From Primary Amines

Tryptamine derivatives (26) were reacted with EMME to give N-[2-(3-indolyl)ethyl]aminomethylenemalonates (27) in nearly quantitative yields (77H1699 79MI1). 

The reaction of additional tryptamine analogues (28) and EMME in boiling ethanol gave the appropriate aminomethylenemalonates (29) in 97-98% yields [85TL1769 87JCS(P 1)2079, 87T191]. 

The reaction of propylamine derivatives (30) with EMME gave amino-methylenemalonates (31) in 80-84% yields (82MI7). Aminomethylene-malonates (32) were prepared in the exothermic reaction of glycine esters and EMME (77H1821). 

The sodium salt of D-phenylglycine was reacted with EMME in boiling benzene for 3 hr, and the ethanol was then azeotropically removed to give the sodium salt of the aminomethylenemalonate (33) in 50% yield [80JAP(K)31040 81CPB1998 86MI2]. 

The mono- and disodium salts of Cephalosporin C were reacted with EMME in aqueous acetone at room temperature for 5-6 hr to give aminomethylenemalonate (34) (80GEP3002659 82EUP45717). 

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Phenylurea Derizatives. These are prepared precisely as those from primary amines, except that the toluene-/)-sulphonyl and benzene sulphonyl derivatives are insoluble in aqueous sodium hydroxide and therefore separate on formation. (M.ps., p. 552.)... 

MISCELLANEOUS COMPOUNDS DERIVED FROM PRIMARY AMINES... 

Thioureas. Thioureas (11) are typically made from primary amines and carbon disulfide. The amine can be ethylamine, butylamine. 

Examples 2 and 3 above produce dibenzyl derivatives from primary amines. 

The present authors have found that the preparation of 7V-acetyl aziridine derivates provides the most secure method of differentiating aziridines from primary amines which are alternate reaction products in a number of cases. The infrared spectra of the former derivatives show only a peak at 1690 cm" for a tertiary amide peaks at ca. 3440 and 1530 cm" indicative of a secondary amide are absent. Acetylation also shifts the aziridine ring protons to a lower field in the NMR by ca. 1 ppm relative to the parent aziridine. The A"-acetyl aziridines are hydrolyzed with 3% methanolic potassium hydroxide. " Published NMR spectra of several 16j5,17j -aziridines reveal resonance patterns resembling those of the respective epoxides. " ... 

The formation of 3-acylpyridinium compounds (59/) from primary amines and l-methoxybutene-3-one can be regarded as the enamine alkylation of a vinylogous amide followed by cyclization and loss of methanol and water. 

The formation of vinylogous amides from primary amines and -dicarbonyl compounds gives rise to hydrolyzable amine derivatives with greatly decreased nucleophilicity of the nitrogen function. Thus these derivatives have found some use as protecting groups in peptide syntheses 617-619). 

Michael reaction, A1<9) octalone, 45, 82 N Mono- and N,N disubstitdted UREAS AND THIOUREAS 45, 69 N Monosubstituted thioureas from primary amines and silicon tetra-lsothiocyanate, 45, 69 N Monosubstituted ureas from primary amines and silicon tetraisocyan-ate, 46, 69... 

Ring-opening products derived from primary amines are attractive precursors for the preparation of (3-lactams [57]. With methylmagnesium bromide as the base, diamino esters 33 cyclized readily in THF and stereospecifically generated anti-3-amino- 3-lactams 34 (Table 12.15). 

Due to instability in air, very few free dithiocarbamic acids have been isolated (18). Dithiocarbamates derived from primary amines are... 

N-Monosubstituted ureas from primary amines and silicon tetraisocyan-ate, 45, 69... 

Aminomethano destannylotion bishomoallyl amines. Methyleneimmonium trifluoroacetates, generated in situ from primary amines and formaldehyde, react with allyltrialkyltin compounds to form bishomoallylic amines in high yield Example ... 

IV-Chloroalkylamines R HCl (R1 = Me, Bu, C7H15, etc.), generated from primary amines and sodium hypochlorite, react with the alkyldimethylboranes R2BMe2 (R2 = CgHi3, cyclopentyl or cyclohexyl) to give the secondary amines R1R2NH in 50-68% yields179. 

A method for the preparation of olefins from primary amines is shown in equation 120. Treatment of 2-(4-bromophenyl)ethylamine (358) with acetic acid, acetic anhydride and sodium nitrite generates the nitroso amide 359, which decomposes to 4-bromostyrene in the presence of rhodium(II) acetate. The procedure is thus a mild, non-basic alternative to the classical Hofmann elimination of amines396,397. 

Crampton24 has also demonstrated that for Meisenheimer complex formation, increased crowding at the reaction site caused by change from primary amines to piperidine results in rate reduction of proton transfer from the complex to the amine catalyst, and Hirst199... 

Selected examples of the synthesis of isonitriles from primary amines... 

The chemistry of the isocyanides began when, in 1859 Lieke formed allyl isocyanide from allyl iodide and silver cyanide, and when, in 1866 Meyer ° produced in the same way 1-isocyano-l-desoxy-glucose. In 1867, Gautier used this procedure to prepare alkylisocyanides, and Hofmann introduced the formation of isocyanides from primary amines, chloroform, and potassium hydro-xyde. Gautier also tried to prepare an isocyanide by dehydrating an amine formiate via its formylamine using phosphorus pentoxide, but this process produced no isocyanide. Gautier had not yet realized that acidic media destroyed the isocyanides. 

Reactions of allylic electrophiles with stabilized carbon nucleophiles were shown by Helmchen and coworkers to occur in the presence of iridium-phosphoramidite catalysts containing LI (Scheme 10) [66,69], but alkylations of linear allylic acetates with salts of dimethylmalonate occurred with variable yield, branched-to-linear selectivity, and enantioselectivity. Although selectivities were improved by the addition of lithium chloride, enantioselectivities still ranged from 82-94%, and branched selectivities from 55-91%. Reactions catalyzed by complexes of phosphoramidite ligands derived from primary amines resulted in the formation of alkylation products with higher branched-to-linear ratios but lower enantioselectivities. These selectivities were improved by the development of metalacyclic iridium catalysts discussed in the next section and salt-free reaction conditions described later in this chapter. 

There is a distinct relationship between keto-enol tautomerism and the iminium-enamine interconversion it can be seen from the above scheme that enamines are actually nitrogen analogues of enols. Their chemical properties reflect this relationship. It also leads us to another reason why enamine formation is a property of secondary amines, whereas primary amines give imines with aldehydes and ketones (see Section 7.7.1). Enamines from primary amines would undergo rapid conversion into the more stable imine tautomers (compare enol and keto tautomers) this isomerization cannot occur with enamines from secondary amines, and such enamines are, therefore, stable. 

The sulphonyl chloride 23 is proposed as a protecting group for the Gabriel synthesis of secondary amines from primary amines. At the deprotecting stage, carbon-sulphur bond cleavage is achieved using zinc and acid as the electron source [109]. 

A published synthetic scheme (36) of a four component Ugi reaction (Fig. 6) has been used as an example to demonstrate the use of the SA optimization protocol for the simultaneous optimization of multiple properties. Because two of the four components are fixed in the scheme, only two diversity sites remain for optimization. These two sites come from primary amines (R1NH2) and aldehydes (R2CHO), respectively. We have collected from the ACD (Available Chemical Directory) structures of primary amines and aldehydes available from ALDRICH and LANCASTER. Compounds with reactive or unstable structural patterns are removed. As a result, 779 primary amines and 246 aldehydes are considered. 

The main drawback to this reaction is the toxicity of diazomethane and some of its precursors. One possible alternative is the use of alkyltriazenes as reactive alkylating agents.52 Alkyltriazenes are readily prepared from primary amines and aryldiazonium salts.53 The triazenes, on being protonated by the carboxylic acid, generate a reactive alkylating agent that is equivalent, if not identical, to the alkyldiazonium ions generated from diazoalkanes. 

PREPARATION OF SECONDARY AMINES FROM PRIMARY AMINES VIA 2-NITROBENZENESULFONAMIDES N-(4-METHOXYBENZYL)-3-PHENYLPROPYLAMINE [Benzenepropanamine, N-[(4-methoxyphenyl)methyl]-]... 

PREPARATION OF SECONDARY AMINES FROM PRIMARY AMINES VIA... 

Scheme 10.3 Formation of ureas from primary amines, CO2, and terminal alkynes.

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