Pyrrolopyrimidine nucleosides. Part XI. Influence of amino-groups at C-4 and C-6 or an amino-group at C-6 on the reactivity of a 5-cyano-group in pyrrolo2,3-dpyrimidine nucleosides

摘要

1975 1253Pyrrolopyrimidine Nucleosides. Part XI. Influence of Amino-groups atC-4 and C-6 or an Amino-group at C-6 on the Reactivity of a 5-Cyano-group in PyrroIo2,3=dpyrimidine NucleosidesBy Karl H. Schram and Leroy B. Townsend," Department of Biopharmaceutical Sciences and DepartmentThe syntheses of 6-amino-7- (~-~-ribofuranosyl)pyrrolo2,3-dpyrimidine-5-carbonitrile (7) and its 4.6-diarnino-analogue (1 2) are described. Nucleophilic addition to the 5-cyano-group of both (7) and (1 2) was found to bemore difficult under both acidic and basic conditions than addition to the nitrile group of toyocarnycin (3) or7-(~-~-ribofuranosyl)pyrrolo2,3-~pyr~m~d~ne-5-carbonitr~le (1 ). The reaction of hydrazine with 6-bromo-7- (p-D-ribofuranosyl) pyrrolo2,3-d pyrimidine-5-carbonitrile, which furnished a tricyclic nucleoside, i s discussed.of Chemistry, University of Utah, Salt Lake City, Utah 841 12, U.S.A.WE have demonstratedl-4 that a 4-amino- or 4-OXO- ring since the rings are somewhat compartmentalized.6group in certain 7-( p-~-ribofuranosyl)pyrrolo2,3-d- Therefore, an amino-group on the pyrrole ring would bepyrimidine-Ei-ca~bonitriles e.g.(1)-(3) can have adeactivating effect towards nucleophilic addition to thecyano-group under both basic and acidic conditions.Although an amino-group in the pyrimidine ring in-fluences the susceptibility of the 5-cyano-group in thethe electron density at the cyano-group, the electroniceffects in this case are more pronounced in the pyrimidinepreceding paper.1971, 4767.in the press.end, J . Ovg. Chem., 1970,35, 236.y-$+j H N b,R R (3 Rpyrrole ring towards nucleophilic attack by increasing ( 1 ) (21 ( 3 )R = p - D - ribofuranosylpart x, €3- c. Hinshaw, K. H. Schram, and L. €3. Townsend, significant deactivating effect2 K. H. Schram and L. B. Townsend, Tetrahedron Letters, L. B. Townsend and G. H. Milne, Ann. New York Acad. Sci.,3 B. C. Hinshaw, J. F. Gerster, R K. Robins, and L. B. Towns- 6 A. Albert, ' Heterocyclic Chemistry,' Oxford Universityexpected to have aPress, New York, 19681254 J.C.S. Perkin Ion the cyano-group than an amino-group on the pyriini-dine ring. This prompted us to synthesize analogues oftoyocamycin (2) with the amino-group on the pyrrolerather than the pyrimidine moiety, and to study theeffect of this transformation on the reactivity of the5-cyano-group.Although there have been reports of electrophilichalogenation reactions of certain 4-substituted pyrrolo-pyrimidine nucleosides 6 and of toyocamycin 7 (2), electro-philic substitution in a pyrrolo2,3-jpyrirnidine nucleo-side with only a strongly electron-attracting substituent(CN, NO,, etc.) at C-5 has not been reported.Treatmentof compound (1) with water saturated with bromine gavethe 6 bromo-derivative (4), the lH n.m.r. spectrum ofwhich showed only two peaks (6 9.05 and 9.30) whichcould be assigned1*6 to aromatic protons. The i.r,Treatment of (4) with liquid ammonia in a sealedvessel at 110-120” for 12 h resulted in displacement* ofthe 6-bromo-group to afford the 6-amino-compound (7)in 74 yield vm 2 200 cm-l; 6 7.9br (2H, exchangeable,6-NH,), 8.6 (H-4), and 9.0 (H-2).Additional evidencethat nucleophilic displacement had occurred was pro-vided by a large bathochromic shift in the U.V. spectrum(Table). The reactivity of the cyano-group of (7) to-wards various nucleophiles was then studied.Treatment of (7) with hydrogen peroxide in base gavean isomer of sangivamycin, 6-amino-7- ( P-D-ribofurano-~yl)pyrr0lo2,3-dpyrimidine-5-carboxamide (8) no v m ;6 6-9 (6-NHJ and 7.95 (CONH,). T.1.c. showed thepresence of at Ieast two highly fluorescent minor products.The low yield of (8) (38) in comparison with the con-version of toyocamycin into sangivamycin (65) lo underNH7(5)R = p- D - ribofuranosylSCHEME Zspectrum indicated retention of the cyano-group.The reaction of (4) with hydrazine could result in eitheraddition to the nitrile function to produce the carbox-amidrazone derivative or displacement of the bromo-group to form the 6-hydrazino-compound.A previousstudy has shown that the second pathway is preferredwith 6-bromotoyocamycin. However, the presence ofan amino-group at C-4 could deactivate the nitrilefunction of 6-bromotoyocamycin towards nucleophilicaddition in comparison to the cyano-group of (4). Thepossibility of competing reactions was therefore en-visaged.The reaction of hydrazine with (4) in fact afforded only(t-1.c.) the 6-hydrazino-compound (5) vm 2 200 crn-l;6 8.60 (s) and 8.57 (s) (H-2 and H-4), 6.35 (d, H-l’), 3.4-5.6 (carbohydrate protons 8 ) , and 5.68br (3H, exchange-able, NHoNH,).Ring closure of (5) to afford 3-arnino-8-( P-D-ribofurano-showing no VCN, was effected by boiling water.The lHn.m.r. spectrum of (6) showed peaks for the aromatic(6 9.45 and 9.25) and carbohydrate protons, lacked thehydrazino-signal 6 5.7, and contained a broad peak in the6 7-8.7 region assigned to the 3-amino-group and thepyrazole proton. This ring closure reaction corroboratedthe site of bromination of (4).* Displacement of a 6-bromo-group in a pyrrolopyrimidinenucleoside has been accomplished by using methanolic ammoniain a sealed vesseI.9J. F. Gerster, B. Carpenter, R. K. Robins, and L. B. Towns-end, J. Medicin.Chem., 1967, 10, 326.R. L. Tolman, R. K. Robins, and L. B. Townsend, J . Hetero-cyclic Chem., 1971, 8, 703.s yl) p~~azolo4’,3’ :4,5 pyrrolo 2,3-d J pyrimidine (6) 3similar conditions indicated that side readions wereoccurring. Since an amino-group in the 6-position of aJ ( 8 ) NH (91R = p-u- ribofuranosylSCHEME 2pyrrolo2,3-dJpyrimidine resides on an electron-rich ringsystem,s it is possible that N-oxidation was occurring8 L. B. Townsend, in ’ Synthetic Procedures in Nucleic AcidChemistry,’ vol. 11, eds. W. W. Zorbach and R. S. Tipson, Wiley,New York, 1973, pp. 267-398.9 M. Bobek, R. L. Whistler and A. B M , J. Mediaot. Chmz.,1972.15, 168.10 R. L. Tolman, R. K. Robins, and L. B. Towmend, J . Amev.Chem. Soc., 1968, 90, 5241975since aniline is oxidized to azobenzene and pyridine isoxidized to pyridine N-oxide by peroxide in base.uU.V.spectra of some pyrrolopyrimidine nucleosidesPH 1 MeOH pH 11Corn- c--Amax ./nm274226303246320261299';;;I302260242330277246293(;;;I304278ax. a9.017.48.021.17.36.99-629.211.816.831.018-415.428.016.014.613-018.115.3h a x . Inm2743 14240(320)248311279(252)236 (;A;)267236338270238292363P;;)6.6 31211-3 232 w;)'f2w;)9.010-3 30426- 1 23214.914.3 23421.421.5 33812.0 26824.6 23824.2 29016.0 36222-823517-9 293(;;;IEmax.10.18-015.017.39-310.023.017-125-120.615.446-019.913.621.216.418.2a E x 10-3.6 Shoulders in parentheses.The reduced reactivity of the cyano-group of (7) incomparison with that of (1) or (2) is clearly shown in thewith hydrogen sulphide in a sealed vessel for 12 h at 120-130".Since the nitrile group of (5) showed a reduced tendencytowards nucleophilic attack under basic conditionsit was e x p t e d that reactions performed under acidicconditions would be extremely slow. The initial reac-tion of a nitrile group under acidic conditions is generallythought to be protonation of the lone pair of electrons onthe nitrogen of the nitrile gr0~p.l~ If protonation of the6-amino-group occurred, this would be expected to retardor prevent protonation at the nitrile. This may ex-plain why the attempted conversion of (7) into the imi-date (10) by hydrogen chloride in ethanol, conditionsidentical with those used to convert toyocamycin (2) intoan imidate, was unsuccessful, even with a prolongedreaction time.Thus transposition of the 4-amino-groupof toyocamycin (2) to the 6-position produces a definitedeactivating effect on the cyano-group towards nucleo-philic attack under both acidic and basic conditions.This prompted us to study the effect of two amino-groups, one in the pyrimidine ring at C-4 and another inthe pyrrole ring at C-6. It was considered that thiswould further decrease the reactivity of the cyano-grouptowards nucleophilic addition.The reaction of 6-brornotoyocamycin lo (1 1) with liquidammonia under conditions similar to those used for thepreparation of (7) gave 6-aminotoyocamycin (12) in 74SSCHEME 3preparation of the thioamide (9).Treatment of (7)with pyridine, triethylamine, and hydrogen sulphideunder conditions essentially identical with those reported8for the conversion of (2) into a 5-thioamide produced noreaction. A recent report l2 states that nitriles unreactiveunder the above conditions can be converted into thio-amides by dimethylformamide, dimethylamine, andhydrogen sulphide. Treatment of (7) in this way gavethe thioamide (9), but in very low yield (300" (Found: C, 41-15; H, 4.5; N, 24.2.Cl,Hl,C1N,04 requires C, 41.0; H, 4.5; N, 23.95).6-A mino- 7- (p-~-ribofuranosyl)pyrrolo 2,3-dpyrimidine-5-carbonitrile (7) .-Method A . The 6-bromo-compound (4)(1.0 g ) and methanolic ammonia (saturated previously at- 5") (75 ml) were mixed and heated at 110-1 15" in a sealedvessel for 16 h.T.1.c. showed a mixture of two majorproducts, RF 0.8 and 0-5, which were bright blue under U.V.light (254 nm) . The mixture was dissolved in the minimumof boiling methanol and kept at 5" for 18 11. The tan crystalswere filtered off and air-dried to yield compound (7) (250 mg,30y0), m.p. 260-261" (Found: C, 49.2; H, 4-55; N, 24.1.Cl,Hl,NB04 requires C, 49-15; H, 4.45; N, 24.05).Liquid ammonia (ca. 3 ml) was added to the6-bromo-compound (4) (680 mg) in a steel vessel. Thevessel was sealed, placed in an oil-bath preheated to 100-llOo, and then heated a t that temperature for 12 h. Theresidue left after evaporation of the excess ammonia wastriturated with methanol (20 ml) at room temperature.The insoluble yellow solid was filtered off and air-dried togive compound (7) (70), identical mixed m.p., i.r.and U.V.spectra data, RF ( O - S ) with that prepared by method A.6-Amino-7- (P-~-ribofuranosyl)fiyrrolo2 , 3-dlpyrimidine-5-carboxamide (8) .-Compound (7) (200 mg), concentratedammonium hydroxide (10 ml), and 30 hydrogen peroxide(2 ml) were mixed and stirred at room temperature for 2 hand then kept at 5" for 12 h. The white precipitate wasfiltered off and recrystallized from the minimum of water tol6 J. M. Bobbitt and D. A. Scola, J . Oyg. Chem., 1960, 25, 561.l7 J. M. Bobbitt and R. E. Doolittle, J . Org. Chem., 1964, 29,H, 4.5; N, 27*45y0).Method B.2298.A. Galat, J . Amer. Chem.SOC., 1948, 70, 39461975give conzpound (8) (120 mg, 38y0), m.p. 257-258" (decomp.)(Found: C, 46.4; H, 4-85; N, 22.6. C,,H,,N,O, requiresC, 46.6; H, 4.85; N. 22.65).6-Amino-7- (13-D-rib0 furanosyl)pyrrolo 2,3-dpyrimidine-5-thiucarbuxamide (9) .-Compound (7) (500 mg) was addedto a solution containing sodium hydrosulphide (200 mg) inmethanol (20 ml) which had been saturated a t room tem-perature with hydrogen sulphide for 40 min. The mixturewas placed in a steel vessel, and the vessel was sealed, heateda t 110-120" for 12 h, then cooled to room temperature.The methanol was removed under reduced pressure and theresidue was dissolved in the minimum of water and keptat 5" for 12 h. The pale orange precipitate was filtered offand air-dried to give compound (9) (120 mg, 21y0), m.p.237"(Found: C, 43-0; H, 4.8; N, 20.85. C,,H,,N,O,S, 0-5H20 requires C, 43.1; H, 4.8; N, 20-95y0).4,6-Diamino-7- ( P-D-ribo furanosyl)pyrrolo 2,3-dpyr imi-dine-5-carbonitrile (6-Aminotoyocamycin) ( 12) .-6-Bromo-toyocamycin (1 1) (200 mg) was added to liquid ammonia(ca. 5 ml) in a steel vessel. The sealed vessel was placed ina preheated (100-110") oil-bath and heated for 22 h a t100-110". The vessel was cooled in ice-water and theammonia was allowed to evaporate. The residue was tri-turated with methanol (20 ml) at room temperature. Thewhite, methanol-insoluble powder was filtered off, recrys-tallized from the minimum of water, and dried in vacuo a t80" for 12 h to give compound (12) (120 mg, 72), m.p.258-260" (decomp.) (Found: C, 44-4; H, 4.95; N, 25.85.C,,H,4N,04,H20 requires C, 44.45; H, 4-95; N, 25.95).4,6-Diamino-7- (P-o-ribo furanosyl)pyrrolo2,3-dpyr imi-dine-5-thiscarboxamide (6-Avninothiosangivamycin) ( 13) .-Amixture of 6-aminotoyocamycin (1 2) (300 mg), sodiumhydrosulphide (100 mg), and methanol (20 ml) (saturated a troom temperature for 45 min with hydrogen sulphide) was1257heated a t 120-130° for 16 h in a sealed vessel and thenallowed to cool to room temperature.The crystals werefiltered off, recrystallized from the minimum of water, anddried under reduced pressure a t 80' for 12 h to give com-powzd (13) (240 mg, 73), m.p. 246-247" (Found: C,42.25; H, 5.0; N, 24.5. C,,H,,N,O,S requires C, 42.35;H, 4.7; N, 24.7).4,6-Diavnino-7- (~-~-ribofuranosyZ)pyrrolo2,3-d~yrimi-dine-5-carboxamide (6-Aminosangivamycin) ( 15) .-Method A .A mixture of 6-aminotoyocamycin (12) (1.1 g) andhydroxylamine Is (1.1 g) in ethanol (80 ml) was heated a treflux temperature for 16 h. The solid was filtered off,recrystallized from the minimum amount of water, anddried under reduced pressure a t 80" for 5 h to give compound(15) (880 mg, 75), m.p. 268-269" (Found: C, 44-2; H,4.75; N, 25-8. C,2H15N60 requires C, 44.45; H, 4-95; N,25.9'70).Method B. 6-Bromosangivamycin (14) (1.0 g) was addedto liquid ammonia (ca. 5 ml) and the mixture was heated a t110-120° in a sealed vessel for 16 h. After removal of theexcess ammonia by evaporation, the residue was trituratedwith ethanol (20 ml) and filtered. Recrystallization of theethanol-insoluble solid from the minimum of water gavecompound (15) (59), identical (m.p., U.V. and i.r. spectra)with that obtained by method A.We thank the Division of Cancer Treatment, NationalInstitutes of Health, US. Public Health Service, for financialsupport, Mr. S. Manning and his staff for the large-scale pre-paration of some starting materials, and Mrs. S. Mason foru.v., i.r., and n.m.r. spectra. K. H. S. was NDEA Title IVrecipient 1970-1 972, Department of Medicinal Chemistry.4/2156 Received, 18th October, 19741lB C. D. Kurd, Inorg. Synth., 1939, 1, 87