Enamines oxygen addition

These reactions are related to the formation of pyrroles and quinolines from aminocarbonyl compounds and acetylenes (582,583) and may be contrasted with the formation of pyran derivatives by electrophilic attack on an enamine, followed by addition of an oxygen function to the imonium carbon (584-590). 

The reaction of 2-polyfluoroalkylchromones (e.g., 323) with l,3,3-dimethyl-3,4-dihydroisoquinolines (e.g., 324) gave zwitterionic 6,7-dihydrobenzo[ ]quinolizinium compounds such as 326 (Scheme 70). The mechanism proposed for this transformation involves an addition-elimination displacement of the chromane heterocyclic oxygen by the enamine tautomer of the dihydroisoquinoline, followed by intramolecular cyclization of the intermediate 325 <20030L3123>. 

There is a rich synthetic potential for enamines in heterocyclic synthesis. Enamines can react as electrophiles or nucleophiles and as new partners in cycloaddition reactions. Various derivatives of nitrogen-, oxygen-, and sulfur-containing heterocycles have been prepared, and these, in turn, are of interest as starting materials for additional syntheses. They represent potential synthons for the development of various new directions in organic chemistry. 

L-Prolinamides (71) with a pendant alcohol act as recoverable bifunctional catalysts of direct nitro-Michael addition of ketones to -nitrostyrenes, giving syn-de s up to 94% and ees up to 80%.204 The pyrrolidine provides enamine catalysis, and the side-chain donors can hydrogen-bond the nitro oxygens. 

If other groups capable of conjugation are adjacent to the enamine system, they can also participate in the salt formation. Thus, in 8-amino-a,j8-unsaturated ketones, in addition to possible protonation at the a-carbon and the nitrogen, protonation could also occur on the carbonyl oxygen.200-202... 

Neutral nucleophiles where nitrogen or oxygen is the nucleophilic centre are relatively weak nucleophiles, and an acid catalyst is generally needed. After nucleophilic addition has taken place, further reactions may occur leading to structures such as imines, enamines, acetals, and ketals ... 

Sensitized photo-oxygenation of 3-morpholino-5a-cholest-2-ene (320) led to a mixture of the 2,3-dione (322) and the 3-morpholino-3-en-2-one (323). Model experiments at low temperature confirmed the formation of an unstable dioxetan (321) as the key intermediate, formed by addition of singlet oxygen on to the olefinic bond of the enamine.253... 

Since this is the first time the radical reactions of enamines are being reviewed, an attempt has been made to cover all the relevant literature. In Section II of this chapter, a brief discussion of the general principles of radical additions to. alkenes with special emphasis on the modifying effect due to the presence of amino group (as is the case in enamines) is included. Section III deals with the reactions of enamines in which the radical addition takes place on the C=C bond of enamines while Section IV describes the reactions with one-electron oxidants such as metal ions and oxygen. 

Formation of an enamine radical cation 45 was proposed as the chain initiation step in the autooxidation of enamines and SchifFs bases of a,/ -unsaturated ketones to give unsaturated 1,4-diones37. Pyrrolidine enamine of 10-methyl-A1(9)-octal-2-one (44) reacts with oxygen at room temperature to produce, after acid hydrolysis, 10-methyl-A1 (9)-octalin-2,8-dione (47) in 20% yield. Addition of a catalytic amount of FeCl3, Cu(OAc)2 or CuCl2 causes a pronounced enhancement in the oxidation rate and increases the yield to 80-85% after 1 h. 

McKay et al,163 reported a 1,4 addition of oxygen to the enamine derivatives (154, 155, and 156). These compounds react with oxygen in chloroform within an hour at room temperature to give 1,2,4-dioxazine derivatives (157, 158, and 159). In the presence of 0.1% cobalt naphthenate, 1 meq of oxygen is taken up in less than 5 minutes. 

Particularly interesting was the case of 3-methylpyrrole in addition to the expected hydroxy- and methoxylactams, compounds 97 and 98 were found.124 This fact was presented as the first evidence for the formation of a cyclic dioxetane intermediate (99) arising from 1,2-cycloaddition of singlet oxygen to the enamine-like 2,3 bond of the pyrrole. 

The crossover product, propionaldehyde-l,3-d-3- C 12, clearly demonstrated that the isomerization occurred via intermolecular 1,3-hydrogen shift. These results are consistent with a modified metal hydride addition-elimination mechanism which involves exclusive 1,3-hydrogen shift through oxygen-directed Markovnikov addition of the metal hydride to the carbon-carbon double bond (Scheme 12.2). The directing effect of functional groups on the selectivity of transition metal catalysis is well presented [9], and an analogous process appears to be operative in the isomerization of allylamines to enamines [10]. 

Inspection of empirical formulas and the corresponding structures of starting material and product reveals that III is solely a dimer of I. Two important facts, however, conspire against this outer-layer simplicity. First, if the deep-blue compound I is allowed to dimerize by itself (and this in fact occurs in solution), the colorless dimeric structure IV (but not III) results. Second, there is an enamine in the medium, which obviously makes the difference. The role of this enamine should not be taken lightly, particularly if the conjugation of the sulfur atoms in I imbues this compound with a behavior reminiscent of oxygen homolog systems, that is, quinonoids. The exocyclic double bond is amenable to a Michael-type 1,4 addition by suitable nucleophiles while the thioketone sulfur is potentially a nucleophilic center (see Scheme 28.1). 

All the examples reported so far for the enantioselective organocatalytic aminox-ylation (nucleophile attacks to the oxygen atom of the nitroso derivative) or hydro-xyamination (nucleophile attacks to the nitrogen atom of the nitroso derivative) have employed an enamine intermediate and nitrosobenzene, but O-selectivity is obtained in majority. In 2007, a selective a-hydroxyamination was disclosed with cinchona alkaloids by Jorgensen and coworkers (Scheme 6.43) [72]. They developed the organocatalytic asymmetric addition of a-aryl-a-cyanoacetates 133 to nitrosobenzene (144) catalyzed by (—(-quinine in high yields and moderate enantioselectivities up to 59% ee. 

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