Azetidines enamines

It was shown that the rate of formation of the enamine of 3,3-dimethyiaziridine is 5 to 10 times faster than that of pyrrolidine with 2-methyIcyclohexanone and 1-tetraIone, probably due to decreased steric hindrance. However, the yields of monomethylated products are significantly lower with the azetidine enamine ... 

The secondary amines used in the preparation of enamines have been primarily simple dialkylamines or cyclic amines of five- or higher-membered rings. Azetidine (4) yields a stable enamine with cyclopentanone (28). No simple enamines formed by condensation of ethylenimine (5) or a substituted ethylenimine with an aldehyde or ketone have been reported. 

A structurally unrelated agent is tazadolene (40). The synthesis of tazadolene begins with P-keto ester 37 and subsequent enamine formation with 3-amino-1-propanol followed by hydrogenolysis to give 38. This phenylhydroxymethyl compound is then dehydrated with hydrochloride acid to form olefin 39. Treatment with bromine and triphenylphosphine effects cycliza-tion to form the azetidine ring of tazadolene [10]. 

Use of an interesting enamine photooxidation reaction has teen made of in the synthesis of P-lactams from 2-azetidine carboxylic esters (6.19) 625>. 

Only a few papers on the formation of compounds with small rings have been published. One example is the [2 + 2]-cycloaddition of electron-rich enamines to Schiff bases under high pressure (1.4 GPa) (87JOC365). The reaction leads to substituted azetidines (1). Four-membered ring heterocycles, thietane derivatives (4), are formed by interaction of sulfene (2) with enamines (3) (86CB257 93JOC3429). 

Cycloaddition reactions represent another route to pyrazoles from enamines. For example, azine (101) and enamines react via a [2 + 2]-cycloaddition with the formation of azetidines that undergo acid hydrolysis... 

Azetidines (215) have been synthesized by high-pressure-promoted [2 + 2] cycloadditions between imines such as 213 and / ,/i-disubstituted enamines such as 50116 in a weak polar solvent so that the dipolar intermediate 214 is neither stabilized nor intercepted (equation 46). The azetidines formed were unstable at a normal pressure and slowly decomposed into starting materials on standing. 

The high-pressure (12 kbar) reaction of isobutyraldehyde pyrrolidine enamine with benzylideneaniline or benzylidenemethylamine in f-butyl methyl ether gives azetidines... 

The enamine TV-vinylpyrrolidinone reacts with the complex imine 7, obtained from tetracyanoethylene and trifluoromethanesulphenyl chloride, CF3SC1, to yield, after hydrolysis, the azetidine 8 (equation 6)23. 

Enamines possessing /7-hydrogen atoms add hexafluoroacetone azine to form transient dipolar azomethine imines 9, as evidenced by low-temperature 19F NMR spectroscopy, which rearrange to hydrazones. If there is no hydrogen atom in the /7-position the betaines cyclize to unstable derivatives 10 of azetidine (equation 7)24. 

Ammonia reacts with 14 to yield the enamine 338 at low ( — 33°C) temperature, but gives a mixture of the diphenylazetidinones 339 under ambient conditions both products result from zwitterion 340. With methylamine, 14 gives an azetidine at either temperature, whilst with aziridine ring-opening occurs. iV-Arylsulphimides and IV-unsubstituted sulphoximines react with 14 by a 1,4-addition process to give ring-cleaved products. ... 

Secondary amines used for reactions with cyclic ketones may be aziridine (52X azetidine (53), pyrrolidine (54), piperidine (55), hexamethylenimine (56), morpholine (57), //-methylpiperazinc (58) and acyclic amines like dimethyla-mine (59). The general order of electrophilic attack of enamines as dependent on the nature of the amine moiety decreases in the sequence pyrrolidine (54) > dimethylamine (59) > hexamethylenimine (56) > piperidine (55) sk azetidine (53) > morpholine (57). This sequence seems to parallel the magnitude of conjugative interaction between the amino group and the C=C double bond as indicated by the H NMR chemical shift of the hydrogen at the jS-carbon. 

Extension of the enamine-mediated carbonyl a-amination strategy to the generation of quaternary stereogenic centers at the a-position of a-branched aldehydes under catalysis by prohne 1 [8, 9], pyrrolidine tetrazole 3 [10, 11], or L-azetidin-2-carboxylic acid 4 [8] has also been explored (Table 11.1). The observed enantio-selectivities ranged from essentially none to >99%. Derivatives of 2-phenylpropanal gave better enantioselectivities than a,a-dialkyl substituted aldehydes. Erase and coworkers [11] employed microwave irradiation to accelerate the rate of proline-catalyzed amination, and found that yields as well as enantioselectivity can be somewhat improved with shorter reaction times. It appears that the pyrrolidine tetrazol 3 was a more effective catalyst than L-proline 1 for the amination of 2-phenylpropanal derivatives [10,11]. Subsequent reduction of adducts and cyclization could be carried out to afford the respective a-amino alcohols or the A-amino-oxazolidinones. 

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