Cyclopropyl Carbinol Rearrangement for Benzo‐Fused Nitrogen Ring Synthesis

Abstract

A synthetic method that relies on gold-catalysed cyclopropyl carbinol rearrangement of 2-tosylaminophenyl cyclopropylmethanols to prepare 2,3-dihydro-1H-benzo[b]azepines and 2-vinylindolines efficiently is reported. The reactions were shown to be chemoselective, with secondary and tertiary alcohol substrates exclusively providing benzo-fused five- and seven-membered ring products, respectively. The ring-forming process was also found to proceed in moderate to excellent yields under mild conditions only in the presence of the gold and silver catalyst combination. The mechanism is thought to involve activation of the alcohol by the (p-CF(3)C(6)H(4))(3)PAuCl/AgOTf (Tf = triflate) catalyst, resulting in ionization of the starting material. The tertiary carbocationic intermediate generated in situ in this manner then triggers ring-opening of the cyclopropane moiety and trapping by the tethered aniline group to give the 2,3-dihydro-1H-benzo[b]azepine. Cyclopropane ring fragmentation of the secondary carbocationic analogue, on the other hand, results in diene formation followed by subsequent intramolecular hydroamination to afford the 2-vinylindoline.

On the Oxidation of the Three‐Dimensional Aromatics [B12X12]2− (X=F, Cl, Br, I)

“…A number of possible pathways could be envisioned for the conversion of this cation species into benzo[ b ]oxepine 8 . One possibility is a concerted intramolecular 7‐ endo ‐ tet cyclization reaction between the pendant hydroxyl group and the cyclopropyl moiety along with a concomitant ring‐opening of the carbocycle to give 8 3a. Alternatively, a stepwise process may occur through the ring‐opening of the cyclopropyl group in II to produce homoallylic cationic intermediate III , which is quenched upon addition of the hydroxyl group to furnish the benzo‐fused seven‐membered ring (path a) 3h.…”

“…The chemoselective preparation of 2 H ‐chromene 9 from the alcohol 7 or benzo[ b ]oxepine 8 by extending the reaction time suggests that the process is thermodynamically controlled. It has been proposed that by increasing the reaction time beyond 3 h, cationic intermediate III may be deprotonated to give diene adduct VI (path b) 3a. Activation of the terminal alkene moiety in 1,3‐diene VI by a metal or Brønsted acid catalyst followed by protonolysis in the case of the former would then furnish 2 H ‐chromene 9 24,25…”

“…In contrast, cyclopropylmethanols have garnered substantially less scientific interest despite their versatility and potential as proelectrophiles 2–4. Recently, we disclosed the gold(I)‐catalyzed preparation of pyrrolidines 3 , benzo[ b ]azepines 5 , and indolines 6 by starting from this class of compounds [Scheme , Equations (1) and (2)] 3a,3d. Further development of this chemistry based on our work on benzo‐fused N‐heterocycles led us to propose that the cycloisomerization of readily accessible 2‐[cyclopropyl(hydroxy)methyl]phenols 7 may furnish benzo[ b ]oxepines 8 , a bioactive motif found in natural products, such as pterulone and radulanin A [Scheme , Equation (3)] 5–9.…”

Metal-Free Synthesis of Oxazinones and Their Reductive Ring Opening to Provide Cyclopropyl Carbinols

“…In total synthesis, both taxol 25 and the epothilones 26,27 have been prepared via cyclopropyl carbinol intermediates. While the utility of these compounds is evident, previous methods to generate them have revolved primarily around the addition of hydride or organometallic reagents to acylcyclopropanes 95 (Scheme 11, A), [28][29][30][31][32][33][34][35][36][37][38][39] and the addition of organometallic cyclopropyl species of the general structure 97 to carbonyl compounds 98 (Scheme 11, B). [40][41][42][43][44] The primary problem with these syntheses is the electrophilic cyclopropyl moiety and its propensity to undergo ring opening reactions (Scheme 12), thus limiting the substrate scope.…”

Intermolecular Mono‐ and Dihydroamination of Activated Alkenes Using a Recoverable Gold Catalyst

“…Copper was successfully used for diamination,3 carboamination4 and hydroamination5 reactions. The usefulness of gold6 was pointed out using alkyne1,6,7 alkene,3,8,10e,10i allene9 and diene2,10 substrates for both intra‐ and intermolecular hydroamination reactions as well as for diaminations. Mechanistic investigations into gold‐catalyzed hydroamination reactions by He et al, and later by Togni et al, have demonstrated that gold precursor was the main catalyst; no Brønsted acid was generated by reaction of cationic gold complexes with amine reagents 11.…”