Abstract
An improved method for the synthesis of 4-hydroxy-2-methyl-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid derivatives is described. The synthetic route involves initial phthalic anhydride aminolysis with alkylaminoacetic acid derivatives, further esterification with diazomethane and final heterocyclization of the phthalamic ester intermediates by alkoxide-induced Dieckmann condensation. The best yields are reached for esters and N,N-disubstituted carboxamides.
Key words
heterocycles - isoquinolinones - cyclization - lactams - enols
References
1a Khan SR.
Mhaka A.
Pili R.
Isaacs JT.
Bioorg. Med. Chem. Lett.
2001,
11:
451
1b Shi J.
Xiao Z.
Ihnat MA.
Kamat C.
Pandit B.
Hu Z.
Li PK.
Bioorg. Med. Chem. Lett.
2003,
13:
1187
1c Jönsson S.
Andersson G.
Fex T.
Fristedt T.
Hedlund G.
Jansson K.
Abramo L.
Fritzson I.
Pekarski O.
Runström A.
Sandin H.
Thuvesson I.
Björk A.
J. Med. Chem.
2004,
47:
2075 ; and references cited therein
1d Brunmark C.
Runström A.
Ohlsson L.
Sparre B.
Brodin T.
Aström M.
Hedlund G.
J. Neuroimmunol.
2002,
130:
163
1e Tsuji K.
Spears GW.
Nakamura K.
Tojo T.
Seki N.
Sugiyama A.
Matsuo M.
Bioorg. Med. Chem. Lett.
2002,
12:
85
1f Folkes A.
Brown SD.
Canne LE.
Chan J.
Engelhardt E.
Epshteyn S.
Faint R.
Golec J.
Hanel A.
Kearney P.
Leahy JW.
Mac M.
Matthews D.
Prisbilla MP.
Sanderson J.
Simon RJ.
Tesfai Z.
Vicker N.
Wang S.
Webb RR.
Charlton P.
Bioorg. Med. Chem. Lett.
2002,
12:
1063
1g Ukrainets IV.
Taran SG.
Gorokhova OV.
Taran EA.
Jaradat NA.
Petukhova IY.
Chem. Heterocycl. Compd. (Engl. Transl.)
2000,
36:
166
1h Ukrainets IV.
Taran SG.
Likhanova NV.
Rybakov VB.
Gorokhova OV.
Jaradat NA.
Chem. Heterocycl. Compd. (Engl. Transl.)
2000,
36:
49
1i Kugalowski JJ.
Baker R.
Curtis NR.
Leeson PD.
Mawer IM.
Moseley AM.
Ridgill MP.
Rowley M.
Stansfield I.
Foster AC.
Grimwood S.
Hill RG.
Kemp JA.
Marshall JR.
Saywell KL.
Tricklebank MD.
J. Med. Chem.
1994,
37:
1402
2a Lombardino JG.
J. Heterocycl. Chem.
1970,
7:
1057
2b Schapira CB.
Abasolo MI.
Perillo IA.
J. Heterocycl. Chem.
1985,
22:
577 ; and references cited therein
2c Kadin SB.
Wiseman EH.
Nature
1969,
222:
275
2d Lazer E.
Miao CK.
Cywin CL.
Sorcek R.
Wong H.-C.
Meng Z.
Potocki I.
Hoermann M.
Snow RJ.
Tschantz MA.
Kelly TA.
McNeil DW.
Coutts SJ.
Churchill L.
Graham V.
David E.
Grob PM.
Engel W.
Meier H.
Trummlitz G.
J. Med. Chem.
1997,
40:
980
3a Blanco MM.
Schapira CB.
Levin G.
Perillo IA.
J. Heterocycl. Chem.
2005,
42:
493 ; and references cited therein
3b Scotese AC, and Santilli AA. inventors; S. African ZA 8000631.
; Chem. Abstr . 1982 , 96 , 6706
3c Scotese AC, Morris RL, and Santilli AA. inventors; US Patent 4301281.
; Chem. Abstr. 1982 , 97 , 23815
3d Armitage BJ, and Leslie BW. inventors; PCT Int. Appl. WO 9611199.
; Chem.Abstr . 1996 , 125 , 114712
3e Nuebling C, Von Deyn W, Theobald H, Westphalen K.-O, Kardorff U, Helmut W, Kappe T, and Gerber M. inventors; Ger. Offen. DE 4227747.
; Chem. Abstr. 1994 , 120 , 323554z
4a Toyama M.
Otomasu H.
Chem. Pharm. Bull.
1985,
33:
5543
4b Alonso-Silva IJ.
Pardo M.
Soto JL.
Heterocycles
1988,
27:
357
4c Beattie JF.
Hales NJ.
J. Chem. Soc., Perkin Trans. 1
1992,
751
4d Khalaj A.
Adibpour N.
Heterocycles
1999,
51:
131
5a Suzuki M.
Nunami K.
Matsumoto K.
Yoneda N.
Miyoshi M.
Synthesis
1978,
461
5b Nunami K.
Suzuki M.
Matsumoto K.
Miyoshi M.
Yoneda N.
Chem. Pharm. Bull.
1979,
27:
1373
5c Miyoshi S, Yoneda N, Matsumoto K, Suzuki M, and Nunami K. inventors; Jpn. Kokai Tokkio Koho 7970285.
; Chem. Abstr . 1979 , 91 , 175221
6 Ease of trans-esterification is related to the presence of an electron-withdrawing group at the α-position to the ester (ref. 7) and it was also observed in Dieckmann cyclizations which lead to hydroxy derivatives of related heterocycles (ref. 8).
7 Janczewski D.
Synoradzki L.
Wlostowski M.
Synlett
2003,
420
8 Blanco MM.
Perillo IA.
Schapira CB.
J. Heterocycl. Chem.
1999,
36:
979 ; and references cited therein
9 This fact is related to the acid character of aniline hydrogen in phthalamic ester 2c which would allow its deprotonation in basic medium, thus resulting in a less probable formation of the carbanion necessary for the heterocyclization. A similar behavior was observed in the alkoxide promoted cyclization of compounds structurally related to 2c (ref. 3a).
10 Lombardino (ref. 2a) describes the reaction product as a solid, formula: C17 H14 N2 O3 ·0.5H2 O, mp 195-197 °C.
11 The nonresolved multiplicity of the methylene and methyl signals is related to stereochemical features of this type of amides: partial double bond character of CO-N amide bond and/or the diastereotopicity of the methylene hydrogens associated with the presence of a chiral axis (ref. 4a).
