Synthesis of ω -(1,1,3-trioxo-1,3-dihydrobenzo[ d ]isothiazol-2-yl)- alkanecarboxylic acids: conventional versus microwave heating

The alkylation of sodium saccharin with alkyl halides to produce the intermediates ω -(1,1,3-trioxo-1,3-dihydrobenzo[ d ]isothiazol-2-yl)-alkanecarboxylic acids can be markedly improved by using microwave irradiation, both in terms of product yield and reaction time. While the process produces high yields with halo esters and halonitriles, the reaction with haloacids, which proceeds smoothly by conventional reflux, gives poorer yields with microwaves. This is due to an acid-base equilibrium produced by the rapid heating of the mixture under irradiation. Esters and nitriles can be converted into the acids by acid hydrolysis, without appreciable loss of the 1,1,3-trioxo-1,3-dihydrobenzo[d]isothiazole ring.


S
Examples of the N-alkylation of saccharin using microwave irradiation in dry media 13 have been described and gave good efficiency, with the transformation completed in only a few minutes.Other N-alkylated saccharin derivatives have been obtained by microwave synthesis in DMF and were used as intermediates in the preparation of 5-HT 1A receptor ligands. 14In our examples, the synthesis 5 was performed by N-alkylation, reacting sodium saccharin with several bromoderivatives 4 in DMF.The processes were performed in parallel, either by conventional reflux or, alternatively, by microwave irradiation in closed vessels.

Results and Discussion
As observed with other systems, the preparation of saccharin derivatives 5 has been more effective with regard to reaction time and yield on using microwave irradiation (Method B).In the microwave reaction with haloacids 4a-e, however, substantial amounts of mixtures of 6 and 7 [or the corresponding salt in the case of other acids (Scheme 2), produced by an acid-base equilibrium] were detected, leading to a reduction in the overall yield of 5.The reduction in yield is more evident in the products 5a-c, in which low molecular weight acids are used that have higher dielectric parameters related to microwave energy absorption.15a It is not clear at which point the effect of microwaves on the mixture of sodium saccharin 1 and the halo acids 4 in DMF, a solvent that acts as the absorber medium, 15a can be related to a thermal effect linked to the characteristics of the acids involved.15b This situation would comparatively favour the acid-base equilibrium indicated in Scheme 2 for the smaller acids, reducing the yield in the N-substitution of saccharin.Thus, conventional reflux (Method A) resulted in better yields in the cases of 5a-c.
ARKAT USA, Inc.  Method A. Conventional reflux was performed for 3 h, at 150 ºC.Method B: Microwave irradiation was performed for 5 min at 150 ºC. a Yields correspond to isolated pure compounds.b Described in ref. 5, with 66% yield after 20 h at 100 ºC.The effect described above was not observed with esters 5g-5l and nitriles 5m-5r, in which the microwave process was more efficient than conventional heating.
In order to assess the possible interconversion of the nitriles and esters into the acids 5e-f, the conversion of nitrile 5r into the ester 5l and of 5l into the acid 5e was performed using acid catalysis.The conversion was easily performed and hydrolysis of the saccharin ring was not detected (Scheme 3).In conclusion, the alkylation of sodium saccharin (1) with halides 4 to produce derivatives 5 can be markedly improved by using microwave irradiation, both in terms of product yield and reaction time.The reaction with haloacids, however, which is very convenient under conventional reflux, produces poorer yields with microwaves -especially with the shorter acids -due to an acid-base equilibrium process competing with N-alkylation.Esters and nitriles can be converted into the acids by acid hydrolysis, without appreciable loss of the 1,1,3-trioxo-1,3dihydrobenzo[d]isothiazole ring.

Experimental Section
General Procedures.All melting points were measured in capillary tubes and are uncorrected.IR spectra were determined on KBr disks using a Nicolet Impact 410 spectrophotometer. 1 H NMR spectra were obtained at 200 MHz ( 1 H) and 125 MHz ( 13 C) using Varian Gemini 200 and Unity Plus spectrometers.Chemical shifts (δ) were determined using TMS as internal standard, and multiplicity (s, singlet; d, doublet; dd, doublet of doublets; t, triplet; q, quartet; m, multiplet) and coupling constants are indicated for each signal.HPLC-MS analyses were performed on an Agilent 1100 apparatus.A Luna C18 (150×4.6 mm) 5 µm Phenomenex chromatographic column was used, with a mobile phase formed by a triple gradient of 4% aq.formic acid (A), water (B) and acetonitrile (C).The gradient started as A (2.5%), B (93%) and C (4.5%) and in 30 min reached A (2.5%), B (4.5%) and (93%).In the mass detector, the fragmenter operated at 70 eV.Elemental analysis was performed on a LECO CHNS-932 instrument.All reactions were performed using DMF dried by routine procedures.Conventional reflux was performed in parallel with a Radley Carousel Reaction Station.MW irradiation was performed with a CEM Discover unit, using sealed 10 ml tubes, with magnetic stirring, and temperature control was fixed at 150 ºC.All yields correspond to isolated pure compounds.

Method A. Conventional heating
A mixture of 0.05 mol of anhydrous sodium saccharin and 0.05 mol of the corresponding compound 4, in 25 mL of dry DMF, was heated under reflux for 4 h.The solvent was evaporated to dryness, ice-water (10 ml) was poured into the residue and the corresponding acid derivative 5 precipitated.The products were recrystallized from the solvent indicated.