Imines equilibrium with enamines

Acyclic dialkylamines are not very reactive as nucleophiles in the oxidative alkylamination, however they are very prone to oxidation and, therefore, they are capable for unexpected behavior. Presumably, transformation 33 41 starts from oxidation of dialkylamme into imine 42, that is in equilibrium with enamine 43 (Scheme 28). The latter, as bifunctional C,W-nucleophile, attacks C-4 atom of the pyridazine ring to form cr -adduct 44, which then undergoes oxidative aromatiza-tion. Subsequent intramolecular oxidative amination of the intermediate 45 yields pyrrole derivative 41. The participation of imines in this process has been confirmed experimentally. In the presence of AgPy2Mn04, pyrimidopyridazine 33 reacts with authentic aldimines and ketimines 42 to give pyrroles 41. Transformation 33 41 represents not only a rare example of the tandem processes but... 

The mechanism begins with the reaction at C(l) to form a phenylhydrazone (p. 793), which consumes the first equivalent of phenylhydrazine. This hydrazone is an imine and imines are in equilibrium with enamines (p. 796), just as ketones are in equilibrium with enols.The imine-enamine equilibrium is shown in Figure 22.32. 

Ultraviolet absorptions ofvinylogous lactams were found by MOLCAO calculations and compared with experimental values (663). Infrared spectroscopic studies of vinylogous amides (664) and some fifty vinylogous urethanes (665) allowed configurational and structural assignments. The effect of enamine-imine equilibrium in a series of benzophenone derivatives was established (666) and the effect of structure on enamine basicity studied (667). 

The intramolecular Heck reaction presented in Scheme 8 is also interesting and worthy of comment. Rawal s potentially general strategy for the stereocontrolled synthesis of the Strychnos alkaloids is predicated on the palladium-mediated intramolecular Heck reaction. In a concise synthesis of ( )-dehydrotubifoline [( )-40],22 Rawal et al. accomplished the conversion of compound 36 to the natural product under the conditions of Jeffery.23 In this ring-forming reaction, the a-alkenylpalladium(n) complex formed in the initial oxidative addition step engages the proximate cyclohexene double bond in a Heck cyclization, affording enamine 39 after syn /2-hydride elimination. The latter substance is a participant in a tautomeric equilibrium with imine ( )-40, which happens to be shifted substantially in favor of ( )-40. 

The detailed mechanism of inhibition of TEM-2 (class A) enzyme with clavulanate has been established (Scheme 1) [23,24], The inhibition is a consequence of the instability of the acyl enzyme formed between the /1-lactam of clavulanate and the active site Ser-70 of the enzyme. In competition with deacylation, the clavulanate acyl-enzyme complex A undergoes an intramolecular fragmentation. This fragmentation initially provides the new acyl enzyme species B, which is at once capable of further reaction, including tautomeriza-tion to an entity C that is much less chemically reactive to deacylation. This species C then undergoes decarboxylation to give another key intermediate enamine D, which is in equilibrium with imine E. The imine E either forms stable cross-linked vinyl ether F, by interacting with Ser-130 or is converted to the hydrated aldehyde G to complete the inactivation. 

Imines (e.g. R CH2-CH=N R or R-CH2-C(R)=N-R) are derived from the reaction of primary amines with aldehydes or ketones respectively, and may exist in tautomeric equilibrium with the corresponding enamine form, but in which the imine form predominates. 

Enamines of primary amines, or even of ammonia, also exist, but only in equilibrium with an imine isomer. The interconversion between imine and enamine is the nitrogen analogue of enoliza-tion, which is discussed in detail in Chapter 21. 

If the ketone is enolizable, this imine is in equilibrium with the corresponding enamine. The important bonds are given in black in the diagram. 

Spectroscopic studies of imine-enamine tautomerism have shown that the equilibrium is almost completely in favour of the imine form for simple aldehydes and ketones372-374. Nevertheless, some secondary enamines are sufficiently stable to exist in detectable amounts in equilibrium with the corresponding imines for example, the f-butylamine imine of cyclohexanone shows signals due to the secondary enamine tautomer in the NMR spectrum (<5=CH 4.6)375. Studies of the imine-enamine equilibria have shown, as expected, that the enamine form is stabilized by methyl or aryl substituents at the -position (Scheme 189). 

In general, the tautomeric equilibrium (equation 1) is completely on the enamine side when an unsaturated electron-accepting substituent substitutes the /Tcarbon of 1 otherwise, the equilibrium lies far on the side of imine 1. However, apart from the two extreme cases above, some secondary enamines are sufficiently stable to exist in detectable amounts in equilibrium with the corresponding imines and thus it becomes possible to investigate the factors affecting the enamine-imine equilibrium51-53. 

It has been demonstrated that imines 410 are in tautomeric equilibrium with their secondary enamine forms 4111,249 (equation 86). Except where the enamine tautomer is stabilized by further conjugation250,251, the equilibrium is almost completely in favor of the imine form. 

Since imines, which exist in equilibrium with their enamines, have been shown to react with (3-... 

Recently, Hickmott has reported an unusual reaction in which methyl acrylate underwent reaction with the relatively small amount of enamine present in equilibrium with the imine of a 2-methylcyclohexa-none. In all cases the major product was the 2,2-disubstituted isomer, although the reaction yields were in general low (13-64%). Fievious reports of this unusual carbon-carbon bond forming reaction are... 

This asymmetric Mannich reaction could also proceed by an enamine pathway because nucleophilic addition of the in situ-generated enamine would be faster to an imine than to an aldehyde. As shown in the Fig. 12.59, the reaction starts with enamine 34 activation of the cyclohexanone by the proline anion and an electrostatic interaction with the imidazolium moiety of the catalyst In a second pre-equilibrium, the aldehyde and aniline produce an imine. Then enamine-activated 35 reacts with the imine to form 35 via transition state A. The last step is a dehydration reaction to afford the corresponding product. The catalyst is regenerated in the subsequent step. 

As in the previous sections, secondary enamines in which either the nitrogen or the double bond is further conjugated with an electron-withdrawing or electron-donating substituent are not reviewed. Metal derivatives of imines (metalloenamines) are discussed in Chapter 25. We are only concerned with secondary enamines, in equilibrium with their imine tautomer, form by condensation of a primary amine with an aldehyde or ketone. Such condensations can readily be carried out using potassium hydroxide as catalyst or by azeotropic distillation in the presence or absence of add catalysts or, for more hindered or acid-sensitive ketones, titanium tetrachloride or dibutyltin dichloride, respectively, may be used. 

A detailed investigation of the photolysis mechanism of enamines has been conducted by Hoffmann and Eicken The rearrangement proceeds through radical processes. When A -acylenamine 73 was irradiated at the wavelength corresponding to the n n -transition of the amide at approximately 200 nm, the amide bond was cleaved to the radical pair. This radical pair could either recombine and revert back to the reactant or undergo a [l,3]-acyl shift to give the imine 74. In turn 74 underwent rapid tautomerization to the enaminone 75, which was in photochemical equilibrium with its isomer 75 (Scheme 6). 

Unfortunately the nitrogen atom lowers the HOMO energy of the diene 24 and it is not a good match with the LUMO of maleic anhydride. Instead the imine 24 is in equilibrium with the enam-ine 27 and, in conformation 27b, this has a high energy HOMO and so the product2 of the reaction is 28. The tautomerism between 24 and 27 may be especially easy as it can be drawn as a [1,5]H sigmatropic shift. This conflict between weakly electrophilic imines and their tautomers, the nucleophilic enamines, is one of the themes of this chapter.1... 

Tautomers are isomers in which the site of a hydrogen atom and a double bond are different. The tautomers are in dynamic equilibrium with each other. We have already met keto-enol tautomerlsm, of which this is a variation, in Chapter 6. Imine-enamine tautomerism is another example ... 

Chiral amines have been transformed into chiral imines RCH=NG, which are usually in equilibrium with the tautomeric enamines. These enamines undergo asymmetric alkylations, and the best results are often obtained with ethers 1.58 or with valine derivatives 1.59 (R = i-Pr, R = tert-Bu) [169, 173,253] in the presence of bases. Enamines, lithioenamines and zinc enamines derived from imines are very potent Michael donors that often participate in highly stereoselective reactions [161, 162, 169, 173, 254, 257, 260, 262, 267], Chiral imines can suffer very selective addition reactions of organomagnesium reagents [139, 253, 254] and allyl-metals [154, 258]. They also suffer stereoselective Ti-catalyzed silylcyanation [268], Strecker reaction [266], and [2+2] or [4+2] cydoadditions [131, 256, 263], When the reaction produces an imine product, the chiral auxiliary is recovered after acidic hydrolysis. However, when an amine is obtained as the product, as is often the case from phenethylamine derivatives, the chiral residue is cleaved by hy-drogenolysis. In such cases, the chiral amine is not, strictly speaking, a chiral auxiliary. But these processes will be discussed anyway because of their importance in asymmetric synthesis. 

The nucleophilic properties of enamines uncovered by Stork have found a wide application in Michael additions. Secondary enamines are usually in equilibrium with the corresponding imines. These imines are generally more stable, unless the tautomeric enamine is stabilized by conjugation (Figure 7.71). The primary product of the reaction of an enamine with an a,P-unsaturated carbonyl compound is a dipolar intermediate 7.108. This intermediate is converted to a 1,5-dicarbonyl compound on exposure to aqueous add. Proton transfers can take place before hydroysis to the ketone occurs, and the stereoselectivity of the process may be determined by such steps. Moreover, the enamine addition reaction can be reversible. These problems notwithstanding, the use of chiral amines to generate imines or enamines for use as Michael donors has been widely developed. The chiral imine/enamine can be preformed or, espedally in the case of intramolecular reactions, the amine can be added to the reaction medium in stoichiometric amounts. 

Diethoxy-2,5-dihydropyrimidine (27) has a flat ring in the crystalline solid phase, and the molecule is not involved in enamine-imine tautomerism in solution <86JOC4623>. The 4,6-diphenyl analogue (28), however, is in equilibrium with its 1,2-dihydro tautomer (29) in solution (Equation... 

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