Amines synthetic utility

Secondary amines cannot form imines, and dehydration proceeds to give carbon-carbon double bonds bearing amino substituents (enamines). Enamines were mentioned in Chapter 7 as examples of nucleophilic carbon species, and their synthetic utility is discussed in Chapter 1 of Part B. The equilibrium for the reaction between secondary amines and carbonyl compounds ordinarily lies far to the left in aqueous solution, but the reaction can be driven forward by dehydration methods. 

The synthetic utility of enamines presupposes their general accessibility. In most cases, ketones are readily converted to enamines by condensation of the carbonyl compound with a secondary amine such as pyrrolidine, morpholine, or piperidine and azeotropic removal of water with a solvent such as benzene (3-19). 

Not surprising, the most prevalent synthetic utility is the assembly of the pyrrolidine ring. N-Chloroamine 27 was obtained by treatment of N-methyl-2-cyclopentylethylamine (26) with N-chlorosuccinimide. Under classic Hofmann-Loffler-Freytag reaction conditions, 27 was rearranged either thermally or by UV irradiation in sulfuric acid to bicyclic amine... 

Inhibition of O-benzyl hydrogenolysis was shown to be due to the presence of an amine, a finding with synthetic utility. 

The dienone, which is prepared essentially as described by Benedikt7 and Calo,8 monobrominates a wide range of primary, secondary, and tertiary aromatic amines almost exclusively in the para-position. The procedure described is of general synthetic utility for the preparation of para-brominated aromatic and heteroaromatic amines in high yields and frequently in a high state of purity. The submitters have used this technique to para-brominate many compounds in quantities... 

As another extension of this process, Davies et al. have developed highly regio-, diastereo- and enantioselective C-H insertions of methyl aryldiazoace-tates into cyclic A-Boc-protected amines catalysed by rhodium(II) S)-N- p-dodecylphenyl)sulfonylprolinate. The best results were obtained in the case of the C-H insertion of methyl aryldiazoacetates into A-Boc-pyrrolidine, which gave, in all cases, a diastereoselectivity and an enantioselectivity greater than 90% de and 90% ee respectively (Scheme 10.77). The synthetic utility of this method was demonstrated by means of a two-step asymmetric synthesis of a novel class of C2-symmetric amines. 

The reaction that is perhaps of the greatest synthetic utility—because it proceeds at relatively low temperatures—is the Cope reaction of tertiary amine oxides, e.g. (82) ... 

A very elegant expansion of the synthetic utility of this intramolecular amination was the insertion reactions into ethereal G-H bonds. Du Bois and co-workers have exploited this reactivity to prepare cyclic sulfamates that are then used as iminium ion equivalents. Upon treatment with a suitable Lewis acid, nucleophilic addition reactions... 

In conjunction with the chiral anion TRIP (156) (10 mol%), diamine 157 (10 mol%) can be used in the catalytic asymmetric epoxidation of a,p-unsaturated ketones (>90% ee) [196], while the secondary amine 158 (10 mol%) can be used for the epoxidation of both di- and trisubstituted a,P-unsaturated aldehydes (92-98% ee) (Fig. 15) [211], The facile nature of these reactions, using commercially available peroxides as the stoichiometric oxidant, together with the synthetic utility of the epoxide products suggests application in target oriented synthesis. 

Ricci and coworkers also investigated the synthetic utility of A-alkyl 0-silylhydroxyl-amines 5c-e in the amination of aryl and heteroaryl higher cyanocuprates and obtained secondary amines in good yields (Scheme 51)" . 

All three compounds (WF6 and MoF6 are best) will bring about a reaction (not a fluorination) that may have synthetic utility at 0CC in l,l,2-trichloro-l,2,2-trifluoroethane (Freon 113) or chloroform they will cleave N,TV-dimethyl- and N-tosylhydrazones and oximes back to the parent carbonyl compounds12,14 (UF6 converts any first-formed aldehydes into acid fluorides1213). All three hexafluorides will convert1215 tertiary amines into carbonyl compounds and carboxylic acids into acid fluorides.16 They also dope polyacetylene to the metallic regime.17... 

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... 

Clearly, the plethora of products to be expected, particularly those resulting from rearrangement (see Exercise 23-31), prevents the reaction of the simple primary amines with nitrous acid from having any substantial synthetic utility. 

Indeed the alcoholysis of metal amides is an excellent method for the synthesis of alkoxides. However, some synthetic utility to this reaction has been found for the synthesis of aminoboranes where the equilibrium can be forced to the right by using either an involatile or a chelating amine.59,60 Hydrocarbon solutions of Mo2Me2(OBu )4 also react with MeNHCH2CH2NHMe (>6 equiv.) to give Mo2(MeNCH2CH2NMe)3 with the liberation of methane (2 equiv.) and /-butyl alcohol.61... 

All of these processes are of limited synthetic utility because of the requirement of the use of stoi chiometric amounts of palladium complexes. However, by judicious choice of reactants and condition the above-mentioned impediments to catalysis can be overcome. For example, an efficient palladium(II) catalyzed cyclization of o-allyl- and o-vinyl-anilines to indoles has been developed (equation 14).28 Be cause arylamines are -106 less basic than aliphatic amines, and because the cyclized product in thi system gave an enamine (indole) stabilized by aromatization, the problems of catalyst poisoning by sub strate or product were circumvented, and catalysis was successfully achieved. The system was quit tolerant of a variety of functional groups and was used to prepare indoloquinones in excellent yieli... 

Palladium acetate triarylphosphine complexes catalyze the addition of vinylic groups from vinylic halides to olefinic compounds in the presence of amines. Conjugated dienes are major products from 0,/3-unsaturated acids, esters, or nitriles while unactivated olefinic compounds react best in the presence of secondary amines where allylic amines are major products. The reactions are usually regio- and stereospecific. The synthetic utility of the reaction is illustrated with a wide variety of examples. 

The synthesis of 2,2-dimethylsuccinic acid (Expt 5.135) provides a further variant of the synthetic utility of the Knoevenagel-Michael reaction sequence. Ketones (e.g. acetone) do not readily undergo Knoevenagel reactions with malonic esters, but will condense readily in the presence of secondary amines with the more reactive ethyl cyanoacetate to give an a, /f-unsaturated cyanoester (e.g. 15). When treated with ethanolic potassium cyanide the cyanoester (15) undergoes addition of cyanide ion in the Michael manner to give a dicyanoester (16) which on hydrolysis and decarboxylation affords 2,2-dimethylsuccinic acid. 

The Hofmann-Loffler-Freytag (HLF) reaction is the oldest known reaction that involves aminium cation radicals (Scheme 14) (50JA2118 60JA1657). This reaction is a remote functionalization reaction where an N-chloro- or N-bromo-amine 46 is converted to a 8-haloamine 49 via the intermediate aminium cation radical 47. Pyrrolidine products are obtained by cyclization of the 8-haloamines under basic conditions. A comprehensive survey of the synthetic utility of this reaction has been reported by Wolff (63CRV55). 

Perhaps of more synthetic utility is the alkylation of co-ordinated amines. As we illustrated in Fig. 5-26, the attempted alkylation of free amines usually results in the formation of numerous products. This is ascribed to the greater nucleophilicity of the alkylated amines with respect to the starting material. As an example, the reaction of 1,2-diamino-ethane with iodomethane yields three major products (Fig. 5-30). 

Further studies have shown that, to obtain an efficient amination, it is necessary to take into account both the difference in oxidation potential between the photocatalysts and the substrates and the positive charge distribution in the cation radicals of the olefin. The synthetic utility of the method was proven by the successful preparation of an aminotetraline, itself an intermediate for the synthesis of a compound with biological activities such as 2-aminoindan (26, Scheme 3.16b) [39]. As with the last synthesis, the redox-photosensitized amination occurred with no need for acids or bases, as usually required when using general protocols. 

Mechanistically, it was suggested [92] that this cyclization does not involve the free a-amino radical formed by cleavage of the C—Si bond of the trimethylsilylmethyl-amine radical cation. Instead, it was pointed out that cleavage of the C—Si a-bond from the delocalized trimethylsilylmethylamine radical cation, produced by a vertical overlap of the C—Si bond and empty p-orbital of nitrogen, is assisted by the 71-orbitals of the olefin. This strategy was applied to the stereoselective synthesis of pyrrolizidine and indolizidine ring systems [93]. The synthetic utility of this reaction is also demonstrated by the synthesis of ( )-iso-retronecanol [94]. 

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