[CONTRIBUTION FROM
THE N
O YCHBYICAL ~ LABORATORY, UNIVERSITY OF ILLINOIS ]
THE ACTION OF ALKYLMAGNESIUM HALIDES ON COUMARIN AND RELATED COMPOUNDS. SYNTHESIS O F 2,2-DIALKYL-l, 2-BENZOPYRANS R. L. SHRINER
AND
A. G . SHARP
Received July 8, 1950
Insecticides such as deguelin (I),l tephrosin, and toxicarol are characterized by the presence of a dihydrobenzopyran ring system (AB) and a dimethylbenzopyran system (DE) as illustrated by formula I. The present’study was undertaken to determine whether portions of this moleCHZO
I
I
I1
cule would possess insecticidal activity, and describes the preparation of a series of 2,2-dialkyl-l, 2-benzopyrans (11). The method used for the synthesis of these compounds is that of Houbeq2 who prepared the first two members of the series by treating coumarin with an excess of the alkylmagnesium halide. Using this same method the series of 2,2dialkyl-1 ,a-benzopyrans (11), in which the alkyl group ranged from methyl to n-heptyl, was prepared. It was found that the yields increased as the size of the alkyl groups increased, ranging from 59 per cent. for the dimethyl derivative to 91 per cent. for the di-n-heptyl.* No proof of the structure of these compounds was given by Houben. Since the Grignard reagent may react with the conjugated system in , ~was, coumarin to yield products formed by either 1,2 or 1 , 4 a d d i t i ~ n it therefore, necessary to establish the structure of the products of this reaction. The physical properties of the compounds were found to be CLARK,J . Am. Chem. Soc., 64, 3000 (1932). HOWEN,Ber., 37, 489 (1904). * The insecticidal activity of these compounds will be reported separately. a HEILBRON AND HILL,J . Chenz. Soc., 1927, 2005. 575 1
576
R. L. SHRINER AND A. 0. SHARP
gradational throughout the series, and all the molecular refractivities indicated that the double bond of the pyran ring was conjugated with the benzene ring (see Table I). The formation of salicylaldehyde by ozonolysis also shows that the double bond was in the 3,4 position, and hence the two alkyl groups in the 2,2 position. Catalytic reduction produced 2,2-dimethylchroman, whose physical properties agreed with those observed by Clai~en.~ The mechanism advanced for this reaction by Houben2 postulated that the lactone ring of coumarin (111) was first broken by the Grignard reagent to give IV. Addition of the reagent to the carbonyl group was followed by ring closure. If this is the correct mechanism, addition of methylmagnesium iodide either to coumarin or to o-hydroxybenzalacetoneshould give the same product, as is shown by the reactions in Series A.
SERIESA 0
V
I1
In order to test this concept, o-hydroxybenzalacetone (V) was treated with methylmagnesium iodide. Decomposition of the reaction mixture yielded 4-(o-hydroxyphenyl)-2-pentanone (VI) (reactions in Series B) , which was characterized as the semicarbazone. When this ketone was heated to its melting point, loss of water occurred, and ring closure took place, forming 2,4-dimethyl-1 ,a-benzopyran (X). The structure of X was shown by the fact that ozonolysis produced o-hydroxyacetophenone. 4
CLAISEN,Ber., 64, 200 (1921).
577
ACTION OF ALKYLMAGNESIUM HALIDES ON COUMARIN
SERIESB
V
VI1
CH,
IX
VI11
CH8
VI
I
CHs
X
The pyran (X) may be formed by hydrolysis of the Grignard adduct to VII, dehydration to VIII, which shifts to its resonance isomer IX, and the latter forms the pyran (X) with the double bond conjugated with the ring. It is evident that coumarin and o-hydroxybenzalacetone react with the alkylmagnesium halides in different fashions, and that the mechanism for the reaction suggested by Houben (Series A) is not correct. Since coumarin is the lactone of cis-o-hydroxycinnamic acid, it was of interest to study the behavior of trans-o-hydroxycinnamic with methylmagnesium iodide. It was found that this reaction produced o-hydroxybenzalacetone, which was identical with the compound obtained by the
578
R. L. SHRINER AND A. G. SHARP
condensation of salicylaldehyde with acetone. The o-hydroxybenzalacetone used in the above experiments was therefore the trans form. The cis form of this ketone has not been prepared. It is evident that stereochemical considerations play a part in determining the mode of action of the Grignard reagent on conjugated systems. Lowenbein6 suggested that the addition of the Grignard reagent to coumarin takes place with no rupture of the lactone ring. Heilbron and Hill4 proposed the mechanism that addition to the carbonyl took place, followed by rupture of the lactone ring. A coumarin with no substituent in the 4 position would then undergo 1 , 4 addition. That this is not the case with n-alkylmagnesium halides is evident from the fact that addition of coumarin to an excess of these aliphatic Grignard reagents gave no 1 , 4 addition product. Benzopyrrylium derivatives have been synthesized from coumarin by Decker and Fellenberg.‘j The Grignard reagent was added to the coumarin in molar amounts. This gave a yellowish precipitate, which was converted to the pyrrylium salt by hydrolysis with concentrated acid. That an oxonium type’ of intermediate is present in the synthesis of 2, a-dialkyl-1 ,2-benzopyrans was indicated by the formation of a very transitory yellowish precipitate when coumarin was added to an excess of the Grignard reagent. Also, addition of the Grignard reagent to coumarin in molar quantities gave a yellowish pasty precipitate. Hydrolysis of this product by dilute ammonium chloride solution regenerated coumarin. Hence, the initial reaction between coumarin and alkylmagnesium chloride probably involves the formation of a coordination compound involving the carbonyl group and the magnesium (XI in Series C). An a,y shift8n9 of the alkyl group in XI would lead to XII, which upon treatment with strong mineral acids would produce the pyrrylium salts (XIII) found by Decker and Fellenberg.6 Further action of the second mole of the Grignard reagent would produce the 2,2-dialkyl-l ,2-benaopyran by double decomposition. This mechanism, which does not involve the opening of the lactone ring and which is similar to that suggested by Johnsong for the normal reaction of the Grignard reagent with a ketone, satisfactorily explains the experimental observations. Since deguelin and similar compounds cause paralysis of the respiratory system of fish, some preliminary tests were carried out on these 2,26
LOWENBEIN, &bid., 67, 1517 (1924).
7
GILMAN,“Organic Chemistry,” John Wiley and Sons, New York, 1938, Vol. I,
* DECKER AND VON FELLENBERG, Ann., 368, 281 (1907). p. 420.
~GILMAN, ibid., Vol. 11, p. 1649. 0 JOHNSON, J . Am. Chem. Soc., 16, 3029 (1933).
ACTION OF ALKYLMAGNESIUM HALIDES ON COUMARIN
579
SERIESC 0
CH
CH
XI
I
X
c1-
O+
I1
XI11
dialkyl-1 ,%bensopyrans. A saturated aqueous solution of the 2,2dimethyl derivative caused paralysis of a goldfish in three minutes, whereas the 2,4-dimethyl derivative required fifteen minutes to produce the same effect. The 2,2-diethyl-l,2-benzopyranhad only a very slight effect, and the higher members of the series none. It is of interest that the 2,2dimethyl-l,2-benaopyran containing only two of the five rings in deguelin did cause paralysis of the respiratory tract. EXPERIMENTAL
d,d-Dialkyl-1,8-benzopyrans. General procedure.-Into a three-necked 500-cc. flask equipped with a reflux condenser, mercury-sealedstirrer, and a dropping funnel, were placed 0.41 mole of magnesium turnings and 75-100 cc. of anhydrousether. The alkyl halide (0.4 mole), dissolved in 75 cc. of dry ether, was then added dropwise
580
R. L. SHRINER AND A. G . SHARP
over a period of three to five hours and stirred for an additional three hours. I n 200 cc. of dry ether was dissolved 0.125mole of coumarin, and this solution added dropwise t o the Grignard reagent over a period of two to four hours. The mixture was decomposed by approximately 200 cc. of 22% ammonium chloride solution to which 2-5 cc. of concentrated hydrochloric acid had been added. The ether layer was separated, and the aqueous solution was extracted once with 50 cc. of ether. The combined ether extracts were dried with calcium chloride, and the ether was
PROPERTIES OF
TABLE I 2,S-DIALKYL-I ,2-BENZOPYRANS(1 I
ALKYL QBOUP
Methyl*.. . . . . . . . Ethyl*.. . . . . . . . . n-Propyl . . . . . . . . n-Butyl . . . . . . . . . %Amyl. . . . . . . . . n-Hexyl . . . . . . . . . n-Heptyl ........
YIELD,
MD'
9i
B.P.
59.0 64.0 68.0 70.0 77.3 83.0 91.5
79-80"/2.5mm. 99-100/2.8mm. 118-120/2.8mm. 13&140/2.8 mm. 156-158/3 mm. 174-176/3 mm. 192-193/3 mm.
Calo'd Found -___
1.0163 1.0049 0.9773 ,9656 .9487 .9351 ,9233
1.5490 49.8 50.1 1.5428 59.0 59.0 1.5320 68.3 68.6 1.5257 77.5 77.5 1.5184 86.8 87.2 1.5136 96.0 96.5 1.5095 105.2 105.2
*Note: The values used to calculate M D were C = 2.42;H = 1-10; 0 (from chromone) = 1.83;carbon double bond = 1.75;conjugation (from cis-isoeugenol) =
1.15. TABLE I1
ANALYSESOF 2,B-DIALKYL-I ,2-BENZOPYRANB ANALYEIS, ALKYL QBOUP
xolh POBYUW
Calc'd
I
70 Found
C C H ~~- _ _ _H
n-Propyl . . . . . . . . . . . . . n-Butyl.. . , : . . . . . . . . . n-Amyl . . . . . . . . . . . . . . . n-Hexyl . . . . . . . . . . . . . . n-Heptyl . . . . . . . . . . . . .
83.34 83.61 83.83 84.01 84.15
9.25 9.83 10.28 10.66 10.96
83.23 83.79 83.87 83.76 83.80
9.36 9.60 10.21 10.50 10.98
distilled. The residual liquid was distilled in a vacuum. The physical properties and analyses of the compounds are summarized in Tables I and 11. Chemical properties,-A clear solution of 2,2-dimethyl-l,2-benzopyranturned to a reddish color on standing, reduced potassium permanganate, and decolorized bromine. Boiling for ten hours in alcoholic alkali, according to the method used by Heyes and Robertson10 to degrade deguelin to acetone, did not affect the compound. Cold concentrated sulfuric acid with these benzopyrans gave a deep-red color, which decreased in intensity with the higher members of the series. The cold 10
HEYES AND ROBERTSON, J . Chem. SOC.,1956, 681.
ACTION OF ALKYLMAGNESIUM HALIDES ON COUMARIN
581
sulfuric acid gave a polymeric product, which, in the case of the dimethylbenzopyran, possessed a molecular weight of 650-800. The addition of ferric chloride t o a n ether or glacial acetic acid solution of the dimethylbenzopyran that had been saturated with dry hydrogen chloride, gave apparently a polymeric product. Boiling acetic acid, according to the method of Lijwenbeins, caused no isomerization of 2,2-dimethyl-l, 2-benzopyran. .Z,B-DimethyZchroman.-Twelvegrams (0.075 mole) of 2,2-dimethy1-1,2-benzopyran was dissolved in 100 cc. of alcohol and reduced by hydrogen with 0.1 gram of platinum oxide catalyst.11 After nine hours, the calculated amount of hydrogen was absorbed. The alcoholic solution was filtered, and the platinum oxide was washed with more alcohol. The alcohol was evaporated on the steam bath and the residue was distilled. The yield was 11 grams (92%) of the chroman; b.p., 67.5-68" (2 mm.), n:, 1.5264; d?, 1.0237. The molecular refractivity: calc'd, 49.10; found, 48.64. The compound has a spicy odor. This compound had been obtained from isoprene and phenol and also synthesized from ethyl o-hydroxycinnamate by Claisen.4 grams of 2,2-dimethyl-1, 2Ozonization of 8, I-Dimethyl4 ,I-benzopyran.-Five benzopyran in 30 cc. of carbon tetrachloride was ozonized and the product was decomposed with 50 cc. of water, 1 g. of zinc dust, and 1 cc. of acetic acid, in the presence of 0.2 g. of hydroquinone. Treatment of the carbon tetrachloride layer with 2,4-dinitrophenylhydrazineyielded the 2,4-dinitrophenylhydrazoneof salicylaldehyde. This melted at 250.5-251' after recrystallization from ethanol. This agrees with the value reported by Campbell.'* The aqueous layer, after filtration, was treated with semicarbazide hydrochloride and sodium acetate. The crude semicarbazone which separated (m.p. 228-230") was fractionally crystallized from 50% ethanol. The only pure compound isolated was the semicarbazone of salicylaldehyde, imp. 231-233'. No indication of the presence of the semicarbazone of a-methylacrolein, one of the possible products of ozonolysis, was obtained. I n another ozonolysis the carbon tetrachloride solution was distilled, and the distillate was tested for a-methylacrolein, which has the boiling point 73.5", very close to that of carbon tetrachloride. However, none could be found. The oil left after distillation was allowed to stand in the air for two days, and was oxidized t o salicylic acid, m.p. 158". No ozonolysis products other than salicylaldehyde could be isolated. Fischer13 has reported that ozone splits ethers into a complex mixture of products. 4-(o-HydrosyphenyE)pentan-%-one.-Seven and one-half grams (0.046 mole) of o-hydroxybenzalacetone, prepared according to the procedure of Harries,'" was dissolved in 400 cc. of dry ether and added during one hour to exactly 0.1 mole of methylmagnesium iodide. A yellow precipitate was formed, which did not dissolve on further stirring for twelve hours. The mixture was decomposed by 150 cc. of 20% ammonium chloride solution, and the ether layer was separated. The aqueous layer was extracted once with ether, and the combined ether extracts were dried with calcium chloride. The ether was carefully evaporated by an air stream, giving 1.5 g. of a solid which was recrystallized from petroleum ether (b.p. 80-120"). This compound melted a t 127-129" with dehydration. 11
GILMAN,Organic Syntheses, John Wiley and Sons, New York, Col. Vol. I,
1). 452.
CAMPBELL, Analyst, 61, 391 (1936). ~ ~ F I ~ C Ann., H E R476, , 233 (1929). 14 HARRIES,Ber., 24, 3180 (1891). 12
582
R. L. SHRINER AND A. Q. BHARP
Anal. Calc'd for C 1 l H I ~ O C, ~ : 74.17; H, 7.86. Found: C, 74.20; H, 8.01. Semicarbazone of 4-(o-hydroxyphenyl)pentan-l-one.-An alcohol solution of the above compound was added t o an aqueous solution of sodium acetate and semicarbazide hydrochloride. After the solution had stood for two days at room temperature, the semicarbazone was extracted by ether and crystallized from alcohol; m.p., 155155.5". Anal. Calc'd for C12HlTN102: N, 17.86. Found: N, 17.91. 3,4-Dimethyl-l ,3-benzopyran.-When 4-(o-hydroxyphenyl)pentan-2-one waa heated at its melting point for ten minutes, there was obtained a liquid which distilled at 79-80" (3 mm.). Its density was 1.0196:' and refractive index, 5,1.5428. The molecular refractivity: calc'd, 49.81; found, 49.44. Anal. Calc'd for CIIHl10: C, 82.51; H, 7.48. Found: C, 82.29; H, 7.67. The hydroxy ketone and benzopyran gave an orange color in concentrated sulfuric acid. The odor of the above benzopyran differed slightly from that of the 2,2-dimethyl-1 ,2-benzopyran. Ozonization of 8,4-dimethyl-l ,9-benzopyran.-Ozonization of 2 cc. of 2,4-dimethyl1,2-benzopyran in carbon tetrachloride, followed by decomposition of the ozonide by water and zinc dust, separation of the carbon tetrachloride layer, and evaporation of the carbon tetrachloride, gave an oil having a boiling-point range of 215-220" and giving a bluish-purple color with ferric chloride. Its semicarbazone was prepared, and after crystallization from ligroin, was found t o melt at 205-207", which agreed with the value reported by Pauly and Lockemannlt for the semicarbazone of o-hydroxyacetophenone. Action of methylmagneaium iodide on trans-o-hydroxycinnamic acid.-Ten grams (0.06 mole) of trans-o-hydroxycinnamic acid prepared according t o the method of Dodge]' was dissolved in a liter of dry ether and added dropwise over a period of two hours to 0.36 mole of methylmagnesium iodide in 250 cc. of ether. The mixture was stirred for three hours, and decomposed by 350 cc. of 20% ammonium chloride solution. The aqueous layer was separated and extracted once with 50 cc. of ether. The combined ether solution was concentrated to 50 cc., and the remainder of the ether was removed by an air stream. The solid which formed was filtered, washed, and recrystallized from petroleum ether. There was obtained 1.5 g. (15%) of o-hydroxybenzalacetone melting a t 136-138'. A mixed melting point with o-hydroxybenzalacetone prepared from salicylaldehyde and acetone showed no depression. SUMMARY
A series of 2,2-dialkyl-l , 2-benzopyrans has been prepared by the action of alkylmagnesium halides on coumarin. The structure of these compounds has been demonstrated by means of their physical constants, ozonolysis to salicylaldehyde, and hydrogenation to 2 ,2dimethylchroman. The mechanism by which these 2,2-dialkyl-l, 2-benzopyrans are produced probably involves the formation of an intermediate coordination compound, in which the alkyl group undergoes an a,y shift. Subsequent reaction with a second mole of the Grignard reagent produces the dialkylbenzopykn. The evidence supporting this mechanism is given. PAULYAND LOCKEMANN, ibid., 48, 28 (1915). D DO DOE, J . Am. Chem. Soc., 38, 446 (1916).
16
