Preparation of methoxyazaisoindolinones

Transcription

1 Issue in Honor of Prof. Jan Epsztajn ARKIVC 007 (vi) Preparation of methoxyazaisoindolinones Andrzej Jóźwiak and Aleksandra K. Szcześniak Department of rganic Chemistry, University of Łódź, Łódź, arutowicza 8, Poland Dedicated to Professor Jan Epsztajn on the occasion of his 75 th birthday Abstract Preparation of methoxyazaisoindolinones 3 and 4 via the reaction of hydroxyazaisoindolinones 1 and with potassium tert-butoxide and iodomethane in,-dimethylformamide is described. Keywords: Azaisoindolinones, Williamson synthesis Introduction 3-Alkoxyphthalimidines have been used among others for preparation of compounds modulating the muscarinic M -receptor and for construction of heterocyclic systems. 1 It is known that a reaction of -acyliminium ions generated from 3-hydroxyphthalimidines and their 7-hydroxypyrrolo[3,4-c]pyridine analogs 3a A with primary and secondary alcohols gave alkoxy derivatives in high yields. Much effort has been devoted to the investigation of 7-substituted,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-ones as cyclic nicotinamide analogues or aza-analogues of phthalimidines, some of which are known to be biologically active compounds. 3 In contrast, in the literature we have not found any information but one 3d concerning alkoxyazaisoindolinones of type B. In this paper we described useful method for their preparation A R 7 H Y X B Alkyl Aryl X =, Y = CH X = CH, Y = ISS Page 188

2 Issue in Honor of Prof. Jan Epsztajn ARKIVC 007 (vi) Results and Discussion Application of -acyliminium ion strategy (MeH, MeS 3 H or H S 4 ) in the case of,7- dihydro-5-hydroxy--aryl-5h-pyrrolo[3,4-b]pyridin-7-ones 1 and,3-dihydro-3-hydroxy--aryl- 1H-pyrrolo[3,4-c]pyridin-1-ones unexpectedly resulted in very low yields of desired methoxyproducts 3 or 4 (less than 10%). Therefore, we focused our attention on Williamson synthesis as an alternative way for the preparation of the methoxy derivatives 3 and 4. n the basis of such viewpoints, the compounds 1 and were converted into the corresponding methoxyazaisoindolinones by reaction with potassium tert-butoxide and next iodomethane H H Me 3 4 Me a: = = H; b: = H, = Me; c: = Ph, = H, In all cases, iodomethane appeared to be insignificantly active towards -alkylation of the pyridine nucleus (under the conditions used). The described methodology represents an effective route for the preparation of methoxyazaisoindolinones 3 and 4. Experimental Section General Procedures. Melting points were determined using a Boetius hot-stage apparatus and they are uncorrected. IR spectra were recorded on a Zeiss-Jena Specord 71-IR. 1 H MR spectra were determined at 00 MHz on a Varian Gemini 00 using TMS as an internal standard. Analytical thin layer chromatography tests (TLC) were carried out on aluminium oxide (Merck, 0F 54 neutral, layer thickness 0. mm) or silica gel (Merck, 0F 54, layer thickness 0. mm). Column chromatography separations were performed on aluminium oxide (90 active, basic, ISS Page 189

3 Issue in Honor of Prof. Jan Epsztajn ARKIVC 007 (vi) Merck mm/70-30 mesh ATSM) or silica gel (Macherey agel & Co mm/ mesh ATSM). Potassium tert-butoxide (Fluka) were used without further purification.,-dimethylformamide used was dried by azeotropic distillation with anhydrous benzene, shaken with activated neutral alumina (Brockmann I), filtered, then distilled under argon at reduced pressure and stored over type 4A molecular sieves. Hydroxyazaisoindolinones 1 and were obtained according to known procedures:,7-dihydro-5-hydroxy--phenyl-5hpyrrolo[3,4-b]pyridin-7-one (1a), (%) m. p o C (methanol), (lit. 5a m. p o C);,7-Dihydro-5-hydroxy--(4-methoxyphenyl)-5H-pyrrolo[3,4-b]pyridin-7-one (1b), (%) m. p o C (methanol), (lit. 5c m. p o C);,7-Dihydro-5-hydroxy-5,-diphenyl-5Hpyrrolo[3,4-b]pyridin-7-one (1c), (5%) m. p o C (acetone : hexane - 1:1), (lit. 5b m. p o C);,3-Dihydro-3-hydroxy--phenyl-1H-pyrrolo[3,4-c]pyridin-1-one (a), (7%) m. p. 3-5 o C (acetone), (lit. 5a m. p. 3-5 o C);,3-Dihydro-3-hydroxy--(4-methoxyphenyl)- 1H-pyrrolo[3,4-c]pyridin-1-one (b), (84%) m. p. 1-3 o C (methanol), (lit. c m. p. 0- o C);,3-Dihydro-3-hydroxy-,3-diphenyl-1H-pyrrolo[3,4-c]pyridin-1-one (c), (5%) m. p o C (methanol), (lit. 5b m. p o C). Conversion of hydroxyazaisoindolinones 1 and in to methoxyazaisoindolinones 3 and 4 Potassium tert-butoxide (0.0 mole) was added to the stirred mixture of compound 1 or (0.01 mole) in,-dimethylformamide (0 ml) at 0 o C. To the obtained solution iodomethane (0.05 mole) was added and the mixture was kept at 0 o C for.5 h. Excess of iodomethane and the solvent was removed under reduced pressure to give a sticky residue. The product was extracted with dichloromethane (4 x 15 ml) and separated by column chromatography. Compounds 3 and 4 were purified by crystallisation. The solvent for crystallisation, the isolated yields and the physical and spectral characterisation of products 3 and 4 are given below.,7-dihydro-5-methoxy--phenyl-5h-pyrrolo[3,4-b]pyridin-7-one (3a). (5%), (silica gel, eluent dichloroethane : ethyl acetate - 1 : 1, R f 0.3), m. p o C (ethyl acetate); (Found: C, 70.1; H, 5.0;, Calc. for C 14 H 1 : C, 9.99; H, 5.03;, 11.%); IR (KBr) 1700 cm -1 (C=); 1 H MR (CDCl 3 ) 8.88 (1H, dd, J = 4.9 and 1.3 Hz, -H), 8.00 (1H, dd, J = 7.7 and 1.3 Hz, 4-H), (H, m, Ph and Ph-H), 7.57 (1H, dd, J = 7.7 and 4.9 Hz, 3-H), (H, m, 3Ph and 5Ph-H), (1H, m, 4Ph-H),.51 (1H, s, 5-H),.93 (3H, s, Me); 13 C MR (CDCl 3 ) 14.5, 15.88, , 13., , , 19.11, 1.3, 15.77, 11.9, 85.5, ,7-Dihydro-5-methoxy--(4-methoxyphenyl)-5H-pyrrolo[3,4-b]pyridin-7-one (3b). (5%), (aluminium oxide, eluent dichloromethane, R f 0.4), m. p o C (ethyl acetate : heptane - :1); (Found: C,.4; H, 5.3;, Calc. for C 15 H 14 3 : C,.; H, 5.;, 10.3%); IR (KBr) 1700 cm -1 (C=); 1 H MR (CDCl 3 ) 8.88 (1H, dd, J = 4.8 and 1.4 Hz, -H), 7.98 (1H, dd, J = 7.7 and 1.4 Hz, 4-H), (H, m, Ar and Ar-H), 7.5 (1H, dd, J = 7.7 and 4.8 Hz, 3- H), (H, m, 3Ar and 5Ar-H),.41 (1H, s, 5-H), 3.83 (3H, s, Me),.9 (3H, s, Me); ISS Page 190

4 Issue in Honor of Prof. Jan Epsztajn ARKIVC 007 (vi) C MR (CDCl 3 ) 14., 157.7, 15.93, , , , 19.59, 1.4, 13.9, , 85.8, 55.47, ,7-Dihydro-5-methoxy-5,-diphenyl-5H-pyrrolo[3,4-b]pyridin-7-one (3c). (5%), (silica gel, eluent dichloroethane : ethyl acetate - 1 : 1, R f 0.5), m. p o C (ethyl acetate : heptane - : 1); (Found: C, 75.; H, 5.3;, 8.8. Calc. for C 0 H 1 : C, 75.93; H, 5.10;, 8.85%); IR (KBr) 170 cm -1 (C=); 1 H MR (CDCl 3 ) 8.85 (1H, dd, J = 4.7 and 1.5 Hz, -H), (1H, m, Ph, 3-H and 4-H), 3.18 (3H, s, Me); 13 C MR (CDCl 3 ) 15.55, 15.4, , 139.9, 137.7, , 131.5, 18.71, 18.59, 18., 1.79, 1.07, 13.8, 95.31, ,3-Dihydro-3-methoxy--phenyl-1H-pyrrolo[3,4-c]pyridin-1-one (4a). (58%), (aluminium oxide, basic, eluent dichloromethane, R f 0.), m. p o C (heptane : ethyl ether - 8 : ); (Found: C, 70.; H, 5.1;, Calc. for C 14 H 1 : C, 9.99; H, 5.03;, 11.%); IR (KBr) 1710 cm -1 (C=); 1 H MR (CDCl 3 ) 8.99 (1H, s, 4-H), 8.9 (1H, d, J = 4.8 Hz, -H), (3H, m, Ph, Ph and 7-H), (H, m, 3Ph and 5Ph-H), (1H, m, 4Ph-H),.0 (1H, s, 3-H),.98 (3H, s, Me); 13 C MR (CDCl 3 ) 14.74, 151.7, , , 13.45, , 19.7, 1.15, 1.0, 117.0, 8.94, ,3-Dihydro-3-methoxy--(4-methoxyphenyl)-1H-pyrrolo[3,4-c]pyridin-1-one (4b). (55%), (silica gel, eluent dichloroethane : ethyl acetate - 1 : 1, R f 0.), m. p o C (ethyl acetate); (Found: C,.7; H, 5.0;, Calc. for C 15 H 14 3 : C,.; H, 5.;, 10.3%); IR (KBr) 1710 cm -1 (C=); 1 H MR (CDCl 3 ) 8.9 (1H, s, 4-H), 8.91 (1H, d, J = 4.8 Hz, -H), 7.81 (1H, d, J = 4.8 J, 7-H), (H, m, Ar and Ar-H), (H, m, 3Ar and 5Ar-H),.49 (1H, s, 3-H), 3.84 (3H, s, Me), 3.00 (3H, s, Me); 13 C MR (CDCl 3 ) 14., , 151.7, , , , 19.17, 14.1, , , 87.40, 55.43, 50.1.,3-Dihydro-3-methoxy-,3-diphenyl-1H-pyrrolo[3,4-c]pyridine-1-one (4c). (50%), (silica gel, eluent dichloroethane : ethyl acetate - 1:1, R f 0.4), m. p o C (heptane); (Found: C, 75.8; H, 5.1;, 8.8. Calc. for C 0 H 1 : C, 75.93; H, 5.10;, 8.85%); IR (KBr) 1710 cm -1 (C=); 1 H MR (CDCl 3 ) 8.87 (1H, d, J = 4.8 Hz, -H), 8.59 (1H, s, 4-H), (1H, two overlapping d, J = 4.8 Hz, 7-H), (10H, m, Ph-H), 3.1 (3H, s, Me); 13 C MR (CDCl 3 ) 15.7, , 145.3, 139.3, , , , 18.80, 18.5, 18.34, 1.44, 1.05, 14.0, , 97.09, Acknowledgements This work was supported by Grant-in-Aid for Scientific Research from the University of Łódź. ISS Page 191

5 Issue in Honor of Prof. Jan Epsztajn ARKIVC 007 (vi) References 1. (a) Botero Cid, H. M.; Tränkle, C.; Baumann, K.; Pick, R.; Mies-Klomfass, E.; Kostenis, E.; Mohr, K.; Holzgrabe, U. J. Med. Chem. 000, 43, 155. (b) Danheiser, R. L.; Kwasigroch, C. A.; Tsai, Y.-M. J. Am. Chem. Soc. 1985, 107, (a) Dunet, A.; Willemart, A. Bull. Soc. Chim. France 1948, 887. (b) Eberle, M. K.; Houlihan, W. J.; Schirm, P. J. rg. Chem. 1973, 38, 387. (c) Scartoni, V.; Morelli, I.; Marsili, A.; Catalano, S. J. Chem. Soc., Perkin Trans. 1, 1977, 33. (d) Kreher, R. P.; Konrad, M. R. Chem.-Ztg. 198, 110, 33. (e) Uozumi, Y.; Mori, E.; Mori, M.; Shibasaki, M. J. rganomet. Chem. 1990, 399, 93. (f) Broquet, C.; Genet, J.-P. C. R. Acad. Sci. Ser. C 197, 5, (a) Goto, T.; Utsunomiya, S.; Aiba, H.; Hayasaka, H.; Endo, M.; Watanabe, R.; Ishizaki, T.; Sato, R.; Saito, M. Bull. Chem. Soc. Jpn., 1991, 4, (b) Hoarau, C.; Couture, A.; Cornet, H.; Deniau, E.; Grandclaudon, P. J. rg. Chem., 001,, 804. (c) Rys, V.; Couture, A.; Deniau, E.; Lebrun, S.; Grandclaudon, P. Synlett, 004, 1, 33. (d) Hamprecht, G.; Zimmermann,.; Weiß, T. D. Eur. J. rg. Chem. 004, (a) Flitsch, W. Ber. 1970, 103, 305. (b) Valters, R. E. Usp. Khim. 1973, 4, 100. (c) ashio, T.; Yamamoto, H. J. Heterocycl. Chem. 1995, 3, (a) Epsztajn, J.; Jóźwiak, A.; Szcześniak, A. K. Synth. Commun. 1994, 4, (b) Epsztajn, J.; Jóźwiak, A.; Czech, K.; Szcześniak, A. K. Monatsh. Chem. 1990, 11, 909. (c) Epsztajn, J.; Grzelak, R.; Jóźwiak, A. Synthesis 199, 11.. Vogel, A. I. Vogel s Textbook of Practical rganic Chemistry, Longman Scientific & Technical: London, 1989; pp 409, 410. ISS Page 19