Primofy amines. A new method for preparation of primary amines involves N-alkylation of this derivative of hydroxylamine, dehydration of the product, 2, to 4, and finally acid hydrolysis of the N-benzylidenealkylamine (4) to the amine 5. HMPT is the solvent of choice for the alkylation step. 2-Fluoro-l-methylpyridinium p-toluenesulfonate (3) is superior to tosyl chloride for the second step. 

Another route to terminal alkynes having one carbon more than the aldehyde precursor is via alkylation of primary alkyl bromides with dichloromethyllithium in the presence of HMPA to yield the 1,1-dichloroalkane. Subsequent dehydrochlorination with three equivalents of n-BuLi followed by hydrolytic workup affords the corresponding terminal alkyne. ... 

Although several methods have been reported, the synthesis of iV-monoalkylhydroxylamines from alkyl halides or sulfonates has remained difficult. Relating to this a new preparation of A -alkylhydroxyl-amines is based upon N-alkylation of isoxazole derivative (52). Besides 2-propyl iodide several primary alkyl halides have been described as the alkyladon agent in this procedure (equation 23). ... 

Direct alkylation of hydrazine itself with halides and sulfates usually gives mixtures of mono- and poly-alkylated hydrazines. It is possible to get useful yields of the monoalkylhydrazine by using an excess of hydrazine. Several specific procedures leading to monoalkylhydrazines are based on selective alkylation of hydrazine derivatives with protecting groups attached. So, easily prepared acetone N-(diethoxyphosphoryl)hydrazone (75) can be used. Phase-transfer catalyzed N-alkylation of (75), followed by deprotection with p-toluenesulfonic acid provides monoalkylhydrazine sulfonates (76 Scheme 17). Similarly, N-alkyl-N-arylhydrazines have been prepared by phase-transfer catalyzed N-alkylation of arylhydrazones (Scheme 18). An efficient, one-pot method for the synthesis of a variety of polysilyl-ated hydrazines employs hexamethyldisilane (equation 30). Polysilylated hydrazines were found to react with aldehydes or ketones to give hydrazones under anhydrous conditions. By treatment with triphenylphosphine and diethyl azodicarboxylate primary and secondary alcohols can be converted to hy-dr ine derivatives (equation 31). ... 

Alkylation of primary amines can be accomplished with Raney nickel (W-2) in the presence of ethanol, as in the preparation of N,N -diethylbenzidine. The mixture is stirred vigorously during the reflux period. 

The same nucleophilic substitution chemistry can be manipulated by means of microwave irradiation to afford a variety of cyclic amines as building blocks in natural product syntheses via double V -alkylation of primary amines (Scheme 11). The protocol circumvents the difficulty associated with running multi-step reactions to assemble Y -aryl azacycloalkanes and avoids the use of expensive metal catalysts in building aryl C-N bonds. Further, reactive functional groups, such as carbonyl, ester, and hydroxyl, remain unaffected under these mild reaction conditions. The V-alkylation reaction is now extended to hydrazines as well. ... 

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