Normal Amines

The nitrogen atoms of the twisted amides discussed on pages 107-108 are to a greater or lesser extent pyramidal, and incipient lone pairs electron density is thus available for reactions with electrophiles. The classic example is the cage lactam [57] first prepared by Pracejus (1959), which has an amide nitrogen with near normal amine basicity. Brown and coworkers have measured rates of alkaline hydrolysis of a series of anilides [58] and [59] with related structures and find that the rate increases with increasing divergence... 

False neurotransmitters are amines which are similar enough in structure to normal amine neurotransmitters that they bind to receptors but are much less active or totally inactive (i.e. they are antagonists). One such false neurotransmitter is octopamine, which is formed from tyrosine by decarboxylation followed by side-chain hydroxylation. 

Benzimidazole lassen sich wie normale Amine mit Saurechloriden in Gegenwart tertiarer Amine385 acylieren. Auch Phasentransfer-Reaktionen sind moglich, erbringen aber nur mittlere Ausbeuten519. 

The ability of [18]crown-6 derivatives to complex primary alkylammonium ions has been elegantly exploited in the protection of primary amines (80CC300). In the presence of primary amines, secondary amines can be acylated selectively by adding [18]crown-6 and a proton source. This strategy has obvious advantages over normal amine protecting groups which require a deprotection step. 

Isotope labelling again proved (21) that the decarboxylation involves only carbon 2 of the oxazolidine-2,5-dione, and studies of the kinetic isotope effect (22) demonstrated that this step is not the rate-determining in the overall process. Therefore, the rate of the overall reaction is determined either by (a) — the formation of the complex, or by (b), viz. by opening of the ring between atoms 1 and 5. This conclusion applies also to the "normal amine-propagated NCA polymerisation. 

The normal amine IR absorption band for NH2 deformation, at 1600 cm 1, was only observed upon drying under N2 atmosphere. Drying in room environment caused peaks at 1575, 1488 and 1332 cm 1. Those were attributed to the formation of an aminebicarbonate salt (-NH3+(HC03) ).42 This salt is formed by reaction of C02 from... 

O Because of resonance, the electron pair on the nitrogen of phthalimide is not very basic or nucleophilic. The hydrogen on the nitrogen is much more acidic than a hydrogen of a normal amine because the conjugate base is stabilized by resonance. It is acidic enough to be removed completely by a base such as hydroxide ion. 

Furthermore, the amine part of the amide group is unlike any normal amine group. Most amines are easily protonated. However, since the lone pair on the amide s nitrogen is tied up in the 7t system, it is less available for protonation or, indeed, reaction with any electrophile. As a result, an amide is preferentially protonated on the oxygen atom but it is difficult to protonate even there (see next chapter, p. 201). Conjugation affects reactivity. 

When X = OAc , the initially coordinated anion is sufficiently basic to neutralize the liberated H+ [Eq. (54)] however, X = Cl requires the presence of external (normally amine) base to effect the same transformation. In both cases the palladium is recovered as the carbonyl derivative, Pd(CO)(PPh3)3 [and/or the related Pd3(CO)3(PPh3)4]. Alkoxycarbonyl derivatives such as Pd(OAc)(COOMe)(PPh3)2 and Pd(COOMe)2(PPh3)2 have been isolated from these systems and are invoked as catalytic intermediates, the total mechanism being described in the Scheme 10. The salient... 

The simple amine, piperidine, will have a normal amine pKaH of about 11 so it will be easy to protonate with even very weak acids. Any mineral acid like HCl will do as would weaker acids like RCO2H. Deprotonation will remove the NH proton as nitrogen is more electronegative than carbon but a very strong base such as BuLi will be needed as the pK will be about 30-35. 

The final example is the most complicated one. There is a normal OH group pK about 16) and a slightly acidic ahcyne (pJbasic group is not a normal amine but an amidine in which the two nitrogen atoms can combine (see arrows) to capture a proton. It will have a pKa of about 12 and so would even be protonated by a phenol though most chemists would use a carboxyhc acid. 

On warming with 30 per cent, hydrogen peroxide in the absence of acid, thebaine is converted to a normal amine oxide, which is reduced to the base by sulphurous acid [99-100] and oxidized to an amorphous brown solid by potassium chromate [101]. 

Mg, MeOH, 8-75% yield. These conditions were used to cleave a tosyl group from an aziridine, a special case over normal amines. The reaction should work better with a benzenesulfonamide. This method is very good for carbamate and amide protected sulfonamides, but does not work with normal aliphatic amines. Since sulfonamides are readily acylated, this constitutes a relatively mild method for the cleavage of sulfonamides. Lactones and esters are compatible with this methodology. 

The section covering henzyl carbamates or normal amines should he consulted since those methods are generally applicable to the formation the heterocyclic derivatives. 

Karl-Thomae [82] have also used a double prodrug strategy on BIBU 52 (28) by masking the amidine as a methylcarbamate. Carbamates of amidines are more labile to hydrolysis than normal amine derived carbamates owing to the presence of the electron-withdrawing imino group. The parent BIBU 52 (28) showed no oral activity in the rhesus monkey, whereas the cor-... 

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