Isobutyraldehyde, enamines

FIGURE 1. pH-rate profile for the hydrolysis of three isobutyraldehyde enamines at 24.84 °C O, morpholine (1) A, piperidine (2) , pyrrolidine (3). Reprinted with permission from Maas et al., J. Org. Chem., 32, 111. Copyright (1967) American Chemical Society1 ld... 

Anhydrides may also be employed instead of an acid chloride. The mixed anhydride of acetic and formic acid reacts with 1-iV-morpholinocyclohexene to give 2-hydro-xymethylenecyclohexanone . Acylation of isobutyraldehyde enamines with trichloroacetic anhydride in tetrahydrofuran at room temperature gives the a-trichloromethyl-j5-trichloroacetyl adduct . This occurs by initial ) -acylation to give the acyl iminium trichloroacetate, followed by decarboxylation and nucleophilic addition of the tri-chloromethyl anion to the iminium group. Trifluoroacetic anhydride under the same conditions just gave the -trifluoroacetyl derivative . 

Shipov and collaborators80 have recently found that (trimethylsilyl)sulfene (93) generated from (trimethylsilyl)methanesulfonyl chloride and triethylamine reacts with an isobutyraldehyde enamine to give a mixture of cis and trans cycloadducts 94a and 94b (equation 74). 

Recently Stamhuis et al. (33) have determined the base strengths of morpholine, piperidine, and pyrrolidine enamines of isobutyraldehyde in aqueous solutions by kinetic, potentiometric, and spectroscopic methods at 25° and found that these enamines are 200-1000 times weaker bases than the secondary amines from which they are formed and 30-200 times less basic than the corresponding saturated tertiary enamines. The baseweakening effect has been attributed to the electron-withdrawing inductive effect of the double bond and the overlap of the electron pair on the nitrogen atom with the tt electrons of the double bond. It was pointed out that the kinetic protonation in the hydrolysis of these enamines occurs at the nitrogen atom, whereas the protonation under thermodynamic control takes place at the -carbon atom, which is, however, dependent upon the pH of the solution (84,85). The measurement of base strengths of enamines in chloroform solution show that they are 10-30 times weaker bases than the secondary amines from which they are derived (4,86). 

The differenee in reaction rates of the amino alcohols to isobutyraldehyde and the secondary amine in strong acidic solutions is determined by the reactivity as well as the concentration of the intermediate zwitterions [Fig. 2, Eq. (10)]. Since several of the equilibrium constants of the foregoing reactions are unknown, an estimate of the relative concentrations of these dipolar species is difficult. As far as the reactivity is concerned, the rate of decomposition is expected to be higher, according as the basicity of the secondary amines is lower, since the necessary driving force to expel the amine will increase with increasing basicity of the secondary amine. The kinetics and mechanism of the hydrolysis of enamines demonstrate that not only resonance in the starting material is an important factor [e.g., if... 

Recent work (5) using kinetic methods has shown that the enamines derived from isobutyraldehyde are indeed less basic than the corresponding saturated tertiary amines. 

Enamines derived from aldehydes disubstituted on the jS carbon such as those derived from isobutyraldehyde (16) are alkylated on nitrogen by alkyl... 

More recently the acylation of aldehyde enamines has been reinvestigated (75) and shown to proceed normally when the enamine is added to the acid chloride. The morpholine enamine of isobutyraldehyde (98), on being added to an ether solution of acetyl chloride, afforded the iminium salt (99), from which the ketoaldehyde (100) was obtained in 66% yield by hydrolysis (75). 

The enamine (191) from isobutyraldehyde on treatment with p-nitrophenyl-diazonium chloride, on the other hand, gave the p-nitrophenylhydrazone of acetone (192) and presumably N-formyl piperidine, although the latter was not isolated. 

The coupling of enamines with aromatic diazonium salts has been used for the syntheses of monoarylhydrazones of a-diketones (370,488-492) and a-ketoaldehydes (488,493). Cleavage of the initial enamine double bond and formation of the phenylhydrazone of acetone and acetophenone has been reported with the enamines of isobutyraldehyde and 2-phenylpropionalde-hyde. Rearrangement of the initial coupling product to the hydrazone tautomer is not possible in these examples. 

Hine has demonstrated that simple amino acids, such as glycine and p-alanine, are not capable of intramolecular deprotonation in the reaction with isobutyraldehyde-2-d (Scheme 8) [62], Apparently, the carboxylate moiety in the iminium ion intermediate 29 is a relatively weak base and, as such, external bases, present in the buffer used (e.g. acetate ions), are largely responsible for the formation of the enamine intermediate 30. 

Typical starting materials, catalysts, and products of the enamine-catalyzed aldol reaction are summarized in Scheme 17. In proline-catalyzed aldol reactions, enantioselectivities are good to excellent with selected cyclic ketones, such as cyclohexanone and 4-thianone, but generally lower with acetone. Hindered aldehyde acceptors, such as isobutyraldehyde and pivalaldehyde, afford high enantioselectivities even with acetone. In general, the reactions are anti selective, but there are aheady a number of examples of syn selective enamine aldol processes [200, 201] (Schemes 17 and 18, see below). However, syn selective aldol reactions are still rare, especially with cychc ketones. 

At present, most enamine-catalyzed aldol reactions are reliable only with electron-poor aromatic aldehyde acceptors, hi addition, a handful of aliphatic aldehydes (e.g. isobutyraldehyde or pivalaldehyde) are often used as acceptors. The use of unbranched aldehyde acceptors is difficult, and generally only modest yields have been obtained. In addition, unsaturated aldehydes are curiously absent from the list of commonly used acceptors. On a positive side, it should be noted that even potentially racemizing a-chiral aldehydes have been employed as acceptors. As an example, in the recent synthesis of caUipeltoside C, MacMillan and coworkers were able to employ protected Roche aldehyde 113 as a starting material (Scheme 22) [204]. 

The existence of the enamine intermediate of proline-catalyzed reaction with acetone as a donor was detected by mass analysis [54], but not by aH NMR. The formation of the presumed enamine intermediate generated from pyrrolidine-acetic acid and isobutyraldehyde was confirmed by 1H NMR [29a]. In this study, the enamine formation in the presence of pyrrolidine-acetic acid was observed within 5 min, but the enamine was shown to form only very slowly in the absence of acid. In these pyrrolidine derivative-acid combination catalysts, the acid component was shown to be important both for faster enamine formation and for the stereocontrol in the C-C bond-forming step. These catalyst systems are essentially split-proline systems that allow for the contributions of the pyrrolidine and carboxylate functionalities of proline to be probed independently. 

Other aromatic aldehydes provided products with similar enantiomeric excess. Although a-unbranched aldehydes such as pentanal did not yield any significant amount of the desired aldol products, the reaction of isobutyraldehyde gave the corresponding aldol product in 97% yield and 96% ee. The reaction is considered to proceed via an enamine mechanism. The enantioselectivity of the reaction can be explained in terms of a metal-free version of a six-membered transition state... 

In contrast to primary amine catalysis, the enamine mechanism has been ruled out for D—H exchange in isobutyraldehyde catalysed by secondary amines. Catalytic rate constants were explained by considering only the... 

Recently, Capon and Wu49 have reported the generation of secondary enamines from their TV-trimethylsilyl derivatives through hydrolysis. In DMSO-d6 (99% v/v)-D20 (1% v/v) solution, enamine 40 is converted to the TV-deuteriated enamine 41 quantitatively in 5-10 min at room temperature. The solution obtained is stable for several hours, but over a period of 2-3 days 41 is oxidized to acetone and iV-deuterio-TV-phenylforma-mide. On adding 15% (v/v) D20/DC1 (0.1 M) to the solution, enamine 41 is completely hydrolyzed to 2-[2//]isobutyraldehyde and aniline without detection of any intermediates. Enamine 42 is formed by the acid-catalyzed hydrolysis of 40 (Scheme 3). Similar results are obtained with other iV-aryl enamines. 

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

Phenyl isocyanate adds to enamines derived from isobutyraldehyde to yield azetidi-nones (equation 8)25,26. 

Enamines derived from isobutyraldehyde react with dimethyldioxirane (315) by oxygen transfer to yield unstable oxiranes which are isolated as the dimers 316 (equation 129)157. 

The reaction of the dimethylamine enamine of isobutyraldehyde with aryl isothiocyanates at or below 50°C leads to the iminotetrahydrothiazine-thiones 333 these compounds rearrange on heating to hexahydropyrimidine-2,6-dithiones 334 (equation 135)164... 

As shown in Scheme 15, cyclohexenone 117 was prepared from commercially available cyclohexanedione mono ethylene ketal 115 through a-phenylselenation followed by oxidation and selenoxide elimination. Compound 117 was treated with TBSOTf and the piperidine enamine of isobutyraldehyde to produce the conjugate addition product 118. Butenyl magnesium bromide was then added to the... 

Houk next examined the aldol reaction of cyclohexanone with benzaldehyde (Reaction 6.20) and isobutyraldehyde (Reaction 6.21) with (6)-proline as the catalyst. Four diastereomeric TSs starting from the enamine formed from cyclohexanone and proline were optimized at B3LYP/6-31G for each reaction. These transitions states, 53 and 55, are shown in Fignre 6.23. In all of these TSs, proton transfer from the carboxylic acid group to the carbonyl oxygen accompanies the formation of the new C-C bond, creating a carboxylale and alcohol product. 

Fig. 14.2 Variation in the conditions affording the maximum yield in the synthesis of morpholine enamines from a series of carbonyl compounds (1) methyl isopropyl ketone, (2) pinacolone, (3) methyl isobutyl ketone, (4) methyl neopentyl ketone, (5) diethyl ketone, (6) diisopropyl ketone, (7) ethyl isobutyl ketone, (8) diisobutyl ketone, (9) isobutyraldehyde,...

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