Imines, isomerization

The thermal hydrazone-azomethine imine isomerization can be easily performed under microwave irradiation in the absence of solvent. The subsequent 1,3-dipolar cydoadditions with electron-defident dipolarophiles occur in only a few minutes to afford the corresponding cycloadducts. The use of pyrazolyl hydrazones 205 leads to valuable compounds, such as bipyrazoles 213, in good yields and this provides a new approach to the preparation of these heterocyclic derivatives [116] (Scheme 9.67). Reactions undertaken with dassical heating under comparable reaction conditions (time and temperature) lead to cydoadduct yields that are considerably lower and, indeed, several dipolarophiles do not react at all. 

Ironically, species such as (89 M Li) are also the major isomers obtained when unsymmetrical ke-timines are deprotonated with LDA at -78 There is a kinetic preference for deprotonation anti to the substituent on nitrogen. At very low temperatures, deprotonations with LDA occur at the less-substituted carbon atom via the less stable (Z)-imine. Rearrangements then occur to the syn, less-substituted imine, which is in turn alkylated. On the other hand, deprotonations conducted at -23 to 0 C with LDA are faster than imine isomerization and the imine anion mixture composition reflects the ( ) (Z) ratio of the starting imine. Anti-syn imine anion isomerization occurs to give predominately the more-substituted fyn-metallated imine (cf. 90), which then undergoes alkylation. These results are summarized in Scheme 46 using the f-butylimine of 2-butanone as an example. 

Keywords Allyl alcohol, Allylamine, Aza-allyl, Azomethine, BINAP, BIPHEMP, Citronellal, Cobalt, DIOP, Enol, Enamine, Imine, Isomerization, Kinetic resolution. Nitrogen-triggered, Rhodium, Ruthenium... 

In the final analysis, it appears that the diastereoselectivity of the reactions of imines and crotylboranes (47, 96) depends on the relative rates of crotyl transfer e.g. 95a —> 93) versus imine isomerization that leads to competitive pathways (e.g. 94d - 92). When R is an aryl group, the rate of crotyl transfer is probably faster than competitive imine isomerization. When R is an alkyl group, however, the relative rates are probably inverted. The driving force for imine isomerization is probably that complex (95a) is not very stable owing to the bulky 9-BBN unit positioned syn to R, while the complex of crotyl-9-BBN (47) and a (Z)-aldimine e.g. 94d) is probably much more stable. It is conceivable, therefore, that the overall rate of reaction via (94d) can be much faster than via (95a) even though the (Z)-imine cannot be detected in solution. Additional research is clearly needed to clarify the stereochemical course of these reactions. 

A base-induced ring-opening imine isomerization/diastereoselective organometallic addition sequence on 4-substituted-2-perfluoroalkyl-l,3-oxazolidines 205 was developed for the asymmetric synthesis of perfluoroalkyl amino alcohols 207 via intermediates 206. Chiral compounds were obtained in good yields and high diastereoselectivity <04OL641>. 

Normally, aqueous acid hydrolysis liberates the imine, which is converted to a carbonyl under the reaction conditions by loss of ammonia. If the intermediate imine is reduced in situ, an amine product such as 1.60 is generated. If the cyano group is conjugated to an ester (or another carbonyl group), the imine isomerizes to the enamine form (an enamine ester). This latter process is illustrated by the reaction of ethyl a-cyanoacetate and ethylmagnesium bromide, and the product was ethyl 3-aminopent-2-enoate, 7.67.33... 

In the final analysis, it appears that the diastereoselectivity of the reactions of imines and crotylboranes (47, 96) depends on the relative rates of crotyl transfer e.g. 95a -> 93) versus imine isomerization that leads to competitive pathways e.g. 94d 92). When R is an aryl group, the rate of crotyl transfer is... 

Recently, 9 (Figure 6.5) was shown to catalyze the biomimetic transformation of a-keto esters to a-amino acids with various functional groups [39]. The reaction is pictured in Scheme 6.17 as involving imine isomerization catalyzed by 9 prior to hydrolysis and the favored formation of the a-amino ester in the (R) configuration. Various phenylalanine derivatives could be obtained by this reaction. The reaction worked equally well for a-keto esters with an aromatic or aliphatic group and for esters with an ether or thioether function in addition to the a-carbonyl group. 

Anilines react with ct-haloacetophenones to give 2-arylindoles. In a typical procedure an W-phenacylaniline is heated with a tw o-fold excess of the aniline hydrobromide to 200-250°C[1]. The mechanism of the reaction was the subject of considerable investigation in the 1940s[2]. A crucial aspect of the reaction seems to be the formation of an imine of the acetophenone which can isomerize to an aldimine intermediate. This intermediate apparently undergoes cyclization more rapidly (path bl -> b2) than its precursor (Scheme 7.3). Only with very reactive rings, e.g, 3,5-dimethoxyaniline, has the alternative cydiz-ation (path al a2) to a 3-arylindole been observed and then only under modified reaction conditions[3],... 

Trifluoromethylisocyanide reacts with hydrogen fluoride to give a mixture of isomeric fluorinated imines [56] (equation 12)... 

The addition of primary amines to fluoroolefins under anhydrous conditions yields imines The hexafluoropropene dimer, perfluoro-2-methyl-2-pcntcne, and ten butylamine react to yield a mixture of two compounds m a 9 4 ratio [4] (equation 3) rather than just the major keteiiimme-imine, as previously reported [5] It IS claimed that this result is possible by means of isomerization to the terminally unsaturated difluoromethylene isomer prior to nucleophilic attack Secondary amines add to fluoroolefins under anhydrous conditions to give fluonnated ternary amines m good yields If the fluoroolefin is added to the amine without cooling the reaction mixture, or if an excess of the secondary armne is used, there is a tendency toward dehvdrofluonnation of the ternary amine The products... 

Anastassiou has summarized in two reviews the knowledge about IH-azonine (41a) [72ACR281 78AHC(23)55]. Compound 41a as well as its salts (N M" ) are aromatic compounds which exist as such and not as imine polyenic forms. Tliis compound demonstrates a valence isomerism 41a/41b similar to that of l//-azepine (14a/14c see Section II,A,1) the transformation 41a 41b occurs upon irradiation. 9-Azabicyclo[6.1.0]nona-2,4,6-triene 41b displays no tendency to thermal isomerization to 41a at ambient temperature (72ACR281). 

Only in 1961 did Woodward and Olofson succeed in elucidating the true mechanism of this interesting reaction by making an extensive use of spectroscopic methods. The difficulty was that the reaction proceeds in many stages. The isomeric compounds formed thereby are extremely labile, readily interconvertible, and can be identified only spectroscopically. The authors found that the attack by the anion eliminates the proton at C-3 (147) subsequent cleavage of the N—0 bond yields a -oxoketene imine (148) whose formation was established for the first time. The oxoketene imine spontaneously adds acetic acid and is converted via two intermediates (149, 150) to an enol acetate (151) whose structure was determined by UV spectra. Finally the enol acetate readily yields the W-acyl derivative (152). 

Substituted TMMs also participate smoothly in imine cycloaddition to generate more structurally elaborate pyrrolidines. The regioselectivity of these reactions is similar to that of olefin addition, although subsequent isomerization of the initial adduct is often observed. For example, the cyano system produced the thermody-... 

Initial imine formation between PMP and cr-keioglutatate is followed by double-bond rearrangement to an isomeric imine and hydrolysis. 

However, valence isomerism in some l//-azepinc-4,5-dicarboxylates, e.g. 3, which is undetectable by NMR spectral measurements, has been confirmed by trapping out the benzene imine tautomers 4, as their bisdipolar cycloadducts 5, with diazomethane.233,234 In contrast, ethyl l//-azepine-l-carboxylate and diethyl l-acetyl-l//-azcpinc-3,5-dicarboxylate, with diazomethane, yield only the C4-C5 dipolar cycloadducts. 

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