Secondary amines, substitution reactions

Treatment with sodium hypochlorite or hypobromite converts primary amines into N-halo- or N,N-dihaloamines. Secondary amines can be converted to N-halo secondary amines. Similar reactions can be carried out on unsubstituted and N-substituted amides and on sulfonamides. With unsubstituted amides the N-halo-gen product is seldom isolated but usually rearranges (see 18-13) however, N-halo-N-alkyl amides and N-halo imides are quite stable. The important reagent NBS is made in this manner. N-Halogenation has also been accomplished with other reagents, (e.g., sodium bromite NaBr02) benzyltrimethylammonium tribromide (PhCH2NMe3 Br3"), and NCS. The mechanisms of these reactions involve attack by a positive halogen and are probably similar to those of 12-47 and 12-49.N-Fluorination can be accomplished by direct treatment of amines °° or... 

If the ring nitrogen atom forms a secondary amine, its reaction with aryl isocyanate can yield substituted ureas and this transformation is strongly related to a N-acylation. In this respect, a publication by Saczewski and Nasal <1995APH237> should be mentioned here these authors described the transformation of 119 with a number of arylisocyanates to the urea 120 in medium to high yields (49-82%) (Scheme 17). 

With more bulky secondary amines, the reaction may stop before total substitution yielding mixed haloamides.1516... 

Reaction CXLI. Action of Acids, Acid Anhydrides and Chlorides on Primary and Secondary Amines.—Substituted amides are usually prepared by treating amines with organic acids, or with acyl chlorides or anhydrides. When the acid is used a salt is first formed from which a molecule of water is eliminated on further heating. 

To summarise, then, it is possible to predict kinetic characteristics from Hammett-type relationships, provided that electron directing and steric characteristics are similar in a series of substituted amines. The mechanism proposed by De La Mere [29] for the oxidation of, for example, a secondary amine, see reaction (18), underlines the complexity of the kinetics that can be expected, unless one particular transition state and one reaction path is the major reaction route. 

By carefully tuning the structure of the starting materials, Orru et al. [21] developed an efficient synthesis of imidazoline 18 by using essentially the same reaction partners (Scheme 15.8). The key to substrate design is the use of a-aryl-substituted a-isocyanoacetate (17) and the primary amine instead of the secondary amine as reaction partner of the aldehyde. The reaction was initiated by nucleophihc addition of the enolate anion of 17 onto the imine 19, generated in situ. However, the lack of an additional acidic proton a to ester in the Mannich adduct 20 made the P-elimination impossible. On the other hand, the Mannich adduct having a secondary amine remained nucleophilic and could add intramolecularly to the divalent isocyano carbon, leading, after protonation, to the imidazoline 18 in... 

Protecting Group. As mentioned above, under basic conditions, secondary amines form with CS2 dithiocarbamates. Subsequent reaction with an organometallic base and one equivalent of electrophile gives, in good yields, the secondary amines substituted in the a-position (eq 8). ... 

Benzenesulphonyl chloride reacts with primary and secondary, but not with tertiary, amines to yield substituted sulphonamides (for full discussion, see Section IV,100,3). The substituted sulphonamide formed from a primary amine dissolves in the alkaline medium, whilst that produced from a secondary amine is insoluble in alkali tertiary amines do not react. Upon acidifying the solution produced with a primary amine, the substituted sulphonamide is precipitated. The reactions form the basis of the Hinsberg procedure for the separation of amines see Section IV,100,(viii) for details. Feebly basic amines, such as o-nitroaniline, react slowly in the presence of allcali in such cases it is best to carry out the reaction in pyridine solution see Section IV,100,3. ... 

Now, contrary to popular opinions, this method need not be conducted in a sealed pipe bomb. Secondary amination by substitution is as much a reaction of opportunity as it is of brute force and heat. In fact, heating can tend to cause the reformation of safrole and isosafrole. So the simplest way to do this would be to use 500mL of ammonium hydroxide or alcoholic ammonia or, for those wishing to make MDMA or meth, 40% aqueous methylamine or alcoholic methylamine (to tell you the truth, methylamine is preferable in this method because it is more reactive that ammonia so yield will increase). This 500mL is placed in a flask and into it is poured a solution of 35g bromosafrole (30g phenylisopropyl-bromide) mixed with 50mL methanol. The flask is stoppered and stirred at room temperature for anywhere from 3 to 7 days. The chemist could also reflux the same mixture for 6-12 hours or she could throw the whole mix into a sealed pipe bomb (see How to Make section) and cook it for 5 hours in a 120-130°C oil bath. 

There also exists an acidregioselective condensation of the aldol type, namely the Mannich reaction (B. Reichert, 1959 H. Hellmann, 1960 see also p. 291f.). The condensation of secondary amines with aldehydes yields Immonium salts, which react with ketones to give 3-amino ketones (=Mannich bases). Ketones with two enolizable CHj-groupings may form 1,5-diamino-3-pentanones, but monosubstitution products can always be obtained in high yield. Unsymmetrical ketones react preferentially at the most highly substituted carbon atom. Sterical hindrance can reverse this regioselectivity. Thermal elimination of amines leads to the a,)3-unsaturated ketone. Another efficient pathway to vinyl ketones starts with the addition of terminal alkynes to immonium salts. On mercury(ll) catalyzed hydration the product is converted to the Mannich base (H. Smith, 1964). 

A) Sn2 substitution at the allylic alcohol with hydrobromic acid followed by reaction with the requisite secondary amine, or... 

Secondary amines give only a monosubstituted product. Both of these reactions are thermally reversible. The product with ammonia (3,3, 3 -nitrilottispropionamide [2664-61-1C H gN O ) (5) is frequently found in crystalline acrylamide as a minor impurity and affects the free-radical polymerisation. An extensive study (8) has determined the stmctural requirements of the amines to form thermally reversible products. Unsymmetrical dialkyl hydrasines add through the unsubstituted nitrogen in basic medium and through the substituted nitrogen in acidic medium (9)). 

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). 

Sequential substitution reactions which transform alcohols into a family of primary, secondary, and tertiary amines. 

Rifamycin S also undergoes conjugate addition reactions to the quinone ring by a variety of nucleophiles including ammonia, primary and secondary amines, mercaptans, carbanions, and enamines giving the C-3 substituted derivatives (38) of rifamycin SV (117,120,121). Many of the derivatives show excellent antibacterial properties (109,118,122,123). The 3-cycHc amino derivatives of rifamycin SV also inhibit the polymerase of RNA tumor vimses (123,124). 

If primary or secondary amines are used, A/-substituted amides are formed. This reaction is called aminolysis. Hydra2ines yield the corresponding hydra2ides, which can then be treated with nitrous acid to form the a2ides used in the Curtius rearrangement. Hydroxylamines give hydroxamic acids. 

An important extension of these reactions is the Mannich reaction, in which aminomethyl-ation is achieved by the combination of formaldehyde, a secondary amine and acetic acid (Scheme 24). The intermediate immonium ion generated from formaldehyde, dimethyl-amine and acetic acid is not sufficiently reactive to aminomethylate furan, but it will form substitution products with alkylfurans. The Mannich reaction appears to be still more limited in its application to thiophene chemistry, although 2-aminomethylthiophene has been prepared by reaction of thiophene with formaldehyde and ammonium chloride. The use of A,iV-dimethyf (methylene) ammonium chloride (Me2N=CH2 CF) has been recommended for the iV,iV-dimethylaminomethylation of thiophenes (83S73). 

With secondary amines such as piperidine or dimethylamine the formal products (169) of cine substitution are obtained with primary amines e.g. /-butylamine), in addition to the displacement product (173), a rearranged product (174) is obtained in which the nitrogen-bearing methyl becomes exocyclic 80CC123). Earlier studies on the reaction of... 

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