J. Org. Chem. 2002, 67, 2375-2377
Regioselective Lithiation and Functionalization of 3-(Benzyloxy)isothiazole: Application to the Synthesis of Thioibotenic Acid
2375 Scheme 1
Lennart Bunch, Povl Krogsgaard-Larsen, and Ulf Madsen* Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark
Scheme 2
[email protected] Received October 18, 2001
Abstract: Direct functionalization of the 3-oxygenated isothiazole heteroaromatic parental system has not yet been reported in the literature. Here, we report the first regioselective lithiation of the 5-position of 3-(benzyloxy)isothiazole (4) using LDA in diethyl ether. The versatility of the methodology was explored by quenching with a variety of electrophiles to give the desired products 7a,b,d-g in 5468% yield. Only benzoylation aiming at the synthesis of 7c was unsuccessful. Furthermore, a highly convergent synthesis of thioibotenic acid (1), the sulfur analogue of the neurotoxic natural product ibotenic acid, was carried out.
Bioisosteric modification of biological active molecules is a well-described and often used strategy in medicinal chemistry research. The 3-hydroxyisoxazole1 moiety is an extensively used carboxylic acid bioisostere.2,3 It is also found in the naturally occurring amino acid ibotenic acid,4,5 a widely used neurotoxin and pharmacological tool for studies of glutamic acid receptors (Scheme 1). Substitution of sulfur for the ring oxygen provides the parental system 3-hydroxyisothiazole, which is less acidic (pKa ∼7) and more lipophilic compared with the 3-hydroxyisoxazole group (pKa ∼5).6 On this basis, we were interested in synthesizing thioibotenic acid (1), the sulfur analogue of ibotenic acid (Scheme 1). A retro-synthetic analysis of thioibotenic acid (1) suggests the formation of the sp2-sp3 carbon-carbon bond as the key step (Scheme 2). A possible strategy would thus be selective generation of the 5-anion of suitably protected 3, followed by the addition to an imine 2.7 However, in contrast to the extensive research in the field of direct functionalization of heteroaromatic rings, no methodology has so far been reported for the functionalization of the 3-oxygenated isothiazole parental system. (1) Sørensen, U. S.; Krogsgaard-Larsen, P. Org. Prep. Proced. Int. 2001, 33, 515-564. (2) Krogsgaard-Larsen P.; Frølund, B.; Kristiansen, U.; Frydenvang, K.; Ebert, B. Eur. J. Pharm. Sci. 1997, 5, 355-384. (3) Madsen, U.; Sløk, F. A.; Johansen, T. N.; Ebert, B.; KrogsgaardLarsen, P. Curr. Top. Med. Chem. 1997, 2, 1-14. (4) Eugster, C. H. In Fortschritte der Chemie Organischer Naturstoffe XXVII; Zechmeister, L., Ed.; Springer-Verlag, New York, 1969; p 261. (5) Krogsgaard-Larsen, P.; Honore´, T.; Hansen, J. J.; Curtis, D. R.; Lodge, D. Nature 1980, 284, 64-66. (6) Frydenvang, K.; Matzen, L.; Norrby, P.-O.; Sløk, F. A.; Liljefors, T.; Krogsgaard-Larsen, P.; Jaroszewski, W. J. Chem. Soc., Perkin Trans. 2 1997, 1783-1791. (7) Recently, the synthesis of several R-aryl and R-heteroaryl glycine derivatives has been reported based on the addition of lithiated aryl and heteroaryl moieties to imine 6. Calı´, P.; Begtrup, M. Synthesis 2002, 63-66.
Scheme 3
The synthesis of 3-hydroxyisothiazole can be achieved in two steps from commercially available 3,3′-dithianedipropionic acid in moderate yield.8 Benzylation provides an easily separable mixture of the O- and N-benzylated derivatives 4 and 5, respectively (90% yield, ratio 2:1), which is in agreement with a previous study9 (Scheme 3). Selective lithiation of the 5-position of isothiazole has been accomplished using n-BuLi in diethyl ether.10 However, this strategy failed completely in the case of 4, presumably due to competing nucleophilic addition of n-BuLi to the hetereoaromatic ring. It was therefore decided to explore the use of more sterically hindered lithium amide bases. Initially, the influence of solvent on stability of the 5-lithio anion of 4 generated from LDA at -78 °C was investigated. In diethyl ether, immediate precipitation and high stability of this salt was evident, while in THF no precipitation was observed, and instead, decomposition proved to be progressing over time. Whereas only one pathway for decomposition of 5-lithio isothiazole seems reasonable, two plausible pathways can be proposed for the decomposition of 5-lithio 3-(benzyloxy)isothiazole (Scheme 4). Only benzyl alcohol was identified as a byproduct when the reaction was run in diethyl ether or in THF. No trace of benzyloxynitrile or the acidcatalyzed hydrolysis product carbamic acid benzyl ester11,12 was detected in the crude product mixture. Thus, we suggest that path b is the preferred pathway of decomposition. We then turned to investigate the influence of the steric bulk and strength of the lithium amide base and reaction time on the percentage of deuterium incorporation. However, only partial incorporation could be achieved using lithium ethylisopropyl amide (LEIA) or LDA, which (8) Beeley, N. R. A.; Harwood: L. M.; Hedger, P. C. J. Chem. Soc., Perkin Trans. 1 1994, 2245-2251 and references therein. (9) Chan, A. W. K.; Crow, W. D.; Gosney, I. Tetrahedron 1970, 26, 2497-2506. (10) Iddon, B. Heterocycles 1995, 41, 533-593. (11) Grigat, E.; Puetter, R. Chem. Ber. 1964, 97, 3018-3021. (12) Buckley, N.; Oppenheimer, N. J. J. Org. Chem. 1997, 62, 540551.
10.1021/jo0162134 CCC: $22.00 © 2002 American Chemical Society Published on Web 03/03/2002
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J. Org. Chem., Vol. 67, No. 7, 2002
Notes
Scheme 4
Table 2. Reaction of 4 with Various Electrophiles Using the General Procedure
Table 1. Investigation of Effects of Lithium Amide Base and Time on the Percentage of Deuterium Incorporationa and Degree of Decompositionb
t ) 15 min
t ) 45 min
base
4 (%)
7a (%)
BnOH
4 (%)
7a (%)
BnOH
LDA LEIA LTMP
38 67 86
57 28 9
5
