Methyl Vinyl Ketone1

[78-94-4]  · C4H6O  · Methyl Vinyl Ketone  · (MW 70.10) (enol)

[59120-04-6]

(reagent for attachment of 3-oxobutyl side chains, i.e. Michael additions;2 reagent for the annulation of cyclohexenones3)

Alternate Names: MVK; 3-buten-2-one.

Physical Data: fp -6 °C; bp 81.4 °C, 36.5-36.8 °C/145 mmHg, 33-34 °C/130 mmHg, 32-34 °C/60 mmHg; d (20 °C) 0.8636 g cm-3, (25 °C) 0.8407 g cm-3; n20D 1.4086; liquid with pungent odor.

Solubility: sol water, methanol, ethanol, ether, acetone, glacial acetic acid; slightly sol hydrocarbons; forms binary azeotrope with water, bp 75 °C (12% water).

Form Supplied in: clear liquid stabilized with 0.1% acetic acid and 0.05% or 1% hydroquinone.

Handling, Storage, and Precautions: should be kept cold. Polymerizes upon standing in the pure form. Readily absorbed through skin; lachrymator; highly toxic and flammable. For best results, dry over K2CO3 and freshly distill at reduced pressure. Use in a fume hood.

Introduction.

As a synthetic reagent, methyl vinyl ketone is commonly viewed as a 3-oxobutyl synthon which undergoes predominantly 1,4 conjugate addition (Michael addition) resulting in the attachment of a 3-ketoalkyl side chain. The resulting products are often poised for a subsequent cyclization step, thus resulting in a cyclohexenone derivative; this tandem is the well-known Robinson annulation.4 In most cases, MVK is the electrophilic partner, but there are a few important nucleophilic (umpolung) derivatives of MVK which also are useful for accomplishing ring construction (see below). MVK itself is particularly susceptible to anionic polymerization, which limited its early use under basic conditions; however, it should be noted that MVK will polymerize under certain acidic and radical conditions as well.5 The many efforts to improve the Robinson ring synthesis have led to monumental synthetic advances with respect to both nucleophilic reactants and MVK synthetic equivalents (3-oxobutyl synthons).

Aside from inducing the anionic polymerization of MVK, enolates as nucleophilic partners in alkylations are limited by O- vs. C-alkylation, mono- vs. polyalkylation, rapid proton transfer, and by the ability to control the regioselectivity of their generation. These problems have found solutions through the development of trimethylsilyl enol ethers,6 in the utilization of enamine chemistry,7 and by employing metalloenamines (imine anions).8 With each of these developments in the nucleophilic partner, improvements in MVK alkylation have resulted in a greatly expanded use of the reagent. Nevertheless, a number of MVK synthetic equivalents have been successfully developed and are briefly reviewed in Table 1. Note that in this context, MVK equivalent is defined as any reagent which contains all four carbon atoms; also the 3-oxo functionality is in place or is one transformation away.

Methyl Vinyl Ketone versus its Synthetic Equivalents (as Alkylating Agents).

Primarily to circumvent the polymerization problem, numerous MVK synthetic equivalents have been developed, and these reagents should also be explored as possible sources of the 3-oxobutyl synthon. However, each reagent is handicapped by the fact that there are additional synthetic steps involved in its preparation, and the newly alkylated adduct often must be transformed into the 3-oxobutyl side chain. It should be noted that the manipulation of the side chain to arrive at the keto side chain may require harsh conditions not compatible with the other functional groups present in the molecule.

One of the first reagents developed as an MVK equivalent was 1,3-Dichloro-2-butene (1) (the Wichterle reagent).9 Relative to MVK, it is generally regarded as a superior alkylating agent, but the stringent hydrolytic conditions for conversion of the vinyl chloride to its corresponding ketone limits its application. An excellent alternative reagent of the same type (i.e. allylic halides) is the iodovinylsilane (2).10 The use of this reagent leads to high yields of alkylated adducts, and the subsequent conversion of the alkylated vinylsilanes to their corresponding ketones is achieved by oxidative rearrangement with m-Chloroperbenzoic Acid. These vinylsilanes can be used with enolates and enamines alike.

Robinson himself recognized that MVK polymerization was compromising the efficiency of the annulation protocol and developed the first in a series of compounds which serve as precursors to MVK. The synthetic equivalents (3),11 (4),12 and (5)13 are characterized by b-elimination to generate MVK in situ, but often the results are still not satisfactory (albeit improved) over the use of MVK itself. The principal problems involve poor yields and polyalkylated adducts and, if the synthetic sequence is extended further, unusual cyclization products.

The strategy of carbonyl protection in MVK in order to retard base-catalyzed polymerization fostered interest in a group of b-halo acetals, mixed acetals, and thioacetals of the type (6). After alkylation with such reagents, the 3-oxo functionality can be easily regenerated under mildly acidic conditions. The haloacetals (6; X = Br, I)14,15 are prepared in two steps by the conjugate addition of the halo acid to MVK followed by acetalization of the b-halo ketone. The corresponding tosylate (6; X = OTs)16 has also been prepared by a similar, albeit longer, route. At first glance, these reagents would seem ideal for appending the 3-oxobutyl side chain, by alkylation followed by mild acidic deprotection of the carbonyl. Unfortunately, in most cases these reagents are poor alkylating agents. A notable exception is the general annulation procedure (eq 1) which employs imine anions (metalloenamines) as the nucleophilic partner and the bromo acetal (6; X = Br) as the MVK equivalent. The sequence commences with the Wadsworth-Emmons alkenation of ketones to afford 2-azadienes, which can be isolated at this point but are usually treated with n-Butyllithium to generate the highly reactive metalloenamine. The imine anions thus generated can be trapped with the bromoacetal (6; X = Br). Hydrolytic workup followed by aldol cyclization-dehydration completes the preparation of 4,4-disubstituted cyclohexenones in yields of 55-65% from the ketones.17

Another pair of MVK equivalents are the a-trialkylsilyl derivatives of MVK itself (7; R = Me, Et).18,19 The trialkylsilyl group stabilizes the incipient negative charge after Michael addition and provides some steric bulk to impede polymerization. The silyl group can then be removed under basic conditions, usually those employed for a cyclization step. These MVK equivalents are especially important in that they allow effective Michael additions to vinyl ketones under aprotic conditions. The major disadvantage of these reagents is the multistep linear synthesis required for their preparation.

Methyl Vinyl Ketone versus its Synthetic Equivalents (Umpolung Reagents).

In those instances in which the 3-oxobutyl side chain is to be connected to pre-existing carbonyl (or other electrophilic) centers, several umpolung-type MVK equivalents have been developed. Although somewhat capricious in its stability, the Grignard reagent (8)20 derived from the bromo acetal (6; X = Br) has been successfully employed in a number of synthetic applications. Particularly useful is the fact that the acetal moiety may be unmasked in the usual hydrolytic workup or carried on as an acetal for removal at a later stage in the synthesis.21 Special mention should be made of the Grignard reagent's use in the presence of catalytic copper salts (9).22 This technique allows for the conjugate addition of the acetal moiety to a,b-unsaturated ketones as well as the direct attachment of the side chain to less complex systems. The related homologous Wittig reagent (10)23 was developed in the late 1960s and the Horner-Emmons variant (11) appeared shortly thereafter.24 Both compounds have been employed as reacting partners with lactones, ultimately leading to cyclohexanone products via an intramolecular Wittig alkenation process.

1,4-Conjugate Additions (Michael Addition Reactions, Achiral).

There are numerous examples of the use of MVK in conjugate 1,4-addition reactions, i.e. the Michael reaction. Although most of these applications are framed in the context of an annulation procedure (e.g. the Robinson annulation), many of these reactions are worthy of discussion in their own right. The prototypical Michael addition of an enolate with MVK is, in fact, the first step of the Robinson annulation (eq 2).

Under basic conditions (e.g. alkylation reactions employing enolates), MVK suffers a high degree of polymerization, leading to the development of the aforementioned MVK equivalents. However, there are derivatives of ketones which are particularly suitable for Michael addition reactions, most notably the silyl enol ethers.25 The development of silyl enol ethers addressed the most serious problems encountered in the alkylations of enolates. Firstly, the reactions are conducted in aprotic media under anhydrous conditions, thus avoiding proton transfer side reactions. Secondly, by judicious choice of the base used to generate the intermediate enolate, the regiochemistry of the alkylation can be controlled. However, the strongly basic conditions required for the regeneration of the enolates themselves preclude successful additions to MVK, resulting in the formation of polymer. Only recently have trimethylsilyl enol ethers been efficiently added to MVK with the assistance of Lewis acid catalysis (eqs 3 and 4).26,27 The acidic conditions not only serve to activate MVK towards Michael addition, but assist in unmasking the enolate as well. These procedures are usually conducted under relatively mild aprotic conditions which also retard MVK polymerization.

b-Keto esters, a-nitro ketones, and a-keto sulfones are but a few of the stabilized enolate derivatives which have been used successfully in efficient Michael additions to MVK. One of the most troublesome examples involving b-keto esters was the condensation of cyclohexanone methyl carboxylate with MVK under equilibrating conditions,28 but this reaction has been developed into a viable synthetic procedure with the use of high pressure techniques under otherwise mild conditions (eq 5).29

Another stabilized enolate family includes the a-nitro ketones; although the nitro group activates the formation of the enolate, it is usually necessary to remove it in a subsequent procedure (eq 6).30 Nevertheless, the overall yields of the products are good.

Simple nitro alkanes have recently been used in an exceptionally mild procedure for the attachment of the 3-oxobutyl side chain using MVK (eq 7). This protocol highlights the use of Alumina at room temperature for the conditions of the Michael addition, and the yields are good to moderate.31

The Michael addition of a-cyanoamines to MVK (eq 8) has also been used for the preparation of 1,4-dione systems,32 which are historically difficult to prepare.33 The reaction occurs under mild conditions; however, the use of Hexamethylphosphoric Triamide as the solvent limits the scale and the widespread use of this procedure. In this sequence, acidic hydrolysis of the alkylated a-cyanoamine leads to the dione system.

b-Methylthio allylic systems have also served as the nucleophilic partner in reactions with MVK (eq 9).34 The procedure employs the hyperbasic media of the Lithium Diisopropylamide/HMPA complex35 and generates a quaternary carbon center in the product.

Recently, dithioenamines have emerged as useful synthetic intermediates in general alkylation methods.36 In their Michael additions with MVK in the presence of Lewis acid catalysts, an intermediate iminium dithiane is generated which is somewhat sluggishly hydrolyzed; however, the overall yields of alkylated adducts are impressive (eq 10).37

1,4-Conjugate Additions (Michael Addition Reactions, Chiral).

In recent years, perhaps the most significant development in synthetic organic chemistry has been the explosion in the field of asymmetric induction. As the reactive intermediates of the enolate, enamine, and imine anions were developed into their chiral counterparts, not only were standard alkylation reactions studied but also Michael additions to a,b-unsaturated systems. It is not surprising that the prototypical model studies involved MVK as the Michael acceptor. While most of these methods are used in asymmetric ring synthesis (see below), some examples terminate at the alkylation step with MVK. All of these methods feature the chiral auxiliary in the nucleophilic reagent. One of the earliest examples of asymmetric induction using MVK was developed by Yamada and utilizes chiral pyrrolidino enamines (eq 11).38 Although the yields of the Michael additions are moderate and the asymmetric induction itself is not particularly impressive by today's standards, this methodology laid the groundwork for many improvements which were to follow. A notable advancement in chiral imine alkylations with MVK is found in the method of d'Angelo, in which the conjugate addition is catalyzed by Titanium(IV) Chloride (eq 12).39 A particularly attractive feature of this method is that the chiral auxiliary, (S)-a-Methylbenzylamine, is readily available, and the chemical yields are good with high asymmetric induction.

Another chiral enamine system which has been used with MVK takes advantage of the high nucleophilicity of imine anions (i.e. metalated enamines). In this method the intermediate enolate from the Michael addition is trapped as its TMS enol ether, which is subsequently hydrolyzed in the workup (eq 13).40 The yields are fair and the asymmetric induction is effective.

A chiral reagent within the family of Horner-Emmons phosphonates has been used with MVK, but the results were disappointing in that the major product was the dialkylated adduct (eq 14). In addition, preparations of these reagents are often multistep and tedious.41

In a recent synthesis of (+)-O-methyljoubertiamine, Taber utilized very mild conditions for the addition of a chiral enolate to MVK in which the chiral auxiliary is the effective naphthyl camphor system (eq 15).42

There are several polymer-based methods which induce some asymmetry to certain substrates. The degree of asymmetric induction is not particularly high (66% ee) and as yet does not appear to be very general. One such example is the cobalt-based diamine polymer which provides modest yields of the Michael adduct (eq 16).43

In terms of high yields and efficiency of asymmetric induction, the Evans procedure using chiral acyl oxazolidones stands apart as a method of choice. In the MVK example the chiral reagent adds, with the assistance of titanium tetrachloride activation at 0 °C, with an impressive 88% chemical yield and 99% ee (eq 17). The oxazolidone can be recycled and the method is general for a variety of a,b-unsaturated systems.44

Alkylation/Cyclization Tandems: The Robinson Annulation.

The most prevalent use of MVK in modern synthesis is the annulation of a six-membered ring onto a pre-existing ketone: the Robinson annulation (see above). In its original format,45 the sequence involves the generation of an enolate under basic conditions followed by Michael addition to MVK, thus affording a 1,5-dione. The dione can be subjected to basic conditions which induce aldol cyclization-dehydration, resulting in a newly formed cyclohexenone appended to the starting ketone (eq 2). Since its inception, the sequence has been handicapped by a variety of problems: (1) proton transfer; (2) regiochemistry of Michael addition to MVK; (3) O- vs. C-alkylation; (4) polyalkylation; (5) poor yields in the conjugate addition step; and (6) base-promoted polymerization of MVK itself. In spite of these drawbacks, the procedure is so synthetically important that development and refinement of Robinson's protocol continues to this very day. Most of the problems which are unique to MVK are often overcome by the use of a synthetic equivalent (see above). This section will deal with the annulation procedures which involve MVK itself and can be grouped into linear vs. spiroannulation sequences. In addition, some of these methods involve asymmetric induction, resulting in chiral cyclohexenones. When chirality is involved, it is usually induced in the alkylation (Michael addition) step, but there are a few examples in which the aldol cyclization of the dione or keto aldehyde features the chiral auxiliary.

The Linear Robinson Annulation.

This was the earliest class of Robinson annulation procedure and represents the majority of examples. When simple ketones are used in this sequence with MVK, the results are often unsatisfactory. However, when acidic dicarbonyl compounds are employed, the results are quite viable and practical. For example, 1,3-diones may be treated with a catalytic amount of base to generate a stable enolate which is subsequently trapped with MVK. The alkylated adduct is then cyclized-dehydrated under standard Knoevenagel conditions (eq 18). The acidic conditions of the cyclization help retard reversible b-elimination of MVK.46

In a classic case of stereochemical control, chiral auxiliaries were not involved, but rather a simple reversal of order in alkylations of enolates resulting in the preparation of isomeric decalenones (eq 19).47 Although this is a dialkylation procedure leading to a specific product, the overall strategy of stereochemical control in the Robinson annulation has been extensively studied and discussed.48

With the advent of kinetic, sterically hindered bases (such as LDA), which could be used under aprotic conditions, the regiochemistry of enolates could be controlled. In the following sequence, a slight excess of the ketone allows the Michael addition to occur at the most hindered site via the thermodynamic enolate, thus resulting in a quaternary carbon center with stereochemical control. Aldol cyclization-dehydration then affords the cyclohexenone in 60% yield (eq 20).49

A highly successful approach to Robinson annulation involves the use of trimethylsilyl enol ethers with MVK under Lewis acid conditions, which thwarts MVK polymerization. The yields of the Michael addition itself are greatly improved (see above), and the resulting diones can be cyclized-dehydrated under standard aldol (basic) conditions. This particular example affords the decalenones in 89% overall yield from MVK (eq 21).27

The Chiral Robinson Annulation.

Perhaps the most important extensions involving the Robinson annulation protocol have concerned the production of chiral cyclohexenones. In general, the asymmetric induction takes place at the Michael addition step with a chiral reactive intermediate and MVK, although there are a few examples in which the aldol cyclization-dehydration step affords the stereochemical control. However, great care must be exercised in the cyclization step in order to avoid epimerization at the newly created chiral center. One of the earliest methods for chiral Robinson annulation is a general procedure in which a chiral Pyrrolidine enamine is condensed with MVK; the resulting keto imines are then hydrolyzed to give the chiral d-keto aldehydes, which in turn are cyclized under (acidic) Knoevenagel conditions, finally affording chiral 4,4-disubstituted cyclohexenones (eq 22).

This methodology was highlighted in the chiral total synthesis of the Sceletium alkaloid (+)-mesembrine.50 More recently, an even milder, shorter sequence was used in the key step for the synthesis of the Sceletium alkaloid (+)-O-methyljoubertiamine. In this case, the chiral auxiliary was the naphthylcamphor system (see above), which governed the condensation of the enolate with MVK using mild Potassium Carbonate as the base (eq 23).42

The use of chiral imines has recently received attention as reactive intermediates for Michael additions to MVK. Their advantage is that they are derived from a-methylbenzylamine, which is affordable and can be recycled. The Michael addition itself is activated with titanium tetrachloride and gives good yields (61%) of the Michael adduct with high ee (91%). Hydrolysis concomitant with cyclization provides the decalenone (eq 24).51

A very useful procedure for inducing chirality in the cyclization step was reported some years ago but has recently been optimized for scale-up. 2-Methyl-1,3-cyclopentanedione serves as the reactive enolate system for the Michael addition with MVK, providing the trione in quantitative yield. The chiral cyclization is a modified Knoevenagel reaction using (S)-Proline as the asymmetric catalyst. This sequence provides the enedione in 93% optical purity (eq 25).52

The Spirocyclic Robinson Annulation.

Procedures which attach two carbocyclic rings to one another by a single carbon atom (spiroannulation)53 are not commonplace. The major synthetic problem to overcome in such an operation is the construction of the common, quaternary carbon center. Although there are a number of ingenious ways to construct quaternary carbon centers,54 those involving spiroannulations with MVK are generally limited to the reactions of trisubstituted enamines with MVK as the conjugate addition step of the sequence (eq 26).55 The starting carbonyl compounds are usually aldehydes, but there is also a highly efficient homologation procedure which commences from ketones.56 In either case, the intermediate at the alkylation stage is a d-keto imine which is subjected to mild acid hydrolysis, thus generating a d-keto aldehyde, which is then cyclized-dehydrated with base. Enamines from Piperidine and Morpholine have been used successfully in this procedure. There is flexibility in the carbonyl starting materials as well: five-, six-, seven-, and eight-membered carbonyl systems have all been satisfactory substrates in this methodology. The spiroannulation procedure of MVK with enamines is summarized below (Table 2).


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53. Review: Krapcho, A. P. S 1974, 383.
54. Review: Martin, S. F. T 1979, 36, 419.
55. (a) Hutchins, R. O.; Natale, N. R.; Taffer, I. M.; Zipkin, R. SC 1984, 14, 445. (b) Kane, V. V. SC 1976, 6, 237. (c) Kane, V. V.; Jones, M., Jr. OS 1983, 61, 129. (d) Kane, V. V.; Jones, M., Jr. OSC 1990, 7, 473.
56. (a) Martin, S. F. JOC 1976, 41, 3337. (b) Martin, S. F.; Gompper, R. JOC 1974, 39, 2814.

John A. Colapret & Paul T. Buonora

Lamar University, Beaumont, TX, USA



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