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Abstract
Thionyl chloride (or oxalyl chloride) has been used as an efficient and cheap acid activator for one-pot synthesis of β-lactams in good to excellent yields by reaction between imines and acids in the presence of triethylamine at room temperature.
Keywords: Thionyl chloride; Oxalyl chloride; β-Lactam; Staudinger reaction; acid activator; Cycloaddition reaction
1. Introduction
Several natural and synthetic β-lactam compounds are of clinical importance because of their high antibiotic activity (Singh, 2004). In addition to their well-recognized antibiotic activity, β-lactams have been shown other biological activities as inhibitors of prostate specific antigen (Adlington, 1997), thrombin (Sutton, 2004), human cytomegalovirus protein (Gonzalez-Muniz, 2004), HIV-1 protease (Tozsera, 2005), human leukocyte elastase (Marchand-Brynaert, 2004) and cholesterol absorption (Bai, 2007), antifungal (Desai, 2006), potential antimalarials (Jarrahpour, 2011) and anticancer (Banik, 2005) properties.
There are numerous methods available for the construction of the β-lactam ring. [2+2] Cycloaddition of ketenes to imines (Staudinger reaction) is perhaps the most widely used (Staudinger, 1907). Several numbers of variousmethods have been introduced for the preparation of ketenes (Tidwell, 2006), the reaction of acyl halides with tertiary amines is the most commonly used (Jarrahpour, 2007). However, in a number of cases, the use of acyl halides produces poor results. For example, when ketenes of acyl halides contain strong electron withdrawing groups, the resulted low yields of the corresponding β- lactams are obtained (Motoyoshiya, 1988). Sometimes, the acid halides are not commercially available and they are prepared from carboxylic acids and halogenating agents such as POCl3, SOCl2 and (COCl)2. Thionyl chloride (SOCl2) has been used as solvent to convert acids into acid chlorides (Munch-Petersen, 1963). The reaction starts at once without warming but it is necessary to reflux for several hours to complete the reaction. A method has been reported whereby acid was first converted into the acid chloride using oxalyl chloride and a catalytic amount of dimethyl formamide (DMF) in dichloromethane, after 24 hours the excess oxalyl chloride was decomposed at low temperature by slow addition of excess DMF (Pal, 2011). Consequently, various methods have been developed to generate ketenes from carboxylic acids using acid activating agents such as 1,1- carbonyldi-imidazole (Nahmany, 2006), triphosgene (Deshmukh, 2002), ethyl chloroformate (Bose, 1979), trifluoroacetic anhydride (Bose, 1973), p-toluenesulfonyl chloride (Jarrahpour, 2010), phosphorus derived reagents (Bhalla, 2006), cyanuric...