Abstract
Simple and fast solid phase methods for the synthesis of heterocycles
will be described. Two different three-step methods are presented.
The first method includes esterifications of N -protected
glycine derivatives to a solid support (Merrifield resin), formation
of aminopropenoates and subsequent reaction with dinucleophiles.
The second method includes methylamination of a Merrifield resin,
formation of aminopropenones via in-situ formation of an active
intermediate in a three-component reaction and finally treatment
with dinucleophiles to form heterocycles. These procedures lead
not only to the formation of heterocycles but also to simultaneous
intramolecular cleavage of the products from the resin giving the
product in pure form in the solution. In addition, the use of microwave
dielectric heating enhanced the velocity of all reaction steps and
was found to be a very efficient complement to the solid phase synthesis.
Key words
solid-phase synthesis - microwave irradiation - combinatorial
chemistry - heterocycles
References
1 Abdulla RF.
Brinkmeyer RV.
Tetrahedron
1979,
35:
1675
2 Stanovnik B.
Svete J.
Synlett
2000,
1077 ; and references cited therein
3 Westman J.
Lundin R.
Stålberg J.
Östbye M.
Franzén AHurynowics.
Combin. Chem. High Throughput
Screen
2002,
57:
565
4 Westman J.
Org.
Lett.
2001,
3:
3745
5a Gisin BF.
Helv. Chim. Acta
1973,
56:
1476
5b Monahan MW.
Gilon C.
Biopolymers
1973,
12:
2513
6 Kaiser E.
Colescott RL.
Bossinger CD.
Cook PI.
Anal.
Biochem.
1970,
34:
595
7a Anderson RC.
Stokes JP.
Shapiro MJ.
Tetrahedron
Lett.
1995,
36:
5311
7b Fitch WL.
Detre G.
Holmes CP.
Shoolery JN.
Keifer PA.
J. Org. Chem.
1994,
59:
7955
8 Wehler T.
Westman J.
Tetrahedron Lett.
1996,
37:
4771
9a Früchtel JS.
Jung G.
Angew. Chem., Int. Ed. Engl.
1996,
35:
17
9b Thompson LA.
Ellman JA.
Chem.
Rev.
1996,
96:
555
9c Balkenhohl F.
Bussche-Hünnefeld C.
Lansky A.
Zechel C.
Angew. Chem.,
Int. Ed. Engl.
1996,
35:
2289
10 In this project SmithSynthesizerTM available
from Personal Chemistry AB was used. This instrument is fully automated equipped
with temperature and pressure control and can run up to 120 unattended
reactions sequentially the process vial is cooled actively by pressurized
air after the irradiation.
11 Gmeiner P.
Kraxner J.
Bollinger B.
Synthesis
1996,
1196
12 Results not shown.
13 Meerwein H.
Borner P.
Fuchs O.
Sasse HJ.
Schrodt H.
Spille J.
Chem. Ber.
1956,
89:
2060
14 Bienaymé H.
Tetrahedron
Lett.
1998,
39:
4255
15 Tietze LF.
Chem.
Rev.
1996,
115
16 To our surprise we could not form
the solid supported benzylmethylamine from methylamine in MeOH under
the same conditions.
17a Tsuge O.
Noguchi M.
Heterocycles
1981,
16:
2149
17b Hermecz I.
Horvath A.
Vasvari-Debreczy L.
Meszaros Z.
Synthesis
1984,
152
18 Smodis J.
Stanovnik B.
Tisler M.
J.
Heterocycl. Chem.
1994,
31:
125
19 Kocevar M.
Polanc S.
Tisler M.
Vercek B.
Synth. Commun.
1989,
19:
1713
