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

Article abstract of DOI:10.1021/acs.joc.8b01624

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 us

Full text of DOI:10.1021/acs.joc.8b01624

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Note
Visible-Light Photocatalytic Difluoroalkylation-induced 1, 2-
Heteroarene Migration of Allylic Alcohols in Batch and Flow
Xiao-Jing Wei, and Timothy Noël
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01624 • Publication Date (Web): 18 Jul 2018
Downloaded from http://pubs.acs.org on July 19, 2018
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Visible-Light Photocatalytic Difluoroalkylation-induced 1, 2-
Heteroarene Migration of Allylic Alcohols in Batch and Flow
XiaoꢀJing Wei and Timothy Noël*
Department of Chemical Engineering and Chemistry, Micro Flow Chemistry & Process Technology, Eindhoven University of Technology, Den
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Dolech 2, 5612 AZ Eindhoven, The Netherlands.
Eꢀmail: t.noel@tue.nl
Website : www.NoelResearchGroup.com
Abstract: A convenient method for the preparation of sp3ꢀrich heterocycles is reported. The method comprises a photocatalytic
difluoroalkylationꢀinduced 1,2ꢀheteroarene 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 sp3ꢀrich fragments (soꢀcalled “escapeꢀfromꢀflatland strategy”) to reduce the
attrition rate in drug discovery.2 To achieve this, the sp3ꢀcharacter of heteroarenes can be enhanced through alkylation via
e.g. radical intermediates.3,4
An intriguing approach to access syntheticallyꢀuseful sp3ꢀrich heteroarenes is the difunctionalization of alkenes initiated by a
radical addition followed by a heteroaryl migration.5,6 Herein, we describe a novel 1,2ꢀheteroarene migration induced by a
photocatalytic radical difluoroalkylation. To prepare the target compounds, we developed a twoꢀstep protocol which starts
from the corresponding heteroaryl ketones and includes a Grignard reaction and subsequent difluoroalkyl radicalꢀinduced
migration reaction. As shown in this work, both reactions benefited substantially from continuousꢀflow 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
continuousꢀflow 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 Tꢀmixer and subsequently introduced in a capillary microreactor (ID 1.65 mm; 700 μL). To avoid microreactor
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clogging, the mixer and microreactor were submerged into a sonicated icebath.8 A broad variety of heteroaryl allylic alcohols
could be prepared in only 5 minutes residence time on a 5ꢀ10 mmol scale as shown in Scheme 1; this includes 4ꢀpyridinyl,
3ꢀpyridinyl, 2ꢀpyridinyl, 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
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Scheme 1: Scope of the continuous-flow Grignard synthesis of allylic alcohols.a
aReaction conditions: Feed 1 contains 1 (5.0 mmol) in 10 mL THF; Feed 2 contains 10 mL vinylmagnesium bromide (1.67 M
in THF). 5 min residence time, 0°C, ultrasound. The reaction is quenched by saturated NH4Cl at the outlet of the reactor.
Reported yields are those obtained after column chromatography. bCarried out on a 10 mmol scale, residence time: 2.5
c
min.
With a diverse set of allylic alcohols in hand, we commenced our investigations towards a broadly applicable
difluoroalkylationꢀinduced 1,2ꢀheteroarene migration with 2ꢀ(pyridinꢀ4ꢀyl)butꢀ3ꢀenꢀ2ꢀol 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 1ꢀ3), the target product could be obtained in encouraging yields (15ꢀ55%) 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).
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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 7ꢀ9).
Table 1. Optimization of the reaction conditionsa
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Entry
Base
Photocatalyst
Ru(bpy)3Cl2.6H2O
Ru(bpy)3Cl2.6H2O
Ru(bpy)3Cl2.6H2O
facꢀIr(ppy)3
Yieldb
31 %
15 %
55 %
67 %
45 %
83 %
57 %
N.D.
N.D.
1
NEt3
2
iPr2NEt
TMEDA
TMEDA
DBU
3
4
5
facꢀIr(ppy)3
6
imidazole
ꢀꢀ
fac-Ir(ppy)3
facꢀIr(ppy)3
7
8c
9d
imidazole
imidazole
--
facꢀIr(ppy)3
aReaction Conditions: 2a (0.2 mmol, 1 equiv.), 3a (o.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 hours. b Isolated yield. c No photocatalyst. d
No light.
Having established the optimal reaction conditions, we set out to examine the substrate scope of the developed
transformation (Scheme 2). 4ꢀPyridineꢀsubstituted allylic alcohols bearing various Rꢀgroups 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 hours 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, 3ꢀsubstituted 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 2ꢀSubstituted pyridine allylic alcohol (4i) and 2ꢀpyrazineꢀsubstituted allylic alcohols (4j-k) underwent efficient
migration under these photocatalytic conditions. Benzothiophene (4l) migrates smoothly as well under our reaction
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conditons. However, other electronꢀrich 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).
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Scheme 2: Substrate scope of the photocatalytic radicalꢀinduced heterocycle migration – variation of the allylic alcohol
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substratea
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aReaction conditions in batch: 2a (0.2 mmol), 3a(o.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 hours. 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
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b
c
minutes. Reported yields are those obtained after column chromatography. Residence time: 15 minutes. Residence time:
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20 minutes. dResidence time: 5 minutes.
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Scheme 3: Substrate scope of the photocatalytic radicalꢀinduced heterocycle migration – variation of the difluoroalkyl radical
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precursor.a
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aReaction 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 minutes. Reported yields are those obtained after column
chromatography.
Based on the experimental data, a plausible mechanism is suggested in Figure 1. Upon light excitation, facꢀ[Ir(ppy)3]* can
be oxidatively quenched by ethyl bromodifluoroacetate, generating the corresponding difluoroalkyl radical species.13
Indeed, radical trapping experiments with BHT (2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylphenol) showed that this species could be
effectively captured (See Supporting Information). The radical subsequently adds to the olefin generating intermediate A,
which undergoes 1,2ꢀheterocycle migration via a key spiro radical intermediate B to produce C. Finally, the intermediate
C was oxidized to obtain the aimed product 4a.
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Figure 1. Proposed mechanism for the photocatalytic radicalꢀinduced heterocycle migration.
In summary, we have developed a novel photocatalytic 1, 2ꢀheterocycle migration method which allows to prepare
heterocycles with a sp3ꢀenriched character. A variety of synthetically useful βꢀdifluorinated αꢀaryl heterocyclic ketones can
be easily prepared under mild reaction conditions with excellent regioselectivity. The application of continuous flow allows to
reduce the reaction time (from 6 hours to 10 minutes), provides higher reaction selectivity and potential for scaling the
chemistry. Interesting also 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 to prepare 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 facꢀIr(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 foils TLC plates (F254, Supelco Sigmaꢀ
Aldrich™) with visualization under ultraviolet light (254 nm and 365 nm) or appropriate TLC staining. NMR (1H, 13C and 19F) analyses were
performed on a BrukerꢀAvance 400 (400 MHz) in solvent CDCl3. 1HNMR spectra are reported in parts per million (ppm) downfield relative to
CDCl3 (7.27 ppm). All 13CꢀNMR 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
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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, a Waters
Micromass Quatro LCZ (ESI); peaks are given in m/z (% of basis peak). The batch and flow reactions were carried out using 123ꢀLEDs,
stripe blue 2.5 m, 12 Watt. The strips were wrapped on the inside of a 3D printed beaker.14
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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 THF, which was subsequently degassed 3 times (freezeꢀpumpꢀthaw: cooled to –78 °C and degassed via vacuum
evacuation (5 min), backfilled with argon, and warm to room temperature) and taken up in a first syringe. Next, 6 mL vinylmagnesium
bromide (1 M in THF) was dissolved in 4 mL 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 flowrate 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.
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2-(pyridin-4-yl)but-3-en-2-ol (2a). The flow experiment was carried out on a 10.0 mmol scale. Purification: Column chromatography
(CH2Cl2/acetone = 30:1), 1.3 g product was isolated as white solid (87% yield). Mp = 88ꢀ92 °C. 1H NMR (400 MHz, CDCl3): δ 8.57 (d, J = 4.0
Hz, 2H), 7.41 (d, J = 4.0 Hz, 2H), 6.17ꢀ6.10 (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. Purification: Column chromatography
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(CH2Cl2/acetone = 30:1), 749.8 mg product was isolated as yellowish oil (92% yield). H 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), 1.92ꢀ1.87 (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. Purification: Column chromatography
(CH2Cl2/acetone = 16:1), 759.5 mg product was isolated as white solid (72% yield). Mp = 134ꢀ136 °C. 1H NMR (400 MHz, CDCl3): δ 8.49 (t, J
= 4.0 Hz, 2H), 7.36ꢀ7.34 (m, 7H), 6.51ꢀ6.44 (m, 1H), 5.41ꢀ5.34 (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. Purification: Column chromatography
(CH2Cl2/acetone = 20:1), 494.1 mg product was isolated as white solid (54% yield). Mp = 54ꢀ56 °C. 1H NMR (400 MHz, CDCl3): δ 8.15(d, J =
4.0 Hz, 1H), 7.39ꢀ7.38(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. Purification: Column chromatography
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(CH2Cl2/acetone = 8:1 to 2:1), 662.8 mg product was isolated as white solid (89% yield). Mp = 27ꢀ29 °C. H NMR (400 MHz, CDCl3): δ 8.63
(s, 1H), 8.41ꢀ8.39 (m, 1H), 7.76 (dd, J = 16.0, 4.0 Hz, 1H), 7.29ꢀ7.26 (m, 1H), 6.20ꢀ6.13 (m, 1H), 5.32 (d, J = 16.0 Hz, 1H), 5.20 (d, J = 12.0
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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.
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2-(6-bromopyridin-3-yl)but-3-en-2-ol (2f). The flow experiment was carried out on a 5.0 mmol scale. Purification: Column chromatography
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(CH2Cl2/acetone = 20:1), 669.5 mg product was isolated as yellow oil (59% yield). H NMR (400 MHz, CDCl3): δ 8.55 (s, 1H), 8.50 (s, 1H),
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7.99ꢀ7.98 (m, 1H), 6.15ꢀ6.08 (m, 1H), 5.35ꢀ5.20 (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.
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2-(5-bromopyridin-3-yl)but-3-en-2-ol (2g). The batch experiment was carried out on a 5.0 mmol scale. Purification: Column chromatography
(DCM/Acetone = 20:1), 374.0 mg product was isolated as brown oil (33% yield). 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), 5.33ꢀ5.21 (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 minutes. Purification:
Column chromatography (CH2Cl2/acetone = 8:1 to 2:1), 676.4 mg product was isolated as yellow oil (83% yield). 1H NMR (400 MHz, CDCl3):
δ 8.62(s, 1H), 8.42ꢀ8.39(m, 1H), 7.78(dd, J = 8.0, 4.0 Hz, 1H), 7.26ꢀ7.22 (m, 1H), 6.19ꢀ6.12 (m, 1H), 5.32 (d, J = 16.0 Hz, 1H), 5.20 (d, J =
8.0 Hz, 1H), 3.48 (brs, 1H),1.96ꢀ1.89 (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.15 1H 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),
1.40ꢀ1.36 (m, 4H), 0.92ꢀ0.88 (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. Purification: Column chromatography
(CH2Cl2/acetone = 8:1 to 2:1), 1.0 g mixture of product and starting material (5:1 based on HNMR) was obtained as yellow oil (80% yield). 1H
NMR (400 MHz, CDCl3): δ 8.55ꢀ8.52 (m, 1H), 7.76ꢀ7.73 (m, 1H), 7.39ꢀ7.36 (m, 1H), 7.26ꢀ7.23 (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), 1.92ꢀ1.87 (m, 2H), 1.46ꢀ1.37 (m, 2H), 1.28ꢀ1.20 (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. Purification: Column chromatography
(CH2Cl2/acetone = 20:1), 390.0 mg product was isolated as colorless oil (52% yield). 1H NMR (400 MHz, CDCl3): δ 8.77 (s, 1H), 8.51ꢀ8.50
(m, 2H), 6.20ꢀ6.12 (m, 1H), 5.42ꢀ5.38 (m, 1H), 5.21ꢀ5.18 (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. Purification: Column chromatography
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(CH2Cl2/acetone = 30:1), 500.0 mg product was isolated as colorless oil (61% yield). H NMR (400 MHz, CDCl3): δ 8.41ꢀ8.30 (m, 2H), 6.09ꢀ
6.01 (m, 1H), 5.66 (brs, 1H), 5.36ꢀ5.20 (m, 2H), 2.65ꢀ2.64 (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.
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2-(benzo[b]thiophen-2-yl)but-3-en-2-ol (2l). The flow experiment was carried out on a 5.0 mmol scale. Purification: Column chromatography
(Cyclohexane/EtOAc = 20:1), 867.0 mg product was isolated as transparent oil (85% yield). 1H NMR (400 MHz, CDCl3): δ 7.81ꢀ7.69 (m, 2H),
7.35ꢀ7.29 (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.
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2-(benzofuran-2-yl)but-3-en-2-ol (2m). The flow experiment was carried out on a 5.0 mmol scale. Purification: Column chromatography
(Cyclohexane/EtOAc = 4:1), 723.8 mg product was isolated as colorless oil (77% yield). 1H NMR (400 MHz, CDCl3): δ 7.56ꢀ7.46 (m, 2H),
7.28ꢀ7.22 (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. Purification: Column
chromatography (Cyclohexane/EtOAc = 4:1), 870 mg product was isolated as colorless oil (80% yield). 1H NMR (400 MHz, CDCl3): δ 7.15ꢀ
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. Purification: Column chromatography
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(Cyclohexane/EtOAc = 4:1), 270.0 mg product was isolated as colorless oil (35% yield). H NMR (400 MHz, CDCl3): δ 7.24 (dd, J = 4.0, 2.3
Hz, 2H), 6.97ꢀ6.96 (m, 2H), 6.23 (d, J = 16.0, 8.0 Hz, 1H), 5.40ꢀ5.16 (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 2ꢀ
heterocycleꢀbutꢀ3ꢀenꢀ2ꢀol 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), was sealed with a rubber septum and
subsequently degassed 3 times (freezeꢀpumpꢀthaw: cooled to –78 °C and degassed via vacuum evacuation (5 min), backfilled with argon,
and warm 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 hours, the reaction mixture was
transferred to a 50 mL flask with about 20 mL 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: 2ꢀHeterocycleꢀbutꢀ3ꢀenꢀ2ꢀol 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), and was subsequently degassed 3 times (freezeꢀpumpꢀthaw: cooled to –78 °C and degassed via
vacuum evacuation (5 min), backfilled with argon, and warm 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 Watts) 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 minutes was utilized. The crude
product was collected at the end of the reactor. Workup and purification were done following the batch procedure.
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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 was obtained in batch and flow, the yield is 83%, 91%, the
product was yellow oil. Purification: Column chromatography (CH2Cl2/Acetone = 30:1). 1H NMR (400 MHz, CDCl3): δ 8.53 (t, J = 4.0 Hz, 2H),
7.11ꢀ7.09 (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 ꢀ104.67ꢀ ꢀ104.80(m). HRMS
(EI) m/z: [M+H]+ Calcd for C13H16F2NO3: 272.1098; Found: 272.1080.
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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, 88.0 mg of product was obtained in batch and flow as a pale yellow oil,
the yield is 89%, 97%. 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), 4.38ꢀ4.15 (m, 2H), 4.06 (dd, J = 7.7, 5.3 Hz, 1H), 3.19ꢀ3.05 (m, 1H), 2.61ꢀ2.36 (m, 2H), 2.40ꢀ2.20 (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, 97.7 mg of product was obtained in batch and flow as a
yellow oil, the yield is 82%, 98%. 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), 4.27ꢀ
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 was obtained in batch with the yield of 87%, 74.6 mg
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was obtained in flow with the yield of 93%, product was pale yellow oil. Purification: Column chromatography (CH2Cl2/Acetone = 20:1). H
NMR (400 MHz, CDCl3): δ 8.31ꢀ8.30 (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). 13
C
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. Purification: Column
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chromatography (CH2Cl2/Acetone = 20:1), 24.4 mg product was isolated as yellow oil (45% yield). H NMR (400 MHz, CDCl3): δ 8.58 (d, J =
8.0 Hz, 2H), 7.57 (td, J = 8.0, 1.9 Hz, 1H), 7.35ꢀ7.32 (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 =
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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
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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
was obtained as a pale yellow oil, the yield is 61%. 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.
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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, 62.2 mg of product was obtained in batch and flow as a
pale yellow oil, the yield is 59%, 66%. 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), 3.05ꢀ2.97 (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, 52.1 mg of product was obtained in batch and flow as a pale yellow oil,
the yield is 57%, 61%. 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), 7.35ꢀ7.32 (m, 1H), 4.20 (dq, J = 7.2, 4.6 Hz, 2H), 4.08 (dd, J = 7.6, 5.6 Hz, 1H), 3.19ꢀ3.05 (m, 1H), 2.54ꢀ2.37 (m, 1H), 2.36ꢀ2.30
(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 was
obtained as a pale yellow oil, the yield is 62%. 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), 4.26ꢀ4.16 (m, 3H), 3.21ꢀ3.03 (m, 1H),
2.57 (dtd, J = 18.4, 15.3, 6.1 Hz, 1H), 2.47ꢀ2.24 (m, 2H), 1.48 (dtd, J = 14.9, 8.2, 6.7 Hz, 2H), 1.30 (t, J = 8.0 Hz, 3H), 1.24ꢀ1.08 (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, 69.3 mg of product was obtained in batch and flow as a pale yellow oil,
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(m, 2H), 4.30ꢀ4.23 (m, 3H), 3.22ꢀ3.08 (m, 1H), 2.71ꢀ2.57 (m, 1H), 2.13 (s, 3H), 1.33 (t, J = 8.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 202.9,
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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,
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CDCl3): δ ꢀ104.33ꢀ ꢀ105.72 (m). HRMS (ESI) m/z: [M+Na]+ Calcd for C12H14F2N2O3Na: 295.0870; Found: 295.0875.
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Ethyl 2,2-difluoro-4-(3-methylpyrazin-2-yl)-5-oxohexanoate (4k). The batch experiment was carried out on a 0.2 mmol scale. Purification:
Column chromatography (CH2Cl2/Acetone = 16:1), 40.5 mg product was isolated as yellow oil (71% yield). 1H NMR (400 MHz, CDCl3): 8.62ꢀ
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), 2.69ꢀ2.54 (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.
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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, 2.2 mL of liquid
was collected. Purification: Column chromatography (Cyclohexane/EtOAc = 50:1 to 40:1), 60.2 mg product was isolated as a pale yellow oil
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(84% yield). H NMR (400 MHz, CDCl3): δ 7.81ꢀ7.71 (m, 2H), 7.38ꢀ7.31 (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), 2.55ꢀ2.49 (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, 33.0 mg of product was
obtained in batch and flow as a pale yellow oil, the yield is 21%, 34%. 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), 7.39ꢀ7.35(m, 1H), 6.92 (s, 1H), 4.33ꢀ4.27 (m, 3H),
4.26ꢀ4.14 (m, 2H), 3.26ꢀ3.07 (m, 1H), 2.67ꢀ2.55 (m, 1H), 2.24 (s, 3H), 1.31ꢀ1.29 (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 was obtained in batch and flow as a pale yellow oil, the yield is 64%. 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),
4.32ꢀ4.26 (m, 3H), 4.25ꢀ4.16 (m, 2H), 4.03 (s, 3H), 3.22ꢀ3.08 (m, 1H), 2.69ꢀ2.55 (m, 1H), 2.24 (s, 3H), 1.32ꢀ1.67 (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. Purification: Column chromatography (Cyclohexane/EtOAc = 20:1 to 8:1), 56.5 mg product was isolated as yellow oil (71%
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yield). H NMR (400 MHz, CDCl3): δ 7.26ꢀ7.25 (m, 1H), 6.89ꢀ6.87 (m, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.33ꢀ4.30 (m, 1H), 4.27ꢀ4.19 (m, 2H),
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3.11 (dtd, J = 17.5, 15.2, 8.0 Hz, 1H), 2.51ꢀ2.29 (m, 1H), 2.21 (s, 3H), 1.38ꢀ1.31 (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 ꢀ93.05ꢀ ꢀ93.13 (m), ꢀ104.81ꢀ ꢀ105.0 (m).
HRMS (ESI) m/z: [M+Na]+ Calcd for C16H18F4O5SNa: 421.0709; Found: 421.0713.
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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, 2.5
mL of liquid was collected. Purification: Column chromatography (Cyclohexane/EtOAc = 8:1 to 2:1), 81.2 mg product was isolated as a
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colorless oil (84% yield). H NMR (400 MHz, CDCl3): δ 7.76 (dd, J = 20.0, 8.0 Hz, 2H), 7.37ꢀ7.30 (m, 2H), 7.18 (s, 1H), 4.54 (q, J = 4.0 Hz,
1H), 4.32ꢀ4.24 (m, 4H), 3.37ꢀ3.20 (m, 1H), 2.53ꢀ2.40 (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, 2.6 mL
of liquid was collected. Purification: Column chromatography (Cyclohexane/EtOAc = 30:1 to 16:1), 83.0 mg product was isolated as a
colorless oil (88% yield). 1H NMR (400 MHz, CDCl3): δ 7.81ꢀ7.71 (m, 2H), 7.38ꢀ7.30 (m, 2H), 7.17 (s, 1H), 4.45 (q, J = 4.0 Hz, 1H), 3.74ꢀ3.61
(m, 8H), 3.31 (dddd, J = 18.3, 16.8, 15.1, 8.1 Hz, 1H), 2.64ꢀ2.50 (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, 2.8
mL of liquid was collected. Purification: Column chromatography (Cyclohexane/EtOAc = 30:1 to 16:1), 89.4 mg product was isolated as a
colorless oil (94% yield). 1H NMR (400 MHz, CDCl3): δ 7.79ꢀ7.70 (m, 2H), 7.36ꢀ7.27 (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, 2.2
mL of liquid was collected. Purification: Column chromatography (Cyclohexane/EtOAc = 30:1 to 16:1), 65.4 mg product was isolated as a
colorless oil (85% yield). 1H NMR (400 MHz, CDCl3): δ 7.79ꢀ7.70 (dd, J = 28.0, 8.0 Hz, 2H), 7.36ꢀ7.29 (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),
1.97ꢀ1.91 (m, 2H), 1.86ꢀ1.78(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.
Acknowledgements:
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X.J.W. and T.N. would like to acknowledge the European Union for a Marie Curie ITN Grant (Photo4Future, Grant No.
641861). We also acknowledge the Dutch Science Foundation (NWO) for a VIDI grant for T.N. (SensPhotoFlow, No.
14150).
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Supporting Information Available:
Description of reaction setꢀups, radical trapping experiments and spectral data of all products. This material is available free
of charge via the Internet at http://pubs.acs.org
References:
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[6] For some selected recent examples on photocatalytic migration chemistry, see: (a) Wu, X.; Wang, M.; Huan, L.; Wang,
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Trebes, C.; Laudadio, G. and Noël, T. Safety Assessment in Development and Operation of Modular ContinuousꢀFlow
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Sustainable Future Engaging Continuous Processsing. J. Flow Chem. 2017, 7, 65ꢀ71. (d) Movsisyan, M.; Delbeke, E. I. P.;
Berton, J. K. E. T.; Battilocchio, C.; Ley, S. V.; Stevens, C. V. Taming Hazardous Chemistry by Continuous Flow
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TechnologyꢀA Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients. Angew. Chem. Int. Ed. 2015, 54, 6688ꢀ
6728. (f) Newby, J. A.; Huck, L.; Blaylock, W.; Witt, P. M.; Ley, S. V.; Browne, D. L. Investigation of a LithiumꢀHalogen
Exchange Flow Process for the Preparation of Boronates by Using a CryoꢀFlow Reactor. Chem. Eur. J. 2014, 20, 263ꢀ271.
(g) Newby, J. A.; Blaylock, D. W.; Witt, P. M.; Pastre, J. C.; Zacharova, M. K.; Ley, S. V.; Browne, D. L. Design and
Application of a LowꢀTemperature Continuous Flow Chemistry Platform. Org. Process Res. Dev. 2014, 18, 1211ꢀ1220. (h)
Newby, J. A.; Blaylock, D. W.; Witt, P. M.; Turner, R. M.; Heider, P. L.; Harji, B. H.; Browne, D. L.; Ley, S. V. Reconfiguration
of a Continuous Flow Platform for Extended Operation: Application to a Cryogenic FluorineꢀDirected orthoꢀLithiation
Reaction. Org. Process Res. Dev. 2014, 18, 1221ꢀ1228. (i) Brodmann, T.; Koos, P.; Metzger, A.; Knochel, P.; Ley, S. V.
Continuous Preparation of Arylmagnesium Reagents in Flow with Inꢀline IR Monitoring. Org. Process Res. Dev. 2012, 16,
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Jensen, K. F.; Buchwald, S. L. PalladiumꢀCatalyzed Amination Reactions in Flow: Overcoming the Challenges of Clogging
via Acoustic Irradiation. Chem. Sci. 2011, 2, 287–290.
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[9] Nagaki, A.; Yoshida, J.ꢀi. Preparation and Use of Organolithium and Organomagnesium Species in Flow. Top.
Organomet. Chem. 2016, 57, 137ꢀ176.
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[10] For the benefits of microreactor technology for photochemistry, see: (a) Noel, T. A Personal Perspective on the Future
of Flow Photochemistry. J. Flow. Chem. 2017, 7, 87ꢀ93. (b) Cambié, D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.;
Noël, T. Applications of ContinuousꢀFlow Photochemistry in Organic Synthesis, Material Science, and Water Treatment.
Chem. Rev. 2016, 116, 10276ꢀ10341. (c) Loubiere, K.; Oelgemoeller, M.; Aillet, T.; DechyꢀCabaret, O.; Prat, L. Continuousꢀ
Flow Photochemistry: A Need for Chemical Engineering. Chem. Eng. Process 2016, 104, 120ꢀ132. (d) Mizuno, K.;
Nishiyama, Y.; Ogaki, T.; Terao, K.; Ikeda, H.; Kakiuchi, K. Utilization of Microflow Reactors to Carry Out Synthetically
Useful Organic Photochemical Reactions. J. Photochem. Photobiol. C 2016, 29, 107ꢀ147.
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[11] Attempts to connect the two steps in one flow protocol failed. Apparently impurities from the Grignard reaction
negatively affect the photocatalytic step. Even using inline purification steps, such as microfluidic extractions, did not solve
this issue.
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