The Carroll Reaction

2-Methylhept-2-en-6-one, usually simply referred to as methylhep-tenone, is a useful synthon for total synthesis of terpenoids. One early 

The disadvantage of this process is that it is not very atom efficient. The elimination of carbon dioxide means that bulk is carried through the process only to be lost towards the end. This is undesirable from both the cost and environmental impact standpoints. 

---

In an imioortant industrial process, the Carroll reaction , an ahphatic version of the Claisen rearrangement occurs. See if you can find the right mechanism ... 

The reductive coupling of the 7r-allylpalladium enolates 679 gives the allylated ketones. This reaction is also possible thermally, as the Carroll reaction, which... 

Linalool can be converted to geranyl acetone (63) by the Carroll reaction (34). By transesterification with ethyl acetoacetate, the intermediate ester thermally rearranges with loss of carbon dioxide. Linalool can also be converted to geranyl acetone by reaction with methyl isopropen ether. The linalyl isopropenyl ether rearranges to give the geranyl acetone. 

The reductive coupling of the 7i-allylpalladium enolates 400 gives the allylated ketones 403. This reaction is also possible thermally and is called the Carroll reaction. Whereas the Carroll reaction proceeds by heating up to 200 °C, the Pd-catalysed Carroll-type reaction can be carried out under mild conditions (even at room temperature) by reductive elimination of the 7t-allylpalladium enolate 400 [177,178], The Pd-catalysed reaction is mechanistically different from the thermal reaction and more versatile, which is explained by the [3,3] sigmatropic rearrangement of the enolate form. For example, thermal Carroll rearrangement of the a,a-disubstituted keto ester 410 is not possible, because there is no possibility of the enolization. However, it rearranges to ketone 411 smoothly with the Pd catalyst, via the 7i-allylpalladium enolate. 

An improved version of the Carroll reaction, the ester enolate Carroll rearrangement, was reported in 1984 by Wilson and Ptice. Dianions of allylic acetoacetates, generated by treatment with 2 equiv. of LDA at -78 °C in THF, were rearranged at room temperature or 65 C to yield >keto acids in 40-80% yield (equation 12). In the course of a synthesis of the sesquiterpene isocomene, Snider and Beal used this method for the rearrangement of acetoacetate (73), prepared in 83% yield from reaction of cyclopen-tene (72) with diketene and a catalytic amount of DMAP (Scheme 11). The ( )-isomer of ketone (74) is obtained stereospecifically, since there is a severe steric interaction between the methyl groups in the Carroll rearrangement transition state leading to the (Z)-isomer. 

A Ciba-Geigy group used the Carroll reaction for the synthesis of hydroxyethylene dipeptide iso-steres. Alcohol (80) was converted with diethyl isopropylmalonate to the mixed malonic ester derivative (81) by Ti(OEt)4 catalysis. Subsequent sigmatropic rearrangement of (81) was also effectively catalyzed by Ti(OEt)4, thereby allowing a one-step conversion of the allylic alcohol (80) to ester (82) (Scheme 13). 

A modification of the Carroll reaction that enables the preparation of y,8-unsatu-rated ketones under milder conditions uses the dianion of allylic acetoacetates in a sequence of reactions depicted below. 

Methylhept-2-en-6-one, usually referred to simply as methylhep-tenone, is a useful synthon for the total synthesis of terpenes. One early synthesis of this intermediate employed the Carroll reaction, the substrate for which is prepared by the addition of acetylene to acetone and subsequent partial hydrogenation to 2-methylbut-3-en-2-ol, as shown in Scheme 4.5. Addition of acetylene to methylheptenone gives dehydrolinalool, which can be hydrogenated to linalool using a Lindlar catalyst. 

The Carroll reaction occurs when a /i-ketoester is treated with an allylic alcohol in the presence of base, or when an allyl ester of a / -ketoacid is heated. Scheme 4.6 shows the mechanism of the latter. 

Use of the Claisen rearrangement achieves the same conversion of methylbutenol into methylheptenone as does the Carroll reaction, but without the loss of carbon dioxide.The methanol produced instead can be recovered and recycled. In this process, as shown in Scheme 4.7, methylbutenol is treated with the readily available 2-methoxypropene to give the allyl vinyl ether, which then undergoes a Claisen rearrangement to give methylheptenone. 

Decarbonylation of the ozonolysis product of ot-pinene gives a methyl trimethylcyclobutyl ketone. Addition of acetylene to this, followed by the Carroll reaction, gives (trimethylcyclobutyl)heptadienone. The cyclobutane ring is opened by acid to give a methylated /-ionone which, on cyclization, produces irones. Once again, the Greek prefixes have the same significance as in the ionone series. 

The Carroll reaction uses an acetoacetate ester (54), made by ester exchange or with diketene (Chapter 33), to give enol (55) which can do the [3,3] sigmatropic shift and give keto acid (56) which decarboxylates under the reaction conditions. The synthesis of (53) is standard acetylene chemistry (Chapter 16). 

The discovery of the Carroll reaction in 1940 allowed significant improvements to be made to Arens and van Dorp s synthesis. The Carroll reaction involves heating the acetoacetate ester of an allyl alcohol. The ester can be formed in situ from the alcohol and ethyl acetoacetate. The reaction is an electrocyclic one which results in the elimination of carbon dioxide and the addition of an acetone fragment to the terminal carbon of the double bond of the alcohol. The mechanism is shown in Figure 9.8. 

Reduced 2,6-dimethyloctane terpenoids are often made by reduction of the terpenoids just discussed, but catalytic reduction of citral to citronellal (2) does not normally give high yields because of interfering 1,4-reduction. Now Easter et al. have found that the addition of a few per cent of water and base prevents carbonyl reduction during palladium-charcoal hydrogenation of citral. Tetrahydrocitral has been made by the reductive carbonylation of either of the two hydrocarbons (54) and (55) (or a mixture of both) in the presence of certain cobalt catalysts.The Carrol reaction has been used in the preparation of... 

As a test of the limitations of the Carroll reaction, Bryson and coworkers were able to demonstrate the versatQity of the reaction when applied to hindered cyclic systems in the pursuit of newly formed tertiary and quaternary carbon-[Pg.401]

Linalool can be converted to geranyl acetone by the Carroll reaction (156). After transesterification with ethyl acetoacetate, the intermediate ester thermally rearranges with loss of carbon dioxide. Linalool can also be converted to geranyl acetone by reaction with methyl isopropenyl ether. The linalyl isopropenyl ether rearranges to give geranyl acetone. Geranyl acetone is an important intermediate in the synthesis of isophytol [505-32-8], famesol [106-28-5], and nerolidol [40716-66-3]. Isophytol is used in the manufacture of Vitamin E and thus linalool is a key intermediate in the synthesis of the latter. All of these reactions are shown in Fig. 8.55 in the section on nerolidol. 

---