Applications nucleophilic amines

Substituted hydroxylamines 1-5 (R = R = H) and their A-mono- or A,A-disub-stituted derivatives 1-5 have been used extensively for electrophilic amination of both carbanions and enolates since the first report in 1938 on the use of 0-methylhydroxylamine 1 (R = Me) for conversion of Grignard reagents to primary amines. Oximes 7 (Z = H) have found limited applicability as amination reagents for carbon nucleophiles and then-use was first reported in 1907. Ketone 0-sulfonyloximes 7 (Z = SO2R) have recently been developed. 

The use of sodium salt (II) is strongly recommended for nucleophilic amination of primary halides under anhydrous conditions. Both reagents (I) and (II) can be considered as useful substitutes of potassium phthalimide, free from well known preparative inconveniences involving application of the latter. 

Fig. 6. 35. Preparation of the dicarbonate ("pyrocarbonate") H ("Boc anhydride," "Boc20") from potassium tert-butoxide, carbon dioxide and phosgene. The tricarbonate E is isolated as an intermediate. Only upon addition of a catalytic amount of the nucleophilic amine F does E react to afford Boc 0, while the analogous ethyl derivative ofthe tricarbonate does so spontaneously. Boc20 applications are shown in Figures 6.37 and 6.38, an application ofthe analogous diethyldicarbonate is given in Figure 13.62.

In the above described carbonylation reactions the nucleophile that reacts with the species released from the catalytic cycle is water or possibly an alcohol. This can be replaced by a more nucleophilic amine, yielding an amide as the product [66]. With this minor variation a different group of products becomes accessible. A striking application of this reaction is the synthesis of the monoamine oxidase B inhibitor Lazabemide [70, 75]. The first laboratory synthesis could be shortened from 8 steps to just one catalytic reaction with a TON of 3000 (Scheme 5.41). The only drawback to the greenness of this reaction is that the metal is removed via an extraction with aqueous NaCN. 

Ring formations by reactions of a 7V-nucleophile on carbonyl groups or their equivalents are shown in Scheme 59, 60 and 61. The most familiar application, reductive amination, was used in the synthesis of azasugar derivative 147 from a diol precursor as shown in Scheme 59 <04TL5751>. 

Polyalkylenimines (PAIs) are a class of cationic polymers that have a generalised structure with secondary or tertiary amines in the main separated by all lene spacers, as shown in Scheme 2.1. Due to the presence of the nucleophilic amine groups in the polymer backbone, their synthesis is more complicated compared to simpler vinyl based polymers. This chapter will focus on the synthesis of the PAIs, their physical properties and a short review of applications, focusing on gene delivery. This chapter will only cover PAI homopolymers and excludes the convoluted area of block copolymers, as this is worth a full review by itself. 

By incorporating chiral binaphthol skeleton with nucleophilic amine and phosphine imit into one molecule, Sasai and co-workers [107] developed new catalysts 55 and 56. Their applications as catalysts in the BH reactions of aldimines with acrolein, MVK, and EVK resulted in good reactivity and excellent enantioselectivities (Scheme 9.30). 

Both variants of this one-pot two-step reaction sequence, following either the radical or nucleophilic pathways, are applicable, although the radical version has some limitations because of orthogonality issues when using functionalized amines. The nucleophilic amine-thiol-ene conjugation is particularly attractive because this 100% atom-efficient polymerization is a very mild process, occurring at ambient conditions without any additive or external trigger. 

Sulfenamides, R2NSR, prepared from an amine and a sulfenyl halide, are readily cleaved by acid hydrolysis and have been used in syntheses of peptides, penicillins, and nucleosides. They are also cleaved by nucleophiles and by Raney nickel desulfurization." The synthesis and application of sulfenamides have been reviewed. ... 

The l ,J -DBFOX/Ph-transition metal aqua complex catalysts should be suitable for the further applications to conjugate addition reactions of carbon nucleophiles [90-92]. What we challenged is the double activation method as a new methodology of catalyzed asymmetric reactions. Therein donor and acceptor molecules are both activated by achiral Lewis amines and chiral Lewis acids, respectively the chiral Lewis acid catalysts used in this reaction are J ,J -DBFOX/Ph-transition metal aqua complexes. 

The major application of the Mitsunobu reaction is the conversion of a chiral secondary alcohol 1 into an ester 3 with concomitant inversion of configuration at the secondary carbon center. In a second step the ester can be hydrolyzed to yield the inverted alcohol 4, which is enantiomeric to 1. By using appropriate nucleophiles, alcohols can be converted to other classes of compounds—e.g. azides, amines or ethers. 

Additions of oxygen and nitrogen nucleophiles to vinyloxiranes can be achieved with Pd(0) catalysis [103, 104]. Acetate, silanols, amines, sulfonamides, and azide have been used as nucleophiles, and the stereochemical outcome of these additions, where applicable, is normally the result of two consecutive SN2 reactions. This is demonstrated by the additions of NaNHTs to vinylepoxides 29 and 30, affording syn- and anti-amino alcohols 31 and 32, respectively, in good yields and with high diastereoselectivities (Scheme 9.22) [105]. 

A novel application of a phenyl aryldiazosulfone was found by Kessler et al. (1990). l-[4-(7V-Chlorocarbonyl-7V-methylamino)phenyl]-2-(phenylsulfonyl)diazene (6.18) is an acid chloride with a potential diazonio group. The above authors showed that in organic solvents (THF, etc.) this compound reacts easily, as expected, with nucleophiles (HNu), e.g., with aliphatic, aromatic, or heterocyclic amines, with cystine dimethyl ester, or with 4-methoxyphenol at the carbonyl function, yielding... 

Thus removal of water from classical rather inactive fluoride reagents such as tetrabutylammonium fluoride di- or trihydrate by silylation, e.g. in THF, is a prerequisite to the generation of such reactive benzyl, allyl, or trimethylsilyl anions. The complete or partial dehydration of tetrabutylammonium fluoride di- or trihydrate is especially simple in silylation-amination, silylation-cyanation, or analogous reactions in the presence of HMDS 2 or trimethylsilyl cyanide 18, which effect the simultaneous dehydration and activation of the employed hydrated fluoride reagent (cf, also, discussion of the dehydration of such fluoride salts in Section 13.1). For discussion and preparative applications of these and other anhydrous fluoride reagents, for example tetrabutylammonium triphenyldifluorosilicate or Zn(Bp4)2, see Section 12.4. Finally, the volatile trimethylsilyl fluoride 71 (b.p. 17 °C) will react with nucleophiles such as aqueous alkali to give trimethylsilanol 4, HMDSO 7, and alkali fluoride or with alkaline methanol to afford methoxytri-methylsilane 13 a and alkali fluoride. 

Acylation reactions can be done at the nucleophilic sites on pyrimidines using activated forms of carboxylic acids. Acylation of functional groups in nucleotides typically is used for protection during synthesis (Reese, 1973). However, for bioconjugate applications, the reactivity of native groups on pyrimidines is not as great as that obtained using an amine-terminal spacer derivative, such as those described in Chapter 27, Section 2.1. Yields and reaction rates are typically low for direct acylation or alkylation of pyrimidine bases, especially in aqueous environments. 

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