Secondary enamines tautomerism

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). 

IR, UV and NMR spectra obtained so far are compatible with the structure of the secondary enamines. The tautomeric enamine structure of some enaminones in the solid state has also been established unambiguously by single-crystal X-ray diffraction analyses21. In agreement with the experimental evidence, theoretical calculations22,23 performed on enaminones 6-8 and nitroenamine 9 indicate that the enamine forms are... 

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. 

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. 

Enamines. The condensation of a secondary amine and a ketone to make an enamine is a well known reaction which has seen wide use in organic synthesis [176-178]. Imines of a primary amine and a ketone exist in a tautomeric equilibrium between the imine and secondary enamine forms, although in the absence of additional stabilization factors cf. Scheme 5.33), the imine is usually the only detectable tautomer. Nevertheless, the enamine tautomer is very reactive toward electrophiles and Michael additions occur readily [179]. The mechanism of the Michael additions of tertiary and secondary enamines are shown in Scheme 5.34. For tertiary enamines, the Michael addition is accompanied by proton transfer from the a -position to either the a-carbon or a heteroatom in the acceptor, affording the regioisomeric enamine as the initial adduct [180]. The proton transfer and the carbon-carbon bond forming operations may not be strictly concerted, but they are nearly so, since conducting the addition in deuterated methanol led to no deuterium incorporation [180]. 

The E-isomer is generally more stable than the Z-isomer due to diminished steric hindrance, so it is assumed that the E-isomer is the major product (shown for 83). Water, a reaction by-product, may be removed to give a better yield of product and azeotropic distillation is used as well as molecular sieves (see Section 18.6.3). Enamines are structurally related to an end (HO—C=C) in that the heteroatom is directly attached to the alkene unit. Enamines are often isolable compounds, whereas enols tautomerize spontaneously to the carbonyl form. Note that when imine 76 is formed from iminium salt 80, there is no enamine product. In fact, the C-H in 80 is much less acidic that the N-H unit, so the product is the imine rather than the enamine. It is noted that there is an equilibrium between an imine and an enamine, known as imine-enamine tautomerism, but it will be ignored in this book. Many different secondary amines can be used in this reaction, including cyclic amines (see Chapter 26, Section 26.4.1) such as pyrrolidine (90), piperidine (91), and morpholine (92). It is important to note that it is generally easier to form an enamine from a ketone than from an aldehyde. 

This type of mesomerisin is much more important in enamines possessing a tertiary nitrogen atom than in those possessing a secondary nitrogen atom since the latter exist largely in the tautomeric imino form (2). 

Analogous compounds with a secondary amino group (a,j8-unsaturated secondary amines) can, in principle, exist in either the form of imines (6) or the tautomeric form of enamines (7). As they practically occur and react in the former structure, it is more convenient to use the group designation imines. ... 

There is a distinct relationship between keto-enol tautomerism and the iminium-enamine interconversion it can be seen from the above scheme that enamines are actually nitrogen analogues of enols. Their chemical properties reflect this relationship. It also leads us to another reason why enamine formation is a property of secondary amines, whereas primary amines give imines with aldehydes and ketones (see Section 7.7.1). Enamines from primary amines would undergo rapid conversion into the more stable imine tautomers (compare enol and keto tautomers) this isomerization cannot occur with enamines from secondary amines, and such enamines are, therefore, stable. 

Tertiary enamines are the most stable ones and are the main subject of this chapter. Secondary and primary enamines tend to revert to the tautomeric imino form [4] (Eq. 3). 

To suppress enamine-derived side products, we explored addition of benzotriazole (BtH) to the reaction mixture. The premise behind these experiments was the ability of BtH to form stable adducts with imines,23,24 thereby blocking tautomerization of 19 to 20 through in situ formation of the benzotriazolyl derivative 21. It was hoped that subsequent hydride displacement of the Bt moiety would afford the desired mono alkylated products 23. Indeed, analytical high-performance liquid chromatography (HPLC) revealed a remarkable improvement in terms of product purity, especially for reactions carried out at room temperature, with the desired secondary anilines 23 being essentially the only products detected. In... 

Since tautomeric rearrangement is not possible when secondary amines react with acetylene, the intermediate enamines can be isolated.312,314 Vinylation with acetylene of heterocyclic nitrogen bases, such as pyrrole, indole, carbazole, was achieved in this way.312,315 However, when terminal alkynes react with secondary amines,... 

The typical behavior of enamines has been mainly observed for compounds possessing a tertiary nitrogen atom.1 The analogous derivatives with a secondary amino group (the a,j8-unsaturated secondary amines) could, in principle, possess either the imino or the tautomeric enamine structure, but the first possibility is preferred practically without exception. In the text, some examples of their properties are quoted for the sake of comparison with those of tertiary enamines on these occasions, the group designation imines is used. Nucleophilic reactions of a limited number of aromatic heterocyclic systems are also included when they are similar to the reactions of enamines and illustrate the specific character of the enamine grouping. 

The tertiary enamines, in contrast to the secondary derivatives, cannot exhibit enamine-imine tautomerism. As the free bases, they exist only in the vinylamino form. Their physico-chemical properties are in agreement with this structure, especially the spectral properties. The bands due to the stretching frequency of the carbon-carbon double bond in their infrared spectra1-25-27 (situated at 1630-1660 cm-1 according to the nature of the substituents) occur at somewhat lower frequencies, but their intensities are greatly increased in comparison to those of simple olefins because of conjugation with the free electron pair on the nitrogen atom. Indications of cis-trans isomerism... 

The review starts with a discussion of the mechanism of keto-enol tautomerisation and with kinetic data. Included in this section are results on stereochemical aspects of enolisation (or enolate formation) and on regioselec-tivity when two enolisation sites are in competition. The next section is devoted to thermodynamic data (keto-enol equilibrium constants and acidity constants of the two tautomeric forms) which have greatly improved in quality over the last decade. The last two sections concern two processes closely related to enolisation, namely the formation of enol ethers in alcohols and that of enamines in the presence of primary and secondary amines. Indeed, over the last fifteen years, data have shown that enol-ether formation and enamine formation are two competitive and often more favourable routes for reactions which usually occur via enol or enolate. 

Enamines containing a primary or secondary amino group can exist in the tautomeric imine form (Scheme 3)42 47 58 60 61. relative stabilities of the tautomers depend on... 

A theoretical study65 based on the semi-empirical AMI method was carried out in order to account for the tautomeric equilibria of enaminones 35. The results obtained were consistent with previous X-ray observations66 and showed the enamine form of acyclic primary and secondary amines with a hydrogen bond between the N and O atoms to be ca 5 kcal mol"1 more stable than its tautomer. 

In the case of primary (and secondary ) )S-keto enamines, the enamino keto form 30a or 31a is stabilized by its push-pull conjugated mesomeric form 30b or 31b and by an intramolecular hydrogen bridge which dominates over the tautomeric imino enol form 30c or 31c (equation 3). Similar results are reported for jff-thioketone enamines . ... 

Nitroenamines with a primary or secondary amino group can exist also in two tautomeric forms the imino-nitro form (511) and the imino-nitronic acid form (512). Although the enamine form represents the thermodynamically more stable tautomer, the imino-nitro form has been observed when severe steric hindrance prevents planarity of the conjugated system Compounds 513, derived from 2-nitrocycloalkanones, have been reportedto exist exclusively as the imino-nitronic acid tautomer, although the spectroscopic evidence presented is also consistent with the enamine form,... 

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