Late-Stage Heteroarene Alkylation via Minisci Reaction with Gaseous Alkanes Enabled by Hydrogen Atom Transfer in Flow

Abstract

The late-stage functionalization of complex molecules is a pivotal strategy in drug discovery, enabling the rapid optimization of lead compounds. However, the use of gaseous alkanes as alkylating agents in these processes remains underexplored due to their inertness and handling challenges. Here we present a photocatalytic platform that facilitates the alkylation of heteroarenes using abundant gaseous C1-C4 hydrocarbons under continuous-flow conditions. Through hydrogen atom transfer (HAT) catalysis, we achieve the efficient alkylation of pharmaceutically relevant compounds without the need for prefunctionalized reagents. Our method is not only scalable and sustainable but also extends to the functionalization of marketed drugs and natural products.

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A. Late-stage functionalization of heteroarenes. B. Impact of light alkyl fragment incorporation in drugs. C. Alkylation of heteroarenes using gaseous alkanes.

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Scope of the alkylation of heteroarenes using ethane as an alkylating agents. Reaction conditions: heteroarene (0.2 mmol. 1.0 equiv), FeCl₃ (20 mol %), NFSI (1.2 equiv), LiCl (50 mol %), and TFA (3.5 equiv) in 2 mL of CH₃CN, G:L = 40:1, 144 W of 365 nm LEDs. All yields are those of isolated products (Supporting Information for experimental details). [a] TFA (2.5 equiv) and 29 W of 365 nm LEDs were used. [b] TFA (2.5 equiv), 14 W of 365 nm LEDs, and 30 min residence time. [c] TFA (2.5 equiv), 30 min residence time. [d] See Supporting Information for experimental details.

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Scope of the alkylation of heteroarenes using propane, butane, and methane as alkylating agents. Reaction conditions: heteroarene (0.2 mmol. 1.0 equiv), FeCl₃ (20 mol %), NFSI (1.2 equiv), LiCl (50 mol %), and TFA (3.5 equiv) in 2 mL of CH₃CN, G:L = 40:1, 144 W of 365 nm LEDs. All yields and regioisomeric ratios (r.r.) are those of isolated products (see Supporting Information for experimental details). [a] TFA (2.5 equiv) and 29 W of 365 nm LEDs were used. [b] See Supporting Information for experimental details. [c] Reaction conditions: heteroarene (0.3 mmol, 1.0 equiv), FeCl₂ (20 mol %), NFSI (1.2 equiv), and LiCl (50 mol %) in 3 mL of CH₃CN–TFA (3:1), G:L = 40:1, 144 W of 365 nm LEDs with 30 min of residence time. All yields are those of isolated products (see Supporting Information for experimental details). [d] Scale-up conditions: heteroarene (5.0 mmol. 1.0 equiv), FeCl₃ (20 mol %), NFSI (1.2 equiv), LiCl (50 mol %), and TFA (2.5 equiv) in 25 mL of CH₃CN (0.2 M), G:L = 20:1, 29 W of 365 nm LEDs (Supporting Information for experimental details). [e] Scale-up performed at a 1.8 mol scale.

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A) Rapid diversification of quinoxyphen using C1–C4 gaseous hydrocarbons as alkylating agents. Reaction conditions: quinoxyphen (0.2 mmol. 1.0 equiv), FeCl₃ (20 mol %), NFSI (1.2 equiv), LiCl (50 mol %), and TFA (3.5 equiv) in 2 mL of CH₃CN, G:L = 40:1, 144 W of 365 nm LEDs. All yields and regioisomeric ratio (r.r.) are those of isolated products (see Supporting Information for experimental details). [a] FeCl₂ (20 mol %), NFSI (1.2 equiv), and LiCl (50 mol %) in 2 mL of CH₃CN–TFA (3:1), G:L = 40:1, 144 W of 365 nm LEDs. B) Branched versus linear regioselectivity for propane and butane. Reaction conditions: heteroarene (0.2 mmol. 1.0 equiv), FeCl₃ (20 mol %), NFSI (1.2 equiv), LiCl (50 mol %), and TFA (3.5 equiv) in 2 mL of CH₃CN, G:L = 40:1, 144 W of 365 nm LEDs. All yields are those of isolated products, and regioisomeric ratios (r.r.) were determined by GC-MS analysis (see Supporting Information for experimental details). [a] FeCl₂ (20 mol %), NFSI (1.2 equiv), and LiCl (50 mol %) in 2 mL of CH₃CN–TFA (3:1), G:L = 40:1, 144 W of 365 nm LEDs. [b] Heteroarene (0.2 mmol. 1.0 equiv), PIFA (2.5 equiv) in 2 mL of CF₃CH₂OH, G/L = 40:1, 184 W of 456 nm LEDs. All yields are those of isolated products, and regioisomeric ratios (r.r.) were determined by GC-MS analysis (see Supporting Information for experimental details).