Methyl vinyl ketone reaction with enamines

A further thought to bear in mind is that an enamine reaction, particularly an annulation process involving a bidentate reagent, rarely gives a single pure product mixtures are usually obtained and, hopefully, the desired product is the one in excess and/or can readily be separated from the rest. For example, in the reaction between methyl vinyl ketone (MVK) with 1-A-pyrrolidinylcyclohexene to give A1,8a-2-octalone... 

An interesting synthesis of (-l-)-mesembrine has been described by Otani and Yamada (55). The approach follows from earlier studies (56) by these authors on the enantioselective synthesis of chiral 4,4-disubstituted cyclo-hexenones (see Scheme 26) in which construction of the t clohexenone ring is effected with Michael addition of methyl vinyl ketone to an enamine (103) formed from L-proline pyrrolidide and the aldehyde 104. In the reactions presented in Scheme 26, the il-(-l-)-isomer of 4-methyM-phenylcyclohexe-none was obtained in S0% enantiomeric access. 

Finally a general approach to synthesize A -pyrrolines must be mentioned. This is tl acid-catalyzed (NH4CI or catalytic amounts of HBr) and thermally (150°C) induced tea rangement of cyclopropyl imines. These educts may be obtained from commercial cyan> acetate, cyclopropyl cyanide, or benzyl cyanide derivatives by the routes outlined below. Tl rearrangement is reminiscent of the rearrangement of 1-silyloxy-l-vinylcyclopropancs (p. 7 83) but since it is acid-catalyzed it occurs at much lower temperatures. A -Pyrrolines constitut reactive enamines and may be used in further addition reactions such as the Robinson anei lation with methyl vinyl ketone (R.V. Stevens, 1967, 1968, 1971). 

The initial product formed when methyl vinyl ketone is mixed with an enamine [such as N,N-dimethylisobutenylamine (10)] is the dihydropyran (11) from a 1,4 cycloaddition (ll,20a,20b). The chemical reactions that the dihydropyran undergoes indicate that it is readily equilibrated with the cyclobutane isomer 12a and zwitterion 12 (11). Treatment of adduct 11 with phenyllithium gives cyclobutane 13, possibly via intermediate 12a (11). 

At higher temperatures the mixture of 10 and methyl vinyl ketone yields the 1,4-carbocyclic compound as described previously. Methyl isopropenyl ketone (5), ethyl acetylacrylate (d), 2-cyclohexenone (21), and 1-acetyl-1-cyclohexene (22) also undergo this type of cyclization reaction with enamines at higher temperatures. This cycloalkylation reaction occurs with enamines made of strongly basic amines such as pyrrolidine, but the less reactive morpholine enamine combines with methyl vinyl ketone to give only a simple alkylated product (7). Chlorovinyl ketones yield pyrans when allowed to react with the enamines of either alicyclic ketones or aldehydes (23). 

Heterocyclic enamines often undergo two-step 1,3 cycloaddition with methyl vinyl ketone. This involves electrophilic attacks by an olefinic carbon and by a carbonyl carbon (24,25). For example, 1,2-dimethyl-Zl -pyrroline (14), when treated with methyl vinyl ketone, produces 1,6-dimethyl-2,3,4,5-tetrahydroindole (15) (24). The requirement which must be met so that this type of cyclization reaction can take place is that the a position of the heterocyclic enamine be carbon substituted. This provides... 

Two-step 1,4 cycloaddition of enamines, such as was observed with methyl vinyl ketone, is not possible with acrylate or maleate esters. This is due to the fact that, following the initial simple substitution, no side-chain carbanion is available for nueleophilic attack on the a carbon of the iminium ion. Likewise two-step 1,3 eycloaddition, such as that found when alicyclic enamines were treated with acrolein, is impossible with acrylate or maleate esters because transfer of the amine moiety from the original enamine to the side chain to form a new enamine just prior to the final cyclization step is not possible. That is, the reaction between a seeondary amine and an ester does not produce an enamine. 

Dihydropyrans have been produced by the 1,3 cycloaddition of methyl vinyl ketone (77) or acrolein (29-J7) with enamines (see Section II.A.2). S-Lactones have been formed as a side product in the reaction of dimethyl ketene with enamines (77), and as the primary products in the reaction of excess ketene with enamines derived from ketones (75) (see Section II.A.4). 

Reactions of 3- and 4-piperidone-derived enamines with a dienester gave intermediates which could be dehydrogenated to tetrahydroquinolines and tetrahydroisoquinolines (678). The methyl vinyl ketone annelation of pyrrolines was extended to an erythrinan synthesis (679). Perhydrophenan-threnones were obtained from 1-acetylcyclohexene and pyrrolidinocyclo-hexene (680) or alternatively from Birch reduction and cyclization of a 2-pyridyl ethyl ketone intermediate, which was formed by alkylation of an enamine with a 2-vinylpyridine (681). 

Another example in which A-methyl-l,2-dihydropyridine (41a) behaves as an enamine rather than a diene is its reaction with methyl vinyl ketone (44) (64JCS2165). The product is a pyran 45, which is obtained in 100% yield, rather than an isoquinuclidine derivative (80JOC1657). 

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. 

Some new observations were published on the peculiar reactivity of the phenyloxazolopiperidine 166 which acts as an equivalent of an enamine, reacting with methyl vinyl ketone in a Michael reaction and with diethyl acetylenedicarboxylate in a [2+2] cycloaddition reaction <00JOC3209>. 

Michael reaction of enamines of u-alkyl- -keto esters. The chiral lithioen-amine (1), prepared from (S)-valine /-butyl ester, does not react with methyl vinyl ketone or ethyl acrylate unless these Michael acceptors are activated by ClSi(CH3)3... 

The reaction of A2-piperideine (115) with methyl vinyl ketone to give (124) is another example of how initial electrophilic attack on the enamine double bond can be used in heterocyclic synthesis (77ACR193). This overall process is an enamine analog of the Robinson annelation and is a useful approach to the perhydroquinoline ring system. 

Enamines of aldehydes react with alkyl vinyl ketones.212 Substituted cyclohexanones may be obtained after hydrolysis. Application of this reaction to a,j8-unsaturated aldehydes leads to substituted glutardialdehydes.269 The ratio of the products from the addition of methyl vinyl ketone to the pyrrolidine enamine derived from jS-decalone depends on the configuration of the decalone.76... 

Figure 12.20 demonstrates that Michael acceptors can also act as electrophiles towards enam-ines. Aqueous workup leads to the regeneration of the carbonyl group, and the Michael addition product C is obtained. An acrylic acid ester would react with the enamine A in complete analogy to the reaction of the acrylonitrile shown here the same holds true for the methyl vinyl ketone. 

The Stork reaction of methyl vinyl ketones and enamines (e.g. 74) is a complementary procedure to the Robinson annulation method (equation 14)49. With this procedure, products from attack of the most reactive less substituted form of the enamine to the... 

On the basis of distribution of products obtained in these reactions with the change of solvents, temperature and molar ratio of reactants, a mechanism has been suggested for the anomalous annulation which does not involve an initial attack of the tetrasub-stituted isomer of the enamine (equation 16)51. Alkylation of the more stable cis isomer of the enamine (80) with methyl vinyl ketone (MVK) would afford zwitterion 81 (attack by the other side of the enamine leads to strong steric interactions in the transition state). Reaction of the thermodynamically less favorable trans isomer 83 gives rise to zwitterions 84 and 89 (both without axial-axial interactions), and ion 84 is sterically able to undergo intramolecular proton shift to afford enamine 85. Zwitterionic intermediates 81 and 89 can be stabilized by conversion to dihydropyrans 82 and 90, or protonated to immonium ions. The pair 81-82 will lead to enamine 85, while the pair 89-90 will afford enamine 91. Then, cyclization of 85 or 91 will afford the enone expected from the normal enamine version of the Robinson annulation. 

Asymmetric induction has been observed in some of these cycloaddition reactions with the use of chiral enamines52-54. For example, reaction of L-proline derived enamines (e.g. 95) with methyl vinyl ketone (equation 17) afforded, after hydrolysis, chiral cyclohexenones (e.g. 96) with optical yields up to 50%52. 

This reaction has been developed by Stevens for a refined access to various alkaloid families. Equation 29 shows the short synthesis of mesembrine, where methyl vinyl ketone is annulated to the endocyclic enamine. The precursors for the imines are usually cyclopropyl aldehydes and the corresponding amines or cyclopropyl nitriles combined with suitable organometallics as demonstrated in a simple myosmine synthesis (equation 30). Additional examples will not be discussed here since excellent review articles exist on this topic ... 

However, the maximum level of stereochemical control in these processes with a variety of electrophiles (CH =CHC02Me, CH2—CHCN, BrCH2CH=CH2, BrCH2C02Et) was below 60% optical purity (corresponding to a ratio no better than 4 1). These results appear to be the result of kinetic control in the transition state for carbon-carbon bond formation. On the other hand, reactions with methyl vinyl ketone can be run under either kinetic or thermodynamic control and the level of stereochemical control is higher under the conditions. - Likewise, the enamine from 2-methoxymethylpyrrolidine... 

Similarly, reaction of an enamine derived from the pyrrolinylamide of proline with methyl vinyl ketone afforded an entry to the natural product mesembrine (equation 31). " ° ... 

Concerted symmetry-allowed [3,3] sigmatropic rearrangements of enamines have been reported One example is the Cope rearrangement 197 (obtained easily from the methyl vinyl ketone dimer 196 by reaction with pyrrolidine on heating to 250 °C) which leads to 2-pyrrolidino-4-acetylcyclohexene 198 (equation 21). Clai-sen , aza-Claisen and aza-Cope rearrangements have also been reported. 

The intermediate (45a) previously employed1" in a synthesis of aspidospermine has been neatly prepared52 by a potentially general method which has already been applied to the syntheses of several other alkaloid systems. The key step is the reaction of a cyclic enamine, in this case (46a), with methyl vinyl ketone and the formation of a homocyclic ring and the required carbonyl function. Scheme 16... 

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