Oxidative ring opening, amine

Starting material for the synthesis of varenicline is o-bromofluorobenzene, which reacts (via benzyne) with cyclopentadiene in a Diels-Alder reaction. Oxidative ring-opening and reductive amination provides a N-benzylbenz-azepine derivative. After N-protection with trifluoroacetic anhydride, nitration with a mixture of nitric andtrifluoromethanesulfonic acids, reduction, and condensation with glyoxal, hydrolysis of the trifluoroacetamide as a final step provides the active compound in good overall yield. [568, 569]... 

The biosynthesis of these novel pyridine analogues of the dienoid Erythrina alkaloids is of considerable interest and it seems likely that they arise by a variant of the pathway leading to the lactonic alkaloids a- and jS-erythroidine (cf. Fig. 5). Thus oxidative ring openings of the C16-C17 bond of erysovine (lb) followed by amination could afford erymelanthine directly. 

Many perfluoroaUphatic ethers and tertiary amines have been prepared by electrochemical fluorination (1 6), direct fluorination using elemental fluorine (7—9), or, in a few cases, by fluorination using cobalt trifluoride (10). Examples of lower molecular weight materials are shown in Table 1. In addition to these, there are three commercial classes of perfluoropolyethers prepared by anionic polymerization of hexafluoropropene oxide [428-59-1] (11,12), photooxidation of hexafluoropropene [116-15-4] or tetrafluoroethene [116-14-3] (13,14), or by anionic ring-opening polymeriza tion of tetrafluorooxetane [765-63-9] followed by direct fluorination (15). 

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... 

The increase in thermodynamic stability of 85 is achieved by easy ring opening (01H127). This knowledge allows one to control the regioselectivity of the oxidative amination of the 6-aryl-l,2,4-tiiazine 4-oxides 53, obtaining either (i) the 5-amino-1,2,4-triazine 4-oxides 56 in the reaction of 53 with amines at low temperature in the presence of the oxidant or (ii) the 3-amino-1,2,4-triazine 4-oxides 88, provided the reaction is carried out in two steps (addition and oxidation) at room temperature or higher. 

Ethylene oxide is a highly active intermediate. It reacts with all compounds that have a labile hydrogen such as water, alcohols, organic acids, and amines. The epoxide ring opens, and a new compound with a hydroxyethyl group is produced. The addition of a hydroxyethyl group increases the water solubility of the resulting compound. Eurther reaction of ethylene oxide produces polyethylene oxide derivatives with increased water solubility. 

The first of the nudeophilic ring-opening reactions of vinylaziridines discussed in this section is diborane reduction, developed by Laurent and coworkers in 1976 (Scheme 2.24). Treatment of N-unsubstituted vinylaziridines 89 with B2H6 gives allyl amines 92 by SN2 reduction via cyclic intermediates 90 [40]. In contrast, treatment with 9-BBN gives 2-(hydroxyethyl)aziridines 93 after oxidative workup (Scheme 2.25) [41]. 

The diazotization of amino derivatives of six-membered heteroaromatic ring systems, particularly that of aminopyridines and aminopyridine oxides, was studied in detail by Kalatzis and coworkers. Diazotization of 3-aminopyridine and its derivatives is similar to that of aromatic amines because of the formation of rather stable diazonium ions. 2- and 4-aminopyridines were considered to resist diazotization or to form mainly the corresponding hydroxy compounds. However, Kalatzis (1967 a) showed that true diazotization of these compounds proceeds in a similar way to that of the aromatic amines in 0,5-4.0 m hydrochloric, sulfuric, or perchloric acid, by mixing the solutions with aqueous sodium nitrite at 0 °C. However, the rapidly formed diazonium ion is hydrolyzed very easily within a few minutes (hydroxy-de-diazonia-tion). The diazonium ion must be used immediately after formation, e. g., for a diazo coupling reaction, or must be stabilized as the diazoate by prompt neutralization (after 45 s) to pH 10-11 with sodium hydroxide-borax buffer. All isomeric aminopyridine-1-oxides can be diazotized in the usual way (Kalatzis and Mastrokalos, 1977). The diazotization of 5-aminopyrimidines results in a complex ring opening and conversion into other heterocyclic systems (see Nemeryuk et al., 1985). 

FIGURE 8.23 One electron oxidation of a cyclopropyl amine leading to ring opening and the formation of a carbon-centered free radical and an iminium ion. 

Oxidation is the first step for producing molecules with a very wide range of functional groups because oxygenated compounds are precursors to many other products. For example, alcohols may be converted to ethers, esters, alkenes, and, via nucleophilic substitution, to halogenated or amine products. Ketones and aldehydes may be used in condensation reactions to form new C-C double bonds, epoxides may be ring opened to form diols and polymers, and, finally, carboxylic acids are routinely converted to esters, amides, acid chlorides and acid anhydrides. Oxidation reactions are some of the largest scale industrial processes in synthetic chemistry, and the production of alcohols, ketones, aldehydes, epoxides and carboxylic acids is performed on a mammoth scale. For example, world production of ethylene oxide is estimated at 58 million tonnes, 2 million tonnes of adipic acid are made, mainly as a precursor in the synthesis of nylons, and 8 million tonnes of terephthalic acid are produced each year, mainly for the production of polyethylene terephthalate) [1]. 

A large variety of metabolic cyclization reactions, counterparts to the reactions of hydrolytic ring opening discussed above, occur without any change in the degree of oxidation, and often nonenzymatically. Such reactions proceed by various mechanisms of intramolecular nucleophilic substitution, with elimination of amine, phenol, halide, or H20. 

MAO oxidizes amine substrates also by a one-electron route via the cyclopropylamine radical cation 8 which undergoes ready ring opening to the iminium radical cation 9 [11]. Then capture by a flavin radical, may cause the enzyme inactivation [12]. This mechanism was established by labeling experiments, Eq.(4) [13]. 

Miiller has used cyclopropyl clock experiments to test for the possible intermediacy of radical species prior to C-N bond formation (Scheme 17.7). The diphenylcyclopro-pane derivative 3, which fragments at a rate of 2x10 ° s , affords nosylated amine 4 no product from ring opening is observed. Such a result mitigates the viability of a productive stepwise oxidation process, though it is important to note that sulfonamide 4 is formed in only 5% yield. 

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