A new vinyl ether type linker for solid-phase synthesis

Article abstract of DOI:10.1016/S0040-4039(00)00927-8

A new vinyl ether type of linker based on 4.-hydroxy phenethyl alcohol is developed for the solid-phase synthesis as demonstrated in the Suzuki type of aryl-aryl coupling reaction for the preparation of various biphenyl tetrazole derivatives. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00927-8

Tetrahedron Letters 41 (2000) 6415±6418
A new vinyl ether type linker for solid-phase synthesis
Sung-eun Yoo,* Young-Dae Gong, Min-Young Choi, Jin-soo Seo and Kyu Yang Yi
The Bio-organic Science Division, Korea Research Institute of Chemical Technology,
and the Center for Molecular Design and Synthesis, PO Box 107, Yusung, Daedeog Sciencetown,
Daejeon 305-606, South Korea
Received 17 April 2000; revised 29 May 2000; accepted 2 June 2000
Abstract
A new vinyl ether type of linker based on 4-hydroxy phenethyl alcohol is developed for the solid-phase
synthesis as demonstrated in the Suzuki type of aryl±aryl coupling reaction for the preparation of various
biphenyl tetrazole derivatives. # 2000 Elsevier Science Ltd. All rights reserved.
There is an enormous interest in the development of solid-phase synthetic approaches to small
molecules, particularly those which embrace biphenyl moiety target molecules.1 In connection
with our research program on the development of angiotensin II receptor antagonist,2 we needed
to prepare all possible regioisomers of biphenyl derivatives and we have an interest in developing
synthetic strategies and chemistries applicable to a combinatorial approach to the molecules.3 We
previously reported the solid-phase Suzuki reaction for the synthesis of biphenyltetrazole
derivatives using a dehydropyran type linker for various functionalities such as alcohols,
imidazoles, and tetrazoles.4 However, diculties in the preparation of the dihydropyran linker
and commercial unavailability prompted us to examine a di€erent vinyl ether type linker for the
same purposes. A vinyl ether moiety has been used as a protecting group for alcohols, imidazoles,
and tetrazole functionality.5
Herein we would like to report a preliminary result on the design of a new vinyl ether type of a
linker 1 and the subsequent solid-phase synthesis, as demonstrated in the Suzuki reaction,6 for the
synthesis of biphenyl derivatives.
* Corresponding author. Fax: +82 42 861 1291; e-mail: seyoo@pado.krict.re.kr
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00927-8

6416
There are two strategies possible. One is attaching the vinyl group onto the hydroxyl group
which is already attached to the polymer, such as the Wang resin. The other way is to prepare the
vinyl ether-containing moiety ®rst and then attach the moiety to the resin. The second strategy
seems to be more logical and practical because it is not generally easy to convert the hydroxyl
group to the vinyl ether group, particularly on a solid support.
To this end, we attempted to prepare the vinyl ether derivative using 4-hydroxybenzyl alcohol,
but we found that the vinyl benzyl ether 8 was not stable due to the elimination, particularly
under the acidic conditions required for the attachment of alcohols. Since this problem was
believed to be unique for the benzylic ether type, we decided to go with a vinyl phenethyl ether
type.
As described in Scheme 1, 4-hydroxy phenethyl alcohol 3 could be eciently synthesized from
commercially available 4-hydroxy benzylic acid 3 and the subsequent vinyl ether formation
reaction was carried out successfully with ethyl vinyl ether and mercury acetate. The vinyl ether
moiety 4 was then attached to the resin under the basic condition.
Scheme 1.
With the desired vinyl ether containing resin 1 in hand, we then examined conditions for
attaching various functional groups to the polymer and found that the condition using
tri¯uoroacetic acid or pyridinium p-toluenesulfonate as a catalyst was quite satisfactory. The
eciency of these reactions was determined by monitoring the amount of compounds released
from the resin by treating the resin with 3% HCl/MeOH for 5 h (Table 1). These processes for the
attachment and detachment of the various functional groups were found to be quite general as
demonstrated with various alcohols, imidazole, and tetrazole derivatives.
Finally, we carried out the actual palladium catalyzed Suzuki reaction7 with the polymer
containing bromo compounds (6a, 6b) and aryl boronic acid, to demonstrate the practicality of
this solid-phase approach. We found that a typical Suzuki reaction provided the desired coupled
products in good overall yield without any signi®cant contamination from by-products or
starting materials (Table 2).

6417
Table 1
Table 2
In conclusion we have demonstrated that vinyl ether type linker 1 is suitable for attaching
alcohol, imidazole, and tetrazole units and also that this system is suitable for the solid-phase
Suzuki type of C C coupling reaction for the preparation of biphenyl derivatives. The
preparation of various polymer-bound biphenyl alcohol derivatives and a subsequent utilization
of these resin-bound intermediates for the synthesis of biologically interesting compounds are the
subjects for our current research.

6418
Acknowledgements
We are grateful to the Ministry of Science and Technology of Korea for ®nancial support of
this research. We also thank SunIl-EYELA Co. for providing the personal organic synthesizer
CCS-600V.
References
1. (a) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385.
(b) Terrett, N. K.; Gardner, M.; Gordon, D. W.; Kobylecki, R. J.; Steele, J. Tetrahedron 1995, 51, 8135.
(c) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555.
2. (a) Carini, D. J.; Duncia, J. V.; Aldrich, P. E.; Chiu, A. T.; Johnson, A. L.; Pierce, M. E.; Price, W. A.; Santella
III, J. B.; Wells, G. J.; Wexler, R. R.; Wong, P. C.; Yoo, S.-e.; Timmermans, P. B. M. W. M. J. Med. Chem. 1991,
34, 2525. (b) Mantlo, N. B.; Chakravarty, P. K.; Ondeyka, D. L.; Siegl, P. K. S.; Chang, R. S.; Lotti, V. J.; Faust,
K. A.; Chen, T.-B.; Schorn, T. W.; Sweet, C. S.; Emmert, S. E.; Patchett, A. A.; Greenlee, W. J. J. Med. Chem.
1991, 34, 2919. (c) De, B.; Winn, M.; Zydowsky, T. M.; Kerkman, D. J.; DeBernardis, J. F.; Lee, J.; Buckner, S.;
Warner, R.; Brune, M.; Hancock, A.; Opgenorth, T.; Marsh, K. J. Med. Chem. 1992, 35, 3714. (d) Kubo, K.;
Inada, Y.; Kohara, Y.; Sugiura, Y.; Ojima, M.; Itoh, K.; Furukawa, Y.; Nishikawa, K.; Naka, T. J. Med. Chem.
1993, 36, 1772. (e) Murrary, W. V. Chemtracts 1993, 6, 263.
3. (a) Bernstein, P. R.; Vacek, E. P. Synthesis 1987, 1133. (b) Wittenberger, S. J.; Donner, B. G. J. Org. Chem. 1993,
58, 4139. (c) Russel, R. K.; Murray, W. V. J. Org. Chem. 1993, 58, 5023.
4. Yoo, S.-e.; Seo, J.-s.; Yi, K. Y.; Gong, Y.-D. Tetrahedron Lett. 1997, 38, 1203.
5. (a) Chladek, S.; Smrt, J. Chem. Ind. (London) 1964, 1719. (b) Meyers, A. I.; Comins, D. L.; Roland, D. M.;
Henning, R.; Shimizu, K. J. Am. Chem. Soc. 1979, 101, 7104. (c) Fukuzawa, A.; Sato, H.; Masamune, T.
Tetrahedron Lett. 1987, 28, 4303.
6. (a) Suzuki, A. Pure Appl. Chem. 1985, 57, 1749. (b) Yoo, S.-e.; Yi, K. Y. Tetrahedron Lett. 1995, 36, 1679.
(c) Frentte, R.; Friesen, R. W. Tetrahedron Lett. 1994, 35, 9177.
7. See Ref. 6.