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Synthesis of 1,3-Substituted Cyclobutanes by Allenoate-Alkene [2 + 2] Cycloaddition Michael L. Conner and M. Kevin Brown* Indiana University, Department of Chemistry, 800 East Kirkwood Ave, Bloomington, Indiana 47405, United States S Supporting Information *
ABSTRACT: A method for the [2 + 2] cycloaddition of terminal alkenes with allenoates is presented. This process allows for the rapid synthesis of 1,3-substituted cyclobutanes in high yield under simple and robust reaction conditions.
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and alkenes (Scheme 1C),16 we became interested in extending the applicability of this strategy to access a broad range of 1,3-
yclobutanes constitute an important class of molecules as they are useful intermediates in chemical synthesis and are present in a range of natural products and other biologically significant molecules.1−3 1,3-Substituted cyclobutanes are particularly important as they are commonly evaluated in drug discovery efforts (Figure 1). This may be due to several
Scheme 1. [2 + 2] Cycloaddition of Allenoates and Alkenes
Figure 1. Representative 1,3-substituted cyclobutanes.
attributes of the cyclobutane ring system: (1) The spatial arrangement of the substituents is relatively well-defined due to the limited flexibility of the cyclobutane ring, which can be favorable in drug design.4 (2) In most cases, the 1,3-substituted cyclobutane core is achiral and therefore enantioselective synthesis is not required.5,6 (3) 1,3-Substituted cyclobutanes have been shown to be isosteric with aromatic ring systems in molecules of pharmacological interest.7−9 Several methods have been reported to access 1,3-substituted cyclobutanes. Commonly used methods include (1) functionalization of commercially available 1,3-substituted cyclobutanes, (2) intramolecular alkylation/decarboxylation strategies utilizing malonate derivatives,10 and (3) [2 + 2] cycloadditions of two π-systems. With respect to the latter, perhaps the most common method is the [2 + 2] cycloaddition of dichloroketene and alkenes.11−13 This process is notable in that a large number of alkenes are compatible in the reaction; however, to access 1,3-substituted cyclobutanes, an additional dehalogenation step is required. Other more recent but less well-established methods include cycloadditions of thioketenes14 and an Fecatalyzed cycloaddition of dienes with terminal alkenes.15 Despite these advances, additional methods are needed, especially protocols that are simple, employ readily available reagents, and enjoy wide substrate scope. On the basis of previous work from our lab regarding catalytic enantioselective [2 + 2] cycloadditions of allenoates © XXXX American Chemical Society
substituted cyclobutanes by utilizing readily available achiral Lewis acid promoters.17 Prior work from Snider and Hoffman demonstrated the general reactivity of allenoates in [2 + 2] cycloadditions with alkenes; however, formation of 1,3substituted cyclobutanes was limited in scope and in some cases required long reaction times (Scheme 1A and B).18,19 In our previous report, we showed that 1,3-substituted cyclobutanes could be prepared; however, the scope was again limited, and in some cases, use of trifluoroethyl 2,3butadienoate, which can be difficult to prepare due to its Received: June 17, 2016
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DOI: 10.1021/acs.joc.6b01446 J. Org. Chem. XXXX, XXX, XXX−XXX
Note
The Journal of Organic Chemistry
electron-withdrawing nature of the phenyl ester as compared to that of alkyl esters. (2) Although the use of 1.5 equiv of EtAlCl2 led to optimal results, decreased Lewis acid loadings could be utilized (Table 1, compare entries 1 and 6−7). It should be noted that EtAlCl2 is inexpensive and easy to use. (3) The use of other common Lewis acids were not effective at promoting the cycloaddition (Table 1, entries 8−12). (4) Although CH2Cl2 proved to be the optimal solvent for conducting the reaction, hexanes was also effective provided that the reaction time was extended. (Table 1, compare entries 1 and 17). (5) The reaction can be carried out in concentrations higher than 0.2 M with a modest decrease in yield (Table 1, entry 18). Additionally, the reaction could be performed utilizing only the residual solvent from the EtAlCl2 (1 M in hexanes) used to promote the reaction (Table 1, entry 19). (6) Finally, the reaction could easily be carried out with benchtop solvents and reagents in air with only a modest decrease in yield, which is likely due to the sensitivity of the Lewis acid to residual water in the reaction (Table 1, entry 20). The phenyl ester allenoate was easily prepared on a large scale (>5 g) utilizing straightforward Wittig olefination of in situ-generated ketene (Scheme 2).20 The allenoate can be easily
volatility, was required (Scheme 1C). Over the course of our investigation, we discovered that phenyl 2,3-butadienoate (1) could be easily prepared and readily underwent Lewis acid promoted [2 + 2] cycloaddition with terminal alkenes using a simple Lewis acid promoter (Scheme 1D). Herein, we report the scope of this method as well as several functionalization reactions. Early efforts led to a set of optimized conditions, which are depicted in entry 1 of Table 1. Under these conditions, the Table 1. Variation Reactions Conditionsa
entry 1 2 3 4 5 6 7d 8 9 10 11 12 13 14e 15 16 17 18 19f 20g
Lewis acid/ equiv
R
alkene equiv
solvent/conc (M)b
Optimized Conditions Ph 2 CH2Cl2/0.2 Change of Ester Substituent EtAlCl2/1.5 Me 2 CH2Cl2/0.2 EtAlCl2/1.5 Et 2 CH2Cl2/0.2 EtAlCl2/1.5 Cy 2 CH2Cl2/0.2 EtAlCl2/1.5 Bn 2 CH2Cl2/0.2 Change of Lewis Acid and Equivalents EtAlCl2/1.0 Ph 2 CH2Cl2/0.2 EtAlCl2/0.5 Ph 2 CH2Cl2/0.2 Me2AlCl/1.5 Ph 2 CH2Cl2/0.2 Me3Al/1.5 Ph 2 CH2Cl2/0.2 BF3OEt2/1.5 Ph 2 CH2Cl2/0.2 TiCl4/1.5 Ph 2 CH2Cl2/0.2 SnCl4/1.5 Ph 2 CH2Cl2/0.2 Change of Reactant Equivalents EtAlCl2/1.5 Ph 1 CH2Cl2/0.2 EtAlCl2/1.5 Ph 1 CH2Cl2/0.2 Change of Solvent and Concentration EtAlCl2/1.5 Ph 2 toluene/0.2 EtAlCl2/1.5 Ph 2 MeCN/0.2 EtAlCl2/1.5 Ph 2 hexanes/0.2 EtAlCl2/1.5 Ph 2 CH2Cl2/1.0 EtAlCl2/1.5 Ph 2 EtAlCl2/1.5 Ph 2 CH2Cl2/0.2
EtAlCl2/1.5
yield (%)c 90 10 30
