Jan., 1950
585
3-AZABENZANTHRONE DYES
method described in procedure (a). Methyl-labeled phenyl acetate was prepared from CI3HJ in the same way. Persulfuric Acid Oxidation of Cho1estenone.-Cholestenone (8.8 9.) in 350 ml. of glacial acetic acid was treated with a solution of 26.4 g. of potassium persulfate and 29.0 g. of 96% sulfwic acid as described by Salamon.ll The mixture was diluted with 530 ml. of acetic acid and allowed to stand at room temperature for one week with frequent shakmg. The sulfuric acid was neutralized by the addition of !50% potassium hydroxide, the salts were removed by filtration, and the filtrate concentrated to small volume. The crude oxidation product was then separated into acidic and neutral fractions by alkaline extraction from ether. Crystallization of the neutral material from dilute acetone gave 2.25 g. of a product, m. p. 114-116’, that did not depress the melting point of a sample of lactone IVb. The acidic fraction was esterified with diazomethane and chromatographed on alumina. The early eluates fu;nished 450 mg. of crystalline material melting at 119-123 ,
[COMMUNICATIONNO. 1295 FROM
which on repeated crystallizati2n from ether gave a pure substance, m. p. 124.5-125.5 , identical in all respects with dihydro Diels ester.2a Alkaline hydrolysis of the d!methyl ester afforded the free acid, m. p. 252-253 , identical with dihydro Diels acid (VII) .
Summary Two methods have been devised for the introduction of isotopic carbon in ring A of steroids. The best procedure involves condensation of an unsaturated ring A lactone with phenyl acetate and has been applied to syntheses of cholestenone-3-C14, testosterone-3-C14, testosterone-4-C14 and testosterone-4-C13. (23) Windaus, Bev., 63, 170 (1919).
THE
CAMBRIDGE 38, MASS.
RECEIVED OCTOBER 24, 1949
KODAKRESEARCH LABORATORIES]
3-Azabenzanthrone Dyes1 BY
c. F. H. ALLEN,*JEANv. cRAWFORD,3 R.H. SPRAGUE, ELEANOR R.wEBSTER4 AND c. v. WILSON
The longest-known representative of dyes containing the 3-azabenzanthrone nucleus is Alizarin Rubinol R (I, R, R1 = H, Rz = CH3),5,6but there are four other Alizarin Rubinolse; the entire series i s characterized by the absence of a substituent in position 1 (R = H). Two other commercial dyes, belonging to the Brilliant Alizarin Light Red Class, have a substituent group in this position. In order to learn the effect of a variety of substituent groups at several positions in the molecule on light absorption in the visible portion of the spectrum, a considerable number of dyes has been prepared. Most of these dyes have arylamino groups in the 6-position, with different substituents in position 1. The reactions used in their preparation are largely found in the patent Iiterature.’-’3 Substances of the general formula 11, in which R = CzH500C, CHsCO and CBH~CO, were prepared by treating 4-bromo-l-methylaminoanthraquinone with ethyl malonate,’ with ethyl acetoacetate7J4 and with ethyl benzoylacetate,7
respectively; while substance 11, R = CeH6, was formed by cyclization of 4-bromo-1-phenylacetylaminoanthraquinone. Substance 11, R = CN, was formed by the action of potassium cyanide on 4-bromo-l-(N-chloroacetyl-N-methylamino)anthraquinone; in the patent literature an alternative procedure, which starts with ethyl cyanoacetate, is given.13 / C Y,.-_--_-, 2; ;OCsHsi
0
1 0 II
ArNHz
J . 0 II
* Harvard University Ph.D. 1924. (1) The modern aza nomenclature has been adopted on account of its marked superiority over the older naming systems. I n the previous paper’ the substances were called “Anthrapyridones.” (2) Allen and Wilson, J . Org. Chcm., 6, 594 (1945). (3) Present address: University of Illinois, Urbana, Illinois. (4) Present address: Radcliffe College, Cambridge, Massachusetts. (5) “Colour Index,” 1st Edition (1D24), No. 1091. (6) Fierz-David, ”Ktinstliche Organische Farbstoffe,” Verlag von Julius Springer, Berlin, 1926, p. 624. (7) German Patent 578,995; Frdl., 19, 1964 (1934). ( 8 ) German Patent 580,283; ibid., 19, 1969 (1934). (9) German Patent 581,161; ibid., 10, 1335 (1935). (10) German Patent 633,308: C. A., SO, 7870 (1936). (11) German Patent 858,114: ibid., 83, 4798 (1938). (12) French Patent 831.691; Cham, &W., 110, Part 2,531 (1939). (la) German Patents 655,650, 655,851; rbid., 109, Part 1. 3700 (1988). (14) U.9. Patent 1,891,317; C. A . , 39, 1892 (1833).
I
NaO&
I11
The bromoazabenzanthrone (11) was then condensed with the appropriate aromatic arnineVJ8 to give the “dye base” (111), which was sulfonatedeJato form the dye, I. Care was taken to use carefully purified intermediates throughout; most of the dye bass (111) were not oulfonated until they had been recrystallized enough
580 C. F. H. ALLEN, J. V. CRAWFORD, R. H. SPRAGUE, E. R. WEBSTERAND C. V. WILSON Vol. 72 TABLE I l - C ~ E ~ O x Y - 3 - ~ n m - B - a DYE ” o BASES Max. absorption of dyes
Substituents
4’-Methyl 4‘-Ethyl 4‘-Isopropyl 4‘-~-Amyl 4’-t-Amyl 2 ’,4’-Dimethyl 4I-Methoxy 3 ’-Trifluoromethyl 3‘-Chloro 4’-Chloro 4’-Bromo 4,4’-Dimethyl ti-( p-Hydroxyethylamino)
Empirical formula
542
M. p., “C.
202-204 174-176 195-197 148-150 198-200 199-201 183-184.5
540
543 546 542
548 546 525 520 532 532 545 521,551
..,....
Analyses, % Carbon Hydrogen Calcd. Found Calcd. Found
74.0 74.3
73.8 5.0 5.2 74.0 5.4 5.4
75.3
75.2
6.4
6.1
74.3
74.5
5.4
5.3
65.9
65.6
3.9
3.9
74.3 74.4 67.3 67.4
5.3
5.1 5.1
....... 215-217
.......
190-192 240-242
5.1
.
Nitrogen Calcd. Found
6.4 6.5 6.2 6.3 6.0 6.2 5.7 5.4 5.7 5.7 6.2 6.1 6.2 6.5 5.7 5.9 C1, 7.6 7.5 C1, 7.6 7.8 Br,15.9 15.7 6.2 6.4 7.1 7.0
TABLE I1 l-CYANO-3-METHYL-6-ANILINO DYE Substituents
4’-Methyl 4’-Ethyl 4’-s-Amyl -l’-t-Amyl 2’,4’-Dimethyl 4’-Methoxy 3’-Chloro 4’-Chloro -l’-Cyano 4’-Acetyl
Max. absorption of dyes
580 584 590 590 587 588 584
554 570 568
M. p., OC.
>300 ind. 310-314
BASES
Carbon Calcd. Found
Analyses, % Hydrogen Calcd. Found
77.0
77.0
4.7
4.9
77.0 73.7
77.1 73.8
4.7 4.2
4.9 4.5
Ind. Ind.
343-350 >350 332-334 368-372 >360 >360
Nitrogen Calcd.
Found
10.7 10.4 9.4 9.4 10.4 10.3 C1, 8.6 10.2 13.9 9.8
10.9 10.7 9.6 9.4 10.6 10.5 8.5 10.0 13.8 9.8
times to give acceptable values upon analysis. property is particularly noticeable in the ethanolSulfonation was carried out a t 20-60°, using 100% amine derivative (VI). sulfuric acid; these conditions were favorable for the introduction of one sulfonic acid group and avoided the undesirable over-sulfonation or ring 0 closure. That the sulfonation does not effect hydrolysis of the carbethoxy group is confirmed by the fact that the product obtained from the dye I (R = CXfsOOC-, R1 = H,Rr = Cl) on treatment with nitric acid is identical with the product obtained by condensing I1 (R = GHsOOC-) with 4-chloro-2-nitroaniline as previously described for I1 (R = H).* 0 0 1 Arylamino 2 keto - 3 - methyl - 3 v IV azabenzanthrones (IV)were obtained by treating 0
-
- -
l-chloro-2-keto-3-rnetyl-3-azabenzanthrone (V)
with an aromatic amine, the dyes being formed by a subsequent sulfonation. The one aliphatic derivative prepared was of the type VI,and was made using ethanolamine. The location of the substituent groups, the maximum absorption of the dyes in aqueous solution, and analyses of the dye bases are listed in 0 Tables I-VI. In some cases the absorption VI maxima of the dye bases in dioxane are included Experimental for comparison. The dyes of the 1-arylamho series (IV)are all somewhat fluorescent, and are Many of the intermediite products have been described not particularly fast to light; the fluorescent in the patent literature. However,to facilitate repetition,
Jan., 1950
587 TULE 111 l-PECENYL-3-KETEYL-6-ANILXNO DYE BASES
Max.
rbsorption of dyes
Substituents
4'-Methyl 4'-~-Amyl 4'-:-Amyl 2',4'-Dimethyl 4'-Methoxy 4'-Chl~~o
Empirical formula
535 536 536 546 538 525
CsoHnNaQ CstHarNsO: Ca4HaaNxOs C:iHuNzOz Ca6InNaOa GsHi&OaCI
M. p., OC.
248-250 232-234 281-282 199-200 245-246 283
Carbon Calcd. Found
81.5
Analyses, % Hydrogen W c d . Found
81.6
5.0
Nitrogen Calcd. Found
5.0 5.6 5.6 6.1 6.1 c1.7.8
5.5 5.7 6.1 6.1 7.7
TABLE IV l-BENZOYL-3-hfFl'IiYL-6-ANILINODYE BASES Substituents
Max. absorption of dyes
Empirical formula
M. p., 'C.
4'-Methyl 4'-Chloro 4'-Methoxy
544 538 545
GiHnnNzOs CioHivClNnOs CaiHzzNz04
27G-277 302-304 255-257
Carbon Calcd. Found
79.1
78.7
Analyses, % Hydrogen Calcd. Found
4.7
5.0
Nitrogen Calcd. Found
6.0 5.7 5.8
6.0
6.0 5.5
TABLE V 1-ACETYL-3-METHYL-6-ANILINO DYEBASES Substituents
4'-Methyl 3'-Methyl 4'-Methoxy 4'-t-Amyl 4'-Chloro
Max. absoiption of dyes Bases Dyes
548 546 541 540 534
547
540 543 534
P
Empirical formula
CtsH~oN20, GsHzrNzOa G~HSNIO, C~aH~N~Oa GsHiiClNnOs
M. p., OC.
210-212
186188 145-148 270-272 243-245
Carbon Calcd. Found
76.4 76.4 73.6 77.6 70.0
76.8 76.2 73.5 78.2 69.5
Analyses, % Hydrogen Calcd. Found
4.9 4.9 4.8 6.1 4.0
5.2 5.0 4.5 5.9 3.5
Nitrogen Calcd. Found
6.9 6.9 6.6 6.0 6.5
6.8 6.7 7.0 6.1 7.1
TABLE VI 1-ANILINO-3-METHYL DYE BASES Substituents
Max. absorption of dyes
Empirical formula
-
Carbon Calcd. Found
M. p., OC.
Analyses, % Hydrogen Calcd. Found
4'-Methyl" 463 Cz4HiaNzOz 239-240 78.7 78.5 4.9 5.2 3'-Methyl 456 Cz~HuNzOz 26245 78.7 78.7 4.9 4.9 4'-ChlOrO 455 238-239 450 &H16ClN~02 71.5 71.3 3.9 3.6 3'-ChlOrO 252-253 65.5 2',5'-Dichloro 440 GrHirCl2N202 194-195 3.3 68.6 68.5 3.6 3.6 447 CzdHlrFaN202 244-245 3'-Trifluoromethyl 4'-Methoxy 467 189-190 l-(p-Hydroxyethylamino) 440 CloHlsN2Ot 204-206 71.2 70.8 5.0 5.0 a A dye containing p-toluidino groups in both the 1- and 6-positions has been reported previously.' maximum is a t 535 mp. a type procedure with essential details is given for each operation.
Nitrogen Calcd. Found
7.7 7.7
8.1 7.5
7.2 6.6 6.7
7.2 6.6 6.4
8.7 8.6 Its absorption
benmylacetate, 30 g. of 4-bromo-1-methylaminoanthraquinone and 2 g. of sodium acetate was heated with stirA. 6-Bromo-l-carbethoxy-2-keto-3-methyl-3-azaben-ring a t 190-195O for one and one-half hours. During this zanthrone (XI, R = -COOC;").-A mixture of 29.5 g. of time any alcohol or ethyl acetate formed was allowed to 4-bromo-l-methylaminoanthraquinone,60 g. of ethyl distil. The contents of the reaction flask were transferred malonate" and 0.1 g. of sodium acetate was heated with to a beaker and diluted with an equal volume of methanol. stirring for four hours a t 185-195". The reaction was The solid obtained was collected on a filter, washed thorcarried out in such a way that the alcohol and ethyl acetate oughly with methanol and dried. The yield of product formed in the reaction distilled out of the mixture. The melting a t 272-275' was 32.5 g. Recrystallization, which reaction product was cooled to about 100' and diluted with is not necessary for the subsequent step, raises the melting 60 ml. of alcohol. The solid that formed was collected on point t o 276-277'. C. l-Acetyl-6-bromo-2-keto-3-methyl-3-azabenzana filter and washed with alcohol. The yield of yellow prodthrone (11, R = -COCHI) is obtained by the procedure uct melting a t 183-185' was 21 g. (60%). B. l-Benzoyl-6-bromo-2-keto-3-methyl-3-azabenzan-used for the benzoyl derivative from 200 ml. of ethyl acetothrone (11, R = -COCdf6).-A mixture of 60 g. of ethyl acetate, 50 g. of 4-bromo-l-methylaminoanthraquinone, heated for six hours a t 160-180°; the yield was 34 g.; m.p. (15) It is essential that the ethyl malonate be free from acid, other235-237 wise the sodium acetate which acts as a catalyst will be destroyed. I). 6-Bromo-2 -keto-3-methyl-1-phenyl-?)-azabenzanIf necessary the ethyl malonate can be shaken with sodium acetate throne (11, R = +&.).-To a mixture of 158 g. of 4DriOT to USC. bromo-1-methylaminoanthraquinone and 1200 ml . of
'.
588 C. F. H.
- ~ L L E N J. ,
V. CRAWFORD, R. H. SPRAGUE, E. R. WEBSTERAND C. V. WILSON Vol. 72
toluene was added 140 ml. of phenylacetyl chloride. The two years. A decomposition of 0- and p-trifluoromethylmixture was refluxed for two hours and then filtered. The phenols in the presence of a basic reagent has been reported filtrate was concentrated to one-fourth its original volume recently as well as polymerization and loss of hydrogen and chilled. The solid that separated was collected on a fluoride from p-aminobtnzotrifluoride a t 200 ' . I f , l 7 filter and washed with ether. The yield was 155 g. (71%). The 6-( 8-hydroryethylamino)-derivative was made using The crude 4-bromo-1-methylamino-N-phenylacetylan- an excess of ethanolamine as solvent and at 100" for two thraquinone melted a t 167-168' (lit. 170-171') and 13 and one-half hours. I t dyes acetate bright pink; the dyed material fluoresces orange and has a poor light stasufficiently pure for the next step. The yield was 88% bility. with one-fifth these amounts. Ring Closure.-To a solutioii of 152 g. of the anthraThe 1-( p-hydroxyethylamino) -derivative required only quinone derivative in 1000 ml. of ethylene glycol mono- one hour a t 100' for its preparation. It dyed acetate ethyl ether a t 120-130" was added 15 g. of potassium hy- greenish-yellow , droxide in 23 ml. of water over one-half hour with stirring. H. Sulfonation.--The dye bases were all sulfonated by There was an immediate formation of a solid and a marked the same general procedure. One part of the dye in 5-6 darkening in color. The mixture was cooled to 20" and parts of monohydrate (lOOOj, sulfuric acid) was stirred at filtered. The resulting orange colored solid was washed room temperature until a sample dissolved in water and with ethylene glycol inonoethyl ether and finally with shaken with benzene imparted little or no color to the benzene layer. In most cases the sulfonation was carried out ether. The yield wds 1-12 g. (97%); m. p . 325-328". It can be purified by recrystallization from cellosolve and overnight but in a few instances, notably with the 1-cyano melts a t 332-334", but it can be used successfully without and 1-benzoyl derivatives, it was found necessary to heat for a short time on the steam-bath to complete the sulthis recrystallization. E. 6-Bromo-I -cyano-2 -keto-3 -methyl-3-azabenzan- fonation. The dyes were generally isolated by pouring throne (11, R = -CN) .--.4 rnixture of 59 g. (0.15 mole) of the sulfonation mixture on ice, collecting the precipitated I-brorno-l-chloroacetylmethylaminoanthraquinone2 and free acid on a filter, dissolving the free acid in dilute am590 ml. of 6-hydroxyethyl acetate was stirred and heated monia, evaporating to dryness (steam-bath) and extractto about 180" in a 2-1. flask until solution was complete. ing the dye from its mixture with ammonium sulfate with \Vhilc stirring was continued, the solution was cooled to methanol, finally recovering the dye by removal of the methanol. If the free acid failed to precipitate when the 'ibout 120°, and a solution of 32 g. (0.5 mole) of potassium cyanide in 60 mi. of water was added all a t once. The sulfonation mixture was poured on ice, the solution was suspension of orange-yellow solid which appeared imme- made basic with ammonia and evaporated to dryness. diately was stirred and heated a t 120-130O for one hour, The dye was then isolated by extraction with methanol as and was allowed to cool slowly. After chilling in an ice- before. The absorption curves of the dyes are given in the bath, the orange-yellow 6-bromo-l-cyano-3-methyl-3- tables. An analysis of the finished dye I (R = C,H,OOC, R1 = azabenzanthrone was filtered and washed thoroughly with methanol, water, methanol and ether. The yield of crude H, R2 = Cl) is given, to show that the ethoxy group is material melting at 328-330" was 44.5 g. (81%). A small not removed during the sulfonation. This dye crystallizes sample crystallized from dioxane melted a t 345-347", but from acetic acid with a molecule of solvent, but this is lost larger samples are more conveniently Crystallized from on recrystallization from dilute alcohol. 1,2,4-trichlorobenzene. The recovery on crystallization Anal. Calcd. for C%Hl&1N2NaO9S~C2H4O2: C, 54.0; is only about 60%; the crude material can be used directly H,3.5; S,5.2. Found: C,53.8; H,3.6; S,5.0. Calcd. in most cases. for CzaHl&lNpNaO&: C, 55.6; H, 3.2; S, 5.7; N, 5.0; F. l-Chloro-2-keto-3-methyl-3-azabenzanthronewas Na, 4.1; CzH50, 8.0. Found: C, 55.0; H, 3.1; S, 6.1; obtained following the published directions. lba N, 4.9; Na, 4.5; C2H60, 7.9. G . The dye bases were all obtained by the same genI. l-Carbethoxy-3-methy1-6-(4'-chloro-2'-nitro)-3eral procedure, illustrated by the preparation of l-car- azabenzanthrone substance was prepared from I1 bethoxy-6-(4'-chloroanilino)-2-keto- 3 -methyl -3 azaben- (R = C2H500C).-This and 4-chloro-2-nitroaniline in the manza.nthrone.-A mixture of 3 g. of 6-bromo-1-carbethoxy- ner previously described2 for the synthesis of 3-methyl-62-keto-3-methyl-3-azabenzanthrone, 3 g. of p-chloroaniline, 1.1 g. of sodium acetate, and a trace of copper acetate (4'-methyl-2'-nitro) -3-azabenzanthrone. It was proved be the same as the product obtained from I (R = was heated in a long test-tube in an oil-bath for five hours to C2H600C. Ri = H, RZ = C1) by treatment with dilute At 160-175" with stirring. The mixture was cooled some- nitric sad,* by analytical results, behavior on heating a mhat and then treated with methanol. The dye which mixture of the two compounds and the identity of the separated war collected on a filter and washed successively absorption curves. with warm water, warm dilute hydrochloric acid, water and Summary methanol. The crude yield was 3.4 g. I t was recrystallized from benzene or nitropropane, from which it sepaA large number of variously substituted 3rated in violet crystals that showed a greenish "oberflasche." The yields varied considerably often being azabenzanthrone dyes have been made, and their quite low. The analytical figures and melting points absorptions recorded. (which are often indefinite) are given in the tables. No 1-arylamino derivatives have been reported p-Aminobenzotrifluoride could n:t be condensed with previously; they are not particularly fast to light. the 6-bromoazabenzanthrone a t 160 ; the solution became red indicating some dye formation, but most of the tri- ROCHESTER 4, KEWYORK RECEIVED OCTOBER 18, 1949 fluoride appeared to polymerize, probably with loss of (16) Jones, T m JOURNAL, 69, 2347 (1947). hydrogen fluoride. The formation of polymer wag (17) #-Nitrobenzotrifluoride, p-aminobenzotri8uoride and the hrought about by heat; it appeared to be accelerated by copper acetate, but hindered by potassium acetate. The acetyl derivative of the latter were prepared by Mr. E. C. Armstrong amine itself appeared to be essentially unchanged after and Miss Eleanor R. Webster' of tbese laboratories. As the pro-
-
iI5a) Dupont Bull sac chrm Belg , 63, 7 (1943). c' A , 38, i 2 1 5 (1944)
cedures used and properties of the substances were essentially the same as those independently reported,lEthey will not be duplicated here.
