A Versatile Room-Temperature Route to Di- and Trisubstituted Allenes Using Flow-Generated Diazo Compounds**

A copper-catalyzed coupling reaction between flow-generated unstabilized diazo compounds and terminal alkynes provides di- and trisubstituted allenes. This extremely mild and rapid transformation is highly tolerant of several functional groups.


General experimental details
All batch reactions were performed using oven-dried glassware (200 °C) under an atmosphere of air unless otherwise stated. All flow reactions were performed using a Uniqsis FlowSyn platform. 1 In-line IR spectroscopy was performed using a Mettler Toledo FlowIR ® device equipped with a SiComp (silicon) head. 2 Solvents were freshly distilled over calcium hydride and lithium aluminium hydride (THF or Et 2 O) or calcium hydride (methanol, CH 2 Cl 2 , hexane and EtOAc). Additional anhydrous solvents were obtained from commercial sources and used directly (DMF, 1,4-dioxane, 2,6-lutidine). DIPEA and Et 3 N were freshly distilled over calcium hydride and stored over 4 Å molecular sieves. All reagents were obtained from commercial sources and used without further purification.
Flash column chromatography was performed using high-purity grade silica gel (Merck grade 9385) with a pore size 60 Å and 230-400 mesh particle size under air pressure. Analytical thin layer chromatography (TLC) was performed using silica gel 60 F 254 pre-coated glass backed plates and visualized by ultraviolet radiation (254 nm) and/or potassium permanganate solution as appropriate.

Synthetic procedures and characterisation for starting materials 2.1. Hydrazone synthesis
General procedure for aldehyde-derived hydrazone formation: To a solution of aldehyde (20.0 mmol, 1.0 equiv.) in methanol (20 mL) was added hydrazine hydrate (1.2 mL, 24 mmol, 1.2 equiv.) and the mixture stirred at r.t. for 1 h. The mixture was then evaporated under reduced pressure to provide the desired hydrazone. The crude hydrazone was used for generation of the corresponding diazo compound without further purification.

General procedure for ketone-derived hydrazone formation:
To a solution of ketone (20.0 mmol, 1.0 equiv.) in methanol (20 mL) was added hydrazine hydrate (2.9 mL, 60.0 mmol, 3.0 equiv.) and the mixture stirred at 80 °C for 3 h in a sealed vial. The solvent was removed under reduced pressure and the residue diluted with water (25 mL) and CH 2 Cl 2 (25 mL). The mixture was separated, the aqueous layer extracted with CH 2 Cl 2 (3 × 25 mL) and the combined organic extracts were dried (MgSO 4 ), filtered and evaporated under reduced pressure to provide the desired hydrazone. The crude hydrazone was used for generation of the corresponding diazo compound without further purification.

Synthetic procedures and characterisation for allenes
General procedure for allene formation with aldehyde-derived hydrazones: Conditioning phase: A solution of hydrazone (0.1 M) and DIPEA (0.2 M) in CH 2 Cl 2 was passed through a column reactor (Omnifit ® column, 6.6 mm i.d. × 50 mm length), packed with activated MnO 2 (0.86 g), at a flow rate of 0.5 mL min -1 for 20 min and the reactor output was monitored using a FlowIR ® device. The flow was switched to solvent (DIPEA, 0.2 M in CH 2 Cl 2 ) for 10 min. The column was then ready for the generation of the diazo compound.
Generation phase: A vial was charged with the appropriate alkyne (0.2 mmol, 1.0 equiv.), copper (I) iodide (3.9 mg, 0.02 mmol, 0.1 equiv.), 1,4-dioxane (2 mL) and Et 3 N (0.05 mL, 0.4 mmol, 2 equiv.) and pre-mixed for 10 min. A solution of hydrazone (0.1 M) and DIPEA (0.2 M) in CH 2 Cl 2 was passed through the pre-conditioned column reactor (Omnifit ® column, 6.6 mm i.d. × 50 mm length), packed with activated MnO 2 (0.86 g), at a flow rate of 0.5 mL min -1 . When the FlowIR ® showed that the intensity of the diazo peak was stable, 3 mL of the output (1.5 equiv. with respect to the hydrazone) was directly added into the reaction vial (over 6 min) containing the copper acetylide and the reaction mixture further stirred at r.t. for 10 min. The mixture was then filtered through a pad of Celite ® , eluting with EtOAc, and the filtrate evaporated under reduced pressure. The residue was purified immediately by silica gel column chromatography to provide the desired di-substituted allene product.
Any excess diazo compound produced during the conditioning phase or the generation phase before steady-state was reached was gently quenched by directing the output of the flow reactor into a stirred suspension of copper (I) iodide (0.10 g) in MeOH (25 mL) (Figure 1).

General procedure for allene formation with ketone-derived hydrazones:
(N.B. Diazo compound generation from ketone-derived hydrazones does not require a preconditioning phase for the MnO 2 column reactor) A vial was charged with the appropriate alkyne (0.2 mmol, 1.0 equiv.), copper (I) iodide (3.9 mg, 0.02 mmol, 0.1 equiv.), 2,6-lutidine (4.6 µL, 0.04 mmol, 0.2 equiv.), 1,4-dioxane (2 mL), Et 3 N (0.05 mL, 0.4 mmol, 2 equiv.) and pre-mixed for 10 min. A solution of hydrazone (0.1 M) and DIPEA (0.2 M) in CH 2 Cl 2 was passed through the column reactor (Omnifit ® column, 6.6 mm i.d. × 50 mm length), packed with activated MnO 2 (0.86 g), at a flow rate of 0.5 mL min -1 . When the FlowIR ® showed that the intensity of the diazo peak was stable, 3 mL of the output (1.5 equiv. with respect to the hydrazone) was directly added into the reaction vial (over 6 min) containing the copper acetylide and the reaction mixture further stirred at r.t. for 10 min. The mixture was then filtered through a pad of Celite ® , eluting with EtOAc, and the filtrate evaporated under reduced pressure. The residue was purified immediately by silica gel column chromatography to provide the desired tri-substituted allene product.
Any excess diazo compound produced during the generation phase before steady-state was reached was gently quenched by directing the output of the flow reactor into a stirred suspension of copper (I) iodide (0.10 g) in MeOH (25 mL) (Figure 1).
Monitoring of the reaction mixture by FlowIR ® indicated that negligible amounts of the diazo compound remained at the end of the reaction (Figure 3). A maximum absorption intensity of 0.01 A.U. at 2039 cm -1 was detected by the end of addition of the diazo compound, decreasing back to background levels after further stirring for 10 min (in comparison, a typical ~0.1 M solution of diazo compound generated using this flow oxidation procedure has an absorption intensity of ~0.2 A.U.). (