Dearomative (3 + 2) Cycloadditions of Unprotected Indoles

Abstract

The (3 + 2) cycloaddition of various indoles with a dithioallyl cation affords dearomatized cyclopentannulated adducts, with complete control of regioselectivity and excellent chemo- and diastereoselectivity. The success of the reaction critically relies on the use of an excess of very strong Brønsted acid, which paradoxically prevents carbocationic side reactions. The reaction tolerates sensitive functionalities such as basic amines or free hydroxyls, and we demonstrate its use in late stage derivatization of highly functionalized, unprotected indoles.

1,4-Dithianes: attractive C2-building blocks for the synthesis of complex molecular architectures

“…More recently, our group was able to extend the scope of dihydrodithiin-mediated cycloadditions to indole substrates [ 30 ]. Indoles are formal styrene analogs, with very different electronic properties and reactivity profiles, and initially gave very poor results with dihydrodithiinmethanol, with incomplete conversion to complex mixtures of diverse addition products.…”

“… Dearomative [3 + 2] cycloadditions of unprotected indoles with 1,4-dithiane-fused allyl alcohol 90 [ 30 ]. …”

“…The optimal reaction times, additives, pH, solvents, and reagents (including reagent grades) can be surprisingly substrate dependent. Nevertheless, given some experimentation, the desired chemoselective transformation can be achieved in almost all cases, including for sensitive substrates such as yohimbine-derived compound 102 [ 30 ]. A common problem is the concomitant hydrogenation of alkenes, which can be hard to avoid, as seen in the hydrodesulfurization of the daucanoid scaffold 109 ( Scheme 20a ) [ 108 ].…”

“…The direct dehydrogenation of 1,4dithiane is somewhat cumbersome [25], and, moreover, 1,4dithiane (1) is surprisingly not available in large quantities at a reasonable cost, in spite of its apparent simplicity. Our lab has found that the synthetic method for dihydrodithiins pioneered by Parham and co-workers to be the most suited (Scheme 4, 12 → 2) [28][29][30]. Parham described a ring expansion of 1,3-dithiolanes derived from α-halocarbonyls into the 1,4-dithianes which then dehydrohalogenate to afford dihydrodithiins.…”

“…The ring expansion involves a 1,2-sulfur migration of a β-haloalkylsulfide via a cyclic sulfonium intermediate, which then ring opens and eliminates the halide to give the unsaturated 1,4dithiane ring. We have found this Parham ring expansion to be the most practical preparatory procedure for 2 on large scale [30]. Thus, a simple condensation of ethane-1,2-dithiol (10) and the dimethylacetal derived from chloroacetaldehyde 11 affords the dithiolane 12.…”