Cu(i)-catalyzed atom transfer radical cyclization of trichloroacetamides tethered to electron-deficient, -neutral, and -rich alkenes: synthesis of polyfunctionalized 2-azabicyclo[3.3.1]nonanes

Abstract

A novel synthetic entry to 2-azabicyclo[3.3.1]nonanes based on a copper(I)-catalyzed intramolecular coupling of amino-tethered trichloroacetamides and unsaturated nitriles, esters and alkenes, as well as enol acetates, is described. A study of the reaction conditions and the scope of the process is reported.

β,β,β‐Trichloroethyl‐NH‐Enamine as Viable System for 5‐Endo‐trig Radical Cyclization via Multifaceted CuI−CuII Redox Catalysis: Single Step Synthesis of Multi‐Functionalized NH‐Pyrroles

“…An increase in the amount of Cu(I)/ tert ‐amine catalyst over the catalytic 40 mol %, due to HCl‐mediated catalyst‐deactivation, even with stronger tetradentate TMPA ligand in the 5‐ endo cyclization of α‐halo‐enamide systems to unsaturated γ‐lactam, is well‐known . Similarly, a high consumption of the AIBN (50 mol %) in Cu(I)/TPMA‐catalyzed 6‐ exo‐trig radical cyclization of trichloroacetamides, a kinetically ‘favored’ system, to 2‐azabicyclo[3.3.1]nonane rings, was reported by Bonjoch, Belderrain and co‐workers. Thus, an increase in quantity of AIBN and CuCl/PMDETA ( entry‐5 , Table ) in the cyclization of 20 a is reasonable due to two reasons.…”

Synthesis of Azabicyclic Building Blocks for Daphniphyllum Alkaloid Intermediates Featuring N‐Trichloroacetyl Enamide 5‐endo‐trig Radical Cyclizations

“…The role of AIBN is to reduce the amount of copper and ligand required for the reaction. This methodology has been employed in the synthesis of five‐membered lactams from bromoacetamides in 5‐ exo ‐ trig and 5‐ exo ‐ dig processes, as well as with electron‐deficient, ‐neutral, and ‐rich alkenes in a 6‐ exo ‐ trig radical cyclization to afford functionalized morphan systems . In an extension of this methodology to the 5‐ endo ‐ trig cyclization, trichloroacetamide 2a was submitted to the ICAR‐ATRC process to afford 3,3‐dichlorohexahydroindole 3a – 2 in 67 % yield ( Table , Entry 1 ).…”

“…This methodology has been employed in the synthesis of five-membered lactams from bromoacetamides in 5-exo-trig and 5exo-dig processes, [28] as well as with electron-deficient, -neutral, and -rich alkenes in a 6-exo-trig radical cyclization to afford functionalized morphan systems. [29] In an extension of this methodology to the 5-endo-trig cyclization, trichloroacetamide 2a was submitted to the ICAR-ATRC process to afford 3,3dichlorohexahydroindole 3a -2 in 67 % yield ( Table 1, Entry 1). In classical ATRC conditions (Entry 2), the yield of 3a -2 was lower, and even more so when the scale of the reaction was increased.…”

“…Compound 28b: 1 . 13 C-NMR (100 MHz, CDCl 3 ): 206.2 (C(5)); 176.7 (C(2)); 172.9 (CO); 137.0 (=CH); 136.8, 128.6, 127.7, and 127.3 (Ph); 116.0 (= CH 2 ); 95.8 (C(6)); 64.1 (C(8a)); 60.4 (OCH 2 ); 53.7 (C(3)); 43.9 (CH 2 Ph); 41.3 (C(3a)); 30.1 (CH 2 ); 27.7 (C(7)); 24.5 (C(4)); 21.9 (CH 3 ); 21.4 (C (8) (29). To a solution of β-keto ester 28a (32 mg, 0.08 mmol) in a mixture of DMSO (1.1 mL) and water (0.1 mL) was added LiCl (34 mg, 0.8 mmol), and the mixture was heated at 130°C for 5 h. The reaction was quenched with NaHCO 3 solution (5 mL), and extracted with Et 2 O, and washed with brine.…”

Radical Reactions in Alkaloid Synthesis: A Perspective from Carbon Radical Precursors

“…Using haloacetamides A to generate α‐carbamoyl radicals in ATRC reactions towards morphan lactams B , an initial abstraction of a halogen atom by Cu(I)[137a] or Ru(II)[137b] provided a stabilized alkyl radical Aa , thereby increasing the oxidation state of the metal. Radical Aa reacted intramolecularly with the double bond of an alkene, resulting in a new C–C bond and a less stable radical Ab .…”