Enamines carbinolamine

Isolated product is an enamine. Carbinolamine intermediate cannot dehydrate to a stable imine. 

Primary amines undergo nucleo philic addition to the carbonyl group of aldehydes and ketones to form carbinol amines These carbinolamines dehydrate under the conditions of their formation to give N substituted imines Secondary amines yield enamines... 

Carbinolamines are formed by nucleophilic addition of an amine to a carbonyl group and are intermediates in the for mation of imines and enamines Carbocation (Section 4 8) Positive ion in which the charge re sides on carbon An example is tert butyl cation (CH3)3C Carbocations are unstable species that though they cannot normally be isolated are believed to be intermediates in certain reactions... 

Carbinolamines are formed by nucleophilic addition of an amine to a carbonyl group and are intermediates in the formation of imines and enamines. 

The study of structure and reactivity of tertiary heterocyclic enamines is associated with the problem of equilibrium of the cyclic enamine form (70) and the tautomeric hydration products 173,174) quaternary hydroxide (71), pseudo base (so-called carbinolamine) (72) and an opened form of amino aldehyde or amino ketone (73). 

The salts of some enamines crystallize as hydrates. In such cases it is possible that they are derived from either the tautomeric carbinolamine or the amino ketone forms. Amino ketone salts (93) ( = 5, 11) can serve as examples. The proton resonance spectra of 93 show that these salts exist in the open-chain forms in trifluoroacetic acid solution, rather than in the ring-closed forms (94, n = 5, 11). The spectrum of the 6-methylamino-l-phenylhexanone cation shows a multiplet at about 2.15 ppm for phenyl, a triplet for the N-methyl centered at 7.0 ppm and overlapped by signals for the methylene protons at about 8.2 ppm. The spectrum of 93 ( = 11) was similar. These assignments were confirmed by determination of the spectrum in deuterium oxide. Here the N-methyl group of 93 showed a sharp singlet at about 7.4 ppm since the splitting in —NDjMe was much reduced from that of the undeuterated compound. 

While the usual eonsequence of hydration of enamines is eleavage to a secondary amine and an aldehyde or ketone, numerous cases of stable carbinolamines are known (102), particularly in examples derived from cyclic enamines. The selective terminal hydration (505) of a cross-conjugated dienamine-vinylogous amide is an interesting example which gives an indication of the increased stabilization of the vinylogous amide as compared to simple enamines, which is also seen in the decreased nucleophilicity of the conjugated amino olefin-carbonyl system. 

At least two pathways have been proposed for the Nenitzescu reaction. The mechanism outlined below is generally accepted." Illustrated here is the indolization of the 1,4-benzoquinone (4) with ethyl 3-aminocrotonate (5). The mechanism consists of four stages (I) Michael addition of the carbon terminal of the enamine 5 to quinone 4 (II) Oxidation of the resulting hydroquinone 10 to the quinone 11 either by the starting quinone 4 or the quinonimmonium intermediate 13, which is generated at a later stage (HI) Cyclization of the quinone adduct 11, if in the cw-configuration, to the carbinolamine 12 or quinonimmonium intermediate 13 (IV) Reduction of the intermediates 12 or 13 to the 5-hydroxyindole 6 by the initial hydroquinone adduct 7 (or 8, 9,10). 

Methylberberine (207) was easily converted to the enamine 208, photolysis of which afforded the two carbinolamines 209a and 209b (124). On exposure to sodium cyanide the mixture was converted to the desired cyanide 210 after separation. Successive oxidation of 210 with potassium ferricyanide... 

The first example of this type of transformation was reported in 1974 [76]. Three catalysts were investigated, namely [Co2(CO)8], [Co(CO)g/PBu ], and [Rh6(CO)i6]. The [Co OJg/PBu ] catalyst showed activity for reductive animation using ammonia and aromatic amines. The [Rh6(CO)16] catalyst could be used for reductive animation using the more basic aliphatic amines that were found to poison the cobalt catalyst. This early report pointed out that the successful reductive animation of iso-butanal (Me2CCHO) with piperidine involves selective enamine hydrogenation, that reductive animation of cyclohexanone with isopropylamine probably involves imine hydrogenation, and that reductive amination of benzaldehyde with piperidine would presumably involve the reduction of a carbinolamine. 

Reaction of methyl- and ethyl-2-cyclopentanone carboxylates with amines to give carbinolamines, enamines, and adipamides [175]. 

It has been reported that some aldehydes react with secondary amines to give first a diamino derivative (aminal) which then decomposes on distillation to give the enamine and the starting secondary amine. Some aromatic aldehydes have been reported to give isolatable carbinolamines first [47]. 

Presumably, the species that undergoes reduction here is a carbinolamine, an iminium ion derived from it, or an enamine. 

The study of the enamine structure may be associated, to a certain degree, with the problem of the so-called pseudobases an instructive, but somewhat specialized, review of these compounds was contributed by the late Professor Beke 47 to the first volume of this series. The name pseudobases was given by Hantzsch,48 towards the end of the last century, to those a-aminocarbinols which undergo a structural change during salt formation and yield salts with the loss of one molecule of water. The liberation of pseudobases from their salts is accompanied by rehydration. This behavior has been observed with a,/3-unsaturated heterocyclic compounds and, to a certain degree, with aromatic heterocyclic pyridine derivatives. As formulated by Gadamer,49 the pseudobases represent a potential tautomeric system of three components, the quaternary hydroxide A, the carbinolamine B, and the open-chain amino-carbonyl derivative C, in which all three components exist in a mobile equilibrium ... 

The salts of some enamines crystallize as hydrates. It is possible that these salts are actually derived from either the tautomeric carbinol-amine or the amino-ketone forms. Steric factors should again be decisive. The salts obtained by an intramolecular cyclization of a bicyclic amino-ketone (13)55 belong to the carbinolamine type their infrared spectra reveal the presence of a hydroxyl group. 

Condensation of aldehydes and ketones with secondary amines in the presence of dehydrating agents (often potassium carbonate69-71) represents a general method of enamine preparation. By this procedure ketones afford the enamines directly, whereas aldehydes are converted in the first step into diamino derivatives which decompose on distillation to give the enamine and a molecule of the secondary amine. In the case of ketones and disubstituted acetaldehydes, the water formed by the reaction can be removed by azeotropic distillation with benzene, toluene, or xylene.27,31,72-75 In the case of derivatives of aromatic aldehydes, the formation of intermediary carbinolamines 76 is sometimes observed. 

Treatment of l-methyl-2-piperidone with phenylmagnesium bromide and subsequent reaction with acetic anhydride and then water gave the acetate 21 in small yield.139 This indicates that the salt of the carbinolamine form is an intermediate which, on liberation, affords the cyclic enamine in the five- and six-membered series, for steric reasons. 

Intermediates in acylation reactions, 47 carbinolamine as, 41 in diazonium coupling, 77 enamine-like, 85... 

An enamine results from the reaction of a ketone or aldehyde with a secondary amine. Recall that a ketone or aldehyde reacts with a primary amine (Section 18-15) to form a carbinolamine, which dehydrates to give the C=N double bond of an imine. But a carbinolamine from a secondary amine does not form a C=N double bond because there is no proton on nitrogen to eliminate. A proton is lost from the a carbon, forming the C=C double bond of an enamine. 

Cyclopropane enamines of type 21, have not been isolated, and only their possible precursors, i.e. carbinolamines such as 22, were isolable154. 

Good yields of 2-alkylidene or 2-benzylidene ketones are readily achieved by condensation of enamines of cyclic ketones with aldehydes146-148. Except for the reaction with chloral149,150, where the intermediate carbinolamine (65) was isolated and hydrolysed to the /Miydroxyketone (66), the corresponding aldol intermediates formed in these reactions could not be isolated (Scheme 54). However, it has recently been shown that in the presence of a slight excess of Lewis acid the reaction can be carried out under very mild conditions and high yields of the crossed aldol products can be obtained from... 

The hydrolysis rate of all three enamines (1-3) undergoes a sharp decline as the pH drops below 1 (for 2 and 3) or 0 (for 1). This result signifies that equation 23 (or 23a) is no longer the rate law and that another change in rate-controlling step has occurred. The last stage of Scheme 1 is the breakdown of the carbinolamine, equations 17-19. At the acidities in question (pH < 1), equations 14-17 are in equilibrium, that is, the enamine is fully protonated ([EH+] = [NH+] + [CH+], see Table 2) as is the hydration product, the carbinolamine72. Equation 24 describes the situation. The observed inverse... 

The vast majority of enamine hydrolyses which have been investigated from the mechanistic point of view fit comfortably the mechanism given in Scheme 1. The sometimes convoluted pH-rate profiles are caused by changes in rate-controlling step from protonation at Cp, to nucleophilic hydration of the intermediate iminium ion, to breakdown of the carbinolamine addition product, probably via a zwitterion. The pH values at which changes in rate-controlling step occur are determined by a combination of structural features of the enamine and, in some cases, by the concentrations of buffer species which might be present these issues are discussed in the text. 

The intermediate results from the addition of an amine to a ketone. The product is an enamine because the amine nitrogen in the carbinolamine intermediate comes from a secondary amine. 

Prior to 2001, when the first serious computational approaches to the problem appeared in print, four mechanistic proposals had been offered for understanding the Hajos-Parrish-Wiechert-Eder-Sauer reaction (Scheme 6.8). Hajos and Parrish proposed the first two mechanisms Mechanisms A and B. Mechanism A is a nucleophilic substitution reaction where the terminal enol attacks the carbinolamine center, displacing proUne. The other three mechanisms start from an enamine intermediate. Mechanism B invokes an enaminium intermediate, which undergoes C-C formation with proton transfer from the aminium group. Mechanism C, proposed by Agamii to account for the nonlinear proline result, has the proton transfer assisted by the second proline molecule. Lastly, Mechanism D, proffered by Jung, proposed that the proton transfer that accompanies C-C bond formation is facilitated by the carboxylic acid group of proline. 

IG and added in the free energy of solvation in DMSO computed with PCM at HF/6-31-l-G(d,p). The lowest energy TS is for the carboxyhc-acid-catalyzed enamine route (Scheme 6.8 D). This barrier is 10.7 kcal mol smaller than that for the barrier without proline acting as a catalyst. The transition state for the enaminium-catalyzed route (Scheme 6.8 B) is 29.0 kcal mol higher than the TS for Scheme 6.8 D. All attempts to locate a TS for the nucleophilic substitution route (Scheme 6.8 A) failed. However, the carbinolamine intermediate that proceeds the TS on path A lies 12.7 kcal mol above the TS for Scheme 6.8... 

Enamine derivatives of steroidal ketones have found most use as protecting groups [220], but also undergo a few useful reactions. Enamine formation involves addition of a secondary amine to the carbonyl group to give a carbinolamine intermediate (5), which then loses a molecule of water. Both steps appear to be involved in determining the over-all rate of reaction [221]. Steroidal A -3-ketones react spontaneously... 

Aldehydes and ketones react with 1° amines to form imines and with 2° amines to form enamines. Both reactions involve nucleophilic addition of the amine to the carbonyl group to form a carbinolamine, which then loses water to form the final product. 

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