M. Meldal and F. Diness
(6ꢁ2 min), DMF (6ꢁ2 min), CH2Cl2 (6ꢁ2 min) and lyophilized. The
compound (14a–d) was cleaved off the resin as described above.
We further explored the copper(II)-catalysed oxidative N-
arylation[20] of the imidazolone products with aryl boronic
acids. The imidazolones proved to be excellent substrates
for this type of coupling and the application of imidazolone
13 gave the corresponding products (14a–d) with purities in
excess of 95% (Scheme 3).
Acknowledgements
The financial support to the SPOCC Center from the Danish National
Research Foundation is gratefully acknowledged.
Keywords: autooxidation
· cross-coupling · solid-phase
synthesis · stereoselective synthesis · urea
[1] a) L. C. Meurer, P. E. Finke, K. A. Owens, N. N. Tsou, R. G. Ball,
S. G. Mills, M. MacCoss, S. Sadowski, M. A. Cascieri, K.-L. Tsao,
G. G. Chicchi, L. A. Egger, S. Luell, J. M. Metzger, D. E. MacIntyre,
N. M. J. Rupniak, A. R. Williams, R. Hargreaves, Bioorg. Med.
orse, M. MacCoss, S. Sadowski, M. A. Cascieri, K.-L. Tsao, G. G.
[2] C. S. Burgey, C. A. Stump, D. N. Nguyen, J. Z. Deng, A. G. Quigley,
B. R. Norton, I. M. Bell, S. D. Mosser, C. A. Salvatore, R. Z. Rut-
ledge, S. A. Kane, K. S. Koblan, J. P. Vacca, S. L. Graham, T. M. Wil-
[3] R. W. Carling, K. W. Moore, C. R. Moyes, E. A. Jones, K. Bonner, F.
Emms, R. Marwood, S. Patel, A. E. Fletcher, M. Beer, B. Sohal, A.
[4] D. B. Reitz, D. J. Garland, M. B. Norton, J. T. Collins, E. J. Reinhard,
R. E. Manning, G. M. Olins, S. T. Chen, M. A. Palomo, E. G. McMa-
Scheme 3. Formation of N-aryl imidazolones. Yields reported are those
of the pure isolated products.
The ability to act selectively as nucleophile or electrophile
under the same reaction conditions and serve as substrate
for copper catalysed cross couplings shows that imidazo-
lones are very versatile compounds in the synthesis of com-
plex heterocyclic scaffolds. The simple procedures and quan-
titative nature of these reactions opens up for facile access
to new types of optically pure compounds with potential use
as pharmaceutical substances.
[5] J. I. Andrꢃs, J. M. Alonso, A. Diaz, J. Fernandez, L. Iturrino, P. Mar-
tinez, E. Matesanz, E. J. Freyne, F. Deroose, G. Boeckx, D. Petit, G.
Diels, A. Megens, M. Somers, J. V. Wauwe, P. Stoppie, M. Cools,
F. D. Clerck, D. Peeters, D. D. Chaffoy, Bioorg. Med. Chem. Lett.
2002, 12, 653.
[6] E. M. Naylor, E. R. Parmee, V. J. Colandrea, L. Perkins, L. Brocku-
nier, M. R. Candelore, M. A. Cascieri, L. F. Colwell, L. Deng, W. P.
Feeney, M. J. Forrest, G. J. Hom, D. E. MacIntyre, C. D. Starader, L.
Tota, P.-R. Wang, M. J. Wyvratt, M. H. Fisher, A. E. Weber, Bioorg.
[8] H.-P. Fiedler, R. Kurth, J. Langhꢄrig, J. Delzer, H. Zꢄhner, J. Chem.
Technol. Biotechnol. 1982, 32, 271.
[11] A. C. B. Sosa, K. Yakushijin, D. A. Horne, J. Org. Chem. 2002, 67,
4498.
Experimental Section
General aspects: All purchased chemicals were used without further pu-
rification. All solvents were HPLC-grade. PEGA800 resin was obtained
from VersaMatrix A/S. See ref. [17] and Supporting Information for the
full characterisation of all products.
Synthesis of imidazolone and EASCy products (3, 4, 6a–f, 7a–d, 11, 12
and 13): Dry PEGA800 resin (50–150 mg, 0.30–0.38 mmolgÀ1, 15–57 mmol)
derivatized with the HMBA linker and amino acid was swelled in DMF
(for the preparation of the funtionalised resin see reference [15b]). The
building block (3.0 equiv) (1, 9a or 9b) was dissolved in DMF (10 mLgÀ1
resin) and the solution was added to the resin. After 12 h the resin was
washed with DMF (6ꢁ2 min), CH2Cl2 (6ꢁ2 min) and lyophilized. The
dry PEGA800 resin with HMBA linker, peptide and building block at-
tached (2a–b, 5a–f, 10a or 10b) was swelled in aqueous 10% TFA (1 h).
The resin was washed with 10% aqeous TFA (2ꢁ2 min). Further reac-
tion with TFA was applied when necessary to complete conversion (see
Supporting Information). The resin was washed with H2O until the
eluate had pH 5–7. The resin was washed with DMF (6ꢁ2 min), CH2Cl2
(6ꢁ2 min) and lyophilized. The compound was cleaved from the resin by
swelling the dry PEGA800 resin with the attached HMBA linker and com-
pound in 0.1m aqueous NaOH (10 mLgÀ1 resin). After 2 h aqueous 0.1m
HCl was used for neutralization. Resin was extracted with H2O (2ꢁ
2 min) and acetonitrile/H2O 70:30 (2ꢁ2 min). The solvent from the ex-
tract was removed in vacuo giving the product (3, 4, 6a–f, 7a–d, 11, 12
and 13), as a solid with a white to pale yellow colour.
[13] For generation of imidazolones in solution see: a) R. Duschinsky,
tanabe, T. Mukaiyama, Chem. Lett. 1974, 401; d) Y. S. Lee, C. S.
Kim, H. Park, Heterocycles 1994, 38, 2605; e) J. A. Markwalder,
R. S. Pottorf, S. P. Seitz, Synlett 1997, 521; f) S. Wendeborn, T. Win-
Celeda, Helv. Chim. Acta 2000, 83, 728; h) S.-H. Lee, B. Clapham,
j) S.-H. Lee, K. Yoshida, H. Matsushita, B. Clapham, G. Koch, J.
ecetto, A. Gerpe. M. Gonzalez, O. E. Piro, E. E. Castellano, Lett.
Copper(II)-promoted N-arylation of imidazolone product of GlyBB-Phe-
Gly-HMBA-PEGA800
~0.35 mmolgÀ1, 21 mmol) was swelled in DMF. Aryl boronic acid (210
mmol), Cu(AcO)2 (7.5 mg, 42 mmol) and DIPEA (134 mg, 1.05 mmol)
ACHTUNGTRENNUNG(14a–d): The imidazolone product 13 (60 mg,
ACHTUNGTRENNUNG
were added to the resin. Crusted molecular sieves 3 ꢂ (~100 mg) was
added and mixture stirred with dry air bubbling through (12 h). The resin
was washed with DMF (6ꢁ2 min), 1% aqueous TFA (3ꢁ2 min), H2O
7046
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 7044 – 7047