TETRAHEDRON LETTERS Tetrahedron Letters 42 (2001) 5993–5995 Pergamon Solid-phase synthesis of arylalkanolamines † T. Srinivasan, P. Gupta and B. Kundu* Medicinal Chemistry Division, Central Drug Research Institute, Lucknow 226001, India Received 26 April 2001; revised 14 June 2001; accepted 28 June 2001 Abstract—A versatile method for the solid-phase synthesis of differentially substituted arylalkanolamines has been developed using immobilized carbamates. The method has been successfully used for the synthesis of arylethanolamines and aryl- propanolamines in high yields and purities. © 2001 Elsevier Science Ltd. All rights reserved. The ability to synthesize large numbers of molecules using the combinatorial approach requires the develop- ment of methods to measure the diversity of such collections of compounds. While large diverse libraries remain a valuable source of novel lead molecules, the overall efficiency of utilizing such compound collections is usually lower than that for rationally designed, directed or pharmacophore based libraries. 1 In continu- ation of our interest in pharmacophore based libraries, 2 we targeted the solid-phase synthesis of arylalk- anolamines as they are a class of therapeutically impor- tant compounds. These prototypes are associated with a wide range of biological activities ranging from hypertension, asthma, obesity, diabetes, NMDA antag- onism, anxiety and depression. Solid-phase syntheses of alkanolamines and arylalk- anolamines have been reported in the literature. 3,4 Purandre and Poss 4 synthesized arylalkanolamines in three steps, comprising reductive alkylation of resin bound amines, alkylation of secondary amines with structurally diverse chloroacetophenones and chloro- propiophenones and, finally, reduction of the resulting ketones to alcohols. However, side reactions such as incomplete alkylation of the resin and partial quater- nary salt formation, were encountered during their solid-phase synthesis. In this paper we present a versatile solid-phase synthe- sis of arylalkanolamines 6, in particular, arylethanolamines and arylpropanolamines, from resin bound carbamates in high yields. We designed our strategy in a manner so as to have at least two compo- nents that can be independently and readily varied (Scheme 1) for introducing diversity. Our solid-phase synthesis of arylalkanolamines commences with the preparation of immobilized carbamates 2 from Wang resin and isocyanates 1 in the presence of an organic base. 5 Alternatively, carbamates 2 can be generated using carbonyldiimidazole 6,7 or 4-nitrophenyl chloroformate 8,9 and amines, but the isocyanate method resulted in higher loading and was also less cumbersome to use. Next, the immobilized carbamates 2 were reacted with phenacyl bromides 3 to afford N -alkylated carbamates 4 in quantitative yields. These reactions were efficiently performed in DMF by activa- tion of the NH group with NaH followed by addition of the phenacyl bromides and heating at 80°C for 12 h. The ketone was cleaved from the resin and character- ized by NMR. 10 The resulting immobilized ketones 4 were then smoothly reduced to the alcohols 5 using sodium borohydride in a THF–alcohol mixture. The cleavage of the final products from the resin 5 with 50% TFA–DCM afforded the arylalkanolamines 6 as enan- tiomeric mixtures in high yield ranging from 75 to 95% and purities from 85 to 93%. Further, to investigate the scope and limitation of our strategy, we synthesized a library of 12 compounds using four isocyanates, two bromoacetophenones and one 3-chloropropiophenone. The compounds were obtained in good yields with purities ranging from 85 to 93% (Table 1 and Ref. 10). The compounds were characterized using HPLC, FAB MS and NMR. 10 In summary, we have developed a versatile approach for the solid-phase synthesis of arylalkanolamines from polymer bound carbamates. It can be successfully used for the generation of libraries of arylalkanolamines. * Corresponding author. Tel.: 0091 522 212 411; fax: 0091 522 223 405; e-mail: bijoy – kundu@yahoo.com † CDRI Communication No. 6163. 0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII:S0040-4039(01)01166-2