3443
4-CARBOXYTROPOLONE AND RELATED COMPOUNDS
July 5, 1959
[CONTRIBUTION FROM
THE
CHEMISTRY DEPARTMENT O F THE UNIVERSITY
OF
ROCHESTER]
4-Carboxytropolone and Related Compounds BY D. STANLEY TARBELL, KENNETH I. H. WILLIAMS AND EUGENE J. SEHM RECEIVEDJANUARY 13, 1959 4-Carboxytropolone and several other 4-substituted tropolones and 4-substituted 2-aminotropones have been prepared from purpurogallin through the 4-styryltropolones. The key step is represented by the oxidation of 4-styryltropolone to 4-formyltropolone by t h e osmium tetroxide-catalyzed periodate procedure. A stable acid chloride has been prepared from 2-acetamino-4-carboxytropone. 4-Formyltropolone has been condensed with malonic acid t o yield 4-(p-carboxyvinyl). . tropolone.
In connection with some projected syntheses in the tropolone field, it was necessary to obtain 4carboxytropolone (IV) and some of its derivatives by practical procedures. The preparation of this compound has been reported by several proc e d u r e s , ’ ~but ~ all are long and the yields are unsatisfactory. Our re-examinations of some of them failed to give a feasible method of preparation, and we have therefore developed a new synthesis of 4-carboxytropolone and various related compounds by the oxidation of 4-styryltropolone. Initial attempts to oxidize 4-styryl-3-carboxytrop o l ~ n e and ~ . ~ the 4-styryltr~polone~ were unpromising, and attention was directed toward the corresponding 3,4-dimethoxy series, I. Oxidation of the methyl ether methyl ester Ia by permanganate in aqueous suspension a t room temperature in the presence of magnesium sulfate gave about 25% yield (after sublimation) of the anhydride 111,2 which was decarboxylated to the acid IV by heating in aqueous solution in a bomb.2 The acid was converted into the new crystalline benzoate IVa by benzoyl chloride and pyridine. This sequence of reactions was not satisfactory because of the number of stages and the low yields in some of them. Because in allof the oxidations tried, including the
I , R = H,R’ = COOH Ia, R = C H , , R’=COOCHB Ib, R = H , R’=COOCHB HOOC / 11, R = R ’ = H O IIa, R = COCsH5, R‘=H
.o O
-
I., R C,HjCH=CH
=
OH
\-a, R = OCHs Vb, R OCOCH, R VC, R = OCOCsHb VI, R NHz VIa, R = NHCOHI V I I , R = NHNHz
(VIII) was oxidized to the 4-carboxytropolone (IV) with fresh silver oxide1,l0in basic solution in 53YG yield. The attempted preparation of the acid chloride of IV with thionyl chloride failed, as expected, as tropolones are known to react with this reagent to form 2-chlorotropone~~~ and also with acid chlorides to give esters. The benzoate IVa suffered decomposition when treated with oxalyl chloride.I2 As 0-acyltropolones are vinylogs of acid anhydrides, i t is not surprising that they are unstable.
VIII, R = H VIIIa, R = C H 3
IX
R
IV, R = H
o-c* 0
neutral permanganate method described above, the tropolone ring appeared to be oxidized more readily than the styryl double bond, we investigated more specific oxidation procedures for carbon-carbon double bonds. Ozonization7 of 4-styryltropolone was unsuccessful, and the permanganate-periodate procedure8was also. However, the osmium tetroxide-catalyzed periodate procedure9 gave an 84cz yield of purified 4-formyltropolone when applied to 4-styryltropolone (V). The 4-formyltropoloiie
IVa, R = COCdHs
111 (1) R . D. Haworth and J. D . Hobson, J . C h i n . Soc., 561 (1951). (2) W. D. Crow, R. D . Hawurth and P. R. Jefferies, i b i d . , 3705 (1952). (3) J . R. Bartels-Keith and A. W. Johnson, Chemistry b Industry, 677 (1950); J. R . Bartels-Keith, A. W. Johnson a n d W. I. Taylor, J . Chem. Soc., 2352 (1951). (4) Y.Kitahara. S c i . Reply. Tohoku Uiczv., 40, 74 (1956). ( 5 ) ( a ) T. Nozoe, Y. K i t a h a r a , K. Doi and M . Endo. Proc. J a p a n Acad., 2S, 32 (1952); (b) D. S. Tarbell, R . F. S m i t h a n d V. Boekelheide, THISJ O U R N A L , 76, 2470 (1954). (6) T. Nozoe, Y.K i t a h a r a , K . Doi a n d S. Masamune, Proc. J a p a n Acad., 2S, 291 (1952).
In order to circumvent this instability of the acylating agents derived from 4-carboxytropolone, various methods of protecting or altering the tropolone hydroxyl group were investigated. Methylation of 4-styryltropolone with diazomethane yielded the known’ ether Va, m.p. 142’; the noncrystalline residue evidently contained the isomeric ether X, because oxidation of these residues by the osmium tetroxide-periodate procedure yielded 2methoxy-4-formyltropone I X which has been de(7) Cf. C. E. Kaslow a n d R. D . Stayner. THISJ O U R N A L , 67, 1716 (1945), for t h e ozonization of styryl heterocycles t o t h e corresponding carboxylic acids. (8) E. van Rudloff, Can. J . Chem., SS, 1714 (1955). (9) R . Pappo, D. S. Allen, Jr., R. U. Lemieux a n d W. S. Johnson, J . Org. Chem., 21, 478 (1966). (10) 1. A. Pearl, THISJOWRNAL, 68, 429 (1946). (11) W. von E. Doering a n d L, H. Knox. ibid.. 74, 5683 (1952). (12) Roger Adams a n d L. H. Ulich, ibrd., 42, 599 (1920).
3'444
D. STANLEY TARBELL, KENNETH 1. H. V'ILLIAMS AND EUGEXE J. SEIIAI
Vol. s1
four portions of ethanol. Both samples gave the SLLIIIC iiifr'tred spectrum and !-ielded the same methyl ether tnetliyl ester Ia . d n a l . (210' sample). Calcd. for C I Y H I ~ OC, ~ : (i5.85; H, 4.91. Found: C, 65.67; H, 4.95. X X I , R = OCH; Methyl Ether Methyl EsterI5Ia of I.--.% mixture of (j.26 g . of 3-carbox~--4-(3,4-dimethoxystyryl)-tropolotie, 8 g . r i f tliS I I , R NH, methyl sulfate, 8.8 g. of powdered anhydrous pi)t;tssiuiii XIII, R = NHCOCHa carbonate and 250 ml. of dry acetone were refluxed with stirring for 23 hr. The mixture mas cooled, filtered and the scribed and oriented by H a ~ o r t h . ' , ' ~Similar oxi- filtrate was freed of acetone. The residue was rubbed with dation of the crystalline methyl ether X yielded 25 rnl. of dilute ammonium hydroxide t o decompose the en2-methoxy-6-formyltropone (VIIIa), the orienta- cess dimethyl sulfate. The resulting yellow solid was collected, dissolved in 60 nil. of methanol, tlie methanol solution of which was based on exclusion. By rela- tion was diluted with 400 ml. of water, and the resultiiig tion to VIIIa the orientation of the crystalline solid was collected, redissolved in methanol and reprecipistyryl methyl ether Va is known as are the orien- tated with water. The yield was 6.6 g. (93y0) of material tations of its derivatives VI, VIa and 1'11 (see melting a t 75-79", n'hen this solid was heated at 1080 for min. or was recrystallized from methanol. the 1i1.p. was Experimental). The orientations of the tropolone 30 raised t o 137-138". Both products gave a negative ferric esters are not known. chloride test and were insoluble in cold saturated bicarhiinnte Treatment of the isomeric aldehydes S-IIIa and solution. IX with fresh silver oxide in cold basic solution ;11zai. Calcd. for C20H200s:C, 67.40; H, 5.66. Found resulted in the hydrolysis of the former to 4- (111.p. i C 5 - 7 9 O ) : C , 67.14; H, 5 . 5 8 . Found ( I X I . ~ . 137formyltropolone and oxidation of the latter to 138"): C, 67.38; H, 5.75. infrared spectra of these two sdtnples indicate tli~tt ?-methoxy-4-carboxytropone(XI). As this com- theThe higher-melting sample has a &-disubstituted double pound yielded an unstable acid chloride when bond (sharp bands a t 947, 792 and 785 c i n - ' ) ; the lowertreated! as the potassium salt, with oxalyl chloride, melting compound is probably a mixture of cis and t ~ a i ~ . ~ further alteration of the tropolone hydroxyl func- forms (weak, broad band a t 911-962 cm.-', no absorptiiiii a t 7 8 G T 9 5 c ~ n - ~ )The . starting acid I has a sharp band a t tion of 4-carboxytropolone was necessitated. 96,5 c m - ' , indicating that it, like its analogs,jb has 3 truizs Treatment of 2-methoxy-J-carboxytropone ( X I ) double bond. with liquid ammonia in a sealed tube a t room temTreatment of I in dioxane with ethereal diazon~cthatic perature gave the crystalline 9-amino-4-carboxy- yielded a small amount of the above dimethyl colnpoutld, 75-79', which was characterized by mixed n1.p. and its tropone (XII) which was converted to the acet- m.p. infrared spectrum. The use of ether instead of dioxane iii amino compound X I I I . This was in turn changed this reaction yielded a yellow solid, m . p . 171-173", whicli to its relatively stable acid chloride, with oxalyl gave a positive ferric chloride test and hence was the methy/ chloride, and characterized by its p-bromoanilide. ester I b ; this was supported by t h e analysis. Anal. Calcd. for C19H180s: C, 66.67; H, 5.30. Foulid: 4-Formyltropolone reacts, in the normal manner of aromatic aldehydes, with malonic acid and C, 67.01; H, 3.41. Several unsuccessful attempts t o oxidize tlie stilbene-tylx: piperidine catalyst in pyridine solution to give double bond of 3-carboxS--4-styryltropoloiie, 3-carboxy-44-(0-carboxyvinyl)-tropolone (XIV). (3,4-dirnethoxystyryl)-tropolone( I ) , 4-styryltropolone ( V ) and of their benzoates were made. These included o z o ~ ~ a tion, perdcid oxidation, permanganate-periodate oxidation, Prevost oxidation, nitric acid oxidation and chromic acid O x o H t~xidation. Tro~olone-3.4-dicarboxvlicAcid Anhvdride (1111. --TI) a s u s p e h o n of g. of the ðyl ether & 3-carboinetho. SI\' (3,4-dimethox!-st!-ryl)-tropolorie (Ia) in 180 ml. of I containing 2 g. of magnesium sulfate was added a soluti Experimentali4 4.48 g. of potassium permanganate in 320 ml. of water. The :~-Carboxy-1-carboxynietl1~-ltropolte was preparcti by oxiaddition was complete in 15 niin. and t h e purple pcrniaudation of p ~ r p u r o g a l l i nfollowing '~ Haworth's procedure,' with ganate color wras gone in :in additional 15 inin. The mixsome inodifications.l6 The use of purpurogallin which had ture was stirred for 1 hr. and the manganese dioxide atid.tlie been purified by crystallization from anisole gave yields of 52unreacted starting materi:tl were removed bl- filtration. Tlie 5.W; crude purpurogallin gave much lower yields, in t h e neutral filtrate was extracted for 1 hr. with 23') inl. of et11c-r. 20-307c range, and the results were frequently erratic. n ' a s acidified to cimgi~red with coucentrxted hytlrrichloric 3-Carboxy-4-(3,4-dimethoxystyryl)-tropolone(I).-.I niix- acid and was the11 extracted ccititinu~iusiywith etlier f ( ~ lri i ture (Jf 9 g. of 3-carboxy-4-carboxynietl1yltropol~11e,80 nil. hr. ( i f acetic acid and 6 ml. of acetic anhydride was stirred a t 7'he cvtract frciiii tlic ncutrul ~iiltiti~iii affiirtlccl 2..j f i . [ i t i t 70' for 1.5 hr., and then cooled to 40'. T h e dark red solu- yellow o i l , which ).iclded ii rctl ~ , ~ - d i ~ i i t r ~ r p l i c i ~ ~ l l i y ~ l ~ ~ t ~ ~ i i i c tion was treated with 3 inl. of pyridine and fi.6 g. o f vera- sliowi t r i t i c that o f \-cr;itraldehydcb y a niiscd m.p. traldehyde, and stirring was continued for 3 hr. a t 40-50". Thc extract frr~inthe acidified solution \viis frccti of c t l ~ c i . , T h e mixture was heated briefly to 'io", then it was allowed with 5 nil. of ether, and the rcto cool slowly t o about 20". The orange solid that separated 850 iiig.) was sublimed at 120 was filtered and washed with ethanol to yield 7.4 g. (56y0) ed 300 nig. (23(j$) o f thc yello\v of product, melting with decomposition a t 195-197". It with cieci,iiipositioli. ~Ilthciugl~ gave an immediate red color with ferric chloride in ethanol. the carbon and hydrogen analysis was not very satisfactiirJ-, In other experiments the product was obtained melting with the agreement of the n1.p. and the infrared spectrum with decomposition a t 208-210'. The lower melting sample was those reportedYindicated t h a t i t w a s tlic anhydride. not converted into the higher melting one by warming with Ikcarboxylation in water2 a t 1iO-180° for 40 niin. g:r\ 46':$, yield of 4-carhr)xytropolone, n1.p. 217-218", in agrec( l : i ) P. Akroyd, I% mixture of 1.5 g. of 2-methoxy-6-styryltropone (Va) and 30 ml of liquid ammonia was allowed to stand in a sealed tube a t room temperature for 45 hr. After evaporation of the ammonia the product was recrystallized from 100 ml. of benzene t o give 0.85 g. of orange plates, m.p. 135-136'. An additional 0.35 g. was obtained by treating the filtrate with decolorizing charcoal and evaporating to 20 ml. T h e total yield was 1.2 g. (86%). Three more crystallizations from benzene (with charcoal treatment) gave t h e analytical sample as sparkling golden plates, m.p. 137-138". Anal. Calcd. for CljH13TO: C, 80.69; H , 5.87. Found: C , 80.24; H, 5.80. T h e acetyl derivative VIa was prepared with acetic anhydride and pyridine, and melted, after three crystallizations from heptane containing 5y0 of benzene, at 179.5181'. Anal. Calcd. for CL7HljNO2:C, 76.96; H , 5.70. Found: C , i6.96; H, 5.98. 2-Hydrazino-6-styryltropone (VII).-To a suspension of 0.238 g . of 2-methoxp-6-styryltropone in 1 ml. of methanol and 1 ml. of dioxane was added 0.1 g. of 95% hydrazine. T h e mixture was warmed on the steam-bath for 5 min. a n d cooled; t h e crystals were collected (0.21 g . , 88%) a n d after three crystallizations from methanol gave brilliant red crystals, m.p. 162.5-163.5'. Anal. Calcd. for C15HldN20: C, 75.60; H , 5.92. Found: C, 75.91; H, 5.79. 4-(p-Carboxyvinyl)-tropolone (XIV).--A mixture of 0.75 g. of 4-formyltropolone, 0.52 g. of malonic acid, 1 ml. of piperidine and 20 ml. of pyridine was heated on the steamb a t h for 12 hr. T h e resulting solution was poured over ice and acidified with 10% hydrochloric acid and t h e acidic solution was continuously extracted with ether for 24 hr. Evaporation of the dried ether solution and recrystallization of t h e solid residue from ethanol gave yellow needles of 4-(~-carboxyvinyl)-tropolone,m.p. 226.5-227.5' dec. (sealed t u b e ) , The compound gave a n immediate greenbrown color with ethanolic ferric chloride solution. Anal. Calcd. for Cl0H8O4: C, 62.60; H, 4.20. Found: C , 62.84; H, 4.37. ROCHESTER 20, N. Y
lCONTRIBUTION KO. 111 FROM THE INSTITUTO DE QU~MICA DE LA UNIVERSIDAD NACIONAL A U T ~ N O M DE A MEXICO]
The Beckmann Rearrangement of the Acetoxime of ~~~*~-Pregnadien-3P-ol-2O-one Acetate with Boron Trifluoride B Y J. R O h f o
AND
A.
R O % f O D E I'IVAR
RECEIVEDDECEMBER 11, 1958 Beckmann rearrangement of A~~~~-pregnadien-3(3-acetoxy-2O-acetoximino ( I b ) with boron trifluoride etherate in benzene afforded dehydro epiandrosterone acetate ( I I b ) , whereas in acetic anhydride t h e rearrangement followed a different course a n d two products were isolated: 17~-methyl-18-nor-A~~1~~14~-isopregnadien-3~,16cr-diol-2O-one diacetate ( I I I a ) and 16-acetyl17-acetylamino-A~~1~-androstadien-3p-ol acetate ( V I I a ) ; several derivatives are described.
The Beckmann rearrangement of A5,iB-pregnadien-3P-ol-20-one 3-acetate 20-oxime (Ia) has been studied by G. Rosenkranz, et a1.l Using p-acetamidobenzenesulfonyl chloride as catalyst, the reaction afforded dehydroepiandrosterone (IIa) and working under appropriate conditions the inter(1) G. Rosenkranz, 0. Mancera, F. Sondheimer a n d C. Djerassi,
J. Org. Chem., 21, 520 (1956).
mediate amide VI could be isolated. I n view of the current interest in this degradation of AL6-2Oketones to androstane derivatives we considered the use of boron trifluoride as catalyst in this reaction. Recently Hauser and Hoffenberg2 have used boron trifluoride in the Beckrnann rearrange(2) Ch. R . Hauser and D. s. Hoffenberg, TEIS J O U R N A L , 77, 4885 (1955).
