Nucleophilic reactions with ammonia, amines, amine derivatives

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. 

Not only acylimino acids (VI. B.) but also 2-alkylidene- and 2-aryli-dene-A -oxazolin-5-ones (55) (pseudooxazolones) add nucleophiles. Simultaneous ring opening is usually observed 195, 237, 238, 239, 397) yielding the corresponding amino acid derivatives. Reaction with ammonia or amines resp. alcohols yields a,a-diamino carboxylic acid esters (56) or a-alkoxy-a-acylaminocarboxylic acid esters (58) respectively. Mercaptans add so rapidly that mercaptooxazolinones (57) can be isolated and then opened with other nucleophiles. 

The reaction of furans with ammonia and its derivatives is of considerable synthetic utility (B-73MI31 too). Substituted furan-2-carbaldehydes and 2-acylfurans on heating with ammonia and ammonium salts, often under pressure, yield 3-hydroxypyridines. The mechanism of this reaction is thought to involve nucleophilic attack of ammonia at the 2-position. Ring opening affords an amino aldehyde or ketone and thence, by reclosure, the 3-hydroxy-pyridine (Scheme 29). A wide range of substitutents is tolerated. Primary amines with furan-2-carbaldehydes yield A-substituted pyrroles, the closure of the intermediate... 

In the case of cationic complexes with unsaturated macrocycles two molecules of nucleophile, such as ammonia, amines and alkoxides, add to carbon atoms of two inline groups. For example, the reaction of [Ni(Bzo[16]octaeneN4)](C104)2 (Table 106) with sodium methoxide or ethoxide yields the compounds (395),2860 while with secondary amines and diamines complexes of type (396) are obtained.28 1 The reaction of (396) with acetone at room temperature yields complex (397) where the enolate anion of acetone, MeC(0)CH2, replaces the diethylamide group (Scheme 58). 2862 The addition of molecules such as bis(2-hydroxyethyl)methylamine and bis(2-hydroxyethyl) sulfide, HOCH2CH2YCH2CH2OH (Y = NMe, S) results in the formation of derivatives which possess one more coordination site just above the plane of the macrocyclic donors (398).2863... 

It is well known that nucleophiles such as ammonia and amines are able to open pyran-2-one rings. The resultant ring-opened products are often able to recyclize under acidic conditions to yield pyridone and benzene derivatives. This section is mainly concerned with ring-transformation reactions induced by nitrogen nucleophiles not previously discussed <1984CHEC>, as well as some novel chemistry involving nitrogen nucleophiles. 

As to the nucleophiles that can be applied in the nucleophilic reactions, ammonia and amines, water and alcohols, and mercaptans have been mentioned already. Sulfide and thiourea have been used only with the achiral ferrocenylmethylium ion [97]. To obtain chiral derivatives of 1-ferrocenyl-ethylmercaptan, substitution of the acetate with potassium thioacetate in acetic acid, followed by reduction with LiAlH4, was found appropriate [98, 99]. Reaction of (R)-l-ferrocenylethanol with NaH and... 

Triazine (1) reacts with various nucleophiles under ring cleavage. Reactions with ammonia, hydroxylamines and amines follow a similar scheme.18 The initial step is a nucleophilic attack of the nitrogen nucleophile to an electron-deficient triazine carbon. The reaction is assumed to proceed via ring opening and further addition of the nucleophile as shown below. The result, in every case is the complete destruction of the triazine ring with formation of three moles of ammonia and three moles of formimidamide derivatives 2.18... 

Addition of an ammonia source to pyrylium salts readily affords pyridine derivatives and provides a good method for the preparation of the pyridine moiety if the corresponding pyrylium salt is accessible. The carbon oxygen double bond present in the pyrylium salt is an oxonium ion however, owing to aromatic stabilization they are easily formed by a variety of methods. The reactivity of pyrylium salts toward nucleophiles makes them useful reagents for the preparation of structurally diverse heterocyclic compounds. Thus pyrylium salts afford pyridines by reaction with ammonia, pyridine-A -oxides by reaction with hydroxylamine and pyridinium salts by reaction with primary amines. 

When the nucleophile has hydrogen atoms, e.g., with ammonia, primary amines, hydroxylamine, hydrazine derivatives, phosphine, hydrogen sulfide, nitromethane (EWG = NO2), acetonitrile (EWG = CN), an ANRORC (attack by nucleophile, ring opening, ring closure) reaction results in the conversion of substituted pyrylium salts into a large variety of six-membered aromatic carbocyclic or heterocyclic compounds. 

A.mina.tlon. Amination describes the introduction of amino groups into aromatic molecules by reaction of ammonia or an amine with suitably substituted halogeno, hydroxy, or sulfonated derivatives by nucleophilic displacement. Although reaction and operational conditions vary, the process always involves the heating of the appropriate precursor with excess aqueous ammonia or amine under pressure. 

Two-step synthetic routes to poly(/i-aminoborazines) from /i-chloroborazines involve initial nucleophilic reaction of the /i-chloroborazine with appropriate linking reagents followed by a deamination reaction of the as-obtained /i-aminoborazine. The 5-tiichloroborazine undergoes nucleophilic attack by ammonia or amine derivatives on the boron atom linked to chlorine atoms. For the same reasons previously quoted a tertiary amine (e.g., Et3N) must be added to precipitate the corresponding hydrochloride. 

The presence of three nitro groups on the aromatic ring of picryl chloride makes the chloro group extremely reactive towards nucleophiles. Picryl chloride (87) is hydrolyzed to picric acid (4) in the presence of hot water or aqueous sodium hydroxide. Aminolysis of picryl chloride in the presence of primary and secondary amines is complete in minutes at room temperature. Picryl chloride is therefore a very useful starting material for the synthesis of a range of other picryl derivatives. The reaction of picryl chloride (87) with ammonia can be used to synthesize 2,4,6-trinitroaniline (53) (picramide). Treatment of picryl chloride with alcohols under reflux forms picric acid and the alkyl chloride of the corresponding alcohol, whereas the same reaction in the presence of alkali metal hydroxides, or the alkoxide anion of... 

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