摘要:
922 J.C.S. Perkin IReactions of Heterocycles with Thiophosgene. Part 1V.l p,4- Dichloro-2-isothiocyanatocinnamaldehyde, a Product from 4,7-DichloroquinolineBy Roy Hull,' Mrs Patricia J. van den Broek, and Michael L. Swain, Imperial Chemical Industries Limited,Pharmaceuticals Division, Alderley Park, Macclesfield, Cheshire4.7- Dichloroquinoline undergoes ring scission on reaction with thiophosgene and barium carbonate. Theresulting P-chloroisothiocyanatocinnamaldehyde [ (6) or (7)] reacts with a wide variety of nucleophiles to give2-substituted 4-formylmethylene-4H-3.1- benzothiazines. Some reactions of the 2-morpholinobenzothiazine(1 3) are described.EARLIER studies on the reaction of thiophosgene withquinoline and isoquinoline had shown that in thepresence of base (hydroxide ion), fission of the hetero-cyclic ring took place to give the o-isothiocyanato-trans-cinnamaldehyde (1) and o-(cis-isothiocyanatovinyl) benz-aldehyde (2), respectively.These ortho-difunctional(1) 12)benzene derivatives offer an interesting source of inter-mediates for the formation of novel heterocyclic com-pounds. We have now continued these studies with4substituted quinolines.4,7-Dichloroquinoline (3) , an intermediate used in themanufacture of the antimalarial chlor~quine,~ reactedsmoothly with thiophosgene and alkali (BaCO,) inmethylene chloride-water * and yielded (58%) the iso-thiocyanate (6) as a reasonably stable compound,vmX. 2000 (NCS) and 1670 cm-1 (conj. CHO), 'c 0.46 (d,J 7-5 Hz, =CH*CHO) and 3-36 (d, J 7.5 Hz, =CH*CHO).We were unable to determine the configuration of theolefin [(6) or (7)] from n.m.r.data.Some Reactions of ~,4-Dichloro-2-isothiocyanatocinnanz-aldehyde [(6) or (7)] .-The isothiocyanate group in thiscompound reacted readily with a wide variety ofnucleophiles; however we were not able in any case toisolate the thioamide (8) ; instead ring closure took placeto yield the substituted benzothiazine (9). Primary andsecondary amines reacted to give, in general, compounds(9; R = NR1R2). The morpholine derivative (13) wasPart 111, F. T. Boyle and R. Hull, J.C.S. Perkin I , 1974,1641.R. Hull, J . Chem. SOC. (C), 1968, 1777.shown to have the stereochemistry indicated by thenuclear Overhauser effect between the exocyclic vinylproton and the 5-H.The i.r. spectra of the amino-benzothiazines generally showed vmSz ca. 1650 cm-1F C l(61orC I( 5 ) I,! c=s(conj. CHO), and the n.m.r. spectra showed the aldehydeproton signal as a doublet ( J 4 Hz) at T ca. 0.1 coupledto the vinyl proton (d, J 4 Hz) at 7 ca. 3.2.2-Aminopyridine yielded the expected product (17)together with 4,7-dichloroquinoline. P-AminoethanolA. R. Surrey and H. F. Hammer, J . Amer. Chem. SOC., 1946,F. D. Popp, W. Blount, and P. Melvin, J . Org. Chem., 1961,69, 113.26,49301975 923reacted in an anomalous fashion: in this case the onlyproduct was 4,7-dichloroquinoline, isolated in 57 yo yield.Presumably in this reaction some stabilisation of theiminium group is set up by the stereochemically favour-able position of the oxygen atom of the ethanolamine, asshown in (22) and (23) (contribution by Dr.P. N.181(211191RNH2 I161(17) NC4H 8NCSHlORNHQCIOMeOPhC H (C02E t l2Edwards of this Department). 2-Aminopyridine pre-sumably forms, in part, a species of type (24) + (25)to account for some formation of 4,7-dichloroquinoline.Methanol and phenol reacted normally with the iso-thiocyanate (6/7) in the presence of alkali and yielded thecorresponding 2-methoxy- (18) and phenoxy- (19)derivatives, respectively. Reaction of diethyl sodio-malonate with the isothiocyanate (6/7) in dimethyl-formamide gave an ester which we regard as having theRI211 (251exomethylene structure (21) rather than the tautomericstructure (20).The n.m.r. spectrum showed the NHsignal as a singlet at 7 3.1. Ethyl carbamate, in thepresence of acid, reacted with the aldehyde (617) to yieldthe bisure t hane (26).The fonnyl group in the benzothiazine (13) yielded anoxime and a semicarbazone under standard conditions.The related alcohol (27) was obtained by reduction ofE. J. Corey, N. W. Gilman, and B. E. Ganem, J. Amer.Chem. SOC., 1968, 90, 5616.the aldehyde (13) with sodium borohydride or lithiumaluminium hydride. Oxidation of the aldehyde (13)with potassium permanganate in acetone gave thebenzothiazinone (28), v,, 1665 cm-l (thiolactone GO).By the method of Corey and his co-~orkers,~ treatmentof the aldehyde (13) with active manganese dioxide andhydrogen cyanide in methanol gave the ester (29) invery low yield, v,, 1690 cm-l (ap-unsat.ester), M+ 338(1 x Cl). The compound was not sufficiently solublefor a satisfactory n.m.r. spectrum to be obtained.EXPERIMENTALN.m.r. spectra were measured with a Perkin-Elmer R-12or Varian A-60 (60 MHz) or HA-100 (100 MHz) instrument.Low resolution mass spectra were determined with aHitachi RMU-6E and high resolution mass spectra with anA.E.I. MS9 or A.E.I. MS 902 S spectrometer.P,4, Dichloro-2-isothiocyanatocinnamaZdehyde [ (6) or (7)] .-Thiophosgene (45 ml) in methylene chloride (180 ml) wasadded dropwise over 30 min to a vigorously stirred sus-pension of barium carbonate (88 g) in water (360 ml) and4,7-dichloroquinoline (89 g) in methylene chloride (360 ml)a t 0".The mixture was stirred for 4 h a t 0" then overnighta t room temperature and filtered through a pad of Supercel.The methylene chloride layer was separated and washedsuccessively with water, 2~-hydrochloric acid, and water,then dried and concentrated to a brown oil which solidifiedon cooling. Crystallisation from light petroleum (b.p.60-80") gave the aldehyde (68 g, 58%) as pale yellowneedles, m.p. 59-61' (Found: C, 46.9; H, 2.3; N, 5.2.C,,H,Cl,NOS requires C, 46.5; H, 1.9; N, 5.4%), v,,(Nujol) 2000br (NCS) and 1670 cm-l (GO), T (CDC1,) 0.46(lH, d, J 7-5 Hz, CHO), 2.65 (3H, s, aromatic), and 3.36(lH, d, J 7.5 Hz, vinylic).2-Amino-7-chloro-4-formylmethylerte-4H-3, l-benzothiazine(lo).-Aqueous ammonia (d 0-88; 1.5 ml) was added to astirred solution of P, 4-dichloro-2-isothiocyanatocinnam-aldehyde (1.5 g) in ethyl acetate (25 ml).After 8 h theprecipitate formed was filtered off, washed with water, andcrystallised from aqueous dimethylformamide to give thearninobenzothiazine (1.0 g) as mustard yellow needles, m.p.>300" (Found: C , 50.1; H, 3-1; N, 11.4. C,,H,ClN,OSrequires C, 50.2; H, 2-9; N, 11-7%), v,, 3200br (NH),1670, and 1640 cm-l (GO?), M+ 238 (1 x Cl).7-ChZoro-.l-formyZmethylene-2-(pyvvolidin- 1-yZ)-4H-3,1-benzothiazine (1 l).-Pyrrolidine (0.3 g) in ethyl acetate( 5 ml) was added to a stirred solution of P,4-dichloro-Z-isothiocyanatocinnamaldehyde (0-S g ) in ethyl acetatJ.C.S. Perkin I(10 ml). After 3 h the supernatant was decanted from aresidual red oil and evaporated to yield an orange solid,which was crystallised from cyclohexane to give thebenzothiazine as yellow needles, m.p.146-146' (Found: C,57.2; H, 44; N, 9.2. C,,H,,ClN,OS requires C, 57.4;H, 4.4; N, 9*6y0), v- (Nujol) 1650 cm-1 (GO), M+ 292(1 x Cl).7-ChZmo-4- fmmylmethylene-2-morpholino-4H-3, l-benzo-thiuzine ( 13) .-~,4-Dichloro-2-isothiocyanatocinnamalde-hyde (1.04 g) in ethyl acetate (10 ml) was added withstimng to morpholine (0.68 g) in ethyl acetate (6 ml) atroom temperature. After 15 min the mixture was filteredand the residue (morpholine hydrochloride) was washedwith ethyl acetate (20 ml). The filtrate was concentratedto yield a yellow solid which was triturated with aqueous2~-acetic acid, filtered off, and dried.Crystallisation fromcyclohexane gave the bemothiazine (0.65 g, 52%) as yellowneedles, m.p. 163-164' (Found: C, 54.4; H, 4.3; N, 8-7.C,,Hl,C1N,02S requires C, 54.4; H, 4.2; N, 9.0%), v-(Nujol) 1650 cm-1 (GO), T (CDCl,) 0.17 (lH, d, J 4 Hz,8-H), 3.00 (lH, dd, J 9 and 2 Hz, 6-H), 3-24 (lH, d, J 4 Hz,vinylic), and 6.28 (8H, s, morpholine), M+ 308 (1 x Cl).The semicarbazone crystallised from benzene as yellowneedles, m.p. 210' (decomp.) (Found: C, 49.6; H, 4.6;N, 19.2. C,,H,,ClW,O,S requires C, 49.2; H, 4.4; N,19.2y0). The oxime crystallised from methanol as yellowneedles, m.p. 184189" (Found: C, 51.7; H, 4.4; N, 12.9.C,,H,,ClN,O,S requires C, 52.0; H, 4.3; N, 13.0%).Similarly was obtained, from piperidine 7-chloro-4-formyZ-methylene-2-Piperidino-4H-3, l-benzothiazine as yellowneedles, m.p.127-128' [from light petroleum (b.p. 60-SO')] (Found: C, 58.4; H, 5.2; N, 9.4. Cl,H,,CIN,OSrequires C, 58.7; H, 4.9; N, gel%), v- (Nujol) 1650 cm-1(GO), T (CDCl,) 0.10 (lH, d, J 4 Hz, CHO), 2.3-3.1 (3H,m, aromatic), 3.24 (lH, d, J 4 Hz, vinylic), and 6.2 and8.3 ( 10H, 2 x s, br, piperidine) .wzethylene-4H-3,l-benzothiazi.Pze (14) .-3-Dimethylamino-propylamine (0.2 g) in ethyl acetate (5 ml) was added to astirred solution of (3,Cdichloro-Z-isothiocyanatocinnam-aldehyde (0.5 g) in ethyl acetate (10 ml). Next day thesolution was evaporated and the residue basified with diluteaqueous sodium hydroxide. The mixture was extractedwith ether and the extract was dried and concentrated.Crystallisation of the residue (0.6 g) from cyclohexane gavethe benzothiazine as orange prismatic needles, m.p.118-119' (Found: C, 56.1; H, 6.8; N, 12.6. Cl,H,,CIN,OSrequires C, 56.9; H, 6-6; N, 12~1%)~ vmz (Nujol) 1630 cm-l(GO), T (CDCl,) 0.20 (lH, d, J 4 Hz, CHO), 2.60 (lH, d,and 2 Hz, 6-H), 3-30 (lH, d, J 4 Hz, vinylic), 6-47 (2H, t,J 7 Hz, CH,), 7.61 (2H, t, J 7 Hz, CH,), 7.79 (6H, s, Me,N),and 8.30 (2H, m, CH,), M+ 323 (1 x Cl).7-Chloro-4-fo~mylmethyle~-2-(o-~tho~yca~bonyZanilino) -4H-3, l-bexzothiazine (15) .-(3,4-Dichloro-2-isothiocyanato-cinnaddehyde (3-9 g), methyl anthranilate (2.2 g), andtriethylamine (1.6 g) were stirred in methyl acetate (30 ml)overnight. The precipitate formed was filtered off, washedwith water, dried, and crystallised from benzene to give thebenzothiazine (145 g) as yellow needles, sintering at 224",m.p.230' (decomp.) (Found: C, 68.4; H, 3.6; N, 7.5.C18H,,C1N20,S requires C, 58.0; H, 3.5; N, 7 ~ 5 % ) ~ v-(Nujol) 1680 (ester GO) and 1650 cm-1 (ap-unsat. CO),M+ 372 (1 x Cl).CHO), 2.43 (lH, d, J 9 Hz, 5-H), 2.81 (IH, d, J 2 Hz,7- Chloro - 2- ( y -dime thy laminopropy lamino) - 4- formy l-J 9 Hz, 5-H), 2.83 (lH, d, J 2 Hz, 8-H), 3.08 (lH, dd, J 97-Chloro-2-(p-chZoroanili.~zo)-4- formylmethylene-4H-3 , 1-benzothiazine (1 6) .-~,4-Dichloro-2-isothiocyanatocinnam-aldehyde (5-2 g) in ethyl acetate (70 ml) was added withstirring to a solution of p-chloroaniline (2-55 g) and tri-ethylamine (2-0 g) in ethyl acetate (30 ml). After 30 minthe mixture was heated under reflux for 15 min and theproduct (2.4 g) was collected and washed with water.Crystallisation from ethanol gave the benzothiazine as yellowneedles, map.256' (decomp.) (Found: C, 55.3; H, 3.1;N, 7.7. C1,H,,Cl,N20S requires C, 55-0; H, 2.85; N,8-05y0).7-Chloro-4-formylmethylene-2- (2-pyridylumino) -4H-3,l-benzothiuzim (17) .-2-Aminopyridine (0.4 g) was refluxedwith ~,4-dichloro-2-isothiocyanatocinnamaldehyde (0-5 g)in ethyl acetate (15 ml) for 2 h. The precipitate formed wasfiltered off and washed successively with water, 5~-aceticacid, and water, and dried. Crystallisation of the residuefrom toluene gave the benzothiazine as fine yellow needles,m.p. >300' (Found: C, 57.2; H, 3-3; N, 12.8. C,,H,,-ClN,OS requires C, 57.1; H, 3.1; N, 13.3%), v,, (Nujol)1650 cm-l (GO), M+ 315 (1 x Cl).The ethyl acetatefiltrate was evaporated and the residue was extractedwith boiling light petroleum (b.p. 40-60'). The yellowneedles deposited on cooling the extract were recrystallisedfrom light petroleum to give 4,7-dichloroquinoline asneedles, m.p. and mixed m.p. with an authentic sample84-85' (lit.,O 86-47'), M+ 197 (2 x Cl).Reaction of ~,4-DichZo~.o-2-isothiocyanatocinnamuldehydem-th 2-Ami.~oethanol.-The aldehyde (2.5 g) in ethylacetate (30 ml) was treated with 2-aminoethanol (1.4 g) inethyl acetate (10 ml). After 8 h, water was added and theorganic layer separated, dried, and evaporated to an orangesolid. The solid was extracted with hot cyclohexane andthe extract evaporated.The residue was crystallised fromlight petroleum (b.p. 40-60") giving 4,7-dichloroquinoline(1.1 g) as white needles, m.p. 85-86' (lit.,, 86-87'),identical (mixed m.p., t.l.c., and i.r. spectrum) with anauthentic sample.7-Chloro-4-formylmethyle~e-2-methoxy-4H-3, l-bemothi-mine (18).-Potassium hydroxide (2 g) in methanol (10 ml)was added to a stirred solution of P,4-dichloro-2-isothio-cyanatocinnamaldehyde (2.0 g) in methanol (20 ml) atroom temperature. After 15 min the orange solution waspoured into water (60 ml) and extracted with ether. Theaqueous phase was separated and acidified with 2~-hydro-chloric acid. The precipitate formed was collected andcrystallised from ethanol to give the benzothiazine (0-6 g,30%) as a yellow powder, m.p.140-142' (Found: C, 52.0;H, 3.1; N, 504%; M+, 252.9949. C,,H,CINOBS requiresC, 52.0; H, 3.2; N, 6.5%; M , 252.9964), vmez (Nujol)1650 cm-1 (GO), T (CDCl,) 0.14 (lH, d, J 3 Hz, CHO),(lH, dd, J 9 and 2 Hz, 6-H) , 3.1 1 (lH, d, J 3 Hz, vinylic),and 5.97 (3H, s, MeO) .7-Chloro-4- formylmethylene-2-phenoxy-4H-3 , l-benzothi-azine (19) .-Powdered potassium hydroxide (1.0 g) inmolten phenol (2.5 g) was added to a stirred solution of p,4-dichloro-2-isothiocyanatocinnamaldehyde (2.0 g) in moltenphenol (2.5 g) a t 90". After a few minutes the masssolidified and was triturated with cold aqueous 2~-potassiumhydroxide. The residual solid was collected, dried, andcrystallised from ethanol-benzene (6 : 1) to give the benzo-6 N. L. Drake, H.J. Creech. D. Draper, J. A. Gorman, S.Haywood, R. M. Peck, E. Walton, and J. O'Neill van Hook,J . Amer. Chem. SOC., 1946, 68, 1214.2.28 (lH, d, J 9 Hz, 5-H), 2.60 (lH, d, J 2 Hz, 8-H), 2.71975thiazine (2.0 g , 82%) as a yellow powder, m.p. 179-181"(Found: C, 60.9; H, 3.2; N, 4-4. Cl,Hl,CINO,S requiresC, 60.5; H, 3.1; N, 4.4y0), vmx. (Nujol) 1650 cm-l (GO),5-H), 24-2-9 (7H, m, 6-H, 8-H, and PhO), and 2.99 (lH,d, J 3 Hz, vinylic).2-Bis (ethoxycarbonyl)methylene-7-chloro-4-for~yZmethylene-1,2-dihydro-4H-3, l-benzothiazine (21) .-P,4-Dichloro-2-iso-thiocyanatocinnamaldehyde (2.0 g) in dimethylformamide(10 ml) was added dropwise to a stirred solution of diethylsodiomalonate [from sodium hydride (0.8 g; 50% dis-persion) and diethyl malonate (2.6 ml)] in dimethylform-amide (10 ml).After h the deep red solution was dilutedwith water, acidified with acetic acid, and extracted withchloroform. The extract was washed with aqueous sodiumcarbonate, dried, and evaporated to a red oil. The oil wasextracted with hot cyclohexane and the extract evaporatedto yield a yellow solid which crystallised from ethanol togive the benzothiazine (0.6 g) as yellow needles, m.p. 139-140" (Found: C, 53.5; H, 4.5; N, 3.5. C,,H1,CINO,Srequires C, 53.5; H, 4.2; N, 3.7%), v- (Nujol) 1650brcm-1 (GO), 7 (CDCI,) -3.1 (lH, s, NH), -0.1 (lH, d,J 2 Hz, 8-H), 3-06 (lH, dd, J 9 and 2 Hz, 6-H), 3-47 (lH,d, J 6 Hz, vinylic), 5.80 (4H, 2q, 2 x CH,O), and 8.70 (6H,2t, 2 x Me), M+ 381 (1 x Cl).1-Chloro- 1 - (4-chloro-52-isothiocyunato~henyl) -3,3-bis(ethoxy-carbony1amino)prop-l-ene (26) .-~,4-Dichloro-2-isothio-cyanatocinnamaldehyde (10.4 g) and ethyl carbamate(7.2 g) were stirred in ethyl acetate (40 ml) with a trace ofhydrogen chloride for 12 h.The mixture was diluted withlight petroleum (b.p. 60-80°), the precipitate was collectedand recrystallised from ethyl acetate to give the bisurefhane(7.2 g) as white needles, m.p. 164-165" (Found: C, 45.8;H, 3-9; N, 10.0. Cl,Hl,C1,N,04S requires C, 45.8; H, 4.0;N, 10.0%), vm (Nujol) 3300 (NH), 2100 (NCS), and 1705cm-l (urethane CO), T (CDCI,) 2-64 (3H, s, aromatic)3-15br (2H, d, 2 x NH), 3-57 (lH, d, J 10 Hz, vinylic),4-55 (lH, t, J 10 Hz, allylic), 5.90 (4H, q, 2 x OCH,*CH,),and 8.80 (6H, t, 2 x CH,CH,O), m/e 417 (2 x C1; M+),382 (1 x C1; M - Cl), 344 (2 x C1; M - CO,Et), andz (CDCI,) 0.09 (lH, d, J 3 Hz, CHO), 2.21 (lH, d, J 9 Hz,J 6 Hz, CHO), 2.56 (lH, d, J 9 Hz, 5-H), 2.93 (lH, d,336 ( 1 x C1; 382 - EtOH).7-Chho-4- (2-hydroxyethylidene)-2-morpholino-4H-3,1-benzothiazine (27) .-Sodium borohydride (0-8 g) was addedin portions to a stirred solution of 7-chloro-4-formyl-methylene-2-morpholino-4H-3,l-benzothiazine (3.0 g) inwarm ethanol (600 ml).After h the solution was con-centrated to small volume and poured into water. Theprecipitate formed was extracted into ether and the etherlayer was separated, dried, and evaporated. The yellowresidue was crystallised from cyclohexane to give the@-unsaturated alcohol (2.3 g, 76%) as prisms, m.p.133-135" (Found: C, 54-2; H, 5.0; N, 9.3. C14H1,C1N,0,Srequires C, 54-1; H, 4.8; N, 9.0%), v- (Nujol) 3350 cm-1(OH), 7 (CDCI,) 2.4-3.4 (3H, m, aromatic in 1,2,4-sub-stituted benzene), 4.07 (lH, t, J 6 Hz, vinylic), 5-90 (2H, d,J 6 Hz, CH,), and 6-55 (8H, s, morpholine).7-Chlmo-2-mor~holino-3,l-benzothiazin-4-one (28) .--Po-tassium permanganate (0.6 g) was added in portions to astirred solution of 7-chloro-4-formylmethylene-2-morpho-lino-4H-3,l-benzothiazine (0.6 g) in acetone. After 12 hat room temperature the excess of oxidant was destroyedwith sodium sulphite and acetic acid. The solution wasdiluted with water and the precipitate formed was collected,dried, and crystallised from cyclohexane, giving thebenzothiazinone (0.3 g) as cream needles, m.p. 159-160'(Found: C, 51.5; H, 4.4; N, 10.1. Cl2Hl1CIN2O2Srequires C, 51.0; H, 3.9; N, 9.9%), vmx. (Nujol) 1665 cm-1(thiolactone CO), 7 (CDC1,) 2.08 (lH, d, J 9 Hz, 5-H),2.65 (lH, d, J 2 Hz, 8-H), 2.90 (lH, dd, J 9 and 2 Hz,6-H), and 6.28 (8H, s, morpholine).7-Chloro-4-methoxyca~bo~ylmethyl~ne-2-morpho2ino-4H-3, l-benzothiazine (29) .-?-Chloro-4-formylmethylene-2-mor-pholino-4H-3, l-benzothiazine (1-5 g) was suspended inmethanol (250 ml) and stirred with sodium cyanide (0-8 g),active manganese dioxide (6-0 g), and acetic acid (0.3 ml) a troom temperature for 48 h. The mixture was refluxedbriefly and filtered hot. Methanol was evaporated fromthe filtrate and the residue was chromatographed onalumina. A yellow band running just ahead of the startingmaterial was eluted with chloroform. Evaporation left asolid which was crystallised from cyclohexane to give theester (100 mg) as pale yellow needles, m.p. 225-5226'(Found: C, 53.5; H, 4.7; N, 8.1. Cl,Hl,CIN,O,S requiresC, 53.2; H, 4.4; N, 8.3%), vmak (Nujol) 1690 cm-1 (+unsat. ester), m/c 338 (1 x C1; M+) and 253 (M - C4H,NO).[4f 1929 Received, 20th September, 1974
ISSN:1472-7781
DOI:10.1039/P19750000922
出版商:RSC
年代:1975
数据来源: RSC