Ester chlorohydrin

Another significant application of the concept of relay deprotection comes from a synthesis of the antitumour macrolides Cryptophycins 1 and 8.644 The penultimate step required a mild method for the introduction of the epoxide ring in the side chain [Scheme 4.340]. A variant of a direct method for the conversion of diols to epoxides developed by Kolb and Sharpless645 was cleverly adapted to the case at hand. Thus diol 340.1 was treated with the 4-azido-1 1,1-tri-methoxybutane in the presence of chlorotrimethylsilane to give the cyclic orthoester 340.2, which decomposed under the reaction conditions with loss of Me SiOMe to give the chlorohydrin ester 3403 (inversion). Selective reduction... 

Epoxide opening. With Eu(dpm)3 as catalyst epoxides give P-chlorohydrin esters... 

The concentration-time curve for the reactants is shown in Fig. 2, and the concentration-time curve for the products is depicted in Fig. 3. Examination of Fig. 3 shows that as well as the desired reaction product (the chlorohydrin ester), there are two other major product components. These were identified as 1,3-dichloropropan-2-ol (OL dichlorohydrin) and glycerol -1,3-di(2-ethylhexanoate) (hydroxy diester). The structure of the hydroxy diester was confirmed by its independent synthesis from glycidyl 2-ethyl hexanoate and 2-ethyl hexanoic acid. The yield of chlorohydrin ester was only 50.4%, the remainder of the 2-ethylhexanoic acid being converted to the undesirable hydroxy diester. Fig. 4 shows the structure of the products obtained in the 1 1 reaction. Fig. 5 depicts the formation of the hydroxy diester from glycidyl 2-ethylhexanoate and 2-ethyl-hexanoic acid. 

A mechanism which is consistent with the experimental observations for the production of the chlorohydrin ester is given in Fig. 6. The first stage of the reaction involves ionisation of 2-ethylhexanoic acid by the catalyst cetyltri-methylammonium bromide. Subsequent attack of the carboxyanion... 

The reaction of epichlorohydrin with 2-ethylhexanoic acid in a 1 1 molar ratio gives rise to only 50% of the desired product, the chlorohydrin ester. The mechanism depicted above indicates that the undesirable hydroxy diester is formed by reaction of 2-ethylhexanoic acid with glycidyl 2-ethylhexanoate. It appears therefore that formation of the hydroxy diester competes directly with the chlorohydrin ester formation (Fig. 9). 

It is apparent therefore that an increase in the epichlorohydrin concentration should promote the formation of the chlorohydrin ester, at the expense of the hydroxy diester. 

At first sight it may not seem undesirable to allow the reaction to continue, in order to allow conversion of the chlorohydrin ester to the epoxy compound (Fig. 12) as the ultimate aim is, in fact, to form glycidyl 2-ethylhexanoate by ring closure of the chlorohydrin ester intermediate. However it was noted that formation of the epoxy compound is accompanied by formation ofOG dichlorohydrin, and it was shown in a separate experiment that further reaction of these two compounds could be effected under the reaction conditions, probably giving rise to further undesirable by-products (Fig. 13). 

The products formed during the reaction of epichlorohydrin with 2-ethylhexanoic acid are governed by the relative concentrations of the two reactants. Epichlorohydrin must be present in excess in order to achieve a high yield of chlorohydrin ester. In order to optimise the yield of chlorohydrin ester the reaction must be terminated when all the acid has been consumed otherwise the reaction is complicated by decomposition and further reactions of this material. 

In order to study the ring closure reaction in detail a masterbatch of the chlorohydrin ester was prepared in 50% toluene solution using a 5 1 molar excess of epichlorohydrin to 2-ethylhexanoic acid. 

The first ring closure process investigated used a technique whereby 50% aqueous sodium hydroxide was added at a constant rate under conditions where the water was removed by azeotropic distillation with the excess epichlorohydrin and toluene solvent, giving a dehydrochlorination under essentially anhydrous conditions. Fig. 14 shows the conversion of chlorohydrin ester to glycidyl 2-ethylhexanoate using two different rates of addition of sodium hydroxide solution (0.25 mol. hr. i and 0.125 mol. hr. ). Excellent conversion to glycidyl 2-ethylhexanoate was obtained which may be seen to be relatively independent of the rate of sodium hydroxide addition. However in order to attain high yields (>99%) it may be seen that 40-50% excess (based on chlorohydrin ester) sodium hydroxide was required. 

The resulting mixture of chlorohydrin ester and glycidyl 2-ethy1hexanoate was resolvated with toluene and retreated with a further portion of sodium carbonate solution at 40 C. 

However it was found that no further conversion of the chlorohydrin ester to epoxy compound was obtained indicating that epichlorohydrin is required in the reaction system to effect ring closure. 

Accordingly, sodium hydroxide (17% aqueous solution) was stirred with the chlorohydrin ester masterbatch prepared above. The reaction was followed at 40 C using a molar ratio of sodium hydroxide to chlorohydrin ester of 2 1. The reaction was followed by gas chromatography. Fig. 18 shows the rates of conversion of epichlorohydrin and chlorohydrin ester during the reaction. Again, it was shown that after 6.5 hours all the sodium hydroxide had been consumed (cf. sodium hydroxide/sodium carbonate reaction at 40 C) at which time only 64% conversion to the epoxy compound was observed. Correspondingly the epichlorohydrin hydrolysis (25%) had increased in comparison to the sodium hydroxide/sodium carbonate method (15.6% at 40 C). 

Modifications to the above techniques may be envisaged for process improvement. In the above reactions epichlorohydrin is present in excess after the initial formation of the chlorohydrin ester (4 molar excess) as a consequence of the requirements of the stage I reaction. However it has been shown that epichlorohydrin hydrolysis competes with the required reaction in stage II of the process. It would therefore be desirable to reduce the concentration of epichlorohydrin prior to ring closure. It has however been shown that epichlorohydrin is required to effect ring closure (transepoxidation) and work is in hand to optimise the concentration of this component during the dehydrochlorination reaction. 

Synthesis of glycidyl esters of carboxylic acids is carried out by two main methods. The first one involves the reaction of ECH with the acid followed by dehydrochlorination of the chlorohydrin ester. The other method is based on the reaction of ECH with an alkali metal carboxylate. Other methods have only a preparative character. 

The reaction of 3-cyclohexene-1-carboxylic acid with ECH (molar ratio 1 8) was investigated at 65-85 °C in presence of a catalyst (KCl or tetramethylammo-nium chloride). After 2 h the formation of the chlorohydrin ester was completed with 100% quantitative yield. However, the hydrochlorination results in a low yield of epoxy groups and a low conversion of chlorohydrin to epoxy groups. The alkali partial consumption for hydrolysis of the ester groups, even at room temperature, is another reason. 

Epichlorohydrin can also be reacted with carboxylic acids using tertiary amines or benzyltrimethylammonium chloride to give the chlorohydrin ester. The latter can be treated with base to give epoxy esters [65]. 

Sodium mercaptides are prepared from the mercaptans and aqueous or alcoholic solutions of sodium hydroxide or alcoholic sodium eth-oxide. The sodium mercaptide reacts with halides, chlorohydrins, esters of sulfonic acid, or alkyl sulfonates [6] to give sulfides in yields of 70% or more. A recent report describes a general procedure for synthesizing aryl thioesters by a nucleophilic displacement of aryl halide with thiolate ion in amide solvents. No copper catalysis is necessary as in an Ullmann-type reaction. 

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