Reactivity of 2-Deoxy-2-iodoglycosyl Isothiocyanates with O-, S-, and N-Nucleophiles. Synthesis of Glycopyranoso-Fused Thiazoles Joaquin Isac-Garcı ´a, Fernando Herna ´ ndez-Mateo, Francisco G. Calvo-Flores, and Francisco Santoyo-Gonza ´ lez* Instituto de Biotecnologı ´a. Departamento de Quı ´mica Orga ´ nica, Facultad de Ciencias, Campus Fuentenueva s/n, Universidad de Granada, Granada, E-18071, Spain fsantoyo@ugr.es Received July 11, 2003 Abstract: The reactivity of 2-deoxy-2-iodoglycosyl isothio- cyanates toward O- and S-nucleophiles gives an easy access to 2-deoxy-2-iodoglycopyranosyl thiocarbamates and dithio- carbamates. Internal nucleophilic displacement of the iodine by the sulfur atom in these compounds allows the prepara- tion of glycopyranoso[1,2-d]-1,3-thiazoles and glycopyranoso- [1,2-d]-1,3-thiazolidin-2-one or -2-thione. Reaction with amines or polyamines as N-nucleophiles led directly to 2-aminogly- copyranoso[1,2-d]-1,3-thiazoles without isolation of the in- termediate thioureas. Methyl 2-deoxy-2-iodoglycopyranosyl thiocarbamates also allow the synthesis of 2-deoxyglycopy- ranosyl thiocarbamates or 2-deoxy-2-iodoglycopyranosyl car- bamates. Sugar isothiocyanates are among the most versatile synthetic intermediates in carbohydrate chemistry. They play a pivotal role in the preparation of a broad series of functional groups such as amide, isonitrile, carbodiimide, and N-thiocarbonyl derivatives allowing, simultaneously, the covalent coupling of a quite unrestricted variety of structures to the saccharide part. 1-3 Moreover, isothio- cyanates are important reagents in heterocyclic chemis- try, which may be exploited in the synthesis of nucleo- sides and other N-glycosyl structures. 4-7 We have contributed to this field 8 with the development of a convenient methodology for the simultaneous introduc- tion of the iodo and isothiocyanate functionalities in a sugar molecule starting from glycals. Thus, electrophilic addition of iodine(I) thiocyanate, generated in situ from silica-supported KSCN and iodine, to the double bond leads exclusively to trans-2-deoxy-2-iodoglycopyranosyl isothiocyanates. These compounds are -iodoalkyl isothio- cyanates which constitute useful and versatile tools in the synthesis of heterocycles. 9 The simultaneous presence of two active electrophilic groups in 2-deoxy-2-iodoglycosyl isothiocyanates (type I compounds, Figure 1) enhance the reactivity of these compounds emerging as valuable starting materials. Thus, it could be anticipated that nucleophilic addition to the isothiocyanate group of O-, S-, and N-nucleophiles should give an easy access to 2-deoxy-2-iodoglycopyra- nosyl thiocarbamates, dithiocarbamates, and thioureas (type II compounds, Figure 1). Moreover, it could be expected that the sulfur atom in these compounds produces the internal nucleophilic displacement of the vicinal iodine atom allowing the preparation of glycopy- ranoso[1,2-d]-1,3-thiazoles (type III compounds, Figure 1) and glycopyranoso[1,2-d]-1,3-thiazolidin-2-one or -2- thione (type IV compounds, Figure 1). The functionality of compounds of type II can be additionally exploited for the synthesis of 2-deoxyglycopyranosyl thiocarbamates (type V compounds, Figure 1) through a reductive deha- logenation or by transformation into the corresponding carbamates (type VI compounds, Figure 1). In this paper, we report the results obtained in the experimental evaluation of these hypotheses and, as a consequence, the implementation of an easy access to a wide variety of 1,3-thiazole-fused carbohydrates. As previously described by us, 8 the monosaccharidic and disaccharidic 2-iodoglycopyranosylisothiocianates 1-4 were obtained from the corresponding glycals. We first investigated the reactions of these compounds with O- and S-nucleophiles. Thus, the reactions of 1-4 with MeOH were performed at room temperature in 1,2- dichloromethane yielding the corresponding thiocarbam- ates 5 and 7-9 in high yield (75-87%) (see Table 1, entries 1 and 3-5, respectively). Reaction with S-nucleo- philes was only carried out in the case of compound 1 using ethanethiol as nucleophile, and by this way the dithiocarbamate 6 was isolated in 95% yield (see Table 1, entry 2). It should be also mentioned that the reaction of 1 with higher alcohols (ethanol, propan-2-ol, 1,2.3,4- di-O-isopropylidene-R-D-galactopyranose) failed in all * To whom correspondence should be addressed. Phone: +34- 958248087. Fax: +34-958243186. (1) Witczak, Z. J. Adv. Carbohydr. Chem. Biochem. 1986, 44, 91- 145. (2) Garcı ´a-Ferna ´ ndez, J. M.; Ortiz-Mellet, C. Sulfur Rep. 1996, 19, 61-169. (3) Garcı ´a Ferna ´ ndez, J. M.; Ortiz Mellet, C. Adv. Carbohydr. Chem. Biochem. 1999, 55, 36-135. (4) Goodman, I. Adv. Carbohydr. Chem. 1958, 13, 215-236. (5) Naito, T.; Sano, M. Chem. Pharm. Bull. 1961, 9, 709-714. (6) Ukita, T.; Hamada, A.; Yoshida, M. Chem. Pharm. Bull. 1964, 12, 2(4), 459-465. (7) Ogura, H.; Takahashi, H. Heterocycles 1977, 8, 125-146. (8) Santoyo-Gonza ´ lez, F.; Garcı ´a-Calvo-Flores, F.; Isac-Garcı ´a, J.; Herna ´ ndez-Mateo, F.; Garcı ´a-Mendoza, P.; Robles-Dı ´az, R. Tetrahedron 1994, 50, 2877-2894. (9) Avalos, M.; Babiano, R.; Cintas, P.; Jimenez, J. L.; Palacios, J. C. Heterocycles 1992, 33, 973-1010. FIGURE 1. 202 J. Org. Chem. 2004, 69, 202-205 10.1021/jo034996i CCC: $27.50 © 2004 American Chemical Society Published on Web 12/09/2003