Visible-Light Photocatalytic Difluoroalkylation-Induced 1, 2-Heteroarene Migration of Allylic Alcohols in Batch and Flow

Abstract

A convenient method for the preparation of sp³-rich heterocycles is reported. The method comprises a photocatalytic difluoroalkylation-induced 1,2-heteroarene migration of allylic alcohols. Here we describe for the first time the benefits of using flow to facilitate such migration reactions, including shorter reaction times, higher selectivities, and opportunities to scale the chemistry.

Heteroarenes are widespread in pharmaceuticals, agrochemicals, and other bioactive molecules. Hence, the functionalization of heteroarenes remains a contemporary goal within synthetic organic chemistry.¹ In recent years, there is a trend in medicinal chemistry to prepare more sp³-rich fragments (so-called “escape-from-flatland strategy”) to reduce the attrition rate in drug discovery.² To achieve this, the sp³-character of heteroarenes can be enhanced through alkylation via e.g. radical intermediates.^3,4

An intriguing approach to access synthetically useful sp³-rich heteroarenes is the difunctionalization of alkenes initiated by a radical addition followed by a heteroaryl migration.^5,6 Herein, we describe a novel 1,2-heteroarene migration induced by a photocatalytic radical difluoroalkylation. To prepare the target compounds, we developed a two-step protocol which starts from the corresponding heteroaryl ketones and includes a Grignard reaction and subsequent difluoroalkyl radical-induced migration reaction. As shown in this work, both reactions benefited substantially from continuous-flow processing.

Allylic alcohols are typically synthesized via a Grignard reaction between a heteroaryl ketone and vinyl magnesium halide. The reaction is exothermic in nature and requires strict cooling to avoid thermal runaway. Here, we have developed a continuous-flow protocol which allowed us to simultaneously handle the exotherm safely and prepare sufficient starting material for the subsequent photocatalytic migration reaction.⁷ The heteroaryl ketone was merged with vinylmagnesium bromide in a T-mixer and subsequently introduced in a capillary microreactor (ID 1.65 mm; 700 μL). To avoid microreactor clogging, the mixer and microreactor were submerged into a sonicated icebath.⁸ A broad variety of heteroaryl allylic alcohols could be prepared using a residence time of only 5 min on a 5–10 mmol scale as shown in Scheme 1; this includes 4-pyridinyl, 3-pyridinyl, 2-pyridinyl, pyrazinyl, benzothiophenyl, benzofuranyl, and thiophenyl bearing allylic alcohols. Notably, the reaction could be carried out at a higher temperature in flow (0 °C vs −78 °C in batch) which resulted in a reduced reaction time (5 min vs 2 h in batch).⁹

Scheme 1. Scope of the Continuous-Flow Grignard Synthesis of Allylic Alcohols.

Reaction conditions: Feed 1 contains 1 (5.0 mmol) in 10 mL of THF; Feed 2 contains 10 mL of vinylmagnesium bromide (1.67 M in THF). Residence time of 5 min, 0 °C, ultrasound. The reaction is quenched by saturated NH₄Cl at the outlet of the reactor. Reported yields are those obtained after column chromatography.

Carried out on a 10 mmol scale.

Residence time: 2.5 min.

With a diverse set of allylic alcohols in hand, we commenced our investigations toward a broadly applicable difluoroalkylation-induced 1,2-heteroarene migration with 2-(pyridin-4-yl)but-3-en-2-ol 2a as the benchmark substrate. Using ethyl bromodifluoroacetate 3a and Ru(bpy)₃Cl₂·6H₂O as the photocatalyst in the presence of a nitrogen base (Table 1, entries 1–3), the target product could be obtained in encouraging yields (15–55%) when the reaction mixture was subjected to blue irradiation. Switching to fac-Ir(ppy)₃ as the photocatalyst improved the yield further to 67% (Table 1, entry 4). Screening other soluble bases revealed that optimal results could be obtained with imidazole (Table 1, entry 6). Several control experiments demonstrate the need for a base, photocatalyst, and light (Table 1, entries 7–9).

Table 1. Optimization of the Reaction Conditions^a.

entry	base	photocatalyst	yieldb
1	NEt3	Ru(bpy)3Cl2·6H2O	31%
2	iPr2NEt	Ru(bpy)3Cl2·6H2O	15%
3	TMEDA	Ru(bpy)3Cl2·6H2O	55%
4	TMEDA	fac-Ir(ppy)3	67%
5	DBU	fac-Ir(ppy)3	45%
6	imidazole	fac-Ir(ppy)3	83%
7	–	fac-Ir(ppy)3	57%
8c	imidazole	–	N.D.
9d	imidazole	fac-Ir(ppy)3	N.D.

^aReaction conditions: 2a (0.2 mmol, 1 equiv), 3a (0.6 mmol, 3 equiv), base (0.4 mmol, 2 equiv), photocatalyst (1 mol %), dichloromethane (1.0 mL), 12 W blue LEDs (λ = 450 nm), room temperature, 6 h.

^bIsolated yield.

^cNo photocatalyst.

^dNo light.

Having established the optimal reaction conditions, we set out to examine the substrate scope of the developed transformation (Scheme 2). 4-Pyridine-substituted allylic alcohols bearing various R-groups were subjected to the reaction conditions resulting in the targeted compounds in good yields (R = Me, Et, Ph, 2a–c). Interestingly, performing the reaction in flow resulted in a substantial reduction (10 min in flow vs 6 h in batch) in reaction time and an increase in yield.^10,11 As a consequence of the reduced exposure to light, the reaction mixture was typically cleaner resulting in a more facile purification by column chromatography. Halides on the pyridine moiety were well tolerated providing opportunities for further functionalization via e.g. cross coupling (4d, 4f, 4g). Surprisingly, 3-substituted pyridine allylic alcohols (4e–h) could also give the aimed product smoothly. However, the yield is probably lower as a result of their lower reactivity in radical processeses.¹² 2-Substituted pyridine allylic alcohol (4i) and 2-pyrazine-substituted allylic alcohols (4j–k) underwent efficient migration under these photocatalytic conditions. Benzothiophene (4l) migrates smoothly as well under our reaction conditions. However, other electron-rich heterocycles, such as benzofuran (4m–n) and thiophene (4o), are susceptible for a double radical attack yielding the corresponding bisfunctionalized compounds in good yield. Also other difluoroalkyl radicals were able to induce the heteroaryl migrations (Scheme 3) using an analogous reaction protocol where ethyl bromodifluoroacetate (3a) was replaced with bromodifluorophosphonate (yielding compound 5a), or various bromodifluoroacetamides (yielding compounds 5b–d).

Scheme 2. Substrate Scope of the Photocatalytic Radical-Induced Heterocycle Migration–Variation of the Allylic Alcohol Substrate.

Reaction conditions in batch: 2a (0.2 mmol), 3a(0.6 mmol), imidazole (0.4 mmol), Ir(ppy)₃ (1 mol %), CH₂Cl₂ (1.0 mL), 12 W blue LEDs (λ = 450 nm), room temperature, 6 h. Reaction conditions in flow: 2a (0.5 mmol), 3a (1.5 mmol), imidazole (1.0 mmol), Ir(ppy)₃ (1 mol %), CH₂Cl₂ (5.0 mL), 12 W blue LEDs (λ = 450 nm), room temperature, residence time: 10 min. Reported yields are those obtained after column chromatography.

Residence time: 15 min.

Residence time: 20 min.

Residence time: 5 min.

Scheme 3. Substrate Scope of the Photocatalytic Radical-Induced Heterocycle Migration–Variation of the Difluoroalkyl Radical Precursor.

Reaction conditions: 2a (1.0 mmol), 3a (3.0 mmol), Ir(ppy)3 (1 mol %), imidazole (2.0 mmol), CH₂Cl₂ (1.0 mL), 12 W blue LEDs (λ = 450 nm), room temperature, residence time: 10 min. Reported yields are those obtained after column chromatography.

Based on the experimental data, a plausible mechanism is suggested in Figure 1. Upon light excitation, fac-[Ir(ppy)₃]* can be oxidatively quenched by ethyl bromodifluoroacetate, generating the corresponding difluoroalkyl radical species.¹³ Indeed, radical trapping experiments with BHT (2,6-di-tert-butyl-4-methylphenol) showed that this species could be effectively captured (see Supporting Information). The radical subsequently adds to the olefin generating intermediate A, which undergoes 1,2-heterocycle migration via a key spiro radical intermediate B to produce C. Finally, the intermediate C was oxidized to obtain the aimed product 4a.

Figure 1.

Proposed mechanism for the photocatalytic radical-induced heterocycle migration.

In summary, we have developed a novel photocatalytic 1, 2-heterocycle migration method which allows preparation of heterocycles with an sp³-enriched character. A variety of synthetically useful β-difluorinated α-aryl heterocyclic ketones can be easily prepared under mild reaction conditions with excellent regioselectivity. The application of continuous flow allows a reduction in the reaction time (from 6 h to 10 min) and provides higher reaction selectivity and potential for scaling the chemistry. Also interesting, the allylic alcohol substrates were prepared in flow via a classical Grignard reaction. The flow method enables safe handling of the reaction exotherm and allows preparation of sufficient quantities of starting material for the consecutive migration chemistry.

Experimental Section

All components as well as reagents and solvents were used as received without further purification, unless stated otherwise. Reagents and solvents were bought from Sigma-Aldrich, Acros Organics, Alfa Aesar, ABCR, and TCI Chemicals. Photocatalyst fac-Ir(ppy)₃ (99%) was bought from Sigma-Aldrich. Technical solvents were bought from VWR International and used as received. Product isolation was performed using silica (60, F254, Merck), and TLC analysis was performed using silica on aluminum foil TLC plates (F254, Supelco Sigma-Aldrich) with visualization under ultraviolet light (254 and 365 nm) or appropriate TLC staining. NMR (¹H, ¹³C, and ¹⁹F) analyses were performed on a Bruker-Avance 400 (400 MHz) in solvent CDCl₃. ¹H NMR spectra are reported in parts per million (ppm) downfield relative to CDCl₃ (7.27 ppm). All ¹³C NMR spectra are reported in ppm relative to CDCl₃ (77.00 ppm). NMR spectra uses the following abbreviations to describe the multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = double doublet, td = triple doublet, dt = double triplet, dq = doublet of quartets, brs = broad singlet, dddd = doublet of doublet of doublet of doublets, ddd = doublet of doublet of doublets, dtd = doublet of triplet of doublets. Mass spectra were recorded on a Finnigan MAT 4200S, a Bruker Daltonics Micro TOF, and a Waters Micromass Quatro LCZ (ESI); peaks are given in m/z (% of basis peak). The batch and flow reactions were carried out using 123-LEDs, stripe blue 2.5 m, 12 W. The strips were wrapped on the inside of a 3D printed beaker.¹⁴

General Procedure for the Preparation of the 2-Heterocycle-but-3-en-2-ol Substrates in Flow

Heterocyclic ketone (5.0 mmol, 1.0 equiv) was dissolved in 10 mL of THF, which was subsequently degassed 3 times (freeze–pump–thaw: cooled to −78 °C and degassed via vacuum evacuation (5 min), backfilled with argon, and warmed to room temperature) and taken up in a first syringe. Next, 6 mL of vinylmagnesium bromide (1 M in THF) was dissolved in 4 mL of THF and taken up in a second syringe. These two syringes (10 mL) were mounted onto a single syringe pump. The reaction mixture was pumped through the PFA capillary microreactor (ID = 1.65 mm, 65 cm), which was submerged in an ice water bath, which was sonicated to prevent microreactor clogging. The flow rate is 0.14 mL/min, which corresponds to a residence time of 5 min. The quenching solvent is saturated NH₄Cl water solution (Flow rate = 0.21 mL/min). The quenched solution was collected at the end of the reactor and was subsequently extracted by diethyl ether (3 × 30 mL). The combined organic layers were washed with brine and dried with MgSO₄. The product was purified via flash column chromatography using DCM/Acetone or cyclehexane/EtOAc as eluent.

2-(Pyridin-4-yl)but-3-en-2-ol (2a)

The flow experiment was carried out on a 10.0 mmol scale; 1.3 g of product was isolated as a white solid (87% yield). Purification: Column chromatography (CH₂Cl₂/acetone = 30:1). Mp = 88–92 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.57 (d, J = 4.0 Hz, 2H), 7.41 (d, J = 4.0 Hz, 2H), 6.17–6.10 (m, 1H), 5.33 (d, J = 16.0, 1H), 5.22 (d, J = 12.0, 1H), 2.36 (brs, 1H), 1.65 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 155.6, 149.5, 149.4, 143.4, 120.4, 113.7, 74.1, 29.1. HRMS (ESI) m/z: [M + H]⁺ calcd for C₉H₁₂NO, 150.0919; found, 150.0921.

3-(Pyridin-4-yl)pent-1-en-3-ol (2b)

The flow experiment was carried out on a 5.0 mmol scale; 749.8 mg of product were isolated as a yellowish oil (92% yield). Purification: Column chromatography (CH₂Cl₂/acetone = 30:1). ¹H NMR (400 MHz, CDCl₃): δ 8.49 (d, J = 4.0 Hz, 2H), 7.37 (d, J = 4.0 Hz, 2H), 6.13 (dd, J = 16.0, 8.0 Hz, 2H), 5.32 (d, J = 16.0 Hz, 1H), 5.20 (d, J = 12.0 Hz, 1H), 2.36 (brs, 1H), 1.92–1.87 (m, 2H), 0.83 (t, J = 8.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 155.0, 150.7, 149.2, 143.0, 120.8, 113.8, 34.4, 7.6. HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₀H₁₄NO, 164.1075; found, 164.1074.

1-Phenyl-1-(pyridin-4-yl)prop-2-en-1-ol (2c)

The flow experiment was carried out on a 5.0 mmol scale; 759.5 mg of product were isolated as a white solid (72% yield). Purification: Column chromatography (CH₂Cl₂/acetone = 16:1). Mp = 134–136 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.49 (t, J = 4.0 Hz, 2H), 7.36–7.34 (m, 7H), 6.51–6.44 (m, 1H), 5.41–5.34 (m, 2H), 3.10 (brs, 1H). ¹³C NMR (100 MHz, CDCl₃): δ 155.0, 149.1, 144.5, 142.1, 128.5, 127.9, 126.9, 121.8, 115.5, 78.6. HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₄H₁₄NO, 212.1075; found, 212.1075.

2-(2-Chloropyridin-4-yl)but-3-en-2-ol (2d)

The flow experiment was carried out on a 5.0 mmol scale; 494.1 mg of product were isolated as a white solid (54% yield). Purification: Column chromatography (CH₂Cl₂/acetone = 20:1). Mp = 54–56 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.15 (d, J = 4.0 Hz, 1H), 7.39–7.38 (m, 1H), 7.23 (dd, J = 8.0, 4.0 Hz, 1H), 6.00 (m, 1H), 5.24 (dd, J = 16.0 Hz, 1H), 5.12 (d, J = 12.0 Hz, 1H), 3.64 (s, 1H), 1.54 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 159.4, 151.4, 149.0, 142.8, 121.1, 119.4, 114.0, 73.8, 28.8. HRMS (ESI) m/z: [M + H]⁺ calcd for C₉H₁₁ClNO, 184.0529; found, 184.0530.

2-(Pyridin-3-yl)but-3-en-2-ol (2e)

The flow experiment was carried out on a 5.0 mmol scale; 662.8 mg of product were isolated as a white solid (89% yield). Purification: Column chromatography (CH₂Cl₂/acetone = 8:1 to 2:1). Mp = 27–29 °C. ¹H NMR (400 MHz, CDCl₃): δ 8.63 (s, 1H), 8.41–8.39 (m, 1H), 7.76 (dd, J = 16.0, 4.0 Hz, 1H), 7.29–7.26 (m, 1H), 6.20–6.13 (m, 1H), 5.32 (d, J = 16.0 Hz, 1H), 5.20 (d, J = 12.0 Hz, 1H), 2.85 (brs, 1H), 1.68 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 147.8, 147.0, 144.1, 144.0, 142.0, 133.4, 123.2, 113.4, 113.3, 73.5, 29.4. HRMS (ESI) m/z: [M + H]⁺ calcd for C₉H₁₂NO, 150.0919; found, 150.0918.

2-(6-Bromopyridin-3-yl)but-3-en-2-ol (2f)

The flow experiment was carried out on a 5.0 mmol scale; 669.5 mg of product were isolated as a yellow oil (59% yield). Purification: Column chromatography (CH₂Cl₂/acetone = 20:1). ¹H NMR (400 MHz, CDCl₃): δ 8.55 (s, 1H), 8.50 (s, 1H), 7.99–7.98 (m, 1H), 6.15–6.08 (m, 1H), 5.35–5.20 (m, 2H), 3.21(brs, 1H), 1.66 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 148.8, 145.2, 144.0, 143.4, 136.1, 120.6, 113.9, 73.0, 29.3. HRMS (ESI) m/z: [M + H]⁺ calcd for C₉H₁₁BrNO, 228.0024; found, 228.0025.

2-(5-Bromopyridin-3-yl)but-3-en-2-ol (2g)

The batch experiment was carried out on a 5.0 mmol scale; 374.0 mg of product were isolated as a brown oil (33% yield). Purification: Column chromatography (DCM/Acetone = 20:1). ¹H NMR (400 MHz, CDCl₃): δ 8.44 (s, 1H), 7.67 (dd, J = 8.0, 4.0 Hz, 1H), 7.44 (J = 8.0, 1H), 6.12 (dd, J = 16.0, 8.0 Hz, 1H), 5.33–5.21 (m, 2H), 2.18 (m, 1H), 1.66 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 147.7, 143.4, 141.2, 140.5, 136.1, 127.5, 113.9, 73.3, 29.4. HRMS (ESI) m/z: [M + H]⁺ calcd for C₉H₁₁BrNO, 228.0024; found, 228.0025.

3-(Pyridin-3-yl)pent-1-en-3-ol (2h)

The flow experiment was carried out on a 5.0 mmol scale (residence time: 10 min); 676.4 mg of product were isolated as a yellow oil (83% yield). Purification: Column chromatography (CH₂Cl₂/acetone = 8:1 to 2:1). ¹H NMR (400 MHz, CDCl₃): δ 8.62(s, 1H), 8.42–8.39(m, 1H), 7.78(dd, J = 8.0, 4.0 Hz, 1H), 7.26–7.22 (m, 1H), 6.19–6.12 (m, 1H), 5.32 (d, J = 16.0 Hz, 1H), 5.20 (d, J = 8.0 Hz, 1H), 3.48 (brs, 1H),1.96–1.89 (m, 2H), 0.84 (t, J = 8.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 147.8, 147.2, 143.3, 141.1, 133.7, 123.0, 113.5, 75.7, 34.6, 7.7. HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₀H₁₄NO, 164.1075; found, 164.1078.

1-(Pyridin-2-yl)hexan-1-one (1i)

The compound was made according to a literature procedure.¹⁵¹H NMR (400 MHz, CDCl₃): δ 8.68 (d, J = 4.0 Hz, 1H), 8.04 (d, J = 4.0 Hz, 1H), 7.82 (t, J = 8.0 Hz, 1H), 7.46 (dd, J = 8.0, 4.0 Hz, 1H), 3.22 (t, J = 8.0 Hz, 2H), 1.73 (t, J = 8.0 Hz, 2H), 1.40–1.36 (m, 4H), 0.92–0.88 (m, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 202.1, 153.5, 148.8, 136.9, 126.9, 121.8, 37.7, 31.5, 23.6, 22.5, 13.9.

3-(Pyridin-4-yl)oct-1-en-3-ol (2i)

The flow experiment was carried out on a 5.0 mmol scale; a 1.0 g mixture of product and starting material (5:1 based on HNMR) was obtained as a yellow oil (80% yield). Purification: Column chromatography (CH₂Cl₂/acetone = 8:1 to 2:1). ¹H NMR (400 MHz, CDCl₃): δ 8.55–8.52 (m, 1H), 7.76–7.73 (m, 1H), 7.39–7.36 (m, 1H), 7.26–7.23 (m, 1H), 6.12 (dd, J = 16.0, 8.0 Hz, 1H), 5.42 (d, J = 16.0 Hz, 1H), 5.34 (br s, 1H), 5.13 (d, J = 16.0 Hz, 1H), 1.92–1.87 (m, 2H), 1.46–1.37 (m, 2H), 1.28–1.20 (m, 4H), 0.84 (t, J = 4.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 162.5, 148.9, 143.0, 136.8, 126.9, 122.3, 121.7, 120.5, 113.8, 76.3, 41.2, 32.0, 22.9, 14.0. HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₃H₂₀NO: 206.1545; found, 206.1542.

2-(Pyrazin-2-yl)but-3-en-2-ol (2j)

The flow experiment was carried out on a 5.0 mmol scale; 390.0 mg of product were isolated as a colorless oil (52% yield). Purification: Column chromatography (CH₂Cl₂/acetone = 20:1). ¹H NMR (400 MHz, CDCl₃): δ 8.77 (s, 1H), 8.51–8.50 (m, 2H), 6.20–6.12 (m, 1H), 5.42–5.38 (m, 1H), 5.21–5.18 (m, 1H), 3.95 (brs, 1H), 1.69 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 159.3, 143.0, 142.9, 142.4, 142.3, 113.8, 73.7, 28.1. HRMS (ESI) m/z: [M + H]⁺ calcd for C₈H₁₁N₂O, 151.0871; found, 151.0872.

2-(3-Methylpyrazin-2-yl)but-3-en-2-ol (2k)

The flow experiment was carried out on a 5.0 mmol scale; 500.0 mg of product were isolated as a colorless oil (61% yield). Purification: Column chromatography (CH₂Cl₂/acetone = 30:1). ¹H NMR (400 MHz, CDCl₃): δ 8.41–8.30 (m, 2H), 6.09–6.01 (m, 1H), 5.66 (brs, 1H), 5.36–5.20 (m, 2H), 2.65–2.64 (m, 3H), 1.67 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 155.9, 152.1, 142.5, 141.3, 138.8, 114.7, 73.3, 25.7, 25.5. HRMS (ESI) m/z: [M + H]⁺ calcd for C₉H₁₃N₂O, 165.1028; found, 165.1029.

2-(Benzo[b]thiophen-2-yl)but-3-en-2-ol (2l)

The flow experiment was carried out on a 5.0 mmol scale; 867.0 mg of product were isolated as a transparent oil (85% yield). Purification: Column chromatography (Cyclohexane/EtOAc = 20:1). ¹H NMR (400 MHz, CDCl₃): δ 7.81–7.69 (m, 2H), 7.35–7.29 (m, 2H), 7.18 (s, 1H), 6.27 (dd, J = 17.2, 10.6 Hz, 1H), 5.42 (dd, J = 17.2, 0.9 Hz, 1H), 5.22 (dd, J = 10.6, 0.9 Hz, 1H), 1.80 (s, 3H) . ¹³C NMR (100 MHz, CDCl₃): δ 152.2, 143.5, 139.7, 139.5, 124.3, 124.1, 123.5, 122.3, 119.7, 113.1, 73.7, 30.0. HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₂H₁₃SO, 205.0687; found, 205.0686.

2-(Benzofuran-2-yl)but-3-en-2-ol (2m)

The flow experiment was carried out on a 5.0 mmol scale; 723.8 mg of product were isolated as a colorless oil (77% yield). Purification: Column chromatography (Cyclohexane/EtOAc = 4:1). ¹H NMR (400 MHz, CDCl₃): δ 7.56–7.46 (m, 2H), 7.28–7.22 (m, 2H), 6.63(s, 1H), 6.25 (dd, J = 17.3, 10.6 Hz, 1H), 5.41 (dd, J = 17.3, 0.8 Hz, 1H), 5.25 (dd, J = 10.6, 0.9 Hz, 1H), 2.38 (brs, 1H), 1.76 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 161.0, 145.3, 144.0, 141.7, 129.8, 123.4, 113.8, 113.4, 106.3, 102.2, 71.8, 55.9, 26.9. HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₂H₁₃O₂, 189.0916; found, 189.0916.

2-(7-Methoxybenzofuran-2-yl)but-3-en-2-ol (2n)

The flow experiment was carried out on a 5.0 mmol scale; 870 mg of product were isolated as a colorless oil (80% yield). Purification: Column chromatography (Cyclohexane/EtOAc = 4:1). ¹H NMR (400 MHz, CDCl₃): δ 7.15–7.14 (m, 2H), 6.79 (dd, J = 5.1, 4.0 Hz, 1H), 6.62 (s, 1H), 6.26 (dd, J = 16.0, 8.0 Hz, 1H), 5.40 (d, J = 20.0 Hz, 1H), 5.23 (d, J = 8.0 Hz, 1H)), 4.00 (s, 3H), 2.50 (brs, 1H), 1.76 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 161.0, 145.3, 144.0, 141.7, 129.8, 123.4, 113.8, 113.4, 106.3, 102.2, 71.8, 55.9, 26.9. HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₃H₁₅O₃, 219.1021; found, 219.1021.

2-(Thiophen-2-yl)but-3-en-2-ol (2o)

The flow experiment was carried out on a 5.0 mmol scale; 270.0 mg of product were isolated as a colorless oil (35% yield). Purification: Column chromatography (Cyclohexane/EtOAc = 4:1). ¹H NMR (400 MHz, CDCl₃): δ 7.24 (dd, J = 4.0, 2.3 Hz, 2H), 6.97–6.96 (m, 2H), 6.23 (d, J = 16.0, 8.0 Hz, 1H), 5.40–5.16 (m, 2H), 2.18 (brs, 1H), 1.75 (s, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 151.6, 144.0, 126.7, 124.6, 123.2, 112.5, 73.3, 30.2. HRMS (ESI) m/z: [M + H]⁺ calcd for C₈H₁₁OS, 155.0531; found, 155.0529.

General Procedure for the Photocatalytic 1,2-Heterocycle Migration in Batch

An oven-dried reaction tube (7.5 mL) was charged with 2-heterocycle-but-3-en-2-ol 2 (0.2 mmol, 1.0 equiv), ethyl bromodifluoroacetate (0.6 mmol, 3.0 equiv), fac-Ir(ppy)₃ (1.3 mg, 1.0 mol %), imidazole (27.3 mg, 0.4 mmol, 2 equiv), and a magnetic stirring bar in dichloromethane (1.0 mL), sealed with a rubber septum, and subsequently degassed 3 times (freeze–pump–thaw: cooled to −78 °C and degassed via vacuum evacuation (5 min), backfilled with argon, and warmed to room temperature). Next the reaction mixture was irradiated with blue LEDs (at approximately 1 cm distance from the light source). The temperature in the reactor was kept at room temperature using pressurized air. After 6 h, the reaction mixture was transferred to a 50 mL flask with about 20 mL of CH₂Cl₂. The solvent was subsequently removed under reduced pressure, and the residue was purified by silica gel column chromatography using dichloromethane/acetone to give the desired product.

General Procedure for the Photocatalytic 1,2-Heterocycle Migration in Flow

2-Heterocycle-but-3-en-2-ol 2 (1.0 mmol, 1.0 equiv), ethyl bromodifluoroacetate (3.0 mmol, 3.0 equiv), fac-Ir(ppy)₃ (6.5 mg, 1.0 mol %), imidazole (136.2 mg, 2.0 mmol, 2 equiv), and a magnetic stirring bar in dichloromethane (10.0 mL) were combined and subsequently degassed 3 times (freeze–pump–thaw: cooled to −78 °C and degassed via vacuum evacuation (5 min), backfilled with argon, and warmed to room temperature). This reaction mixture was then transferred into a syringe (10 mL) and mounted onto a syringe pump. The reaction mixture was pumped through the microreactor with the desired flow rate (0.053 mL min^–1). The microreactor assembly was irradiated with a blue LED array (1.5 × 3.12 W) at room temperature. The continuous reaction was allowed to reach steady state prior to collection of the product fractions. A standard residence time of 10 min was utilized. The crude product was collected at the end of the reactor. Workup and purification were done following the batch procedure.

Ethyl 2,2-Difluoro-5-oxo-4-(pyridin-4-yl)hexanoate (4a)

The batch reaction was carried out on a 0.2 mmol scale, and the flow experiment was carried out on a 0.5 mmol scale (2.5 mL liquid was taken); 44.9 mg and 61.7 mg were obtained in batch and flow (83%, 91% yields). The product was a yellow oil. Purification: Column chromatography (CH₂Cl₂/Acetone = 30:1). ¹H NMR (400 MHz, CDCl₃): δ 8.53 (t, J = 4.0 Hz, 2H), 7.11–7.09 (m, 2H), 4.13 (dq, J = 8.0, 4.0 Hz, 2H), 3.97 (dd, J = 8.0, 4.0 Hz, 1H), 3.03 (dtd, J = 17.2, 15.3, 5.6 Hz, 1H), 2.27 (dtd, J = 17.2, 15.3, 5.6 Hz, 1H), 2.05 (s, 3H), 1.24 (t, J = 8.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 203.9, 163.5 (t, J = 33.0 Hz), 150.6, 146.1, 123.3, 114.8 (t, J = 250.0 Hz), 63.1, 51.7 (t, J = 3.0 Hz), 36.2 (t, J = 23.0 Hz), 29.0, 13.7. ¹³F NMR (376 MHz, CDCl₃): δ −104.67 to −104.80(m). HRMS (EI) m/z: [M + H]⁺ calcd for C₁₃H₁₆F₂NO₃, 272.1098; found, 272.1080.

Ethyl 2,2-Difluoro-5-oxo-4-(pyridin-4-yl)heptanoate (4b)

The batch reaction was carried out on a 0.2 mmol scale, and the flow experiment was carried out on a 0.5 mmol scale (3.2 mL liquid was taken); 50.7 mg and 88.0 mg of product were obtained in batch and flow as a pale yellow oil (89%, 97% yields). Purification: Column chromatography (CH₂Cl₂/Acetone = 30:1 to 10:1). ¹H NMR (400 MHz, CDCl₃): 8.60 (d, J = 4.0 Hz, 2H), 7.20 (d, J = 4.0 Hz, 2H), 4.38–4.15 (m, 2H), 4.06 (dd, J = 7.7, 5.3 Hz, 1H), 3.19–3.05 (m, 1H), 2.61–2.36 (m, 2H), 2.40–2.20 (m, 1H), 1.32 (t, J = 8.0 Hz, 3H), 1.00 (t, J = 8.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 206.8, 163.5 (t, J = 32.0 Hz), 150.1, 146.9, 123.4, 114.8 (t, J = 250.0 Hz), 63.2, 50.8 (t, J = 3.0 Hz), 36.6 (t, J = 23.0 Hz), 35.3, 13.8. ¹⁹F NMR (376 MHz, CDCl₃): δ −104.79(m). HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₄H₁₇F₂NO₃Na, 308.1074; found, 308.1076.

Ethyl 2,2-Difluoro-5-oxo-5-phenyl-4-(pyridin-4-yl)pentanoate (4c)

The batch reaction was carried out on a 0.2 mmol scale, and the flow experiment was carried out on a 0.5 mmol scale (3.0 mL liquid was taken); 54.7 mg and 97.7 mg of product were obtained in batch and flow as a yellow oil (82%, 98% yields). Purification: Column chromatography (CH₂Cl₂/Acetone = 20:1). ¹H NMR (400 MHz, CDCl₃): δ 8.55 (brs, 2H), 7.94 (dd, J = 8.0, 4.0 Hz, 2H), 7.55 (t, J = 8.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 4.98 (t, J = 8.0 Hz, 2H), 4.27–4.10 (m, 2H), 3.28 (dtd, J = 18.2, 15.3, 7.8 Hz), 2.52 (dtd, J = 18.0, 14.9, 5.1 Hz), 1.26 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 196.1, 163.5 (t, J = 33.0 Hz), 150.2, 147.1, 135.2, 133.8, 128.8, 128.7, 123.4, 114.9 (t, J = 250.0 Hz), 63.1, 46.0, 37.8 (t, J = 23.0 Hz), 13.7. ¹³F NMR (376 MHz, CDCl₃): δ −104.43 (ddd, J = 57.3, 18.0, 15.1 Hz). HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₈H₁₇F₂NO₃Na, 356.1074; found, 356.1078.

Ethyl 4-(2-Chloropyridin-4-yl)-2,2-difluoro-5-oxohexanoate (4d)

The batch reaction was carried out on a 0.2 mmol scale, and the flow experiment was carried out on a 0.5 mmol scale (2.5 mL liquid was taken); 53.0 mg were obtained in batch with a yield of 87%, and 74.6 mg were obtained in flow with a yield of 93%. The product was a pale yellow oil. Purification: Column chromatography (CH₂Cl₂/Acetone = 20:1). ¹H NMR (400 MHz, CDCl₃): δ 8.31–8.30 (m, 1H), 7.17 (d, J = 1.5 Hz, 1H), 7.04 (dd, J = 5.1, 1.6 Hz, 1H), 4.17 (dq, J = 7.2, 4.2 Hz, 2H), 3.98 (dd, J = 7.3, 5.7 Hz, 1H), 3.01 (dtd, J = 18.5, 15.2, 7.4 Hz, 1H), 2.26 (dtd, J = 18.1, 14.9, 5.6 Hz, 1H), 2.08 (s, 3H), 1.26 (t, J = 8.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 203.2, 163.4 (t, J = 32.0 Hz), 152.4, 150.4, 149.2, 123.8, 121.9, 114.7 (t, J = 250.0 Hz), 63.3, 51.3 (t, J = 3.0 Hz), 36.2 (t, J = 23.0 Hz), 29.2, 13.8. ¹⁹F NMR (376 MHz, CDCl₃): δ −104.70 (dd, J = 47.0, 4.3 Hz). HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₃H₁₄ClF₂NO₃Na, 328.0528; found, 328.0520.

Ethyl 2,2-Difluoro-5-oxo-4-(pyridin-3-yl)hexanoate (4e)

The batch experiment was carried out on a 0.2 mmol scale; 24.4 mg of product were isolated as a yellow oil (45% yield). Purification: Column chromatography (CH₂Cl₂/Acetone = 20:1). ¹H NMR (400 MHz, CDCl₃): δ 8.58 (d, J = 8.0 Hz, 2H), 7.57 (td, J = 8.0, 1.9 Hz, 1H), 7.35–7.32 (m, 1H), 4.21 (dq, J = 7.2, 5.4 Hz, 2H), 4.09 (t, J = 4.0 Hz, 1H), 3.11 (dtd, J = 16.7, 15.1, 7.3 Hz, 1H), 2.37 (dtd, J = 16.4, 15.0, 5.9 Hz, 1H), 2.14 (s, 3H), 1.32 (t, J = 8.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 204.5, 163.6 (t, J = 32.0 Hz), 149.4, 149.0, 135.7, 133.3, 124.2, 114.9 (t, J = 250.0 Hz), 63.2, 49.7 (t, J = 4.0 Hz), 36.5 (t, J = 24.0 Hz), 29.0, 13.8. ¹⁹F NMR (376 MHz, CDCl₃): δ −104.67(s). HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₃H₁₅F₂NO₃Na, 294.0918; found, 294.0918.

Ethyl 4-(6-Bromopyridin-3-yl)-2,2-difluoro-5-oxohexanoate (4f)

The batch reaction was carried out on a 0.2 mmol scale; 42.6 mg of product were obtained as a pale yellow oil (61% yield). Purification: Column chromatography (CH₂Cl₂/Acetone = 30:1). ¹H NMR (400 MHz, CDCl₃): δ 8.31 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.40 (d, J = 8.0, 1H), 4.24 (dq, J = 8.0, 4.0 Hz, 2H), 4.06 (t, J = 8.0 Hz, 1H), 3.08 (dtd, J = 17.6, 15.5, 7.3 Hz, 1H), 2.34 (dtd, J = 17.2, 15.3, 5.9 Hz, 1H), 2.15 (s, 3H), 1.33 (t, J = 8.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 204.1, 163.4 (t, J = 32.0 Hz), 150.0, 141.9, 137.7, 132.4, 128.7, 114.8 (t, J = 250.0 Hz), 63.3, 48.9 (t, J = 4.0 Hz), 36.5 (t, J = 24.0 Hz), 29.1, 13.8. ¹⁹F NMR (376 MHz, CDCl₃): δ −104.68 (s). HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₃H₁₄BrF₂NO₃Na, 372.0023; found, 372.0026.

Ethyl 4-(5-Bromopyridin-3-yl)-2,2-difluoro-5-oxohexanoate (4g)

The batch reaction was carried out on a 0.2 mmol scale, and the flow experiment was carried out on a 0.5 mmol scale (2.7 mL liquid was taken); 41.1 mg and 62.2 mg of product were obtained in batch and flow as a pale yellow oil (59%, 66% yields). Purification: Column chromatography (CH₂Cl₂/Acetone = 30:1). ¹H NMR (400 MHz, CDCl₃): δ 8.63 (s, 1H), 8.45 (s, 1H), 7.69 (s, 1H), 4.16 (dq, J = 8.0, 4.0 Hz, 2H), 4.00 (t, J = 4.0 Hz, 1H), 3.05–2.97 (m, 1H), 2.28 (dtd, J = 17.2, 15.4, 5.8 Hz, 1H), 2.09 (s, 3H), 1.25 (t, J = 8.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 203.9, 163.4 (t, J = 32.0 Hz), 150.5, 147.7, 137.8, 134.7, 121.1, 114.7 (t, J = 250.0 Hz), 63.2, 49.1 (t, J = 4.0 Hz), 36.5 (t, J = 24.0 Hz), 29.1, 13.8. ¹⁹F NMR (376 MHz, CDCl₃): δ −104.70(s). HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₃H₁₄BrF₂NO₃Na, 372.0023; found, 372.0026.

Ethyl 2,2-Difluoro-5-oxo-4-(pyridin-3-yl)heptanoate (4h)

The batch reaction was carried out on a 0.2 mmol scale, and the flow experiment was carried out on a 0.5 mmol scale (3.0 mL liquid was taken); 32.5 mg and 52.1 mg of product were obtained in batch and flow as a pale yellow oil (57%, 61% yields). Purification: Column chromatography (CH₂Cl₂/Acetone = 20:1). ¹H NMR (400 MHz, CDCl₃): δ 8.58 (d, J = 4.0 Hz, 2H), 7.56 (m, 1H), 7.35–7.32 (m, 1H), 4.20 (dq, J = 7.2, 4.6 Hz, 2H), 4.08 (dd, J = 7.6, 5.6 Hz, 1H), 3.19–3.05 (m, 1H), 2.54–2.37 (m, 1H), 2.36–2.30 (m, 1H), 1.32 (t, J = 7.2 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 207.5, 163.6 (t, J = 32.0 Hz), 149.5, 149.1, 135.4, 133.5, 124.0, 114.9 (t, J = 250.0 Hz), 63.1, 49.6, 36.8 (t, J = 24.0 Hz), 35.1, 13.8. ¹⁹F NMR (376 MHz, CDCl₃): δ −104.76 (s). HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₄H₁₇F₂NO₃Na, 308.1074; found, 308.1079.

Ethyl 2,2-Difluoro-5-oxo-4-(pyridin-2-yl)decanoate (4i)

The batch reaction was carried out on a 0.2 mmol scale; 40.5 mg of product were obtained as a pale yellow oil (62% yield). Purification: Column chromatography (CH₂Cl₂/Acetone = 16:1). ¹H NMR (400 MHz, CDCl₃): δ 8.56 (d, J = 4.0 Hz, 1H), 7.67 (td, J = 8.0, 4.0 Hz, 1H), 7.25 (s, 1H), 7.20 (ddd, J = 8.0, 4.0, 1.1 Hz, 1H), 4.26–4.16 (m, 3H), 3.21–3.03 (m, 1H), 2.57 (dtd, J = 18.4, 15.3, 6.1 Hz, 1H), 2.47–2.24 (m, 2H), 1.48 (dtd, J = 14.9, 8.2, 6.7 Hz, 2H), 1.30 (t, J = 8.0 Hz, 3H), 1.24–1.08 (m, 4H), 0.80 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 206.5, 163.8 (t, J = 33.0 Hz), 157.2, 149.6, 137.4, 123.5, 122.6, 115.4 (t, J = 249.0 Hz), 63.0, 53.9, 41.5, 35.6 (t, J = 23.0 Hz), 23.2, 22.3, 13.8. ¹⁹F NMR (376 MHz, CDCl₃): δ −104.72 (s). HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₇H₂₃F₂NO₃Na, 350.1544; found, 350.1548.

Ethyl 2,2-Difluoro-5-oxo-4-(pyrazin-2-yl)hexanoate (4j)

The batch reaction was carried out on a 0.2 mmol scale, and the flow experiment was carried out on a 0.5 mmol scale (2.8 mL liquid was taken); 42.5 mg and 69.3 mg of product were obtained in batch and flow as a pale yellow oil (78%, 91% yields). Purification: Column chromatography CH₂Cl₂/Acetone = 20:1). ¹H NMR (400 MHz, CDCl₃): δ 8.63 (s, 1H), 8.57–8.54 (m, 2H), 4.30–4.23 (m, 3H), 3.22–3.08 (m, 1H), 2.71–2.57 (m, 1H), 2.13 (s, 3H), 1.33 (t, J = 8.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 202.9, 163.6 (t, J = 22.0 Hz), 153.1, 144.9, 144.6, 143.7, 115.2 (t, J = 250.0 Hz), 63.2, 52.2, 35.0 (t, J = 23.0 Hz), 28.9, 13.9. ¹⁹F NMR (376 MHz, CDCl₃): δ −104.33 to −105.72 (m). HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₂H₁₄F₂N₂O₃Na, 295.0870; found, 295.0875.

Ethyl 2,2-Difluoro-4-(3-methylpyrazin-2-yl)-5-oxohexanoate (4k)

The batch experiment was carried out on a 0.2 mmol scale; 40.5 mg of product were isolated as a yellow oil (71% yield). Purification: Column chromatography (CH₂Cl₂/Acetone = 16:1). ¹H NMR (400 MHz, CDCl₃): 8.62–8.27 (m, 2H), 4.37 (t, J = 8.0 Hz, 1H), 4.23 (dq, J = 7.2, 3.0 Hz, 2H), 3.11 (dtd, J = 20.7, 15.5, 5.3 Hz, 1H), 2.72 (s, 3H), 2.69–2.54 (m, 1H), 2.03 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 202.5, 163.6 (t, J = 32.0 Hz), 152.9, 151.8, 142.7, 142.1, 115.3 (t, J = 250.0 Hz), 63.1, 50.5 (t, J = 2.0 Hz), 34.8 (t, J = 23.0 Hz), 29.7, 28.4, 21.7, 13.8. ¹⁹F NMR (376 MHz, CDCl₃): δ −104.97 (ddd, J = 64.6, 20.0, 14.9 Hz). HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₃H₁₆F₂N₂O₃Na, 309.1027; found, 309.1034.

Ethyl 4-(Benzo[b]thiophen-2-yl)-2,2-difluoro-5-oxohexanoate (4l)

The flow experiment was carried out on a 0.5 mmol scale, and 2.2 mL of liquid were collected; 60.2 mg of product were isolated as a pale yellow oil (84% yield). Purification: Column chromatography (Cyclohexane/EtOAc = 50:1 to 40:1). ¹H NMR (400 MHz, CDCl₃): δ 7.81–7.71 (m, 2H), 7.38–7.31 (m, 2H), 7.17 (s, 1H), 4.37 (dd, J = 7.7, 5.3 Hz, 1H), 4.18 (qq, J = 10.8, 7.2 Hz, 2H), 3.19 (dtd, J = 17.2, 15.4, 7.8 Hz, 1H), 2.55–2.49 (m, 1H), 2.24 (s, 3H), 1.29 (t, J = 8.0 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃): δ 203.6, 163.6 (t, J = 32.0 Hz), 139.7 (t, J = 23.0 Hz), 124.7, 123.5, 122.3, 114.9 (t, J = 250.0 Hz), 63.1, 47.8, 37.0 (t, J = 24.0 Hz), 28.6, 13.8. ¹⁹F NMR (376 MHz, CDCl₃): δ −104.77 (d, J = 40.4 Hz). HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₆H₁₆F₂O₃SNa, 349.0686; found, 349.0674.

Ethyl 4-(7-(2-Ethoxy-1,1-difluoro-2-oxoethyl)benzofuran-2-yl)-2,2-difluoro-5-oxohexanoate (4m)

The batch reaction was carried out on a 0.2 mmol scale, and the flow experiment was carried out on a 0.5 mmol scale (2.2 mL liquid was taken); 18.2 mg and 33.0 mg of product were obtained in batch and flow as a pale yellow oil (21%, 34% yields). Purification: Column chromatography with (Cyclohexane/EtOAc = 30:1). ¹H NMR (400 MHz, CDCl₃): δ 7.58 (d, J = 4.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.39–7.35(m, 1H), 6.92 (s, 1H), 4.33–4.27 (m, 3H), 4.26–4.14 (m, 2H), 3.26–3.07 (m, 1H), 2.67–2.55 (m, 1H), 2.24 (s, 3H), 1.31–1.29 (m, 6H). ¹³C NMR (100 MHz, CDCl₃): δ 201.8, 163.5, 155.2, 154.4, 125.5, 124.4, 120.7 (t, J = 7.0 Hz), 114.0, 104.9, 62.3, 62.2, 46.4, 34.0, 33.8, 28.6, 22.3, 13.9, 13.8. ¹⁹F NMR (376 MHz, CDCl₃): δ −102.95 (d, J = 41.1 Hz), −105.06 (s). HRMS (ESI) m/z: [M + Na]⁺ calcd for C₂₀H₂₀F₄O₆Na, 455.1094; found, 455.1094.

Ethyl 4-(4-(2-Ethoxy-1,1-difluoro-2-oxoethyl)-7-methoxybenzofuran-2-yl)-2,2-difluoro-5-oxohexanoate (4n)

The batch reaction was carried out on a 0.2 mmol scale; 59.0 mg of product were obtained in batch and flow as a pale yellow oil (64% yield). Purification: Column chromatography (Cyclohexane/EtOAc = 30:1). ¹H NMR (400 MHz, CDCl₃): δ 7.42 (d, J = 8.0 Hz, 1H), 6.88 (s, 1H), 6.83 (d, J = 8.4 Hz, 1H), 4.32–4.26 (m, 3H), 4.25–4.16 (m, 2H), 4.03 (s, 3H), 3.22–3.08 (m, 1H), 2.69–2.55 (m, 1H), 2.24 (s, 3H), 1.32–1.67 (m, 6H). ¹³C NMR (100 MHz, CDCl₃): δ 201.7, 164.0 (t, J = 36.0 Hz), 163.5 (t, J = 32.0 Hz), 154.5, 147.2, 144.3, 127.2, 122.1, 117.3 (t, J = 27.0 Hz), 116.2, 114.9 (t, J = 250.0 Hz), 113.7 (t, J = 251.0 Hz), 106.1, 105.2, 70.6, 63.1, 56.2, 46.3 (t, J = 3.0 Hz), 34.0 (t, J = 24.0 Hz), 28.6, 26.5, 23.2, 22.3, 13.9, 13.8. ¹⁹F NMR (376 MHz, CDCl₃): δ −102.07 (d, J = 41.1 Hz), −105.06 (s). HRMS (ESI) m/z: [M + Na]⁺ calcd for C₂₁H₂₂F₄O₇Na, 485.1199; found, 485.1194.

Ethyl 4-(3-(2-Ethoxy-1,1-difluoro-2-oxoethyl)thiophen-2-yl)-2,2-difluoro-5-oxohexanoate (4o)

The batch experiment was carried out on a 0.2 mmol scale; 56.5 mg product were isolated as a yellow oil (71% yield). Purification: Column chromatography (Cyclohexane/EtOAc = 20:1 to 8:1). ¹H NMR (400 MHz, CDCl₃): δ 7.26–7.25 (m, 1H), 6.89–6.87 (m, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.33–4.30 (m, 1H), 4.27–4.19 (m, 2H), 3.11 (dtd, J = 17.5, 15.2, 8.0 Hz, 1H), 2.51–2.29 (m, 1H), 2.21 (s, 3H), 1.38–1.31 (m, 6H). ¹³C NMR (100 MHz, CDCl₃): δ 203.3, 163.4 (t, J = 32.0 Hz), 163.0 (t, J = 35.0 Hz), 143.3 (t, J = 2.0 Hz), 134.1 (t, J = 30.0 Hz), 128.7 (t, J = 5.0 Hz), 126.4, 114.6 (t, J = 250.0 Hz), 111.2 (t, J = 250.0 Hz), 63.6, 63.2, 47.0, 37.5 (t, J = 24.0 Hz), 28.6, 13.9, 13.8. ¹⁹F NMR (376 MHz, CDCl₃): δ −93.05 to −93.13 (m), −104.81 to −105.0 (m). HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₆H₁₈F₄O₅SNa, 421.0709; found, 421.0713.

Diethyl (3-(Benzo[b]thiophen-2-yl)-1,1-difluoro-4-oxopentyl)phosphonate (5a)

The flow experiment was carried out on a 0.5 mmol scale, and 2.5 mL of liquid were collected; 81.2 mg of product were isolated as a colorless oil (84% yield). Purification: Column chromatography (Cyclohexane/EtOAc = 8:1 to 2:1). ¹H NMR (400 MHz, CDCl₃): δ 7.76 (dd, J = 20.0, 8.0 Hz, 2H), 7.37–7.30 (m, 2H), 7.18 (s, 1H), 4.54 (q, J = 4.0 Hz, 1H), 4.32–4.24 (m, 4H), 3.37–3.20 (m, 1H), 2.53–2.40 (m, 1H), 2.27 (s, 3H), 1.39 (q, J = 8.0 Hz, 6H). ¹³C NMR (100 MHz, CDCl₃): δ 203.8, 140.8, 139.6, 139.5, 124.6, 124.5, 123.4, 122.9, 122.3, 120.7 (t, J = 259.0 Hz), 118.6 (t, J = 260.0 Hz), 64.7 (t, J = 6.0 Hz), 47.0 (q, J = 5.0 Hz), 36.6 (td, J = 20.0, 5.0 Hz), 28.7, 16.4, 16.3. ¹⁹F NMR (376 MHz, CDCl₃): δ −111.81–109.54 (m). HRMS (ESI) m/z: [M + H]⁺ calcd for C₁₇H₂₁F₂O₄PS, 391.0944; found, 391.0945.

4-(Benzo[b]thiophen-2-yl)-2,2-difluoro-1-morpholinohexane-1,5-dione (5b)

The flow experiment was carried out on a 0.5 mmol scale, and 2.6 mL of liquid were collected; 83.0 mg of product were isolated as a colorless oil (88% yield). Purification: Column chromatography (Cyclohexane/EtOAc = 30:1 to 16:1). ¹H NMR (400 MHz, CDCl₃): δ 7.81–7.71 (m, 2H), 7.38–7.30 (m, 2H), 7.17 (s, 1H), 4.45 (q, J = 4.0 Hz, 1H), 3.74–3.61 (m, 8H), 3.31 (dddd, J = 18.3, 16.8, 15.1, 8.1 Hz, 1H), 2.64–2.50 (m, 1H), 2.25 (s, 3H).¹³C NMR (100 MHz, CDCl₃): δ 204.0, 161.5 (t, J = 28.0 Hz), 140.8, 139.6, 139.5, 124.6, 124.5, 123.5, 122.9, 122.3, 118.2 (t, J = 253.0 Hz), 100.0, 66.6, 48.0, 46.5, 43.3, 37.4 (t, J = 22.0 Hz), 28.7, 26.9. ¹⁹F NMR (376 MHz, CDCl₃): δ −98.02(s). HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₈H₁₉F₂NO₃SNa, 390.0951; found, 390.0945.

4-(Benzo[b]thiophen-2-yl)-2,2-difluoro-1-(piperidin-1-yl)hexane-1,5-dione (5c)

The flow experiment was carried out on a 0.5 mmol scale, and 2.8 mL of liquid were collected; 89.4 mg of product were isolated as a colorless oil (94% yield). Purification: Column chromatography (Cyclohexane/EtOAc = 30:1 to 16:1). ¹H NMR (400 MHz, CDCl₃): δ 7.79–7.70 (m, 2H), 7.36–7.27 (m, 2H), 7.17 (s, 1H), 4.46 (dd, J = 8.0, 4.0 Hz, 1H), 3.57 (td, J = 20.0, 4.0 Hz, 4H), 3.31 (dddd, J = 18.3, 16.8, 15.1, 8.1 Hz, 1H), 2.56 (dddd, J = 18.3, 16.8, 15.1, 8.1 Hz, 1H), 2.24 (s, 3H), 1.65–1.56 (m, 6H).¹³C NMR (100 MHz, CDCl₃): δ 204.2, 161.1 (t, J = 28.0 Hz), 141.0, 139.6, 139.5, 124.5, 124.3, 123.4, 122.7, 122.2, 118.4 (t, J = 253.0 Hz), 48.1 (t, J = 4.0 Hz), 46.7 (t, J = 6.0 Hz), 44.3, 37.6 (t, J = 23.0 Hz), 28.6, 26.3, 25.5, 24.3. ¹⁹F NMR (376 MHz, CDCl₃): δ −98.0(s). HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₉H₂₁F₂NO₂SNa, 388.1159; found, 388.1155.

4-(Benzo[b]thiophen-2-yl)-2,2-difluoro-1-(pyrrolidin-1-yl)hexane-1,5-dione (5d)

The flow experiment was carried out on a 0.5 mmol scale, and 2.2 mL of liquid were collected; 65.4 mg of product were isolated as a colorless oil (85% yield). Purification: Column chromatography (Cyclohexane/EtOAc = 30:1 to 16:1). ¹H NMR (400 MHz, CDCl₃): δ 7.79–7.70 (dd, J = 28.0, 8.0 Hz, 2H), 7.36–7.29 (m, 2H), 7.16 (s, 1H), 4.48 (q, J = 4.0 Hz, 1H), 3.64 (q, J = 4.0 Hz, 2H), 3.46 (q, J = 6.8 Hz, 2H), 3.26 (tdd, J = 17.4, 14.9, 8.3 Hz, 1H), 2.55 (qd, J = 16.3, 4.3 Hz, 1H), 2.24 (s, 3H), 1.97–1.91 (m, 2H), 1.86–1.78 (m, 2H). ¹³C NMR (100 MHz, CDCl₃): δ 204.2, 161.6 (t, J = 29.0 Hz), 140.8, 139.6, 139.5, 124.5, 124.4, 123.4, 122.8, 122.2, 117.6 (t, J = 252.0 Hz), 48.0 (t, J = 4.0 Hz), 47.4, 46.6 (t, J = 23.0 Hz), 37.0 (t, J = 24.0 Hz), 28.6, 26.9, 26.4, 23.2. ¹⁹F NMR (376 MHz, CDCl₃): δ −101.50(s). HRMS (ESI) m/z: [M + Na]⁺ calcd for C₁₈H₁₉F₂NO₂SNa, 374.1002; found, 374.1003.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b01624.

• Description of reaction setups, radical trapping experiments, and spectral data of all products (PDF)

The authors declare no competing financial interest.