Efficient Synthesis of Medium‐Sized Rings Incorporating Indole or Pyrrole Units by Samarium Diiodide Induced Cyclizations

Abstract

Samarium diiodide promoted the intramolecular reductive couplings of N-alkylated indole and pyrrole derivatives 9-12 and 14 to afford products 15-19 that incorporate seven-and eight-membered rings. They were obtained in good yields and generally with excellent diastereoselectivities. Up to four contiguous stereogenic centres are controlled in this transfor-4989 mation, which is explained by a highly ordered transition structure with the samarium alcoholate moiety preferring an equatorial position.(structures are obviously "privileged" [7] since these heterocycles are present in a myriad of pharmaceutically important compounds. [8] Scheme 2. Synthesis of precursor indoles 9-11 and pyrroles 12-14.tron transfer and subsequent regioselective protonation leading to the corresponding product. [17] Scheme 3. Formation of seven-membered heterocyclic compounds 15 and 16 by samarium diiodide induced cyclization of precursors 9 and 12.

A computational study of samarium diiodide‐induced cyclizations of N‐oxoalkyl‐substituted methyl indole‐3‐carboxylates—A rationale of the diastereoselectivity

“…Cis and trans characterize the position of the substituent R with respect to C‐7. The experiments indicate that the configuration at position C‐1 is under thermodynamic control for the protonation, but that it is under kinetic control for the alkylations because these are definitely not reversible. The protonations led to the cis ‐products 14a/b‐H with high preference, whereas the alkylations of related precursors almost exclusively provided the trans ‐products similar to 15a/b‐Me and 15a/b‐Et .…”

“…Due to a proposal of Kise's group, a pathway via an allyl type radical G/G′ was also considered as a feasible mechanistic alternative (Fig. , pathway b) . This latter mechanism is based on electrochemical experiments that used a lead cathode for the reduction, affording a much lower stereoselectivity of the cyclization with respect to C‐7 than the SmI 2 mediated reaction.…”

Samarium Diiodide Induced Cyclizations of γ‐, δ‐ and ε‐Indolyl Ketones: Reductive Coupling, Intermolecular Trapping, and Subsequent Transformations of Indolines

“…The indolyl ketones were generally obtained by simple acylation of the corresponding indole derivatives with different acid chlorides or lactones (Weinreb protocol [18] ), a procedure already described and optimized by our group. [14] For a first systematic investigation we chose 3'-methoxycarbonyl-substituted indole derivative 1, which was subjected to the standard cyclization/alkylation procedure (2.2-2.5 equiv of SmI 2 and 10.0 equiv of HMPA in THF, 3.0-10.0 equiv of trapping reagent). [18] In analogy to previous results of the cyclization of 3'-cyano-substituted indolyl ketone 3, [14d] it was possible to irreversibly trap the intermediate samarium enolate D (see Scheme 4) in the presence of HMPA with a series of electrophiles including allyl and alkyl halides or a-bromo esters (Table 1).…”

“…As described in our previously published work, the SmI 2 -induced 6-exo-trig cyclizations of 3'-methoxycarbonyl-substituted indolyl ketones proceed even in the absence of HMPA. [14,21] However, subsequent successful trapping of the enolate D requires the presence of HMPA to achieve high yields.…”

“…[12] An obvious extension of the described SmI 2 -induced cyclization-dearomatization reaction involved the employment of N-heteroaromatic ring systems, such as quinoline, [13] pyrrole, and indole derivatives. [14] The general importance of N-heterocycles, of indole derivatives in particular, [15] originates from their ubiquitous presence in natural products and pharmaceutically relevant compounds. Among these, strychnos alkaloids belong to the most fascinating indole derivatives.…”