Structural Studies of 2-Methyl-7-substituted Pyrazolo[1,5-a]pyrimidines Clarissa P. Frizzo, a * Marcos A. P. Martins, a Mara R. B. Marzari, a Patrick T. Campos, a Rosa M. Claramunt, b M. A ´ ngeles Garcı ´a, b Dionisia Sanz, b * Ibon Alkorta, c and Jose ´ Elguero c a Nu ´cleo de Quı ´mica de Heterociclos (NUQUIMHE), Departamento de Quı ´mica, Universidade Federal de Santa Maria, 97105-900 Santa Maria-RS, Brazil b Departamento de Quı ´mica Orga ´nica y Bio-Orga ´nica, Facultad de Ciencias, UNED, Senda del Rey 9, E-28040 Madrid, Spain c Instituto de Quı ´mica Me ´dica, CSIC, Juan de la Cierva, 3, E-28006 Madrid, Spain *E-mail: clarissa.frizzo@mail.ufsm.br or dsanz@ccia.uned.es Additional Supporting Information may be found in the online version of this article. Received September 17, 2009 DOI 10.1002/jhet.377 Published online 20 August 2010 in Wiley Online Library (wileyonlinelibrary.com). Dedicated to our friend Professor Luis Castedo on the occasion of his 70th birthday. Six pyrazolo[1,5-a]pyrimidines bearing a 7-trifluoromethyl (three compounds), a 7-trichloromethyl (two compounds), and a 7-ethoxycarbonyl (one compound) have been structurally characterized. The new X-ray structures of 2-methyl-5-(p-bromophenyl)-7-trifluoromethylpyrazolo[1,5-a]pyrimidine (3) and 2-methyl-7-trichloromethylpyrazolo[1,5-a]pyrimidine (4) are reported. The combined use of GIAO/ B3LYP/6-311þþG(d,p) calculations with NMR spectroscopy in solution and in the solid state allows to establish some general rules that can be useful for characterizing related compounds. Compounds 3 and 4 present in the solid-state interesting intra- and intermolecular halogen bonds. J. Heterocyclic Chem., 47, 1259 (2010). INTRODUCTION Pyrazolo[1,5-a]pyrimidines are purine analogues and as such have useful properties as antimetabolites in purine bio- chemical reactions. Compounds of this class have attracted wide pharmaceutical interest because their activity as inhib- itors of HMG-CoA reductase [1], COX-2 [2], AMP phos- phodiesterase [3], KDR kinase [4], and as selective periph- eral benzodiazepine receptor ligands [5] as well as antianxi- ety agents [6]. Recently, other pharmaceutical activities have been reported, for example, as compounds for the treatment of sleep disorders [7], as oncological agents [8], and estrogen receptor ligands [9]. Other activities include hypnotic [10] inhibitors of human cyclin-dependent kinase 2 [11] and high affinity for GABA A receptors [12]. These examples explain the high interest in variously substituted pyrazolo[1,5-a]pyrimidines. As a conse- quence, the synthesis of these compounds has been approached by different methods [13]. In the literature, there is a large number and variety of such type of fused heterocycles bearing a CF 3 substituent at position 7 [14] but 7-trichloromethyl substituted pyrazolo[1,5-a]pyrimi- dines are much less frequent [15]. Because most studies on these compounds are related to their synthesis or to their biological properties, we decided to devote one paper to a structural study to es- tablish the general patterns for their characterization. The six compounds 1–6 that we have analyzed are reported in Scheme 1 together with their atom numbering. V C 2010 HeteroCorporation November 2010 1259