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Studies with Condensed Azines: New Routes toPyrazolo[3,4-b]pyridines andPyrrolo[3,2-b]pyridines

 

作者: Saleh M. Al-Mousawi,  

 

期刊: Journal of Chemical Research, Synopses  (RSC Available online 1997)
卷期: Volume 0, issue 9  

页码: 318-319

 

ISSN:0308-2342

 

年代: 1997

 

DOI:10.1039/a702276j

 

出版商: RSC

 

数据来源: RSC

 

摘要:

N N NH2 Me Ph 1 O Ph X NMe2 2 N N Me NH Ph O Ph X 3 N N Me NH2 Ph X 4 Ph O N N Me N Ph Ph X 5 N N Me Ph X 6 Ph N a X = H b X = CN 2–6 N N Me NH2 Ph 1 PhCH C CN CN 7 CN CN EtO N N Me N Ph CN 8 N N Me N NH2 Ph CN 9 H H Ph NH2 or N N Me NH2 CN Ph CN 10 N N Me NH NC Ph CN 11 or N N Me N Ph CN 12 N N Me N NH2 Ph CN 13 NH2 N N NH2 Me Ph 1 N N NH2 Me Ph 14 NaNO2 HCl ON CH2(CN)2 EtOH/pip H2N CN CN CN N N N N N Me Ph NH2 NH2 N N NH2 CN N N Me Ph NH2 15 16 17 CN CN 318 J. CHEM. RESEARCH (S), 1997 J.Chem. Research (S), 1997, 318–319 J. Chem. Research (M), 1997, 2026–2038 Studies with Condensed Azines: New Routes to Pyrazolo[3,4-b]pyridines and Pyrrolo[3,2-b]pyridines Saleh M. Al-Mousawi, Kamini Kaul, Mohammad A. Mohammad and Mohamed H. Elnagdi* Department of Chemistry, Faculty of Science, University of Kuwait, P.O. Box 5969, Safat 13060, Kuwait Several condensed pyrazole derivatives are obtained from the reaction of 3-methyl-1-phenylpyrazol-5-amine (1) with a,b-unsaturated ketones, a,b-unsaturated nitriles and isothiocyanates.In conjunction with our previous interest in the chemistry of azoloazines,5,6,7 we report here the novel syntheses of pyrazolo[ 3,4-b]pyridines and pyrrolo[3,2-b]pyridines. We found that 3-methyl-1-phenylpyrazol-5-amine (1) reacts with 1-phenyl-3-dimethylaminoprop-2-en-1-ones 2a,b in the presence of zinc chloride and pyridine, respectively, to yield addition products with the elimination of dimethylamine and water.The products can thus be formulated as 5 or the isomeric structure 6. Structure 6 was established based on 1H NMR data and NOE experiments. NOE difference experiments showed that the methyl group and pyridine H-4 interact through space. Thus, irradiating the methyl signal at d 2.62 and 2.68 enhanced the pyridine H-4 signal at d 8.45 and 9.07 in 6a and 6b respectively. Moreover, when 1 and 2a were refluxed in ethanol, compound 4a was isolated in good yield. It could then be cyclised to 6a on fusion with ZnCl2.Compound 1 also reacted with benzylidenemalononitrile (7) in refluxing pyridine to yield an addition product which then underwent auto-oxidation to give 8 or the isomeric structure 9. Again, structure 8 was established based on the shielding effect of the methyl signal by the aromatic ring current and by NOE experiments. Thus irradiating the methyl signal at d 1.86 little enhanced the phenyl protons at d 7.21 while no enhancement of the NH2 protons was observed.The observed small effect is perhaps due to the existence of phenyl o-H’s out of plane as shown in structure (8). The observation that the methyl protons are shifted upfield to d 1.86 (expected position is ca. d 2.45) further supports this conclusion. Compound 1 also reacted with ethoxymethylidenemalononitrile to yield a product that may be formulated as acyclic 10 and 11 or cyclic 12 and 13. 1H NMR revealed an absence of any signal for a pyrazole H-4 and thus the acyclic form 11 was excluded. 13C NMR indicated the presence of only one CN carbon at d 109.85 and thus the acyclic form 10 could also be excluded. NOE difference experiments showed no interaction between the methyl protons at d 2.45 and the 6-H pyridine proton at d 8.48. It showed in contrast that the methyl protons and amino protons are proximal. Thus irradiating the methyl signal at d 2.45 enhanced the amino proton signal at d 5.8 and vice versa. Hence structure 12 was excluded and structure 13 was established.When the same reaction was carried out in refluxing ethanol for 2 h, compound 11 was formed instead of 13. 1H NMR revealed the presence of the pyrazole H-4 signal at d 6.33. Compound 11 was cyclised to give 13 on refluxing in ethanol for a few more hours. Thus structure 13 was further established. *To receive any correspondence.N N Me NH2 Ph 1 O Ph N C S MeCN N N Me Ph NH NH O Ph S N N Me Ph N S NHCOPh 18 19 Br2 AcOH N N Me Ph NH X Y Z X = OEt X = NMe2 20a Me OEt O O N O OR Me H NH2 N MeO O Me H N H Ph CN O a R = Me b R = Et 21 H2NCH2CN NaOMe N MeO O Me H N H O CN Ph 23 24 CN CO2Et Ph 2 N MeO O Me Me N OMe CN Ph 25 J. CHEM.RESEARCH (S), 1997 319 Attempted diazotisation of 1 gave the nitroso derivative 14 which reacted with malononitrile to yield a product of molecular formula C16H12N8. The same product was also obtained by reacting 14 with the malononitrile dimer 15. It was thus assumed that malononitrile first dimerises under the reaction conditions, which then condenses with 14 to yield a product that can be formulated as 16 or isomeric 17.Structure 17 was established on the basis of 13C NMR which revealed the presence of only one CN signal. Moreover, compound 17 was recovered almost unreacted when boiled in acetic acid: a condition expected to effect cyclisation of 16 into 17. Compound 1 also reacted with benzoyl isothiocyanate (prepared in situ) in acetonitrile to give the thiourea derivative 18.Compound 18 on treatment with bromine in acetic acid gave pyrazolo[3,4-d]thiazole 19. The fact that 1 reacted with 2a,b, 7 and nitrous acid at C-4 while reaction with benzoyl isothiocyanate and ethoxymethylidenemalononitrile occurred preferentially at the exocyclic amino group can be interpreted as follows. Firstly reaction with nitrous acid was conducted in acid solution. Under such conditions, the exocyclic amino group is protonated and the attacking reagent is thus directed to C-4.For the reactions with 2a,b, ethoxymethylidenemalononitrile and benzoyl isothiocyanate, we believe that both the exocyclic amino and C-4 are potential sites for attack, with the former being more reactive. Thus in reaction with benzoyl isothiocyanate, the addition at the exocyclic amino is irreversible, and thus the reaction product with the amino function was isolated. In reactions with 2a,b and 7, the reaction at the exocyclic amino group is reversible while the one at C-4 is irreversible.Thus the reaction is thermodynamically controlled and the products are exclusively those of addition at C-4. Although adducts 20a,b seem to be structurally related, the fact that EtOµ is a better leaving group than NMe2 has resulted in ready elimination of EtOµ from the adduct 20a, leading to the formation of 11, while reaction leading to 3 will revert to the starting material. Methyl 4-amino-2-methyl-1H-pyrrole-3-carboxylate (21a) was generated in situ via reacting ethyl acetoacetate with aminoacetonitrile in sodium methoxide solution as has been described earlier8 (21a was formed instead of 21b due to transesterification in methanol).The pyrroleamine 21a reacted with ethyl benzylidenecyanoacetate 22 to yield a product that may be formulated as 23 or the isomeric 24. This compound underwent methylation with methyl iodide to give the dimethyl derivative 25, the structure being confirmed by NOE which revealed steric interaction between the methyl signal at d 2.66 and the N-methyl signal at d 3.08 and the phenyl protons at d 7.53. This work was financed by the University of Kuwait under research grant Sc 080. We are grateful to the general facility projects in the Department of Chemistry for the analytical and spectral measurements. Techniques used: IR, NMR, (1H, 13C, NOE) and microanalysis References: 8 Received, 3rd April 1997; Accepted, 30th May 1997 Paper E/7/02276J References cited in this synopsis 5 M. H. Elnagdi, M. R. H. Elmoghayer and K. U. Sadek, Adv. Heterocycl. Chem., 1990, 48, 223. 6 M. H. Elnagdi, N. Al-Awadi and A. W. Erian, Comprehensive Heterocyclic Chemistry II, ed. A. R. Katritzky and C. W. Rees, Elsevier, Amsterdam, 1996, volume 7, p. 431 and references cited therein. 7 A. El-Enzy, B. Al-Saleh and M. H. Elnagdi, J. Chem. Res., 1997, (S) 4; (M) 0110. 8 G. H. Birnberg, W. J. Fanshawe, G. D. Francisco and J. W. Epstein, J. Heterocycl. Chem., 1995, 32, 1293.

 



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