Heteropoly Acid-catalyzed Direct Substitution of 2-Propynyl Alcohols with Sulfonamides J. S. Yadav, B. V. Subba Reddy, T. Srinivasa Rao, B. Bala. M. Krishna, and G. G. K. S. Narayana Kumar Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India (Received August 23, 2007; CL-070904; E-mail: yadavpub@iict.res.in) Direct substitution of the hydroxy group in 2-propynyl alcohols with sulfonamides has been achieved using 5 mol % of phosphomolybdic acid supported on silica gel (PMA/SiO 2 ) under mild reaction conditions to produce 2-propynyl amides in excellent yields and with high selectivity. Aryl amines are found in a number of drug molecules such as cetirizine hydrochloride (histamine H 1 -receptor), SNC80 (an opioid receptor agonist) and sertraline (anti-depressant). 1,2 The nucleophilic substitution of alcohols by amines is one of the direct and most important methods for carbon–nitrogen bond formation. However, the catalytic activation of alcohols is difficult due to the poor leaving ability of the hydroxy group. Consequently, hydroxy groups are generally transformed into the corresponding halides, carboxylates, carbonates, phospho- nates, or related compounds. 3 However, such processes inevita- bly produce stoichiometric amounts of salt waste and also substi- tution with halides requires a stoichiometric amount of base which limits their use in large scale synthesis. Therefore, the development of catalytic methods for the synthesis of amines continues to be a challenging and active area of research. 4,5 However, little has been explored on nucleophilic substitution of 2-propynyl alcohols with amides. 6,7 In most cases, either a high reaction temperature or a promoter is required to enhance the leaving ability of the hydroxy group. Thus, the direct catalyt- ic substitution of alcohols with amides using an efficient, cost- effective, and recyclable catalyst is highly desirable. Recently, the use of heteropoly acids, HPAs, as environmen- tally friendly and economically viable solid acids, is increasing continuously owing to their ease of handling, high catalytic ac- tivities, and reactivities. 8 These compounds possess unique properties, such as well-defined structure, Brønsted acidity, pos- sibility to modify their acid–base and redox properties by chang- ing their chemical composition (substituted HPAs), ability to ac- cept and release electrons, high proton mobility, etc. 9 In view of green chemistry, the substitution of harmful liquid acids by reus- able solid HPAs as catalysts in organic synthesis is the most promising application of these acids. 10 Among them, phospho- molybdic acid (PMA, H 3 PMo 12 O 40 ) is one of the less expensive and commercially available catalysts. 11 In continuation of our efforts to explore the synthetic utility of phosphomolybdic acid supported on silica gel (PMA–SiO 2 ), 12 we herein report a direct and efficient nucleophilic substitution of 2-propynyl alcohols with sulfonamides. Initially, we attempt- ed the amidation of 1,3-diphenyl-2-propyn-1-ol (1) with TsNH 2 (2) in the presence of 5 mol % of PMA/SiO 2 . The reaction went to completion at room temperature over 6.0 h to give the product, N -(1,3-diphenyl-2 - propynyl)- 4 -methyl -1-benzenesulfonamide (3A) in 86% yield (Scheme 1). This remarkable catalytic activity of PMA/SiO 2 provided the incentive for further study of reactions with different 2-pro- pynyl alcohols. Interestingly, various 2-propynyl alcohols such as 1-(2,5-dimethoxyphenyl)-3-phenyl-2-propyn-1-ol, 1-(2-naph- thyl)-2-nonyn-1-ol, 1-(4-nitrophenyl)-2-nonyn-1-ol, and 3-phen- yl-1-(2-thienyl)-2-propyn-1-ol reacted readily with sulfon- amides to provide the corresponding propargylic amides in excellent yields (Entries B–L, Table 1). In addition, doubly activated (E)-1,5-diphenyl-1-penten-4-yn-3-ol underwent facile nucleophilic substitution with sulfonamides to furnish the respective 2-propynyl amide (Entries M and N, Scheme 2, Table 1). The 2-propynyl alcohols reacted regioselectively at the 2- propynyl position. No allenic products were detected as a result of amide attack at the triple bond. Interestingly, allyl alcohols al- so reacted rapidly with TsNH 2 at room temperature to afford the corresponding allylic amides (Entries O and P, Scheme 3, Table 1). In cases of allyl alcohols (Entries M–P, Table 1), no allylic rearrangement was observed which was confirmed by NMR spectrum of the crude product. Furthermore, secondary cyclic sulfonamide, saccharin also reacted easily with 2-propynyl alco- hol (Entry D, Table 1). Other sulfonamides such as methanesul- fonamide and benzenesulfonamide were also effective substrates for this conversion. However, carbamates and carboxamides were not so effective coupling partners for this reaction. In all cases, the reactions proceeded in excellent yields with high se- lectivity and were complete within 4.0–8.0 h. In the absence of PMA/SiO 2 , no reaction was observed. This method is compati- ble with alkene, alkyne, ester, nitro, and ether functionalities. To know the effect of the solvent, the reaction was carried out in various solvents such as dichloroethane, acetonitrile, tetrahydro- furan, and ethanol. However, dichloroethane was the solvent of choice. The effects of various silica supported acid catalysts such as HClO 4 /SiO 2 ,H 2 SO 4 /SiO 2 , and NaHSO 4 /SiO 2 were tested 3A + OH 5 mol % PMA/SiO 2 DCE, r.t. NHTs Ts NH 2 Scheme 1. + 5 mol % PMA/SiO 2 DCE, r.t. NHSO 2 Ph OH 3N PhSO 2 NH 2 Scheme 2. 3O CH3 OH CH 3 NHTs + 5 mol % PMA/SiO 2 DCE, r.t. Ts NH2 Scheme 3. 1472 Chemistry Letters Vol.36, No.12 (2007) Copyright Ó 2007 The Chemical Society of Japan