Studies on Lignin and Related Compounds. LXXIX. Synthesis and

HERBERTE. FISHER, MARSHALL KUI,IL~ AND HAROLD HIBBERT

596

[CONTRIBUTION FROM

THE DIVISI@N OF INDUSTRIAL AND

Vol. 66

CELLULOSE CHEMISTRY, MCGILLUNIVERSITY]

Studies on Lignin and Related Compounds. LXXIX. Synthesis and Properties of 3-Hydroxy- 1- (3,4-dirnethoxyphenyl)-2-propanonel BY HERBERT E. FISHER, -\RSMXIdI, K L - ~ K AA S D HAROLD HIBBERT

I n a previous communicationL the allylic and SOCI? CH&* K --CH,-COOH R-CHB-COC1 d dismutation rearrangements attendant upon the 1'111 IX conversion of the two halides, 1-bromo-l-(3,Cdi HzO methoxyphenylj-2-propanoneand 3-chloro-l-(3K ---CH2-CO-CHN2 R-CH~-CO-CH~OH 4-dimethoxyphenyl)-2-propanone,to the corrcX XI sponding alcohols, acetates and ethyl ethers were (R = 3,4-dimethoxyphenyl) reported, and the bearing of these transformations on the relative validity of the Freudenberg and Synthesis of the homoveratric acid (VIII) inHibbert theories of lignin structure was discussed. volved considerable investigation. Among methDuring the course of that investigation, the ods investigated were those of Hahn, Stiehl and ~ and Sturgis* and Arndt and synthesis of seventeen of the eighteen possible S c h ~ l t z ,Julian compounds formed by substitution of bromine, E i ~ t e r t .A~ modification of the last-named proceacetyl, hydroxyl and ethoxyl groups in the side dure was finally adopted. This involved rearrangechains of 1-(3,4-dimethoxyphenyl)-2-propanonc ment of the diazoketone (VI) to the methyl ester (I)and 1-(3,4-dimethoxyphenyl)-l-propanone (11) (VII) followed by saponification of the latter to was completed and the properties of these derira homoveratric acid (VIII), rather than conversion tives summarized. This communication deals of (VI) to homoveratric amide and subsequent with the synthesis and properties of the eighteenth hydrolysis as employed in the original procedure, member of this series (A@), Table I), namely, This rapid modified Amdt-Eistert synthesis 3-hydroxy-l-(3,4-dimethoxyphenyl) -2-propanone, yielded easily purifiable intermediate products in the veratryl analog of the keto form of @-oxy- a higher yield (60% based on veratric aldehyde coniferyl alcohol, Its properties provide further ( H I ) ) than by other methods. Conversion of the support for the mechanism2Jz4 suggested to ac- homoacid (VIII) to homoveratroyl chloride (IX) count for the presence of the ethyl ethers of with thionyl chloride, thence to homoveratroyl the benzoins, l-hydroxy-1-(4-hydroxy-3-methoxy- diazomethane (X) using diazomethane in ether phenyl)-2-propanone6 and 2-hydroxy-1- (4-hy- was effected by the procedure used by Haworth droxy-3-methoxypheny1)-1-propanone6 in the eth- and Atkinsonlo for the synthesis of 3-chloro-l(3,4-dimethoxyphenyl)-2-propanone. Hydrolysis anolysis products of s p i c e wood i ABLE

r

REFERENCE COMPOUNDS OF THE VERATRYL PROPANONE SERIES R-CHz-CQCHa, I R-CO-CHz-CHa, A

(i) (ii) (iii) (iv)

R-CHa-CO-CHs'Br R-CHZ-CO-CH~OAC K-CH~-CO-CHnOH R-CH~-CO--CH~OEt

I1 D

C

Ii

R-CHBr--CO--CH3 R-CO-CHBr--CH8 R.-CHOAc-CO-CHa R-CO-CHOAc-CHa R---CHOH-CO-CH, R-CO-CHOH-CHa Itined solution, which was maintained under an atmosphere of carbon dioxide throughout the reactioii period, and the solution thrn refluxed for four hours. The sludge of metallic silver aiid silver oxide was removed by filtrarioii, and fresh silver oxide (from 2 g. of silver nitrate) was added, in four portions, as before, a t 5560'. 0 1 1 completion of the second series of additions, the mixture was again refluxed for three hours, until a drop of I hc solutioii, tested with concentrated hydrochloric acid, evolvctl no nitrogen, indicating complete reaction of the diazoketonc. The reaction mixture was then filtered, and the filtrate freed from solvent tinder reduced pressure (carbon dioside atmosphere) a t 50", Iraving a crude oily product weighing 12.4 g. (98%'). Oil distillation of t h e crude product in high vacuum a t 135~-145"(bath temperature), two fractions were obtained: (1) b. 110-l13° (0.03 mm.); 9.10 g. UT%); n 2 6 01.5300; ~ straw-colored mobile liquid. !TI1 b. p. 128-130 (0.03 mm.) : 1.48 p. ( I 2Y71: semi-crystalline. The first fraction, 011 analysis, proved to be pure methyl humoveratrate. A n d . Calcd. for C11N1404: C, 63.0; 13, 6.74: OCHI, 29,6. Found: C, 63.1; H, 6.90; OCHa, 29.4. The secoud fraction was not investigated. Homoveratric Acid.-Methyl homoveratrate (9.0 9,) was saponified by the procedure described by Snyder, Buck and Ide..l7 The uhitc crystalline product (7.85 g., 95% yield) was recrystallized from benzene-petroleum ether (60-71)"); white plates, m. p. 98-99'. A mixed melting pain: \ k ; i t h homoveratric acid showed no depression. Synthesis of 3-Hydroxy-l-(3,4-dimethoxyphenyl)-2propanone Homoveratroyl Chloride.-Homoveratric acid (10.0 g,) was refluxed gently for forty-five minutes with freshly purified16 thionyl chloride (20 cc.) in an all-glass apparatus under an atmosphere of carbon dioxide. Four portions (25 cc.) of benzene were successively added and removed by distillation under reduced pressure (carbon dioxide) in order to free the acid chloride from excess thionyl chloride. The dark red oil (10.9 g., loo%, yield) was treated, without purification, as follows: Homoveratroyl Diazomethane.--The homoveratroyl chloride (10.9 9.) was dissolved in benzene (50 cc.) and added slowly, with stirring, a t 0' to a solution of diazomethane (from 40 g. nitrosomethyl urea) in ether (400 cc.). The solution was allowed to warm slowly to room temperature and react overnight. On removal of the solvents under reduced pressure (carbon dioxide) a t room temperatitre, a red oily product weighing 11.2 g. (100%) was obtained. 3-Hydroxy-1 -(3,4-dimethoxyphenyl)-2-propanone.-The honioveratroyldiazomethane (11.2 g.) was dissolved in absolute ethanol (90 cc.) and added, over a period of thirty rniiiutes, to water (500 CC.)heated to 70°, with stirring. After addition of the diazoketone was complete, the reaction mixture was refluxed for three hours, cooled, and concentrated a t room temperature under reduced pressure (carbon dioxide) to remove ethanol. The aqueous solution was then extracted five times with chloroform, the extract Concentrated to a small volume (60 cc.) under reduced pressure (carbon dioxide) aiid precipitated three timea successively in a thin stream from this solvent into rapidly stirred petroleum ether (b.p. 30-50"). The latter solvent mas then removed and the residual oil distilled at 150-160O (bath temperature) and 0.05 mm., yielding a pale yellow oil, +D 1.5486,weighing 6.0 g. (56%). A d . Calcd. for (17) Snyder, Buck ani! Ide, "Organic Syntheses," 16, 31 (1935)

Vol. 66

C I I H I ~ O ~C,: 63.0; H, 6.74; OCHa, 29.6. Found: C , 62.8; H, 6.78; OCHr, 29.6. Semicarbazone of J-Hydroxy-l-(3,4-dimethoxyphenyl)Z-propanone.-White microscopic needles from water, m. p. 123-124'. Anal. Calcd. for CIZHI,O~NB:C, 53.9; H, 6.42: OCHs, 23.2. Found: C, 53.7; H, 6.83; OCHs, 23.1. Characterization of 3-Hydroxy-l-(3,4-dimethoxyphenyl)2-propanone Acetylation.-Oily 3-hydroxy-l-(3,4-dimethoxyphenyl)2-propanone (C.505 9.) was acetylated with acetyl chloride ( 4 8.) in toluene (30 cc.) to which pyridine (6 cc.) had been added. The mixture was allowed to react for eleven hours a t room temperature, after which the complex was decomposed by the addition of distilled water (500 cc.). The toluene layer was separated, washed three times with water, filtered and dried over anhydrous sodium sulfate. On removal of the solvent under reduced pressure (Cog) a t 35", a viscous oily product remained weighing 0.450 g. (75%). This was dissolved in ether, filtered, petroleum ether (b. p. 30-50') added, and the solution chilled to -15'. On scratching, a white crystalline product was obtained which was filtered off, recrystallized from dilute ethanol, and dried in wacuo; m. p. 55-56', A mixed melting point determination with an authentic sample of 3-acetoxy-l~3,1-dimethox~lieiiyl~-2-propanonez showed no depression. The mixed melting point with 2-acetoxy-1-(3,4dimethoxypheny1)-1-propanonewas 45'. Properties of 3-Hydroxy-l-( 3,4-dimethoxyphenyl)-2propanone Action of 5V0 Sulfuric Acid.-The ketol (0.529 g.) was mixed with 5% sulfuric acid (50 cc.) and refluxed for twenty-four hours. The amorphous black residue was filtered off, the portion adhering to the flask dissolved in chloroform, the main product added, and the solutiori evaporated to dryness; yield, 0.103 g. (19.5%). Action of 72% Sulfuric Acid.-The ketol (0.505 g.) was treated with 72% sulfuric acid (4 cc.) a t room temperature for two hours. The dark solution was then diluted to 150 cc. with distilled water, refluxed for four hours, cooled, and the amorphous dark brown lignin-like product filtered, wash:d with water, and dried in an Abderhalden drier a t 61 ; product, 0.101 g. The filtrate from the amorphous precipitate was extracted three times with chloroform, the extract concentrated, under reduced pressure, to a small volume (7 cc.) and precipitated into rapidly-stirred low-boiling petroleum ether (75 cc.). An additional quantity of amorphous product, dry weight 0.215 g., was thus obtained; total yield 0.316 g. (62.5%). Action of 1% Sodium Hydroxide at 100".-The ketol (0.514 9 . ) was refluxed with dilute (1%) aqueous sodium hydroxide (50 cc.) for twenty-four hours. After neutralization (congo red) of the mixture with dilute sulfuric acid, the product was filtered, the amorphous residue dissolved in chloroform, evaporated to dryness, and the residue dried similarly and weighed; yield of amorphous product, 0.276 g. (54%). Action of 3% Aqueous Sodium Hydroxide at Room Temperature.-The ketol (0.250g.) was allowed to stand a t room temperature for seventy-two hours with 3 % aqueous sodium hydroxide. After neutralization of the mixture with 10% hydrochloric acid (4 cc.) the polymer was filtered off, washed with water, and dried; yield of amorphous brown product, 0.200 g. (80%). Action of 3% Ethanolic Sodium Hydroxide at Room Temperature.-The ketol (0.120 g.) was dissolved in ethanol (5 cc.) and 6% aqueous sodium hydroxide (5 cc.) added. After standing a t room temperature for three days, chloroform ( 5 cc.) was added, and carbon dioxide allowed to bubble through the solution for three days. After extraction of the reaction mixture with six portions of chloroform, the extract was washed with water, dried over anhydrous sodium sulfate, concentrated to a small volume (3 cc.) and precipitated, in a fine stream, into rapidlystirred petroleum ether (b. p. 30-50'). The flaky white polymer was filtered and dried; wt., 0.020 g. (17%).

Action of 5% Aqueous Potadum Acetate.-The ketol removing a portion of the material, and then with absolute (1.02 g., n% 1.5490) was r d u x e d with.5% aqueous potas- ethanol, which dissolwd the remainder. Addition of ' sium acetate (100 cc.) for twelve hours m an atmosphere of petroleum ether t o this ethanol solution and chilling to 0 carbon dioxide. The resulting solution was extracted four for several daps resulted in the formation of a very small times with chloroform, the extract dried as above and the amount of long, light red, rod-like crystals; m. p. 138solvent removed at room temperature under reduced pres- 139'. (A possible product of the reaction, 1-(3,4-dimethoxyphenyl)-1,2-propanedione,m. p. 68-69', was thus sure (COS). Distillation of the residual oil a t 160-160' bath temperature and 0.015 mm. pressure yielded a pale eliminated.) The product was not i d e n t i h i No result was observed on addition of petroleum ether ~ yellow oil weighing 0.75 g. (75%); n * &1.5485. Seeding a small portion of the product with the isomeric to the ether washings, and chiiing to 0". The combined 1-hydroxy -1 (3,Cdimethoxyphenyl)-2-propanone ethanol and ether washings were evaporated to dryness, ketol, produced no efIect, and its relatively low refractive index and tested for the presence of the diketone (1-(3,4-dimeth(1.5485) indicated absence of the isomeric 2-hydroxy-l- oxyphenyl)-1,2-propanedione)by dissolving the residue fn (3,4-dimethoxyphenyl)-l-propanone(n% 1.5610). The ethanol (10 cc.), adding water (50 cc.), hydroxylamine semicarbazone of the product was prepared and recrystal- sulfate (0.2 g.), sodium acetate (1.0 g.) and 5% aqueous l i i from water; m. p. 122-123'. A mixed melting point nickel chloride (1.5 cc.) and rduxing the solution gently determination with an authentic sample of the semicarba- under an atmosphere of carbon dioxide for twenty-four hours. Only a small amount (0.02 8.) of amorphous zone of 3-hydroxy-l-(3,4dimeth~xyphenyl)-2-propanone showed no depression. Thus so far as could be ascertained, brown precipitate was formed; the characteristic red treatment of 3-hydroxy-l-(3,4-dimethoxyphenyl)-2-pro- crystalline nickel glyoxime of the diketone was not obpanone with 50/, aqueous potassium acetate did not tained. The action of 2% ethanolic hydrogen chloride on 3induce rearrangement of the ketol. hydroxy-l-(3,4dimethoxyphenyl)-2-propanonethus proAction of 2% Ethanolic Hydrogen Chloride.+-Hydroxy-l-(3,4-dimethoxyphenyl)-2-propanone (2.86 g.) was duced the allylic rearrangement product, l-ethoxy-lr d u x e d for forty-eight hours under an atmosphere of (3,4-dimethoxyphenyl)-2-propanone, and its dismutation carbon dioxide in an all-glass apparatus with 2% ethanolic isomer 2-ethoxy-1-(3,4-dimethoxyphenyl)-1-propanone, in hydrogen chloride (300 CC.).~At the conclusion of the yields of 56 and 24%, respectively, together with a small reaction period the solution was cooled, water (5cc.) added, amount of unidentified bisulfite soluble material. and the solution neutralized (Congo red) by the addition of Acknowledgment.-The authors wish to exsmall portions of solid sodium bicarbonate. After filtration, the solution was evaporated to dryness under reduced press their thanks to the Gottesman Foundation pressure (carbon dioxide) a t room temperature. The fund for the award of a scholarship to one of them residue was dissolved in benzene, the solution filtered, thexi (H. F.) through which this work was rendered extracted three times with 10% sodium bisulfite sqlution. After the bisulfite extract had been back-extracted twice possible. with benzene, the combined benzene solutions were washed summary once with water, treated with decolorizing charcoal, and dried over anhydrous sodium sulfate (Extract I). 1. The synthesis of 3-hydroxy-l-(3,4-dimethThe bisulfite entract, after neutralization (Congo red) with dilute sulfuric acid, was freed from sulfur dioxide oxyphenyl)-2-propanonehas been carried out, the under reduced pressure (carbon dioxide) and extracted process involving a modification of the Amdtthree times with benzene. The benzene extract was Eistert synthesis for the preparation of the interwashed with water, 1% aqueous sodium bicarbonate, mediary homoveratric acid. again with water, and dried over anhydrous sodium sulfate 2. Acids, and to a greater degree alkalies, (Extract 11). Extract 1.-After removal of the solvent under reduced readily convert the ketol into a lignin-like product pressure (carbon dioxide) the residual oil was distilled a t in high yield. 125-135' (bath temperature) and 0.01 mm. pressure, 3. When subjected to the ethanolysis procedyielding a pale yellow distillate, weighing 2.304 g., which slowly crystallized to a semi-solid yellow mass on cooling. ure, as used for the extraction of lignin from The undistilled residue (polymerized by heat) weighed wood, 3-hydroxy-l-(3,4-dimethoxyphenyl)-2-pro0.276 g. The total bisulfite-insoluble fraction weighed panone gives a mixture of l-ethoxy-l-(3,4-&rneth2 . F g..(80% of the theoretical ethylated product). The oxyphenyl)-2-propanone and 2-ethoxy-1-(3,4-disemi-sobd product was washed with warm petroleum ether (10 cc.), then filtered on a glass nail and dried in vacuo; methoxypheny1)-1-propanonein a combined yield weight of crystalline product, 0.640 g. (28%). R e s t a l - of 80%. lization from dilute ethanol yielded a white crystalline 4. The formation of these products undoubtmaterial, m: p. 82-83'. A mixed melting point deter- edly takes place through the medium of an allyl mination with an authentic sample of 2-ethoxy-1-(3,4s h f t followed by dismutation changes. Such dimethoxypheny1)-1-propanoneshowed no depression. The 2 , 4 d m i t r o p h e n y l h y d n e of the noncrystalline transformations are regarded as providing valumaterial (n% 1.5220) recovered from the petroleum ether able support for Hibbert's postulation of their washings, after recrystallization from absolute ethanol, presence (as guaiacyl derivatives) in the ethanolymelted at 139-141'. A mixed melting poipt determination with an authentic sample of l-ethoxy-l-(3,4-dimeth- sis mixture from spruce wood as the result of simioxyphenyl)-2-propanone2,4-dinitrophenylhydrazone gave lar reactions involving a 8-oxyconiferyl type of no depression. lignin building unit present in spruce native lignin. Extract XI.-Removal of the solvent under reduced presQUEBEC, CANADA swe (carbon dioxide) left a crystalline residue weighing MONTREAL, RECEIVED DECEMBER 10, 1943 0.350 g. The residue was washed with diethyl ether, this

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