Secondary amines substitution

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. 

All TCAs are either secondary- or tertiary-amines of a dibenzazepine nucleus (Fig. 20.3), and they all inhibit neuronal reuptake of noradrenaline and/or 5-HT but are much less potent as dopamine reuptake blockers. A common claim is that secondary amines (e.g. desipramine) are preferential inhibitors of noradrenaline uptake whereas the tertiary derivatives (e.g. imipramine, doxepin and amitryptyline) preferentially inhibit 5-HT uptake. However, when Richelson and Pfenning (1984) actually compared the effects of a wide range of antidepressants on the synaptosomal uptake of [ H]monoamines in vitro, and compared their A s, instead of merely ranking /C50S collected from different studies, they found that tertiary- and secondary-substituted compounds were equi-potent inhibitors of [ H]noradrenaline uptake. Moreover, all the TCAs turned out to be more potent inhibitors of [ H]noradrenaline than of [ H]5-HT uptake. Tertiary amines are even less convincing inhibitors of 5-HT reuptake in vivo, because any such action is diminished by their metabolism to secondary amines (e.g. imipramine to desipramine amitriptyline to nortriptyline). Only clomipramine retains any appreciable 5-HT uptake blocking activity in vivo with (an unimpressive) five-fold selectivity for 5-HT versus noradrenaline. 

It is well known that alkyl substitution changes the basicity of amines. However, solvation effects lead to an anomalous order of basicities in solution (NH3 tertiary amine < primary amine < secondary amine). From gas-phase proton affinity data the intrinsic effects of alkyl substituents can be evaluated and a quite regular order (NH3 < primary amine < secondary amine < tertiary amine) is obtained91. 

Palladium-catalyzed, Allylic Amination. Allylic substitution of mono-saccharidic hex-2-enopyranoside 4-acetates with secondary amines in the presence of tetrakis (triphenylphosphine)palladium(O) liad led to a large variety of 4-aminated 2-enosides, with retention of configuration (56-58). The method was applied to the disaccaridic enoside 1 to give, with benzylmethylamine or dibenzylamine, the 4-amino sugar derivatives g in yields of 92 and 67% (46). Studies concerning hydrox-ylation of t)ie double bond and subsequent deprotection are incomplete. 

RDX, Cyclonite, Hexahydro-l,3,5-trinitro-l,3,5-triazine under Secondary Aliphatic Amines Ring-Substituted Aromatics Saturated Alkyl Halides Secondary Alcohols... 

The hydrogen atoms of ammonia can be replaced, one by one, by equivalent radicles—methyl, CH3 ethyl, C2H5 to form a series of compounds called the amines or substituted ammonias in which nitrogen is undoubtedly tervalent. The amines are distinguished as primary, secondary, or tertiary, according as one, two, or three of the hydrogen atoms in ammonia are replaced by these radicles. Thus ... 

The azocane nitrogen undergoes reactions characteristic for secondary amines nucleophilic substitutions (alkylations and acylations), oxidations, and modifications to ring substituents. Alkylations. Halo derivatives were reported to react readily with azocanes to afford in good yields compounds with diverse applications in life sciences (Scheme 101 <1997JME1578 . 

If pure 9-chloroacridine is desired, the crude product is dissolved in a little boiling alcohol, and 0.5 per cent ammonia is added until the solution becomes milky. About 0.5 g. of Norite is then added the solution is quickly filtered and at once cooled i n an ice bath. White crystals, melting at 119-120°, are obtained. The product keeps best in a desiccator over potassium carbonate, by warming 9-chloroacridine with various primary and secondary amines, many substituted 9-aminoacridines are readily obtained. 

Dideoxynucleosides show potent anti-retroviral activity against HIV-specific reverse transcriptase80-83. In particular, 2, 3 -dideoxy-3 -C-cyano-2 -substituted thymidine derivatives (33 A and 33 B) with a free 5 -hydroxy function (R1 = H) are potential inhibitors of the HIV-reverse transcriptase-promoted c-DNA synthesis. As these compounds have yet to be prepared by another method, the 3 -ene-nitrile 3284 was subjected to conjugate addition reactions with ammonia, primary amines, secondary amines and carbon nucleophiles. Most of these nucleophilic amine addition reactions give either the trans-isomer 33 A as the sole product (e.g., reaction with pyrrolidine, piperidine, morpholine), or as the major product along with the c/s-isomer (e.g., reaction with methylamine, benzylamine), except for the reaction with ammonia where the cts-isomer 33B is formed as the major product84. 

The acylation of ammonia or primary and secondary amines by chloro-formic esters (chlorocarbonates) is the most general method for the synthesis of urethanes. Chlotoformates are obtained by the action of phosgene on alcohols (method 289) and, without purification, are converted to carbamates by cold concentrated ammonium hydroxide. Over-all yields from primary and secondary alcohols range from 55% to 94%. N-sub-stituted carbamates result in similar yields when primary" or secondary" amines are substituted from ammonia in the reaction. Aqueous sodium hydroxide is sometimes used to neutralize the acid formed. ... 

Thus reaction of cyclohexanone, n-propylamine, and sodium cyanoborohydride in methanol at pH 6-8 at 25° for 24 hr. gives n-propyleyelohexylamine in 85 % yield. The reaction is general for ammonia and primary and secondary amines aromatic amines are somewhat sluggish. All aldehydes and relatively unhindered ketones can be reduc-tively aminated. Yields are improved by use of 3A molecular sieves to absorb the water generated in the reaction. Note that reductive amination of substituted pyruvic acids with ammonia leads to oi-amino acids. Thus alanine can be obtained from pyruvic acid in 50 % yield. A pH of 7 is optimum for. synthesis of a-amino acids. 

Whereas the reaction of small primary amines with 2-(chloromethyl)quinazoline 3-oxides 1 leads to ring-enlarging rearrangement to 1,4-benzodiazepines (cf. p 159), weak primary amines.secondary amines, hydroxylamine, thiolates, " thiocyanate. cyanide, and the carbanions of nitroethane and nitropropane lead only to products 2 derived from substitution of the halogen. In a few cases, also in the reaction of 2-(chloro-methyl)quinazoline 3-oxides with methylamine, the unrearranged 2-[(methylamino)methyl]-quinazoline 3-oxide products are isolated. " ... 

On treatment with ammonia or primary amines, 6-substituted 2-chloromethyl-4-phenylquin-azoline 3-oxides 1 undergo rearrangement to 2-amino derivatives of 7-substituted 5-phenyl-3//-1,4-benzodiazepine 4-oxide 2, Reaction with secondary amines proceeds without rearrangement with formation of the expected 2-(aminomethyl)-4-phenylquinazoline 3-oxides (cf. Section 6.3.1.1.10.3.). 2o. s2i... 

Whether an amine is primary, secondary, or tertiary is best shown by the Hinsberg test. The amine is shaken with benzenesulfonyl chloride in the presence of aqueous potassium hydroxide (Sec. 23.6). Primary and secondary amines form substituted sulfonamides tertiary amines do not—if the test is carried out properly. 

It is well known that halomethyleneiminium salts, often prepared in situ (see Section 2.1.2.2) react with ammonium salts, primary amines, secondary amides, urea and IV-substituted ureas to afrbrd amidinium salts, from which the free amidines can be obtained by addition of bases. > 4 Some recent results are given below. Dimethylformamide chloride and other 7V,iV-disubstituted formamide chlorides were reacted with acetanilides, chloroacetanilides, 6-aminopenam derivatives, 2-aminopyrimidine, 4-aminouracil, 2-amino-4-chloropyridazine, 2-aminothiazole, 2-aminobenzothiazole and thiobenzamides to give the amidines via the amidinium salts. In the reaction of MA -disubstituted formamide chlorides with thiobenzamides the solvent seems to be decisive for the course of the reaction. In tertiary formamides the thiobenzamides are desulfurized to nitriles, whereas in CHCI3 or CCI4 amidinium salts (296 Scheme 45) are formed. From trimethylsilyl isocyanate and the fluorinated amine (297) the /V-fluorocarbonylamidine (298) is accessible. ... 

Convenient syntheses for ammonium311 320 and alkali metal salts (from trimethylsilyl dithiocarboxylates and alkali metal fluorides),321,322 useful for preparative purposes of their metal complex and organometallic derivatives, are now available. The reactions of bis(thioacyl)disul-fanes, [RC(S)S]2 (R = Pr , Ph, p-MeOC6H4, p-Tol, p-ClC6H4, CK-C10H7) with secondary amines yield substituted ammonium dithiocarboxylates, [R NHJP CSJ.323... 

When chloral is cleaved by treatment with a primary or secondary amine, the substituted formamide is obtained in good yield (cf. page 545) ... 

Aziridines unsubstituted on the N-atom behave like secondary amines A-substituted aziridines behave like tertiary amines. They react with acids to give aziridinium salts ... 

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