[CONTRIBUTIONFROM THI SCHOOL OF CHEMISTRY OF THE UNIVERSITY OF MINNESOTA]
THE CHEMISTRY O F VITAMIN E. XXVI.' 5-HYDROXY-4,6,7TRIMETHYLCOUMARAN, 5-HYDROXY-2,2,4,6,7-PENTAMETHYLCOUMARAN, 6-HYDROXY-2,2,5-TRIMETHYL-7,8BENZOCHROMAN, AND 5-HYDROXY-2,4-DIMETHYL-6,7BENZOCOUMARON. LEE IRVIN SMITH, STANLEY WAWZONEK, AND HENRY C. MILLER Received November 16, 1940
In connection with an investigation of the behavior at the dropping mercury electrode of substances related in structure to the tocopherols, a wide variety of p-hydroxy-coumarans and -chromans was needed. Several of these substances, obtained in connection with previous work in the field, were already available, but these did not include enough different types for a general study of the kind contemplated. In particular, the only p-hydroxycoumarans available were those which carried only one substituent in the 2-position, and for purposes of comparison it was desired to include in the study coumarans of this type unsubstituted in the 2-position, as well as those carrying two substituents in this position. This paper reports the synthesis of one p-hydroxycoumaran, 5-hydroxy-4,6,7trimethylcoumaran (VI), unsubstituted in the 2-position, and another, 5-hydroxy-2 ,2,4,6,7-pentamethylcoumaran (XIII), carrying two substituents in the 2-position, as well as a new benzochroman, 6-hydroxy2,2,5-trimethy1-7,8-benzochroman(XX) and a benzocoumaron, 5-hydroxy-2,4-dimethyl-6,7-benzocoumaron(XXI). The syntheses were planned with a view to using readily available starting materials, and known reaction steps, so that in the final cyclization there could be little doubt as to the size of the resulting heterocyclic ring. Most of the reactions proceeded smoothly and gave good yields, and the methods used appear to be of quite general applicability. 5-Hydroxy-4,6,7-trimethylcoumaran(VI) was prepared by demethylation and cyclization of the carbinol V, which in turn was obtained by two methods, as shown in the chart. In one of these methods the carbinol V was obtained by action of nitrous acid upon the corresponding amine (IV) ; in this case, although a small amount of the pure carbinol was obtained, the entire crude product of the reaction-a yellow oil-was cyclized to the coumaran VI. In the second method, the carbinol V was obtained 1
Paper XXV, Chem. Rev., 27, 287 (1940); XXIV, J . Am. Chem. Soc., 62, 1869
(1940).
229
230
SMITH, WAWZONEK, AND MILLER
by action of the Grignard reagent X upon ethylene oxide, and from the product of this reaction a good yield of the pure carbinol was easily obtained.
0 CH3 H3C f I C H 2 CH2NH2 --+
Ha C f F 2 CN pt
*
HsC\,CH, 0 CH3 I H3C ( j i ; H3 C\
H2
H 3 C x CH3 OCH3 I11
OCH3 I1
CH3 0
-
CH2NHz HC1
__f
H3C { E 3 H3
OCH3
CH2 OH
Cb
OCH3 V
IV
'\ \ OCHa
VI
\\
OCH3
-+ H 3 C f k H 3 __+ H 3 C r x H 3 -+ H3
c\
0 VI1
H3
OH
VI11
c\
0 CH3
OCH3
IX
X
5-Hydroxy-2,2,4,6,7-pentamethylcoumaran(XIII) was synthesized from ethyl 2,5-dimethoxy-3,4,6-trimethylphenylacetate (XII) (1) via the carbinol XIIa. The carbinol was obtained as an oil from which no solid could be crystallized. Consequently the crude product was demethylated and cyclized directly to the coumaran XIII.
H 3C\,CH3 H3 C{?~C0OR
-
0 CH3 XI, R = H XII, R = CzHs
C(OH)(C&)z 0 CH3 XIIa
~~
H, C
Ho\
r
y
CH3 XI11
HC H33
I-
231
SYNTHESIS OF COUMARANS AND CHROMANS
6-Hydroxy-2,2 5-trimethyl-7 ,8-benzochroman (XX) was synthesized from 2-methyl-1 ,4-naphthohydroquinone (XIV) by a series of reactions similar to that employed in previous work (2) for the synthesis of 6-hydroxy-2,2,5,7,8-pentamethylchroman.The steps in the synthesis are shown below.
XIV, R = H XV, R = CH3
XVI
XVII
xx 5-Hydroxy-2,4-dimethyl-6,7-benzocoumaron( X I ) was synthesized from %methyl-1 ,4-naphthoquinone and acetoacetic ester, using a variant of the method of Smith and MacMullen (1) for the preparation of p-hydroxycoumarons. 0
CH,
4
[$CH3 0
c
"[PCH3
XXI
232
SMITH, WAWZONEK, AND MILLER
EXPERIMENTAL^ p-Acetaminoethylpseudocumohydroquinone dimethyl ether (11). 3,6-Dimethoxy2,4,5-trimethylbenzylcyanide(1) (9.7g.) was dissolved in acetic anhydride (90 cc.) and the solution was shaken with platinum oxide catalyst (0.25g.) under forty pounds (2.7atoms.) of hydrogen for twenty-four hours. Acetic acid was added to dissolve the solid formed in the reaction. The catalyst was filtered off and the filtrate was poured into water. The white precipitate (9.1g . , m.p. 160")was removed and crystallized from benzene. It formed silky needles which melted a t 160-161'. Anal. Calc'd for C I ~ H Z ~ NC,O 67.93; ~: H, 8.68. Found : C, 67.57;H,8.89. B-Aminoethylpseudocumohydroquinone dimethyl ether (111). B-hcetaminoethylpseudocumohydroquinone dimethyl ether (11) (9.19.) was refluxed with potassium hydroxide (25.0g.) in methanol (125 cc.) for nine hours. Water (25 cc.) and potassium hydroxide (25 g.) were added and the solution was refluxed for three hours longer. After standing overnight the mixture was poured into water and acidified. Extraction with ether removed 1.53g. of the starting material (11). Addition of alkali followed by extraction with ether gave a light yellow oil (5.45g.) which was distilled. The amine was obtained as a colorless liquid which boiled a t 170-175"under 20 mm. Anal. Calc'd for C1JH21x02: C, 69.95;H, 9.42. Found: C, 69.17;H, 9.50. Hydrochloride (IV). Passing dry hydrogen chloride through a carbon tetrachloride solution of the above amine (111) precipitated a white hydrochloride, which after one crystallization from a mixture of absolute ethanol and absolute ether melted a t 263-265" (decomp.). Anal. Calc'd for ClsH22ClN02: C, 60.11;H, 8.48. Found: C, 60.24;H, 8.65. 6-Hydroxy-4,6,7-trimethylcoumaran (VI). To the above amine hydrochloride (IV) (2.65g.) in 50 cc. of water was added sodium nitrite (1.50g.), and the resulting solution was heated a t 100' until all gas evolution had ceased. The cooled mixture was extracted with ether. Removal of the solvent gave an oily product (2.47 g.) from which only a small amount of the carbinol (V), m.p. 65-70', could be isolated. When mixed with the carbinol (m.p. 69.5-72') prepared by the Grignard reaction (see below), the substance melted a t 65-70'. The oil was not purified further but was dissolved in acetic acid (10 cc.) containing hydrobromic acid (3 cc., 40%) and the solution was refluxed for four hours. Water was added and the mixture was steam distilled. From the distillate was obtained coumaran VI (0.55 g.), which after one crystallization from petroleum ether (b.p. 60-68") melted at 144-146",alone or when mixed with the coumaran prepared from the pure carbinol. Bromopseudocumoquinone (VII). To a solution of pseudocumoquinone (5.0 g.) in ether (15 cc.) was added slowly liquid bromine (1.8 cc.). Removal of the solvent followed by crystallization of the residue from ethanol gave the bromoquinone (6.07 g.) in bright yellow needles melting at 77-80". Smith and Johnson (3) report 79-80' as the melting point. Bromopseudocumohydroquinone (VIII). A solution of pseudocumohydroquinone (24 g.) in ether (600 cc.) was placed in a three-necked flask equipped with a stirrer and condenser. Bromine (9 cc.) was slowly added from a dropping-funnel. After the reaction was complete the solvent was removed under a vacuum. The black crystals were dissolved in ethanol (200 cc.), sodium hydrosulfite (10 9.) was added, a
Microanalyses by E. E. Renfrew.
SYNTHESIS OF COUMARANS AND CHROMANS
233
and the mixture was refluxed for forty-five minutes and filtered while hot. The cooled filtrate deposited 27 g. of the hydroquinone, which melted a t 172-173" (decamp.). A further 6 g. could be obtained by evaporating the filtrate to 100 cc. Smith and Johnson (3),by reducing bromopseudocumoquinone with stannous chloride and hydrochloric acid, obtained a product which melted at 185" (decomp.). However, the hydroquinone prepared as described above was sufficiently pure for use in the next step. Bromopseudocumohydroquinone dimethyl ether (IX). This substance was prepared from the hydroquinone using the procedure of Smith and Johnson (3). 3,6-Dimethoxy-d, 4,b-trimethylphenylmagnesiumbromide (X). T o 2.0 g. of magnesium was slowly added (45 minutes) a solution of bromopseudocumohydroquinone dimethyl ether (IX) (10 g.) and ethyl bromide (3.0 cc.) in absolute ether (40 cc.). The mixture was refluxed throughout the course of the reaction. ,!3-Hydrozyethylpseudoeumohydroquinone dimethyl ether (V). The above Grignard reagent was cooled (salt-ice mixture and flask fitted with a reflux condenser containing water below 10") and to i t was added dry ethylene oxide (15g.) over a period of twenty minutes. The cooling bath was removed and the mixture was allowed t o reflux spontaneously for forty-five minutes, then heat was applied until the mixture set to a thick transparent gel. Iced sulfuric acid (25%) was added and unchanged bromopseudocumohydroquinone dimethyl ether (1.25g.) was removed by steam distillation. The residue was extracted with ether and the solvent was evaporated. The residual yellow oil (5.276.) crystallized when its solution in petroleum ether was cooled. The carbinol weighed 2.70 g. and melted a t 69.5-72". After several crystallizations from a mixture of ether and petroleum ether i t melted at 73.5-75'. Anal. Calc'd for C18H2gOS: C, 69.64;H, 8.93. Found : C, 69.86;H, 8.51. li-Hydroxy-Q,6,7-trimethylcoumaran (VI). 6-Hydroxyethylpseudocumohydroquinone dimethyl ether (V) (1.0g.) was dissolved in acetic acid (10 cc.) containing hydrobromic acid (3.25 cc., 40%) and the solution was refluxed for three hours. Water was added and the coumaran was removed by steam distillation. The product weighed 0.5 g. and melted a t 144-146'. After crystallization from petroleum ether (b.p. 60-68") i t formed white needles which melted at 145-146'. Anal. Calc'd for CllHl4Oz: C, 74.16;H, 7.86. Found: C, 74.42;H, 8.26. Ethyl 9,6-dimethoxy-2,4,b-trimethylphenylacetate(XII). 3,6-Dimethyoxy-2,4,5trimethylphenylacetic acid (1) (XI) (1.74g.) was dissolved in absolute ethanol (50 cc.) containing concentrated sulfuric acid (1 cc.). The solution was refluxed for eight hours, then was poured into water and the product filtered off. The ester was purified by steam distillation. It weighed 1.2 g. and melted a t 79-80'. Anal. Calc'd for ClsHzz04:C, 67.67;H, 8.27. Found : C, 67.69;H, 8.28. li-Hydroxy-Z,Z,4,6, '7-pentamethylcoumaran (XIII). A solution of ethyl 3,6dimethoxy-2,4,5-trimethylphenylacetate (XII) (1.2 9.) in absolute ether (10 cc.) and dry benzene (20 cc.) was refluxed with excess methylmagnesium iodide (0.02 moles in 40 cc. of ether) for ten hours. After decomposition in the usual way, removal of the ether left an oil which could not be crystallized. The oil was dissolved in acetic acid (10 cc.) and hydrobromic acid (10 cc., 40%) and the solution was refluxed for three hours. Addition of water precipitated the coumaran as a white solid (0.75 g.), which after crystallization from petroleum ether (b.p. 60-68") melted at 125-126.5'. Anal. Calc'd for ClsHlsOz: C, 75.72;H, 8.74. Found: C, 75.57;H, 8.63.
234
SMITH, WAWZONEK, AND MILLER
1,4-Dimethoxy-B-methylnaphthalene(XV). The following directions are amodification of those given by Ansbacher, Fernhola, and Dolliver (4). In a flask fitted with reflux condenser and stirrer were placed 1,4-dihydroxy-2-methylnaphthalene(5) (8.7 g.), absolute methanol (50 cc.), and dimethyl sulfate (63 g.). The mixture was heated to the boiling point, heating was then discontinued and a hot solution of potassium hydroxide (60 9.) in methanol (300 cc.) was added in portions as rapidly as possible without causing the material to be thrown out through the condenser. After the addition of the alkali was complete the mixture was boiled for one-half hour and then steam distilled. Ether extraction of the distillate gave a n oil which solidified upon cooling. After crystallization from petroleum ether (b.p. 60-68") the product formed a white solid (6.38 g.) which melted a t 35-36". Ansbacher, Fernholz, and Dolliver report the melting point 48-49' for a product that had been distilled before crystallization. 1,4-Dimethoxy-~-methyl-J-chloromethylnaphthalene (XVI). I , 4-Dimethoxy-2methylnaphthalene (XV) (32 g.), concentrated hydrochloric acid (120 g.), and formalin (24 g.) were stirred a t 70" for seven hours while a stream of dry hydrogen chloride was passed through the mixture. The red product was poured into water and extracted with ether. Removal of the solvent left an oil which was distilled (b.p. 222' at 32 mm.). After two crystallizations from petroleum ether (b.p. 60-68") and one vacuum sublimation a t 28 mm., the compound melted a t 71-72". Anal. Calc'd for C14HI&1O2: C, 67.07; H, 5.99. Found: C, 67.02; H, 6.16. Ethyl ~-(1,~-dimethoxy-B-methylnaphthyl)-a-acetyZpropionate (XVII). T o a stirred solution of sodium acetoacetic ester prepared from acetoacetic ester (9.75 9.) and sodium (1.725 g.) in absolute ethanol (100 cc.) was added a solution of 1,4dimethoxy-2-methyl-3-chloromethylnaphthalene(18.8 9.) in absolute ethanol (100 cc.) and absolute ether (35 cc.). The resulting solution was stirred for three hours, refluxed for one hour, and then allowed to stand overnight. Acidification followed by removal of the solvent under a vacuum gave the product as a solid. A portion of this solid was crystallized twice from petroleum ether (b.p. 60-68'). It then melted at 75-76.5". Anal. Calc'd for CZ0HzaO6: C, 69.77; H, 6.98. Found : C, 69.66; H, 7.23. 1-(1,4-Dimethoxy-B-methyl-tnaphthyl)butanone-!l (XVIII). The moist solid (XVII) obtained in the above experiment was stirred with aqueous sodium hydroxide (100 cc., 7%) for four hours and then allowed to stand overnight. After the addition of ethanol (50 cc.) the solution was refluxed for one hour and filtered. T h e cooled filtrate was made acid t o Congo red with dilute sulfuric acid. The precipitate was removed and crystallized from ethanol. The product weighed 18.0 g., and melted at 85-87". A second crystallization from ethanol gave white prisms melting at 87.5-88'. Anal. Calc'd for C1,HloOs: C, 75.00; H, 7.35. Found : C, 74.60; H, 7.70. 1-(l,~-Dimethoxy-~-methyl-~-naphthyl)-d-methyll-~ (XIX). To a solution of methylmagnesium iodide (0.075 moles) in absolute ether (60 cc.) was added a solution of 1-(1,4-dimethoxy-2-methyl-3-naphthyl)butanone-3 (XVIII) (6.8 9.) in ether (70 cc.) and the mixture was refluxed for three hours. Decomposition with iced ammonium chloride solution followed by extraction with ether gave a white solid (6.6 9.) which after two crystallizations from petroleum ether (b.p. 60-68")melted at 73-75'. Anal. Calc'd for CteH2rOs: C, 75.00; H, 8.33. Found : C, 74.71; H, 8.66.
SYNTHESIS OF COUMARANS AND CHROMANS
235
6-Hydroxy-2,2,6-trimethyl-7,8-benzochroman (XX). 1-(1,4-Dimethoxy-2-methyl3-naphthyl)-3-methylbutanol-3(XIX)(6.0g.) was dissolved in acetic acid (50 cc.) containing hydrobromic acid (15 cc., 40%). The mixture was refluxed for four hours under nitrogen. The resulting solution was poured into water and extracted with ether. Removal of the ether gave a red oil which was chromatographed on aluminum oxide into two fractions. The first of these, a pale yellow oil, insoluble in Claisen's alkali, was probably the methyl ether of the chroman. The second fraction was a brownish oil (1.579.) which solidified upon the addition of petroleum ether (b.p. 60-68'). After three crystallizations from petroleum ether (b.p. 60-68") and one vacuum sublimation a t 22 mm. the chroman melted a t 117-118'. Anal. Calc'd for ClsHlsOz: C, 79.34;H, 7.44. Found: C, 79.68;H, 7.66. 6-Hydroxy-2,~-dimethyl-6,7-benzocoumaron (XXI). A solution of 2-methyl-l,4naphthoquinone (8 9.) in a mixture of absolute ethanol (60 cc.), benzene (20 cc.), and dry ether (20 cc.) was dropped slowly and with stirring into a solution of sodium acetoacetic ester [prepared by adding acetoacetic ester (7.5 cc.) in dry alcohol (15 cc.) to a solution of sodium (1.15 9.) in dry ethanol (50cc.)]. After standing at room temperature for sixteen hours, the resulting purple solution was poured into iced hydrochloric acid and extracted with ether. Removal of the ether left a solid from which the coumaron was separated by steam distillation. Extraction of the distillate with ether gave 1.05 g. of coumaron melting at 115";after two crystallizations from aqueous ethanol, the substance melted a t 118-119'. The residue from the steam distillation was a dark gummy material which was not investigated further. Anal. Calc'd for CllH1202: C, 79.25;H, 5.66. Found: C, 78.62;H, 6.35. SUMMARY
1. Four methods, of general applicability, have been outlined for the synthesis of p-hydroxy-chromans and -coumarans. In these syntheses, the cyclization was the final step, and the substances cyclized were such that there could be little doubt concerning the size of the heterocyclic ring formed. By these methods the following new compounds were prepared : 5-hydroxy-4 ,6,7-trimethylcoumaran, 5-hydroxy-2 ,2 ,4 6,7-pentamethylcoumaran, 6-hydroxy-2 ,2,5-trimethy1-7 ,8-benzochroman1 and 5-hydroxy-2,4-dimethyl-67-benzocoumaron. MINNEAPOLIS, MINN. REFERENCES (1) SMITHAND MACMULLEN, J . Am. Chem. SOC.,68,629 (1936). (2) SMITH, UNGNADE,OPIE, PRICHARD, CARLIN,AND KAISER, J . Org. Chem., 4, 323 (1939). (3) SMITHAND JOHNSON, J . Am. Chem. Soc., 69,673 (1937). (4) ANSBACHER, FERNHOLZ, AND DOLLIVER, J . Am. Chem. SOC.,62, 155 (1940). CAMPBELL, FRY,AND GATES,J . Am. Chem. SOC., 61,3216 (1939). (5) FIESER,
