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
<A NAME="RF17204SS-1A">1a</A>
Cortizo L.
Santana L.
Raviña E.
Orallo F.
Fontenla JA.
Castro E.
Calleja JM.
de Ceballos ML.
J. Med. Chem.
1991,
34:
2242
<A NAME="RF17204SS-1B">1b</A>
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
<A NAME="RF17204SS-1C">1c</A>
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
<A NAME="RF17204SS-2">2</A>
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
<A NAME="RF17204SS-3">3</A>
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
<A NAME="RF17204SS-4">4</A>
Daniela B,
Giorgio C,
Maria GGA,
Mario G, and
Silvano R. inventors; Patent WO 0027815.
; Chem. Abstr. 2000, 132, 347490
<A NAME="RF17204SS-5">5</A> 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
<A NAME="RF17204SS-6">6</A>
Masaguer CF.
Raviña E.
Tetrahedron Lett.
1996,
37:
5171
<A NAME="RF17204SS-7">7</A>
Casariego I.
Masaguer CF.
Raviña E.
Tetrahedron Lett.
1997,
38:
5555
<A NAME="RF17204SS-8">8</A>
Pita B.
Casariego I.
Masaguer CF.
Raviña E.
Tetrahedron Lett.
2000,
41:
9829
<A NAME="RF17204SS-9A">9a</A>
Hasegawa E.
Kitazumi T.
Suzuki K.
Tosaka E.
Tetrahedron Lett.
1998,
39:
4059
<A NAME="RF17204SS-9B">9b</A>
Chung SH.
Cho MS.
Choi JY.
Kwon DW.
Kim YH.
Synlett
2001,
1266
<A NAME="RF17204SS-9C">9c</A>
Sugi M.
Sakuma D.
Togo H.
J. Org. Chem.
2003,
68:
7629
<A NAME="RF17204SS-9D">9d</A>
Bowman WR.
Westlake PJ.
Tetrahedron
1992,
48:
4027
<A NAME="RF17204SS-9E">9e</A>
Chatgilialoglu C.
Timokhin VI.
Ballestri M.
J. Org. Chem.
1998,
63:
1327
<A NAME="RF17204SS-10">10</A>
Comprehensive Heterocyclic Chemistry
Vol. 2:
Katritzky AR.
Rees CW.
Pergamon;
London:
1984.
<A NAME="RF17204SS-11">11</A>
We also conducted bromo- or iodomethylation using other bases (t-BuOK, DBU, and Cs2CO3), but the attempts ended in incomplete conversion or complex mixture.
<A NAME="RF17204SS-12">12</A>
Newton RF.
Reynolds DP.
Synth. Commun.
1981,
11:
527
<A NAME="RF17204SS-13">13</A>
Bromination of 9a using CBr4 and PPh3 resulted in lower yield (45%).
<A NAME="RF17204SS-14">14</A>
The stereochemistry of compounds 10 and 11 was determined by their NOEs. The details are listed in the experimental section.
<A NAME="RF17204SS-15">15</A>
Thummel RP.
Lefoulon F.
Cantu D.
Mahadevan R.
J. Org. Chem.
1984,
49:
2208
<A NAME="RF17204SS-16">16</A>
Glassco W.
Suchocki J.
George C.
Martin BR.
May EL.
J. Med. Chem.
1993,
36:
3381
<A NAME="RF17204SS-17">17</A>
Lardenois P.
Frost J.
Dargazanli G.
George P.
Synth. Commun.
1996,
26:
2305
<A NAME="RF17204SS-18">18</A>
Huang Y.
Hartmann RW.
Synth. Commun.
1998,
28:
1197
<A NAME="RF17204SS-19">19</A>
Mosti L.
Menozzi G.
Schenone P.
J. Heterocycl. Chem.
1983,
20:
649
<A NAME="RF17204SS-20">20</A>
Schenone P.
Mosti L.
Menozzi G.
J. Heterocycl. Chem.
1982,
19:
1355
