[CONTRIBUTION FROM TEE
DEPARTMENT OF CHEMISTRY , SYRACUSE
UNIVERSITY]
THE CHEMISTRY OF CITRININ. I. THE SYNTHESIS OF 2,4DTMETHOXY-3-ETHYLBENZOICACID, AND 2 ,6-DIMETHOXY3-METHYLBENZOIC ACID' R. D. SPRENGER'
AND
P. M. RUOFF
Received December 18, 1946
In the course of certain citrinin studies begun in 1940 (1) it seemed advisable to examine some of the evidence presented by Coyne, Raistrick, and Robinson (2) in support of their proposed structure of citrinin (A), a metabolic product of the mold, Penicillium citrinum. According to these investigators the course of the degradation of citrinin was as shown in Figure 1. Since none of the degradation products (B-F) was known at the time, they based these structural deductions upon chemical behavior and the analysis of certain derivatives. In the case of the two acids (E) and (F), they relied rather heavily upon the divergent chemical behavior of certain pure specimens of the dimethyl ethers of orsellinic acid (2,4-dihydroxy-6-methylbenzoicacid) and p-orsellinic acid (2,6-dihydroxy-4-methylbenzoicacid) which they had on hand. Since the major portion of their arguments for the structure of citrinin is based on the correctness of these deductions, a comparison of the properties of the corresponding synthetic compounds is highly desirable. Accordingly, we have synthesized the acids, 2,4-dimethoxy-3-ethylbenxoic acid ( [V) and 2 ,6-dimethoxy-3-methylbenzoic acid (VII) using straightforward methods as shown in Figure 2 and Figure 3, respectively. A marked divergency in the melting points of the acids (E) and (F) as obtained by Coyne, Raistrick, and Robinson and the synthetic acids (IV) and (VII) is to be noted. See Table I. Such results would indicate that the proof of structure based on synthesis of the degradation products of citrinin as well as of citrinin, itself, has yet to be accompli~hed.~ 1 From a thesis t o be submitted t o the Faculty of the Graduate School in partial fulfillment of the requirements for the degree, Doctor of Philosophy, Syracuse University. Eat,on Foundation Fellow, 194346. 8 The synthesis of 2-ethyl-4-methylresorcinol (C) has now been reported (3, 4, 5 ) , but Robinson and Shah (3) were unable to establish its identity with the corresponding phenolic degradation product of citrinin since the latter, as they stated, "had deteriorated; originally of m.p. 98-99', i t had m.p. 65-70' after an interval of two or three years." We have also synthesized the dialkyl resorcinol (C) using the methods of Yanagita, Shah and Shah, and Robinson and Shah, starting in the latter case, however, with 2-ethylresorcinol as prepared by the method of Russell, Frye, and Mauldin (6). In each case the same product (m.p. 100-101', after sublimation) was obtained as confirmed by mixed melting points. Its color reactions however corresponded to those reported by Yanagita. It is of interest, also, t o note that in our hands an attempt to obtain the phenolic degradation product (C) from citrinin, itself, gave us a product whose melting point was 67-70' (see above) instead of 97-99' as previously reported (2). 189 f
190
R. D. SI'RENGER AND P. M. RUOFF
TABLE I COMPARISON OF PHYSICAL PROPERTIES cokrP0c"D
M.P.'C (UNCOB.)
Acid (E)... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,4-Dimethoxy-3-ethylbenzoicm i d (IV) ....................... Acid (F).. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2,6-Dimethoxy-3-methylbenzoicmid (VII) ....................
COOH
97-99 (2) 128-129 142-146 (2) 117-118
OH
+ HCOOH + COS B
A
1
NaOH
OH
OCHI
c2H'o I
I
HO
I
CHs C
C Ha
D
+I
KMnO4
oca I
""9
CHSO
COOH
E
OCHs
+
O/ C OCHs OOH CHs
F FIG.1. :DEQRADATION OF CITRININ
191
CHEMISTRY OF CITRININ
Acknowledgment. This investigation was made possible by the generous action of the Eaton Laboratories, Norwich, N. Y., in establishing a t Syracuse University the Eaton Foundation Research Fellowships. We wish to thank Dr. A. B. Scott and Dr. F. Austin of the Eaton Laboratories for their interest and encouragement. OH
OCHi
I
I1
oca3
OCHa
I
I
HIOI
t -
COOH
IV FIG.
I11
2. SYNTHESIS OF 2,4-DIMETgOXY-3-ETHYLBENZOICACID
OH
OCHO
I
''
(CHJSSOI
--+
QOH
NzC&
($cocHO / OCHs
C&
CHI
VI
V FIG.
3. SYNTHESIS OF
OCHs --+
()cooH / OCHa
CHa
VI1
2,6-DIMETaOXY-3-METHYLBENZOICACID
EXPERIMENTAL
An attempt t o prepare 2,4-dimethoxy-3-ethylbenaoicacid (IV) by the direct methylstion of 2,4-dihydroxy-3-ethylbenzoic acid wm unsuccessful. Although the latter compound has not been reported in the literature it was readily obtained by the carboxylation of 2-ethylresorcinol. Methylation with dimethyl sulfate or with methyl iodide gave a crystalline compound but the product melted over a wide range and the neutral equivalent indicated only a monomethoxy compound. A strong color reaction with ferric chloride
192
R. D. SPRENGER AND P . M. RUOFF
also indicated incomplete methylation. Use of diazomethane gave a n alkali-insoluble compound but hydrolysis of the ester resulted in a compound which corresponded again to the monomethoxy derivative. Accordingly, the following synthesis was utilized. 9,6-Dimethosyethylbenzene(Zi') 2-Ethylresorcinol (I) (m.p. 94-95') as prepared by the method of Russell, Frye, and Mauldin (6) was methylated in the usual fashion with dimethyl sulfate and alkali giving the methoxy compound, which melted at 57-58"after recrystallization from 80% alcohol (70% yield). Anal. Calc'd for CloHla02:( 2 , 72.26; H, 8.49. Found: C, 71.98; H, 8.12. 8,4-Dimetkoxy-b-e~hylbenzaldehyde (ZZI), T o a mechanically stirred solution of 7 g. (0.042 mole) of the 2,6-dimetho:;yethylbenzenein 40 cc. of dry ether cooled by a freezing mixture, 10 g. (0.085 mole) of zinc cyanide was added followed by 11.3 g. of aluminum chloride (0.085 mole) in 40 cc. of d y ether. Dry hydrogen chloride was passed in for four hours. After keeping the mixture in the refrigerator for 24 hours, the ether was decanted, the aldimine hydrochloride washed with ether and decomposed by heating with 75 CC. of water on the steam-bath for 30 minutes. When cooled, a pale yellow oil separated which crystallized on standing. Deccdorization and recrystallization from alcohol gave 5 g. (50%) of yellow needles melting at 59-60'. The p-nitrophenylhydrazone was prepared and crystallized from glacial acetic acid giving orange-red needles melting sit 219-220'. Anal. Calc'd for ClrHloNsOl: N, 12.76. Found: N, 12.98. %,Q-Dimethory-d-ethyEbenzoicacid (ZV). To a solution of 30 cc. of 5% sodium hydroxide and 60 cc. of 3% hydrogen peroxide warmed to 65-70' was added 2 g. (0.01 mole) of the aldehyde (111). After addition of 20 cc. of alcohol the mixture was shaken and heated at 70-75" for twenty minutes. An additional 20 cc. of hydrogen peroxide was added and the mixture warmed for two minutea longer. After cooling, the solution was ether extracted to remove unreacted aldehyde and the aqueous layer made acid to Congo Red with hydrochloric acid. Recrystallization of the precipitated acid from ligroin gave colorless needles (1 g., 47% yield), melting at 128-129". Anal. Calc'd for C11H1,04:Mol. wt. 210.2: C, 62.84; H, 6.71. Found: C, 62.32; H, 6.54; N. E., 208.4. The acid thus obtained gave no color reaction with either aqueous or alcoholic ferric chloride. It was soluble in alcohol and benzene, slightly soluble in cold and moderately soluble in hot water. S ,6-Dimethoxy-b-methyZbenzoicacid (TTZZ) 2,6-Dihydroxy-3-methylacetophenone(V) (m.p. 138-139') as prepared by the method of Yanagita (4) was methylated in the usual manner with dimethyl sulfate and alkali. A pale yellow oil was obtained which solidified on standing in the cold (m.p. 20-229 (70% yield). The methoxy ketone (VI) was oxidized directly without further purification as follows : Ctllorine gas mas passed into a solution of 18.4 g. (0.46 mole) of sodium hydroxide in a mixture of ice (120 g.) and water (30 cc.) until the solution was neutral to litmus. A solution containing 3.4 g. of sodium hydroxide in 10 cc. water was then added. The mixture was warmed t o 60-70' and 6 g. (0.03 mole) of the methoxy ketone (VI) added with vigorous stirring. After stirring for two hours a t 60-70' the solution was cooled and treated with 10 g. of sodium bisulfite in 30 cc. of water to destroy excess hypochlorite. Following a n ether extraction to remove unrericted ketone, the aqueous layer was acidified with hydrochloric acid. The precipitated acid (3 g., 50% yield) on recrystallization from a benzenepetroleum ether mixture was obtained in the form of colorless prisms which melted a t 117118". It was soluble in benzene and alcohol, slightly soluble in cold water, and moderately soluble in hot water. No color was given with ferric chloride in either aqueous or alcoholic solution. O ~ :wt. 196.2; C, 61.21; H, 6.17. A n d . Calc'd for C ~ O H I ~Mol. Found: C, 60.83; H, 6 04; N. E. 197.
.
.
CHEMISTRY OF CITRININ
193
SUMMARY
2,4-Dimethoxy-3-ethylbenzoic acid and 2,6-dimethoxy-3-rnethyIbenzoic acid have been prepared. Their melting paints do not correspond to those reported for the degradation products of citrinin. SYRACUSE, X. Y. REFERENCES (1) HIRSCHY AND RUOFF, J . Am. Chem. SOC.,64, 1490 (1942). (2) COYNE,RAISTRICK, AND ROBINSON, Trans. Roy. SOC.(London) B, 220, 297 (1931); Bee also, OXFORD,Ann. Rev. Biochem., 14, 757 (1945). AND SHAH,J. Chem. SOC.,1491 (1934). (3) ROBINSON (4) YANAGITA, Ber., 71, 2269 (1938). (5) SHAHAND SHAH,J . Chem. SOC.,949 (1939). (6) RIJSSELL, FRYE,AND MAULDIN, J . Am. Chem. SOC.,62, 1441 (1940); see also, Org. Syntheses, 21, 22 (1941).
