[ CONTEIBUTIONZfldM THE SCHOOL OF CHEMISTRY OF THE UNIVERSITY OF MINNESIYFA 1
THE: CHEMISTRY OF VITAMIN E. XI. INTRODUCTION OF THE p-HYDROXYL GROUP INTO CHROMANS AND COUMARANS'.* LEE IRVIN SMITH, HARVEY H . HOEHN,
AND
HERBERT E. UNGNADE
RECEiVEd March 81, 1939
Previous papers have dealt with the synthesis of tocopherols from phytyl bromide and appropriate hydroquinones,2 the direct introduction of allyl groups into phenols and hydroquinone~~ and with the addition of dienes to phenols and hydroq~inones.~In the case of trimethylhydroquinone, the reaction with dienes and with allylic halides gave good yields of products which were readily purified, but when more than one position of the hydroquinone molecule was vacant, these reactions led to complications, and mixtures were produced with both allylic halides and dienes. This is due to the ease with which the nucleus of the polymethylated hydroquinone is substituted, and it is especially troublesome when the halides are used. Thus when m-xylohydroquinone reacts with phytyl bromide, there is produced not only the tocopherol I, but also the phytyl derivative of this, I1 (R = 3,7,1l-trimethyldodecyl-1).
I., R' = H 11.)R' = CzoH39
I11
With the 0- and p-xylohydroquinones, the complexities are still greater, because in these cases the second phytyl group enters a position adjacent to a :hydroxyl group, and the phytyl derivatives, analogous to 11, may undergo ring closure leading to double chromans, such as 111.
* Presented (in part) at the 96th meeting of the American Chemical Society, Milwaukee, Sept. 5-9, 1938. 1 Paper X: J. ORG.CHEM.,4, 342 (1939). 2 Paper IV: J. ORG.CHEM.,4, 298 (1939). Paper V: J. ORG. CHEM.,4, 305 (1939). Paper VI: J. ORG. CHEM.,4, 311 (1939). 351
352
L. I. SMITH, H. H. HOEHN, AND B. E. UNGNADE
Since pheriols are much less troublesome than hydroquinones as far as these byproducts are concerned, we have explored the possibility of synthesizing p-hydroxychromans and coumarans from phenols by first closing the heterocyclic ring and then, in the final step, introducing the hydroxyl group para to the bridge oxygen atom. For the model experiments, which are reported in this paper, we selected 2,3,5-trimethylphenol,t which mas condensed with isoprene4 to give the chroman IV m.p. 4041" in good yield. For the introduction of the hydroxyl group into position 6 , three methods were investigated. In the first two of these, the aim was the introduction of an amino group, to give VII, either by nitration, or by coupling with a diazonium compound, followed by reduction of the respective intermediates VI and V. It was then planned to convert the aminochroman VI1 to the hydroxychroman VI11 by mild oxidation to the quinone, followed by reduction and r e c y c l i ~ a t i o n . ~I n~ ~the third method, the aim was to introduce the hydroxyl group via the bromo compound IX, either by oxidation of the Grignard reagent produced from IX, or by hydrolysis of the bromo compound with hot alkali under pressure.
VI
VI1
VI11
IX
t
We are greatly indebted t o Dr. E. C. Williams of the Shell Development Company for a most generous supply of this phenol. JOHN, 2. physiol. Chem., 262, 222 (1938). 4 KARRER, ESCHER,FRITZSCHE, RINGIER,AND SALOMON, Helv. Chim. Acta., 21, 939 (1938).
CEf%UISTRY OF VITAMIN E
353
While the chroman IV developed a color with diazotized sulfanilic acid, coupling was extremely slow, and it was not possible to obtain more than traces of the azo compound V under the conditions used. Nitration of the chroman produced in good yield a mono nitro compound having lthe composition of VI, but this nitro compound was extremely inert-so much so that the ordinary qualitative tests for nitrogen failed completely and it was only after nitrogen was determined quantitatively (micro Dumas) that we could be certain that the substance actually was a nitro compound. The substance was recovered unchanged after the action of tin and hydrochloric acid, and also after being subjected to the action of hydrogen (45 Ibs.) in the presence of a platinum catalyst. The nitro compound was attacked by sodium and butanol, but the product was an oil which gave a strong phenol test, but which could not be crystallized. These two routes to VI11 therefore were abandoned temporarily. The route to VI11 via the bromo compound IX was more successful. Bromination of the chroman IV in carbon tetrachloride gave a good yield of IX, and the bromo compound was converted into the Grignard reagent by the method of entrainment. Oxidation of the Grignard reagent by tank oxygen, followed by hydrolysis of the metallic derivative, produced the hydroxychroman VIII, m.p. 94-94.5', although in poor yield. The bomb hydrolysis of the bromochroman I X was not tried, but in view of the results obtained when this method was applied to the analogous bromocoumaran, it is unlikely that the hydroxychroman would have been produced. For the experiments in the coumaran series, the tetramethylcoumaran X was prepared from the phenol by rearranging the allyl ether to the o-allylphenol and cyclizing the latter.3 The coumaran was readily brominated in ca,rbon tetrachloride, giving a good yield of a mono bromo compound XI,' which gave no precipitate with alcoholic silver nitrate and which was inert to further action of bromine. Action of oxygen upon the Grignard reagent obtained from this bromo compound, gave a phenolic compound. Although this product was obtained only in very small amounts, it melted a t 115-118' without recrystallization, and when mixed with the known 2,4,6,7-tetramethyl-5-hydroxycoumaran(m.p. 129-130') it melted a t 120-122'. Hence in the coumaran series also, it is possible to introduce the p-hydroxyl group by this method, although the yields in both series-chromans and coumarans-are very small. When the bromo compound X I was heated to 300' in a bomb with 10% sodium hydroxide, the product was a solid which melted at 87-88', and 7 ADAMSAND RINDFUSZ, J. Am. Chem. Soc., 41, 648 (1919), have been, so far, the only ones to investigate the action of bromine on coumarans. They obtained 5-bromo-2-methylcoumaranby bromination of 2-methylcoumaran.
354
L. 1. SMITH,
X
a.
H. BOEBN, AND IEf.
XI
a.
UNGNABg
XI1
after crystallization, at 93-94’. The substance was strongly phenolic (Folin test), and was soluble in 575 sodium hydroxide and in dilute sodium carbonate, but not in bicarbonate. Since the hydroxycoumaran XI1 melts at 129-130’, it was at first thought that the product was more likely trimethylallylhydroquinone, but it could not be cyclized by heating it with pyridinium chloride; moreover, the analysis did not check for any simple substance containing two oxygen atoms. When brominated, the substance formed a solid dibromo compound melting a t 147-148’. The melting points and analyses of the substance and its dibromo derivative* were sufficient to identify the hydrolysis product of the bromocoumaran XI as 2 ,3 ,5-trimethylphenol. Hence, the action of alkali at high temperatures upon the bromocoumaran X I consists in elimination of the heterocyclic ring completely, and replacement of the bromine by hydrogen. This effect of “positive” halogen has been known to us for some timeg in connection with the dibromotetramethylbenzenes. Thus, dibromodurene under high-temperature alkaline hydrolysis gives, not durohydroquinone, but durenol. In a recent study, Suter and Smithlo have observed the same sort of reaction when certain dibromobiphenyls were heated with potassium benzoate in boiling benzoic acid, the products being the benzoates of monohydroxylated biphenyls. The simultaneous cleavage of a side-chain at the nucleus, however, has been observed by John, Dietzel, and Gunther” in connection with the tocopherols, which give polymethylated phenols, and certain mono ethers of hydroduroquinone, which give, along with durenol, some 2,3,5-trimethylphenol. But in these cases the reagent was hydriodic acid, and not alkali. We have under way further investigation of this interesting reaction, a report of which will be made in a later paper. 8 ( a ) EDLER, B e y . , 18, 630 (1885), and (b) JACOBSEN,ibid., 19, 1220 (1886), both give the m.p. of 4,6-dibromo-2,3,5-trimethylphenol as 152’. 9 Unpublished work by Mr. A. C. Key1 of this Laboratory. lo SUTER AND SMITH, J . Am. Chem. Soc., 61, 166 (1939); other references to this effect are also given. 1* JOHN, DIETZEL, AND GUNTHER, 2.physiol. Chem., 262, 208 (1938).
CHEMISTRY OF VITAMIN E
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EXPERIMENTAL
Coupling reaction of the chroman ZV.-In this experiment, the procedure of Meyer and Lenhardt12 for coupling of resorcinol dimethyl ether was followed, because the ehroman is, in effect, a phenol ether. Sulfanilic acid dihydrate (5.25 g.) was diazotized in the usual manner and the white precipitate of the diazonium compound was collected by filtration and a t once dissolved in cold acetic acid (60 cc.). The solution was added to a cold solution of the chroman IV (5.1 9.) and sodium acetate (2.05 9.) in acetic acid (60 cc.). The reaction mixture was kept in the ice box for one week, with occasional shaking. A bright-red color developed, and a small amount of pink solid was deposited. This was found to consist largely of unchanged diazonium compound together with traces of a red substance, presumed to be the azo compound. K O further precipitate was deposited even on long standing, or when the solution was diluted with water. 8,2,5,7,8-Pentamethyl-6-nitrochroman (VI).-A solution of pentamethyl chroman IV (1 $ 5 . ) in acetic acid (5 cc.) was cooled to 0" and nitric acid (0.3 cc.) in acetic acid (5 cc.) was added. After standing for one hour, the reaction mixture was diluted with a a t e r and extracted with ether. The ether was removed and replaced by alcohol. On cooling, the nitrochroman crystallized in light-yellow plates which after crystallization from ethanol melted a t 125-125.5'; yield 0.7 g. A n d . Calc'd for ClrHlpNOa: C, 67.43; H, 7.69; N, 5.62. Found: C, 67.12; H, 7.71; N, 6.38. The substance gave a negative phenol test (Folin) and was insoluble in aqueous sodium carbonate, sodium hydroxide (even on boiling), and in Claisen's alkali. It gave an olive-brown color with cold sulfuric acid, and no reaction with bromine in carbon tetrachloride. Reduction experiments (A).-The substance (100 mg.) was dissolved in ethanol (25 cc.), platinum oxide catalyst (.01 g.) was added, and the mixture was shaken under hydrogen a t 45 lbs. pressure. The nitro compound (m.p. 124-125') was recovered unchanged. ( B ) The nitro compound (100 mg.) was boiled with excess tin and cmcentrated hydrochloric acid for 2 hours. Ether extraction of the cooled mixture removed unchanged material, m.p., 123.5-125'. (C) The nitro compound (100 nig.) was dissolved in butanol (50 cc.), sodium (0.7 g.) was added, and the solution was refluxed for 2 hours. Some of the butanol was removed by distillation, water was added and the mixture was acidified with 30y0 sulfuric acid and extracted with ether. The ether solution was steam distilled to remove the ether and the last traces of butanol. The residue was a strongly phenolic oil which could not be crystallized. .2,8,5,7,8-Pentamethyl-6-bromochroman (IX).-Bromine (2 cc.) in carbon tetrachloride (10 cc.) was added to a solution of the chroman IV (5 9.) in the same solvent (10 cc.). The reaction mixture was allowed to stand until no more hydrobromic acid was evolved (20-30 minutes). Excess bromine was removed by shaking with a little aqueous sodium bisulfite, ether was added and the ether-carbon tetrachloride layer was removed. The solvents were pumped off, and the solid residue was crystallized from dilute alcohol several times. It weighed 6.2 g., and melted at 69-70'. Anal. Calc'd for ClrH190Br:C, 59.35; H, 6.77. Found: C, 59.34; H, 6.76. l2
MEYERAKD LEXHARDT, Ann., 398, 74 (1913).
356
L. I. SMITH, H. H. HOEHN, AND H. E. UNGNADE
8,8, 6,7,8-Pentamethyl-6-hydrosychroman (VIII).-The bromochroman (4 g.) and ethyl bromide (1.54 9.) in ether (12 cc.) were dropped slowly (1 hour) onto magnesium (688 mg.). After disappearance of any further visible reaction, the mixture was refluxed for a n hour. Oxygen from a tank was then bubbled through for 2 hours. Iced hydrochloric acid was added, and the mixture was thoroughly extracted with ether. The ether was removed under vacuum, but the residual oil could not be crystallized. It was taken up in petroleum ether and thoroughly extracted with Claisen's alkali. The alkaline extract was diluted with water, acidified, and extracted with ether. Removal of the ether left a n oil which deposited crystals when its solution in dilute alcohol was cooled. The solid was removed and crystallized from petroleum ether. It formed large white crystals which weighed 250 mg. and which melted at 94-94.5' alone and when mixed with a n authentic specimen. 2,4,6,7-Tetrarnethyl-6-bromocoumaran (XI).-The coumaran X (5 9.) in carbon tetrachloride (10 cc.) was brominated by addition of bromine (1.55 cc.) in the same solvent (10 cc.). The solution was washed with bisulfite, ether was added, and the organic layer was removed. The solvents were evaporated under reduced pressure, and the residue, a white solid, was crystallized from alcohol. The product weighed 4.9 g., and melted at 76-77'. Anal. Calc'd for ClzHllOBr: C, 56.46; H, 5.93. Found: C, 55.93, 55.92; H, 5.90, 5.89. The substance gave a strong positive test for halogen (Beilstein), was inert toward bromine, and gave no precipitate with alcoholic silver nitrate. 2,4,6,7-Tetramethyl-6-hydroxycoumaran(XII).-A Grignard reagent was prepared from magnesium (0.3 g.), ethyl bromide (1 g.) and the bromocoumaran (0.7 9.) in ether (25 cc.). The ether was replaced by benzene and the mixture was refluxed for an hour. Then oxygen was passed through for a n hour. The product, isolated in the usual way, was a semi-solid from which some starting material was isolated. The remainder was extracted with Claisen's alkali and the alkaline extracts were manipulated as described under the preparation of the chroman VIII. The product, only a few milligrams, was a white solid which melted a t 115-118'. When mixed with an authentic sample of X I 1 (m.p. 129-30'), i t melted a t 120-122'. The substance gave a positive phenol test. Bomb hydrolysis of the bromo coumaran.-The bromo compound XI, (4.3 g.) was suspended in sodium hydroxide (5 g.) and water (40 cc.) in a small hydrogenation bomb. Cuprous oxide (0.75 g.) and copper powder (3 g.) were added, the bomb was closed and heated to 200" for 5 hours. At this temperature there was no reaction, and the bromo compound was recovered unchanged. The experiment (4.8 g. of bromo compound) was repeated a t a higher temperature (300') for 5 hours. The copper and copper oxide were removed by filtration, and the filtrate was extracted with ether. The alkaline aqueous layer was acidified and again extracted with ether. Removal of the ether left an oil (ca. 2.5 g.) which after much manipulation, involving great losses, was finally separated from the t a r by distillation in a sausage flask under reduced pressure. The nearly colorless distillate (0.8 g.) solidified on cooling (m.p. 87-88'). The solid was crystallized from petroleum ether, then from ethanol after the solution was decolorized with charcoal, and finally from petroleum ether. It then melted a t 93-94'. When mixed with known 2,3,5-trimethylphenol (m.p., 95"), It was insoluble in aqueous sodium bicarbonate, the substance melted a t 93.5-94.5'. but soluble in carbonate and in sodium hydroxide (5%). The phenol test was strongly positive; the iodoform test was negative, and silver nitrate in methanol was reduced only very slovvly. The product was halogenfree. Heated with pyridin-
CHEMISTRY OF VITAMIN E
357
ium chloride (1 g.) for 1 hour a t 210°, the substance (0.359 . ) was recovered practically unchanged (m.p., 86-88’). Anal. Calc’d for COHIZO:C, 79.41; H, 8.82. Found: C, 79.30; H, 9.27. The substance was further identified as 2,3,5-trimethylphenol by preparation of the dibromo derivative. After crystallization from ethanol, this melted a t 147148 (literature$, m.p. 152”). A n d . Calc’d for CgHloBrzO: C, 36.93; H, 3.40. Found: C, 36.90; H, 3.40. SUMMARY
1. The introduction of a hydroxyl group para to the bridge oxygen in 2,2 5,7 ,8-pentamethylchroman and in 2 4 6 7-tetramethylcoumaran has been accomplished by brominating these substances and oxidizing the Grignard reagents formed from the resulting para bromo compounds. 2. Diazotized sulfanilic acid coupled extremely slowly with the chroman under the conditions used. 3. The chroman formed a very stable and inert mono nitro compound, which could not be reduced, by any of the methods tried. 4. The bromocoumaran is cleaved by alkali at 300’ to give 2,3,5-trimethylphenol, an interesting example of the “positive” bromine effect, and a reaction which parallels the reaction of hot hydriodic acid upon the tocopherols.
