Oct. 3 , 1'Jt53
3109
4-HYDROXY-3-NITROCINNOLINE [CONTRIBUTION FROM
AVERYLABORATORY, UNIVERSITY
O F XEBRASRA]
Cinnolines. 11. 4-Hydroxy-3-nitrocinnoline and Derivatives1, BY HENRYE. BAUMGARTEN RECEIVED APRIL22, 1955 The reaction of 3-nitrocinnoline with hydroxylamine yielded 4-amino-3-nitrocinnoline and alkaline hydrolysis of the latter gave 4-hydroxy-3-nitrocinnoline, the properties of which were in substantial agreement with those of a nitro-4-hydroxycinnoline obtained bl- Schofield and Simpson3as one product iri the nitration of 4-hydroxycinnoline. Several derivatives of l-hydroxv-,~-nitrocinriolineand of 4-amino-3-nitrocinnoline are described, including the previously inaccessible 3,4-diaminocinnoline.
Schofield and Simpson3 have reported that the nitration of 4-hydroxycinnoline gave, depending upon the conditions, as many as three isomeric mononitro-4-hydroxycinnolines, two of which have been shown to be 6-nitro-4-hydro~ycinnoline~ and 8-nitro-4-hydroxycinnoline. To the third isomer, obtained in largest yield when the nitration was carried out a t 30" in the absence of sulfuric acid, tentatively has been assigned the structure 3-nitro-4-hydroxycinnoline (111) on the basis of the non-identity of the substance with authentic 5 , 6-, 7- or 8-nitr0-4-hydroxycinnoline.~~~ Inasmuch as the third isomer may play a role of some importance in any complete description of the nitration of heterocyclic systems,ja7we have undertaken and report here the unambiguous synthesis of 111. In the first paper2of this series we described a synthesis of 3-nitrocinnolines from o-aminoaryl compounds, which, however, was not successful when applied to anthranilic acid, the substance which might have yielded I11 directly. The present preparation of I11 started from 3-nitrocinnoline (I), a substance readily prepared by the earlier synthesis.
nitroquinoline, respectively. Application of this reaction to I gave 4-amino-3-nitrocinnoline (11) in 50-62% yield. The identity of I1 was established by reduction with stannous chloride and hydrochloric acid to 3,4-diaminocinnoline (IV) in 767" yield and condensation of the latter with phenanthrenequinone to form $),lo,11,16-tetraazotribenzo [a,c,h]anthracene (V). The identification of V was based on analysis and the display of the halochromy in concentrated sulfuric acid said to be characteristic of many quinoxaline derivatives. l U The preparation of I V is of interest per se, for earlier attempts to prepare 3,4-diaminocinnolines by the ammonolysis of 3,4-dihalocinnolines were unsuccessfu1.l' Although we first contemplated the replacement of the amino group in I1 by hydroxyl through treatment of I1 with nitrous acid, attempts to bring about this exchange in dilute or concentrated hydrochloric or sulfuric acids, a t low or high temperatures, gave unsatisfactory results, no significant amount of I11 being formed. However, warming I1 with dilute aqueous potassium hydroxide
SHi
OH
?
SnCl?
c1
C1
~
+ r I. I?
The reactions of Znitronaphthalene and 3-nitroquinoline with hydroxylamine have been shown to yield 2-nitro-1-naphthylamine8 and 4-amino-3(1) This work was supported in p a r t b y grant G-1090 of t h e National Science Foundation (2) P a p e r I, THISJ O U R N A L , 76, 3489 (1954). (3) K . Schofield a n d 1. C. E . Simpson, J . C h e m . S o c . , 512 (1945). (4) J . C . E . Simpson, i b i d . , 237 (1947). ( 5 ) K. Schofield and T . Swain, ibid., 1367 (1949). (6) K. Schofield and R . S. Theobald, rbid., 204 (1949). (7) K . Schofield, Q u a r f . Reus.. 4, 382 (1950). (8) J. Meisenheimer and E . Patzig, B e r . , 39,2533 (1906).
\-I I
VI11 C&OH
c ~ c ~ ~ r ; OCsN, 1
' \
')--SO? ! \"
IX
_____
s
(9) M. Colonna and F. Lfontanari, G a m . c h i m . i f a l . , 81, 744 (1951). (10) J. C. E . Simpson, "Condensed Pyridazine a n d Pyrazine Ring-,'' Interscience Publishers, Inc., S e w York, N. Y., 19.53, p . 203. (11) IC. Schofield and T Swain, J . C h e m . Soc., 392 (1930).
5110
HENRYE. BAV~IGARTEN
Yol. 77
brought about the rapid hydrolysis of I1 to 111 in which gave under similar conditions only the 47 5 4 3 % yield. Comparison of the melting point phenoxy derivatives or, in a single instance,16 a and infrared spectrum of our 111 with the melting mixture of the 4-amino and the 4-phenoxy derivapoint and infrared spectrum of the original nitration tives. 3-Sitro-4-phenoxycinnoline (X) could be product obtained by Schofield and Simpsona indi- prepared in rather poor yield by treatment of VI1 cated that the two substances were identical. l 2 with phenol and potassium carbonate (or potassium Definite identification of 111 as a nitration product hydroxide). of 4-hydroxycinnoline lends support to the sugThe reaction of VI1 with aniline gave 4-anilino-3gestion of Schofield and Swain5 that the nitrations nitrocinnoline (IX) in 727, yield. Compound I X of 4hydroxycinnoline and 4-hydroxyquinoline a t dissolved readily in cold 10% aqueous potassium higher temperatures in the absence of sulfuric acid hydroxide, forming a bright red solution from may follow similar paths, yielding in part products which IX could be recovered essentially unchanged nitrated in the hetero ring, although the reasons for on acidification. This interesting behavior sugsuch nitration remain o b s c ~ r e . ~ gests that I X forms a potassium salt, the anion of The reaction of 111 with methyl sulfate in alka- which might be represented by a hybrid of several line solution gave a substance to which has been structures, among which may be assigned tentatively the structure 1-methyl-3-nitro9 XcsH5 4-cinnolone (VI) based on the behavior of the other isomeric nitr0-4-hydroxycinnolines.~~~ The course of the reaction of I11 with phosphorus oxychloride showed a considerable dependence on the reaction conditions. Thus, treatment of I11 8 with aged phosphorus oxychloride a t 95" for 15 to 20 minutes gave 4-chloro-3-nitrocinnoline (1711) in 50Experimental l9 6 i 7 0 .yields, whereas with aged phosphorus oxy4-Amino-3-nitrocinnoline (11).-To a stirred mixture of chloride and phosphorus pentachloride I11 reacted 5.0 g. (0.028 mole) of 3-nitrocinnoline,* 12.5 g. (0.18 mole) rapidly to give a mixture of a t least two products, of hydroxylamine hydrochloride and 300 ml. of 95% ethV I 1 and 3,4-dichlorocinnoline (VIII) (identified by anol in a flask placed in a water-bath at 27" was added dropover a period of 0.5 hour a filtered solution of 25 g. (ca. its melting point and by preparation from it of the wise 0.38 mole) of potassium hydroxide in 100 ml. of methanol. known 3-chloro-4-phenoxycinnoline13) . l 4 , I 5 FurtherAddition of the methanolic potassium hydroxide caused the more, when VI1 was heated with aged phosphorus temperature of the bath to rise to 30". At this point the oxychloride and phosphorus pentachloride a t 110" solution contained a voluminous precipitate and was bright in color. (Addition of this precipitate and solufor three hours, VI11 was formed in 87% yield, indi- orange-red tion to water yielded none of the desired product but gave an cating that replacement of the 3-nitro group may amorphous precipitate after standing 24 hours.) The have (and probably did) occur after replacement of solution was heated nith stirring to 50" and held a t that the hydroxyl group. This replacement of the 3 - temperature for 0.5 hour. The bath was removed and was continued for 0.5 hour. The mixture of rednitro group by chlorine in VI1 is reminiscent of the stirring brown solution and precipitate was poured into 1.5 1. of ice replacement of a &nitro group by chlorine in T- and water mixture. After standing one hour the cold mixchloro-6-nitro-4-hydroxycinnoline15 and of the re- ture was filtered, and the crude, yellow product was dried in placement of a 3-bromo group by chlorine in sev- D U C U O , giving 3.4 g. (64%) of crude i-amino-3-nitrocinnoline, m.p. 302-304". In three similar experiments the crude eral compounds12under similar conditions. yields were 50, 56, 62%; in three experiments using three The reaction of VI1 with phenol and ammonium times the above quantities the yields were 50, 50, 55%. carbonate gave I1 in essentially quantitative yield. The crude material could be used satisfactorily for the of 4-hydroxy-3 -nitrocinnoline. This behavior is different from that of the other ni- preparation The product vias not very soluble in the following organic tro-4-hydroxycinnolines studied previously.6,17.1*solvents, which are listed in the order of decreasing solvent (12) We are deeply indebted t o Dr. K . Schofield b o t h f o r making a comparison of t h e two products in his own laboratory and f o r sending us a sample of t h e original nitration product. ( 1 3 ) K . Schofield a n d T. Swain, J . Chein. S O C .384 , (1950). (14) After treatment of 111 with fresh phosphorus oxychloride a t 120° f o r t w o hours, I11 could be recovered quantitatively unchanged. With f r e s h phosphorus oxychloride and phosphorus pentachloride VI1 could be obtained somewhat more slowly, in somewhat lower yield and a t t h e expense of some decomposition. T h e variability in t h e activity of phosphorus oxychloride with age had been observed earlier by A. Albert a n d XT'. Gledhill, who found t h a t hydroxyacridines reacted more readily with t h e aged t h a n with t h e fresh reagent. They attributed t h e difference in activity t o t h e presence of phosphoric acid in t h e aged reagent. Whether or not this explanation is entirely correct, in t h e present work t h e addition of a small amount of sirupy phosphoric acid t o a mixture of I11 and fresh phosphorus oxychloride did enhance t h e reactivity of t h e latter, although t h e result was n o t quite as satiTfactory a s t h a t obtained with naturally aged phosphorus oxychloride. I n a limited series of experiments t h e similar addition of polyphosphoric acid t o fresh phosphorus oxychloride appeared t o h a v e n o beneficial effect. (15) A Albert and W.Gledhill, J . SOL.Chem. I n d . , 64, 169 (1945). (16) J. R . Keneford, J. S . Morley and J. C . E. Simpson, J . Chein. .Coc., 1702 (19-18) (17) J . R. Keneford. K . Schofield and J . C . E . Simpson, i b i d . . 8 3 8 (19.18). (18) J. R . Keneford and J. C. E:. Simpson, i b i d . , 3.74 (lR48).
power: ethanol, ethyl acetate, methanol, acetone, benzene, chloroform. The product was best purified by dissolution in refluxing ethanol, in which it dissolved only very slowly and to the extent of about 0.15 g. per 100 ml. of hot solvent followed by rapid chilling of the solution in ice. The above preparation gave 2.7 g. (50%) of pure 4-amino-3-nitrocinnoline, m.p. 308-308.5", as a yellow, cottony solid, which under the microscope appeared as tiny yellow needles. On the Kofler hot-stage the needles underwent a characteristic change of crystal form a t 289-291" t o large flat plates melting a t 305-306". Anal. Calcd. for CsH6N402:C, 50.53; H, 3.18; S , 29.46. Fountl: C, 50.42; H, 3.00; S , 29.32. 3,4-Diaminocinnoline (IV).-To a mixture of 2.0 g . (0.011 mole) of 4-amino-3-nitrocinnoline in 40 ml. of concd. hydrochloric acid was added a solution of 10.0 g. (0.044 mole) of stannous chloride dihydrate in 25 ml. of concd. hydrochloric acid. The resultant suspension was heated gently on the steam-bath for two hours, poured onto crushed ice, made alkaline with 275 g. of cold 33% potassium hydroxide, chilled and filtered. The pale yellow prod119) 1Iicroanalyses by Clark Microanalytical Laboratory, Urbana. Ill. 31elting points, which a t e corrected, were taken using hard glass capillaries in a n internally, electrically heated Hershherg apparatus w i t h ;i r a t e of heating of 1-2' per minute unless otherwise specified.
Oct. 3, 1955
'&HYDROXY-3-NITROCINNOLINE
5111
uct was dried in ZJUCUO. The crude product, 1.6 g. (94%), A 1:l mixture of the two products softened a t 279" and was recrystallized from 70 ml. of water (charcoal), giving melted at 283.5-284.5' dec.21 The infrared spectra of the 1.3 g. (76%) of 3,4-diaminocinnoline, m.p. 220-220.5' dec. two compounds determined on Sujol mulls were identical, both compounds showing peaks a t 655 (w), 720 (w), 740 For analysis a sample was recrystallized a second time from (w), 765 (m), 812 (m), 859 (m), 892 (m), 920 (m), 1150 water and dried to constant weight, the melting point being (m), 1170 (m), 1227 (m), 1245 (m), 1258 (m), 1271 (m), unchanged. Anal. Calcd. for CsHsNl: C, 59.99; H , 5.04; N, 1326 (s), 1346 (s), 1365 (s), 1436 (s), 1495 (s), 1538 (s), 1588 (s), 1606 (s), 1638 (m) and ca. 3160 crn.-l. The ultra34.98. Found: C, 59.51; H , 4.83; N, 35.13. violet spectrum of the product prepared in this work was A mixture of 20 mg. of the above product and 26 mg. of determined on a 10-4 M solution of the product in 95% phenanthrenequinone in 1 ml. of glacial acetic acid was ethanol using a Cary recording spectrophotometer and disheated on the steam-bath for one hour, cooled and filtered. played the following maxima (log E ) , 210 m p (4.30), 334 mp The orange solid was recrystallized from 3 ml. of pyridine, (4.05); inflection points, 235 mp (4.01), 263 m p (3.46), giving 30 mg. (72%) of 9d10,11,16-tetraazatribenz[a,c,h] - 346 m p (3.96) and minimum, 282 m p (325).22 anthracene, m.p. 315-316 , identical with that described l-Methyl-3-nitro-4-cinnolone (VI).-To a solution of 1.20 below. g. (0.0063 mole) of 4-hydroxy-3-nitrocinnoline and 1.4 g. of A mixture of 0.50 g. (0.0026 mole) of 4-amino-3-nitropotassium hydroxide (ca. 0.02 mole) in 150 ml. of wster cinnoline and 2 g. (0.009 mole) of stannous chloride dihy- heated to 50" on the steam-bath was added 3 ml. of dimethyl drate in 8 ml. of 1 N hydrochloric acid was heated for five sulfate in 1-ml. increments with vigorous stirring. The hours on the steam-bath. The mixture was diluted to 200 precipitated product was collected by filtration, washed ml. with distilled water and the resultant solution was nith 5% potassium hydroxide and with water and recryssaturated with hydrogen sulfide. The filtered solution was tallized from 200 ml. of ethanol (charcoal), giving 0.77 evaporated t o dryness a t 40" under reduced pressure and g. (59%) of pale yellow needles, m.p. 232.5-233.5'. Anthe crude product was washed onto a filter with ether, giving other experiment using one-half the above quantities gave a 0.41 g. (80%) of crude bright yellow 3,4-diaminocinnoline crude yield of 0.45 g. (71%) and purified yield of 0.26 g. monohydrochloride, m.p. 316-317" dec. A 0.2-g. portion (41%) of l-methyl-3-nitro-4-cinnolone. The product darkof the product was recrystallized from 15 ml. of absolute ened rapidly on exposure to light. ethanol giving 0.09 g. of bright yellow crystals, m.p. 320Anal. Calcd. for CgH~N303: C, 52.68; H , 3.44; N, 331.5' dec. 20.48. Found: C, 52.70; H , 3.35; K,20.58. Anal. Calcd. for CsHgy4c1: C, 48.86; H, 4.61; SI Reaction of 111with Phosphorus Oxychloride.-The aged 28.50. Found: C, 48.45; H, 4.23; N, 27.92. phosphorus oxychloride used in these experiments was 9,1O11l,16-Tetraazatribenz [ a ,c, h ]anthracene (V) .-A sus- taken from an imperfectly sealed bottle that had been pension of 0.20 g. (0.001 mole) of crude 3,4-diaminocinnostored for some time (as evidenced by corrosion of the label, line hydrochloride, 0.6 g. of fused potassium acetate and paper wrapper and interior of the protective metal can). 0.20 g. (0.001 mole) of phenanthrenequinone in 10 ml. of This material was a pale yellow in color. The fresh phosglacial acetic acid was heated on the steam-bath for one hour, phorus oxychloride came from a bottle showing no evidence during which time orange needles slowly separated from of leakage and was a colorless liquid. solution. The cooled solution was filtered and the orange I n Table I are listed the quantities of reactants and the solid was washed with water, giving 0.16 g. (50%) of bright essential reaction variables for some typical experiments, all orange needles, m.p. 312-315.5'. The product was twice of which were conducted using the following procedure. recrystallized from 10 ml. of pyridine (charcoal), giving The mixture of reactants was heated under reflux in the oil0.08 g. of 9,10,11,16-tetraazatribenz[a,c,h]anthracene, bath for the specified time. In experiments using aged m.p. 315.5-316', as bright orange needles. The product phosphorus oxychloride the solids dissolved giving a clear was soluble in hot pyridine, slightly soluble in hot benzene, yellow solution in five minutes or less. In experiments ethanol, dioxane and ethyl acetate and insoluble in hot using fresh phosphorus oxychloride and phosphorus pentaacetone and petroleum ether. n'ith concd. sulfuric acid chloride the solids dissolved in 15 to 30 minutes giving a the compound gave a red-violet color (changing to a fine tan t o dark brown solution. After the heating period the red precipitate on standing) on the spot plate. solution was chilled and poured onto crushed ice. The Anal. Calcd. for C22Hl~ri4: C, 79.50; H , 3.64; N, mixture was stirred vigorously until the excess phosphorus 16.86. Found: C, 80.03; H , 3.71; IS,16.64. oxychloride was decomposed, neutralized to congo red with solid sodium acetate and filtered. The dried solid23 was 4-Hydroxy-3-nitrocinnoline (In).-A suspension of 5.0 g. (0.026 mole) of 4-amino-3-nitrocinnoline in a solution of 5 g. recrystallized from Skellysolve C,*4 using 20 ml. of solvent (0.13 mole) of sodium hydroxide in 75 ml. of water was for each 0.1 g. of 4-chloro-3-nitrocinnoline or for each 0.6 heated on the steam-bath for one hour. The amino com- g. of 3,4-dichlorocinnoline. The two products could be pound dissolved slowly in the hot alkaline solution, giving separated fairly readily by fractional crystallization from a deep red solution (acidification of this red solution gave a this solvent. very impure and difficultly purified product) which slowly An analytical sample of 4-chloro-3-nitrocinnoline (VII) changed in color to yellow or yellow-orange. The hot solu- was prepared by recrystallizing one sample of product, tion was treated with charcoal, filtered and chilled. Acidi- m.p. 168-169', twice from Skellysolve C, giving pale yellow fication of the solution with acetic acid and collection and needles, m.p. 169-170'. On the hot-stage the compound drying of the precipitate gave 4.6 g. (92%) of crude 4- sublimed a t ca. 140", forming nearly perfect rhombic plates, Although the compound was stable toward hydroxy-3-nitrocinnoline, m.p. 274-278", as a pale yellow m.p. 169-170'. storage for short periods, after five months the above solid. Similar experiments using the same proportions of sample melted a t 153-163". reagents gave crude yields of 8 5 9 9 % . Recrystallization of the crude product from 275 ml. of 95% ethanol (charcoal) Anal. Calcd. for C8HaiY3OrC1: C, 45.85; H, 1.92; K,. gave 3.4 g. (69%) of pure 4-hydroxy-3-nitrocinnoline, m.p. 20.05. Found: C, 46.29; H , 2.35; N, 19.78. 284.5-285.5', as light yellow needles. By working up the A mixture of 0.75 g. (0.0036 mole) of crude 4-chloro-3ethanolic filtrate an additional 0.4 g. ( 8 % ) of product could nitrocinnoline (m.p. 164-168'), 1.0 g. of phosphorus pentabe recovered. chloride and 5 ml. of aged phosphorus oxychloride was Anal. Calcd. for CsHjN303: C, 50.46; H , 2.77; S , heated under reflux a t 110' for three hours, cooled, poured 21.71. Found: C, 50.27; H, 2.64; iX,21.98. on ice, neutralized and worked up as described above, giving A sample of 4-hydroxy-3-nitrocinnoline obtained from the 0.73 g. of crude product. Recrystallization of the latter nitration of 4-hydroxycinnoline3~12was compared with the (21) Dr. Schofield reported to us t h e following uncorrected m.p.'s: above product. The nitration product was in the form of pale brown needles (which, under the microscope, differed yellow crystals, 272-274'; brown crystals, 274-275'; mixture, 272274'. little in appearance from the yellow product obtained in this (22) We are indebted t o Miss E. M. Shelton for t h e determination of work) and melted in our apparatus a t 278-279.5' dec.20 (20) T h e melting points of b o t h materials were depressed when determinations were made in carefully washed s o f t glass capillaries. T h e yellow crystals melted a t 276-277' dec. a n d t h e brown crystals a t 275-276' dec.
t h e infrared a n d ultraviolet spectra. (23) Preferably dried in t h e vacuum desiccator. Although the solid could be dried in t h e oven, t h e hot solid evolved vapors t h a t were quite irritating t o t h e skin. ( 2 4 ) A hydrocarbon solvent, b.p. 88-98',
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