X OVEMBER, 1964 dl-N-Acetylphenylalanine (11).-Following a modification of two procedures21*22a distilling flask charged with 382 mg. (1.25 mmoles) of I and 2.0 ml. of 10yc sodium hydroxide was stoppered and allowed to stand at room temperature for 5 days, after which time ester hydrolysis was complete. The solvent, containing the labeled ethyl alcohol, was distilled without heating into a cold trap under vacuum. T o the residue were added 1.7 ml. of 3 N hydrochloric acid and 2.0 ml. of water, and the solution was refluxed for 1.5 hr. The hot, acidic solution was filtered, the flask was washed with 2.0 ml. of water, and the combined solutions were evaporated in a stream of air to about 2 ml. Overnight refrigeration deposited white granular crystals of N-acetylphenylalanine which were recrystallized from water to m.p. 145-146", in a yield of 229 mg. (86%). p-Bromophenacyl Acetate (111).-To one-half of the aqueous alcohol distilled after hydrolysis of diester I , there were added 267 mg. of potassium permanganate, 141 mg. of magnesium sulfate, and 2 ml. of water. The reaction mixture was allowed to stand a t room temperature for 20 hr. Upon addition of 1.5 ml. of 4870 hydrobromic acid and sodium bisulfite a clear colorless solution resulted. The solvent, containing the labeled acetic acid, was distilled with gentle heating under vacuum into a cold trap. The distillate was adjusted to pH 5-6 with sodium carbonate, 202 mg. of p-bromophenacyl bromide and 4 ml. of ethanol were added, and the solution was refluxed for 1.5 hr. A small amount of water was added and the solution was refrigerated to give crude p-bromophenacyl acetate, which was recrystallized from petroleum ether to m.p. 83-84". Ethyl p-Nitrobenzyl Xanthate (IV).-To the aecond half of the aqueous alcohol distilled after hydrolysis of I, the following were added with cooling: 1.5 g. of potassium hydroxide, 0.5 ml. of acetone, and 0.5 ml. of carbon disulfide.23 After shaking fof 10 min., the yellow precipitate was extracted into 10 ml. of acetone, and 193 mg. of p-nitrobenzyl chloride was added to the extract. The potassium chloride which formed after warming gently for a few minutes was removed by filtration, the solvent was evaporated, and the residue was taken up in 8 ml. of benzene. The extract was washed with 10-ml. portions of 10% sodiumhydroxide, the first containing 8 drops of mercaptmcetic acid. After drying over calcium chloride, the benzene was evaporated leaving a residue which was recrystallized from petroleum ether. Long yellow needles of ethyl p-nitrobenzylxanthate, m.p. 6@61°, 121 mg., resulted. An unlabeled sample prepared in the same manner was analyzed. Anal. Calcd. for C1oHnN0&: C, 46.68; H , 4.31. Found: C, 46.90; H , 4.33.24 Deacetylation of dl-N-Acetylphenylalanine (11). Base Procedure b.-A solution of 201 mg. (0.971 moles) of I1 in 2.0 ml. of 10% sodium hydroxide was refluxed for 5 hr.; after acidification with 1.0 ml. of 48Yc hydrobromic acid, the solvent containing the labeled acetic acid was distilled into a cold trap under vacuum. The residue was taken up in 6 ml. of water, the solution was filtered, and the filtrate was reduced in volume in an air stream and was brought to pH 5 with ammonia. On refrigeration, dlphenylalanine precipitated and was recrystallized several times from aqueous ethanol containing a few drops of benzene. The final white product weighed 49 mg. (317,) with m.p. 240-245" dec. p-Bromophenacyl Acetate (VIIb).-The distillate from the above experiment was adjusted to pH 5-6 with sodium carbonate, and the p-bromophenacyl acetate was prepared as described for 111. A sharp separation from contaminating p-bromophenacyl bromide was effected by chromatography on 9 g. of activated alumina using 1: 1 v./v. benzene-hexane as eluent. Recrystallization from petroleum ether eventually gave 34.7 mg. of pure white needles, m.p. 83-84'. Deacetylation of dl-N-Acetylphenylalanine (11). Acid Procedure a.-This acid hydrolysis was done only on sample 2, from which these data were taken. To 450 mg. of dl-N-acetylphenylalanine was added 2.0 ml. of 48% hydrobromic acid, and the solution was refluxed for 2 hr. After cooling, 1 ml. of concentrated ammonium hydroxide was added and the still-acidic solution was submitted to vacuum distillation into a cold trap. The dlphenylalanine was isolated from the residue as described above. From the distillate p-bromophenacyl acetate VIIa was prepared and purified as described for VIIb. (21) N. F. Albertson and S.Archer, J. Am. Chem. SOC.,67, 308 (1945). (22) H. R.Snyder, .I. F. Bhekleton. and C. D. Lewis, 67, ibid., 310 (1945).
(23) G. Uulmer and F . G. M a n n , J. Chem. SOC.,666 (1945). (24) Microanalysis by Mr. William Saschek, Microanalytical Laboratory, University of Chicago.
NOTES
3445
dl-N-Acetylphenylalanine (Vb) .4l-Phenylalanine (51 mg.) was reacetylated by the method of du Vignea~d,~5 using acetic anhydride in base with cooling. The product waa recrystallized several times from water to give 50 mg. (79%) of dl-N-acetylphenylalanine, m.p. 149-151 '. The sample was quantitatively diluted with carrier. Benzoic Acid (VIb).-A solution of 381 mg. (1.84 mmoles) of Vb, 2.39 g. of potassium permanganate, 1.0 ml. of 10% sodium hydroxide, and 7.0 ml. of water was refluxed for 2 hr. The reaction mixture wm filtered, and the filtrate was acidified and extracted with ether. Evaporation of the ether followed by sublimation of the residue yielded 71 mg. (32oj,) of fine, long white needles of benzoic acid, m.p. 122".
Acknowledgment.-The authors are grateful to Dr. Fred Greenberg for synthesizing the starting material, and to Dr. K. E. Wilzbach of the Argonne National Laboratory for performing the irradiations. (25) V. du Vigneaud and C. E. Meyer, J. B i d . Chem., 98, 295 (1932).
Two Abbreviated Syntheses of Flavones and Flavone Analogs L. L. WOODSA N D JOHN SAPPI Division of Natural and Physical Sciences, Texas Southern University, Houston, Texas 77004 Received May 26, 1964
Two abbreviated methods for the synthesis of flavones and their analogs are described in this report and are elaborations of a procedure developed previously.2 The direct condensation of phenols with malonic acid under the influence of trifluoroacetic acid to give the flavones, none of which are naturally occurring13listed in Table I provides an effective one-step method to obtain such substances in good yield. The general course of the reaction may be adequately visualized from the specific equation given for the preparation of compound 1 in Chart I under method A. Substitution of malononitrile for malonic acid provides an alternate route to the synthesis of flavones but the method cannot, in the strictest sense, be considered to be a one-step procedure as shown in Chart I, method B, for the preparation of compound 5 ; however, two of the five compounds listed in Table I are identical with those prepared by the malonic acid method. Compound 6, previously reported2 as having a melting point of 1 4 5 O , does indeed have such a melting point when recrystallized once from ethyl acetate, but two recrystallizations from ethanol give the value recorded in Table I and confirm the results of Wilson and Daniels.* At the end of Table I the names of the several compounds are given, observing the orienting influences which have been fully discussed previously.2 The p-nitrobenzoates, prepared by the method of Hickenbottom,6 of the different compounds synthesized (1) Abstracted from a thesis submitted in partial fulfillment of the requirements for the M.S. degree. (2) L. L. Woods, J. Ore. Chem., 27, 696 (1962). (3) T. A. Geismann, "The Chemistry of Flavonoid Compounds." T h e Macmillan Co., New York, N. Y., 1962,pp. 415-431. (4) R. F. Wilson and R. C. Daniels, 2. Anal. Chem., 187, 100 (1962). (5) W. J. Hickenbottom, "Reactions of Organic Compounds," 3rd Ed., Longmans, Green and Co., New York, N. Y., 1957, p. 121.
NOTES
3446
VOL. 29
CHART
I
METHOD - A
1 METHOD
-B
Ho-o-oH +
NC-CH,-CN
~ 0 - 0 - 0 1 - 1 ~ 0 - 0 - 0 ~ -f;.-CHe-$ 2HeO I NH NH I OH OH
TFA
AH
-
+
i
I
H 0
-2NH,
5 TABLE I FLAVONES AND FLAVONE ANALOGS Compd. no.
Phenol used
Yield,
M.p.,
%
OC.
Method(s) used5
Empirical formula
-Carbon, %Calcd. Found
-Hydrogen, %Calcd. Found
-Chlorine, %Calod. F o u n d
112-113.5 CisHioOs 66.66 66.29 3 . 7 2 4.26 A 100 Resorcinol 56 99 56.48 2.81 3.20 218-220 CiTHioOg A 63 Resorcylic acid CisHaClzOs 53.12 52.94 2.37 2.51 20.90 20.77 100 A,B 4-C hlororesorcinol 108-108.5 3d C29H1807 72.79 72.62 3 . 7 9 3 . 9 6 150-151 A, B 77 2,4Dihydroxy4“ benzophenone >300 B Ci5HioO7 59.60 59.97 3 . 3 3 3.58 100 Phloroglucinol 5/ 158-159 B Ci5Hi009 53.90 53.58 3 . 0 1 2.74 63 Kojic acid 6g B C15HsC1207 48.54 48.07 2.17 2.30 19.10 18.62 168.5 29 a-Chloro-a-deoxy7h 169.5 kojic acid 2‘,4‘,a Compounds prepared by both methods A4 and B are identical as shown by their infrared spectra and mixture melting points. 7-Trihydroxyflavone. 2’,4’,7-Trihydroxy-5’,6-dicarboxyflavone. 2’,4’,7-Trihydroxy-5’,6-dichloroflavone. e 2’,4’,7-Trihydroxy5’,6-dibenzoyl5avone. f 2’,4’, 5,6’,7-Pentahydroxyflavone. 2-Hydroxymethyl-6( 2’-hydroxymethyl-5’-hydroxy-4‘-pyrone-6 ‘-pyranyl2-C hloromethyl-6( 2’-chloromethyl-5’-hydroxy-4’-pyrone-6’-pyranyl[3,2-b] )pyran-4,8-dione. [3,2-b])pyran-4,8-dione. I*
2c
Q
TABLE I1 SPECTRAL CHARACTERISTICS A N D ~ N I T R O B E N Z O AOF T ETHE S DIFFERENT COMPOUNDS IN TABLE I Compd. no.
Infrared absorption bands in the range of 6-6.5 p , cm. -la
Ultraviolet abaorption bands in the range of 200-350 mlrb (log 4
Formula
M.P., ‘C.
-Nitrogen, Calod.
%-Found
c ... ... 281.5 (2.92) ... 108-110 5.22 5.03 CasHieN& 267.5 (3.22), 299,5 (4.01) 230-231 5.34 5.32 C3aHx~Cl~NaOi4 3 1618, 1600 291.5 ( 3 . 3 3 ) 4.53 4.42 158- 159 CsoHz~NaOis 294.9 (4.31),328.2 4 1656,1595, 1555 (4.33) 6.69 6.45 130-131 C60H25N~022 5 1634,1613, 1592 291 (3.04) 6 1656, 1608, 1580 287 (3.63) Cs6Hi~NaOis 212-2 13 5.37 5.33 13,9Tid 13.46d 152-154 CuHiiCLNOio 7 1653,1618, 1585 286,7 ( 3 . 6 9 ) Spectra determined on Bausch and Lomb Spectronic-505 in Spectrograde a Spectra of KBr pellets taken on Beckman IR-5. Chlorine analysis. Nitrobenzoate was not crystalline (see ref. 5 for method of preparation). methanol.
1 2
1605 (broad) 1626 (broad)
NOVEMBER, 1964
NOTES
by the two methods are given in Table I1 along with the ultraviolet absorption characteristics of the flavones. The device used in reporting the infrared data involves enumerating only those bands from 6-6.5 p after the manner of Xakanishi.6 Therefore, characteristic absorption bands of 4-pyrones are usually a triplet or doublet in the range of 6-6.3 p. Those compounds showing a single absorption band, in many cases, can be separated to a doublet or a triplet by instruments capable of high resolution. However, the values given in Table I1 are in accord with the observations of Looker and Hannernan.'
cause of the unusual chemical properties associated with this ring system14it was of interest to examine the behavior of this structural unit in diene syntheses.5 Treatment of compound I with maleic anhydride over a temperature range of 35-120' failed to produce a crystalline adduct. Fair to excellent recoveries of I could be achieved depending on the temperature employed. Similar results were observed when Nphenylmaleimide was utilized as the dienophile. The adduct 11, however, was successfully obtained in 19.6% yield (based on a sizeable quantity of recovered I) when equimolar amounts of I and dimethyl acetylenedicarboxylate were heated without solvent at 120130' for 3 hr. In contrast, compound I reacted readily with tetracyanoethylene in tetrahydrofuran solution to afford a quantitative yield of the adduct I I I a . Admixture of equimolar quantities of the two components in tetrahydrofuran at room temperature produced a deep violet-brown coloration. The color of the Tcomplex had completely faded within 30 min. to give a pale yellow solution. Similarly, 1,3,5,7-tetramethyland l-ethyl-3,5,7-trimethyl-1,3-dihydro-2H-azepin-2ones reacted rapidly with tetracyanoethylene and gave rise to I I I b and IIIc in yields of 74 and 91%, respectively.
Experimental* Preparation of Compounds of the 1-7 Series. Method A.-A mixture consisting of 0.2 mole of the phenol, 0.1 mole of malonic acid, and 30 ml. of trifluoroacetic acid was heated for 18 hr. under a reflux assembly in a Fisher Hitemp oil bath a t a temperature of 100". Upon completion of the reaction period the product was diluted with 150-200 ml. of water, chilled, and filtered to obtain the yield. Compounds 1 and 3 were soluble in water, so their solutions were neutralized with sodium bicarbonate and extracted with ethyl acetate. Evaporation of the solvent from the solutions gave solids upon standing open to the atmosphere for 1 week. Analytical samples were obtained by recrystallizing the compounds twice from boiling heptane or by taking them up in ethyl acetate and precipitating them from heptane and by repeating this process for a second recrystallization. Method B.-Malononitrile (0.1 mole) was mixed with 0.2 mole of the phenol and 25 ml. of trifluoroacetic acid (in the case of phloroglucinol 45 ml. of trifluoroacetic acid was used). The mixture was refluxed for 4 hr. (2 hr. in the case of phloroglucinol) in the hood. At the termination of this initial period and without any interruption of the heating of the solutions 50 ml. of water was carefully added. Refluxing of the mixture was continued for an additional 18 hr. The solutions were diluted with an additional 100-150 ml. of water, cooled, and filtered. Purification of the compounds was the same as with the malonic acid products.
3447
k0 cH36 MeOOC
COOMe
0
H
T
CH3
CH3
H CHS
Acknowledgment.-The authors acknowledge with thanks the financial support of the Robert A. Welch Foundation. (6) K. Nakanishi, "Infrared Absorption Spectroscopy," Holden-Day Inc., San Francisco, Calif., 1962, p. 204. (7) J. H. Looker and W. W. Hanneman, J . Org. Chem.. 97, 381 (1962). See Tables I and 11; also see C. N. R. Rao, "Chemical Applications of Infrared Spectroscopy," Academic Press, Inc., New York, N. Y., 1963, p. 457. (8) Analyses were performed b y Dr. Carl Tiedcke, Teaneck, N. J., and b y Galbraith Laboratories, Knoxville, Tenn. All melting points were taken on a Fisher-Johns melting point block.
Some Diels-Alder Studies of the 1,3-Dihydro-2H-azepin-2-ones'
IIIa, R = H b, R = CH3 C, R = CH*CH,
The observation6 that 3,5-~ycloheptadienone undergoes isomerization to the conjugated 2,4-cycloheptadienone before, or during, reaction with dienophiles such as N-phenylmaleimide is readily explained on the basis of extremely facile double bond mobility in the unconjugated dienone. Although a similar situation is obviously present in the dihydroazepinone I (+ IV),
LEOA. PAQUETTE~
NC, C N
Department of Chemistry, The Upjohn Company, Kalamazoo, Michigan Received June 26, 1964
IV
In view of the newly discovered ready availability of 1,3-dihydr0-2H-azepin-2-onessuch as I3 and be(1) P a r t X of the series on Unsaturated Heterocyclic Systems. I X : L. A. Paquette, J . A m . Chem. S o c . , 86,4096 (1964).
Paper
(2) Department of Chemistry, T h e Ohio S t a t e University, Columbus 10, Ohio. (3) L. A. Paquette, J. Am. Chem. Soc., 84, 4987 (1962); i b i d . , 86, 3288 (1953); W. Theilacker, K. Ebke, L. Seidl, and S. Schwerin. Anpew. Chem., 76,208 (1963).
V
(4) L. A. Paquette; Bee ref. 1 and earlier references cited therein. ( 5 ) Of especial pertinence t o this study were t h e observations t h a t cycloheptsdienes react noticeably more slowly with dienophiles than do corresponding cyclohexadienes [K. Alder and H . H. Molls, Chem. B e r . , 89, 1960 (1956)I and t h a t the related 2(1H)-pyridones have remained unreactive (as dienes) t o the conditions of the Diels-Alder reaction (13. S. Thyagarajan and K. Rajaaopalan, Tetrahedron, 19, 1483 (1963)l. (6) J. Meinwald. 9. L. Emerman, N. C. Yang, a n d G. Riichi, d . Am. Chem. Soc., T T , 4401 (1955): 0.L. Chapman, D. J. Peeto, and A. A. Griswold,ibid., 84,1213 (1962).
