Abstract
Development of a convenient and efficient synthetic route for functionalized tetrahydrocycloheptapyridines was accomplished by stepwise iodomethylation and subsequent radical ring expansion using a Bu3SnH/AIBN reaction system. Thus, 8- or 5-oxotetrahydroquinolines 4a and 4d and 8- or 5-oxotetrahydroisoquinolines 4b and 4c afforded the 5,6,7,8-tetrahydrocycloheptapyridine-9-ones 3a and 3d and 6,7,8,9-tetrahydrocycloheptapyridine-5-ones 3b and 3c, respectively, in moderate total yields (37-61%). It was also found out that this reaction sequence was applicable to the preparation of other heterocyclic fused cycloheptanones.
Key words
cycloheptanone - hydroxymethylation - iodomethylation - ring expansion - radical reaction
References
1a
Cortizo L.
Santana L.
Raviña E.
Orallo F.
Fontenla JA.
Castro E.
Calleja JM.
de Ceballos ML.
J. Med. Chem.
1991,
34:
2242
1b
Raviña E.
Nergeira J.
Cid J.
Masaguer CF.
Rosa E.
Rivas ME.
Fontenla JA.
Loza MI.
Tristán H.
Cadavid MI.
Sanz F.
Lozoya E.
Carotti A.
Carrieri A.
J. Med. Chem.
1999,
42:
2774
1c
Fontenla JA.
Osuna J.
Rosa E.
Castro ME.
G-Ferreiro T.
Loza-García I.
Calleja JM.
Sanz F.
Rodríguez J.
Raviña E.
Fueyo J.
F-Masaguer C.
Vidal A.
de Ceballos ML.
J. Med. Chem.
1994,
37:
2564
2
Brea J.
Rodrigo J.
Carrieri A.
Sanz F.
Cadavid MI.
Enguix MJ.
Villazón M.
Mengod G.
Caro Y.
Masaguer CF.
Raviña E.
Centeno NB.
Carotti A.
Loza MI.
J. Med. Chem.
2002,
45:
54
3
Forbes IT.
Cooper DG.
Dodds EK.
Douglas SE.
Gribble AD.
Ife RJ.
Lightfoot AP.
Meeson M.
Campbell LP.
Coleman T.
Riley GJ.
Thomas DR.
Bioorg. Med. Chem. Lett.
2003,
13:
1055
4 Daniela B, Giorgio C, Maria GGA, Mario G, and Silvano R. inventors; Patent WO 0027815.
; Chem. Abstr. 2000, 132, 347490
5 Indeed, replacement of the benzene ring with a pyridine ring changed the physicochemical properties in the case of an endothelin receptor antagonist we developed, see: Niiyama K.
Mase T.
Takahashi H.
Naya A.
Katsuki K.
Nagase T.
Ito S.
Hayama T.
Hisaka A.
Ozaki S.
Ihara M.
Yano M.
Fukuroda T.
Noguchi K.
Nishikibe M.
Ishikawa K.
Bioorg. Med. Chem.
2002,
10:
2461
6
Masaguer CF.
Raviña E.
Tetrahedron Lett.
1996,
37:
5171
7
Casariego I.
Masaguer CF.
Raviña E.
Tetrahedron Lett.
1997,
38:
5555
8
Pita B.
Casariego I.
Masaguer CF.
Raviña E.
Tetrahedron Lett.
2000,
41:
9829
9a
Hasegawa E.
Kitazumi T.
Suzuki K.
Tosaka E.
Tetrahedron Lett.
1998,
39:
4059
9b
Chung SH.
Cho MS.
Choi JY.
Kwon DW.
Kim YH.
Synlett
2001,
1266
9c
Sugi M.
Sakuma D.
Togo H.
J. Org. Chem.
2003,
68:
7629
9d
Bowman WR.
Westlake PJ.
Tetrahedron
1992,
48:
4027
9e
Chatgilialoglu C.
Timokhin VI.
Ballestri M.
J. Org. Chem.
1998,
63:
1327
10
Comprehensive Heterocyclic Chemistry
Vol. 2:
Katritzky AR.
Rees CW.
Pergamon;
London:
1984.
11 We also conducted bromo- or iodomethylation using other bases (t-BuOK, DBU, and Cs2CO3), but the attempts ended in incomplete conversion or complex mixture.
12
Newton RF.
Reynolds DP.
Synth. Commun.
1981,
11:
527
13 Bromination of 9a using CBr4 and PPh3 resulted in lower yield (45%).
14 The stereochemistry of compounds 10 and 11 was determined by their NOEs. The details are listed in the experimental section.
15
Thummel RP.
Lefoulon F.
Cantu D.
Mahadevan R.
J. Org. Chem.
1984,
49:
2208
16
Glassco W.
Suchocki J.
George C.
Martin BR.
May EL.
J. Med. Chem.
1993,
36:
3381
17
Lardenois P.
Frost J.
Dargazanli G.
George P.
Synth. Commun.
1996,
26:
2305
18
Huang Y.
Hartmann RW.
Synth. Commun.
1998,
28:
1197
19
Mosti L.
Menozzi G.
Schenone P.
J. Heterocycl. Chem.
1983,
20:
649
20
Schenone P.
Mosti L.
Menozzi G.
J. Heterocycl. Chem.
1982,
19:
1355
