Rapid Asymmetric Synthesis of Disubstituted Allenes by Coupling of Flow‐Generated Diazo Compounds and Propargylated Amines

Abstract

We report herein the asymmetric coupling of flow‐generated unstabilized diazo compounds and propargylated amine derivatives, using a new pyridinebis(imidazoline) ligand, a copper catalyst and base. The reaction proceeds rapidly, generating chiral allenes in 10–20 minutes with high enantioselectivity (89–98 % de/ee), moderate yields and a wide functional group tolerance.

Copper-catalyzed cyanothiolation to incorporate a sulfur-substituted quaternary carbon center

“…Firstly, when using 1,2-di- p -tolyldisulfane and TMSCN as the substrates, 2a was generated in 78% yield (Scheme 2, eqn (1)), which indicated that thiocyanate could be generated in a good yield under the standard conditions with TMSCN as the cyano source. To validate that the copper carbene species would promote the S–CN bond cleavage, we next mixed (1-diazoethyl) benzene 18 and 2a in the reaction system without a base. However, 3aa was generated in only 21% yield (Scheme 2, eqn (2a)), which might be due to the instability of the diazo compound at higher temperatures.…”

The Generation of Diazo Compounds in Continuous‐Flow

“…In this context, the authors reported on aliphatic substrates, propargylic alcohols, amines and two examples of the late stage functionalization of a steroid (norethindrone) and a propargylated alkaloid (quinine) ( 15 c , 15 d , Scheme b) . This concept was then extended in an enantioselective reaction using a chiral copper complex and propargylic amines providing a convenient access to homo allenic amines ( 17 ) with high enantiocontrol …”

“…[31] This concept was then extended in an enantioselectiver eactionu sing ac hiral copper complex and propargylic amines providing ac onvenient access to homo allenic amines (17)w ith high enantiocontrol. [32] Shortly after their seminalp ublication, Leya nd co-workers furthere xploredt his concept in the metal-free cyclopropanation of donor diazo compounds with dehydro amino acid derivative(19)a nd ethylidene malonates and were able to obtain ar ange of different ester-substituted cyclopropanes (20,Scheme7). Furthermore, Ley and co-workerse stablished af low protocol, which comprises the generationo ft he diazo compoundi nf low andt he consecutive cyclopropanation in a second flow reactor.…”

“…As ignificanta dvantage of this methodi st hat Scheme23. Synthesis of diazoalkanes by UV photolysisand consecutive batchr eaction with boronic acids by Ley et al basic elimination of N-nitroso compounds donord iazo compounds tube-in-tube reactoraccesstod iazomethane not reported [22] oxidation of hydrazones donor diazoc ompounds donor-acceptord iazo compounds columnp acked with MnO 2 or Ts NIK pured iazo compounds simple and straightforward up to 0.4 mmol [29][30][31][32] Bamford-Stevens reaction donor diazoc ompounds columnp acked with base pure diazo compounds up to 0.4 mmol [37] Bamford-Stevens reaction donor-acceptor diazo compounds phase separation module required pure diazo compounds not reported [39] Regitz diazo transferdonor-acceptor diazo compounds phase separation module required pure diazo compounds up to 22 gdiazo compound [43] inorganic nitrites for diazotization acceptor-onlyd iazo compounds phase separation module tube-in-tube reactorrequired pure diazoc ompounds up to 24 g/day of EDA [53] organic nitritesf or diazotization all classesphase separation module for pure diazo compounds simple setup few limitations to the nature of the diazo compound up to 275 g/day of TMSCHN 2 [65] UV-photolysis bis-donor diazo compounds flow photoreactor bench-stable precursors up to 0.5 mmol [67] the diazo compound can be obtained in an operationally very simple manner,w ithout further purification steps, in good chemicalpurity. The alternative is Bamford-Stevens reaction conditions, which enables av ery elegant entry to donor-only diazo compounds, though being limited as the diazo compound is either not furtherp urified or an in-line organic/aqueous separation module is required.…”

Cu(I)‐Catalyzed Cross‐Coupling of Diazo Compounds with Terminal Alkynes: An Efficient Access to Allenes

“…Following their previous synthesis of di ‐, and tri‐ substituted allene through the coupling of non‐stabilized flow‐generated diazo compounds with terminal alkynes, Ley and coworkers in 2017 reported catalytic asymmetric reaction using flow‐generated diazo compounds with propargylated amine derivatives in the presence of chiral pyridinebis(imidazoline) ligand/Cu(I) catalyst and base (Figure ) . The reaction proceeds rapidly, generating chiral allenes in 10–20 minutes with high enantioselectivities and a wide functional group tolerance.…”