4,4-Bis(2-amino-6-methylpyrimidyl) Disulfide

[69945-13-7]  · C10H12N6S2  · 4,4-Bis(2-amino-6-methylpyrimidyl) Disulfide  · (MW 280.37)

(in combination with phosphines, induces lactonization of o-hydroxy acids1)

Physical Data: mp 207-209 °C.

Solubility: sol benzene, acetonitrile.

Form Supplied in: not available from commercial sources.

Preparative Methods: readily prepared from commercially available 2-amino-4-chloro-6-methylpyrimidine, which is treated with NaS.H2O (5 equiv) in degassed propylene glycol at 140 °C for 3 h. The solution is diluted with H2O and neutralized with acetic acid. The collected precipitate is recrystallized from ethanol, giving pure 2-amino-4-mercapto-6-methylpyrimidine, which is dimerized with iodine in boiling methanol containing potassium carbonate.

Purification: by crystallization from ethanol or chromatography on silica gel (chloroform-ethanol, 1:1).

4,4-Bis(2-amino-6-methylpyrimidyl) disulfide and Triphenylphosphine form the corresponding thioesters of o-hydroxy acids, which under high dilution conditions and in the presence of Silver(I) Perchlorate as a thiol scavenger give the corresponding macrolides (eq 1). Optimal conditions involve 1.5 equiv of both the disulfide and the phosphine, and 1.1 equiv of the silver salt, in refluxing dry benzene for 5 h.1

2,2-Dipyridyl Disulfide and related compounds have also been used as a method for macrolide formation; the addition of thiophilic metal cations and/or pyridine derivatives has been found to assist this process.2

This oxidation-reduction condensation,3 using 2,2-dipyridyl disulfide, constitutes an excellent strategy for the solid-phase synthesis of peptides. This method does not affect amino acids sensitive to oxidation, proceeds under mild conditions without the requirement of basic or acid catalysts, and has the advantages of minimizing both racemization of carboxyl component and side-reactions of certain amino acids.4 Furthermore, it has been successfully applied to phosphorylation reactions, such as the synthesis of coenzyme A,5 oligothymidilates, and nucleotide cyclic phosphates,6 and nucleotides from O2,2-cyclouridine.7

1. Nimitz, J. S.; Wollenberg, R. H. TL 1978, 3523.
2. (a) Corey, E. J.; Nicolaou, K. C. JACS 1974, 96, 5614. (b) Gerlach, H.; Thalmann, A. HCA 1974, 57, 2661. (c) Corey, E. J.; Nicolaou, K. C.; Melvin, L. S., Jr. JACS 1975, 97, 653. (d) Corey, E. J.; Nicolaou, K. C.; Melvin, L. S., Jr. JACS 1975, 97, 654. (e) Corey, E. J.; Nicolaou, K. C.; Toru, T. JACS 1975, 97, 2287. (f) Masamune, S.; Kamata, S.; Schilling, W. JACS 1975, 97, 3515. (g) Gerlach, H.; Oertle, K.; Thalmann, A.; Servi, S. HCA 1975, 58, 2036. (h) Gerlach, H.; Thalmann, A. HCA 1977, 60, 2866.
3. Mukaiyama, T.; Matsueda, R.; Suzuki, M. TL 1970, 1901.
4. Mukaiyama, T.; Matsueda, R.; Ueki, M. in The Peptides; Gross, E.; Meienhofer, J. Eds.; Academic: New York; 1979, Vol. 2, pp 383-416 (CA 1980, 93, 150 603h).
5. Hashimoto, M.; Mukaiyama, T. CL 1972, 595.
6. Mukaiyama, T.; Hashimoto, M. JACS 1972, 94, 8528.
7. Ogilvie, K. K.; Iwacha, D. J. CJC 1974, 52, 1787.

Fernando Albericio & Steven A. Kates

Millipore Corporation, Bedford, MA, USA

Ramon Eritja

CID-CSIC, Barcelona, Spain

Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.