2,809,216 United States Patent Office Patented Oct. 8, 1957 2 ammonium salt solutions. The above operations lead to 2,809,216 the formation of polyene compounds with two secondary POLYENE ALDEHYDE AND ALCOHOLS hydroxy groups. A particularly valuable mode of procedure of the above Hans Herloff Inhofen, Braunschweig, Germany, and Otto process is the condensation of the C10-dialdehyde with 2 Isler, Basel, and Paul Zeller, Neuallschwil, Switzerland, assignors to Hoffmann-La Roche Inc., Nutley, N.J., equivalents of a Grignard compound of the general for a corporation of New Jersey mula R-MgBr, R standing for example for one of the radicals. No Drawing. Application December 23, 1953, Serial No. 400,124 Claims priority, application Switzerland December 31, 1952 5 Claims. (C. 260-601) 15 The present invention concerns polyene compounds and a process for the manufacture thereof, which process comprises treating a 2,7-dimethyl-octa-2,6-dien-4-yne-1,8- diol with an oxidation agent, condensing the 2,7-dimethyl octa-2,6-dien-4-yne-1,8-dial (hereinafter called Co-dialde hyde) with a metal organic compound and hydrolyzing the condensation product formed. The process according to the invention may be repre sented as follows. HOHC-C=C-CEC-C=C-CHOE 25 ch, The said Grignard compounds may be prepared in the usual manner. Thus, methylmagnesium iodide is formed OEC-CacC-CC-C-C-CHO for example by reacting methyl iodide and in bH, diethylether. The acetylene Grignard compounds may be produced preferably by reacting ethyl magnesium bro mide with the acetylene compounds in . For each one of the active atoms of the acetylene 35 compounds, one molecule of the ethyl magnesium bro mide is necessitated. The condensation of the Grignard compounds formed with the C10-dialdehyde is performed in the usual organic solvents, such as for example diethyl ether or tetrahydrofurane. The acetylene compounds 40 may in turn be prepared as follows: Methylbutenyne is formed by condensing acetylene with acetone and by splitting off water from the condensation product. RX-metal organic compound (as defined hereinafter). 1-hydroxy-3-methyl-pent-2-en-4-yne is formed by con The starting material I, i. e. 2,7-dimethyl-octa-2,6-dien 45 densation of acetylene with methylvinylketone and subse 4-yne-1,8-diol, may be prepared by aminotropic rearrange quent allyl rearrangement by treatment with acid. Upon ment of 2,7-dimethyl-octa-1,7-dien-4-yne-3,6-diol (con reacting the product formed with dihydropyrane in the densed from ot-methyl-acroleine and acetylene dimagne presence of acid, the tetrahydropyranylether of 1-hydroxy sium dibromide) in aqueous acetone by means of sulfuric 3-methyl-pent-2-en-4-yne is produced. acid; yield about 60 percent. The product crystallizes in 50 3-hydroxy-3-methyl-5-(2,6,6'-trimethyl-cyclohex-1- and melts at 08.5-109.5 C. Ultraviolet max en-yl)-pent-1-yne is prepared by reacting dihydro-5- ima at 272.5 mu, (e=23,500) and 288 mu, (e=18,830). with acetylene in liquid ammonia by means of lithium The oxidation of 2,7-dimethyl-octa-2,6-dien-4-yne-1,8- acetylide. When water is split off from the said product, diol I is carried out by the action of high-valent metal 3-methyl-5-(2,6,6'-trimethylcyclohex-1-en-yl)-pent-3-en oxides. The reaction is conducted in an organic solvent, 55 such as acetone, ether, tetrahydrofuran or methylene chlo 1-yne is formed. ride, at a temperature between 0 C, and the boiling point According to another mode of procedure of the present of the solvent used. Especially well suited as an oxida invention, the CG-dialdehyde oitained by oxidation is con tion agent is manganese dioxide, which is used at room densed with 2 molecules of a lithiu in connpound R-Li, R' temperature in dry acetone. If the oxidation is conducted Standing for the same radicals as acve described for the in a large amount of acetone, in the presence of manga Grignard condensation, preferably nese dioxide in excess, the yield of C10-dialdehyde II ob --C3 -C=CH -C=C-C=C its tained is almost quantitative. The Co-dialdehyde formed &H, crystallizes in a mixture of petroleum ether and ether in COO CH5 yellowish needles melting at 68 C. Ultraviolet absor 5. --C C-C-C-C H-cí tion maxima at 314 and 330 m. The Co-dialdehyde is condensed with 2 equivalents of a metal organic com &H, Yc OOCs pound RX, R standing for an organic radical and X for HC Chs the term MeIIHal or Mei (MeII or Mei represent di- or monovalent metals), especially MgHal, ZnHal or 70 | and lithium. The condensation products III thus obtained CE are hydrolyzed by the action of water, weak acids or of C 2,809,216 3. 4. The preparation of the said lithium compounds is is purified by recrystallization from benzene. Colorless achieved in usual manner. For example methyllithium crystals of 90-93° C. are obtained. Ultra may be prepared from methyl iodide and lithium in di violet maxima in ethanol at 273 ms (e=23,800) and 288 ethyl ether. The lithium acetylide compounds are prefer In (e=20,000). ably prepared in liquid ammonia by reacting the acetylene The condensation product IVa thus obtained compounds with lithium or lithium amide. For each one IW OH OH of the active hydrogen atoms of the acetylene compounds one molecule of lithium is required. The condensation of CH-CH-C=CH-C=C-CH=C-CH-CH, the lithium acetylene compounds formed with the C10-dial Ha (bH, dehyde is carried out preferably in liquid ammonia. The O when oxidized with manganese dioxide yields 3,8-dimeth lithium condensation is the preferred manner of condens yl-deca-3,7-dien-5-yne-2,9-dion of melting point 109-110 ing the Cio-dialdehyde with acetylene and with 4-methyl C. Ultraviolet maxima in ethanol at 234 m.p. (e=7,300) hex-3-en-5-yne-1,1- diethylester. The and 314 mu (e=27,300). latter is in turn prepared by reacting 1-bromo-3-methyl pent-2-en-4-yne with sodium-malonic acid diethylester. 5 EXAMPLE 3 The condensation of the C10-dialdehyde may be per Condensation with methylbutenyne formed in an analogous manner also with the sodium 7 parts by weight of methylbutenyne in 100 parts by compounds of the said acetylene compounds. It is pre volume of ether are added dropwise while cooling to an ferred to operate in liquid ammonia. However, the so ether solution of ethylmagnesium bromide (prepared from dium condensations lead to the formation of more side 20 2.5 parts by weight of magnesium, 9 parts by volume of products and offer therefore no advantage over the lithium ethylbromide and 50 parts by volume of ether. The mix condensations. ture is first stirred at room temperature for 30 minutes According to an additional mode of procedure of the and then at 40° C. for 1 hour. The Grignard compound invention, the C10-dialdehyde may be condensed with of the methylbutenyne is formed. After cooling down compounds. The zinc condensations take in principle 25 a solution of 4.8 parts by weight of C10-dialdehyde in 15u the same course as the Grignard reactions and the lithium condensations. The zinc condensations are particularly parts by volume of ether is added, and the mixture is re valuable in reacting the C10-dialdehyde with c-bromo fluxed for 1 hour. Working up as usual yields 8.1 parts acetic acid ester and the vinylogs thereof, such as prefer by weight of a viscous oil of n21 = 1.5653. The Zere ably the y-bromotiglic acid ester. The latter is formed 30 witinoff determination gives values corresponding to 1.96 by heating the corresponding tiglic acid ester with 1.1 mol of "active hydrogen.” Ultraviolet maxima in ethanol equivalent of N-bromosuccinimide in carbontetrachloride at 223 mu and 291 mut. while exposing to light, The condensation product IVb thus obtained has the When subjecting the condensation product of C10-dial formula dehyde and 2 equivalents of y-bromotiglic acid ester to a 35 IW ph OE dehydration procedure, the 8,8'-dehydro--diester is formed, and by subsequent partial hydrogenation of the triple bond and by isomerisation of the hydrogenation and may be converted into the crocetindialdehyde by par products, the all-trans-crocetin-diester may be obtained. tial hydrogenation of the triple bonds, allyl rearrangement The products of the present invention are valuable in 40 of the secondary hydroxy groups and subsequent oxida termediates for the synthesis of natural coloring agents, tion of the primary hydroxy groups formed. such as more particularly 3-caroteine, and crocetin. EXAMPLE 4 EXAMPLE 1. Condensation with 1-hydroxy-3-methyl-pent-2-en-4-yne Oxidation to C10-dialdehyde 45 An ethylmagnesium bromide solution is prepared from 10 parts by weight of 2,7-dimethyl-2,6-octadien-4-yne 6 parts by weight of magnesium, 21 parts by volume of 1,8-diol are dissolved in 1500 parts by volume of dry ace ethyl bromide and 50 parts by volume of ether. A mix tone; 150 parts by weight of manganese dioxide (prepared ture of 12 parts by weight of 1-hydroxy-3-methyl-pent-2- according to J. Chem. Soc. 1952), page 1094) are added en-4-yne and 200 parts by volume of tetrahydrofuran is and the mixture is mechanically shaken for 2 hours. The 50 added dropwise thereto and the clear Grignard solution manganese dioxide is sucked off, washed with acetone is heated at 50 C. for 1 hour. After cooling down, a until the filtrate runs off nearly colorless, whereupon the solution of 4.8 parts by weight of C10-dialdehyde in 200 yellow acetone solution is concentrated in vacuo. Ap parts by Volume of tetrahydrofuran is added and the mix prox. 9.7 parts by weight of a solid, yellow residue, which ture is stirred overnight at room temperature. When is recrystallized from ether/petroleumether is obtained. 55 worked up in usual manner, the tetrahydroxy compound The 2,7-dimethyl-2,6-octadien-4-yne-1,8-dial has the melt IV of the formula W O O

C Hs s bH, ing point 68 C. Ultraviolet maxima in ethanol at 314 is obtained as a sirupy residue. Ultraviolet maxima in mu (e=29,000) and 330 m (es26,200). ethanol at 225 mu, 278 mu, and 292 m. EXAMPLE 2. 55 EXAMPLE 5 Condensation with methylmagnesium iodide Condensation with the pyranylether of 1-hydroxy-3- A solution of 1.9 parts by weight of C10-dialdehyde in methyl-pent-2-en-4-yne tetrahydrofurane is added dropwise to a Grignard solu To a solution of ethylmagnesium bromide (prepared tion (prepared from 0.9 part by weight of magnesium, 2.5 O from 3 parts by weight of magnesium, 10 parts by volume parts by volume of methyl iodide and ether) and stirring of ethyl bromide, 50 parts by volume of ether and 100 is continued at room temperature for 2 hours. Hydrol parts by volume of tetrahydrofuran) is added a solution ysis of the magnesium iodide salt formed by means of of 11 parts by weight of the pyranylether of 1-hydroxy-3- water, separating the ether layer and evaporating the sol methyl-pent-2-en-4-yne (boiling pointo. 60-61. C., vent yields 2 parts by weight of a viscous residue, which 75 n=14845) in 50 parts by volume of tetrahydrofuran 2,809,216 5 6 and the mixture is heated at 40-50° C. for 1 hour. After sulfate and concentrated in vacuo. The condensation having cooled down, a solution of 2.4 parts by weight product thus obtained has the Formula IVf of C10-dialdehyde in 100 parts by volume of tetrahydro- IVf OH OH furan is added dropwise and stirred overnight at room HC=C-5E-C=CH-C=C-CH=C- H-c=ch temperature. The reaction mixture is poured into a so- 5 ch, ch, lution of ammonium acetate in ice water and extracted with ether. The ether solution is washed with sodium EXAMPLE 8 hydrogen carbonate solution and water, dried with so- Condensation with 4-methyl-hex-3-en-5-yne-1,1-dicarbox dium sulfate and concentrated. The condensation prod- O ylic acid ethylester uct IVd of the formula A solution of lithium in liquid ammonia is prepared

Wd

HC ce CH OH OH of,ce CBI He O bH-O-CH-CH=(-C=C-bti--CH-C=C-CH-i-bH-C=C--CH-CH-O-(bH, ch, &H, ÖH, O h, is a viscous oil. Ultraviolet maxima in ethanol at 225 mp, and 2.4 parts by weight of 4-methyl-hex-3-en-5-yne-1,1- 278 mu, and 292 mu. dicarboxylic acid ethylester (boiling point12 150 C., n=1.466) are added dropwise thereto. At the end EXAMPLE 6 the blue color of the lithium disappears. Hereafter Condensation with 3-hydroxy-3-methyl-5-(2,6',6'-tri- 25 solution of 0.84 part by weight of Co-dialdehyde in ab methyl-cycloher-I'-enyl)-pent-I-yne solute ether is added. After 1 hour, a small quantity An ethylmagnesium bromide solution is prepared from of ammonium chloride is added and the solvent is evapo 2.2 parts by weight of magnesium, 6.2 parts by volume rated. The residue is dissolved in ether, the solution is of ethyl bromide and 100 parts by volume of absolute washed neutral, dried and evaporated. The remaining ether. 10 parts by weight of 3-hydroxy-3-methyl-5- 30 sirup is distributed between petroleum ether and 95 per (2,6,6'-trimethyl-cyclohex-1'-enyl)-pent-1-yne (boiling cent methanol. The methanolic fraction contains the pointo.02 76-78° C., n=1.492) in 100 parts by volume condensation product IVg sought for: IV HCOOC O OB CO OCBs HCOOC Bo-ch-ch--C=C-ch, E--OH-C=C-CH--bit-c=c--CH-CH-c6bH, &H, ch, COO CH of ether are added thereto. The mixture is refluxed for U. W. maxima in ethanol at 225 mi, 278 mu, and 1 hour. After having cooled down, a solution of 3.3 292 mu, parts by weight of C10-dialdehyde in 300 parts by volume EXAMPLE 9 ofrefluxed ether foris then3 hours. added Workingdropwise. up asThe usual mixture for Grignard is again 45 Condensation with y-bromotiglics acid ester condensations yields 14 g. of a sirupy residue of 16.5 parts by weight of amalgamated zinc are covered n20=1.520. The Zerewitinoff determination gives values with 10 parts by volume of tetrahydrofuran. 3.9 parts corresponding to 3.96 moles of "active hydrogen." Ultra- by weight of C10-dialdehyde are separately dissolved in violet maxima in ethanol at 277 mu, and 292 m. 25 parts by volume of tetrahydrofuran and 28 parts by The condensation product IVe thus obtained has the 50 volume of y-bromotiglic acid methylester (boiling pointil formula 90-92 C.) likewise in 20 parts by volume of tetrahy

IWe HC CH HC CH CH-OH,-b-c-c-b-c-ch-C=C-CH-C-E-C=C-C-CH-OH,O OB OH O &H, bH, &H, ch, C C and possesses the carbon skeleton of B-. Con- drofuran. To start the reaction, a small quantity of the version into B-carotene may be effected by partial hydro- ?y-bromotiglic ester solution is added to the zinc and the genation of the triple bonds, two allyl rearrangements mixture is heated until the solution boils up and becomes and the splitting off of 4 moles of water. 5 turbid. Then the C10-dialdehyde solution and the y EXAMPLE 7 6 bromotiglic ester solution are added at such a rate, that the reaction mixture remains boiling actively, Once the Condensation with lithiumacetylide addition of the reactants is complete, boiling is continued y w for one further hour. After cooling down, 250 parts 1.6 parts by weight of C10-dialdehyde are dissolved by volume of 10 percent acetic acid are added and the in 50 parts by volume of tetrahydrofuran and added 70 mixture is extracted with benzene. The benzene extract dropwise to a solution of lithiumacetylide (from 0.5 part is evaporated. The yellow oil remaining back has ultra by weight of lithium) in liquid ammonia. After approx. violet maxima at 277 mu and 295 mu. By distillation 2 hours, 0.5 part by weight of ammonium chloride is under a pressure of 0.01 mm. and at an air bath tem added. Once the ammonia has evaporated, the mixture perature of 160 C., the major part of the side product, is taken up in ether, washed neutral, dried with sodium which is formed by a Wurtz reaction of the y-bromotiglic 2,809,216 7 8 ester, can be removed. The residue of the distillation ester of melting point 213.5 C. (non-corrected) in the (11.7 parts by weight), which contains the condensation form of red, caterpillar-like crystal plates. Ultraviolet product IVh sought for of the formula maxima in petroleum ether 40-50° C.: 315 mu, (e=6650), IW OE O Chooc-C=CH-CH-CH C=CH-C-C-C-C &H CH-CH=C-COOC &H, &H, ba, may be converted by splitting off water into the 8,8'- 399 mu (e=81,000), 422 mu, (e=135,300) and 448 mu, dehydrocrocetin-dimethylester and the latter in turn by O (e=139,000). Subsequent partial hydrogenation and isomerisation into We claim: the trans-crocetindimethylester as follows: 1, 2,7-dimethyl-octa-2,6-dien-4-yne-1,8-dial. The residue of the distillation is dissolved in 130 parts 2. A compound of the general formula by volume of benzene and, for the purpose of splitting off water, boiled for 10 minutes with 2 parts by weight of solid p-toluenesulfonic acid, using a downward con denser. Thereafter, the p-toluenesulfonic acid is washed ÖH, (H, out from the reaction solution by means of sodium hy wherein R represents a member selected from the group drogen carbonate solution. The solution is concentrated, consisting of hydrogen and lower aliphatic hydrocarbon filtered through an aluminumoxide column, rinsed with 20 radicals. benzene, whereupon in order to remove low-boiling im 3. A compound according to claim 2 wherein R rep purities the concentrated residue of the first filtrates is resents hydrogen, subjected anew to a high vacuo distillation. On cooling, 4. A compound according to claim 2 wherein R rep the distillation residue crystallizes. Recrystallization resents the radical from benzene/methanol yields 8,8'-dehydro-crocetin-di methylester of melting point 167-167.5 C. showing the 25 following ultraviolet maxima in petroleum ether 40-50 C.: 401.5 mu (e=82,200) and 427 mu (e=82,000). 5. A process of making a compound according to claim The hydrogenation of 8.8'-dehydro-crocetin-dimethyl 2 which comprises condensing 2,7-dimethyl-octa-2,6-dien ester in highly purified benzene with 1 mol of hydrogen 30 4-yne-1,8-dial with two mols of a metal-organic com in the presence of palladium catalyst, the activity of pound R-CEC-X, wherein R represents a member se which is reduced by means of lead (Helvetica Chimica lected from the group consisting of hydrogen and lower Acta, volume 35, page 447), yields 8,8-cis-crocetin-di aliphatic hydrocarbon radicals, and X represents a mem methylester of melting point 146 C. (non corrected), ber selected from the group consisting of HalMg- and Li light, water and iodide being thoroughly excluded dur 35 and hydrolyzing the condensation product obtained. ing the hydrogenation. Red needles from benzene/ methanol. Ultraviolet maxima in petroleum ether 40 References Cited in the file of this patent 50° C.: 314 mu (e=39,700), 397.5 m (e=60,500), UNITED STATES PATENTS 420 mu (e=90,500) and 446 mu, (e=81,000). The isom Inhofen et al. ------Sept. 2, 1952 erisation of said compound to the trans- or y-crocetin 40 2,609,396 dimethylester may be effected, for example, in petroleum OTHER REFERENCES ether solution in the presence of iodine by exposure to light of a 500-watt-Philips-Foto-bulb. For purification Johnson: "The Chemistry of the Acetylenic Com purposes, the product is suitably chromatographed on an pounds,' 1946, pages 290 and 307. aluminum oxide column. Eluating the strongly adsorbing Karrer: "Organic Chemistry,’ 1946, page 79. orange colored Zone yields the trans-crocetin-dimethyl Heilbron et al.: J. Chem. Soc. 1943, 268-70.