DECEMBER
1957
1717
NOTES
phenyl- and ptolyllithium, respectively,2 but no product could be isolated. We have been able, however, to carry out this series of reactions and have obtained products which could be isolated and identified. The compounds were purified by fractional crystallization from absolute ethanol. The product from each of the reactions was found to be l-phenyl-(l-ptolyl)-1,2dihydroisoquinoline. This fact was demonstrated by a mixture decomposition point and identical infrared spectra. Both of the spectra contained a 1,4 disubstituted phenyl band at 12.3 p , a phenyl ring band at 6.15 p , and a N-H band at 3.1 p .
EXPERIMENTAL^ Reaction of pTolyllithium with I-Phenylisoquinoline. Into a 500-ml., 3-necked, round-bottomed flask which was equipped with a mechanical stirrer, reflux condenser, and a dropping funnel, there was placed 16 g. (0.08 mole) of 1phenylisoquinoline in 200 ml. of anhydrous ether. To this vigorously stirred solution, there was added dropwise a solution of p-tolyllithium (0.08 mole) in 90 ml. of anhydrous ether. After the addition of 2, 5, and 8 ml. of the ptolyllithium solution, the reaction mixture became light red, light brown, and, finally, dark green in color. The dark green color wm present throughout the remainder of the addition. On completion of the addition, the reaction mixture was refluxed for 45 min. a t which time Color Test I 4 w a ~ negative. The reaction mixture was hydrolyzed with a saturated solution of ammonium chloride, and the ethereal extract was dried over anhydrous sodium sulfate. The ether wm re moved by distillation, and the residue was dissolved in absolute ethanol, This solution was treated with charcoal, filtered, and evaporated by means of dry air to give a compound which decomposed between 176-178". The yield was 0.5 g. or 2.5%. Anal. Calcd. for C P Z R ~ ~N,N4.69. : Found: N, 4.68,4.55. Reaction of phenyllithium with l-p-tolyliso~inoline.Into a 500-ml., 3-necked, round-bottomed flask, which WM equipped as described above, there was placed 19 g. (0.09 mole) of 1-ptolylisoquinoline in 200 ml. of anhydrous ether. To this solution there was added 0.09 mole of phenyllithium in 100 ml. of anhydrous ether. The color of the reaction mixture became dark green after the addition of the first 8 ml. of the phenyllithium solution, and the color was retained for the remainder of the addition. Color Test I 4 was negative within 15 min. after the addition was completed. The reaction mixture was worked up in the same manner as described above to give a product which decomposed between 176-178'. The yield was 0.,5 g. or 2.5%.
Acknowledgment. The authors wish to express their appreciation t o R. M. McCord, E. M. Layton, and Dr. V. A. Fassel of the Institute for Atomic R e search, Iowa State College, for obtaining the infrared spectra of the compounds. This work was supported by the United States Atomic Energy Commission under contract No. AT(l1-1)-59, and the reactions were used in connection with organic liquid solution scintillators to (2) G. C. Gainer, doctoral dissertation, Iowa State College, Ames, Iowa, 1946. (3) All melting points are uncorrected. (4) H. Gilman and J. Schulze, J . Am. Chem. SOC.,47, 2002 (1925).
be evaluated by Drs. W. H. Langham, F. N. Hayes, and D. G. Ott of the Los Alamos Laboratories. THEDEPARTMENT OF CHEMISTRY IOWA STATECOLLEGE AMES, IOWA
Derivatives of o-Phenylenedioxyacetic Acid as Plant Growth-Regulators'
HOWARD A. HARTZFELD,~ ROBERT G.
JOHNSON,3 AND
HENRYGILMAN Received April 26,1967
A reasonable extension of studies4 on the plant growth-regulator activity of phenoxyacetic acid derivatives seemed to be the investigation of derivatives of o-phenylenedioxyacetic acidlSI.
I
Accordingly, we have prepared and are reporting here the synthesis of a number of derivatives of I. We are also reporting the plant growth-regulating activity of these compounds as measured by the leaf repression method.6 The acid (I) and its ethyl ester were reported initially by Christiansen and Dolliver.' Subsequently, Burger and coworkers8 prepared the acid and a number of its derivatives for testing for antispasmodic activity. After the work reported here had been completed, a paper by Cavill and Fordg on the subject of o-phenylenedioxyacetic acid and its chloro derivatives appeared in the literature. These latter workers seem t o be the only ones other (1) Abstracted from a Dissertation submitted by H. A. H. to the Graduate School of Iowa State College in partial fulfillment of the requirements for the Ph.D. degree in chemistry, December 1953. (2) Present address: Research Division, Phillips Petroleum Company, Bartlesville, Okla. (3) Present address: Department of Chemistry, Xavier University, Cincinnati, Ohio. (4) Studies carried out under contract with the Chemical Corps ofthe U.S. Army. Dr. R. L. Weintraub, Fort Detrick, Md., arranged for the biological testing. (5) Cavill and Ford (ref. 9) name this compound, benzol :3-dioxol~-2-carboxylicacid and Chemical Abstracts refers to it as 1,3-benzodioxole-2-carboxylicacid. (6) J. W. Brown and R. L. Weintraub, Botan. Gaz., 111, 448 (1950). (7) W. G. Christiansen and M. A. Dolliver, J. Am. Chem. Soc., 66,312 (1944). (8) A. Burger, D. G. Markees, W. R. Nes, and W. L. Yost, J . Am. Chem. SOC.,71,3307 (1949). (9) G. W. I(.Cavill and D. L. Ford, J . Chem. Soc., 1388 (1954).
1718
NOTES
than the writers to recognize the potential of derivatives of I as plant growth- regulator^.^" The method employed for the synthesis of the ethyl esters of I and its 4-chloro derivative was, in essence, that used earlier by other workers.' The ethyl ester of I was then converted to the corresponding amide, anilide, hydrazide, and n-butyl ester. The last three of these compounds and ethyl 4-chloro-o-phenylenedioxyacetate have not been reported previously. The high order of chemical reactivity exhibited by ethyl o-phenylenedioxyacetate is worthy of note. The reaction of the ester with ammonia a,nd with hydrazine occurred a t room temperature and excellent yields of the products were obtained after short reaction times. It was observed also that, a sample of this ethyl ester darkened considerably on storage for a period of several months. -4n additional observation was that extraction with ether did not completely remove the ethyl ester of I from a 5% sodium hydroxide solution containing some ethanol; however, the extraction could be made from a 5% sodium bicarbonate solution. This suggests that the alpha-hydrogen in ethyl o-phenylenedioxyacetate exhibits a certain degree of acidic character. EXPERIMENTAL l o
Ethyl o-phenylenedioxyacette. To a cold solution of sodium ethoxide prepared from 46.0 g. (2.0 g. atoms) of sodium and 1500 ml. of absolute ethanol was added 110 g. (1.0 mole) of catechol. Over a period of 20 min., 157 g. (1.0 mole) of ethyl dichloroacetate was added with stirring to the dark reaction mixture. The reaction mixture was stirred for 1 hr. at room temperature, then for 6 hr. at reflux temperature. After the solvent had been removed a t aspirator vacuum with the aid of a steam bath, the residue was stirred with a mixture of 600 ml. of ether and 300 ml. of 5% sodium bicarbonate solution. The layers were separated and the ether layer was extracted with an additional 300 ml. of 5% sodium bicarbonate solution, then washed with 100 ml. of water. A quantity of tar was separated with the aqueous phase. The ethereal solution of the ester was dried over anhydrous sodium sulfate. Following removal of the solvent, the residual ester was distilled under vacuum. The crude yield of 68.1 g. of ester was collected over the range 81-89' (0.3 mm.). Since some catechol (mixture m.p.) had been carried over into the receiver during the distillation, the crude ester was washed with two 30 ml. portions of 5y0 sodium bicarbonate solution, then with 30 ml. of water. After drying, 53.4 g. (2857,) of ethyl o-phenylenedioxyacetate was collected a t 79-81" (0.3 mm.), n",' 1.5127. (sa) A referee has called to the authors' attention a recent paper by Zimmerman et al., Contrib. Boyce Thompson Inst., 18, 453 (1957). This paper which appeared a t about the same time our Note was submitted for publication records the preparation of our structure I, a mono- and a dichloroderivative of I, and the ethyl esters of these acids. The acids were tested on a wide variety of plants; it was concluded that the effects of these compounds were similar to those of 2,4-D except that higher concentrations of the former were required. (10) All melting points and boiling points are uncorrected.
VOL.
22
Another sample distilled a t 92-94' (0.7 mm.), ng 1.5084.11 Anal. Calcd. for CloHlo04:C, 61.85; H, 5.19; mol. wt., 194. Found: C, 61.41, 61.38; H, 5.26, 5.36; mol. wt. (cryoscopic in benzene) 169,175. o-Phenyknedioxyacetic acid amide. A mixture of 3.9 g. (0.020 mole) of the ethyl ester of I and 20 ml. (0.30 mole) of concentrated ammonium hydroxide was shaken for 10 min. An exothermic reaction took place and a solid separated immediately. The solid material, 2.63 g. (80%), was removed by filtration. The m.p. of 110-112' for the crude material was not raised by recrystallization from water. 1 2 The amide was obtained as 2.12 g. of white flakes. Anal. Calcd. for CsH?NO3:C, 58.18; H, 4.27; N, 8.48. Found: C, 58.18, 58.18; H. 4.25, 4.32; K, 8.52, 8.53. 0-Phenylmedioxyacetic acid hydrazide. When 4.0 ml. (0.082 mole) of hydrazine hydrate (99-100%) was added to 3.9 g. (0.020 mole) of the ethyl ester of I, a white solid precipitated immediately. The mixture was heated on a steam bath for 10 min., 40 ml. of ethanol having been added to give a homogeneous solution a t the reflux temperature. On cooling, there separated 2.15 g. (60y0) of hydrazide, m.p. 182-185'. Recrystallization of the crude product from ethanol yielded 1.80 g. (5001,) of white needles, m.p. 185187". There was no increase in the melting point after a second recrystallization from ethanol. Anal. Calcd. for C8H8N2Q3: C, 53.33; H, 4.48; N, 15.55. Found: C, 53.26, 53.37; H, 4.49,4.51; N, 15.61, 15.63. o-Phenylenedioxyacetic acid anilide. The anilide was prepared by a procedure analogous to that used by Hardy.'$ A solution of ethylmagnesium bromide was prepared from 1.0 g. (0.041 g. atom) of magnesium and 5.0 g. (0.046 mole) of ethyl bromide in 30 ml. of anhydrous ether. To this cold solution of the Grignard reagent was added 4.0 g. (0.043 mole) of aniline. After evolution of gas (ethane) had ceased, 3.9 g. (0.020 mole) of the ethyl ester of I was added, and the mixture was warmed on a steam bath for 10 min. The reaction mixture was then cooled and acidified with 40 ml. of 1:2 hydrochloric acid. After removal of the ether by distillation, the residue was cooled and filtered. The yield of nearly white solid was 3.99 g. (8301,), m.p. 118-128'. Recrystallization from ethanol-water gave 3.29 g. (69%) of white flakes, m.p. 135-137". The melting point was not elevated by a second recrystallization from ethanol. Anal. Calcd. for CI4Hl1NO3:C, 69.70; H, 4.60; N, 5.81. Found: C, 69.71, 69.70; H, 4.64, 4.72; N, 5.89, 5.85. n-Butyl o-phenyZer)edioxyacetate. A mixture of 15.5 g. (0,080 mole) of the ethyl ester of I, 46 ml. (0.50 mole) of 1-butanol, and 2 drops of concentrated hydrochloric acid was refluxed for 24 hr. Excess ethanol and butanol were removed by distillation on a steam bath a t aspirator vacuum. The residue was distilled in vacuo to give 14.0 g. of colorless liquid, b.p. 84-102' (0.3 mm. ). Since some catechol was evident in the distillate (mixture m.p.), the crude ester was washed with two 5-mi. portions of 5% sodium bicarbonate solution. The ester then was washed with 5 ml. of water, dried over calcium chloride, and distilled. Ten grams (56%) of colorless liquid was obtained, b.p. 100-102" (0.3 mm.), ny 1.4907, dzB 1.1250. Anal. Calcd. for C12H1404: C, 64.85; H, 6.35; MRD, 56.76.14Found: C, 64.30, 64.39; H, 6.56, 6.52; MRD, 57.19. .&Chloroeatechol. This compound was prepared in 33 %
(11) For this compound, b.p. 115-117" (12.5 mm.) has been reported (ref. 7); however, the analysis of the earlier preparation is not entirely satisfactory. (12) A melting point of 105-106' has been reported for this amide (ref. 8). (13) D. V. N. Hardy, J. Ghem. Soc., 398 (1936). (14) A. Weissberger, editor, Physical Methods of Organic Chemistry, 2nd. ed. rev., Interscience Publishers, Inc., New York, 1949, Part I, p. 1163.
DECEMBER
1957
1719
NOTES
WAVES PER CM. yield by the method of Frejka, Sefrsnek, and Zika.u More 4000 Zoo0 1500 1000 900 800 700 satidactory was the method of Wrede and Miihlroth16 loo,' , which atforded a 51% yield of the chlorophenol. Ethyl 4 - c h l o r o - o - p h e n y l o x y ~ e ~A~ solution . of sodium ethoxide was prepared from 46.0 g. (2.0 g. atoms) of sodium and 1500 ml. of absolute ethanol. To this solution was added 145 g. (1.0 mole) of 4chlorocatechol. Then 157 g. (1.0 mole) of ethyl dichloroacetate was added, under a nitrogen atmosphere, to the reaction mixture over a period of 20 min. The reaction mixture was stirred a t room temperature for 1 hr., then refluxed for an additional 6 hr. The solvent waa removed on a steam bath a t aspirator vacuum and the residue was stirred with a mixture of 800 ml. of ether and 400 ml. of 5% sodium bicarbonate solution. The ether layer waa separated and extracted with an additional 400 ml. of 5% sodium bicarbonate solution followed by two 200ml. portions of water. The ethereal extract then waa dried over anhydrous sodium sulfate. The solvent waa removed by distillation and the residue was distilled through a Vigreux column at reduced pressure. The yellow-colored 20 PHASE IU ester (81.4 g., 36%) WFM collected at 108-109° (0.80.5 mm.), ny 1.5331, d;",' 1.325. 2 3 4 5 6 7 8 9 IO II 12 13 1415 A d . Calcd. for CloH&lO,: C1, 15.51; MRD, 52.39.14 WAVELENGTH, MICRONS Found: Cl, 15.14, 15.14; MRD, 53.56. ABSORPTION SPECTRA IN POTASSIUM FIG. 1. INFRARED Plant growth-regula& activity. The MOLARAE values for BROMIDE. Disks of different polymorphic phaaes of 2those compounds tested are: ethyl o-phenylenedioxyacetate, 57; o-phenylenedioxyacetic acid amide, 634; o-phenylene methylthio4amino-5-hydmxymethylpyrimidine. dioxyacetic acid anilide, 185; o-phenylenedioxyacetic acid crystal forms has been confirmed by the entirely hydrazide, 147; and ethyl 4chloros-phenylenedioxyacetate, different x-ray powder diagram for the three phases 215. Though these compounds did exhibit activity aa measured (Table I). That these forms are the same compound by the leaf repression method of assay, the activity values is confirmed by the fact that they give the same were of a very low order of magnitude; cf. 2 , 4 D which haa a infrared and ultraviolet spectra in solution and MOLARA of 21,900.17 As might have been expected, the chlorine-contsining that, after heating above the melting point, the ester waa found to be almost four times aa active aa the potassium bromide disks show the same infrared corresponding unchlorinated compound (I). Further studies absorption. on chlorinated o-phenylenedioxyacetic acids and derivatives TABLE I thereof are currently in progress. PHASES OF 2-METHYLTHI04 The relatively high activity of o-phenylenedioxyacetic X-RAYPATl'ERNS FOR THREE AMINO-~-HYDROXYMETHYLPYRIMIDINE~ acid amide waa unexpected but might be attributed, at least in part, to the appreciable solubility of the amide in Phase I PhaaeII , Phase I11 water (and hence in plant fluids). Relative Relative Relative DEPARTMENT OF CHEMISTRY d, b. intensities d, A. intensities d, b. intensities IOWA STATECOLLEGE h s , IOWA 12.20 80 7.94 33 8.26 >lo0 7.16 45 5.98 39 5.19 16 (15) J. Frejka, B. Sefranek, and J. Zika, CoUectim 6.49 38 5.60 11 4.34 22 C m b l o v . Chem. Commun., 9, 238 (1937); Chem. Abstr., 6.07 >lo0 4.93 19 4.30 80 31,7046(1937). 5.30 8 3.82 95 4.10 11 (16) F. Wrede and 0. Mithlroth, Ber., 63, 1931 (1930). 4.42 25 3.49 8 3.86 17 (17) R. L. Weintraub, J. W. Brown, and J. A. Throne, 4.36 94 3.42 100 3.71 5 J . Agr. Food Chem., 2, 996 (1954). 4.25 13 3.22 72 3.49 64 4.10 37 3.00 8 2.98 6 4.03 >lo0 2.67 8 2.79 48 13 1.81 22 2.71 8 Polymorphic Forms of 2-Methylthio-4-amino- 3.82 3.74 11 1.80 17 2.39 7 5-hydroxymethylpyrimidine. I 3.33 40 2.37 6 23 2.11 3.22 3.18 8 2.03 TAKUO OKWDA AND CHARLES C. PRICE^ 3.04 20 1.96 6 3.01 39 1.92 6 Remked April 99,1967 2.66 29 1.82 7 2.55 7 8 Samples of I2recrystallized by different proced- 2.49 2.39 7 ures were found to give quite different infrared pat16 terns when measured in the crystal state in potas- 2.17 1.99 6 sium bromide disks (Fig. 1).The existence of three 7 1.97 1.95 6 Supported by a grant from the National Cancer Institute f CY-2714). We are indebted to R. E. Hughes a n d N Kornblau for ( 2 j T. L. V.'TJlbricht and C. C. Price, J. Org. Chem., 21, these data, obtained with Ni-mtered CUId radiation at 85 567 (1956). kv. and 20 ma. with a Norelco diEractometer. I
I
I
I
I
I
I
I
I
i
' t
