Two efficient N-acylation methods mediated by solid-supported reagents for weakly nucleophilic heterocyclic amines

Synlett

Volumn , Issue 12, 1999, Pages 1957-1959

  Kim, Kyungjin ^a   Le, Kang ^a  

^a HOFFMANN LA ROCHE INC   (United States)

Author keywords

Acylation; Amide; Chemoselective purification; Combinatorial chemistry; Solid supported reagents

Indexed keywords

HETEROCYCLIC AMINE;

ACYLATION; ARTICLE; CHEMICAL REACTION; CHEMICAL STRUCTURE; PHARMACOPHORE; STEREOCHEMISTRY;

EID: 0032755128     PISSN: 09365214     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-1999-2987     Document Type: Article

References (12)

1. Green, T.W.; Wuts, P.G.M Protective groups in organic synthesis; Wiley Interscience: John Wiley, 1991, 349-357 and references therein.
2. (a) Carpino, L.A.; Cohen, B.J.; Lin, Y.Z.; Stephens, Jr. K.E.; Triolo, S.A. J. Org. Chem. 1990, 55, 251-259.
3. (b) Cohen, B.J.; Karoly-Hafeli, H.; Patchornik, A. J. Org. Chem. 1984, 49, 922-924.
4. (c) Pop, I.E.; Deprez, B.P.; Tartar, A.L. J. Org. Chem. 1997, 62, 2594-2603.
5. (d) Reichwein, J.F.; Liskamp, M.J. Tetrahedron Lett. 1998, 39, 1243-1246.
6. (a) Schwesinger, R. Chimia 1985, 39, 269-272.
7. (b) Xu, W.; Mohan, R.; Morrissey, M.M. Bioorg. Med. Chem. Lett. 1998, 8, 1089-1092: polymer-bound BEMP is available from Fluka Chemical Corp.
8. Polymeric 4-hydroxy-3-nitrobenzophenone 3 was prepared according to reference 2(b).
9. Base induced acylation was also investigated including a strong base such as potassium tert-butoxide.
10. 2O containing 0.02 TFA and monitored at 215 nm using a UV detector and by SEDEX 55 Evaporative Light Scattering Detector (ELSD). The purity scores reported herein are based on ELSD.
11. Booth, R.J.; Hodges, J.C. J. Am. Chem. Soc. 1997, 119, 4882: polymer-bound trisamine is available from Argonaut Technologies (San Carlos, CA).
12. FlexChem™ reaction block (48 well) of Robbins Scientific Corp. was used for acylations and typical experimental procedures are as follows: The mixture of amine (0.2 mmol), acyl chloride (0.4 mmol), and polymer-bound BEMP (0.3 mmol) in 2 ml THF solution was slowly agitated at room temperature. After overnight reaction, polymeric trisamine (3.76 mmol/g, 1.0 mmol) was dispensed by ArgoScoop™, a pre-calibrated scoop from Argonaut Technologies, to remove excessive acyl chloride and then the mixture was shaken for 5 h and filtered to a 48 well plate to provide amides, respectively. If necessary, the filtrate was passed through a silica gel pad packed in a 48-well block of FlexChem™ to provide highly pure amide products.