Amines, open chain

There are two important routes to nitrones both start from hydroxyl amines. Open-chain nitrones are usually made simply by imine formation between a hydroxylamine and an aldehyde. 

Some azoliums give open-chain products primary and secondary amines with 1,2-dithiolyliums generally give (188) (80AHC(27)l5l). 

Besides the salts (458) and (459) previously described, aminopyrazolium salts can be obtained from the reaction between amines and chloropyrazolium salts (Section 4.04.2.3.7(ii)) or by quaternization of iminopyrazplines as in (461)—> (462) (72BSF2807). The lithium aluminum hydride reduction of the salt (462) affords mixtures of reduced and open-chain pyrazoles (Figure 23 Section 4.04.2.1.6(i)). 

Lehn s approach is slightly more complex than that illustrated above in that the diol is chloromethylated and then treated with cyanide. Hydrolysis then affords the diacid which may be carried through as shown. It should also be noted that once the bis-acyl halide is in hand, it may be treated directly with an open-chained amine to yield a lipophilic diazacrown, after reduction ... 

The next seven references are cited not because of the experimental procedures described but because they indicate diversification in the types of enamines prepared and studied. Both Paquette (25) and Kasper 26) have condensed 2,5-methylene-l,2,5,6-tetrahydrobenzaldehyde (5-nor-bornene-2-carboxyaldehyde) (2) with several cyclic and open-chain aliphatic secondary amines. Kasper studied the ratio of endo to exo aldehyde formed upon hydrolysis of these enamines and the dihydro enamines. Paquette investigated the addition of sulfene to the enamines. -Fluoro-... 

Experiments designed to clarify the situation were carried out by Wittig and Mayer (40). It was shown that changing the molar ratio of amine (diethylamine, di- -butylamine, or diisobutylamine) to -butyraldehyde from 1 1 to 2 1 did not affect the yield of enamine (53- 64%, based on the aldehyde). Contrariwise, changing the ratio of amine (morpholine, piperidine, or pyrrolidine) to n-butyraldehyde from 1 1 to 2 1 boosted the yields from 52-57 % to 80-85 %. The authors interpret these data as indicating that the cyclic amines form aminals with n-butyraldehyde, while the open-chain do not. Infrared evidence is stated as having shown that the aminal originates not from attack of excess amine on the enamine, which is stable under the conditions of the reaction, but from the N-hemiacetal (17). 

The reaction of a secondary amine with a ketone or with an open-chain aldehyde gives a mixture of isomers 164 and 165 (R = H, alkyl, or aryl). No consistent policy has been established as to which isomer is considered... 

Apparently, cyclization involves the formation of open-chain intermediates 342, 343, further closing up to imidazolidines 344 and oxazolidines 345 which eliminate the secondary amine, thus leading to imidazolines 346 and oxazolines 347. The latter exist in the solution exclusively in the enolic forms 348, 349 which are stabilized by conjugation and intramolecular hydrogen bonds. 

Another pathway for the aromatization of the cr -adducts was found in the reactions of 3-pyrrolidino-l,2,4-triazine 4-oxide 81 with amines. Thus the treatment of 1,2,4-triazine 4-oxide 81 with ammonia leads to 5-amino-1,2,4-triazine 4-oxides 54—products of the telesubstitution reaction. In this case the cr -adduct 82 formed by the addition of ammonia at position 5 of the heterocycle undergoes a [l,5]sigmatropic shift resulting in 3,4-dihydro-1,2,4-triazine 83, which loses a molecule of pyrrolidine to yield the product 54. This mechanism was supported by the isolation of the key intermediates for the first time in such reactions—the products of the sigmatropic shift in the open-chain tautomeric form of tiiazahexa-triene 84. The structure of the latter was established by NMR spectroscopy and X-ray analysis. In spite of its open-chain character, 84 can be easily aromatized by refluxing in ethanol to form the same product 54 (99TL6099). 

Similarly, ring opening was found in reactions of 6-aryl-1,2,4-triazine 4-oxides 53 with aliphatic amines, yielding open-chain 6-amino-1-hydroxy- 1,4,5-triazahex-atrienes 85. In this case, however, the nucleophile adds to the 3 position of the... 

Derivatives of pyrrolidine containing the ring in its fully reduced form are discussed in earlier sections of this book. To recapitulate, compounds containing this moiety seldom show activities that differ greatly in kind from the corresponding open-chain tertiary amine. 

Heterocyclic amines are compounds that contain one or more nitrogen atoms as part of a ring. Saturated heterocyclic amines usually have the same chemistry as their open-chain analogs, but unsaturated heterocycles such as pyrrole, imidazole, pyridine, and pyrimidine are aromatic. All four are unusually stable, and all undergo aromatic substitution on reaction with electrophiles. Pyrrole is nonbasic because its nitrogen lone-pair electrons are part of the aromatic it system. Fused-ring heterocycles such as quinoline, isoquinoline, indole, and purine are also commonly found in biological molecules. 

C-coupling is of outstanding importance in the azo coupling reaction for the synthesis of azo dyes and pigments. An aromatic or heteroaromatic diazonium ion reacts with the so-called coupling component, which can be an aromatic primary, secondary, or tertiary amine, a phenol, an enol of an open-chain, aromatic, or heteroaromatic carbonyl compound, or an activated methylene compound. These reactions at an sp2-hybridized carbon atom will be discussed in Chapter 12. In the... 

Allyl p-tolyl sulphoxide 535 reacts with sodium methoxide in methanol by initial prototropic isomerization and subsequent addition of methanol to give 536 (equation 333). Protic solvents are photochemically incorporated by the open chain olefinic bond of trans methyl )S-styryl sulphoxide 537 in a Markovnikov regiospecificity (equation 334). Mercaptanes and thiophenols add to vinyl sulphoxides in a similar manner (compare also Reference 604 and Section IV.B.3) to give fi-alkylthio(arylthio)ethyl sulphoxides 538 (equation 335). Addition of deuteriated thio-phenol (PhSD) to optically active p-tolyl vinyl sulphoxide is accompanied by a low asymmetric a-induction not exceeding 10% (equation 336) . Addition of amines to vinyl sulphoxides proceeds in the same way giving )S-aminoethyl sulphoxides in good to quantitative yields depending on the substituents at the vinyl moiety When optically active p-tolyl vinyl sulphoxides are used in this reaction, diastereoisomeric mixtures are always formed and asymmetric induction at the p- and a-carbon atoms is 80 20 (R = H, R = Me) and 1.8 1 (R = Me, R = H), respectively (equation 337) ... 

The abasic sites (3, Scheme 8.2) resulting from the loss of alkylated bases from DNA are both cytotoxic and mutagenic. " The cyclic acetal (3) exists in equilibrium with small amounts (—1%) of the open chain aldehyde (4). The acidic nature of a-proton in the aldehyde form of the abasic lesion facilitates 3-elimination of the 3 -phosphate residue to yield a strand break. " This reaction occurs with a half-life of about 200 h under physiological conditions (pH 7.4, 37°C), but can be accelerated by heat, basic conditions, or the presence of various amines. " ... 

Catalyst Study. Equivalent amounts of p-phenylenebis(4,4-dimethyl-2-oxazol1n-5-one ) (2) and Jeffamine D-2000 (polyoxypropylenediamine from Texaco Chemical Co., amine equiv. weight 1023) were mixed with 5 mole % of the desired catalyst. The stirred mixture was heated at 240°C under argon for 30 minutes, then an additional 1.5 hours under vacuum (<1 torr) and collected. The amount of cyclization was estimated by 1H-NMR in CDC 13 by comparison of the Integrated intensities of the absorptions due to the gem-dimethyl substituents. These absorptions appeared at 1.39 ppm in the cyclic form and at 1.73 ppm in the open-chain form of the polymer (see Scheme 4). Results are listed in Table I. 

Waldmann used (R) and (5>aminoacid methyl esters and chiral amines as chiral auxiliaries in analogous aza-Diels-Alder reactions with cyclodienes.111 The diastereoselectivity of these reactions ranged from moderate to excellent and the open-chain dienes reacted similarly. Recently, the aza-Diels-Alder reaction was used by Waldmann in the asymmetric synthesis of highly functionalized tetracyclic indole derivatives (Eq. 12.45), which is useful for the synthesis of yohimbine- and reserpine-type alkaloids.112... 

Early work focused on compounds with open-chain carbenes generally synthesized in the coordination sphere of the gold atom, for example, by addition of amines or alcohols to isocyanide ligands in the corresponding gold complexes. Subsequent synthetic approaches have relied on the in situ deprotonation of onium salt precursors by a... 

And how to insert the nitrogen in the open chain synthetic intermediates (one more retrosynthetic step) With the same approach, insertion of an amine or an azide on an electrophilic carbon. Which means that in principle the nitrogen can be inserted at the same time on both positions. The example reported in Fig. 34 is an application of this approach. 

The open-chain unsaturated tertiary amine is again exhaustively methylated and its quaternary ammonium base, in its turn, decomposed as before. 

FIGURE 2. Plot of experimental IPs for cyclic N-methyl amines ( ). Experimental ( ) and calculated ( ) IPs for open-chain methyldialkylamines having the same number of carbon atoms are also shown. Reproduced with permission from Reference 24... 

The effect of steric hindrance was further studied by comparing the reactivity of primary and secondary amines of different steric requirements with 2,3,5,6-tetrachloronitro-benzene, 24 (Scheme 10)140. It is shown in Table 18 that open-chain amines give higher yield of the nitro-substitution products. 

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