Indium(III) chloride – catalyzed Michael addition of thiols to chalcones : a remarkable solvent effect

Indium(III) chloride in methanol efficiently catalyzes Michael addition of aromatic and aliphatic thiols to chalcones and related compounds. This reaction is remarkably solvent selective and it does not proceed in conventional solvents such as tetrahydrofuran, methylene chloride and water


Introduction
The Michael addition of thiols to electron deficient alkenes is a very useful process for making carbon-sulfur bond.This addition to chalcone derivatives is very interesting and challenging as it is less facile compared to the addition to aliphatic acyclic enones and thus it is not always satisfactory with the conventional reagents used for general 1,4-addition.Recently, a number of procedures involving a variety of catalysts such as synthetic diphosphate Na 2 CaP 2 O 7 , 1a natural phosphate, 1b InBr 3 , 1c fluorapatite, 1d have been reported.
Indium halides, particularly indium(III) chloride have emerged as a potent Lewis acid for various organic transformations in recent times. 2 As a part of our interest in indium(III) chloride catalyzed reactions 3 we discovered that although InCl 3 has been used in the Michael addition of silylenol ethers, 4a amines, 4b pyrroles 4c and indoles 4d to electron-deficient alkenes no report has been found demonstrating the use of InCl 3 for addition of thiols to chalcones and related systems.This prompted us to investigate this reaction and we observed that very interestingly InCl 3catalyzed addition of thiol to chalcone derivatives is very much solvent dependent and it does not proceed at all in conventional solvents like CH 2 Cl 2 , THF and H 2 O usually chosen for indium halide mediated reactions. 3,4However, we discovered that the reaction goes very efficiently in dry methanol (Scheme 1).

Results and Discussion
The experimental procedure is very simple.A solution of chalcone and thiol in dry methanol was stirred at room temperature in the presence of a catalytic amount of indium(III) chloride.Usual work up with ether furnished the product.
Aliphatic as well as aromatic thiols underwent facile additions to a variety of chalcones by this procedure to provide the corresponding adducts in high yields.The results are summarized in Table 1.The electron withdrawing and electron donating substituents on the aromatic ring of the chalcone derivatives did not influence the progress of reaction.Additionally, additions of thiophenols with different substitutions also proceed efficiently.A vinylogous chalcone (entry 12) underwent bis-additions to provide the corresponding bis-adduct.This procedure also works well with chalcone like systems where the other ends are Me in place of Ph (entries 13-15).
The reactions are in general, considerably fast, clean and high yielding.The crude products obtained are sufficiently pure and purification by filtration through a short column of silica gel is enough to get pure samples in most of the reactions.All the products were characterized by spectroscopic data (IR, 1 H and 13 C NMR) together with elemental analysis for new compounds.It has been observed that the addition does not proceed at all in the absence of indium(III) chloride.
Table 1.Michael addition of thiols to chalcone derivatives and related systems a The yields refer to those of pure isolated products characterized by spectro-scopic ( IR, 1H and 13C NMR ) data.b The yield refers to bis -addition product.
The reactions are accomplished most efficiently with 10 mol% of InCl 3 with respect to chalcone; however with the lower amount than that the reactions are found to be slow.The influence of methanol as solvent towards progress of this InCl 3 catalyzed reaction, though interesting is not unprecedented. 5n conclusion, the present procedure catalyzed by indium(III) chloride provides an efficient methodology for the Michael addition of thiols to chalcone derivatives and related systems.The mild reaction conditions (room temperature), simple operation, high yields of adducts, relatively low catalyst loading and much lower cost of indium(III) chloride compared to indium(III) bromide that has been used earlier for this conjugate addition 1c make this procedure an attractive alternative to the existing procedures.Moreover, this work demonstrates the potential of indium(III) chloride as a Lewis acid and the remarkable effect of solvent in promoting catalytic activity.

Experimental Section
General Procedures.NMR spectra were recorded on a Bruker DPX 300 instrument at 300 MHz for 1 H and at 75 MHz for 13 C NMR in CDCl 3 solutions.IR spectra were measured on a FT-8300 Shimadzu spectrometer in neat for liquids and in KBr pellet for solids.Methanol was distilled over sodium metal.Chalcones were prepared by standard procedure. 9Thiols were distilled before use.Indium(III) chloride (98%) was purchased from Aldrich and was used as such.