2-Butanone enamines

Enamines of several methyl ketones have been prepared and their isomer content estimated by NMR spectroscopy (13,39,43). The reaction of Ti[N(CH3)2l4 as the amine source and 3-methyl-2-butanone gave only 26 (Ri = Rj = CH3), which could be isomerized by prolonged heating to a 1 1 mixture ofthatenamine and enamine 27 (R, = Rj = CH3)(39). The reaction of morpholine and 3-methyl-2-butanone in benzene with a trace of acetic... 

The initial reaction between a ketene and an enamine is apparently a 1,2 cycloaddition to form an aminocyclobutanone adduct (58) (68-76a). This reaction probably occurs by way of an ionic zwitterion intermediate (75). The thermal stability of this adduct depends upon the nature of substituents Rj, R2, R3, and R. The enolic forms of 58 can exist only if Rj and/or R4 are hydrogens. If the enamine involved in the reaction is an aldehydic enamine with no 3 hydrogens and the ketene involved is di-substituted (i.e., R, R2, R3, and R4 are not hydrogens), then the cyclo-butanone adduct is thermally stable. For example, the reaction of dimethyl-ketene (61) with N,N-dimethylaminoisobutene (10) in isopropyl acetate... 

Scheme 2.11 shows some examples of Robinson annulation reactions. Entries 1 and 2 show annulation reactions of relatively acidic dicarbonyl compounds. Entry 3 is an example of use of 4-(trimethylammonio)-2-butanone as a precursor of methyl vinyl ketone. This compound generates methyl vinyl ketone in situ by (3-eliminalion. The original conditions developed for the Robinson annulation reaction are such that the ketone enolate composition is under thermodynamic control. This usually results in the formation of product from the more stable enolate, as in Entry 3. The C(l) enolate is preferred because of the conjugation with the aromatic ring. For monosubstituted cyclohexanones, the cyclization usually occurs at the more-substituted position in hydroxylic solvents. The alternative regiochemistry can be achieved by using an enamine. Entry 4 is an example. As discussed in Section 1.9, the less-substituted enamine is favored, so addition occurs at the less-substituted position. 

In the simplest example, 2-chloropyrazine can be treated with methylhydrazine to afford 244a Commencing with 244a, treatment with 3-methyl-2-butanone gives an enamine, which, after thermal Fischer-type cyclization, leads to 245 (Equation 88) <1994MI17>. 

Problem 17.43 Show how acetone can be converted into 4-phenyl-2-butanone using enamine alkylation. M... 

Treatment of 1-morpholino-l-cyclohexene with ketene gives l-morpholino-2-acetyl-l-cyclohexene251 as the main product, whereas enamines prepared from aliphatic aldehydes yield cyclo-butanones.252,253 Ketene may be generated directly in the reaction medium from acid chlorides and triethylamine. 

The alkylation of acyclic imines with electrophilic alkenes such as acrylonitrile, methyl acrylate or phenyl vinyl sulphone is also sensitive to steric effects and again, as a consequence, only mono-alkylation occurs398. The regioselectivity of the reaction in methanol varied from 100% attack at the more substituted a-position to 70% attack at the less substituted a -position depending upon the steric inhibition manifested and the stabilization of the competing secondary enamine tautomers (vide infra) (Scheme 204). In contrast, the reaction of butanone and other methyl ketone imines with phenyl vinyl ketone occurs twice at the more substituted a-position but this is then followed by a double cyclization process (Scheme 205). Four carbon-carbon bonds are formed sequentially in this one-pot synthesis of the bicyclo[2.2.2]octanone 205 from acyclic precursors399,400. 

Formyl-2-cyclohexenones (e.g. 129) react with 3-methyl-2-pyrrolidino-l-butene (130) to give, after hydrolysis, bicyclic ketols, e.g. 134, which on dehydration with trifluoroace-tic acid gave octaline diones such as 135 (equation 24)67. This type of [3 + 3] carbocyclization requires a molar ratio enamine enalone of 2 1 for optimum results, which is explained by the exchange of the enamine 130 with hydroxymethylene ketone 131 to form pyrrolidinomethylene ketone 132 and 3-methyl-2-butanone. 

Their more directed approach to hirsutic acid utilized 341 as starting material (Scheme 53).335 This diketo ester was the major product obtained from alkylation of the pyrrolidine enamine of340 with 3-bromo-2-butanone and aldolization in aqueous base. Reesterification with diazomethane and catalytic hydrogenation generated the cis-fused bicyclooctane nucleus. The subsequent Claisen alkylation of 342 proved to be stereoselective, affording 343 as the major product. Cyclization as before furnished 344 whose further transformations are currently being examined. 

The shift values obtained in CDCb are at approximately 0.1 p.p.m. lower field. The large upfield shift of this proton from simple alkenes is, of course, the result of lone pair electron delocalization into the tt-system, resulting in an increase in electron density at the 3-carbon. The ease with which this delocalization can occur crudely correlates with the kinetic reactivity of the various enamines where the most reactive are generally the pyrrolidine enamines. A similar analysis of the proton spectra for enamines derived from 2-butanone and a variety of amines has also been made. Again, the pyrrolidine enamine absorption occurs upfield from both the piperidine and morpholine enamines. The vinylic... 

Synthesis of the morpholine enamine from pinacolone (3,3-dimethyl-2-butanone) by the modified TiC -method discussed above was complicated by considerable self-condensation of the ketone. 

In Chapters 12 and 17 it was discussed how an undesired side reaction could be suppressed by adjusting the experimental conditions, in the synthesis of the enamine from 3,3-dimethyl-2-butanone. The undesired product was formed by... 

You have a choice here either you first form an enol(ate) from butanone and do an aldol reaction with the aromatic ketone or you first make an imine and then form enamines from that. In either case, you would expect enol or enamine formation on the more substituted side in acid but the less substituted side in base. 

Cordova et al. demonstrated in 2005 that the aldol condensation between 4-nitrobenzaldehyde (5 R=p-N02) and cyclic ketones or butanone in the presence of acyclic primary amino acids led to the antz-isomer 6 (Scheme 12.3). One year later, this author described the structure-activity relationship between acyclic amino acids and the aldol derivatives, the synthetic scope of catalysis by acyclic amino acids in aqueous media and water, and studies concerning the reaction mechanism. Excellent enan-tioselectivities (ee up to >99%) were achieved in several cases. As an example of the anh -induction, the (E)-enamine arising from cyclohexanone and the acyclic amino acid could display a proton transfer from the carboxylic acid function to the alkoxide, giving a six-membered chair-like conformation. The favoured approach of the aldehyde would then lead to an anfi-isomer. 

The initial version of the reaction (as illustrated by entry 1) used an in situ source of methyl vinyl ketone. The quaternary salt of 4-dimethylamino-2-butanone decomposes easily to the unsaturated ketone. In more recent procedures—for example, entries 2-4—the a,j8-unsaturated ketone is added directly. Entry 3 illustrates the use of the enamine of a ketone as the reactive nucleophile in a Robinson annelation. 

Having precursor 407 in hand. Brooks et al. were able to synthesize anguidine (376) in a further 17 steps. Thus, precursor 407 was converted into enamine 409, which was hydrolyzed to hydroxymethylene derivative 410. Michael reaction with butanone afforded the exo product 411. Followed by an intramolecular Michael aldol condensation, enone 412 was obtained, which was methylated to the allyl alcohol 413 using methyl iodide. Subsequent reduction with Ufliium aluminum hydride led to tetraol 414. This was converted to the triacetate and selectively deprotected to diol 415. Acid-catalyzed cycUzation and protection of the free OH group afforded the trichothecene skeleton 416. Afterwards, the acetal 416 was deprotected and the ketone was reacted in a Wittig reaction to the olefin, which was treated with TBAF to afford compound 417. Epoxidation with /n-CPBA, followed by acetylatiOTi and final mono-deprotection, afforded the trichothecene, anguidine (376) (Scheme 8.4). 

Suggest a reason why the enamine formed by the reaction of 3,3-dimethyl-2-butanone and diisopropylamine is more hkely to be A than B. 

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