1977 2517Cytotoxic Compounds. Part 22.l Reaction of 2,2'-lminodiethanol withSome ChloronitrobenzenesBy Anthony J. Abela Medici. Leonard N. Owen,' and Constantine Sflomos, Department of Chemistry,Imperial College, London SW7 2AYConditions have been established for the reaction of 2.2'-iminodiethanol with 2.3.. 2.4.. and 2.5-dichloronitro-benzene to give, as major products, the 2- (bis-2-hydroxyethylamino)-cornpounds ; 3.4-dichloronitrobenzene and4-chloro-3-nitrobenzoic acid gave the 4-(bis-2-hydroxyethyIamino) -compounds. Minor products were thecorresponding 2-hydroxyethylamino-con-~pounds and the amino- or azo-compounds formed by reduction of thenitro-group.Conversion of the bis-2-hydroxyethylamino-compounds into the bis-2-chloroethylarnino-derivatives, followedby catalytic hydrogenation of the nitro-group and reaction of the resultant primary arnines with aryl chloroformates.led to mustard carbamates of potential interest as anti'-tumour agents.AROMATIC nitrogen mustards (ring-substituted Nh'-bis-2-chloroethylanilines) are prepared from the correspond-ing diols, which are usually made by bishydroxyethyl-ation of the ring-substituted aniline, a reaction which isimpracticable when the basic character of the amine isdiminished by the presence of an 0- or p-nitro-group.Thus it was not possible to prepare the diols (1) and ( 5 )by reaction of ethylene oxide with 4-chloro-2-nitroanilineor with 2-chloro-4-nitroaniline, respective1y.l In prin-ciple, however, these diols should be accessible by nucleo-philic aromatic substitution.Part 21, X.J . Abela Medici, L. N. Owen, and C. Sflomos,J . Degutis and V. Bieksa, Liet. T.S.R. Akad. Davbaa,Sev. B, 1965. 42(3), 71; 0. Barauskaite, V. Bieksa, and J.Degutis, L i e t . T.S.R. Mokslu Akad. Darbai, Seu. B , 1971, 66(3),139.J . C . S . Pevkin I , 1977, 2258. * K. F. Waldkotter, Rec. Trav. chim., 1939, 58, 132.Waldkotter prepared NN-bis-2-hydroxyethyl-2,4-dinitroaniline by treatment of l-chloro-2,4-dinitro-benzene with 2,2'-iminodiethanol, and a similar reactionhas been carried out on some 4-bromo-3-nitrobenzene-s~lphonamides,~ but 2-chloronitrobenzene gave only amixture of N-(2-aminophenyl)morpholine, 2,2'-dichloro-azobenzene, 2-chloroaniline, and 2-nitrophenol, whilstthe sole product obtained from 4-chloronitrobenzene was4,4'-di~hloroazobenzene.~ Only tars, with reductionand hydrolysis products, were obtained by heatingvarious dichloronitrobenzeiies with iminodiethanol a t175 "C in the presence or absence of sodium carbonate.5Notwithstanding the unpromising nature of these* M.hleltsner, L. Greenstein, G. Gross, and M. Cohen, J .5 C. B. Kremer and A. Bendich, J , Amer. Chem. Soc., 1940,Amev. Chem. Soc., 1937, 59, 2660.62, 12792518 J.C.S. Perkin I'was present in the iminodiethanol was ruled out byg.1.c. analysis of the reagent, and it therefore appears thatloss of a 2-hydroxyethyl group, either from imino-diethanol or from the NN-bis-2-hydroxyethylaniline,must be occurring as a minor side-reaction.React ion of iminodie t hanol with 4-chloro-3-nitro-benzoic acid also proceeded satisfactorily ; the crudeproduct was difficult to purify because of its low solu-bility, and it was therefore esterified to give the methylreports, the reaction was considered to be worthy offurther study, under milder conditions, as a potentialsource of NN-bis-2-hydroxyethylanilines containing onenitro-group and one other function as additional ring-substituents.Such products, after sequential con-version into the mustards, reduction of the nitro-group,and reaction of the resultant primary amines with anaryl chloroformate, would lead to certain hitherto in-accessible mustard carbaniates of potential interest asR1 R 2 R 1 R2 R 1 R 2( 7 ) 4 - C L 2-NO2 ( 1 2 ) 4 - C 1 2 - N H a CO 2 .c ~ H ,t+C L ( O )( 8 ) 6 - C I 2-NO2 ( 1 3 ) 6-CL 2- N H*C02*C6H4C I ( 0 )( 1 4 ) 2 - C l ~ - N H * C O ~ * C G H ~ C L ( 0 )( 1 ) 4 - C l 2-NO2( 2 ) 6 - C L 2 - N O 2( 3 ) 5 - C l 2-NO2 ( 9 ) 5-CL 2-NO2( 4 ) 3-C1 4- NO2 ( 1 0 ) 2 - C l 4 - N o 2 ( 1 5 ) 4-CO2Me 2-NHoC02Ph( 5 ) 2-c1 4-NO2(6) 4-CO2Me 2-NO2anti-tumour agents1 This approach proved to befruitful.Treatment of 2,5-dichloronitrobenzene with imino-diethanol at 110 "C gave the required 5-chloro-2-(bis-2-hydroxyethy1amino)nitrobenzene (1) as the main pro-duct (54) ; small amounts of 2,2',5,5'-tetrachloroazo-benzene (4) and the 2-hydroxyethylamino-compound(7) (2) were also isolated. Under similar conditions,2,3-dichloronitrobenzene gave the diol (2) (49y0), 2,3-dichloroaniline (3y0), and the 2-hydroxyethylamino-compound (8) (4).2,4-Dichloronitrobenzene gave thediol (3) (74y0), the isomeric diol (4) (6), and the 2-hydroxyethylamino-compound (9) (2) ; it is known 697that the 2-position is much more reactive than the 4-position in 2,4-dichloronitrobenzene, and there is onlyone previous record of the isolation of a minor amount of4-substituted product, the nucleophile then beingammonia.8 The relatively low reactivity of the 4-position towards reaction with iminodiethanol was alsoevident when 3,4-dichloronitrobenzene was used, a muchlonger reaction time being necessary to obtain the diol(5) in good yield (61y0), the by-products being 3,3',4,4'-tetrachloroazobenzene (9) and the 2-hydroxyethyl-amino-compound (10) (2).The origin of the monohydroxy-compounds (7)-( 10)is obscure.The possibility that some 2-aminoethanol6 A. F. Holleman, W. J . De Mooy, and J. Ter Weel, Rec.Trav. chim., 1915, 55, 1; J. F. Bunnett, Quart. Rev., 1958', 12, 1./ester (6). In contrast, 4-chloro-3-nitroanisole gave only2-chloro-5-methoxyaniline and 2,2'-dichloro-5,5'-dime-thoxyazobenzene, the activating effect of the o-nitro-group on the reactivity of the halide towards nucleo-philic displacement being completely overshadowed bythe deactivation caused by the 9-methoxy-group.By reaction with phosphoryl chloride the diols (1)-(6) were converted into the corresponding bis-2-chloro-ethylamino-compounds, small amounts of the N-aryl-morpholines (1 1) also being formed.Catalytic hydrogen-ation of the nitro-mustards derived from the diols (l),(2), (5), and (6), followed by reaction of the crude amino-mustards with phenyl or 2-chlorophenyl chloroformate,gave the mustard carbamates (12)-( 15).EXPERIMENTALlH N.m.r. spectra were recorded for solutions in deuterio-chloroform. (Varian T-60 instrument) ; signals due tohydroxy- or amino-protons were identified by deuteriumexchange; resonances for aromatic protons are omitted,though the integrals were in accord with those of otherquoted resonances. 1.r. spectra were recorded for routinestructural confirmations but are not reported here. Kiesel-gel GF,,, (Merck) was used for t.1.c. Petroleum refers tothe fraction of b.p. 40-60 "C.C.B. Kremer and A. Bendich, J . Amer. Chem. Soc., 1939,8 H. J. den Hertog and C. Jouwersma, Rec. Trav. chim., 1953,61, 2658.72, 441977Reactions with 2,2'-IminodiethanoZ.-(a) A mixture of2,5-dichloronitrobenzene (5 g) and iminodiethanol (10 ml)was stirred a t 110 "C (oil-batb) for 3 h, then allowed tocool, and partitioned between water and dichloromethane.The organic layer was washed with water, then dried, andconcentrated to an oil, which was separated by t.1.c. (ether)into the following fractions (in order of increasing RF):(i) 2-(bis-2-hydroxyethyZamino)-5-chZoronitrobenzene (1) (3.6g), an oil, T 6.33 (4 H, t , OCH,), 6.67 (4 H, t, NCH,),7.lbr (2 H, OH) (Found: C, 45.8; H, 5.0; C1, 13.6; N,10.7. CloH13C1N,04 requires C, 46.1; H, 5.0; C1, 13.6; N,10.75) ; (ii) 2,2',5,5'-tetrachloroazobenzene (118 mg),1ii.p.188 "C (from benzene) (lit.,9 189 "C) ; and (iii) 5-chloro-2-( 2-hydroxyethy1amino)nitrobenzene (7) (86 mg), orangeneedles (from dichloromethane-petroleum) , m.p. and mixedm.p. 106-108 "C (lit.,' 107.5 "C), T 1.67br (1 H, NH),6.00 ( 2 H, t, OCH,), 6.43 ( 2 H, t, NCH,), and 8.3 br ( 1 H,OH).(b) Similar treatment of 2,3-dichloronitrobenzene (5 g)with 2,2'-iminodiethanol (10 ml) for 5 h a t 115 "C gave thefollowing fractions (t.1.c. in dichloromethane) : (i) Z-(bis-2-hydroxyethylamino)-3-chZo~onit~obenzene ( 2 ) (3.35 g),yellow needles (from aqueous ethanol), m.p. 70-71 "C,T 6.35 (4 H, t, OCH,), 6.70 (4 H, t , NCH,), and 7.5br( 2 H , OH) (Found: C, 46.15; H, 4.9; C1, 13.8; N, 10.8);(ii) 3-chloro-2-( 2-hydroxyethy1amino)nitrobenzene (8) (0.21g), an oil (lit.,7 oil), T 3.2br (1 H, NH), 6.3 (4 H, m, CH,), and7.7br (1 H, OH); (iii) 2,3-dichloroaniline (0.16 g) N-acetyl derivative, m.p.159 "C (from water) (lit.,lo 156-157 "C) ; and (iv) unchanged 2,3-dichloronitrobenzene(c) Reaction of 2,4-dichloronitrobenzene (5 g) withiminodiethanol (10 ml) for 2 h a t 108 "C gave (t.1.c. inether) (i) 4-(bis-2-hydroxyethylamino)-2-chlo~on~trobenze~e (4)(0.38 g), yellow needles (from aqueous ethanol), m.p. 78-79 OC, T 6.05 (4 H, t, 0-CH,), 6.30 (4 H, t, NCH,), and 7.lbr( 2 H, OH) (Found: C, 46.2; H, 5.1; C1, 13.3; N, 10.7);(ii) 2-(bis-2-hydroxyethyZa~zno)-4-chlo~on~trobenzene (3) (5.1g), an orange oil, T 6.35 (4 H, m, OCH,), 6.63 (4 H, m,NCH,), and 7.0br (2 H, OH) (Found: C, 46.0; H, 5.1 : C1,13.2; N, 10.7) ; and (iii) 4-chloro-2-(2-hydroxyethyl-amino)nitrobenzene (9) (0.12 g), m.p.116-117 "C (frompetroleum) (lit.,7 116 "C), T 1.7br (1 H, NH), 6.03 ( 2 H, t ,0-CH,), 6.50 ( 2 H, t , NCH,), and 7.4br (1 H, OH).(d) 3,4- Iichloronitrobenzene (5 g) and iminodiethanol(10 ml) were heated together for 24 h at 118 "C. Theproduct, isolated as previously described, was a black oil,which, when dissolved in dichloromethane and set aside,deposited orange crystals (0.23 g) (m.p. 150-154 "C) ofthe azo-compound described below. The filtrate was con-centrated and the residue subjected to t.1.c. (ethyl acetate)t o give (i) 4-(bis-2-hydroxyethyZamzno)-3-chlo~on~t~obe~~~ene(5) (4.15 g), an orange oil, T 6.30 (8 H, sext, CH,) and 7.4br( 2 H, OH) (Found: C, 46.0; H, 5.2; C1, 13.8; N, 10.8);(ii) 3-chloro-4- (2-hydroxyethy1amino)nitrobenzene ( 10)(0.13 g), m.p.115-117 "C (from ether-petroleum) (lit.,'120 "C) ; and (iii) 3,3',4,4'-tetrachloroazobenzene (0.15 g),m.p. 152-154 "C (from ether) (1it.,l1 158 "C) (Found: C,44.6; H, 2.1; C1, 44.6; N, 9.0. Calc. for Cl,H,C14N,: C,45.0; H, 1.9; C1, 44.3; N, 8.75).(e) A mixture of 4-chloro-3-nitrobenzoic acid (25 g) and2,2'-iminodiethanol (50 ml) was heated a t 105 "C for 5 h,lo F. Beilstein and A. Kurbatow, Annalen, 1879, 196, 214.l1 J . F. Corbett and P. F. Holt, -1. C h ~ m . SOC., 1963, 2386.(1.3 g).T. de Crauw, Rec. Trav. chim., 1931, 50, 753.then worked up to give an oil which was dissolved inmethanol (350 ml) containing sulphuric acid (80 ml).This solution was boiled under reflux for 20 h, then neutral-ised with aqueous sodium hydrogen carbonate, concentrated,and extracted with ethyl acetate to give methyl 4-(bis-2-hydroxyethyZamino)-3-n~trobenzoate (6) ( 11.7 g), an oil,purified by t.1.c.(ethyl acetate), T 6.03 (3 H, s, CO,Me),6.25 (4 H , t , 0-CH,), 6.44 (4 H, t, N-CH,), and 7.0br (2 H ,requires C, 50.7; H, 5.7; N, 9.850/,).(f) 4-Chloro-3-nitroanisole (5 g) and iminodiethanol(10 ml) were mixed and heated a t 116 "C for 77 h. Asolution of the washed and dried product in dichloromethanedeposited orange crystals ( 1.92 g) of 2,2'-dichloro-5,5'-dimethoxyazobenzene, m.p. 175-1 76 "C (from dichloro-methane) (1it.,l1 172 "C).The filtrate was concentratedand purified by t.1.c. (dichloromethane) to give 2-chloro-5-methoxyaniline (1.3 g), T 6.Obr ( 2 H, NH,) and 6.29 (3 H, s,OMe), characterised as the N-acetyl derivative, m.p.102 "C (from water) (1it.,l2 99 "C).Ring-substituted (Bis-2-chZoroethy1amino)nit~obenzenes.-(a) Phosphoryl chloride (3 nil) in benzene (4 ml) was addedto a solution of 5-chloro-2- (bis-2-hydroxyethylamino) -nitrobenzene (1.6 g) in benzene (6 ml). The mixture wasboiled under reflux for 4 h, then cooled, stirred with aqueoussodium hydrogen carbonate, and extracted with dichloro-methane to give an oil. T.1.c. (dichloromethane) gave (i) 2-(bis-2-chZoroethylaunino)-5-chZoronit~obenzene ( 1.6 g) , anorange oil, T 6.45 (8 H, s, CH,) (Found: C, 40.3; H, 3.8;C1 36.0; N, 9.45.C,oH,lC13N20, requires C, 40.4; H,3.7; C1, 35.7; N, 9.4) ; and (ii) N-(4-chZoro-2-nitrophenyl)-morpholine (55 mg), orange needles, m.p. 45-46 "C (fromcarbon tetrachloride-petroleum) Found : C, 49.35 ; H,4.35; C1, 14.6; N, 11.75. ClOHllC1N2O3 requires C, 49.5;H, 4.6; C1, 14.6; N, 11.5).(b) Similar treatment of 2- (bis-2-hydroxyethylamino)-3-chloronitrobenzene (1.5 g) gave (i) 2-(bis-2-chZoroethyl-amino)-3-chZoronitrobenzene (0.9 g), an oil, T 6.47 (8 H, s,CH,) (Found: C, 41.0; H, 3.7; C1, 35.7; N, 9.1); and(ii) N-(2-chZoro-6-nitrophenyZ)morphoZine (0.26 g), yellowneedles, m .p. 97 "C (from carbon tetrachloride-petroleum)(Found: C, 49.5; H, 4.7; N, 11.5). Separation of thesetwo products was difficult because the difference in RF wassmall.(c) 2- (Bis-2-hydroxyethylamino)-4-chloronitrobenzene(1.5 g) gave (i) 2-(bis-2-chZoroethyZam~no)-4-chZoronit~o-benzene (1.3 g), an oil, T 6.44 (8 H , s, CH,) (Found: C, 40.4;H , 3.7; C1, 35.5; N, 9.5); and (ii) N-(5-chZoro-2-nitro-phenyZ)morphoZine (87 mg), orange needles, m.p.70-71 "C(from carbon tetrachloride-petroleum), T 6.14 (4 H, t ,O*CH,) and 6.92 (4 H, t, N-CH,) (Found: C, 49.7; H, 4.3;C1, 14.8; N, 11.4).(d) 4-( Bis-2-hydroxyethylamino)-2-chloronitrobenzene(0.46 g) gave (i) 4-(bis-2-chZoroethylamino)-2-chZoronitro-benzene (93 mg), yellow needles, m.p. 115 "C (from carbontetrachloride), T 6.40 (8 H, s, CH,) (Found: C, 40.6; H ,3.8; N, 9.2) ; and (ii) N-(3-chZoro-4-nitrophenyl)mor~holine(44 mg), yellow needles, m.p.124-125 "C (from carbontetrachloride-petroleum) (Found: C, 49.5; H, 4.7; C1,14.7; N, 11.5).(e) 4-( Bis-2-hydroxyethylamino)-3-chloronitrobenzene(1.5 g) gave (i) 4-(bis-2-chZoroethylamino)-3-chZoronitroben-zene (1.3 g), an oil, T 6.30 (8 H, q, CH,) (Found: C, 40.6;l2 J. A. Cummins and M. L. Tomlinson, .I. C h ~ m . Soc., 1955,3475.OH) (Found: c , 51.0; H, 5.8; N, 9.7. CI2Hl6N2oJ.C.S. Perkin IH, 3.7; C1, 35.7; N, 9.5); and (ii) N-(2-chloro-4-nitro-pheny2)morpholine (60 mg), yellow plates, m.p. 130 "C (fromcarbon tetrachloride-petroleum), T 6.06 (4 H, t, OCH,) and6.76 (4H, t, NCH,) (Found: C, 49.2; H, 4.4; C1, 14.5; N,11 .6y0).(f) Methyl 4-(bis-2-hydroxyethylamino)-3-nitrobenzoate(1 1.0 g) gave methyl 4-(bis-2-chloroethylamino)-3-nitroben-zoute (9.8 g), an oil, 'c 6.05 (3 H, s, C0,Me) and 6.35 (8 H, s,CH,) (Found: C, 44.9; H, 4.3; C1, 22.2; N, 8.7. C12H14-C12N,04 requires C, 44.9; H, 4.4; C1, 22.1; N, 8.7).N- 2- (Bis- 2-chloroethylamino) -5-chloro-~henylcurbumute ( 12) .-A solution of 2-(bis-2-chloroethyl-amino)-5-~hloronitrobenzene (1.35 g) in methanol (250 ml),containing 10 palladium-charcoal (0.15 g), was shaken inhydrogen until the calculated amount of gas had beenabsorbed.The solution was then filtered into 50 hydro-gen chloride in methanol (30 ml), and the mixture wasevaporated to give a solid hydrochloride which rapidlybecame brown: I t was therefore treated, in benzene (25 ml)and pyridine (0.7 g), with 2-chlorophenyl chloroformate l3(0.7 g), and after being boiled under reflux for 12 h the solu-tion was cooled and washed with 10 hydrochloric acidand with water, then dried and evaporated to give thecurbamate (0.7 g), m.p.98 "C (from ether-petroleum),T 1.llbr (1 H, NH) and 6.58 (8 H, q, CH,) (Found: C,48.2; H, 3.9; C1, 33.5; N, 6.6. Cl,H,,C14N20, requiresN- 2- (Bis- 2-chloroethylamino) - 3-chloro-phenylcurbamute ( 13) .-By a similar procedure, hydrogen-ation of 2-(bis-2-chloroethvlamino)-3-chloronitrobenzene2-ChlorophenylC, 48.4; H, 3.8; C1, 33.6; N, 6.6).2-Chlorophenyl(0.5 g) gave a crude hydrochloride, which on reaction with2-chlorophenyl chloroformate (275 mg) in benzene (10 ml)and pyridine (1 ml) afforded the carbumate (200 mg), m.p.103-105 "C (from ether-petroleum), T 0.70br (1 H, NH)and 6.10 (8 H, s, CH,) (Found: C, 48.3; H, 3.9; C1, 33.8;N, 6.7).2-Chlorophenyl N-4-(Bis-2-chZoroethylamino)-3-chloro-phenylcarbamute ( 14) .-Hydrogenation of 4- (bis-2-chloro-ethylamino)-3-chloronitrobenzene under the same conditionsgave a crude hydrochloride, which afforded the curbamate,m.p. 28-32 "C (from ether-petroleum), T 2.0-3.0 (8 H, m,aromatic and NH) and 6.48 (8 H, s, CH,) (Found: C, 48.3;H, 4.2; C1, 32.9; H, 6.5).N- 2- (Bis- 2-chloroethylamino) -5-methoxycurbonyl-phenyZcurbamate (15) .-Prepared in a similar way frommethyl 4-(bis-2-chloroethylamino)-3-nitrobenzoate (4.0 g) ,the crude hydrochloride reacted with phenyl chloroformate(3 ml) in pyridine (6 ml) and benzene (50 ml) (4 h underreflux) to give the carbumate (1.8 g), m.p. 111-113 "C(from ether), T 1.27 (1 H, s, NH), 6.08 (3 H, s, CO,Me), and6.52 (8 H, m, CH,) (Found: C, 55.3; H, 4.9; N, 6.55.Cl,H,,Cl,N,O, requires C, 55.5; H, 4.9; N, 6.8).PhenylWe thank the Commonwealth Scholarship Commissionfor a Scholarship (to A. J. A. M.) and the State ScholarshipFoundation of Greece for an award (to C. S.).7/1100 Received, 3rd June, 19771l3 R. E. Oesper, W. Broker, and W. A. Cook, J . Amer. Chem..Soc., 1925, 47, 2609.0 Copyright 1977 by The Chemical Societ
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