L> \ \ I b ,
88
\T71STHIIOlJ, 'lHOhL.l.iS, HERl 1)etwrcn the o,o'-positions of t h plwn>.l rings i n :ic,tivity c)ausetl 1)y t IIC introtiuctiriri in tiiphenylaretamide lvere :rlso evaluated. The e bridge inti, certain other benxhydryl rontaininy antic,onvulsants t o give their dibenzo [:i>d]i :in:tlog w r e foiintl to possess giiod anti:indugs was studied. The title cwmponnd and its c~~c~lc,hept:rtriene convulsant, artivities in m i c ~with ICJW orders of tcisiiity and nriirotosicity.
cyaiiodibeiizo [a,djcycloheptadieilc ivith sodamidc and dimethyl sulfate galre the corimpoiiding ,?-methyl dei*j\.at,ive. The attempt'ed coiit'rolled hydrolyses;' of ;i-cyaiiodibeiizo [a,d]cyclolieptadirneto t'he carboxamide usiiip c~)ncrntratedsulfuric acid at 25', boiling hydrochloric acid, hot polyphosphoric acid, or hydrogen peroxide i n aclueous sodium hydroxide were unsuccessful. Tlir amide \vas obtained in 41yoyield by heating the iiit'rilc with a mixture of rqual pal of sulfuric acid, acet,ic acid, and \vatel*aiid in 70% eld using potassium hydioxide i n boiliiig etliariol for 18 hi. Heating diphenylacetonitrile with t'lie latt,er reagent for 2 111.. g a \ a~ (By:) I CONHz CONHz yicld of diplie~ivlacctamide~" while 9-cyaiioxar1thciic~ I I1 ga1.e t lic coi~rcspondingcarhoxamide in 60yoyield aftcr licatiiig for 20 mill. with aqueous, alcoholic potassium A bcrie5 of ti icyclie carboxamideb \\'a; prepayed I I I . ~ I ndditional J method, suitable foi. th(1 Iiydroxitlr.411 oidei t o study the effect on activity caused by the intiopiqxuatioii of tlic dibenzo [a,d]cycloheptadiei~t '-,,-tal'duction of suhstituents 011 the ring and on the amide hoxamides;, involved saturating a suspension of t h c apnitrogen atom as well as the effect of changing the juxtapropriat,e nitrile i l l acpeous acetic acid with Iioroii t1.iposition of the benzene rings by altering the bridgnig Applicat'ioii of tllis procedure to kyaiiogioups. Cai boxamide derivatix es of dibeiizo [a,d]dik)~iizo [a,e]cyclo~ic~ptatrieiie however, gave 011ly t a u \ cycloheptadienes, dibenzo [a,e]cycloheptatrienes, 9.10pi,odiicts. 111 this case t'he iiitrile \vas first Jiydi~~lyzed dihydroanthraceiie~, dibenzo[a,d]cyclooctadiene, a i d t o t8hc carboxylic acid with hoiliiig, aclucous sulfuric thioxanthene were prepared (see Table I). Seveial acid, aiid the amid? was prepared cia the acid ehloridc. known tricyclic carboxamides were also prepared foi It cvuld also he obtairicd hy direct hydrolysis of tlw comparison and are listed in Table 11. llaiiy of the iiitrilc \vith alcollolic pot'assium liydimicle. carboxamides were synthesized iza the eoiiespondiiig He\.eid alt'eriiative routes to dihciizo[a,c.]cgc'lotiitriles which 111 turn were obtained bv treatiiig the apIitptat i,ic.iie-.i-c;~i.l,osylic acid n-et'e iii\wtigatcd. I ) j piopriate chloio compound with silver cyanide in diy h w z o [n,e]cycloheptstrierie \$-as metalated witli (.it 1 1 ~ 1 , 1)eiizcnt.. The 5-cyanodibenzo [a,r]cycloIieptatrieiir~ t)utyllithium5 or putassium amide6 aiid the. mcltal (11,w ~ iconveuieiitly pi epared by adding a dilute solutiori iivati1.c. was carlmiiated t,o give low yields of t,hc carof the halide very slowly t o the silver cyanide in ordei hoxylic acid. 'The required hydrocarboil \vas rcadil?. t o s~ippressthe formation of side pioducts. 5-Cyanoobtained by a modification of the p i ~ c e d u r eof l'aidicu.' clibetizo [a,e]cycloheptatrieiie itself could also be prr'I'reat,meiit8of 5-chlorodihenzo la,e]cycloheptatrienc with pared by treatment of the corresponding dielie witli lithium in t'etrali!.drofiiraiix followed h y carhotlation b!omitie follon ed by distillatioil, or with ?;-bromo5 . 3 1 ( ' . I:. 1laiisr.r m i l 11. i. Iluffenhc.rr, $1. Or(/. ( ' h ( m . , 20, I U 8 ( i iuceinimide a i d si11)sequentheating wit11 trietliylami~lr li. I L O I U I ~ , : i r i r ~ . , 233, :j+ii l m i j : h) 1 111 tmth cabeb, howe\ er, thc pioduct was obtained in lon < ' l t i m . l m d . S r i . H u r i q . , 32, 4 i : i (lCjli2). yield and \va. difficult to purity Tiwitmelit of 3PI-, a n d ,J. I I . 13it.1. 1.. d. Patr,ni 2 , 9 8 . ~ ~ ( i l ii (I!)lii l I. 1)uring the course of an investigation into iiew pbycliotropic agents it was necessai y to prepare dibenzo[a,d]cycloheptadiene-5-carboxylic acid. Hydrolysis of the corresponding ;-cyano compound by aqueous sulfuric acid gave the carboxylic acid together with minor aniouiits of dibenzo [a,d]cycloheptadiene-.5-carhoxamidr ( I ) . The latter was found t o possess a high order of aiiticoiiviilsant activity and was more potent oi-ally than dipheiiylacetamide (11), the open-ring analog.
I
(1
-
1 I \I i I ) a i 16 0 \\ i n t l l r u i ) J - t ( u r i l t I \ 'liniili'irri l l t i r I lied Chrni 6 , l i l ( I Y l , < ) < [Ob( And \ I ', hl,lClllldli I!! \ I t dlclrl,Ll ( iifI l l l i t 1 (1 , l d l n \\ 1lf 1 u r d \oils In1 , \ ( 1, 1 vrh \ 1 I I
)
ind i
('jfltm..
I:. .I. Villani. C'. .\. I X I i b , 6 . 37:: (I9(i?l. ,
(n li!llt
-oiiewit'li hydrosylaminc~ hydrocliloi~idt~ i i i aqueous pyridine gave the 5-oxime n-Iiich was rcxluccd catalyt8icallyto the >-amino compoui~d.~ 'Uic ~ ~ c i ~ i d oproduct from the ltydrogeiiatioii \vas acetylated dilectly to furnish Z-acetamidodibenzo[a,d]cyclolicptadiriic. The t\vo dibenzo [a,d]cyelolieptadieiiyl ureas w r * epitpaled by methods similar to t Iiow used f o r the corresponding herizhydryl compouiids. " I Thus 5-chlorodibenzo [a,d]cycloheptaj 3
(x
( I : { ) 11. I C . SI,:rriti i i n d 'V. .J. I ' u t n o i ~ i . E p i i e p s i n . (21 3 , 51 (1945j. 1 1 1) .\. 12nliman a n d SI. 0. Farooii. Satur~r~issensciinjten, 41, 1.5 (1113-tI. (15) C. 11. Iiao and S,-Y. l I a , Scirripe R e p t . S a t l . Tsing Hua l-r~ic.. S e r . 1 1 , 1, 17 (1931); Chr~m..1hstr., 26, 1>92 (IS132). ( l i b ) 11. \ . Ihivis, I'. '\. Hunaliura. Y. I l e r r , ani! I < . Giiudr?, .J. .\led. ( ' l i t m.,6 , ;11:1 (l$!li:$), ( l i ) ,J. I I . Hillitiziri n i i d I'. 11. l i i c l ~ - , t i n . Chenr. ,Sw., 6 6 , 7 0 0 ( l < l l : $ ) . (18) Set, rvf. 2 . 1,. 1.19. ' 1 9 ) See rrf. 2 , 11. 4 2 . ( 2 0 ) I'reiiarntion of this c o ~ i ~ l i u u n IJY i i a difTt.rent yrocedure has hcrn n 1iurtc-d by .I. Rernstein and I-an
January, 1964
ANTICONVULSANTS. I TABLEI11
PHARMbCOLOGICAL ISVESTIGATIOSS
Bntipentylenetetrazole
1
LDsii. ing./kg., i.p. 630 i 31a
2
550
3
> 1200
4
550
Foii~pound
850
0
>zoo
> 700
7 8
582 i 33
9
650
10
380
11
250
12
320
13
>800
14
350
I5
>IO00
16
>1200
17
1300
18
1150 i 01
19
750
20
> 1200
21
>1200
22
730
23
350
24
1300
Plienoharbital sodiuin Diplienylhydantoin Priinidone
249 i 12
'I
170
w./kg., i.p./oral 25 i 1 33 i 3 . 5 72 i 5 280 i 30 >400 47 i 4 69 i 4 125 i 10 166 i 10 62 i 5 64 f 6
> 1400
5
16.5 i 1 22.5 f 2 11.8 i 1 35 i 1 25 f 1 42 i 7 >75 > 100 37.5 i 5 08 i 0 34 i 2 . 7 GG f 0.8 49 i 3 >300 >400 >400
132 i 11 299 i 0 20 i 4 50 i 2 . 3 100 i 9 410 i 37 30 i 2 62 i 5.4 54 i 3 53 i 3 19 i 1 2 0 5 i 1 3 11.7 i 1 18.8 1.G 31 i 2 3 4 . 5 zt 4 11.0 i 1.4 1 7 . 8 =t 2 . 0 9.6 i 1 6 8.9 & 0.8 17 i 3 llj i 3
=
I
13
290 i 21
m./kg., oral
-4taxia EDsa, Ing./kg., oral
14.5 i 3
100 i 44
84 i 6
>400
>400
>a00
M E 6 EDsa
EDaa,
49 i 0
4 6 5 i 41
158 i 5
>800
30 f 4
430 f 31
13
105 i 20
2
8 1 1
310 zt 14
1 5 zt 2
175 f 20
46.5 i 4
70 f 5
29 f 3
205 f 36
61 i 5
> 100
34.5 f 6
>ooo
53 i 20
>400
205 3t 8
>I400
30.5 i 5
470 rt 18
45 f 10
340 i 12
22.5 i 6
400-000
43 i 0
>ti00
2 1 . 5 3t 1 . 8
17ti i 22
11.5 f 2
(jG
20 i 3
>300
3 0 zt 0 . 0
76 i 3 . 6
7 i 0.5
84 i 9
2 f 0.0
>250
=
(i7
Standard error.
The results of the pharmacological investigation are given in Table 111. The anticonvulsant activity (LLIES, i.p.) of diphenylacetamide (18)2 was maintained or increased by the introduction of an ethylene, ethylidene, or methylene bridge between the o,c'-positions of the phenyl rings (1, 8, 10). The oral activities of these compounds mere significantly greater than that of diphenylacetamide. On the other hand, the bridging of the phenyl rings by a trimethylene, sulfur, or oxygen function (12, 13, 21) somewhat decreased the activity. The isopropylidene bridge gave a compound (11) which was inactive against MES even a t ataxic doses. In general the doses required to protect against the tonic seizures caused by pentylenetetrazole were smaller than those required for anti-LIES effect. An exception was compound 19 (a position isomer of 1) which had a negligible anti-MES effect orally but had significant antipentyleiietetrazole activity.
01
Within the series of dibenzo [a,d]cycloheptadiene-3carboxamides, substitution either on the ring or on the carboxamido function invariably decreased the activity (2-7). The dibenzo [b,f ]azepine-5-carboxamides ( 2 2 , 23)27had good anticonvulsant activities but were considerably more neurotoxic (ataxia) than their corresponding carbocyclic analogs. The dibenzo [a,d]cycloheptadiene analogs of the known benzhydryl anticonvulsants (1517) were found to be practically inactive against MES but 15 and 16 had some antipentylenetetrazole effects. The ratios of the toxicity, neurotoxicity, and anticonvulsant effects of compounds 1, 8, and 9 compare favorably with those of leading antiepileptic drugs, Further investigations with these compounds are in progress.
Experimental Melting points were read on a Thomas-Hoover Uni-melt apparatus. Dibenzo[a,e]cycloheptatriene.-A solution of the p-toluenesulfonate ester of Y-hydroxymethyl-9,lO-dihydroanthracene7 (28.7 g.) in anhydrous formic acid (200 ml.) was heated under reflux for 6 hr. and then chilled. The solid was filtered, washed with water, and dried. There was obtained 14.0 g. (93%) of product, m.p. 131-132" (raised to 132-133" on one recrystalliza" : :A 285 mp ( e 14,300); lit.'m.p. 131-132", tion from 2-propanol) 285 mp ( e 13,800). 2-Benzyl-a,a-dimethylbenzylAlcohol (111).-Methyl 2-benzylbenzoate12 [b.p. 109-112" (0.1 mni.)] was prepared from the corresponding acid.28 A solution of the ester (22.6 g., 0.1 mole) in dry ether (100 ml.) was added dropwise to methyllithium derived from methyl iodide (71.0 g., 0.5 mole) and lithium (6.9 g., 1.0 g. atom) in ether (500 m1.j. The mixture was heated under reflux for 3 hr., cooled, and poured onto ice and ammonium chloride. The organic solution was combined with the ethereal extracts of the aqueous layer, dried, and evaporated. There was obtained 21.6 g. of an oil which gradually solidified. Recrystallization from pentane gave a sample of product, m.p. 66-67". Anal. Calcd. for C16H180: C, 84.91; H, 8.02. Found: C, 84.63; H, 8.00. 9,s-Dimethyl-9,lO-dihydroanthracene(IV).2g-A well stirred mixture of alcohol 111 (12.4 g. j and 7OY0 aqueous sulfuric acid (w./w., 25 nil.) was heated on the steam bath for 1.5 hr. The mixture was diluted with water, the product taken into benzene, and the organic layer was washed with sodium bicarbonate solution and dried. Evaporation left an oil which contained a small amount of an anthracene derivative. Distillation gave a fraction b.p. 109-116" (0.3-0.4 mm.), n ' , ~1.5937 - 1.5940 (8.4 g.) consisting of IY together with a trace of the isomeric styrene derivative (Y)(weak band for terminal methylene a t 1.5-1.6 p ) . Thick layer chromatography on silica gel from hexane afforded a purified sample of IT as an oil which developed a blue fluorescence 255,262,269 mp ( e 744,895, 864). ~ on standing; n Z 51.5916; Anal. Calcd. for CI6H16: C, 92.26; H, 7.71. Found: C, 91.89; H, 7.88. From a similar reaction using a sample of the alcohol which had not been purified there was obtained, in addition to the expected product, a 5% yield of 9-methylanthracene, m.p. 79-80' (from 257 nip ( e 189,000); lit.3o m.p. 79-80", A,,, 256 hexane), "::A: mp ( E 182,000).31 : 93.71; H, 6.29. Found: C, 93.39; Anal. Calcd. for C l v H l ~C, H, 6.41. Oxidation of 9,s-Dimethyl-9,10-dihydr0anthracene.-A solution of 11' (2.0 g., 0.01 mole) in glacial acetic acid (20 m1.j was kept a t 50" and treated dropwise with chromiuni trioxide (1.4 g., 0.014 mole) dissolved in acetic acid (50 nil.) and water (50 ml.); little or no reaction took place below 50". The bulk of the acetic acid was evaporated, the residue was stirred with water, and then (27) VV, T h e o b a l d a n d H. A. Kunz, .4rzneimitteZ-Forsch.. 13, 122 (1903). (28) J. Rigaudy and L. Nedelec. Bull. Soc. Chim. France. GX8 (1959). (29) T h e pre2aration of this compound has been disclosed b u t no details Belgian P a t e n t 601,1(i8 (1901). or physical properties are g i \ r n ; C;eigy 8 . 1.. (30) F. Iirollpfeiffer and F. Branshied, Bet,., 66. lli17 (1928). (31) R. S. Jones, J . Am. Chem. S o c . , 67, 2127 (1943).
January, 1964
AKTICONVULSANTS. I
filtered, and stirred with dilute sodium hydroxide solution. A little insoluble material was removed and acidification of the filtrate gave 6.6 g. (86% yield) of product, m.p. 230-240". Recrystallization of a sample from chloroform-hexane gave m.p. 241-242", 288 mp ( e 14,300); lk39m.p. 234-237'. Anal. Calcd. for C I ~ H ~ ~C,O81.34; ~: H, 5.12. Found: C, 81.27, H, 4.82. (b).-A solution of 5-chlorodibenzo [a,e]cycloheptatriene (5.0 g., 0.022 mole) in dry tetrahydrofuran (25 ml.) was added dropwise while stirring (nitrogen atmosphere) to a wspension of finelycut lithium wire (0.61 g., 0.088 g. atom.) in the same solvent (15 ml.). A precipitate soon formed and the mixture developed a deep red color after being stirred a t room temperature overnight. It was poured onto an excess of crushed Dry Ice, the mixture hydrolyzed by the addition of dilute hydrochloric acid, and the product was taken up in chloroform. The organic layer was extracted with dilute alkali and the aqueous layer was separated and acidified. One recrystallization of the product from chlorolorm-hexane gave a sample (1.8 g., 354.j;,); m.p. 238-240" after sintering a t 233"; 285 mp ( C 11,940). The neutral product from the reaction appeared to be biH-(5dibenzo[a,e]cycloheptatrienyl). Recrystallization from toluene gave a sample (0.4 g.), m.p. 315-316", 296 m p ( e 20,400). Bnal. Calcd. for C30H22: C, 94.20; H, 5.80. Found: C, 93.71; H, 5.57. (e).-A 15.1y0 solution of n-butyllithium in hexane (Foote Chemical Co., 0.030 mole) was added dropwipe under a nitrogen atmosphere to a solution of dibenzo[a,e] cycloheptatriene (5.3 g., 0.028 mole) in dry tetrahydrofuran (60 ml.). The reaction was slightly exothermic and a deep brown color developed. The mixture was stirred for 3.5 hr. at room temperature, poured onto crushed Dry Ice, and processed in the usual manner. The product, after one recrystallization from ethanol-hexane, had m.p. 240-241" (2.0 g., 31y0). Carrying out the reaction in dry ether in place of tetrahydrofuran gave only a 5y0yield of acid together with a 54Torecovery of starting material. (d).-A solution of the dibenzo[a,e]cycloheptatriene(5.3 g., 0.028 mole) in dry ether (200 ml.) was added to potassium amide derived from potassium (1.2 g., 0.031 g.-atom.) in liquid ammonia (200 ml.). The ammonia mas allowed to evaporate and the mixture was carbonated and processed as previously described to give of product, m.p. 241-242". 1.2 g. (20c0) (e).-A mixture of dibenzo [a,e]cycloheptatriene-5-01 (6.2 g., 0.03 mole) and sodamide (1.3 g., 0.033 mole) in dry benzene (70 ml.) was warmed gently for 1.5 hr., cooled, and treated with methyl iodide (8.5 g., 0.06 mole) in benzene (20 ml.). The mixture was heated under reflux for 1.5 hr., filtered, and the solution was washed with water, dried, and evaporated. The residual oil (6.4 g., ether a t 1087 and 1120 em.-'; Xrsx 264-282 mpj ( e 12,500) was distilled to give a fraction (4.0 g.) of b.p. 142-144" (0.5 mm.), T L ~ ~1.6408-1.6430. D An alloy was prepared from sodium (0.56 g.) and potassium ( 2 . 2 g.) in xylene. The xylene was replaced by dry ether and the preceding methyl ether (4.8 9 , ) was added. The mixture was stirred a t room temperature for 1 hr. during which time the color turned through green to dark brown. It was heated under reflux for 4 hr. and carbonated. There was obtained 1.2 g. of crude carboxylic acid, m.p. 202-210", A, 282 mp ( e 8900). Recrystallization from chloroform-hexane afforded 0.2 g. of product, m.p. 235-236". 2,4-Dimethyldibenzo[a,d]cycloheptadiene-5-carboxylicAcid.A4solution of 5-chloro-2,4-dimethy1dibenzo[aJd] cycloheptadiene (5.1 g., 0.02 mole) in dry tetrahydrofuran (40 ml.) was added dropwise to a suspension of lithium (60% dispersion in oil; 0.5 g., 0.044 g. atom) in tetrahydrofuran (20 nil.) and the mixture was heated under gentle reflux for 3 hr. The lithio derivative thus formed was carbonated and processed in the manner described above to give 0.6 g. (10%) of the carboyxlic acid, n1.p. 184-185" (from benzene-hexane). Anal. Calcd. for Cl8H1802: C, 81.17; H, 6.81. Found: C, 81.36; H , 6.77. 9,10-Dihydroanthracene-9-carboxylic Acid.-A solution of nbutyllithiuni prepared40 from n-butyl bromide (37.7 g., 0.27 mole) and lithium wire (4.8 g., 0.07 mole) in dry ether (I50 ml.) was added dropwise under a n atmosphere of dry nitrogen t o a suspension of 9,lO-dihydroanthracene (45.0 g., 0.25 mole) in ether (39) 9. J . Cristol a n d R. Ii. Bly. J . 47% Chem. S o c . , 83,63135 (1900). (10) H. Gilman, J . A. Beel, C. G. Brannen, XI. TI'. Bullock, G. E. D u n n , a n d L. S. Miller, J . Am. Chem. Soc., 71, 1499 (1949).
93
(400 ml.). The dark solution was stirred a t room temperature for 2 hr. and then heated under reflux for 45 niin. It was poured onto an excess of crushed Dry Ice and processed in the usual manner to give 29.9 g. (537,) of acid, m.p. 206-208". 9,9-Dimethyl-9,10-dihydroanthracene-l0-carboxylicAcid.The lithio compound derived from the interaction of 9,9-dimethyl-9,lO-dihydroanthracene (8.4 g., 0.04 mole) and butyllithium (0.05 mole) in tetrahydrofuran (100 ml.) was carbonated and processed in the usual manner to give 5.3 g. (52%) of the 267 (i), 263, carboxylic acid, m.p. 182-183" (from benzene); A":, 271 mp ( e 408, 526, 426). The isomeric Z-(a-methylvinyl)diphenylacetic acid, an o,a-disubstituted styrene, would be expected to have no ultraviolet absorption maxima.41 Anal. Calcd. for C1;HIGOZ: C, 80.92; H, 6.39. Found: C, 80.69; H, 6.29. Dibenzo[a.dl cvclooctadiene-5-carboxvlic Acid.-The immre . nitrile (4.7 g.) obtained from the interaction of 5-chlorodibenzo[a,d]cyclooctadiene with silver cyanide was heated under reflux for 12 hr. with 57cc sulfuric acid (70 nil.). There was obtained 1.8 g. of acid, m.p. 182-183" (from chloroform-hexane). dnul. Calcd. for CliH,,O?: C, 80.92; H, 6.39. Found: C, 80.74; H, 6.32. Bis-(5-dibenzo[a,d]cyclooctadienyl).-A solution of 5-chlorodibenzo[a,d]cyclooctadiene (12.0 g., 0.05 mole) in dry tetrahydrofuran ( 5 5 ml.) was added dropqise to lithium (40% dispersion in oil, 3.5 g., 0.20 g.-atom) suspended in tetrahydrofuran (45 ml.). The mixture was heated under reflux for 42 hr. with occasional irradiation from a high intensity ultraviolet light; a t no time was there any evidence of the formation of a lithio compound. The excess of lithium was destroyed by the cautious addition of a little ethanol followed by water. The product (10.4 g., 100%) was filtered and purified by sublimation in vacuo; m.p. 345-346'. Anal. Calcd. for Ca:H30: C, 92.71; H, 7.29. Found: C, 92.43; H, 7.44. Dibenzo[a,e]cycloheptatriene-5-carbonyl Chloride.-A suspension of dibenzo [a,e]cycloheptatriene-5-carboxylic acid (20.9 g., 0.09 mole) in dry benzene (200 ml.) was treated with thionyl chloride (30.0 g., 0.25 mole) dissolved in benzene (60 ml.). The reaction mixture was heated under reflux for 2.5 hr. and evaporated. One recrystallization of the residue from carbon tetrachloride-hexane gave 15.7 g. (695,) of product, m.p. 128130". An analytical sample had m.p. 129-130'. .4nal. Calcd. for CtbHllClO: C, 75.45, H, 4.35; C1, 13.92. Found: C 75.18; H, 4.31; C1, 13.85. Dibenzo[a,d]cycloheptadiene-5-carboxamide. (a)-A stream of boron trifluoride was passed over the surface of a stirred suspension of 5-cyanodibenzo [a,d]cycloheptadiene (11.0 g., 0.05 mole) in acetic acid (60 ml.) and water (11 ml.) until saturation was complete. The internal temperature rose spontaneously to 135' ; in preparations involving larger quantities i t was necessary to apply external heating in order to complete the reaction. The mixture was cooled, made alkaline by the gradual addition of 6 N sodium hydroxide, and the precipitate was collected, washed with water, and dried. The solid was then extracted with hot acetonitrile and ethyl acetate and the combined organic solutions were evaporated. One recrystallization of the residue from acetonitrile furnished 10.1 g. (85%) of the amide as long needles, m.p. 193-194". (b).-A stirred suspension of 5-cyanodibenzo[a,d]cycloheptadiene (0.9 g., 0.004 mole) in 1 ml. each of sulfuric acid, acetic acid, and water was heated under reflux for 1 hr. The mixture was cooled, diluted with water, and the precipitate was collected, washed n ith dilute sodium hydroxide, then with water, and dried. One recrystallization from acetonitrile gave 0.4 g. (41%) of amide, m.p. 193-194". (c).-A solution of 5-cyanodibenzo[a,d]cycloheptadiene (2.0 g,) and potassium hydroxide (6.0 g.) in ethanol (100 ml.) was heated under reflux for 18 hr. The solvent was removed zn vacuo, water n a s added and the precipitate was collected and dried. It was slurried with a small quantity of ether, filtered, and recrystallized once from methanol giving 1.5 g. (7Oyo), of amide, m.p. 191-193'. Acidification of the aqueous alkalilie filtrate gave only a trace of the corresponding carboxylic acid. Dibenzo[a,d]cycloheptadiene-5-N-methylcarboxamide.-~~solution of dibenzo [a,d]cycloheptadiene-5-carbonyl chloride' (7.8 g., 0.033 mole) in dry acetone (30 nil.) was added dropwise to methylamine (257, aqueous solution; 60 ml). The mixture was /
,
(41) Y. Hirschberg, ibid., 71, 3211 (1949).
