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3,030,359 United States Patent Office Patented Apr. 17, 1962

2. 3,030,359 group, an aliphatic, aromatic, araliphatic or alicyclic PROCESS FOR THE PREPARATION OF c.f3-UN hydrocarbon rest. SATURATED CARBONYL COMPOUNDS Josef Ferdinand Arens and Hendrik Jan Takob. Bos, An advantage of the present process over the known Groningen, and Hendrik Vieregge, Haren, Netherlands, 5 processes is that it can be applied with different com assignors to Organon Inc., West Orange, N.J., a corpo pounds, by means of which a very great number of com ration of New Jersey pounds, part of which was difficult of access so far, can No Drawing. Fied Aug. 15, 1960, Ser. No. 49,431 be prepared in this manner. Claims priority, application Netherlands Aug. 24, 1959 Other advantages are that the process can be carried 6 Claims. (C. 260-239.55) O out very easily, that high yields are obtained, that it The invention relates to the preparation of cy,6-unsat quickly leads to the object required and that it takes urated carbonyl compounds from carbonyl compounds, place under mild conditions. the molecule of which has at least 2 carbon atoms less. Lewis acids that are very suitable to be used in the A number of reactions in which a carbonyl compound present process are, for example, metal halides, such as is converted into an c.f3-unsaturated carbonyl compound 5 aluminium chloride, ferric chloride, stannic chloride, having a greater number of carbon atoms, is described boron fluoride and zinc chloride. in literature. Of these known reactions the following are In particular the compounds that by coordination with mentioned: the oxygen atom of the carbonyl group activate the car (1) The aldol-condensation, followed by dehydrata bon atom of that group-render it positive-have proved tion. This reaction can only be used with a small number 20 good catalysts. Besides the said metal halogenides such of compounds and is applied in industry in a very limited as for example compounds as boric acid esters and alu number of cases only; mention may be made here of the minium sulphate are also quite suitable. Preferably BF preparation of acrolein from acetaldehyde and formalde is used, because with it slightly reactive carbonyl groups, hyde. too, can be activated and because with this compound (2) The Perkin-reaction, in which an aromatic alde 25 excellent yields are generally obtained. hyde is reacted with the anhydride of an aliphatic acid The amount of the Lewis acid used can differ very in the presence of a salt of the same acid to form an O.f3 greatly. The best results are obtained when per gram unsaturated acid. molecule of the carbonyl compound use, 1-gram-mole (3) The Claisen-reaction, in which an aromatic alde cule of the Lewis acid is used. With smaller amounts hyde is reacted with ethylacetate or a similar ester in the 30 of the Lewis acid it is also possible, however, to obtain presence of metallic sodium and a trace of alcohol. In reasonable yields. this reaction the ester of an ox,6-unsaturated acid is When boron trifluoride is used this compound is pref --- formed. erably first reacted with ether, after which the thus (4) The Reformatsky-reaction, in which a carbonyl formed boron trifluoride etherate is added to the reaction compound is reacted with an cy-halo-ester and Zinc; after 35 mixture. In this way more accurate dosaging of the hydrolysis and dehydratation the ester of an ox.6-unsat added catalyst is possible, which is more difficult when urated acid is obtained. the gaseous BF is used. (5) The coupling of a carbonyl compound with a metal The reaction is preferably carried out at a temperature derivative of ethoxy-ethyne, in which after hydrolysis below 0°C., because at higher temperatures polymerisa an ethoxyethyne carbinol is formed, which, by treatment 40 tion of the alkyne compound may occur under the influ with an acid, can be converted into an o,6-unsaturated ence of the Lewis acid, which may give rise. to dis ester or-after partial reduction of the ethyne bond colouration and contamination of the reaction product. into an ox,6-unsaturated aldehyde. As reaction medium solvents can be used that do not It was found now that c.f3-unsaturated carbonyl com fake part in the reaction. In general they are solvents pounds can be prepared from carbonyl compounds hav 45 without reactive groups, such as hydroxyl, keto, and ing at least 2 carbon atoms less, by reacting then with an amino groups. Solvents that qualify for the purpose are, alkyne compound in an indifferent solvent in the presence for example, carbon disulfide, ethers, dioxane, petroleum of a Lewis acid, ether, chloroform, and aromatic hydrocarbons. Prefer The reaction taking place in the present process can ably diethyl-ether is used, because most compounds read be represented by the following equation: 50 ily dissolve in it, because good yields are obtained when it is used and because the ether can be easily removed R R Rs by evaporation when the reaction is completed. High N Lewis acid N. yields are also obtained with carbon disulfide as solvent. c=0 - R3 CECR --> C-C-G-R, The amounts of the reaction components are prefer RS R 55 ably chosen so that there are equivalent amounts of the carbonyl compound and the alkyne compound. In the case of an excess of the carbonyl compound there is a in which possibility that when the reaction is completed, this ex R represents hydrogen, an aliphatic, aromatic, araliphatic cess polymerises under the influence of the Lewis acid, or alicyclic hydrocarbon rest, 60 thus giving rise to contamination of the reaction mixture. R represents hydrogen, a substituted hydroxyl group, an . An excess of the alkyne compound is likewise less de amino group whether or not substituted, an aliphatic, sirable, because after completion of the reaction desired, aromatic, araliphatic or alicyclic hydrocarbon rest, or this excess may react with the cy,6-unsaturated carbonyl R1 and R2 together form an alicyclic ring with the adja conpound formed, which causes the reaction mixture to cent carbon atom, 65 become contaminated and the yield to decrease. Rs represents hydrogen, an alkyl, aryl, araikyl or an The following examples illustrate the invention. Yields salicyclic hydrocarbon rest and are always calculated on the basis of the carbonyl com R represents hydrogen, an alkoxy group, an alkylthio pound. 3,030,359. 3. 4. EXAMPLES acting in the manner of Example I 14.8 g. of ethylformate, 14 g. of ethoxy-ethyne in 50 ml. of ether under the in I fluence of 20 g. of BFs-etherate. Yield 65%. The com pound is purified by vacuum distillation and boils at a Cinnamic Acid Ethyl Ester pressure of 15 mm. Hg at 90° C. 21 g of benzaldehyde are dissolved in 100 ml. of ether, VIII whereupon after cooling to 0 C., 28 g. of borontrifluoride etherate are added to this solution, after which 14 g. of p-Methyl-Thiocrotonic Acid Ethyl Ester. ethoxy-ethyne are slowly added dropwise, the tempera ture of the mixture being kept at 0° C. After standing O The B-methyl-thiocrotonic acid ethyl ester is obtained 24 hours the reaction mixture is successively washed with by reacting in the manner of Example, 11.6 g. of acetone, a solution of potassium carbonate and water. After dry 17.6 g. of ethylthio-ethyne in 50 ml. of ether under the ing over sodium sulphate the ether is evaporated, where influence of 25 g. of BF-etherate. The product distils upon the cinnamic acid ethyl ester is obtained by distill at a temperature of 65° C. at a pressure of 15 mm Hg. lation in vacuum. Boiling point (15 mm. Hg): 140 C., 5 yield 90%. IX I Acrylic Acid Ethyl Ester Cinnamic Acid Ethyl Ester 20 The acrylic acid ethyl ester is prepared in the manner In the same way, as described in Example I the cin of Example I, by reacting 6.0 g. of formaldehyde and 14 namic acid ethyl ester is prepared, this time, however, by g. of ethoxy-ethyne in 30 ml. of ether in the presence of using 37 g. of magnesium bromide instead of boron tri 25 g. of BF-etherate. The compound distils at about fluoride. Yield 72%. 100° C. Part of the product is obtained as polyacrylate. 25

Crotonic Acid Methyl Ester B-Dimethylamino-Acrylic Acid Ethyl Ester and Trimesic 11.2.g. of methoxyethyne are added to a solution of Acid-Tri-Ethyl Ester 8.8 g. of acetaldehyde and 28.4 g. of BF-etherate in 50 30 ml. of ether cooled to -10° C. After standing 24 hours By putting 14 g. of ethoxy-ethyne in 20 g. of dimethyl the crotonic acid methyl ester formed is isolated by wash formamide containing 30 g. of BF-etherate and allowing ing the reaction mixture with a soda solution and water, the mixture to stand for 24 hours at 0° C. the f3-dimethyl drying it with sodium sulphate, evaporation of the ether amino acrylic acid ethyl ester is formed. It is obtained and distillation. Boiling point 118-121 C, yield 83%. 35 by washing with a potassium carbonate solution at -10 C. and extraction with ether, after which the ether is . V evaporated from the ether extract to obtain the above mentioned acrylic acid ester. Yield 40%. Boiling point ab-Dimethyl Acrylic Acid Ethyl Ester at 1 mm. Hg 68 C. The residue contains the trimesic 40 acid triethylester, which is obtained by recrystallising a In the manner as described in Example I the 3,8-di few times from aqueous methanol; melting point 132 methyl acrylic acid ethyl ester is prepared starting from 134 C. This ester is obtained as main product, by 5.8 g. of acetone, 7 g. of ethoxyethyne and 14.2 g of treating the reaction mixture not directly with a potas BF3-etherate. Yield 72%. Boiling point at a pressure 8ium carbonate solution, but by keeping it first for 24 of 30 mm. Hg is 61° C. 45 hours at room, temperature after adding ethanol. W XI ce,6-Dimethyl Thiocrotonic Acid Ethyl Ester g-Methyl-o-Ethyl-Crotonic Acid Ethyl Ester A solution of 11.6 g. of acetone and 25 g, of BF etherate is prepared in 50 ml. of ether. This solution is 50 The 6-methyl-O-ethyl crotonic acid ethyl ester is pre cooled to -10°C. To the cooled solution 20 g. of ethyl pared in the manner of Example I, by reacting 11.6 g. of . thiopropyne are added, after which the solution is allowed acetone, 19.6 g. of ethoxybutyne and 28.4 g. of BF to stand for 20 hours at -10° C. The reaction mixture etherate in 60 mi. of ether. Yield 78%. Boiling point is washed with a solution of sodium carbonate and dis 55 166-168 C. tilled water, and dried with sodium sulphate. The ether X is evaporated and the ol,6-dimethyl thiocrotonic acid ethyl ester formed, purified by distillation under vacuum. This Benzal-Acetophenone ester, which has not been described before in literature, has a boiling point of 90° C. at a pressure of 15 mm. Hg. 21.2g, of benzaldehyde are dissolved in 50 m), of ether, SO to which solution 20 g. of BFs-etherate are added at V room temperature. Then 20.4 g. of phenyl acetylene are added, after which the mixture is left to stand one night. g-Ethoxy Crotonic Acid Ethyl Ester After washing the mixture with sodium carbonate and Water the ether is evaporated and the residue distilled in In the manner of Example 8.8 g. of ethyl acetate, 65 vacuum. The product obtained is recrystallised from a 7.g. of ethoxy-ethyne and 14 g. of BFs-etherate are re mixture of ether and petroleum ether. Thus the benzal acted. The B-ethoxy-crotonic acid ethyl ester is obtained acetophenone is obtained. Melting point 62° C. Yield in pure-condition by vacuum distillation; the boiling point 60%. is at 15 mm. Hg 90° C. Yield 72%. XI. O VII Benzal-Acetophenone g-Ethoxy Acrylic Acid Ethyl Ester In the manner of Example XII benzal-acetophenone is prepared. Instead of boron trifluoride aluminium chlo The b-ethoxyacrylic acid ethyl ester is obtained by re 75 ride is used as a catalyst. Now the yield is 48%. 3,030,859 5 6 XIV TABLE Benzal-Acetophenone Boiling point or Yield In the manner of Example XII benzal-acetophenone Carbonyl compound Reaction product melting point n is prepared, but instead of boron trifluoride magnesium 5 percent bromide is used as a catalyst. formaldehyde (triox-. acrylic acid ethyl B.P. 98-04-...---- 37 The magnesium bromide used as a catalyst is pre ane). ester. pared by the reaction of bromine on a suspension of acetaldehyde------crotonic acid B.P. 128-132. 4. magnesium in ether. Yield of pure benzal-acetophenone: ropionaldeldehyd 6------3-ethylacrylic E; B.P. 50-64/10 28 29%. . 10 prop y acid ethyester. butyraldehyde.---...-- g-propylacrylic B.P. 72-98°111 22 XV acid ethylester. t acrolein------B-vinylacrylic B.P. 50-60°/10 29 6-Ionylidene Acetic Acid Ethyl Ester acid ethylester, crotonaldehyde------sorbic acid , B.P. 75.5-76/10 52 19.3 g of 6-ion one are dissolved in 50 ml. of ether, ethylester. benzaldehyde------cinnamic acid B.P. 94-98,510.8 48-50 to which solution, which is cooled to 0° C., 14 g. of BF 5 ethylester. etherate and 7 g. of ethoxy-ethyne are added, after anisaldehyde------p-methoxy cinna M.P. 47.5-49. 54 which the mixture is allowed to stand for 15 hours. nic acid ethyl ester. Then the reaction mixture is washed with a solution of p-nitrobenzaldehyde. p-nitrocinnamic M.P. 34.5-136. 25 acid ethylester. sodium carbonate and with water, and dried over sodium o-naphthaldehyde---- B-naphthyl-(1)- M.P. 37-375 50 sulphate. After evaporation of the ether the 6-ionylidene acrylic acid 20 ethylester. acetic acid ethyl ester is obtained by means of distilla thiophehaldehyde...-- g-(a-thienyl)-acryl B.P. 80-86°/0.5-1 53 tion under high vacuum. Yield 58%. ic acid ethylester. acetone------f-methylcrotonic B.P. 140-56------82 XV acid ethylester. butanone------6-methylo, g: B.P. 170-172°f 71 pentenic acid 770. In Ethyl Ester of the Vitamin A-Acid 25 ethyester. diethylketone.------B6-diethylacrylic B.P. 69-69.5°f 25.8 g. of the so-called C-ketone of the vitamin acid ethylester. 10. A-synthesis are dissolved in 70 ml. of ether, whereupon acetophenone.------6-methylcinnamic B.P. 91-1151 acid ethylester. 0.7 m. after cooling to 0° C., 14.2 g of BF3-etherate and 7 g. cyclopentanone-...---- cyclopentylidee B.P. 88-88,51 of ethoxy-ethyne are added to the solution. After stand acetic acid ethyl 10 Inn. 30 - ester. ing 20 hours the ethyl-ester of the vitamin A-acid is cyclohexanone------cyclohexylidere B.P. 02-1051 obtained in the manner of Example XV. Yield 65% acetic acid ethyl 2nn, ester. cycloheptanone.------cycloheptylidene B.P. 115-116°, XVI acetic acid ethyl 10 a.m. ester. Sionone.------6-ionylidene acetic B.P. 126-1311 3-Ethylene Glycol Ketal of A4,17-3,11-Diketo acid ethylester. 0.5II. Pregnadiene-21-carboxylic Acid Methyl Ester ethylformiate------B-ethoxyacrylic B.P. 86-90° acid ethylester. 3 mm. dimethylformamide-- $8,6-dimethyiacryl B.P. 63-63.5°f 25.2 g. of the 3-ethylene glycol ketal of A4-3,11,17 ic acid ethyester. Inn. triketo-androstene are dissolved in 150 ml, of ether. After cooling to -5° C., 5.6 g. of methoxy-ethyne and 40 In an analogous manner acetone has been reacted with 14.2 g of BF-etherate are added to the solution, after For the which the mixture is allowed to stand for 24 hours at the alkyn compounds mentioned in Table II. -5 C. The reaction mixture is washed with a solution reaction products obtained and further details see said of sodium carbonate and Water, and then dried over so table. dium sulphate. After evaporation of the ether the resi TABLE I due is recrystallised a few times from a mixture of ethyl 45 Yield acetate and petroleum ether to obtain the pure product; Alkyn compound Reaction product Boiling point in melting point 188 C.; Yield 58%. percent XVI isobutoxypropyne. of-dimethyl crotonic 70-86F15 mm...------50 acid isobutyl ester. According to the following example the reaction prod meth Oxyheptyne. - ox-pentyl-3-Inlethyl 44.0-44.2,0.4 42. erotonic acid ucts of Tables I and I are prepared. nethyl-ester, 0.1 molecule of boron trifluoride etherate diluted with ethoxyisopeltyne. ag-isopropyl-6-methyl 69-70.10 mm... 4. erotonic acid ethyl 50 ml. of absolute ether are passed into a flask fitted ester. with stirrer, dropping funnel and thermometer. After ethoxyheptyne.----- a-penty-5-methyl 46.0-46.20.2 5. cooling to -10° 0.1 molecule of the carbonyl compound 55 crotonic acid ethyl l ester. (aldehyde, ketone, ester, acid amide) dissolved in 50 methoxypentyne.-- cy-propyl-6-methyl 65.5-66.5/10 59 Iml, of absolute ether is added in 15-30 minutes, when rotonic acid l usually a slight heat effect is noticeable and in some cases methyl-ester. a precipitate of a BF-complex is formed. Next 0.1 mole cule of ethyne ether dissolved in 75 ml. of absolute 60 What we claim is: ether is added dropwise in 2-3 hours at -10. During 1. Process for the preparation of c,6-unsaturated car the addition evolution of heat takes piace and in most bonyl compounds of the general formula: cases a light yellow to brown precipitate is formed. After bringing the temperature of the reaction mixture R. up to 0° hydrolysis takes place with a solution of 20% 65 potassium carbonate (0.1 molecule KCO) which is added in 20-30 minutes. Under considerable evolution in which of heat decomposition of the complex takes place. After R is a member of the group consisting of a radical the evolution of carbonic acid has ceased the ethereal forming an alicyclic ring with the adjacent carbon solution is separated, washed with a KaCO3 solution and 70 atom and RR2 in which water, and dried on CaSO4. After evaporation of the R represents a member of the group consisting of ether the reaction product is obtained by fractionated hydrogen, an aliphatic, aromatic, araliphatic and distilation. alicyclic hydrocarbon radical The carbonyl compounds mentioned in Table I have Ra represents a member of the group consisting of hy been reacted with ethoxy-ethyne as ethyne ether. 75 drogen, a substituted hydroxyl group, an amino 8,030,359 7 3 group, a substituted amino group, an aliphatic, aro 3. Process according to claim 1, in which the re matic, araliphatic-and-alicyclic hydrocarbon radical action is carried out, below:0' C. R3 represents a member of the group consisting of 4. Process according to claim 1, in which the reaction hydrogen, an alkyl, aryl, aralkyl and an alicyclic is carried out in ethyl ether. hydrocarbon radical and 5. Process according to claim 1, in which the reaction R4 represents a member of the group consisting of an is carried out in carbon disulfide. alkoxy group, an alkylthio group, an aliphatic, aro 6. Process according to claim 1, in which the reaction matic; arilliphatic and alicyclic hydrocarbon radical, is carried out in the presence of a Lewis acid which, by comprising reacting-a carbonyl compound of the general coordination with the oxygen atom of the carbonyi formula R=C=O with an alkyne compound of the gene. O group in the carbonyl compound, activates the carbon eral formula R3CsCR4 in an inert solvent in the presence atom of that group. of a Lewis acid. 2. Process', according to claim 1, in which boron, tri No references cited. fluoride: is used as Lewis acid.