1 -Butanone, 3-methyl-1 - synthesis

Synthetic sequences for both disconnections a and b are shown. The best route is probably not the one discussed but rather the first one shown in the diagram, which involves conversion of 19 to 1-bromomethyl-propane and reaction with enolate 32 (see sec. 9.2, 9.3.A) derived from 3-methyl-2-butanone. This synthesis is considered to be better than the second one shown (based on disconnection b), since it involves simpler reagents and is shorter (fewer chemical steps). The synthetic chemist must make the choice as to which is best, however, based upon his or her own experience and goals. The best route is a subjective judgment, although it usually makes more sense to follow a short and simple route rather than a long and complex one. 

Out first example is 2-hydroxy-2-methyl-3-octanone. 3-Octanone can be purchased, but it would be difficult to differentiate the two activated methylene groups in alkylation and oxidation reactions. Usual syntheses of acyloins are based upon addition of terminal alkynes to ketones (disconnection 1 see p. 52). For syntheses of unsymmetrical 1,2-difunctional compounds it is often advisable to look also for reactive starting materials, which do already contain the right substitution pattern. In the present case it turns out that 3-hydroxy-3-methyl-2-butanone is an inexpensive commercial product. This molecule dictates disconnection 3. Another practical synthesis starts with acetone cyanohydrin and pentylmagnesium bromide (disconnection 2). Many 1,2-difunctional compounds are accessible via oxidation of C—C multiple bonds. In this case the target molecule may be obtained by simple permanganate oxidation of 2-methyl-2-octene, which may be synthesized by Wittig reaction (disconnection 1). 

Hydroxybenzaldehyde has an agreeable aromatic odor, but is not itself a fragrance. It is, however, a useful intermediate in the synthesis of fragrances. The methyl ether of -hydroxybenzaldehyde, ie, -anisaldehyde, is a commercially important fragrance. Anisaldehyde can be made in a simple one-step synthesis from hydroxybenzaldehyde and methyl chloride. Another important fragrance, 4-(p-hydroxyphenyl)butanone, commonly referred to as raspberry ketone, can be prepared from the reaction of -hydroxybenzaldehyde and acetone, followed by reduction (see Flavors and spices). 

Methyl vinyl ketone can be produced by the reactions of acetone and formaldehyde to form 4-hydroxy-2-butanone, followed by dehydration to the product (267,268). Methyl vinyl ketone can also be produced by the Mannich reaction of acetone, formaldehyde, and diethylamine (269). Preparation via the oxidation of saturated alcohols or ketones such as 2-butanol and methyl ethyl ketone is also known (270), and older patents report the synthesis of methyl vinyl ketone by the hydration of vinylacetylene (271,272). 

The most recent, and probably most elegant, process for the asymmetric synthesis of (+)-estrone appHes a tandem Claisen rearrangement and intramolecular ene-reaction (Eig. 23). StereochemicaHy pure (185) is synthesized from (2R)-l,2-0-isopropyhdene-3-butanone in an overall yield of 86% in four chemical steps. Heating a toluene solution of (185), enol ether (187), and 2,6-dimethylphenol to 180°C in a sealed tube for 60 h produces (190) in 76% yield after purification. Ozonolysis of (190) followed by base-catalyzed epimerization of the C8a-hydrogen to a C8P-hydrogen (again similar to conversion of (175) to (176)) produces (184) in 46% yield from (190). Aldehyde (184) was converted to 9,11-dehydroestrone methyl ether (177) as discussed above. The overall yield of 9,11-dehydroestrone methyl ether (177) was 17% in five steps from 6-methoxy-l-tetralone (186) and (185) (201). 

The idea of kinetic versus thermodynamic control can be illustrated by discussing briefly the case of formation of enolate anions from unsymmetrical ketones. This is a very important matter for synthesis and will be discussed more fully in Chapter 1 of Part B. Most ketones, highly symmetric ones being the exception, can give rise to more than one enolate. Many studies have shown tiiat the ratio among the possible enolates that are formed depends on the reaction conditions. This can be illustrated for the case of 3-methyl-2-butanone. If the base chosen is a strong, sterically hindered one and the solvent is aptotic, the major enolate formed is 3. If a protic solvent is used or if a weaker base (one comparable in basicity to the ketone enolate) is used, the dominant enolate is 2. Enolate 3 is the kinetic enolate whereas 2 is the thermodynamically favored enolate. 

On the other hand, as mentioned in the preceding subsection, a preparative-scale enzymic synthesis of 1-deoxy-D-r/ireo-pentulose can be achieved, according to Reaction 1, in the presence of an extract of B. pumilus. Obviously, this raises the question of the relevance of Eq. 1 to the production of the pentulose in microorganisms. Acetoin in Reaction 1 could be replaced by 3-hydroxy-3-methyl-2-butanone (then the by-product is acetone). More interestingly, it can be also replaced by pyruvate, then the pentulose is synthesized according to Reaction 3 ... 

A rapid and efficient one-pot synthesis of substituted 2(5H)-furanones has been reported starting from 3-hydroxy-3-methyl-2-butanone 88 and ethyl... 

The preparation of enantiomerically pure chemicals is also the theme of the next group of four procedures. The biopolymer polyhydroxybutyric acid, which is now produced on an industrial scale, serves as the starting material for the large scale synthesis of (R)-3-HYDROXYBUTANOIC ACID and (R)-METHYL 3-HYDROXYBUTANOATE. Esters of (-)-camphanic acid are useful derivatives for resolving and determining the enantiomeric purity of primary and secondary alcohols. An optimized preparation of (-)-(1S,4R)-CAMPHANOYL CHLORIDE is provided. The preparation of enantiomerically pure a-hydroxyketones from ethyl lactate is illustrated in the synthesis of (3HS)-[(tert)-BUTYL-DIPHENYLSILYL)OXY]-2-BUTANONE. One use of this chiral a-hydroxyketone is provided in the synthesis of (2S,3S)-3-ACETYL-8-... 

In contrast to Mori s synthesis, Pawar and Chattapadhyay used enzymatically controlled enantiomeric separation as the final step [300]. Butanone H was converted into 3-methylpent-l-en-3-ol I. Reaction with trimethyl orthoacetate and subsequent Claisen-orthoester rearrangement yielded ethyl (E)-5-methyl-hept-4-enoate K. Transformation of K into the aldehyde L, followed by reaction with ethylmagnesium bromide furnished racemic ( )-7-methylnon-6-ene-3-ol M. Its enzyme-catalysed enantioselective transesterification using vinylacetate and lipase from Penicillium or Pseudomonas directly afforded 157, while its enantiomer was obtained from the separated alcohol by standard acetylation. 

An efficient general synthesis of a variety of 3(2i/)-furanones has been developed. Aldol condensation of aldehydes with the enolate derived from 3-methyl-3-(trimethylsiloxy)-2-butanone (183) followed by Collins oxidation afforded 1,3-diketones (184). Acid catalyzed cyclodehydration leads to the corresponding 3(2//)-furanones (185) (Scheme 43)... 

Note 7. The Russian authors prepared this compound in 45% yield by a Fischer synthesis between 3-phenyl-2-butanone and 1-methyl-l-phenylhydrazine. The first substance is not easily available, and the second reactant is expensive. The ketone and phenylhydrazine give the expected 2,3-dimethyl-3-phenylindolenine, but... 

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. 

With aldehydes 73 and 74 in hand, two alternatives were considered for the completion of the synthesis of preswinholide A, i.e. carrying out the butanone aldol reaction on either the methyl or the ethyl side first (see Scheme 9-24). Initially, the former option was investigated. While the reaction of the kinetic boron enolate of butanone with aldehyde 73 did not favour the desired Felkin adduct 83, the addition of allyl silane 84 (a masked butanone equivalent) proved selective in the desired sense (Scheme 9-27). This change in selectivity indicates the stereochemical reversal possible when switching from a cyclic to an acyclic transition state. 

Given this problem, the attachment of the butanone synthon to aldehyde 74 prior to the methyl ketone aldol reaction was then addressed. To ovenide the unexpected. vTface preference of aldehyde 74, a chiral reagent was required and an asymmetric. syn crotylboration followed by Wacker oxidation proved effective for generating methyl ketone 87. Based on the previous results, it was considered unlikely that a boron enolate would now add selectively to aldehyde 73. However, a Mukaiyama aldol reaction should favour the desired isomer based on induction from the aldehyde partner. In practice, reaction of the silyl enol ether derived from 87 with aldehyde 73, in the presence of BF3-OEt2, afforded the required Felkin adduct 88 with >97%ds (Scheme 9-29). This provides an excellent example of a stereoselective Mukaiyama aldol reaction uniting a complex ketone and aldehyde, and this key step then enabled the successful first synthesis of swinholide A. 

Steroid synthesis. In developing a method of cyclization which has been of immeasurable -walue in the total synthesis of steroids, Robinson at first experimented with the condensation of ketones with methyl vinyl ketone itself, but encountered difficulties associated with the tendency of the ketone to polymerize. He then turned to possible prectnsors and met with some success with methyl /3-chloroacetyl ketone, CHsCOCHzCH CI. Still better, however, was the methiodide (2) of the Mannich base (1), l-diethylamino-3-butanone. Treated with a strong base such as sodamide in... 

Another three-step synthesis of cerpegin (118) was described by Villemin and Liao (236). Condensation of 3-hydroxy-3-methyl-2-butanone (365) with diethyl malonate in the presence of cesium carbonate, and with Aliquat as... 

Experiments were first conducted with acetic and polyphosphoric acids, and with several concentrations of H2SO4. As expected for a methyl ketone, with 1-phenyl-2-propanone phenylhydrazone use of PPA catalyst resulted in a large variation in isomer ratio (see Table 1). With 3-heptanone the variations resulting from use of different acids were much smaller. Of several active zeolite catalysts tested, H-beta was found to be the most selective heterogeneous catalyst for the synthesis of the linear isomer from 3-heptanone and l-phenyl-2-butanone phenylhydrazones whereas, in contrast, H-Na-Y gave about equal amounts of both isomers. 

---