Tilcotil^® Studies [3+2] additions with isothiazol‐3(2H)‐one 1,1‐dioxide

Abstract

Derivatives of isothiazolL3(2H)-one 1,l -dioxide react regiospecifically with 1,3-dipolar agents. The main regiocontrolling factor is ascertained to be the C=O group of the dipolarophile. The topology of the adducts is also in general agreement with predictions based on perturbation theory. Several adducts can be aromatized to heterocyclic equivalents of saccharin, and may then be elaborated into structural analogs of tenoxicam (Tilcotil") and piroxicam (Feldene'"').1. Introduction. -The widely used anti-inflammatory drug Feldene@ (Piroxicam, 1; Scheme I ) and the more recently introduced TilcotiP (Tenoxicam, 2) are the two bestknown representatives of a new class of antirheumatic agents referred to as oxicams [ 11. A valuable synthetic approach to oxicams results from an observation by Abe et al. [ 2 ] , i.e. that the saccharin derivative 3 (Scheme I) undergoes a methoxide-induced ring enlargement to the thiazinone 4; the procedure has subsequently been extended [3] to the rearrangement of 5, which similarly yields 6. Piroxicam 1 is then obtained from 6 by a chemoselective methylation, affording 7, followed by aminolysis with 2-aminopyridine [4].

Zur Oxidation von 1,2‐Thiazolen: Ein einfacher Zugang zu 1,2‐Thiazol‐3(2H)‐on‐1,1‐dioxiden

“…Leider sind alle Versuche, eine Diels-Alder -Reaktion von 2,3-Dimethylbuta-l,3-dien und 101 zu realisieren, negativ verlaufen: Weder bei 145-205" (Bombenrohr) in CH,C12 oder in 2,3-Dimethylbuta-1,3-dien als Losungsmittel noch bei 0" in Gegenwart von BF,.Et,O wird die Bildung des gewunschten Propellans beobachtet, obwohl Diels-Alder -Reaktionen mit ahnlichen Verbindungen bekannt sind. Allerdings weisen die in der Literatur beschriebenen Dienophile des Typs 10 keine tetrasubstituierten, sondern nur di-oder trisubstituierte Doppelbindungen auf (R' = R2 = H [25] [26]; R' = H, R2 = C1 [26] und R' = C1, R2 = H [25]). Das Misslingen der Diels-Alder-Reaktion rnit 101 (R'-R2 = -(CH,),-) muss deshalb wohl rnit sterischer Hinderung der Addition an der tetrasubstituierten Doppelbindung erklart werden.…”

“…In einem weiteren Versuch, gesattigte Derivate von Verbindungen des Typs 10 herzustellen, ist lop in Analogie zu [25] in CCl, rnit 2 equiv. Br, versetzt und 18 h unter Ruckfluss erhitzt worden (Schema 3 ) .…”

Alkyne Surrogates in Cycloaddition Reactions for the Preparation of Molecules of Interest

“…Vinyl halides have been also extensively employed as alkyne surrogates in 1,3‐dipolar cycloaddition reactions. In 1989, Burri's group reported the highly regioselective synthesis of oxicam derivatives based on (3+2) cycloaddition reaction of ethyl diazoacetate or diphenylnitrile imine with 4‐bromoisothiazolone, acting as a strained cycloalkyne equivalent after final dehydrobromination [8] . More recently, Hammee II and coworkers described the preparation in good yields of 1,3,4,5‐tetrasubstituted pyrazoles by a regioselective cycloaddition reaction of nitrile imine, generated in situ from N ‐phenylbenzenehydrazonoyl chloride, with α‐bromocinnamaldehyde (Scheme 1).…”

“…In 1989, Burri's group reported the highly regioselective synthesis of oxicam derivatives based on (3 + 2) cycloaddition reaction of ethyl diazoacetate or diphenylnitrile imine with 4-bromoisothiazolone, acting as a strained cycloalkyne equivalent after final dehydrobromination. [8] More recently, Hammee II and coworkers described the preparation in good yields of 1,3,4,5tetrasubstituted pyrazoles by a regioselective cycloaddition reaction of nitrile imine, generated in situ from N-phenylbenzenehydrazonoyl chloride, with α-bromocinnamaldehyde (Scheme 1). [9] In this process, the nature of substituents on the hydrazonoyl chloride partner does not affect either the reactivity or the regioselectivity.…”

Five‐Membered Heterocycles: 1,2‐Azoles. Part 2. Isoxazoles and Isothiazoles

“…For instance, isothiazol-3(2H)-one 1,1-dioxides react with nitrile imines and nitrile oxides to give the expected cycloadducts (Scheme 9.116) [364]. In the case of reaction with azides and diazo compounds, the presence of a substituent at 4-position makes all the difference in the outcome of the reaction (Scheme 9.117) [360].…”