Electrophilic substitution in indoles. Part 13. The synthesis and rearrangement of 2-deuteriospiro[cyclopentane-3′-indolenine]

Abstract

2-Deuterioindole was prepared from N-phenylsulphonylindole by lithiation, quenching with D, O, and hydrolysis. Treatment of the 2-deuterioindole Grignard reagent with succinic anhydride gave 4-(indol-3-yl) -4-oxobutanoic acid with partial loss of the deuterium from the 2-position. 2,3-Dideuterioindole (prepared by acid-catalysed deuteriation of 2-deuterioindole) when treated in the same way, gave the indolyl oxobutanoic acid, 92% deuteriated at the indolyl 2-position. Reduction to the deuterioindolylbutanol and treatment of its toluene-p-sulphonate with potassium t-butoxide give 2-deuterio-spiro[cyclopentane-3'-(3H)indolel which was 88% deuteriated at the 2-position. The kinetics of the acid-catalysed rearrangement of the deuterioindolenine and its non-deuteriated analogue were measured and the ratio k,/k, of the pseudo-first-order rate constants was found to be 1.08, showing that the isotope effect was very small.

Strictosidine Synthase: Mechanism of a Pictet−Spengler Catalyzing Enzyme

“…12,55 Notably, direct evidence for formation of the spiroindolenine intermediate by isotopic scrambling has been observed with several indole substrates. 10,11,13,57 There is only an 8 kcal/mol barrier to form the spiroindolenine intermediate, so that if deprotonation ( Figure 1, step 5) is slower than kT/h e (−8/kT) , accessing the spiroindolenine during the course of the reaction could reasonably be expected to occur. Interestingly, the free energy landscape shows that the spiroindolenine (structure G, Figure 7) provides a relatively low-energy pathway for interconversion of cisand trans-iminium isomers.…”

“…Evidence for both mechanisms in solution exists, and the predominant mechanism is not entirely clear. [10][11][12][13] The mechanism for the enzymatic reaction is not known.…”

One-Pot Formation of Functionalized Indole and Benzofuran Derivatives Using a Single Bifunctional Ruthenium Catalyst

“…Finally we focused our attention on synthesis of deuterated heterocycles (Scheme 4). Previous attempts to make deuterated indoles required the NH to be protected [24][25][26]. It has still been difficult to deuterate both 2 and 3 positions of these heterocycles, and in fact 2,3-d 2 -benzofuran is unknown.…”

Silver(I)‐ or Copper(II)‐Mediated Dearomatization of Aromatic Ynones: Direct Access to Spirocyclic Scaffolds

“…Indolenines 6iand 6jwere also formed rapidly in excellent yields under the standard conditions ( Table 2, entries 9a nd 10). Indolenine 10 [15] was also synthesized, through ad esilylation/spirocyclization sequence,b y stirring ynone 9 with 0.2 equivalents of AgNO 3 [16] in acetone at room temperature for 16 h, affording spirocyclicc yclopentenone 10,w hich is unsubstituted at C3 (Table 2, entry 12). Thesix-membered-ring product 6k was also formed using ynone homologue 5k.I n this case,t he reaction was slower and required moderate heating (35 8 8C) in order to reach completion within 16 h, but nonetheless,t he desired product was still obtained in good yield (Table 2, entry 11).…”