Synthesis of Vicinal Quaternary All-Carbon Centers via Acid-catalyzed Cycloisomerization of Neopentylic Epoxides

Abstract

We report our studies on the development of a catalytic cycloisomerization of 2,2-disubstituted neopentylic epoxides to produce highly substituted tetralins and chromanes. Termination of the sequence occurs via Friedel–Crafts-type alkylation of the remote (hetero)arene linker. The transformation is efficiently promoted by sulfuric acid and proceeds best in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) as the solvent. Variation of the substitution pattern provided detailed insights into the migration tendencies and revealed a competing disproportionation pathway of dihydronaphthalenes.

Recent Advances on Synthetic Methodology Merging C–H Functionalization and C–C Cleavage

“…As happened in the case of the strained systems, it is possible to perform the functionalization of C–H bonds along with the cleavage of unstrained C–C bonds in the presence of Lewis or Brønsted acids, or basic conditions. Recently, Magauer et al established an acid-catalyzed route to tetralin and chromane derivatives 648 through the cycloisomerization of neopentylic epoxides 647 ( Scheme 84 ) [ 179 ]. The presence of 10 mol% of H 2 SO 4 in HFIP promoted the opening of the epoxide ring with subsequent 1,2-migration of the neighbouring alkyl group.…”

Fluorinated alcohols: powerful promoters for ring-opening reactions of epoxides with carbon nucleophiles

“…The partitioning of mechanistic pathways leading to products 42 and 43 is consistent with carbenium ion intermediates. 42 As depicted in Figure 4, ring expansion exclusively occurs (path a) with strained cyclobutyl epoxide 41a and is favored with cyclopentyl epoxide 41b. With the unstrained cyclohexane attached to epoxide 41c, the 1,2-methyl shift (path b) exclusively occurs.…”

“…34 The Magauer laboratory reported the acid-catalyzed cycloisomerizations of neopentyl epoxides tethered to electron-rich aromatic rings. 42 In the course of cyclization of substrate 37 to tetralin product 38, a methyl group underwent 1,2-alkyl shift. Cyclizations were unsuccessful or proceeded in low yield in most solvents (Table 6, entry 1 for a representative example) but improved in fluorinated alcohol solvents, with HFIP outperforming TFE (entries 2 vs. 3).…”

“…43 Page 95 © AUTHOR(S) The phenyl substrate 39a also produced the corresponding tetralin 40a (Table 7, entry 1). 42 The reaction conditions tolerated aryl ether tethers in 39b to form chromane 40b (entry 2). With electron-donating substituents, cycloisomerization favored the para-isomers 40c-d with varying levels of regioselectivity (entries 3, 4).…”

“…Neopentyl epoxide substrates containing cycloalkyl rings showed divergent behavior, depending on the degree of ring strain (Table 8). 42 The cyclobutyl and cyclopentyl substrates 41a-41b favored the corresponding ring-expansion fused products 42a and 42b (entries 1, 2), whereas the cyclohexyl substrate 41c produced exclusively the spiro isomer 43c arising from a 1,2-methyl shift. The partitioning of mechanistic pathways leading to products 42 and 43 is consistent with carbenium ion intermediates.…”