World Journal of Organic Chemistry, 2017, Vol. 5, No. 1, 6-10 Available online at http://pubs.sciepub.com/wjoc/5/1/2 ©Science and Education Publishing DOI:10.12691/wjoc-5-1-2 Solvent Effects on the [3+2] Cycloaddition of 2-Furfural Oxime and Ethyl Propiolate: Unexpected Change in Regioselectivity Promi Rahman 1 , Amy Glanzer 1 , Jaffarguriqbal Singh 1 , Nanette M. Wachter 1 , Jonathan Rhoad 2 , Richard W. Denton 3,* 1 Department of Chemistry, Hofstra University, Hempstead, United States of America 2. Department of Chemistry, Missouri Western State University, St. Joseph, United States of America 3 Department of Chemistry, Barnard College, New York, United States of America *Corresponding author: rdenton@barnard.edu Abstract The effect of solvents on the 1,3-dipolar cyclization reaction between ethyl propiolate and 2-furfuryl nitrile oxide was studied in various organic solvents. As expected, the major product was ethyl-3-(2-furanyl)-5- carboxylate. The relative ratio of the 3,5- to 3,4- disubstituted isoxazoles in dichloromethane, toluene, ethanol and dimethyl sulfoxide were 3.4, 2.0, 1.9 and 1.5 respectively. Experimental regioselectivity was found to be dissimilar to density functional theory predictions. Keywords: 1,3-Dipolar cyclization, isoxazole, solvent effect, regioselectivity, density functional theory calculations Cite This Article: Promi Rahman, Amy Glanzer, Jaffarguriqbal Singh, Nanette M. Wachter, Jonathan Rhoad, and Richard W. Denton, “Solvent Effects on the [3+2] Cycloaddition of 2-Furfural Oxime and Ethyl Propiolate: Unexpected Change in Regioselectivity.” World Journal of Organic Chemistry, vol. 5, no. 1 (2017): 6-10. doi: 10.12691/wjoc-5-1-2. 1. Introduction Isoxazoles possess a wide range of biological properties including antitumor, antifungal, antibiotics, antimalarial, antituberculosis and herbicidal activities [1,2,3,4]. Classic examples include the mefloquine-isoxazole carboxylic ester 1 [1], the penicillin-resistant antibiotics oxacillin (2) [4], and the histone deacetylase (HDC) inhibitor 3 [3]. While 3,5-disubstituted isoxazoles are well-documented for their medicinal properties and as synthetic precursors [3,4,5,7], their 3,4-disubstituted counterparts are less prevalent. Notwithstanding, the latter also exhibits significant biological activities and are key starting materials for some natural products. Examples within this class of compounds include the tetrahydroindazole-isoxazole (4), a mild inhibitor of Myco-bacterium Tuberculosis [9], compound 5 (a voltage-gated sodium (NaV1.8) channel modulator) and the carboxamide carboxylic isoxazole 6, a growth inhibitor of some phytopathogenic fungi [10]. Other examples include key precursors for the biologically active natural product trachyspic acid [11]. Compounds 7 and 8 were side products prepared in an attempt to construct the perhydrophenanthrene system of the anti-inflammatory triterpenoid, celastrol [12], (Figure 1). Several methods are used to prepare isoxazoles, including the reaction of hydroxylamine with  - unsaturated carbonyl compounds [13,14] and the intermolecular [3+2] cycloaddition of alkynes and nitrile oxides [15,16]. The latter is efficient, convergent and among the more popular methods. Previous studies reveal that this type of regioselectivity favors the 3,5- to the 3,4-disubstituted adduct [13,15,16]. Molecular orbital calculations highlighted that a more favorable overlap of the HOMO of the dipolarophile and the LUMO of the dipole aligned with the selectivity observed experimentally [18,19]. Sharpless and coworkers synthesized these isoxazoles using copper as catalyst. Under these reaction conditions the 3,5-isomer were prepared selectively and with high yields [20]. Other groups have capitalized on their results and applied this method of synthesis to their research [21]. The synthesis of the 3,4-disubstituted isoxazole adduct is hardly reported in the literature [9,16,22]. The most recent citation by Chalyk and coworkers. exploited the 1,3-dipolar cycloaddition reaction between in situ generated nitrile oxides and enamines to generate 3,4- disubstituted isoxazole products [16]. Using hybrid density functional theory (DFT) calculations, the Houk’s group predicted and explained that the regioselectivity for the unfavored 3,4-isomer in the cycloaddition reaction between mesitonitrile oxide and the methyl propiolate should increase in non-polar solvents [19]. This regioselectivity was due to the lesser polar character of the 3,4-disubstutued isoxazole transition state in comparison to that of the 3,5 –disubstituted one. Herein, we report the effect of solvent on the regioselectivity of the uncatalyzed [3+2] cycloaddition reaction between the in situ generated 2-furfuryl nitrile oxide 10 and ethyl propiolate 11. DFT calculations revealed an unexpected disparity between theory and experimental regioselectivity.