Abstract
Under microwave irradiation conditions, the imines/enamines formed between aminopyridines
and ketones are converted in moderate to good yields to the corresponding 4-, 5-,
6- or 7-azaindoles via the Hegedus-Mori-Heck reaction (intramolecular Heck reaction).
A systematic examination of all isomeric azaindoles synthesis revealed this one-pot
procedure to be general in scope.
Key words
microwave - azaindole - pyrrolopyridine - palladium - Heck reaction
References
For reviews on indoles and azaindoles synthesis, see:
<A NAME="RM01205SS-1A">1a</A>
Gribble GW.
J. Chem. Soc., Perkin Trans. 1
2000,
1045
<A NAME="RM01205SS-1B">1b</A>
Mérour J.-Y.
Joseph B.
Curr. Org. Chem.
2001,
5:
471
<A NAME="RM01205SS-2A">2a</A>
Trejo A.
Arzeno H.
Browner M.
Chanda S.
Cheng S.
Comer DD.
Dalrymple SA.
Dunten P.
Lafargue J.
Lovejoy B.
Freire-Moar J.
Lim J.
Mcintosh J.
Miller J.
Papp E.
Reuter D.
Roberts R.
Sanpablo F.
Saunders J.
Song K.
Villasenor A.
Warren SD.
Welch M.
Weller P.
Whiteley PE.
Zeng L.
Goldstein DM.
J. Med. Chem.
2003,
46:
4702
<A NAME="RM01205SS-2B">2b</A>
Sanderson PEJ.
Stanton MG.
Dorsey BD.
Lyle TA.
McDonough C.
Sanders WM.
Savage KL.
Naylor-Olsen AM.
Krueger JA.
Lewis SD.
Lucas BJ.
Lynch JJ.
Yan Y.
Bioorg. Med. Chem. Lett.
2003,
13:
795
<A NAME="RM01205SS-2C">2c</A>
Ujjainwalla F.
Walsh TF.
Tetrahedron Lett.
2001,
42:
6441
<A NAME="RM01205SS-3">3</A>
Blache Y.
Sinibaldi-Troin M.-E.
Voldoire A.
Chavignon O.
Gramain J.-C.
Teulade J.-C.
Chapat J.-P.
J. Org. Chem.
1997,
62:
8553
<A NAME="RM01205SS-4">4</A>
Blache Y.
Sinibaldi-Troin M.-E.
Hichour M.
Benezech V.
Chavignon O.
Gramain J.-C.
Teulade J.-C.
Chapat J.-P.
Tetrahedron
1999,
55:
1959
<A NAME="RM01205SS-5">5</A>
Nazaré M.
Schneider C.
Lindenschmidt A.
Will DW.
Angew. Chem. Int. Ed.
2004,
43:
4526
<A NAME="RM01205SS-6">6</A>
Abramovitch RA.
Adams KAH.
Can. J. Chem.
1962,
40:
864
<A NAME="RM01205SS-7">7</A>
Kelly AH.
Parrick J.
J. Chem. Soc. C
1970,
303
<A NAME="RM01205SS-8">8</A>
Mann FG.
Prior AF.
Willcox TJ.
J. Chem. Soc.
1959,
3830
<A NAME="RM01205SS-9A">9a</A>
Gedye R.
Smith F.
Westaway K.
Ali H.
Baldisera L.
Laberge L.
Rousell J.
Tetrahedron Lett.
1986,
27:
279
<A NAME="RM01205SS-9B">9b</A>
Giguere RJ.
Bray TL.
Duncan SM.
Majetich G.
Tetrahedron Lett.
1986,
27:
4945
For reviews on microwave irradiation, see:
<A NAME="RM01205SS-10A">10a</A>
Kappe CO.
Angew. Chem. Int. Ed.
2004,
43:
6250 ; and references therein
<A NAME="RM01205SS-10B">10b</A>
Hayes BL.
Aldrichimica Acta
2004,
37:
66 ; and references therein
<A NAME="RM01205SS-10C">10c</A>
Perreux L.
Loupy A.
Tetrahedron
2001,
57:
9199
<A NAME="RM01205SS-11">11</A>
Larhed M.
Hallberg A.
J. Org. Chem.
1996,
61:
9582
<A NAME="RM01205SS-12">12</A>
Lachance N, and
Sturino CF. inventors; WO Patent, 111047/A2.
<A NAME="RM01205SS-13">13</A>
Pyrex cylindrical reaction tubes adapted to the Smith CreatorTM (Biotage/Personal Chemistry) were used. The temperature was measured by IR detection
and maintained constant by modulated irradiation of 8-300 W.
<A NAME="RM01205SS-14">14</A>
Scott T. L.
Söderberg B. C. G.
Tetrahedron
2003,
59:
6323
<A NAME="RM01205SS-15">15</A>
Condensation of 3-amino-4-chloropyridine (22) with 1,3-cyclohexanedione (2.6 equiv) and PTSA (0.05 equiv) in refluxing benzene
for 2.5 h delivered 5 (55%).
<A NAME="RM01205SS-16">16</A> Compounds 6-8, see:
Couture A.
Deniau E.
Grandclaudon P.
Simion C.
Synthesis
1993,
1227
<A NAME="RM01205SS-17">17</A>
Absence of Pd(PPh3)4 resulted in the recovery of starting enamine 1.
<A NAME="RM01205SS-18">18</A>
Chen C.
Lieberman DR.
Larsen RD.
Verhoeven TR.
Reider PJ.
J. Org. Chem.
1997,
62:
2676
<A NAME="RM01205SS-19">19</A>
Napieraj A.
Zawadzki S.
Zwierzak A.
Tetrahedron
2000,
56:
6299
<A NAME="RM01205SS-20">20</A>
Love BE.
Ren J.
J. Org. Chem.
1993,
58:
5556
<A NAME="RM01205SS-21">21</A>
Lachance N.
Chan WY.
J. Heterocycl. Chem.
2003,
40:
289
<A NAME="RM01205SS-22">22</A>
Mazéas D.
Guillaumet G.
Viaud M.-C.
Heterocycles
1999,
50:
1065
<A NAME="RM01205SS-23">23</A>
For comparison, we have repeated the condensation step at 160 °C for 20 min with PPTS
(0.05 equiv) for entries 4 and 5 from Table
[3]
. Azaindole 28 has been obtained in 62% isolated yield whereas only decomposition was observed when
22 and 25 were submitted to the same conditions.
<A NAME="RM01205SS-24">24</A>
Roy PJ.
Dufresne C.
Lachance N.
Leclerc J.-P.
Boisvert M.
Wang Z.
Leblanc Y.
Synthesis
2005,
in press
<A NAME="RM01205SS-25">25</A>
Ujjainwalla F.
Warner D.
Tetrahedron Lett.
1998,
39:
5355 ; and references therein
<A NAME="RM01205SS-26">26</A>
Mazéas D.
Guillaumet G.
Viaud M.-C.
Heterocycles
1999,
50:
1065
<A NAME="RM01205SS-27">27</A>
Frydman B.
Reil SJ.
Boned J.
Rapoport H.
J. Org. Chem.
1968,
3762
<A NAME="RM01205SS-28">28</A>
Fisher MH.
Matzuk AR.
J. Heterocycl. Chem.
1969,
775
