Amines, as nucleophiles

Problem 25.28 Which N atom in each drug is more basic  

Problem 25.29 Rank the N atoms in histamine (Section 25.6B) in order of increasing basicity. 

Amines react as nucleophiles with electrophilic carbon atoms. The details of these reactions have been described in Chapters 21 and 22, so they are only summarized here to emphasize the similar role that the amine nitrogen plays. 

The nature of the product depends on the carbonyl electrophile. These reactions are limited to 1° and 2° amines, because only these compounds yield neutral organic products. 

Reaction of 1° and 2° amines with aldehydes and ketones (Sections 21.11-21.12) 

Aldah ketM ctw U mi t form imines and with 2° amines to form enammesTBotn reactions inv e luicKtqmm iaaition of the amine to the carbonyl group to form a carbinolamine, which then loses water to form the final product. 

Acid chlorides and anhydrides react with NH3, 1° amines, and 2° amines to form 1°, 2°, and 3° amides, respectively. These reactions involve attack of the nitrogen nucleophile on the carbonyl group followed by elimination of a leaving group (CP or RCOO ). The overall result of this reaction is substitution of the leaving group by the nitrogen nucleophile. 

More recently, Hartwig reported on the use of a zinc variant of LHM DS, namely Zn(HMDS)2, as a mild ammonia equivalent in combination with LiCl or R,NX as additives and P(t-Bu)3 as ligand [173]. This protocol has the advantage of extended functional group tolerance, allowing the use of substrates with, for example, eno-Hzable groups. Hence, when (S)-naproxen methyl ester was deliberately added to the amination reactions no racemization occurred, yet addition of the stronger base LHMDS led to almost complete racemization. 

Benzophenone imine was used extensively as an ammonia equivalent by various research groups [49,174], mostly with BINAP or dppf as ligands [2]. Diallylamine 

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We will begin with an examination of the reactivity of amines as nucleophiles m Sn2 reactions... 

The catalyst [Ir(COD)Cl]2/P(OPh)3 was highly effecHve also for allyhc airuna-Hons. Branched monoallylahon products were mainly obtained with primary amines as nucleophiles and Hnear fE)-allylic substrates. In contrast, mixtures of Hnear mono- and disubsHtuHon products are usually produced with Pd-catalysts. Many types of amine could be used, for example benzylairune, piperidine and anihne [14]. In terms of allyhc substrates, carbonates were more suitable than acetates. With regards to the solvent, the best results were obtained with ethanol, with complete conversion typicaUy being achieved after a reacHon time of 3 h at 50°C. The reacHons of (Z)-aUylic carbonates to give Hnear fZj-propenylamines proceeded with perfect stereospecificity. 

Using amines as nucleophiles, sulfonyl chlorides are readily converted into sulfonamides, exemplihed here by the formation of p-aminobenzenesulfonamide (sulfanilamide). 

Inaba and coworkers reported that a Ti-BINOL complex is an effective catalyst for the desymmetrization of epoxide 44 using primary amines as nucleophiles. Of significant note is the efficiency of this reaction, with only 1 mol% catalyst necessary to attain high yields and selectivities [Eq. (10.11)]. Unfortunately, this epoxide is uniquely effective in this reaction. Cycloheptene oxide, dihydrofuran oxide, and an acyclic version of 44 each provided negligible yields under these reaction conditions ... 

Amines may also behave as nucleophiles (Lewis bases). Primary amines are stronger nucleophiles than secondary amines, which, in turn, are stronger nucleophiles than tertiary amines. As nucleophiles, amines attack acid chlorides to form amides. Later in this chapter you see that they re important in the formation of sulfonamides. 

The conjugate addition of heteronucleophiles to activated alkenes has been used very often in organic synthesis to prepare compounds with heteroatoms [3 to various activating functional groups, e.g. ketones, esters, nitriles, sulfones, sulfoxides and nitro groups. As in the Michael reaction, a catalytic amount of a weak base is usually used in these reactions (with amines as nucleophiles, no additional base is added). 

Yasuda, Pac, and Shima reported the photoamination of aromatic compounds by use of ammonia and primary amines as nucleophiles in the presence of m-di-cyanobenzene as an electron acceptor [30,32], Irradiation of an acetonitrile-water (9 1) solution containing phenanthrene and m-dicyanobenzene in the presence of ammonia or primary amines gives 9-amino-9,10-dihydrophenanthrene deriva-... 

One of our initial forays into Mo(CO)6-promoted carbonylations included the investigation of intermolecular reactions using amines as nucleophiles to form secondary and tertiary aromatic amides from aryl bromides and iodides [27]. Subsequent work using the activating preligand f-Bu3PHBF4 has allowed for the extension of this chemistry into examples using aryl chlorides as substrates (Scheme 1) [30]. 

As illustrated in the following reaction, this method provides acceptable yields of tertiary amines, using secondary amines as nucleophiles. Quaternary ammonium salts can also be prepared from tertiary amines as nucleophiles. 

Less attention has been paid to the use of amines as nucleophiles in the telomerization reaction. A single report from Nolan and co-workers [233] has shown that well-defined cationic palladium complexes are efficient catalysts in the telomerization of butadiene with amines under mild conditions (Table 10). In the case of primary amines, the concentration of the reactants and their steric hinderance dictates the formation of a mono- or double-alkylated product. 

The search for electrophilic catalysis could in principle be aided by use of tertiary amines as nucleophiles, in which case an intramolecular or solvent assisted proton shift, formulated in [13] and [14], is eliminated. Thus Ayediran, Bamkole and Hirst (1974) studied salt effects on the reactions of 4-fluoro- and 4-chloronitro-benzene with trimethylamine in DMSO, which proceed according to equations (29) and (30). It had been noted (Suhr, 1967) that the... 

Such substitutions using lithium amides, secondary and in some cases tertiary amines as nucleophiles, have been introduced in early sixties as the first expedient method for this unique class of compounds. It is relevant that / ,/ -difluoro- and chlorofluorole-fins readily available through modified Wittig reaction from aldehydes constitute also good ynamine precursors. In the past decade, however, the more versatile lithium aminoacetylide method has gained more prominence. Substitution reactions are still used, among others, for phenyl, tert.-butyl, cinnamyl and cyclopropyl ynamines. 

Epoxides react cleanly with amines to give amino-alcohols. We have not so far featured amines as nucleophiles because their reactions with alkyl halides are often bedevilled by overreaction (see the next section), but with epoxides they give good results. 

Ring formations by nucleophilic substitution at saturated carbon atoms with primary amines as nucleophiles have rarely been carried out because the resulting secondary amines as a rule are more nucleophilic than the primary ones, and therefore competition reactions are favored. The synthesis of secondary amines often starts from toluene sulfonamides which can easily be deprotonated and alkylated. A large number of methods for detosylation exists especially the acidic cleavage with H2SO4 or with HBr/phenol have proved to be reliable. 

Use of resolved PhCHMeNHMe as conq>lexing agent and nucleophile in this reaction causes asymmetric induction in the amino acetate, with de 20-60% alternatively, resolved PhCHMeNMe2 can be used as complexing agent, followed by an achiral amine as nucleophile, but ee of only 3-12% was achieved.Related transformations, but this time trans stereospecific, can be achieved using mercury activation in these cases the mercury itself is the oxidant (Scheme 55). 

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