摘要:
1976 465Synthesis of Some 9-Aminoacridines with Bulky SubstituentsBy R. Morrin Acheson and Charles W. C. Harvey, Department of Biochemistry, South Parks Road, OxfordOX1 3QU2-s-Butyl-, 2-t-butyl-. and 2,7-di-t-butyl-9-aminoacridine, and other acridines, have been synthesised from thecorresponding 2-carboxydiphenylamines (diphenylamine-2-carboxylic acids). Their l H n.m.r. spectra haveshown that earlier assignments made for 9-aminoacridine must be revised. The n.m.r. spectra for intermediates inthe syntheses show a steric effect for the t-butyl group and indicate the presence of geometric and rotationalisomers of the sterically hindered benzimidates. which were rearranged to give the carboxydiphenylaminederivatives. The t-butyl group was eliminated in all attempts to prepare 9-t-butylaminoacridine.Acridine,9-aminoacridine, and a number of other derivatives could not be alkylated a t position 10 by a variety of largealkylating agents because preferential elimination took place.AMINOACRIDINES have an immense range of biologicalactivity,l much of which may be due to their ability toreact with nucleic acids. Two types of interaction withDNA have been characterised experimentally.2 In one,for which the binding energy is ca. 25-42 kJ mol-l, theacridine molecule is thought to slip into the double helixbetween successive base pairs, and ca. 0.2 mol acridineis bound per mol of DNA phosphate. In the other, forwhich the binding energy is much less (< ca. 10 k J mol-l) ,the acridine is considered to be attached to the outsideof the helix (ca.1 mol per mol of DNA phosphate).To study the steric requirements for binding withinand without the helix, a number of 9-aminoacridines(1)-(8) with bulky substituents have been synthesised.The binding experiments are in progress and will bereported elsewhere.The 9-aminoacridines (l), (2), and (8) were obtainedfrom the appropriate 2-carboxydiphenylamines (diphen-vlamine-2-carboxylic acids by successive treatment withphosphoryl chloride and ammonium carbonate, the carb-oxylic acids being prepared by Ullmann reactions.6-Amino-2-s-butylacridinium chloride (3) was synthesisedfrom 2-carboxy-5-nitro-4'-s-butyldiphenylamine bysuccessive treatment with phosphoryl chloride, hydro-chloric acid, sodium amalgam, and iron(I11) chloride.1c 1 -5 H A( 1 ) 9 - N H 2 - 2 - B u S( 2 ) 9 - N H z - 2 - B u t( 3 1 6- NH2- 2- B u s( 4 ) 9 - N H z - 2 , 7 - 8 u t 2( 5 1 ( + ) - 9 - B u S N H( 6 ) ( - ) - 9 - B u S N H( 8 ) 9 - N H 2 - 2 - B u S - 6 - N 0 2 ( b a s e 1( 7 ) 9 - N H 2 - 4 - E tChapman rearrangement, was examined (Scheme).Although the benzimidate (10) did not rearrange andthe benzoyldiphenylamine (15) resisted hydrolysis, thesynthesis of 9-amino-2,7-di-t-butylacridine (4) wasachieved.A \ C02Mec 1 -C=NI C OOHIP hCorn p o u n d A B C( 9 1 , ( 1 4 1 , ( 1 8 1 B u t B u t H( 1 0 1 B u t H B u t( 1 1 ) , ( 1 5 ) , ( 1 9 1 H H B u t( 1 2 1 , ( 1 6 ) H H M e( 1 3 1 , ( 1 7 ) H B u t HSCHEMEAll at tempts to prepare 9-t -but ylaminoacridine failed,the butyl group being eliminated: cyclisation of 2-t-but ylcarbamoyldiphenylamine with phosphoryl chlorideor phosphorus pentachloride, and the reactions of9-chloro- and 9-phenoxy-acridine and their 2.7-di-t-As the 2-carboxydiphenylamines required for the butyl derivatives-with cbutylamine, gave only .the 9-synthesis of the 4-t-butyl- and 2,5- and 2,7-di-t-butyl- aminoacridines.9-aminoacridine could not be obtained by the Ullmann As the s-butylacridines (1) and (3) could not bereaction, the Jamieson-Turner synthesis> involving the resolved into their optical isomers by chromatography' The Acridines,' ed.R. M. Acheson, 2nd edn., Wiley, New J. M. F. Gagan, in ref. 1, p. 161.Tork, 1973. M. M. Jamison and E.E. Turner, J . Chent. SOL., 1937, 1954;A. R. P. Peacocke, in ref. 1, p. 723. J. M. F. Gagan, in ref. 1, p. 171466 J.C.S. Perkin Ion Woelm acetylcell~lose,~ or by crystallisation of thesalts of (+)-camphor-lO-sulphonic acid or 3-bromo-(+)-camphor-8-sulphonic acid, (+)- and (-)-9-s-butyl-aminoacridinium chlorides (5) and (6) were synthesisedfrom 9-phenoxyacridine by treatment with (+)- and(-)-s-butylamine in phenoL6 These amines were separ-ated from the racemic mixture by multiple crystallis-ation of the hydrogen tartrates,' monitored by formationof N-s-butylbenzamide.8 (+) -s-Butylamine was ob-tained optically pure, but (-)-s-butylamine was onlyobtained in 71.5% optical purity by this procedure.Attempts to prepare (9,lO)acridinophanes (a 9,lO-bridge would shield one side of the aromatic system frominteraction with nucleic acids) were unsuccessful. The3% yield of 9-( 1 l-methoxyundecy1)acridan from acridineand 1 1-methoxyundecylmagnesium bromide could notbe increased.1 l-Bromoundecylamine with 2-chloro-carbonyldiphenylamine surprisingly gave the diacyl-arnine, whatever the conditions, so cyclisation of themonoamide to the 9-aminoacridine and intramolecularquaternisation could not be attempted. Attempts weremade to quaternise acridine, methyl acridine-9-carb-oxylate, methyl 3-(acridin-9-yl)propionate, and 9-amino-acridine with n-propyl iodide, methyl chloroacetate,chloroacet onitrile, chloroacetic acid, methyl 3-iodo-propionate, methyl 6-iodo- and 6-bromo-hexanoate,methyl 1 l-iodo-, 1 l-bromo-, and 1 l-tosyl-undecanoate,and l-iodo-ll-methoxyundecane without solvent and indimethylformamide, xylene, nitrobenzene, and butanol,in the expectation that this could be followed eventuallyby cyclisation and lead to an acridinophane.Howeverno quaternary salts were obtained except from acridineand n-propyl iodide in xylene, in general agreement withthe less extensive results of Zanker et aL9 Acridiniumchloride was obtained from acridine in nitrobenzenewith methyl chloroacetate, chloroacetic acid, and chloro-acetonitrile, and acridinium iodide was obtained bothfrom acridine and all the iodo-compounds in butanoland from methyl 3-iodopropionate in all the solvents.9-Arninoacridinium iodide was obtained from 9-amino-acridine in xylene with n-propyl iodide, and methyl6-iodohexanoate and 11-bromoundecanoate, in agree-ment with the observation of Ioffe and Selezneva 10 that9-aminoacridine could not be quaternised with groupslarger than the ethyl group.There is clearly a strongtendency towards Hoffmann elimination, rat her thanakylation in the acridine series, and this can be associ-ated with the steric hindrance caused to 10-substituentsby the 4- and &hydrogen atoms.The n.m.r. spectra of the acridines and their syntheticprecursors are presented in Table 1 (and the Supple-mentary Publication). The n.m.r. spectrum for acridine6 A. Luttinghaus, U. Hess, and H. J. Rosenbaum, 2. Nutur-6 D. 3. Dupr.6 and F. A. Robinson, J . Chem. Soc., 1945, 549.7 A.Fleury-Larsonneau, Bull. Soc. chim. Frame, 1939,6,1676.8 P. Bruck, I. N. Denton, and A. H. Lamberton, J . Chem. Soc.,B V. Zanker, E. Erhardt, F. Mader, and J. Thies, 2. Nutur-forsch., 1967, 22b, 1296.1966, 921.forsch., 1966, 21b, 102.at 60 MHz has previously been simulated l1 to h0.1 Hz,and almost as good agreement has now been obtainedby using the same parameters and a LAOCOON I11calculation for the 100 MHz spectrum. The assignmentof the particular resonances to the 1-, 2-, 3-, and 4-protons respectively could have been made in thereverse order, but are correct for they agree with thedefinite assignments which are possible for 2,7,9-trideuterioacridine.12 Unambiguous proton assign-ments can also be made for 9-amino- and 9-chloro-2,7-di-t-butylacridine, and comparing the resonance positionsof the protons in the former compound with thosereported for the computer simulated spectrum of9-aminoacridine,11 shows that the four-spin system forthis last compound was previously assigned the wrongway round.The lowest field aromatic protons for both9-amino-2,7-di-t-butylacridine (4) and its hydrochlorideare at positions 1 and 8, and the downfield shifts forprotons on cation formation are in the order H-3 >H-1 > H-4 > H-2, the last hardly changing position.This can be correlated with the impossibility of placingthe formal positive charge of the cation at position 2.The 1- and 8-protons of methyl acridine-9-carboxylateare not significantly deshielded by the ester group,which must therefore be forced out of the ring plane bythe nearby atoms; however these protons are sig-nificantly deshielded by a 9-chlorine atom or a 9-cyano-group, and in dimethyl acridin-9-ylmalonate.The n.m.r.spectra of the 2-carboxydiphenylamines(Table 1 and Supplementary Publication) could beassigned on the assumption that the lowest field proton(7 ca. 2) was ortho to the carboxy-group, and that theamino-group exerts its usual shielding effect on orth-and $am-hydrogen atoms. The unambiguous assign-ments which can be made for 2-carboxy-4,4'-di-t-butyl-diphenylamine are consistent with these interpretations.Restricted rotation about the N-C bond for variousamides, which may be considered due to contributionsfrom charged resonance structures [ e g .(24)J and not tonitrogen inversion, accounts for the variable tem-perature n.m.r. phenomena shown by several amides,the coalescence temperatures for NN-dimeth ylbenz-amide l3 and 2-benzoylisoindoline l4 being 11 and 56 "Crespectively. The variable temperature phenomenashown by the diphenylamides (15) and (16) are toocomplex (Table 2) to be accounted for solely on asimilar hypothesis. The single ring-methyl resonancefor the amide (16) splits into two, then three, and thenfour peaks on lowering the temperature, although theester-methyl signal remains as a singlet, while for (15)the t-butyl and the ester-methyl resonances split intotwo peaks at ca. 55 and 30 "C, respectively. Two types10 I. S. Ioffe and N. A.Selezneva, J . Gen. Chem. (U.S.S.R.),11 J. P. Kokko and J. H. Goldstein, Sfiectrochim. Ada, 1963,19,12 R. G. Bolton, D.Phi1. Thesis, Oxford, 1970.l3 M. T. Rogers and J. C. Woodbrey, J . Phys. Chern., 1962,68,1* K. Farigand J. T. Gerig, J . Amer. Chem. Soc., 1969,91,3046.1961, 81, 62.1119.5401976 467TABLE 1internal reference)Acridines [in (CD,) ,SO]Unsubstituted 1,8-H,, 1.98; 2,7-?&, 2.60; 2,6-H,, 2.21;9-c1 1,8-H,, 1.77m; 2,7-H2, 2.53m; 3,5-H,,N.m.r. spectra (100 MHz; T values; J in Hz; Me,SiProton resonances4,5-H,, 1.75; 9-H, 0.902.31m; 4,5-H,, 1.88m2,7-But2-9-C1 1,8-H,, 1.67d; 3,6-H,, 2.08q; 4,5-H,, 1.80d;J 1 . 3 1.5; J3,4 9.0; But,, 8.50s9-CN a 1.8-H,, 1.75m; 2,7-H,, 2.26m; 3,6-H,,2.13m; 4,5-H,, 1.68m9-CH (CO2Et) 2 l,8-H2, 1.58m; 2,7-H,, 2.22m; 3,6-H,,1.98m; 4,5-H,, 1.68m; CH(CO,Et),,3.31s; (CH,*CH,),, 5.71q; (CH,*CH,),7.91t9-C02Me a 1,8-H,, 2.02m; 2,7-H,, 2.44ni; 3,6-H,,2.22m; 4,5-H,, 1.76m; Me, 5.81s9-Me 1,8-H,, 1.92m; 2,7-H,, 2.53m; 3,6-H,,2.30m; 4,5-H,, 1.83m; Me, 7.45sAcridiniurn chlorides [in (CD,) ,SO]9-NH2 1,8-H,, 1.14; 2,7-H,, 2.4m; 3,4,5,6-H,,9-NH2 ' l,8-H2, 2.14m; 2,7-H2, 2.66m; 3,6-H,,9-NH2-2,7-But2 1,8-H,, 1.35m; 3,6-H,, 1.85m; 4,5-H,,9-NH,-2,7-But, d 1,8-H,, 1.83;C 3,6-H,, 2.38;c 4,5-H,, 2.38;C2-Carboxydiphenylamines [in (CD,),SO]4'-But 3-H, 2.50~1; 4-H.3.21m; 5-H. 2.60m; 6-H,1.9m2.35m; 4,5-H,, 1.56m2.05ni; 10-H, 0.09br, s ; J3,4 9But,, 8.60s4,4' -But 22.80;d j 3 , , 8;. J3,5 1.5;J 5 . 6 8 ; 2',6'-H,, 2.80;'J2t.3,.8 ; But, 8.63s3-H, 2.10d; 5-H, 2.58q ; 6.J s B 6 8; 2',6'-H,, 2.90d;Jze.3.8.6; But,, 8.73s-H, 2.86d; J3.5 2;3',5'-H,, 2.66d;Benzene derivatives [in CDCl,]3-H, 2.90s; 4-H, 3.47m; 5-H, 3.08m;l-NH2-4-But 2,6-H2: 3.40d; 3,6-H2, 2.83d; J 2 . 3 8.5;But, 8.70s; NH,, 6.58br, s2,4-(NO2)2-l-But g 3-H, 1.75d; 5-H, 1.66q; 6-H, 2.16d;J3,5 2.5; J5,6 8.5; But, 8.61sl-No2-4-B~~ 9 2,6-H,, 2.45d; 3,5-H,, 1.85d; J z , 3 8 . 5 ; But,8.60s1-NO2-2-But ArH,, 2.35-2.75m; But, 8.60sa In CDC1,. b Free base; lit. value.1l CApparent singlet,but showed signs of splitting. Resonances overlap. e In(CD,),SO. f Disappears in D,O. 9At 60 MHz.TABLE 2N.m.r. spectra of some N-benzoyl-Z-methoxycarbonyl-diphenylamines (in CDCl, at 100 MHz; Me,Si asinternal reference ; T values)Compd. Proton resonances(14) ArH,,, 2.0-3.0m; But2, 8.68, 8.73 (1 : 1); OMe,(15)(16) ArH,,, 1.8-3.2m; Me, 7.60br,' 7.80a (1 : 1); OMe,(17) ArH,,, 2.0-3.0m; But, 8.74s; OMe, 6.20s(19) 6 ArH,,, 2.0-3.2m; But, 8.48, 8.81 (4 : 3)b Unchanged from+50 to -75 "C and a t 60-80 "C single resonance at 8.55observed. c Unchanged from +25 to -75 "C; single reson-ance a t 6.28 between + 35 and + 70 "C.d Singlet at 7.65 above35 "C in o-dichlorobenzene; in CDCI, splits t o resonances at7.41, 7.61, and 7.77 from -12 t o -48 OC, and t o 7.45, 7.65,7.75, and 7.85 a t -67 to -75 "C. In (CD,),SO. The shiftsof the double peaks are followed, in parentheses, by their rela-tive intensities expressed as ratios.6.18sBut, 8.35,b 8.71 b (2 : 3); OMe, 6.27,c 6.35 c (2 : 3)6.19s0 In pyridine, aromatic region obscured.of geometric isomerism are therefore being detected, andthese arise from restricted rotation about the amideC-N bond and about the aryl-N bonds; in structure(24) the R and ester groups can be ' cis ' or ' trans,' andexamples of this type of isomerism are known.15 It isnot possible to be certain which type of isomerism isresponsible for the first peak splitting observed oncooling the hot solutions, but it is likely that this is dueto restriction of rotation of the N-aryl substituents, asthese are the closest groups [particularly in the case ofthe t-butyl compound (15)].As diphenylamines arerelatively non-basic, the contribution of the lone pairof the nitrogen atom to charged resonance structuressuch as (24) would be less than in the case of NN-dialkylamides, which could result in lower coalescencetemperatures.The n.m.r.spectra of the benzimidates (9)-(13) and(20)-(23) in deuteriochloroform (Table 3) showednormal features, but in trifluoroacetic acid (Table 4),TABLE 3Me,Si internal reference; 100 MHz)spectra of benzimidates (in CDCl, ; T values ;Proton resonancesArH,,, 2.0-3.5m; But,, 8.68s, 8.79s; OMe, 6.12sArH,,, 1.9-3.8m; But,, 8.68s, 8.79s; OMe, 6.14sBut, 8.65s; OMe, 6.20sArH,,, 1.8-3.6m; Me, 7.89s; OMe, 6.10sArH,,, 1.9-3.5m; But, 8.75s; OMe, 6.10sArH,,, 2.2-3.5m; But, 8.62sArH,,, 1.9-3.4m; But, 8.65s; OMe, 6.10sArH,,, 2.2-3.5m; But, 8.64sArH;;, 2.4-3.5m; CH,CH,, 5.51q; CH,CH,.8.59t;But , 8.72s0 In pyridine, aromatic region obscured.TABLE 4N.m.r. spectra of benzimidates (in CF,-C0,H; T values;Me,Si internal reference ; 60 MHz) *Proton resonancesBut,, 8.57, 8.59, 8.63, 8.65 (1 : 5 : 5 : 1); OMe, 5.84,But,, 8.39, 8.42, 8.65 (1 : 2 : 1); OMe, 5.83, 5.90 (1 : 1)But, 8.33, 8.45 (1 : 1); OMe, 5.96, 6.02 ( 1 : 1)Ring Me, 7.42, 7.62 (1 : 1); OMe, 5.85, 5.97 (1: 1)But. 8.60, 8.67 ( 2 : 1); OMe, 5.87, 5.98 (1 : 2)But, 8.38, 8.55 (3 : 2)But, 8.55,8.65 (1 : 1); OMe, 5.85,5.97 (1 : 1)But, 8.60sBut, 8.59s; CH,CH,, 5.20q; CH,*CH3, 8.41t, J 7 Hz5.96 (5 : 1)* The shifts of the multiple peaks are followed, in parentheses,by their relative intensities expressed as ratios.where N-protonation is expected, all except (22) and(23) showed two or more resonances each for both ringalkyl and ester methyl groups.The phenomenon canbe associated with the presence of ortho-substituents onthe aryl groups. The spectra of compounds (10) and(11) did not alter over 5 days, and the compounds wererecovered unchanged. Protonation of the benzimidatesa t the nitrogen atom could give two geometricallyisomeric cations (25), and models show that ortho-substituents on either aryl group could cause restrictedR. M. Acheson and I. A. Selby, J.C.S. Perkin I, 1974, 423468 J.C.S. Perkin Irotation, A combination of these two types of geo-metrical isomerism, as for the benzoyldiphenylamines(24), could be the cause of the multiple resonances.The n.m.r. spectra of relatively few t-butylbenzenes(Table 1 and Supplementary Publication) have beenrecorded; the steric effect of the large alkyl group onadjacent substituents is of interest.The usual de-shielding effect of the nitro-group on the ortlzo-protonsPhR1 R 2( 2 0 ) Ph 2 - B u t( 2 1 1 4-But-Z-CO2Me.C~H~ H( 2 2 ) Ph 4 - B u t( 2 3 ) E t 4 - B u t( 2 4 1(7 1.85) of l-nitro-4-t-butylbenzene is much reduced inthe 2-t-butyl isomer (ArH4 2.35-2.75m) where thenitro-group cannot be coplanar with the ring; there islittle difference between the chemical shifts of theortho-protons of the corresponding amines. As theresonance position ( T 1.75) for the 2-proton of 2,4-dinitro-l-t-butylbenzene shows less deshielding thanthat of the &proton (1.66), it appears that the non-planar 2-nitro-group exerts a small shielding effect inthis situation.The shifts caused to the ortho-protonsby introducing a t- or s-butyl group varied by up to0.2 p.p.m.EXPERIMENTALThe U.V. spectra of the aminoacridines in sodium phos-phate buffer at pH 6.9 were recorded with a Cary 14spectrophotometer ; the other instruments and procedureshave been described.lb Light petroleum had b.p. 60-80".The n.m.r. spectra for the substituted alkanes and acridines,2-carboxydiphenylamines, and butylbenzenes not detailedhere and the U.V. spectra and analytical data for newcompounds are available as Supplementary PublicationNo. SUP 21647 (10 pp., 1 microfiche).* The compoundnumbers (26)-(47) are used to refer to data in the Supple-mentary Publication; they do not refer to illustratedstructures.* For details of Supplementary Publications, see Notice toAuthors No.7, J.C.S. Perkin I , 1976, Index issue.l6 P. W. B. Harrison, J. Kenyon, and J. R. Shepherd, J . Chsm.SOC., 1926, 658.l7 H. C. Duffin, E. D. Hughes, and C . Ingold, J . Chern. SOC.,1959, 2734.l8 D. Craig, J . Amcr. Chem. SOC., 1935, 57, 195.Preparation of 9-A mino-2-s-butyl- and -2-t-butyl-acridiniuwChlorides .- 1 -A mino-4-s-butylbenzene. 1 -Nitro-4-s-bu tyl-benzene (25 g), obtained in 65% yield [b.p. 141-144' a t100 mmHg (lit., 142-144' a t 12 mmHg)] as described,lswas shaken with palladium-charcoal (1 g) in methanol(300 ml) under hydrogen (5 atm) until absorption ceased.After filtration, distillation gave 1-amino-4-s-butylbenzene(20.2 g), b.p.116-118" a t 13 mmHg [lit.ls (differentprocedure), 118" a t 15 mmHg].1-A mino-4-t-butylbenzene was prepared similarly fromthe nitro-compound ; 1' b.p. 113" a t 50 mmHg, nD20 1.5389(1it.,l8 b.p. 228-230" at 762 mmHg, nD20 1.5380).2-Ca~boxy-4'-s-butyZdi~henylamine (26). Potassium car-bonate (25 g) was added slowly, with vigorous stirring, to2-chlorobenzoic acid (10 g) in refluxing cyclohexanol(60 ml).Water and cyclohexanol were distilled off until the refluxtemperature reached 162 "C. Activated copper catalyst lg# 2o(1 g) and 1-amino-4-s-butylbenzene (10 g) were thenadded, and the mixture was refluxed for 2 h. Cyclo-hexanol (20 ml) was distilled off and then refluxing wascontinued for 3 h.Solvent was then removed by steamdistillation and the aqueous residue was boiled for 10 minwith charcoal (Norite) (3 g ) and filtered hot. The filtratewas acidified to pH 4 at the boil with concentrated hydro-chloric acid. The black precipitate yielded the acid (26)(35%) as pale yellow needles (from toluene; washed withlight petroleum), m.p. 179-181".9-ChZoro-2-s-butylacridine was prepared from this di-phenylamine in the usual way,21 except that the chloro-form-soluble materials in toluene were chromatographed ondeactivated alumina, and was obtained initially as a brownoil.9-Arnino-2-s-butylacridiniullz chloride ( 1), obtained fromthe 9-chloroacridine in the usual way,21 was treated withconcentrated hydrochloric acid-methanol (1 : 1 ) to give9-a~ino-2-s-butyZacridinium chloride (60%) as yellow micro-needles (from water) , m.p.289-291". Treatment withsodium hydroxide yielded 9-amino-2-s-butylacridine asyellow rhombs, m.p. 209-210".2-Carboxy-4'-t-butyldiphenylamine was produced (48%),by the method used for the 4'-s-butyl acid, as pale yellowplates (from ethanol; washed with light petroleum), m.p.205-206" (1it.,l2 205-206").9-Chloro-2-t-butylacridine (27). 2-Carboxy-4'-t-butyldi-phenylamine (6 g), by the method used for 9-chloro-2-s-butylacridine, yielded 9-chloro-2-t-butylacridine (3.5 g,58%) as yellow needles (from light petroleum), m.p.9-Amino-2-t-butylacridiniuvn chloride (2). 9-Chloro-Z-t-butylacridine (3 g), by the method used for 9-amino-2-butyl-acridinium chloride, yielded 9-amino-2-t-butylacridiniumchloride (2.9 g, 89%) as brilliant yellow needles (fromwater), 1ii.p.300-310' (decornp.). Dissolution of thiscompound in water and treatment with sodium hydroxide( 2 ~ ) yielded 9-amino-2-t-butylacridine as yellow needles,m.p. 114-1 15".Preparation of 9-Amino-6-nitro-2-s-butyZacridine and 6-Amino-2-s-butylacridinium Chloride.-2-Carboxy-5-nitro-4'-s-butyldifihenylarnine (28). 2-Chloro-4-nitrobenzoic acid, bythe procedure used for 2-carboxy-4'-s-butyldiphenylamine19 R. Q. Brewster and T. Groening, Org. Syntlz., Coll. Vol. 2,1946, p. 445.20 R. C. Fuson and E. A. Cleveland, Org. Synth., Coll. Vol. 3,1955, p. 339.21 A. Albert and B. Ritchie, in Org. Synth., Coil. Vol. 3, 1955,67-70".p. 531976escept that isopentyl alcohol was used and the refluxtemperature was 1 2 8 "C, yielded 2-carboxy-5-rtitr0-4'-~-butyldiphenylamine (58%) as orange microcrystals (fromtoluene), m.p.184-185".9-Chloro- 6-nitro- 2-s-butylacridine (2 9) . 2-Carboxy-5-nitro-4'-s-butyldiphenylamine (1 g ) , by the method usedfor 9-chloro-2-s-butylacridine, yielded 9-chloro-6-nitro-2-s-butylacridine (0.55 g, 55%) as pale yellow needles (fromlight petroleum), m.p. 149-150".9-Amino-6-nitro-2-s-butylacridine ( 8 ) 9-Chloro-6-nitro-2-s-butylacridine (0.4 g), by the method used for 9-amino-2-s-butylacridinium chloride, yielded 9-amino-6-nitro-2-s-butylacridinium chloride which, on dissolution in water andpouring into sodium hydroxide ( 2 ~ ) , gave 9-amino-6-nitro-2-s-butylacridine (0.18 g) (45%) as a dark red amorphoussolid (purified by alkaline precipitation from a solution ofthe hydrochloride), m.p.156156".6-Natro-2-s-butyl-9-acridone (30). 2-Carboxy-5-nitr0-4'-~-butyldiphenylamine (1 1 g) yielded, by the literaturemethod 22 for 4-nitro-g-acridone, 6-nitro-2-s-butyZ-9-acridone(7 g, 63%) as yellow needles (from toluene-ethanol, 4 : l),m.p. 334-335" (blackened a t 320").6-Amiwo-2-s-butylacridan. 6-Nitro-2-s-butyl-9-acridone(6 g) was reduced, by the literature method for 4-amino-a ~ r i d a n , ~ ~ with sodium amalgam (4y0),24 to give 6-amino-2-s-butylacridan (4.5 g, 93%), which was too quicklyoxidised by air to give good analytical data.6-Amino-2-s-butylacridinium chloride (3). 6-Ainino-2-s-butylacridan (4 g) was oxidised by iron(m) chloride, by theliterature method for the conversion of acridans intoacridines,2b to give crude 6-amino-2-s-butylacridine, whichwas briefly boiled with hydrochloric acid ( 2 ~ ) ; the solutionwas filtered and kept overnight at 0 "C to give 6-amino-2-s-butylacridinium chloride (72%) as deep red microcrystals(from 2~-hydrochloric acid), m.p.169-170'.2-Hydroxy-5-t-butylbenzoic Acid (3 1) .+-t-Butylphenol(50 g) under the optimum conditions for carboxylation ofp-creso1,26 yielded 2-hydroxy-5-t-butyZbenmic acid (49.9 g,73%) as needles (from benzene), m.p. 159". Acetylation,by the procedure described for acetylsalicyclic acid,27yielded 2-acetoxy-5-t-butylbenzoic acid (32) (52%) as plates(from acetic acid) (30%), m.p.120-130"; esterificationwith methanol and sulphuric acid gave methyl 2-hydroxy-5-t-butyZbenzoate (33) as plates (from methanol), m.p.1-Benzamido-4-t-butylbenzene was prepared (65%), by theliterature method for benzanilide,28 as plates (from ethanol),m.p. 143-144" (lit.,18 134").N- (4-t-Butylphenyl) benzimidoyl Chloride .-1-Benzamido-4-t-butylbenzene (20 g) was refluxed for 2 h with thionylchloride (80 ml) : the excess was removed in vacuo and theresulting oil kept in vacuo a t 70 "C for 0.5 h. The residualcrude benzimidoyl chloride was immediately used in thepreparation of the benzimidates. This procedure was usedfor all the benzimidoyl chlorides employed in the synthesisof the benzimidates (Table 5 ) by the literature procedure.4Rearrangement as described gave (Table 6) the correspond-ing N-benzoyl-2-methoxycarbonyldiphenylamines.23 A.Albert and W. Gledhill, J . SOC. Chem. I d , 1946, 64,169.23 G. R. Clemo, W. H. Perkin, and R. Robinson, J . Chew. SOC.,24 L. F. Fieser and M. Fieser, ' Reagents for Organic Syntheses,'25 A. Albert and J. B. Willis, J . SOC. Chem. Ind., 1946, 85, 26.26 D. Cameron, H. Jeskey, and 0. Baine, J . Org. Chem., 1960,51.5-52.5'.1924, 125, 1751.Wiley, New York, 1967, p. 1180.15, 233.2-Carboxy-4,4'-di-t-butyZdiphenylamine ( 18). N-Benzoyl-2-methoxycarbonyl-4,4'-di-t-butyldiphenylamine, by thegeneral literature m e t h ~ d , ~ yielded 2-carboxy-4,4'-di-t-butyZ-di9henyZamine (91%) as pale yellow needles (from toluene),9-Chloro-2,'I-di-l-butylamidine (34) .-2-Carboxy-4,4'-di-t-butyldiphenylamine, by the method for 9-chloro-2-s-butylacridine, yielded 9-chZoro-2,7-di-t-butyZmridi~e (6 1 %)as yellow needles (from light petroleum), m.p. 124-125".m.p.218-219".TABLE 5Synthesis of benzimidatesCompd. Yield (yo) M.p. ("C) Appearance a61 1 1 6 1 1 6 Needles74 109-110 Needles91 131-132 Rhombs 691 79-81 Needles88 116-117 Plates16 49-60 Needles80 106-106 Needles69 84-85 Needles96 64.5-65 Needles(9)(10)(11)(12)(13)(20)(21)(22)(23)a From ethanol. "Attempted rearrangements of (10) failed.C From benzene-light petroleum.TABLE 6Rearrangement of benzimidatesProduct Yield (%) M.p. ("C) Appearance089 146 Rhombs78 146-147 Needles85 139-140 Needles87 109-1 10 Needles(14)(la)(16)(17)* From ethanol.9-Amino-2,7-di-t-butylacridinium Chloride (4) .-9-Chloro-2,7-di-t-butylacridine, by the method for 9-amino-2-s-butylacridinium chloride, yielded 9-amino-2,7-di-t-butyl-acridiHium chloride (87 yo) as brilliant orange needles (fromethanol), m.p.314-316". Dissolution of this compound inwater and treatment with sodium hydroxide ( 2 ~ ) yielded9-amino-2,7-di-t-butylacridire, m.p. 190-1 92".Attempted Preparation of 9-Amino-2,5-di-t-butylac~idiniumChZoride.-2,4-Dinitro- l-t-butylbenzene was prepared in90% yield as reported; o9 reduction as for m-dinitro-aniline 30 yielded first 2-nitro-4-t-butylanilinium chloride(35) (78%) as needles (from B~-hydrochloric acid), m.p.165-166", and then, after treatment with concentratedaqueous ammonia, l-amino-3-nitro-4-t-butylbenzene asyellow plates (from ethanol-water), m.p.55" (lit.,sl 557.1-Amino-2-t-butylbenzene was prepared (almost quanti-tatively) by the procedure for l-amino-4-s-butylbenzeneexcept that Raney nickel and 1-t-butyl-2-nitrobenzene 91were used, and obtained (70%) as an oil, b.p. 105-106° a t20 mmHg (lit.,as 102' at 10 mmHg), which afforded whiteneedles (from ethanol), m.p. 199-200".N-Benzoy2-2-carboxy-2'-t-butyZdifihenylamine (1 9) .-N-Benzoyl-2-methoxycarbonyl-2'-t-butyldiphenylamine, onhydrolysis, yielded N-benzoyl-2-carboxy-2'-t-butyZdiphenyl-amine (87%) as pale yellow plates (from ethanol), m.p.27 A. I. Vogel, 'A Textbook of Practical Organic Chemistry,'28 Ref.27, p. 682.J. B. Shoesmith and A, Mackie, J . Chew. SOC., 1928, 2334.30 Ref. 27, p. 674.31 J. F. Bunnett and M. M. Rauhut, J. Org. Chem., 1966, 21,Longmans, London, 1966, p. 996.934470 J.C.S. Perkin233-235'; all attempts to remove the benzoyl groupfailed.2-Bromo-4-nitro-l-t-butylbenzeneJ obtained in 66%yield,2a did not undergo the von Richter rearrangement.31A ttempts to prepare 9-t-Butylaminoacridinium Chlorideand 9-t-Butylarnino-2,7-di-t-butylacridinium Chloride.-t-Butylamine ( 10 ml) was slowly stirred into 2-chloroformyl-diphenylamine 33 (10 g) in dry benzene (100 Inl). Thebenzene was removed in vacuo and the residue stirred withsodium hydroxide ( 2 ~ ) ; filtration gave 2- (t-butylcarbamoyl)-diphenylamine (37) (10.1 g, 78%) as needles (from ethanol),m.p.121-122".9-Pheno~y-2~7-di-t-butylacridine (38).-By the procedurefor 9-chloroacridine, the 2,7-di-t-butyl derivative yielded9-phenoxy-2,7-di-t-butylacridine (75%) as yellow needles(from light petroleum-benzene), m.p. 168-170".Preparation of Optically Active Acridines.-9-Amino-2-s-butylacridinium (+)-camfihor-l O-sulphonate (39) was ob-tained when the base (4 g, 1 mol) in the minimum ofacetone was added to (+)-camphor- 10-sulphonic acid(3.3 g, 1 mol) in the minimum of acetone. After 0.5 h,filtration yielded bright yellow rhombs (from ethanol-water) , m.p. 112-1 13".The appropriate acridines similarly gave 6-anzino-2-s-butylacridinium (+ )-camphor- 10-sulphonate (40) as deepred plates (from ethanol-water) , m.p. 125-126", 9-amino-2-s-butylacridiniurn 3-bromo-( +)-camphor-8-sulphonate (41)as bright yellow needles (from ethanol-water), m.p.106-107", and S-anzino-2-s-butylacridiniunz 3-brOmO-( +)-camphor-8-sulphonate (42) as deep red needles (from ethanol-water) ,m.p. 132-133'.Repeated slow crystallisations of all these salts fromethanol-water, acetone, dimethylformamide, nitromethane,and propan-2-ol-water gave, after regeneration of the freebase with alkali, material with no detectable opticalrotation at the sodium D-line.(+)- and ( -)-s-Butylammonium Chlorides.-s-Butyl-amine yielded , by the published procedure, optically pure(+)-s-butylammonium chloride as needles, m.p. 151-152"(lit. ,8 152-1 53") , and (-)-s-butylammonium chloride of71.5% optical purity and m.p.150-151' (lit.,8 152-153").(+)- and ( -)-9-~-Butylaminoacridinium Chlorides [(5)and ( S ) ] .-g-Phenoxyacridine and (+)- and (-)-s-butyl-ammonium chlorides yielded, by the general literatureprocedure,G (+) - and (- )-9+butylaminoacridinium chlorides(69 and 60% , respectively) as yellow needles (precipitationwith ether from hot methanol), m.p. (both compounds)279-282" (decomp.), for the (+)-compound +413'and for the (-)-compound -295'.l-Iodo-1 1-methoxyundecane.-This was prepared in 85%32 N. B. Ackerman, P. K. Haldorsen, F. H. Tendick, and E. F.a3 L. Duhamel, Ann. Chirn. (Fvance), 1963, 8, 315.Elslager, J . Medicin. Chew., 1968, 11, 315.G. Schill, Chem. Ber., 1965, 98, 3439.yield [m.p. 26-27' (lit., 27")] by the reported generalmethod 28 from the tosylate from 1 l-methoxyundecanol,~3and was refluxed for 3 h with sodium iodide (58 g) in theminimum of acetone.Solvent was removed in vacuo, thesolid residue was stirred with ether (200 ml), the solid wasfiltered off, and the filtrate was distilled to give l-iodo-ll-methoxyundecane (24 g), b.p. 118-120" at 0.15 mmHg(lit.,33 llP-116" at 0.15 mmHg).9- ( 1 l-Methoxyundecyl) acridan (43) .-The Grignard re-agent from 1-iodo-1 1-methoxyundecane (4 g), magnesiumturnings (0.3 g ) , and dry ether (10 nil) was poured on toacridine (1.2 g). The mixture was refluxed for 2 days,then stirred well into sulphuric acid (10%; 50 ml) and ice(50 g), and extracted with chloroform (3 x 25 ml). Theextracts were dried (Na,S04) and evaporated; the residueon trituration with benzene (2 ml) gave 9-(ll-methoxy-undecyl)acridan (0.08 g) as dark green rhombs (fromethanol) , n1.p.145-146". The filtrate, when chromato-graphed on deactivated alumina with benzene as eluant,yielded as the first band 1-nzethoxyulzdecane (44) (3 g) asneedles (from light petroleum at - 70 "C) , m.p. 25-26".NN-Bis-(2-anilinobenzoyl)-l l-bromoundecylamine (45) .-1 1-Bromoundecylammonium bromide 34 (3.2 g) was shakenwith benzene (10 ml) and sodium hydroxide (20 ml; 2 ~ ) .2-Chloroformyldiphenylamine (2.3 g) in dry benzene (10 ml)was added to the benzene extract immediately after separ-ation. The gelatinous orange-red mixture was refluxed for40 min, cooled, and filtered to yield ll-bromoundecyl-ammonium chloride (1.2 g) as needles (from benzene), m.p.134-135' (lit.,35 135"). The filtrate was evaporated toabout 3 ml and chromatographed on deactivated alumina(benzene as eluant) to yield, as first band, a yellow oil thatcrystallised on addition of a little ethanol to give the imide(45) (0.78 g, 12%) as plates (from ethanol), map. 114-115'.Methyl 1 l-Iodoundecanoate (46) .-Methyl 1 l-bromoun-decanoate (24 g), sodium iodide (70 g), and ethyl methylketone (250 ml) were refluxed for 16 h; the mixture wascooled, filtered, and distilled to give methyl 1 l-iodoundecanoate(27.5 g ) as an oil, nD20 1.4895, b.p. 131-132" a t 0.1 mmHg.Methyl 1 l-Tosylundecanoate (47) .-Methyl 1 l-hydroxy-undecanoate 36 (30 g), by the general method for tosylates,26but a t 0 "C for 1 week, yielded methyl ll-tosylundecanoate(29 g, 60%) as rhombs (from light petroleum a t -70 "C),m.p. 28-29".We thank the M.R.C. for a Studentship (to C. W. C. H.),Drs. A. R. Peacocke and D. G. Dalgliesh for their interestin the work, and Mrs. E. E. Richards, Mr. P. J. Abbott, Dr.I. A. Selby, and Dr. M. S. Verlander for the n.m.r. spectra.[5/486 Received, 12th March, 1975135 A. A. Goldberg and W. Kelly, J . Chem. SOC., 1947, 1369.36 R. Dulou and Y . Chr&ien-Bessi&re, Bull. SOC. chim. France,1969. 1362
ISSN:1472-7781
DOI:10.1039/P19760000465
出版商:RSC
年代:1976
数据来源: RSC