Heterocyclic enamines oxidation

The dehydrogenation of 2,3-dihydro- and 2,5-dihydro-l//-l-benzazepines to 3//-l-benz-azepincs with heterocyclic enamines in the presence of boron trifluoride diethyl ether complex has been achieved in moderate yields (30-35%).241 In contrast, electrochemical oxidation of 2,5-dihydro-1 H- -benzazepines in buffered acetic acid solution furnishes initially 5//-l-benz-azepines in 35-45% yield.242... 

The recently reported (757) conversion of 5-pyrazolones directly to a,j8-acetylenic esters by treatment with TTN in methanol appears to be an example of thallation of a heterocyclic enamine the suggested mechanism involves initial electrophilic thallation of the 3-pyrazolin-5-one tautomer of the 5-pyrazolone to give an intermediate organothallium compound which undergoes a subsequent oxidation by a second equivalent of TTN to give a diazacyclopentadienone. Solvolysis by methanol, with concomitant elimination of nitrogen and thallium(I), yields the a,)S-acetylenic ester in excellent (78-95%) yield (Scheme 35). Since 5-pyrazolones may be prepared in quantitative yield by the reaction of /3-keto esters with hydrazine (168), this conversion represents in a formal sense the dehydration of /3-keto esters. In fact, the direct conversion of /3-keto esters to a,jS-acetylenic esters without isolation of the intermediate 5-pyrazolones can be achieved by treatment in methanol solution first with hydrazine and then with TTN. 

The reductive route used to prepare heterocyclic enamines has the advantage of avoiding the hydroxylation reaction sometimes found in the mercuric acetate oxidation of saturated heterocyclic amines [126]. The lithium-n-propyl-amine reducing system has been used by Leonard to reduce julodine to A5-tetrahydrojulolidine (66% yield) and l-methyl-l,2,3,4-tetrahydroquinoline to a mixture of enamines (87% yield), consisting of l-methyl-A8-octahydro-quinoline and 1-methyl-A9-octahydroquinoline [135] (Eqs. 51, 52). 

Biochemical oxidation of a tertiary amine has been shown to proceed through the intermediacy of a heterocyclic enamine, formed upon two-electron oxidation at the level of microsomes91 (Scheme 68). 

Leonard and coworkers " have developed the mercuric acetate oxidation of cyclic tertiary amines into a eneral method for the synthesis of heterocyclic enamines. This method has been used by other authors , A solution of the amine with a four-molar excess of mercuric acetate in 95% aqueous acetic add was refluxed on a steam bath and, after 1.5 hours, the mercurous acetate had precipitated and the amine obtained in 60-80% yield. It was assumed that 1,2-elimination, which requires an antiperiplanar arrangement of the nitrogen-electron pair and the eliminated hydrogen atom, took place, and that elimination of the hydrogen atom on the tertiary carbon atom is preferred, Oyeroxidation can be avoided by adding disodium ethylenediamine-tetraacetate to the reaction mixture . 

Oxidation with ruthenium tetroxide was also used on A-acyl and Af-ethoxycarbonyl heterocyclic enamines (Scheme 64). 

In the above reactions of enamine derivatives with oxazolidines and oxazinanes, pyridine systems did not constitute direct targets but were formed, in a few cases, by air oxidation of initially formed dihydropyridine derivatives. Oxazolidines 30, possessing electron-withdrawing groups in C-2 substituents, exist mainly as tautomeric acyclic enamines 28 (Section II.C.2), which in the presence of an acid would also generate iminium cations such as 54 that should react with nucleophiles. Thus, it has been found that such oxazolidines in presence of an acid, react with acyclic, cyclic, and heterocyclic enamine derivatives in 1 1 stoichiometry to provide a unique synthesis of pyridine, quinolinone, and pyridopyrimidine derivatives (98T935). 

Typical nucleophiles known to react with coordinated alkenes are water, alcohols, carboxylic acids, ammonia, amines, enamines, and active methylene compounds 11.12]. The intramolecular version is particularly useful for syntheses of various heterocyclic compounds[l 3,14]. CO and aromatics also react with alkenes. The oxidation reactions of alkenes can be classified further based on these attacking species. Under certain conditions, especially in the presence of bases, the rr-alkene complex 4 is converted into the 7r-allylic complex 5. Various stoichiometric reactions of alkenes via 7r-allylic complex 5 are treated in Section 4. 

As shown in Scheme 2, two heteroatom-carbon bonds are constructed in such a way that one component provides both heteroatoms for the resultant heterocycle. By variation of X and Z entry is readily obtained into thiazoles, oxazoles, imidazoles, etc. and by the use of the appropriate oxidation level in the carbonyl-containing component, further oxidized derivatives of these ring systems result. These processes are analogous to those utilized in the formation of five-membered heterocycles containing one heteroatom, involving cyclocondensation utilizing enols, enamines, etc. 

The generation of other heteroq cles from Bfx and Fx has been the subject of exhaustive investigation. The most important transformation of Bfx to other heterocycles has been described by Haddadin and Issidorides, and is known as the Beirut reaction . This reaction involves a condensation between adequate substituted Bfx and alkene-type substructure synthons, particularly enamine and enolate nucleophiles. The Beirut reaction has been employed to prepare quinoxaline 1,4-dioxides [41], phenazine 5,10-dioxides (see Chap. Quinoxahne 1,4-dioxide and Phenazine 5,10-dioxide. Chemistry and Biology ), 1-hydroxybenzimidazole 3-oxides or benzimidazole 1,3-dioxides, when nitroalkanes have been used as enolate-producer reagent [42], and benzo[e] [ 1,2,4]triazine 1,4-dioxides when Bfx reacts with sodium cyan-amide [43-46] (Fig. 4). 

This new impurity proved to be derived from the Pd-catalyzed oxidation of DIPA to the enamine via P-hydride elimination. In fact, mixing Pd(OAc)2 with DIPA in DMF-d7 readily formed Pd black along with two species, primary amine and acetone, presumably derived from the enamine through hydrolysis. The resulting enamine or acetone then underwent a coupling reaction with iodoaniline 28. Heterocyclization through the arylpalladium(II) species provided 2-methyl indole 71, as shown in Scheme 4.19. 

The mercury(II) acetate oxidation of tertiary amines is frequently used to introduce unsaturation into piperidine derivatives. The iminium ion is believed to be an intermediate in this reaction. These ions can give the enamine or react further with nucleophiles to give more complex heterocycles (Scheme 4). 

The 5,6-dihydro-2/T- and-AH- 1,2-oxazines and -thiazines are interrelated by prototropy, being enamines and imines respectively. In the case of the oxazines the imine form is favoured and there are several well-established examples of this system, including the parent heterocycle (18). This compound is obtained by oxidation of tetrahydro-l,2-oxazine with lead tetraacetate and, although it is reasonably stable, on standing it slowly trimerizes (Scheme 4) (72JCS(Pl)170l). 

Reissert compounds (l-acyl-l,2-dihydro-2-quinolinecarbonitriles) have been prepared on cross-linked polystyrene and C-alkylated in the presence of strong bases (Entry 8, Table 15.25). Treatment of polystyrene-bound C-alkylated Reissert compounds with KOH leads to the release of isoquinolines into solution (Entry 9, Table 15.25). The reaction of support-bound quinoline- and isoquinoline /Y-oxides with acy-lating agents followed by treatment with electron-rich heteroarenes and enamines has been used to prepare alkylated and arylated derivatives of these heterocycles (Entry 10, Table 15.25 see also Table 15.26). 

If we use a 1,3-diketone instead we will get a five-membered heterocycle and the imine and enamine formed are enough to give aromaticity without any need for oxidation. The product is a pyrazole. 

Many common reactions of aliphatic amines, ethers, and sulfides 1 involve initial addition of an electrophilic reagent utilizing the lone pair of electrons on the heteroatom salts, quaternary salts, coordination compounds, amine oxides, sulfoxides, and sulfones are formed in this way. Corresponding reactions are very rare (cf. Section 3.3.1.3) with pyrroles, furans, and thiophenes. These heterocycles react with electrophilic reagents at the carbon atoms 2, 3 rather than at the heteroatom. Vinyl ethers and enamines 4 show intermediate behavior, reacting frequently at the -carbon but sometimes at the heteroatom. 

A number of syntheses have been devised which lead to heterocyclic derivatives of cholestanes. 4-Aza-5a-sitostane (321 R = H, X = H2) and its N-methyl derivative (321 R = Me, X = H2) have been prepared by way of oxidative opening of ring A of 4-sitosten-3-one to give a 3,5-seco-5-oxo-3-oic acid which was cyclized by reaction with ammonium hydroxide or methylamine to give A5-enamine lactams these upon hydrogenation gave the lactams (321 R = H or Me, X = O) respectively. Hydride reduction completed the route to the required 4-aza-steroids.179... 

Potassium permanganate oxidizes a heterocyclic compound, acetoneberberine, containing an enamine-type subunit61 (Scheme 44). Different products were obtained, however, when the enamine / -carbon had a methyl group. 

The 26 chapters, written by experts from 14 countries, cover a wide spectrum of topics related to the chemistry of enamines, including theory, structural chemistry, spectral properties, formation, reactions and stereochemistry, acidities, rearrangements, oxidation and reduction, as well as other topics. In two chapters, the material related to enamines was meagre. Hence, the chapter on radiation chemistry also deals with compounds with non-conjugated C=C and amino groups, and the chapter on synthesis and uses of isotopically labelled enamines includes enamines in which the nitrogen is part of a heterocyclic system. 

An unusual transformation occurred when triethylamine reacted with disulfur dichloride and 1,4-diazabicy-clo[2.2.2]octane (DABCO) to form heptathiocane 103 (mp 72-73 °C) and thienopentathiepine 104 (Scheme 7) <20030L1939>. The proposed mechanism involved the adduct 102 and oxidation of the intermediate complex 105, followed by the formation of enamines 106 and 107. The intermediate 106 outlined a pathway to the extended polysulfur chain, such as in 107, which cyclized into heptathiocane 103. Incorporation of only one carbon into the heterocyclic ring from the ethyl group rather than both was presumably controlled by the reactivity of the enamine 107. For the mechanism of formation of thienopentathiepine 104, Chapter 13.17, CHEC-3 should be consulted. The rare heptathiocane ring stmcture was proved by X-ray crystallography (Section 14.09.3.3). 

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