Condensation of σt -butyl chloroacetate and ketones by means of magnesium in
ether or benzene alone was carried out but the excellent yields of P-hydroxy
ester could not be obtained, and the results of the condensation of t -butyl
bromoacetate and ketones by means of magnesium and mercuric chloride in
benzene were also disappointing.
When a mixture of benzene and ether was used as solvent in the condensation
of t-butyl chloroacetate and ketone in the presence of magnesium and
mercuric chloride, the yields of p-hydroxy esters from cyclohexanone and
methyl isobutyl ketone were 62 and 71 % respectively, and were comparable with
those of other condensing methods

Moriwake, Tosio

Okayama University Scientific Achievement Repository

MEMOIRS OF THE SCHOOL OF ENGINEERING, OKAYAMA UNIVERSITY, Va!. 1, No.1, MARCH, 1966Condensation of Ketones and t-Butyl Chloroacetate inthe Presence of Magnesium.Tosio MORIWAKEDepartment of Industrial Chemistry(Received November 20, 1965)Condensation of t -butyl chloroacetate and ketones by means of magnesium inether or benzene alone was carried out but the excellent yields of P-hydroxyester could not be obtained, and the results of the condensation of t -butylbromoacetate and ketones by means of magnesium and mercuric chloride inbenzene were also disappointing.When a mixture of benzene and ether was used as solvent in the condensa-tion of t-butyl chloroacetate and ketone in the presence of magnesium andmercuric chloride, the yields of p-hydroxy esters from cyclohexanone andmethyl isobutyl ketone were 62 and 71 % respectively, and were comparable withthose of other condensing methods.A number of researches l ) has been made onthe Reformatsky reaction with chloroesterswhich have the advantage of lacking the lachry-matory property usually associated with thebromoesters. However, the yields of {1-hydroxyesters obtained by methyl or ethyl chloroacetateare considerably lower than those realized bythe brominated analogs. It is reported thatvarious additive agents2• 3) such as copper pow-der have been used for accelerating the reactionbut the successful results could not be obtainedexcept of the condensation of benzaldehydewith a-chloroesterl).On the other hand, S-hydroxy ester can bescarcely obtained as condensation product whenmagnesium was used as condensing agent in theReformatsky reaction, which is considered morereactive than zinc. Nord et aLl) tried to addmercuric halides as additive agents and obtainedmethyl {1-methylcinnamate in a 68 % yield fromacetophenone and methyl chloroacetate in thecase of mercuric bromide. Henbest et a1. 4)recommended to add mercuric chloride whenthe practice of reaction is difficult.It may be expected that the condensation ofketones and chloroacetate in the presence ofmagnesium is performed by excellent yield bythe use of i-butyl chloroacetate as ester compo-nent, since it prevents the formation of {1-keto-ester by the self-condensation of a-haloesteritself5). Thus, to a mixture of magnesium andether there was added a few drops of methyliodide, then an ethereal solution of i-butylchloroacetate and ketone. The reaction mixturewas decomposed with dilute acid. Since S-hydr-oxy esters could not be obtained in the reaction,a small amount of iodine was added to acceleratethe reaction before a mixture of ketone and i-butyl chloroacetate was added. The results aresummarized in Table I. In the case of aceto-Table I Condensation of t-Butyl Chloroacetate with KetonesM. p. or B. p., °CFound I Mm. I Reported6) IMm.Yield,%ProductKetone--------------- ----Acetophenone t-Butyl P-hydroxy.p- 48 138-145 8 125-126 6phenylbutyratet-Butyl P-hydroxy-p, P- M.p.Benzophenone diphenylpropionate 45 92-92.5 92- 92.2Methyl Isobutyl Ketone t-Butyl P-hydroxy-p- 44 122-128 22-23 114-115 18isobutylbutyrateBenzalacetone t -Butyl p-methyl-p- 35 135-140I2 160-165 5styrylacrylate5152 Tosio MORIWAKE (Vol. 1,phenone, benzophenone and methyl isobutylketone, the yields of i-butyl J9-hydroxy esterswere 48, 45 and 44 % respectively. When abenzalacetone was used as ketone, a, J9-unsatu-rated ester was obtained, as in the case of i-butylbromoacetate6), in a 35 % yield.In some cases these results were better thanthose reported. Thus, the condensation of i-butyl chloroacetate with acetophenone and ben-zophenone was realized in yields of 48 and 45 %respectively, whereas the Reformatsky reactionusing ethyl chloroacetate has been reported toproduce J9-hydroxy esters in yields of 40 and 30%respectively2l. Nord et al. l ) obtained methylJ9-methylcinnamate in a 68.3 % yield, by thedehydration of the condensation product, fromacetophenone and methyl chloroacetate usingmagnesium and mercuric bromide as condensingagent.By heating the reaction mixture to the boilingpoint the Reformatsky condensation can beeffected in shorter time, and the use of a mix-ture of equal amount of benzene and toluene,which permits refluxing at temperature between90° and 105°, is especially advantageous whenthe carbonyl component is a ketone7). It is ex-pected that the use of benzene in place of etheras solvent is effected in the condensation be-tween i-butyl bromoacetate and ketone, but theexcellent results could not be obtained. Thusthe present author added mercuric chloride asadditive agents as Nordl) had done. Theseresults, summarized in Table II, cannot bearcomparison with those realized in the case ofether as solvent. Similar results were obtainedin the case of i-butyl chloroacetate.Table II Condensation of t-Butyl Bromoacetate with Ketones by Means ofMagnesium and Mercuric Chloride in BenzeneKetoneIYield,IB.p., °CProduct% I I I Mm.Found Mm. Reported6)Acetophenone t-Butyl fJ-hydroxY-fJ- 59 142 8 125-126 6phenylbutyrateCyclohexanone t -Butyl I-hydroxy- 33 113-114 8 125-127 13cyclohexylacetateMethyl Isobutyl Ketone t-Butyl fJ-hydroxy-fJ- 61 99-100 10 114-115 18isobutylbutyrateBenzalacetone t-Butyl fJ-methyl-fJ- 37 142-145 3 160-165 5styrylacrylateWhen a mixture of benzene and ether wasused as solvent in the case of i-butyl chloroace-tate, yields of J9-hydroxy esters from cyclohexan-one and methyl isobutyl ketone were compara-ble with those of corresponding J9-hydroxy estersobtained by another method. Thus, the conden-sation of i-butyl chloroacetate with cyclohexan-one and methyl isobutyl ketone were realizedin yields of 62 and 71 % respectively, whereasthe condensation of i-butyl bromoacetate withcyclohexanone and methyl isobutyl ketone inether was realized in 80 and 78 % yield respec-tively6).On the other hand, Vul'fsonBl reported thatthe yields of J9-hydroxy esters are increased byadding thiophene to benzene when the Refor-matsky condensation is carried out in benzene.From this report and our results it might beconcluded that the presence of solvent possess-ing lone electron pair accelerates the formationof enolate anion of ester to increase the yieldesof J9-hydroxy esters.Experimental*lt-Butyl chloroacetate was prepared by theaction of chloroacetyl chloride**) on i-butylalcohol in the presence of dimethylaniline9).The product, which was obtained in a 65%yield, b. p. 51-52°/11 mm. (lit. 9) b. p. 48-49° /11 mm.), when shown to be acidic, was washedwith saturated sodium bicarbonate solution anddistilled in the presence of a trace of magnesiumoxide.*) All melting and boiling points are uncorrected.**) In a cooled flask, 120 g. of chloroacetic acid wasplaced and 200 g. of thionyl chloride was then addedall at once. The resulting mixture was allowed tostand at room temperature for 1 hr. and refluxed for 6hr. to complete the reaction. The excess of thionylchloride was distilled through a column and the residuewas distilled subsequently. The yield of chloroacetylchloride boiling at 104-105° was 129 g. (92 %).1966) ContJenasation 0/ Ketones and t-Butyl Chloroacetate 53Condensation of Acetophenone and t-Butyl Chloroacetate by Means of Magne-sium in Ether. - To a mixture of 2.0 g. ofmagnesium, a piece of iodine and 30 m!' ofanhydrous ether there was added a few drops ofmethyl iodide. When the reaction had started,a solution of 6.0 g. of acetophenone and 7.8 g,of i-butyl chloroacetate in 20 ml. of ether wasadded with stirring and a piece of iodine wasadded to the resulting mixture. After the mix-ture was refluxed for 2 hr., it was decomposedwith 10 % sulfuric acid and ice. The organiclayer was separated and the aqueous layer wasextracted with ether. The organic layers werecombined, washed with saturated sodium bicar-bonate solution and with water, dried overanhydrous sodium sulfate and the solvent wasremoved. The residue was distilled in the pres-ence of a trace of magnesium oxide, and t-butyl8-hydroxy-8-phenylbutyrate (5.6 g. 48 % yield)was obtained as a pale-orange oil, b. p. 138-145°/8 mm. Reported b. p. is 111-112.5°/2mmlO) and 125-126°/6 mm6).The other i-butyl $-hydroxy esters cited inTable I were prepared similarly.Condensation of Acetophenone and t-ButylBromoacetate in Benzene by Means of Mag-nesium and Mercuric Chloride. - A mixtureof 2.0 g. of magnesium, 0.2 g. of mercuric chlo-ride and 30 ml. of anhydrous benzene was heatedto reflux and a few drops of a mixture of aceto-phenone and i-butyl bromoacetate was added.When the reaction had started, a solution of6.0 g. of acetophenone and 10.0 g. of i-butylbromoacetate in 30 m!. of benzene was addedover a 60-min. period. Stirring was then con-tinued for 200 min. at the boiling point of themixture. After cooling the contents were decom-posed with 10 % sulfuric acid and treated in thesame manner as described above. Distillationgave t-butyl j3-hydroxy-j3-phenylbutyrate in a59 % yield.The other t-butyl j3-hydroxy esters cited inTable II were prepared similarly.Condensation of Acetophenone and t-ButylChloroacetate in Benzene. - A few drops ofmethyl iodide was added to a mixture of 2.0 g.of magnesium and a piece of iodine in 30 m!' ofbenzene, and heated to the boiling point. Whenthe reaction had started, a solution of 6.0 g. ofacetophenone and 7.7 g. of i-butyl chloroacetatein 20 m!' of benzene was added over a 25-min.period and refluxed for 100 min. After treatingas usual, t-butyl 8-hydroxy-j3-phenylbutyratewas obtained in a 35 % yield.When acetophenone was replaced by cydohe-xanone, the yield of 8-hydroxy ester was 26 %.Condensation of Benzophenone and t-Butyl Chioroacetate in a Mixture of Ben-zene and Ether by Means of Magnesium andMercuric Chloride. - To a mixture of 2.0 g.of magnesium and 0.2 g. of mercuric chloride in30 m!' of ether was added a few drops of methyliodide. When the reaction had started, a solu-tion of 9. 1 g. of benzophenone and 8.0 g. of i-butyl chloroacetate in 40 m!' of benzene wasadded to obtain the moderate refluxing over a25-min. period, and refluxing was continuedfor 90 min. After treating as usual, the recrys-tallization of the residue from ethanol gave1O.Og. (67 %) of t-butyl 8-hydroxy-j3, j3-diphenyl-propionate, m. p. 92-92.5°. The reported m. p.is 92-92.2°6).Similar condensation of i-butyl chloroacetatewith cydohexanone or methyl isobutyl ketonegave the corresponding j3-hydroxy ester in yieldsof 62 and 71% respectively.References1) R. F. Miller and F. F. Nord, ]. Org. Chem., 16,(1951) 728.2) J. A. Nieuwland and S. F. Daly, ]. Am. Chem.Soc., 53, (1931) 1824.3) G. A. R. Kon and K. S. Nargund, ]. Chem. Soc.,(1932) 246l.4) H. H. Henbest, E. R. H. Jones and I. M. S. Walls,]. Chem. Soc., (1949) 2696.5) J. C. Shivers, M. L. Dillon and C. R. Hauser, ].Am. Chem. Soc., 69, (1947) 119.6) T. Moriwake, ]. Org. Chem., 31, (1966) 983.7) S. Natelson and S. P. Gottfried, ]. Am. Chem.Soc., 61, (1939) 970.8) N. S. Vul'fson, Khim. Re/erat. Zhur., 4, (1942)No. 7-8, 54; Chem. Abstr., 37, (1943) 6657.9) C. R. Hauser, B. E. Hudson, B. Abramovitch andJ. C. Shivers, "Organic Syntheses", Coli. Vol.III, (1955) p. 142.10) C. R. Hauser and W. H. Puterbaugh, ]. Am.Chern. Soc., 75, (1953) 1068.

Condensation of Ketones and t-Butyl Chloroacetate in the Presence of Magnesium.

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