Iridium-catalyzed Synthesis of Saturated N-Heterocycles from Aldehydes and SnAP Reagents with Continuous Flow Photochemistry

Abstract

Commercially available tin amine protocol (SnAP) reagents provide a simple approach to the synthesis of a wide variety of saturated N-heterocycles from aldehydes. In this report, we disclose that the copper(II) promoter and hexafluoroisopropanol can be replaced by photocatalytic conditions using Ir[dF(CF)ppy](dtbbpy)PF in CHCN. Continuous flow photochemical conditions provide a clean, scalable approach to valuable products including morpholines, piperazines, thiomorpholines, diazepanes, and oxazepanes from aldehyde starting materials.

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

“…In subsequent publications of the same group, catalytic variants of the SnAP protocol were also reported, in addition to the previously reported stoichiometric ones, where a catalytic amount of Cu II is used in conjunction with a ligand, or an iridium catalyst along with irradiation in a continuous flow reaction (Figure D) …”

“…SnAP and modifications thereof, for the synthesis of morpholines. Conditions: A, (yield: 60‐94%): (a) 4 Å MS, CH 2 Cl 2 (0.2 M), 2 hours, rt; (b) Cu(OTf) 2 (1.0 equiv), 2,6‐lutidine (1.0 equiv), 4:1 CH 2 Cl 2 /HFIP (0.05 M), 12 hours, rt; B, (yield: 62%): (c) 3 Å MS, C 6 H 6 , 12 hours, 82 o C; (d) Cu(OTf) 2 (1.0 equiv), 2,6‐lutidine (1.0 equiv), 3:1 HFIP/1.2‐dichloroethane (0.05 M), 14 hours, rt; C, (yield: 38‐45%): (e) polymer bound triphenylphosphine, THF, 12 hours, 55 o C; (d) Cu(OTf) 2 (1.0 equiv), 2,6‐lutidine (1.0 equiv), 3:1 HFIP/1.2‐dichloroethane (0.05 M), 14 hours, rt; D. (yield: 39‐57%) hours, rt; (g) Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 (2.5 mol%), MeCN/2,2,2‐trifluoroethanol 1:1, blue light: (f) 4 Å MS, CH 2 Cl 2 , 2 to 1 2 …”

Morpholine As a Scaffold in Medicinal Chemistry: An Update on Synthetic Strategies

“…Later studies of the same group explored catalytic variants of the SnAP protocol, in addition to the previously reported stoichiometric ones. In these cases, either a ligand is conjugated with a catalytic amount of Cu II , or an iridium catalyst under irradiation is used, in a continuous flow reaction (Scheme ) . In general, these variations of the SnAP protocol lead to robust synthetic routes, unaffected by air and moisture, with a broad spectrum of applications.…”

“… Catalytic variants of the SnAP protocol. Reagents and conditions : a) 4 Å MS, DCM, 2–12 h, rt; b) Cu(OTf) 2 (5–20 mol %), (±)‐PhBox (5–20 mol %), HFIP, rt, 20 h, (overall yield: 32–82 %); c) Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 (2.5 mol %), MeCN/TFE 1 : 1, blue light (overall yield: 33–57 %) . (PhBox: phenyl‐bis(oxazoline), TFE: 2,2,2‐trifluoroethanol).…”

Stereocontrolled Synthesis of Functionalized Azaheterocycles from Carbocycles through Oxidative Ring Opening/Reductive Ring Closing Protocols

“…A large number of synthetic methodologies have been developed to the access of azaheterocycles including aziridines, azetidines, pyrrolidines, piperidines or azepanes . In organic and pharmaceutical chemistry, the creation of novel saturated N ‐heterocycles is a field explored deeply.…”