N-iodoamides. Cyclisation of biphenyl-2-carboxamides

摘要

1974 2353N-lodoamides. Cyclisation of Biphenyl-2-carboxamidesBy Stephen A. Glover and Andre Goosen,rsquo; Organic Research Laboratory, University of Port Elizabeth, PortElizabeth, South AfricaThe reaction of biphenyl-2-carboxamide and its N-methyl and N-phenyl derivatives with t-butyl hypochlorite-iodine in t-butyl alcohol containing potassium t-butoxide gave phenanthridones, as well as the corresponding4rsquo;-t- butoxy- and 4rsquo;-oxoisoindoline-1 -spirocyclohexa-2rsquo;,5rsquo;-dien-3-ones. Both potassium t-butoxide and t- butylalcohol suppress the iodination of aromatic substrates by iodine monochloride. The role of potassium t-butoxideand t-butyl alcohol in the formation of the isoindoline-1 -spirocyclohexa-2rsquo;,5rsquo;-dien-3-ones and the mechanismof formation of the 4lsquo;- ketone from the 4rsquo;-t-butoxyisoindoline-l -spirocyclohexa-2lsquo;,5lsquo;-dien-3-ones are discussed.T H E addition reactions of amidyl radicals with olefinshave been explained on the basis of their electro-phi1icity.l Iurtherniore the electrophilic nature ofamidyl radicals has been invoked to account for thecyclisation of biphenyl-2-carboxamides (I) with leadtetra-acetatc-iodine,2 per~ulphate,~ or t-butyl hypo-clilorite-i~dine.~ This last reagent, which has beenshown to convert amides into N-iodo-derivatives,5 gavethe corresponding 2-iodophenanthridones from bi-phenyl-2-carboxamide and its iV-methyl derivative.N-Methylbiphenyl-2-carboxamide (I ; R = Me) withlead tetra-acetate-iodine gave, in addition to N-methyl-phenanthridone (V; R = Me), cis- and tuans-4rsquo;-acetoxy-N-met hylisoindoline- 1 -spirocyclohexa-2rsquo;,5rsquo;-dien-3-one(VII; R = Me, R1 = OAc, R2 = H).These resultswere explained4 on the basis of cyclisation of theamidyl radical (11; R = Me) at the 1rsquo;- and 2rsquo;-positionsof biphenyl-2-carboxaniide to form the intermediateradicals (IV; R = Me) and (111; R = Me), respectively.Since 110 spirocyclohexadienes (VII) were isolatedfrom the reaction of AT-methylbiphenyl-2-carboxarnide( I ; K = Me) with t-butyl Iiypochlorite-iodine, the re-13. Toucharcl and J. Lessard, Tetrahedron Lettevs, 1970, 4887.2 D. H. Hey, G. 13. Jones, and A1. J . Perkins, J . Chem. SOC. ( C ) ,3 A. R. Foncstcr, A . S. Ingram, and K. H. Thomson, J.C.S.1071, 116.Perkin 1, 1972. 1972.action was carried out in the presence of potassiumt-butoxide in an effort to trap any spirocyclohexadienj.1iodide (VII; R = Me, R1 = I, R2 = H) or carbocation(VI; R = Me) which could have been formed byoxidation of the intermediate radical (IV; R == Me).N.m.r.analysis of the crude product showed (from thecharacteristic iV-methyl and olefinic resonances) thepresence of the 4rsquo;-t-butoxyspirocyclohexadieiie (VII ;R = Me, R1 = OBut, R2 = H) S 2.86 (3H, s), 5.32(2H, d), and 6.18 (2H, d)! and the spirocyclohexadien-4lsquo;-one (VII; R = Me, R1R2 = 0) 18 3.0 (3H, s) and6.45-6.54 (4H, s ) . Surprisingly, the spectrum indi-cated that the major product was the N-methylphen-anthridone (V; R = Ne) and not the 2-iodo-derivativepostulated to arise from the reaction of the phen-anthridone with ICl, obtained in previous experimentsin which the reaction mixture did not contain potassiumt-butoxide. In order to improve the yield of spiro-cyclohexadiene-type compounds the reaction was carriedout with t-butyl alcohol as solvent.The reactionmixture gave the N-methylphenanthridone (V; R =Me) N-met hyl-4rsquo;-t -but oxyisoindoline- 1 -spire-cyclohexa-2lsquo;,5rsquo;-dien-3-one (VII; R = Me, R1 = OBut,S. A. Glover, A, Goosen, and H. A. H. Laue, J.C.S. Pevkin I ,D. H. R. Barton, -bsol;. L. J . Beckwith, and A. Gooscn, J .(33 ) ,1973, 1647.C h ~ i i t . SOC., 1965, 1812354R2 = H) (16y0), and N-methylisoindoline-l-spirocyclo-hexa-2rsquo;,5rsquo;-diene-3,4lsquo;-dione (VII; R = Me, R1R2 = 0)(28). Biphenyl-2-carboxamide (I; R = H) and theN-phenyl derivative (I; R = Ph) gave similar products+I+ NR 2k 0Rrsquo; 1 R2 B* (MIunder the same conditions (Table 1).However N-phenylbiphenyl-2-carboxamide also gave 2-chloro-N-phenylphenanthridone (6).57+, and M - 73+ peaks arisingdisplayed formulae).J.C.S. Perkin Ifrom a-fission (seeryrsquo; w- 56*At - 731rsquo;When the reaction with N-methylbiphenyl-2-carb-oxamide (I; R = Me) was carried out without thepotassium t-butoxide, but with t-butyl alcohol assolvent, the total yield of cyclisation products was lower.However the relative yields of N-methylphenanthridone,t-butoxyspirocyclohexadiene, and spirocyclohexadienonewere the same. This result indicates that t-butylalcohol inhibits the aromatic iodination reaction of IC1and in addition that in the presence of an excess oft-butyl alcohol the potassium t-butoxide does not serveas a trapping reagent but merely increases the amount ofpositive iodinating species by reacting with ICI (to giveButOI).This postulate was confirmed by the formationof an N-iodo-derivative when p-nitrobenzamide wastreated with a filtered solution of potassium t-butoxideand iodine monochloride in benzene.The inhibition of aromatic iodination by t-butylThe t-butoxyspirocyclohexadienes could not be puri-fied by distillation, as under these conditions rearrange-ment to the phenanthridone occurred. Their massspectra showed characteristic M+, M - 56+, M -R. M. Keefer and L. J. Andrews, J . Awer. Chem. Soc., 1966,78, 6623; L. J. Andrews and R. M. Keefer, ibid., 1967, 79, 1412;R.0. C . Norman and R. Taylor, lsquo; Reaction Mechanism inOrganic Chemistry,rsquo; Monograph 3, ed. C. Eaborn, Elsevier,Amsterdam, 1965.- 57+TABLE 1Products from biphenyl-2-carboxamides and t-butyl hypochlorite-iodineR Solvent Y OMe But OH 33Me Benzene ca. 90H But OH 26Ph ButOH 13H $ 00Y Oca. 16 285 3 4.8ca. 26 33ca. 14 330lsquo; /lsquo;aalcohol was further investigated. Iodine chloride iswell established as an aromatic iodinating agent and wehave shown that t-butyl hypochlorite-iodine alsoeffects aromatic iodination. The rates of iodination ofanisole with iodine chloride in methylene chloride andin t-butyl alcohol were compared by g.1.c. analysis ofrsquo; S. A. Glover, A. Goosen, and H. A. H. Laue, J . S. AfricanChem.Inst., 1973, 26, 771974 2355reaction mixtures. It has been shown that the rate ofdisappearance of anisole when treated with IC1 andt-butyl hypochlorite-iodine reagent corresponds to therate of formation of $-iodoanisole. This study showedthat the iodination reaction was completely suppressedby t-butyl alcohol. Further it was demonstrated thatt-butyl alcohol also effectively quenches the iodinationof anisole with t-butyl hypochlorite-iodine.The results thus show that the t-butoxyspirocyclo-hexadiene is formed by reaction of the intermediate withpotassium t-butoxide or t-butyl alcohol. However,when potassium t-butoxide and t-butyl alcohol are usedin the reaction the potassium t-butoxide reacts with theexcess of iodine 5 and iodine chloride and the t-butylalcohol is thus mainly responsible for the ether formation.The potassium t-butoxide thus increases the amount ofpositive iodine; hence the oxidising power of thereaction mixture. Since the cyclisation reaction iseffected by light it is proposed that the amidyl radicalfrom the biphenyl-Zcarboxamide cyclises either at the1rsquo;- or the Srsquo;-position to form the intermediate radical(IV) or (III), respectively. The butoxyspirocyclohexa-diene (VII; R = Me, R1 = OBut, R2 = H) is thuseither formed from the intermediate carbocation (VI ;R = Me) generated from the radical (IV; R = Me) byoxidation with a positive iodine species by reaction witht-butyl alcohol or t-butoxide anion, or from the spiro-cyclohexadienyliodide (VII; R = Me, R1 = I, R2 = H)formed from iodine and the radical (IV; R = Me) byan amp;-type reaction with t-butoxide anion or t-butylh ypoiodi te.The process whereby the spirocyclohexadien-4rsquo;-ones(VII; R1R2 = 0) are formed was next investigated.The concurrent formation of spirocyclohexadien-4lsquo;-onesand 4rsquo;-t-butoxyspirocyclohexadienes by reaction of thespirocyclohexadienyl cation with water followed byoxidation of the alcohol seemed unlikely since thereactions were carried out in the presence of potassiumt-butoxide. I t seemed more probable that the spiro-cyclohexadienones were formed from the butoxyspiro-cyclohexadienes.This postulate was confirmed by theformation of the spirocyclohexadien-4rsquo;-one in good yieldfrom 4rsquo;-t-butoxyisoindoIine-1-spirocyclohexa-2rsquo;,5rsquo;-dien-one when it was irradiated in t-butyl alcohol orbenzene with t-butyl hypochlorite-iodine at roomtemperature.This reaction most likely takes place by abstractionof the diallylic proton by t-butoxyl radicals to yield astabilised radical (VIII), which either suffers eliminationof t-butyl radical or is trapped by iodine or oxidised tothe carbocation.If the carbocation is formed it mustreadily suffer elimination of t-butyl carbocation, sincethe n.m.r. spectrum of the unprocessed reaction mixtureshowed the presence of the spirocyclohexadien-4rsquo;-one.The 4rsquo;-iodo-4rsquo;-t-butoxyspirocyclohexadiene (VII ; R1 =OBut, R2 = I), if formed, must more readily eliminatet-butyl iodide than rearrange to the phenanthridone.C. Walling, lsquo; Free Radicals in Solution,rsquo; Wiley, New York,1957.Since no evidence for the presence of t-butyl iodide wasfound in the reaction mixture which contained anexcess of iodine, known to be an effective radical trap,*Y0I Y m lthe t-butyl group is most likely eliminated via an ionicprocess. However, efforts to trap and identify thet-butyl fragment were unsuccessful.EXPERIMENTALM.p.s were determined with a Kofler hot-stage apparatus.Merck silica gel G was used for preparative t.1.c.N.m.r.spectra were determined with a Perkin-Elmer R 12Aspectrometer and mass spectra with an A.E.I. MS9 instru-ment a t the N.C. R.L./C. S. I.R. laboratories. G.1.c. analyseswere carried out with a Packard-Becker 420 instrument(flame ionisation detector).Irradiation of N-Methylbiphenyl-2-carboxamide with t-Butyl Hypochlorite-Iodine in the Presence of Potassiumt-Butoxide in t-Butyl A ZcohoZ.-(a) t-Butyl hypochlorite(1-54 g, 0.014 mol) and iodine (4.12 g, 0.016 mol) in t-butylalcohol (80 ml) were stirred in the dark a t room temperaturefor 5 min.Potassium t-butoxide (2.5 g, 0.022 mol) wasthen added and stirring was continued for a further 5 min.N-Methylbiphenyl-2-carboxamide (1 g, 0.00476 mol) wasadded and the mixture irradiated with a 1000 W tungstenlamp a t room temperature. The same quantities oft-butyl hypochlorite, iodine, and potassium t-butoxidewere added after 2.5 h. After 5 h the mixture was pouredinto water (500 ml), treated with Na,S,O, and extractedwith CHCI, (3 x 100 ml); the extract was washed, dried(Na,SO,), and concentrated to a gum (1.56 g).The gumwas separated into two fractions by preparative t.1.c. onsilica gel.The fraction of the higher IZp value was a solid (0.329 g)which crystallised from CCI, as opaque crystals of N-methylphenanthridone, m.p. 105-107rdquo; (lit.,4 108-logrdquo;),identical (i.r. , n.m.r.) with an authentic specimen.The other fraction (0-41 g ) was separated into a portioninsoluble in benzene-petroleum (b.p. 4Cr-SOrdquo;) (0.13 g) and asoluble gum (0-2 g) . The insoluble material crystallisedfrom benzene-petroleum (b.p. 4@-6Oo) as transparent platesof N-methylisoindoline- 1-spirocyclohexa-2rsquo;, 5rsquo;-diene-3,4rsquo;-dione, m.p. 218-219rdquo; (lit.,g 217-218rdquo;), M+, 225, wmaX. 3458,1699, and 1685 crn-l, 6 (CDCI,) 3.0 (3H, s), 6.45-6.54(4H, s), and 7-22.-8.0 (4H, m).The benzene-petroleum-soluble portion (0.2 g) wasseparated by preparative t.l.c., with numerous develop-ments, into three bands.The middle band (0.16 g) con-tained the starting amide (12), identified by n.m.r.spectroscopy, and N-methyl-4rsquo;-t-butoxyisoindoline-l-spiro-cyclohexa-2rsquo;,5rsquo;-dien-3-oneJ M+ 284, wmx. 1680 cm-1,* D. H. Hey, J. A. Leonard, T. M. Moynehan, and C . W. Rees,J . Chem. SOC., 1961, 2322356 J.C.S. Perkin I6 (CDCl,) 1.35 (9H, s), 2-86 (3H, s), 4.40-4.63 (H, m), 5.32(2H, dd), 6.18 (2H, dd), and 7.3-7.9 (4H, m).This procedure was employed for other analogousexperiments.(b) The experiment was carried out as in (a) with benzeneas solvent. The crude product, analysed by comparingthe N-methyl n.m.r.signals, contained N-methylphen-anthridone (90) (8 3-58) and spirocyclohexadienes (6 2.98and 2.86) (10).(c) An experiment carried out as in (a) without potassiumt-butoxide gave starting material (6 2.63) (56y0), 4rsquo;-t-butoxyisoindoline-l-spirocyclohexa-2rsquo;,5rsquo;-dien-3-one (6 2-86)(6.8), isoindoline- l-spirocyclohexa-2rsquo;,5rsquo;-diene-3,4rsquo;-dione(6 2-98) (12y0), and N-methylphenanthridone (6 3-72) (25).Irradiation of Biphenyl-2-carboxamide.-Irradiation ofthe amide (1.5 g, 0.00714 mol) gave isoindoline-l-spiro-cyclohexa-2rsquo;,5lsquo;-diene-3,4rsquo;-dione (0-5 g), m.p. 215-240rdquo;(decomp.), M+ 211, vms. 3420, 1706, and 1678 cm-1,6 (CDCl,) 6.48 (4H, s) and 7-2-8-0 (4H, m) (Found: C,73.7; H, 4.3; N, 6-1. Camp;QNO, requires C, 73.9; H,4.3; N, 6.66) ; phenanthridone (0-36 g), m.p.288-290rdquo;(lit.,3 290-292rdquo;), M+ 195, vmax. 3165sh and 1663 cm-l;and 4rsquo;-t-bu toxyisoindoline- 1 -spirocyclohexa-2rsquo;, 5rsquo;-dien-3-one, M f 287, vmx. 3425 and 1695 cm-l, 6 (CDCl,) 1.32 (9H,s), 4.28-4.68 (lH, m), 5.01 (2H, dd), 6.05 (2H, dd), and7.2,5--7.9 (4H, m).Irradiation of N-Phenylbipkenyl-2-carboxamide.-Irradi-ation of the amide (1.3 g, 0.00476 mol) gave IS-phenyliso-indoline-l-spirocyclo?~exa-2rsquo;,5rsquo;-diene-3,4lsquo;-dione (0.52 g), 1n.p.206-207O, M+ 287, vms. 1709 and 1678 cm-l, 6 (CDCl,)6.38 (2H, d), 6-7 (2H, d), and 7.15-8-1 (9H, m) (Found:C, 79.0; H, 4.6; N, 5.0. C,gH,3N0, requires C, 79.45;H, 4.55 ; N, 4.85) ; N-phenyl-4rsquo;-t-butoxyisoindoline-l-spirocyclohexa-2rsquo;,5rsquo;-dien-3-one (0-23 g), m.p.155-158O,M+ 345, v,,, 1696 cm-l, 6 (CDCl,) 1.24 (9H, s), 4-14-4-35(lH, m), 5.1 (2H, dd), 6.04 (2H, dd), and 7-1-8.0 (9H, m);N-phenylphenanthridone (0.17 g), m.p. 227-229rdquo; (lit.,,222-224rdquo;), M+ 2rsquo;71, vmas. 1655 cm-1, 6 (CDCl,) 6.57-6-82(lH, ni), 7-15-7.91 (9H, m), and 8-14-8.61 (3H, m)(Found: C, 84.0; H, 4.6; N, 5.2. Calc. for ClgHl,WO:C, 84-1 ; H, 4.85; N, 5-150;,) ; and 2-chloro-N-:-metJzyl~hen-nnthridone (0.11 g), m.p. 107-198.5rdquo;, M+ 305, vmx. 1660cni-l, 6 (CDCZ,) 6.62 (lH, d), 7-03-7.87 (8H, m), and 7.99-8.56 (3H, m) (Found: C, 74.6; H, 4-0; N, 4-7. C,gH,,CINOrequires C, 74.3; H, 3.95; h-, 4.55).Reaction of Iodine Monoddoride with Anisole.-Iodinechloride (1.625 g, 0.9 mol) and anisole (0.463 g, 0.005 mol)were made up to 50 ml with solvent and shaken at roomtemperature. Samples (2 ml) withdrawn a t intervals weretreated with 0.27~-sodium iodide in acetone (2 ml) and a0 .0 0 5 ~ internal standard solution of nitrobenzene int-butyl alcohol (2 ml). The samples were analysed byg.1.c. Carbowax 20M on Chroniosorb M (80-100 mesh)15 : 25 column; T 190rdquo;, carrier gas 45 ml min-l; retentiontimes anisole 47 s, nitrobenzene 165 s, fl-iodoanisole 316 s.The results are in Table 2.Reaction of t-Butyl Hypochlorite-Iodine with 4 niso1e.-t-Butyl hypochlorite (0.543 g, 0.005 mol) and iodine (1.27 g,0.006 mol) were made up to 80 ml with t-butyl alcohol andshaken in the dark at room temperature for 10 miii.Anisole (0.463 g , 0-005 mol) was added and the mixture wasanalysed as before (see Table 3).TABLE 2Reactions of iodine chloride with anisole: (a) in t-butylalcohol; (b) in methylene chlorideTime Anisole Anisole(min) concn.() Time (min) concn. (7;)97.5 8 96-60 Q1 96-25 16 94.752 96.25 30 92-64 95.00 90 93-45Anisole p-Iodoanisole(4Time (min) concn. (yo) concn. ()4 96(b) ! 0 100TABLE 3Reaction of t-butyl hypochlorite-iodine with anisoleTime (min) concn. () Time (min) concn. (x) Anisole Anisole97.5 8 100100 16 9698 30 98!24 99Irradiation of 4lsquo;-t-Butoxyisoindoline- l-s~irocyclohexa-2rsquo;,5rsquo;dien-3-one in the Presence of t-Butyl Hypochlorite-Iodine.-(a) t-Butyl hypochlorite (0.03 g, 0-00028 mol) and iodine(0.071 g, 0.00028 mol) in t-butyl alcohol (20 ml) werestirred in the dark a t room temperature for 5 min.4rsquo;-t-Butoxyisoindoline- l-spirocyclohexa-2rsquo;,5rsquo;-dien-3-one (0.05 g ,0-000186 mol) was added and the mixture was irradiated atroom temperature for 2-5 h. The mixture was thendiluted with water (200 ml), treated with an excess ofaqueous sodium thiosulphate, ancl extracted with chloro-form (50 ml). The extract was dried (Na,SO,) and concen-trated to a gum (0.05 g). N.m.r. analysis showed thepresence of isoindoline- 1-spirocyclohexa-2rsquo;, 5rsquo;-diene-3,4rsquo;-dione (6 6.48) (76) and 4rsquo;-t-butoxyisoindoline- l-spiro-cyclohexa-2rsquo;,5rsquo;-dien-3-one (6 5.01-6-05) (24).(b) Experiment (a), repeated with benzene as solvent,gave isoindoline- l-spirocyclohexa-2rsquo;, 5rsquo;-diene-3,4rsquo;-dione (66.48) (73) and 4rsquo;-t-butoxyisoindoline-l-spirocyclo-hexa-2rsquo;,5rsquo;-dien-3-one (6 5.01-6.05) (27) (n.m.r. analysis).Reaction ofrsquo; p-Nitrobenzamide wit11 the Filteved Solutioiifrom the Reaction of Iodine Monochloride with Potassiumt-Butoxide.-Iodine monochloride (0-41 g, 0-005 mol) andpotassium t-butoxide (0.56 g, 0.005 mol) in benzene (25 ml)were shaken in the dark at 0 ldquo;C for 6 min. Filtration gavea purple solution which on treatment with an excess ofp-nitrobenzamide gave N-iodo-p-nitrobenzamide contain-ing lOOyo positive halogen (iodometry), identical with anauthentic specimen.We thank the South A4frican Council for Scientific andIndustrial Research for grants, a bursary (to S. A. G.), andrecording of mass spectra (Dr. R. H. Hall).4/358 Received, 2 2 . d Febvuary, 1974