Continuous Flow Synthesis of Quinolines via a Scalable Tandem Photoisomerization-Cyclization Process

European Journal of Organic Chemistry

Accepted Article

Title: Continuous Flow Synthesis of Quinolines via a Scalable Tandem

Photoisomerization-Cyclization Process

Authors: Mara Di Filippo and Marcus Baumann

This manuscript has been accepted after peer review and appears as an

Accepted Article online prior to editing, proofing, and formal publication

of the final Version of Record (VoR). This work is currently citable by

using the Digital Object Identifier (DOI) given below. The VoR will be

published online in Early View as soon as possible and may be different

to this Accepted Article as a result of editing. Readers should obtain

the VoR from the journal website shown below when it is published

to ensure accuracy of information. The authors are responsible for the

content of this Accepted Article.

To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000957

Link to VoR: https://doi.org/10.1002/ejoc.202000957

01/2020

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Continuous Flow Synthesis of Quinolines via a Scalable Tandem

Photoisomerization-Cyclization Process

Mara Di Filippo^[a]and Dr Marcus Baumann*^[a]

[a]

School of Chemistry, University College Dublin, Science Centre South, Belfield, Dublin D04 N2E2, Ireland

E-mail: marcus.baumann@ucd.ie , website: https://people.ucd.ie/marcus.baumann/

Supporting information for this article is given via a link at the end of the document.

Abstract: A continuous photochemical process is presented that

renders a series of quinoline products via an alkene isomerization and

cyclocondensation cascade. It is demonstrated that a high-power LED

lamp generates the desired targets with higher productivity and

efficiency than a medium-pressure Hg-lamp. The scope of this

tandem process is established and allows for the generation of

various substituted quinolines in high yields and with throughputs of

greater than one gram per hour. Finally, this effective flow process is

coupled with a telescoped hydrogenation reaction to render a series

of tetrahydroquinolines including the antimalarial natural product

galipinine.

irradiation.^[13,15]Finally, we planned for demonstrating the

scalability of such a continuous photochemical approach that

should give rise to gram quantities per hour.

To this end we decided to exploit a variation of the Friedländer

quinoline synthesis^[16]in which a Z-configured enone undergoes

intramolecular cyclocondensation with a pendent amine group

(Scheme 1). Importantly, this approach requires the isomerization

of the E-configured enone (3) in a process that can either be

achieved under acidic¹⁷or photochemical¹⁸conditions. As we

were targeting the latter approach, we identified 2-aminophenyl-

enones (3) as key intermediates, which would be generated from

their corresponding nitro-precursors (4).

A

simple aldol

condensation was considered to access these nitro-precursors

from readily available 2-nitrobenzaldehyde derivatives (5) and

methyl ketones (6).

Introduction

Quinolines are amongst the most prevalent bioactive

heterocycles and thus are frequently encountered entities in

alkaloid natural products and medicines alike.^[1]In recent years

interest in quinoline-based drug candidates has further increased

due to their potential as antimalarial^[2]and anti-inflammatory^[3]

agents. In addition, chemists can draw from a rich history of

classical and contemporary quinoline syntheses^[4]that have been

exploited extensively for the preparation of quinoline-based drugs

and related scaffolds.^[5]

In order to provide more efficient access towards valuable target

structures, recent years have witnessed a steady uptake of new

enabling technologies to enrich the organic chemist’s toolbox and

facilitate synthetic efforts. Amongst those, continuous flow

synthesis stands out as one of the most powerful techniques due

to its inherent benefits that have enabled widespread uptake

across academia and industry.^[6]

Consequently, flow chemistry has become a method of choice in

various fields including multi-step^[7]and API^[8]synthesis as well as

natural product^[9]chemistry, use of harmful reagents and reaction

conditions,^[10]organometallic chemistry,^[11]polymer chemistry,^[12]

photochemistry^[13]and most recently, electrochemistry.^[14]

In view of the value of both quinoline-based compounds and

continuous flow processing, we wished to merge these fields and

evaluate the merits of developing a continuous flow synthesis of

quinolines. More specifically, we decided to implement a strategic

photochemical approach that would garner the target compounds

under mild and green reaction conditions. This seemed

particularly appropriate as light is not only considered a clean and

traceless reagent, but moreover the use of light-driven

transformations benefits from continuous flow processing due to

short pathlengths (narrow tubing diameter) and uniform irradiation

profiles thus minimizing decomposition due to over-

Scheme 1. Synthesis route towards quinoline targets.

Results and Discussion

We commenced our studies by accessing a set of suitable enone

species (3) following literature precedent, i.e. a base-mediated

aldol condensation between 2-nitrobenzaldehyde and selected

methyl ketones (see SI for full details).^[18a]The corresponding

aldol products were obtained in generally high yield and allowed

for further elaboration of the nitro group into the desired amine

species. To achieve this chemoselective reduction we opted to

employ iron powder (~10 equiv.) in the presence of catalytic

amounts of acid (HCl aq.) in hot ethanol,^[18a]which provided the

target compounds not only in a simple and short procedure, but

moreover in generally high yield as the E-isomer (see SI for full

details). Interestingly, our studies also identified small amounts

(<5%) of 2-acylindole species (e.g. 7c, 7o, Scheme 2) as

separable side products that were not recognized in previous

reports on this reaction, although indole species have been

prepared from analogous nitro substrates under different reducing

conditions.^[19]As outlined in Scheme 2 this approach allowed for

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quickly providing access to a number of different enone

substrates including those bearing substitution patterns on the

aniline moiety as well as aromatic and aliphatic motifs on the

ketone part. Whilst the resulting amino enones were in most

cases found to be isolable and stable entities, we decided to

directly use product solutions bearing a methylenedioxy moiety

on the aniline ring (e.g. 3o and 3p) as concentrating these crude

reaction mixtures was found to trigger further reactions.

furthermore felt advantageous as it allowed for a detailed

comparison with respect to efficiency, selectivity and throughput

for such a continuous photochemical process which is scarcely

reported in the literature.

Table 1. Comparison between light sources used.

UV150 Hg lamp

High-power LED

Power range

75-150 W

50-100 W

adjustable

(with cooling)

adjustable

(with cooling)

Emission range

UV, visible and

IR^{[a], [b]}

UV-A: 365 nm

[a] see SI for emission spectra. [b] broadband filters available.

To conduct this comparative study, we selected phenyl

substituted amino-enone (3c) as model substrate. Ethanol was

identified as best solvent, however our studies indicated that

alternative solvents (such as acetone, EtOAc and MeCN) can be

used. We next defined both concentration and residence time as

key variables, whilst keeping the internal reactor temperature

constant at ~30 °C. For all experiments reported in Table 2 this

allowed to further establish the reaction throughput (defined as

mmol quinoline product per hour) as a measure for the efficiency

and potential scalability of this process.

Table 2. Comparative study of light sources on the efficiency of the quinoline

formation (3c to 1c).

light source

c [mM]

residence

time [min]

¹H-NMR

yield^[c]

throughput

[mmol/h]^[d]

1

2

3

4

5

6

7

8

9

10

Hg-lamp^[a]

UV-LED^[b]

20

60

20

60

20

15

10

7.5

98

0.20

0.52

1.20

0.17

0.56

2.79

4.32

3.80

5.64

7.18

20

87

100

20

36^[e]

85

20

94

Scheme 2. Preparation of amino enone substrates 3a-p, ^ayield estimated by

HPLC without isolating amine product.

100

150^[f]

100

93

96

95^[g]

94

Next, we embarked on the key transformation which would render

the quinoline targets via a photoisomerization of the enone moiety

(E to Z) followed by an intramolecular cyclocondensation reaction.

It is worth mentioning that this process has desirable

characteristics: it does not require any additives or catalysts and

produces water as the sole by-product. To effectively execute this

light-mediated tandem process we made use of a Vapourtec E-

series flow reactor system in combination with different light

sources. The reactor coil (10 mL volume, FEP tubing) is thereby

placed around the light source within a closed compartment. The

chosen set-ups included the established UV150 module^[20]which

is based on a tunable medium-pressure Hg-lamp (75-150 W,

complemented with exchangeable broad band filters) as well as a

high-power LED system emitting light at 365 nm (50-100 W, see

Table 1). The availability and use of these two light sources were

90

[a] Operating at 110 W in combination with a low-pass filter (see SI). [b]

Operating at 75 W. [c] Using 1,3,5-trimethoxybenzene as internal standard (¹H

relaxation time: 25 s). [d] With respect to quinoline product 1c. [e] Remaining

substrate: 62%. [f] Using 10% acetone as co-solvent in ethanol. [g] Isolated

yield: 91%.

The data in Table 2 reveal that the medium-pressure Hg-lamp

combined with

concentrations (20 mM) giving full conversion of substrate and

high ¹H-NMR yields for residence times of 60 and 20 min,

a

low-pass filter performs well at low

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respectively (entries 1 and 2). Most notably, upon increasing the

concentration to 100 mM a significant drop in conversion is

observed with the medium-pressure Hg-lamp giving only 36% of

the quinoline product (entry 3). While the high-power LED lamp

shows a similar performance at low concentration (20 mM, entries

4 and 5), it is superior at higher concentration (100 mM), where a

high yield of 93% is maintained (entry 6). Further increase of

concentration to 150 mM (using 10% acetone as co-solvent with

ethanol) allows for 96% yield and a throughput of 4.3 mmol/h

(entry 7). Next, the reduction of residence time was studied for the

LED lamp while maintaining the concentration at 100 mM. This

indicated a constant yield of above 90% (entries 8, 9 and 10) that

was mirrored by an isolated yield of 91% for entry 8. Importantly,

this allows for significantly increasing the throughput, reaching

7.18 mmol/h for entry 10, which is equal to 1.47 g/h for this

quinoline product (1c).

Scheme 3. Quinoline product scope.

Thus, incorporation of various substituents at the 2-position of the

quinoline scaffold was readily achieved including alkyl, aryl and

heteroaryl moieties. Furthermore, substitution on the 6- and 7-

position was tolerated for incorporating amino as well as various

ether groups. The connectivity of the quinoline structures was

furthermore verified via single crystal X-ray diffraction

experiments on selected products (Figure 1).

In summary, this study indicates that the high-power LED lamp

outperforms the medium-pressure Hg-lamp in this application as

it allows for greater efficiency and yield at higher concentrations.

This observation is paralleled by a distinctly lighter color of the

exiting product solution for the LED lamp compared to the Hg-

lamp, which may indicate higher selectivity due to near-

monochromatic light being used.^[21]Thus, it can be stated that the

high-power LED was found to be superior to the Hg-lamp in terms

of performance (yield and throughput), selectivity (avoiding

colored impurities) and energy efficiency (LED: 75 W input power

vs. Hg-lamp: 110 W).

Figure 1: X-ray structures of quinolines 1c, 1e, 1j and 1n.

In view of the effectiveness of this flow process we next wished to

evaluate its scalability over a period of several hours. We selected

substrate 3a for this study as a previous report^18ahad evaluated

its scaled preparation in a photochemical batch operation yielding

1.49 g of the desired quinoline product (1a, 10.4 mmol, 93% yield)

over a period of 5 days using a blue LED lamp (5 W power). To

generate sufficient quantities of substrate 3a we opted to use a

modified 2-step approach as reported by List^[22]to avoid the

formation of indigo dye as a consequence of a competing Baeyer-

Drewson reaction.^[23]This batch process generated the aldol

adduct, which was subsequently dehydrated under acidic

conditions (pTSA) as outlined in Scheme 4.

Having established the advantages of the high-power LED

module, we next turned our attention to studying the scope of this

continuous quinoline synthesis. We employed the LED module

(75 W, ~30 °C) in combination with a residence time of 10-15

minutes and substrate concentrations of 100 mM (EtOH, solubility

permitting). Pleasingly, it was found that all enone substrates 3a-

p underwent the desired photochemical tandem process and

rendered the desired quinoline products in high yield (Scheme 3).

Scheme 4. Scaled flow synthesis of quinoline 1a.

Next, we prepared a stock solution of substrate 3a (220 mM in

EtOH) matching the concentration previously reported^18aand

processed this solution through the flow system (LED, 75 W, 0.8

mL/min, 12.5 min residence time, ~30 °C) over a period of 2.4

hours. After evaporation of the solvent and passing the crude

product over a plug of silica (eluent 5% EtOAc/hexanes) 3.25 g of

the pure quinoline product was isolated as a yellow oil. This

renders a throughput of 9.5 mmol/h which is ~110-fold higher than

the reported batch throughput and clearly demonstrates the value

of this photochemical flow process in rapidly generating

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significant amounts of target product that would not be achievable

in batch mode.

underwent the chemoselective nitro reduction under the

previously established conditions (Scheme 6).

A solution of 10 (50 mM, EtOH) was then passed through the LED

reactor (residence time 15 min) cleanly generating the

corresponding quinoline (11) bearing an alkene moiety in the 2-

position (alkene mixture ~7:1). Initially, this alkene mixture was

subjected to flow hydrogenation conditions in the absence of acid

(EtOH, 1 mL/min, 10% Pd/C, rt, 15 bar) providing quinoline

derivative 12 as the sole product. It is of note that this structure

has been reported as a natural product with molluscicide activity

previously.^[28]In contrast, when performing this hydrogenation in

the presence of acid (HOAc), the formation of the corresponding

tetrahydroquinoline product is observed (13, des-methyl

galipinine). Furthermore, upon addition of formaldehyde (2 equiv.

HCHO aq.) the alkene hydrogenation is coupled with both the

formation of the tetrahydroquinoline and the N-methylation thus

directly furnishing galipinine 14 in racemic form.^[29]Finally, the

optimized flow sequence comprising of the photochemical

quinoline synthesis and the hydrogenation cascade was

performed in a telescoped manner as before producing galipinine

in 72% yield from amine precursor 10 (Scheme 6).

As stated earlier, it was noted that this flow process is not only

remarkably efficient, but moreover generates the quinoline targets

in high yield and purity without recourse to using additives in the

form of photocatalysts or sensitizers. The high purity of the

quinoline solution exiting the LED reactor system further

prompted us to investigate the possibility of directly telescoping a

subsequent chemical reaction to diversify the heterocyclic

products in a streamlined manner.

In view of this we decided to evaluate the conversion of the

quinoline products into tetrahydroquinolines via a telescoped flow

hydrogenation process. This was additionally fueled by the

therapeutic value of tetrahydroquinolines that have been popular

bioactive targets of flow-based transformations before.^[24]

We thus decided to pass the quinoline solution exiting the LED

reactor directly into an H-Cube Mini™ equipped with a catalyst

cartridge containing a Pd-catalyst (10% Pd/C, 70 mm length).

Precedent from the literature reports this approach as a powerful

means to achieve the saturation of various azacyclic aromatic

substrates.^[25]A set of test reactions using quinoline 1c as a model

substrate demonstrated that suitable reaction conditions were

based on lowered concentration (20-50 mM EtOH, containing 0.1

equiv. HOAc) with a flow rate of 1 mL/min while the catalyst

cartridge was maintained at 50 °C under a pressure of 15 bar. The

telescoped process was subsequently realized by firstly diluting

the quinoline stream with EtOAc (1-4 mL/min, cat. HOAc) prior to

transferring the solution (now 20-50 mM) via a holding reservoir^[26]

into the H-Cube™ Pd-cartridge (50 °C, 15 bar, 1 mL/min).

Pleasingly, this set of conditions proved effective in generating the

desired tetrahydroquinoline products 8 in high yields with

residence times for the hydrogenation of less than 1 min. Scheme

5 summarizes the reaction set-up and the tetrahydroquinolines

accessed via this telescoped flow process.

Scheme 6. Telescoped flow synthesis of galipinine 14.

Conclusion

In summary we have developed a continuous photochemical

quinoline synthesis that exploits readily available amino enones

and renders the target heterocycles in high yield and efficiency. A

new high-power LED light source was thereby identified as a more

effective means than an alternative medium-pressure Hg-lamp.

Scheme 5. Telescoped flow synthesis of tetrahydroquinolines 8.

[30]

Scalability via this optimized set-up was demonstrated

providing quinoline products at a rate greater 1 g/h. The high

purity of the quinoline stream furthermore allowed for telescoping

the photochemical synthesis into a subsequent Pd-catalyzed

hydrogenation stage to deliver a set of tetrahydroquinolines.

Finally, this process was applied to the telescoped flow synthesis

of the antimalarial alkaloid galipinine that was generated in high

yield and purity showcasing the value of utilizing this new high-

power LED lamp for continuous photochemical transformations.

The success of this telescoped flow sequence enabled us to

furthermore apply our method to the synthesis of a target structure,

namely the antimalarial natural product galipinine (14) which has

seen considerable interest by the synthetic community in recent

years.^[27]We envisioned that a suitable dienone precursor (9)

prepared by a sequential aldol condensation process from 2-

nitrobenzaldehyde, acetone and piperonal could be subjected to

the iron-mediated nitro-reduction to render the required amine

building block (10) for our telescoped reaction sequence. Indeed,

precursor

9 was prepared uneventfully and successfully

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(E)-4-(2-Nitrophenyl)but-3-en-2-one, (4a):³¹off-white solid. Melting

range 59-61 °C. Yield: 78% (570 mg, 3.0 mmol). ¹H-NMR (400 MHz,

CDCl₃) δ/ppm 8.06 (d, J = 8.7 Hz, 1H), 7.96 (d, J = 16.2 Hz, 1H), 7.68 –

7.61 (m, 2H), 7.54 (ddd, J = 8.6, 6.7, 2.2 Hz, 1H), 6.55 (d, J = 16.2 Hz, 1H),

2.41 (s, 3H). ¹³C-NMR (100 MHz, CDCl₃) δ/ppm 198.0 (C), 148.3 (C),

138.9 (CH), 133.7 (CH), 131.9 (CH), 130.8 (C), 130.4 (CH), 129.1 (CH),

125.0 (CH), 27.0 (CH₃). IR (neat) ν/cm^-1: 3067 (w), 1685 (s), 1605 (s), 1515

(s), 1342 (s), 1293 (s), 1183 (s), 975 (s), 859 (m), 783 (m), 734 (s), 560

(m). HR-MS (TOF ES): calculated for C₁₀H₁₀NO₃192.0661, found

192.0656 (M+H+).

Experimental Section

Unless otherwise stated, all solvents were purchased from Fisher Scientific

and used without further purification. Substrates and reagents were

1

purchased from Fluorochem or Sigma Aldrich and used as received. H-

NMR spectra were recorded on the indicated instruments and are reported

relative to residual solvent: CHCl₃(δ 7.26 ppm) or DMSO (δ 2.50 ppm).

¹³C-NMR spectra were recorded on the same instruments and are

reported relative to CHCl₃(δ 77.16 ppm) or DMSO (δ 39.52 ppm). Data for

¹H-NMR are reported as follows: chemical shift (δ/ ppm) (multiplicity,

coupling constant (Hz), integration). Multiplicities are reported as follows:

s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, m = multiplet, br.

s = broad singlet, app = apparent. Data for ¹³C-NMR are reported in terms

of chemical shift (δ/ ppm) and multiplicity (C, CH, CH₂or CH₃). Data for

¹⁹F-NMR were recorded at a frequency of 376 MHz using CFCl₃as

external standard. DEPT-135, COSY, HSQC, HMBC and NOESY

experiments were used in the structural assignment. IR spectra were

obtained by use of a Bruker Platinum spectrometer (neat, ATR sampling)

with the intensities of the characteristic signals being reported as weak (w,

<20% of tallest signal), medium (m, 21-70% of tallest signal) or strong (s,

>71% of tallest signal). High-resolution mass spectrometry was performed

using the indicated techniques on a micromass LCT orthogonal time-of-

ﬂight mass spectrometer with leucine-enkephalin (Tyr-Gly-Phe-Leu) as an

internal lock mass. Melting points were recorded on a Stuart SMP10

melting point system and are uncorrected. Flow chemistry experiments

were performed with a Vapourtec E-series system in combination with the

UV150 photochemistry module (medium-pressure Hg lamp or high-power

LED).

General procedure for the preparation of 4b-p and 9a,b: To a solution

of a 2-nitrobenzaldehyde derivative (1 equiv.) and methyl ketone (1 equiv.)

in acetonitrile (1 M) was added a solution of NaOH (1.0 equiv, 1 M

water/ethanol, 50/50 by volume) dropwise at room temperature. Upon

stirring the desired aldol condensation product precipitated within 60

minutes and was collected by filtration. After washing with cold

ethanol/water (~50/50 by volume) und drying under suction the desired

product was isolated as a coloured solid, which can be recrystalized from

hot ethyl acetate.

(E)-4,4-Dimethyl-1-(2-nitrophenyl)pent-1-en-3-one, (4b):³²yellow oil.

Yield: 83% (385 mg, 1.6 mmol). ¹H-NMR (500 MHz, CDCl₃) δ/ppm 8.06 (d,

J = 15.5 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.67 – 7.62 (m, 2H), 7.56 – 7.51

(m, 1H), 7.01 (d, J = 15.5 Hz, 1H), 1.24 (s, 9H). ¹³C-NMR (125 MHz, CDCl₃)

δ/ppm 203.2 (C), 148.7 (CH), 138.1 (CH), 133.3 (CH), 131.4 (C), 130.0

(CH), 129.2 (CH), 125.6 (CH), 124.9 (CH), 43.3 (C), 26.1 (3CH₃). IR (neat)

ν/cm^-1: 2955 (w), 1680 (m), 1600 (m), 1523 (s), 1469 (m), 1335 (s), 1291

(m), 1082 (s), 984 (s), 751 (s), 567 (m). HR-MS (TOF ES): calculated for

C₁₃H₁₆NO₃234.1130, found 234.1141 (M+H+).

Procedure for the preparation of aldol product 4a’ and 4a:

(E)-3-(2-Nitrophenyl)-1-phenylprop-2-en-1-one, (4c):³³white solid.

Melting range 120-121 °C. Yield: 85% (430 mg, 1.7 mmol). ¹H-NMR (500

MHz, CDCl₃) δ/ppm 8.15 (d, J = 15.7 Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H),

8.03 (d, J = 7.2 Hz, 1H), 8.02 (s, 1H), 7.76 (d, J = 7.3 Hz, 1H), 7.70 (t, J =

7.3 Hz, 1H), 7.63 – 7.56 (m, 2H), 7.53 (t, J = 7.7 Hz, 2H), 7.33 (d, J = 15.7

Hz, 1H). ¹³C-NMR (125 MHz, CDCl₃) δ/ppm 190.4 (C), 148.5 (C), 140.1

(CH), 137.4 (C), 133.6 (CH), 133.1 (CH), 131.3 (C), 130.3 (CH), 129.2

(CH), 128.8 (2CH), 128.7 (2CH), 127.3 (CH), 125.0 (CH). IR (neat) ν/cm^-1:

1667 (m), 1602 (m), 1510 (s), 1445 (m), 1339 (s), 1288 (s), 1214 (m), 1010

(m), 858 (m), 740 (s), 682 (s). HR-MS (TOF ES): calculated for C₁₅H₁₂NO₃

254.0817, found 254.0806 (M+H+).

L-Proline (0.3 equiv.) was added to a mixture of DMSO/acetone (1:4 by

volume, 0.2 M) and the suspension was left to stir for 15-20 min at room

temperature. While stirring, 2-nitrobenzaldehyde (1 equiv.) was added to

the suspension. The reaction was monitored by TLC (EtOAc/Hex, 25:75).

After competition, a saturated aqueous solution of NH₄Cl was added and

the product was extracted with EtOAc. After evaporation of the solvent, the

product was dissolved in toluene (0.1 M) containing pTSA (50 mol%). The

solution was left to stir for 2 h at 120 °C. After competition, a saturated

aqueous solution of NaHCO₃was added and the organic layer was

separated and evaporated. The brown oil obtained was purified through

trituration from Hex/EtOAc (9:1) generating an off-white powder.

4-Hydroxy-4-(2-nitrophenyl)butan-2-one, (4a’):³¹brown oil. Yield: 84%

(E)-1-(2-Fluorophenyl)-3-(2-nitrophenyl)prop-2-en-1-one, (4d): off-

white solid. Melting range 128-131 °C. Yield: 91% (2.47 g, 9.1 mmol). ¹H-

NMR (400 MHz, CDCl₃) δ/ppm 8.08 (dd, J = 15.9, 1.7 Hz, 1H), 8.02 (d, J

= 8.2 Hz, 1H), 7.81 (td, J = 7.6, 1.9 Hz, 1H), 7.72 (dd, J = 8.0, 1.5 Hz, 1H),

7.65 (t, J = 7.6 Hz, 1H), 7.57 – 7.48 (m, 2H), 7.28 – 7.21 (m, 2H), 7.14 (dd,

J = 10.9, 8.2 Hz, 1H). ¹³C-NMR (100 MHz, CDCl₃) δ/ppm 188.4 (d, J = 2

Hz, C), 161.3 (d, J = 253 Hz, CF), 148.6 (C), 139.9 (CH), 134.4 (d, J = 8

Hz, CH), 133.6 (CH), 131.1 (d, J = 2 Hz, CH), 130.9 (C), 130.5 (CH), 130.1

(d, J = 6 Hz, CH), 129.2 (CH), 126.3 (d, J = 13 Hz, C), 124.9 (CH), 124.6

(d, J = 4 Hz, CH), 116.6 (d, J = 23 Hz, CH). ¹⁹F-NMR (376 MHz, CDCl₃)

δ/ppm -110.7. IR (neat) ν/cm^-1: 1664 (m), 1602 (m), 1512 (s), 1474 (m),

1451 (m), 1199 (m), 1018 (m), 966 (m), 745 (s), 726 (m) HR-MS (TOF ES):

calculated for C₁₅H₁₁FNO₃272.0717, found 272.0719 (M+H⁺).

1

(1.75 g, 8.4 mmol). H-NMR (500 MHz, CDCl₃) δ/ppm 7.97 (dd, J = 8.2,

1.2 Hz, 1H), 7.91 (dd, J = 7.9, 1.3 Hz, 1H), 7.68 (td, J = 8.1, 1.0 Hz, 1H),

7.45 (td, J = 8.4, 1.4 Hz, 1H), 5.69 (dt, J = 9.5, 2.4 Hz, 1H), 3.74 (d, J = 3.0

Hz, 1H), 3.15 (dd, J = 17.8, 2.1 Hz, 1H), 2.74 (dd, J = 17.8, 9.4 Hz, 1H),

2.25 (s, 3H). ¹³C-NMR (125 MHz, CDCl₃) δ/ppm 208.8 (C), 147.2 (C),

138.3 (C), 133.8 (CH), 128.3 (CH), 128.2 (CH), 124.4 (CH), 65.7 (CH),

51.0 (CH₂), 30.5 (CH₃). IR (neat) ν/cm^-1: 3411 (broad, w), 2962 (w), 1707

(m), 1521 (s), 1343 (s), 1259 (m), 1064 (m), 790 (m), 742 (m). HR-MS

(TOF ES): calculated for C₁₀H₁₁NO₄Na 232.0586, found 232.0584 (M+Na).

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(E)-1-(2,4-Difluorophenyl)-3-(2-nitrophenyl)prop-2-en-1-one,

(4e):

(E)-3-(2-Nitrophenyl)-1-(thiophen-2-yl)prop-2-en-1-one, (4i):³⁶red solid.

1

orange solid. Melting range 100-103 °C. Yield: 68% (984 mg, 3.4 mmol).

¹H-NMR (400 MHz, CDCl₃) δ/ppm 8.12 (dd, J = 15.6, 1.6 Hz, 1H), 8.04 (dd,

J = 8.2, 1.1 Hz, 1H), 7.90 (td, J = 8.6, 6.6 Hz, 1H), 7.72 (dd, J = 7.8, 1.5

Hz, 1H), 7.66 (td, J = 7.3, 0.8 Hz, 1H), 7.55 (td, J = 7.9, 7.4, 1.6 Hz, 1H),

7.27 - 7.19 (m, 1H), 7.03 – 6.96 (m, 1H), 6.89 (ddd, J = 11.0, 8.7, 2.4 Hz,

1H). ¹³C-NMR (100 MHz, CDCl₃) δ/ppm 186.7 (d, J = 3 Hz, C), 165.6 (dd,

J = 258, 12 Hz, CF), 162.1 (dd, J = 258, 12 Hz, CF), 148.6 (C), 140.2 (CH),

133.5 (CH), 133.1 (dd, J = 11, 4 Hz, CH), 130.9 (C), 130.5 (CH), 129.7 (d,

J = 7 Hz, CH), 129.2 (CH), 125.0 (CH), 122.8 (dd, J = 13, 3 Hz, C), 112.4

(dd, J = 22, 3 Hz, CH), 104.8 (dd, J = 27 26 Hz, CH). ¹⁹F-NMR (376 MHz,

CDCl₃) δ/ppm -101.7, -105.7. IR (neat) ν/cm^-1: 3076 (w), 1660 (m), 1601

(s), 1521 (s), 1422 (m), 1281 (s), 1229 (s), 1097 (s), 989 (s), 867 (m), 754

(s), 554 (w). HR-MS (TOF ES): calculated for C₁₅H₉NO₃F₂Na 312.0448,

found 312.0437 (M+H+).

Melting range 125-128 °C. Yield: 65% (1.69 g, 6.5 mmol). H-NMR (400

MHz, CDCl₃) δ/ppm 8.19 (d, J = 15.5 Hz, 1H), 8.06 (dd, J = 8.1, 1.1 Hz,

1H), 7.87 (dd, J = 3.8, 1.0 Hz, 1H), 7.73 – 7.65 (m, 3H), 7.55 (ddd, J = 8.4,

7.4, 1.6 Hz, 1H), 7.24 (d, J = 15.6 Hz, 1H), 7.20 (dd, J = 3.8, 1.1 Hz, 1H).

¹³C-NMR (100 MHz, CDCl₃) δ/ppm 181.7 (C), 148.6 (C), 144.6 (C), 139.3

(CH), 134.5 (CH), 133.5 (CH), 132.6 (CH), 131.2 (C), 130.3 (CH), 129.3

(CH), 128.3 (CH), 126.9 (CH), 125.0 (CH). IR (neat) ν/cm^-1: 1650 (m), 1602

(m), 1508 (s), 1411 (m), 1339 (m), 1289 (m), 1234 (m), 1062 (w), 968 (m),

848 (m), 714 (s), 582 (m). HR-MS (TOF ES): calculated for C₁₃H₁₀NO₃S

260.0381, found 260.0378 (M+H⁺).

(E)-1-(4-Fluoro-3-(trifluoromethyl)phenyl)-3-(2-nitrophenyl)prop-2-

en-1-one, (4j): beige solid. Melting range 146-148 °C. Yield: 88% (2.98 g,

8.8 mmol). ¹H-NMR (400 MHz, CDCl₃) δ/ppm 8.29 – 8.25 (m, 1H), 8.25 –

8.20 (m, 1H), 8.15 (d, J = 15.6 Hz, 1H), 8.08 (dd, J = 8.0, 1.3 Hz, 1H), 7.75

– 7.66 (m, 2H), 7.58 (ddd, J = 8.6, 6.8, 2.0 Hz, 1H), 7.34 (t, J = 9.2 Hz, 1H),

7.25 (d, J = 15.6 Hz, 1H). ¹³C-NMR (100 MHz, CDCl₃) δ/ppm 187.7 (C),

162.5 (dq, J = 263, 2 Hz, CF), 148.5 (C), 141.6 (CH), 134.7 (d, J = 10 Hz,

CH), 133.7 (CH), 133.7 (C), 130. 9 (C), 130.7 (CH), 129.3 (CH), 128.5 –

128.2 (m, CH), 126.0 (CH), 125.1 (CH), 122.1 (qd, J = 273, 2 Hz, CF₃),

119.0 (qd, J = 34, 15 Hz, C), 117.6 (d, J = 20 Hz, CH). ¹⁹F-NMR (376 MHz,

CDCl₃) δ/ppm -61.6 (d, J = 13 Hz), -106.6 (m). IR (neat) ν/cm^-1: 3073 (w),

1667 (m), 1618 (m), 1603 (m), 1519 (s), 1323 (s), 1275 (s), 1173 (s), 1128

(s), 1056 (m), 842 (s), 752 (s). HR-MS (TOF ES): calculated for

C₁₆H₁₀F₄NO₃340.0591, found 340.0594 (M+H+).

(E)-1-(4-Methoxyphenyl)-3-(2-nitrophenyl)prop-2-en-1-one,

(4f):³⁴

light green solid. Melting range 92-94 °C. Yield: 48% (137 mg, 0.48 mmol).

¹H-NMR (500 MHz, CDCl₃) δ/ppm 8.11 (d, J = 15.7 Hz, 1H), 8.06 (dd, J =

8.2, 1.1 Hz, 1H), 8.04 (app. d, J = 8.9 Hz, 2H), 7.74 (dd, J = 7.8, 1.3 Hz,

1H), 7.68 (t, J = 8.0 Hz, 1H), 7.56 (t, J = 8.4 Hz, 1H), 7.32 (d, J = 15.7 Hz,

1H), 6.99 (app. d, J = 8.9 Hz, 2H), 3.90 (s, 3H). ¹³C-NMR (125 MHz, CDCl₃)

δ/ppm 188.7 (C), 163.7 (C), 148.6 (C), 139.2 (CH), 133.5 (CH), 131.6 (C),

131.2 (2CH), 130.3 (C), 130.1 (CH), 129.3 (CH), 127.4 (CH), 125.0 (CH),

114.0 (2CH), 55.5 (CH₃). IR (neat) ν/cm^-1: 2839 (w), 1651 (m), 1592 (s),

1512 (s), 1338 (m), 1259 (s), 1180 (s), 977 (s), 835 (s), 756 (s), 572 (m).

HR-MS (TOF ES): calculated for C₁₆H₁₄NO₄284.0923, found 284.0908

(M+H+).

(E)-1-(5-Methylfuran-2-yl)-3-(2-nitrophenyl)prop-2-en-1-one (4k): grey

1

solid. Melting range 126-128 °C. Yield: 85% (2.18 g, 8.5 mmol). H-NMR

(E)-1-(1H-Indol-3-yl)-3-(2-nitrophenyl)prop-2-en-1-one, (4g): dark

yellow solid. Melting range ~190 °C (decomposition). Yield: 71% (250 mg,

0.86 mmol). ¹H-NMR (500 MHz, DMSO-d₆) δ/ppm 12.19 (s, 1H), 8.75 (d,

J = 2.7 Hz, 1H), 8.33 (d, J = 7.2 Hz, 1H), 8.20 (d, J = 7.7 Hz, 1H), 8.06 (d,

J = 8.0 Hz, 1H), 7.88 (d, J = 15.4 Hz, 1H), 7.84 (d, J = 15.4 Hz, 1H), 7.82

(t, J = 6.9 Hz, 1H), 7.66 (t, J = 7.7 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.25

(m, 2H). ¹³C-NMR (125 MHz, DMSO-d₆) δ/ppm 183.3 (C), 149.3 (C), 137.4

(C), 135.9 (CH), 134.2 (CH), 133.9 (CH), 130.9 (CH), 130.5 (C), 129.6

(CH), 129.5 (CH), 126.2 (C), 125.0 (CH), 123.8 (CH), 122.5 (CH), 122.2

(CH), 118.0 (C), 112.7 (CH). IR (neat) ν/cm^-1: 3221 (w), 1641 (m), 1586

(m), 1515 (s), 1440 (s), 1342 (m), 1239 (m), 1153 (m), 962 (m), 744 (s),

584 (m), 422 (m). HR-MS (TOF ES): calculated for C₁₇H₁₃N₂O₃293.0921,

found 293.0926 (M+H+).

(400 MHz, DMSO-d₆) δ/ppm 8.09 (dd, J = 7.8, 1.4 Hz, 1H), 8.05 (dd, J =

8.1, 1.3 Hz, 1H), 7.90 (d, J = 15.4 Hz, 1H), 7.82 – 7.76 (m, 2H), 7.66 (td, J

= 7.9, 1.5 Hz, 1H), 7.62 (d, J = 15.5 Hz, 1H), 6.44 (dd, J = 3.5, 1.2 Hz, 1H),

2.39 (s, 3H). ¹³C-NMR (100 MHz, DMSO-d₆) δ/ppm 175.6 (C), 159.7 (C),

152.0 (C), 149.2 (C), 137.0 (CH), 134.1 (CH), 131.4 (CH), 130.0 (C), 129.7

(CH), 126.8 (CH), 125.1 (CH), 122.9 (CH), 110.2 (CH), 14.2 (CH₃). IR

(neat) ν/cm^-1: 3104 (w), 1651 (s), 1597 (s), 1571 (m), 1505 (s), 1333 (s),

1289 (s), 1067 (m), 1029 (s), 977 (s), 793 (s), 751 (s). HR-MS (TOF ES):

calculated for C₁₄H₁₂NO₄258.0761, found 258.0762 (M+H+).

(E)-1-(Benzo[d][1,3]dioxol-5-yl)-3-(2-nitrophenyl)prop-2-en-1-one,

(4l): light brown solid. Melting range 106-108 °C. Yield: 90% (2.67 g, 9.0

mmol). ¹H-NMR (400 MHz, CDCl₃) δ/ppm 8.08 (d, J = 15.6 Hz, 1H), 8.04

(dd, J = 8.2, 1.3 Hz, 1H), 7.71 (dd, J = 7.8, 1.6 Hz, 1H), 7.68 – 7.64 (m,

1H), 7.62 (dd, J = 8.2, 1.8 Hz, 1H), 7.53 (td, J = 7.7, 1.6 Hz, 1H), 7.49 (d,

J = 1.8 Hz, 1H), 7.27 (d, J = 15.6 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 6.05 (s,

2H). ¹³C-NMR (100 MHz, CDCl₃) δ/ppm 188.1 (C), 152.0 (C), 148.5 (C),

148.4 (C), 139.4 (CH), 133.5 (CH), 132.2 (C), 131.4 (C), 130.2 (CH), 129.2

(CH), 127.0 (CH), 125.2 (CH), 124.9 (CH), 108.5 (CH), 108.0 (CH), 101.9

(CH₂). IR (neat) ν/cm^-1: 2906 (w), 1654 (m), 1595 (s), 1523 (s), 1441 (s),

1343 (s), 1245 (s), 1110 (s), 1038 (s), 815 (s), 748 (s). HR-MS (TOF ES):

calculated for C₁₆H₁₂NO₅298.0710, found 298.0712 (M+H+).

(E)-1-(2,4-Dimethoxyphenyl)-3-(2-nitrophenyl)prop-2-en-1-one,

(4h):³⁵light green solid. Melting range ~146 °C (decomposition). Yield:

84% (2.61 g, 8.4 mmol). ¹H-NMR (400 MHz, CDCl₃) δ/ppm 8.00 – 7.93 (m,

2H), 7.75 (d, J = 8.6 Hz, 1H), 7.68 (dd, J = 7.8, 1.5 Hz, 1H), 7.62 (td, J =

7.6, 1.3 Hz, 1H), 7.49 (ddd, J = 8.5, 7.4, 1.5 Hz, 1H), 7.35 (d, J = 15.6 Hz,

1H), 6.55 (dd, J = 8.6, 2.3 Hz, 1H), 6.47 (d, J = 2.3 Hz, 1H), 3.88 (s, 3H),

3.85 (s, 3H). ¹³C-NMR (100 MHz, CDCl₃) δ/ppm 189.8 (C), 164.5 (C),

160.5 (C), 148.7 (C), 136.8 (CH), 133.2 (CH), 133.1 (CH), 131.9 (CH),

131.6 (C), 129.8 (CH), 129.2 (CH), 124.8 (CH), 121.3 (C), 105.4 (CH), 98.6

(CH), 55.7 (CH₃), 55.6 (CH₃). IR (neat) ν/cm^-1: 3014 (w), 2843 (w), 1649

(m), 1591 (s), 1522 (s), 1421 (s), 1268 (m), 1251 (s), 1012 (s), 965 (s), 823

(s). HR-MS (TOF ES): calculated for C₁₇H₁₆NO₅314.1023, found 314.1026

(M+H+).

(E)-1-(4-Methoxyphenyl)-3-(5-morpholino-2-nitrophenyl)prop-2-en-1-

one (4m): orange solid. Melting range 159-161 °C. Yield: 86% (1.58 g, 4.3

mmol). ¹H-NMR (400 MHz, DMSO-d₆) δ/ppm 8.15 – 8.08 (m, 3H), 8.04 (d,

J = 9.4 Hz, 1H), 7.71 (d, J = 15.5 Hz, 1H), 7.25 (d, J = 2.8 Hz, 1H), 7.07

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(m, 3H), 3.84 (s, 3H), 3.73 (t, J = 4.9 Hz, 4H), 3.46 (t, J = 4.9 Hz, 4H). ¹³C-

NMR (100 MHz, DMSO-d₆) δ/ppm 187.9 (C), 163.9 (C), 154.4 (C), 141.2

(CH), 137.9 (C), 134.2 (C), 131.6 (2CH), 130.5 (C), 128.0 (CH), 126.2 (CH),

114.5 (2CH), 114.1 (CH), 113.1 (CH), 66.2 (2CH₂), 56.1 (CH₃), 47.0 (2CH₂).

IR (neat) ν/cm^-1: 2967 (w), 1597 (s), 1568 (m), 1497 (m), 1296 (s), 1252

(s), 1167 (m), 1117 (m), 1042 (m), 904 (m), 815 (s), 750 (m). HR-MS (TOF

ES): calculated for C₂₀H₂₁N₂O₅369.1445, found 369.1450 (M+H+).

101.6 (CH₂), 27.5 (CH₃). IR (neat) ν/cm^-1: 2905 (w), 1669 (m), 1642 (s),

1622 (s), 1596 (s), 1499 (s), 1441 (s), 1236 (s), 1103 (s), 1036 (s), 977 (s),

926 (s), 803 (s). HR-MS (TOF ES): calculated for C₁₁H₁₁O₃191.0703,

found 191.0704 (M+H+).

(1E,4E)-1-(Benzo[d][1,3]dioxol-5-yl)-5-(2-nitrophenyl)penta-1,4-dien-

3-one, (9b): yellow powder. Melting range 175-177 °C. Yield: 92% (2.67 g,

8.3 mmol). ¹H-NMR (400 MHz, DMSO-d₆) δ/ppm 8.04 (d, J = 8.0 Hz, 1H),

7.97 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 15.8 Hz, 1H), 7.79 (d, J = 7.5 Hz, 1H),

7.74 (d, J = 15.8 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.40 (d, J = 1.7 Hz, 1H),

7.29 (d, J = 15.8 Hz, 1H), 7.23 (dd, J = 8.2, 1.7 Hz, 1H), 7.10 (d, J = 15.8

Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 6.06 (s, 2H). ¹³C-NMR (100 MHz, DMSO-

d₆) δ/ppm 188.5 (C), 150.1 (C), 149.1 (C), 148.6 (C), 144.3 (CH), 137.3

(CH), 134.2 (CH), 131.3 (CH), 130.4 (C), 129.8 (CH), 129.6 (CH), 129.4

(C), 126.1 (CH), 125.2 (CH), 124.4 (CH), 109.1 (CH), 107.1 (CH), 102.2

(CH₂). IR (neat) ν/cm^-1: 2911 (w), 1650 (s), 1593 (s), 1507 (s), 1452 (s),

1341 (s), 1253 (s), 1193 (s), 1034 (s), 975 (s), 931 (s), 862 (s), 799 (s),

747 (m). HR-MS (TOF ES): calculated for C₁₈H₁₄NO₅324.0866, found

324.0867 (M+H+).

(E)-1-(2-Fluoro-4-methoxyphenyl)-3-(2-nitro-5-(2,2,2-trifluoroethoxy)-

phenyl)prop-2-en-1-one (4n): grey powder. Melting range 136-139 °C.

Yield: 84% (1.68 g, 4.2 mmol). ¹H-NMR (400 MHz, DMSO-d₆) δ/ppm 8.13

(d, J = 9.2 Hz, 1H), 7.94 (d, J = 15.6 Hz, 1H), 7.86 (t, J = 8.7 Hz, 1H), 7.54

(d, J = 2.9 Hz, 1H), 7.50 (dd, J = 15.6, 2.5 Hz, 1H), 7.29 (dd, J = 9.1, 2.8

Hz, 1H), 6.95 (dd, J = 13.4, 2.4 Hz, 1H), 6.91 (dd, J = 8.5, 2.5 Hz, 1H),

5.00 (q, J = 8.8 Hz, 2H), 3.84 (s, 3H). ¹³C-NMR (100 MHz, DMSO-d₆)

δ/ppm 186.8 (d, J = 3 Hz, C), 165.0 (d, J = 12 Hz, C), 162.9 (d, J = 254 Hz,

CF), 160.8 (C), 143.0 (C), 138.9 (CH), 133.5 (C), 132.8 (d, J = 4 Hz, CH),

130.3 (d, J = 5 Hz, CH), 128.0 (CH), 124.1 (q, J = 278 Hz, CF₃), 119.1 (d,

J = 12 Hz, C), 117.2 (CH), 115.1 (CH), 111.6 (d, J = 3 Hz, CH), 102.6 (d,

J = 27 Hz, CH), 65.5 (q, J = 35 Hz, CH₂), 56.6 (CH₃). ¹⁹F-NMR (376 MHz,

DMSO-d₆) δ/ppm -72.5 (t, J = 8.8 Hz), -107.8 (ddd, J = 12.8, 9.1, 2.6 Hz).

IR (neat) ν/cm^-1: 3106 (w), 1660 (w), 1620 (s), 1597 (s), 1572 (m), 1513

(s), 1240 (s), 1223 (s), 1171 (s), 1154 (s), 1115 (s), 1096 (s), 1017 (m),

960 (m), 860 (s), 832 (m). HR-MS (TOF ES): calculated for C₁₈H₁₄NO₅F₄

400.0808, found 400.0813 (M+H⁺).

General procedure for the preparation of 3a-p, and 7c,7o,10: To a

suspension of aldol product 4 (1 equiv.) in EtOH (0.5 M) was added iron

powder (10 equiv.) and HCl (10 mol%, aqueous). The resulting mixture

was stirred at 70 °C until TLC indicated full conversion of substrate (~1 h).

The resulting mixture was allowed to cool to ambient and diluted with

EtOAc (10 mL) before filtering over a pad of celite (~10 cm) to remove

residual iron. Further purification was achieved by silica column

chromatography using EtOAc/hexanes (20-30%) as eluent allowing

isolation of 7c and 7o.

(E)-3-(6-Nitrobenzo[d][1,3]dioxol-5-yl)-1-phenylprop-2-en-1-one, (4o):

light green solid. Yield: 88% (2.61 g, 8.8 mmol). ¹H-NMR (400 MHz, CDCl₃)

δ/ppm 8.10 (d, J = 15.5 Hz, 1H), 7.98 (dd, J = 8.4, 1.4 Hz, 2H), 7.61 – 7.55

(m, 1H), 7.54 (s, 1H), 7.52 – 7.45 (m, 2H), 7.19 (d, J = 15.5 Hz, 1H), 7.07

(s, 1H), 6.16 (s, 2H). ¹³C-NMR (100 MHz, CDCl₃) δ/ppm 190.6 (C), 152.1

(C), 149.1 (C), 143.3 (C), 140.7 (CH), 137.5 (C), 133.0 (CH), 128.7 (2CH),

128.7 (2CH), 128.0 (C), 126.4 (CH), 107.4 (CH), 105.8 (CH), 103.4 (CH₂).

IR (neat) ν/cm^-1: 3055 (w), 2919 (w), 1657 (m), 1597 (s), 1500 (s), 1481

(s), 1317 (s), 1263 (s), 1211 (s), 1011 (s), 967 (s), 925 (s), 755 (s). HR-MS

(TOF ES): calculated for C₁₆H₁₂NO₅298.0710, found 298.0715 (M+H+).

(E)-4-(2-Aminophenyl)but-3-en-2-one, (3a):³⁷orange oil. Yield: 93%

(115 mg, 0.77 mmol). ¹H-NMR (400 MHz, CDCl₃) δ/ppm 7.68 (d, J = 15.9

Hz, 1H), 7.40 (dd, J = 7.8, 1.5 Hz, 1H), 7.19 (ddd, J = 8.2, 7.3, 1.5 Hz, 1H),

6.78 (t, J = 7.2 Hz, 1H), 6.71 (dd, J = 8.1, 0.9 Hz, 1H), 6.67 (d, J = 15.9 Hz,

1H), 3.97 (s, 2H), 2.37 (s, 3H). ¹³C-NMR (100 MHz, CDCl₃) δ/ppm 198.1

(C), 145.8 (C), 138.6 (CH), 131.6 (CH), 128.2 (CH), 126.8 (CH), 119.9 (C),

119.1 (CH), 116.9 (CH), 28.0 (CH₃). IR (neat) ν/cm^-1: 3438 (m), 3243 (w),

1664 (s), 1636 (s), 1590 (s), 1488 (s), 1316 (m), 1248 (s), 1159 (m), 974

(m), 751 (m). HR-MS (TOF ES): calculated for C₁₀H₁₂NO 162.0913, found

162.0916 (M+H+).

(E)-3-(6-Nitrobenzo[d][1,3]dioxol-5-yl)-1-(thiophen-2-yl)prop-2-en-1-

one (4p): yellow powder. Melting range 162-165 °C. Yield: 83% (2.51 g,

1

8.3 mmol). H-NMR (400 MHz, CDCl₃) δ/ppm 8.17 (d, J = 15.4 Hz, 1H),

7.85 (dd, J = 3.8, 1.3 Hz, 1H), 7.68 (dd, J = 5.1, 1.1 Hz, 1H), 7.53 (s, 1H),

7.17 (dd, J = 5.0, 3.7 Hz, 1H), 7.11 (d, J = 15.4 Hz, 1H), 7.06 (s, 1H), 6.16

(s, 2H). ¹³C-NMR (100 MHz, CDCl₃) δ/ppm 181.8 (C), 152.0 (C), 149.1 (C),

144.7 (C), 143.4 (C), 139.7 (CH), 134.4 (CH), 132.4 (CH), 128.3 (CH),

127.8 (C), 125.9 (CH), 107.4 (CH), 105.8 (CH), 103.4 (CH₂). IR (neat)

ν/cm^-1: 3111 (w), 2916 (w), 1644 (m), 1610 (m), 1585 (m), 1503 (s), 1480

(s), 1411 (s), 1266 (s), 1031 (s), 970 (s), 864 (m), 730 (s), 520 (m). HR-

MS (TOF ES): calculated for C₁₄H₁₀NO₅S 304.0274, found 304.0276

(M+H+).

(E)-1-(2-Aminophenyl)-4,4-dimethylpent-1-en-3-one, (3b):³⁷red oil.

Yield: 88% (627 mg, 3.1 mmol). ¹H-NMR (400 MHz, CDCl₃) δ/ppm 7.81 (d,

J = 15.4 Hz, 1H), 7.41 (dd, J = 7.8, 1.5 Hz, 1H), 7.15 (ddd, J = 8.2, 7.4, 1.5

Hz, 1H), 7.03 (d, J = 15.3 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.68 (dd, J =

8.1, 0.9 Hz, 1H), 3.98 (s, 2H), 1.21 (s, 9H). ¹³C-NMR (100 MHz, CDCl₃)

δ/ppm 204.3 (C), 146.0 (C), 138.1 (CH), 131.2 (CH), 127.9 (CH), 120.9

(CH), 120.3 (C), 118.7 (CH), 116.6 (CH), 43.1 (C), 26.4 (3CH₃). IR (neat)

ν/cm^-13367 (w), 2965 (m), 1672 (m), 1586 (s), 1459 (m), 1330 (s), 1262

(w), 1158 (m), 1077 (s), 1007 (m), 748 (s), 577 (w), 460 (w). HR-MS (TOF

ES): calculated for C₁₃H₁₈NO 204.1383, found 204.1386 (M+H+).

(E)-4-(Benzo[d][1,3]dioxol-5-yl)but-3-en-2-one, (9a): light yellow

powder. Melting range 110-113 °C. Yield: 90% (1.71 g, 9.0 mmol). ¹H-NMR

(400 MHz, CDCl₃) δ/ppm 7.40 (d, J = 16.1 Hz, 1H), 7.04 – 6.97 (m, 2H),

6.80 (d, J = 7.9 Hz, 1H), 6.53 (d, J = 16.1 Hz, 1H), 5.99 (s, 2H), 2.33 (s,

3H). ¹³C-NMR (100 MHz, CDCl₃) δ/ppm 198.2 (C), 149.8 (C), 148.4 (C),

143.2 (CH), 128.8 (C), 125.3 (CH), 124.8 (CH), 108.6 (CH), 106.5 (CH),

(E)-3-(2-Aminophenyl)-1-phenylprop-2-en-1-one, (3c):³⁷yellow solid.

Melting range 121-123 °C. Yield: 89% (382 mg, 1.5 mmol). ¹H-NMR (500

MHz, CDCl₃) δ/ppm 8.04 – 7.95 (m, 3H), 7.60 – 7.43 (m, 5H), 7.19 (ddd, J

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= 8.2, 7.3, 1.5 Hz, 1H), 6.78 (t, J = 7.3 Hz, 1H), 6.71 (dd, J = 8.1, 0.9 Hz,

1H), 4.06 (s, 2H). ¹³C-NMR (125 MHz, CDCl₃) δ/ppm 190.2 (C), 146.2 (C),

140.1 (CH), 138.3 (C), 132.7 (CH), 131.6 (CH), 128.6 (2CH), 128.4 (2CH),

128.1 (CH), 121.8 (CH), 120.3 (C), 118.9 (CH), 116.8 (CH). IR (neat) ν/cm^-

¹: 3333 (w), 3222 (w), 3031 (w), 1650 (m), 1569 (s), 1485 (m), 1341 (s),

1211 (s), 1155 (m), 1039 (s), 728 (s), 684 (s). HR-MS (TOF ES) calculated

for C₁₅H₁₄NO 224.1075, found 224.1076 (M+H⁺).

(C), 137.2 (C), 136.3 (CH), 134.5 (CH), 131.1 (CH), 127.8 (CH), 126.5 (C),

123.4 (CH), 122.8 (CH), 122.2 (CH), 122.1 (CH), 119.2 (C), 118.2 (C),

116.7 (CH), 116.7 (CH), 112.5 (CH). IR (neat) ν/cm^-1: 3322 (w), 2928 (w),

1628 (m), 1519 (s), 1442 (s), 1311 (m), 1157 (s), 966 (m), 858 (w), 735 (s),

639 (m), 519 (m), 431 (m). HR-MS (TOF ES): calculated for C₁₇H₁₅N₂O

263.1179, found 263.1183 (M+H+).

(E)-3-(2-Aminophenyl)-1-(2,4-dimethoxyphenyl)prop-2-en-1-one,

(3h): yellow oil. Yield: 89% (1.26 g, 4.45 mmol). ¹H-NMR (400 MHz, CDCl₃)

δ/ppm 7.83 (d, J = 15.6 Hz, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.44 (dd, J = 7.8,

1.6 Hz, 1H), 7.43 (d, J = 15.4 Hz, 1H), 7.14 (ddd, J = 8.4, 7.4, 1.5 Hz, 1H),

6.75 (td, J = 7.6, 7.2, 1.3 Hz, 1H), 6.68 (dd, J = 8.0, 1.2 Hz, 1H), 6.54 (dd,

J = 8.6, 2.3 Hz, 1H), 6.47 (d, J = 2.2 Hz, 1H), 4.06 (s, 2H), 3.87 (s, 3H),

3.84 (s, 3H). ¹³C-NMR (100 MHz, CDCl₃) δ/ppm 190.3 (C), 164.2 (C),

160.4 (C), 146.0 (C), 137.4 (CH), 132.9 (CH), 131.0 (CH), 128.3 (CH),

127.2 (CH), 122.3 (C), 120.8 (C), 118.7 (CH), 116.6 (CH), 105.2 (CH), 98.6

(CH), 55.7 (CH₃), 55.5 (CH₃). IR (neat) ν/cm^-1: 3446 (m), 3357 (m), 3243

(w), 2940 (w), 1644 (m), 1597 (s), 1572 (s), 1456 (m), 1329 (s), 1288 (s),

1248 (s), 1206 (s), 1159 (s), 1124 (s), 1020 (s), 748 (s), 730 (s). HR-MS

(TOF ES): calculated for C₁₇H₁₈NO₃284.1281, found 284.1285 (M+H+).

(E)-3-(2-Aminophenyl)-1-(2-fluorophenyl)prop-2-en-1-one,

(3d):

yellow powder. Yield: 83% (1.00 g, 4.2 mmol). ¹H-NMR (500 MHz, CDCl₃)

δ/ppm 7.95 (dd, J = 15.4, 2.0 Hz, 1H), 7.84 (td, J = 7.5, 2.0 Hz, 1H), 7.56

– 7.49 (m, 2H), 7.35 (dd, J = 15.4, 3.0 Hz, 1H), 7.29 – 7.25 (m, 1H), 7.23

– 7.14 (m, 2H), 6.80 (t, J = 7.6 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 4.08 (s,

2H). ¹³C-NMR (125 MHz, CDCl₃) δ/ppm 188.9 – 188.8 (m, C), 161.3 (d, J

= 253 Hz, CF), 146.4 (C), 140.2 (CH), 133.9 (d, J = 9 Hz, CH), 131.8 (CH),

131.0 (d, J = 3 Hz, CH), 128.5 (CH), 127.3 (d, J = 13 Hz, C), 125.4 (d, J =

7 Hz, CH), 124.5 (d, J = 3 Hz, CH), 120.1 (C), 119.0 (CH), 116.8 (CH),

116.5 (d, J = 23 Hz, CH). ¹⁹F-NMR (376 MHz, CDCl₃) δ/ppm -110.7. IR

(neat) ν/cm^-1: 3346 (br), 3235 (w), 1661 (m), 1610 (s), 1583 (s), 1451 (m),

1340 (s), 1260 (m), 1202 (m), 1157 (m), 774 (m). HR-MS (TOF ES):

calculated for C₁₅H₁₃FNO 242.0976, found 242.0978 (M+H+).

(E)-3-(2-Aminophenyl)-1-(thiophen-2-yl)prop-2-en-1-one,

(3i):³⁷

(E)-3-(2-Aminophenyl)-1-(2,4-difluorophenyl)prop-2-en-1-one, (3e):

orange solid. Melting range 115-117 °C. Yield: 58% (253 mg, 0.98 mmol).

¹H-NMR (400 MHz, CDCl₃) /ppm 7.96 – 7.86 (m, 2H), 7.48 (dd, J = 7.9,

1.4 Hz, 1H), 7.31 (dd, J = 15.4, 3.2 Hz, 1H), 7.19 (ddd, J = 8.2, 7.3, 1.4 Hz,

1H), 7.01 – 6.95 (m, 1H), 6.89 (ddd, J = 11.0, 8.8, 2.4 Hz, 1H), 6.78 (t, J =

7.3 Hz, 1H), 6.70 (dd, J = 8.1, 0.7 Hz, 1H), 4.04 (s, 2H). ¹³C-NMR (100

MHz, CDCl₃) /ppm 187.1 (d, J = 4 Hz, C), 165.5 (dd, J = 257, 12 Hz, CF),

161.9 (dd, J = 257, 12 Hz, CF), 146.4 (C), 140.3 (CH), 132.9 (dd, J = 11,

4 Hz, CH), 131.9 (CH), 128.4 (CH), 124.7 (d, J = 8 Hz, CH), 123.7 (dd, J =

13, 4 Hz, C), 119.9 (C), 118.9 (CH), 116.8 (CH), 112.2 (dd, J = 21, 3 Hz,

CH), 104.7 (dd, J = 28, 26 Hz, CH). ¹⁹F-NMR (376 MHz, CDCl₃) δ/ppm -

102.8, -105.7. IR (neat) ν/cm^-1: 3403 (w), 1655 (w), 1590 (s), 1561 (s),

1487 (m), 1340 (m), 1229 (m), 1097 (s), 970 (m), 851 (s), 730 (s). HR-MS

(TOF ES): calculated for C₁₅H₁₂F₂NO 260.0881, found 260.0882 (M+H+).

orange solid. Melting range 138-140 °C. Yield: 65% (447 mg, 1.9 mmol).

¹H-NMR (500 MHz, CDCl₃) /ppm 8.02 (d, J = 15.3 Hz, 1H), 7.87 (dd, J =

3.8, 1.0 Hz, 1H), 7.69 (dd, J = 4.9, 1.0 Hz, 1H), 7.53 (dd, J = 7.8, 1.2 Hz,

1H), 7.38 (d, J = 15.3 Hz, 1H), 7.24 – 7.19 (m, 2H), 6.81 (t, J = 7.5 Hz, 1H),

6.74 (d, J = 8.1 Hz, 1H), 4.08 (s, 2H). ¹³C-NMR (125 MHz, CDCl₃) /ppm

182.0 (C), 146.3 (C), 145.7 (C), 139.3 (CH), 133.7 (CH), 131.7 (CH) 131.6

(CH), 128.2 (CH), 128.1 (CH), 121.5 (CH), 120.1 (C), 118.9 (CH), 116.8

(CH). IR (neat) ν/cm^-1: 3331 (w), 1647 (m), 1574 (s), 1458 (m), 1413 (m),

1218 (m), 977 (m), 857 (w), 746 (m), 696 (s), 593 (w). HR-MS (TOF ES):

calculated for C₁₃H₁₂NOS 230.0634, found 230.0633 (M+H+).

(E)-3-(2-Aminophenyl)-1-(4-fluoro-3-(trifluoromethyl)phenyl)prop-2-

en-1-one, (3j): yellow solid. Melting range 117-120 °C. Yield: 80% (1.22 g,

4.0 mmol). ¹H-NMR (400 MHz, CDCl₃) δ/ppm 8.27 (dd, J = 6.9, 2.3 Hz,

1H), 8.21 (ddd, J = 8.6, 4.7, 2.3 Hz, 1H), 8.03 (d, J = 15.3 Hz, 1H), 7.51

(dd, J = 7.8, 1.5 Hz, 1H), 7.41 (d, J = 15.3 Hz, 1H), 7.30 (t, J = 9.1 Hz, 1H),

7.23 – 7.18 (m, 1H), 6.82 – 6.76 (m, 1H), 6.71 (d, J = 8.5 Hz, 1H), 4.10 (s,

2H). ¹³C-NMR (100 MHz, CDCl₃) δ/ppm 187.2 (C), 162.2 (dq, J = 263, 2

Hz, CF), 146.6 (C), 141.5 (CH), 134.6 (C), 134.2 (d, J = 10 Hz, CH), 132.2

(CH), 128.1 (CH), 128.1 – 127.7 (m, CH), 122.2 (qd, J = 273, 2 Hz, CF₃),

120.0 (CH), 119.7 (C), 119.0 (CH), 118.5 (qd, J = 34, 13 Hz, C), 117.3 (d,

J = 21 Hz, CH), 117.0 (CH). ¹⁹F-NMR (376 MHz, CDCl₃) δ/ppm -61.6 (d, J

= 13 Hz, CF₃), -107.6 (m, CF). IR (neat) ν/cm^-1: 3367 (m), 3068 (w), 1659

(m), 1616 (s), 1577 (s), 1502 (m), 1322 (s), 1196 (s), 1129 (s), 1055 (m),

755 (m). HR-MS (TOF ES): calculated for C₁₆H₁₂F₄NO 310.0850, found

310.0852 (M+H+). X-ray data (CCDC2013440): for C₁₆H₁₁NOF₄; C2/c, α =

90, β = 111.0975(9), γ = 90, a = 20.3756(2), b = 5.12105(5), c = 27.8472(3).

(E)-3-(2-Aminophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one, (3f):³⁷

1

green solid. Melting range 94-96 °C. Yield: 56% (100 mg, 0.4 mmol). H-

NMR (400 MHz, CDCl₃) /ppm 8.04 (app. d, J = 9.0 Hz, 2H), 7.97 (d, J =

15.4 Hz, 1H), 7.53 – 7.47(m, 2H), 7.19 (ddd, J = 8.2, 7.4, 1.5 Hz, 1H), 6.98

(app. d, J = 9.0 Hz, 2H), 6.79 (t, J = 7.2 Hz, 1H), 6.72 (dd, J = 8.1, 0.9 Hz,

1H), 4.06 (s, 2H), 3.89 (s, 3H). ¹³C-NMR (100 MHz, CDCl₃) /ppm 188.5

(C), 163.4 (C), 146.1 (C), 139.3 (CH), 131.4 (CH), 131.2 (C), 130.7 (2CH),

128.1 (CH), 121.7 (CH), 120.5 (C), 118.8 (CH), 116.7 (CH), 113.8 (2CH),

55.5 (CH₃). IR (neat) ν/cm^-1: 3337 (w), 1650 (m), 1579 (s), 1458 (m), 1334

(m), 1253 (s), 1214 (s), 1161 (s), 1015 (m), 746 (s). HR-MS (TOF ES):

calculated for C₁₆H₁₆NO₂254.1176, found 254.1175 (M+H+).

(E)-3-(2-Aminophenyl)-1-(1H-indol-3-yl)prop-2-en-1-one, (3g): yellow

solid. Melting range ~200 °C (decomposition). Yield: 85% (130 mg, 0.5

(E)-3-(2-Aminophenyl)-1-(5-methylfuran-2-yl)prop-2-en-1-one, (3k):

yellow solid. Melting range 122-124 °C. Yield: 78% (890 mg, 3.9 mmol).

¹H-NMR (400 MHz, CDCl₃) δ/ppm 7.97 (d, J = 15.5 Hz, 1H), 7.48 (dd, J =

8.1, 1.6 Hz, 1H), 7.27 (d, J = 15.6 Hz, 1H), 7.20 (d, J = 3.5 Hz, 1H), 7.17 –

7.11 (m, 1H), 6.77 – 6.71 (m, 1H), 6.68 (dd, J = 8.1, 1.3 Hz, 1H), 6.17 (d,

J = 3.6 Hz, 1H), 4.13 (s, 2H), 2.39 (s, 3H). ¹³C-NMR (100 MHz, CDCl₃)

1

mmol). H-NMR (600 MHz, DMSO-d₆) δ/ppm 12.00 (s, 1H), 8.63 (d, J =

3.0 Hz, 1H), 8.33 (d, J = 7.1 Hz, 1H), 7.86 (d, J = 15.3 Hz, 1H), 7.68 (d, J

= 7.9 Hz, 1H), 7.55 (d, J = 15.3 Hz, 1H), 7.46 (d, J = 7.7 Hz, 1H), 7.19 (m,

2H), 7.05 (t, J = 8.0 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 6.57 (t, J = 7.5 Hz,

1H), 5.53 (s, 2H). ¹³C-NMR (150 MHz, DMSO-d₆) δ/ppm 184.5 (C), 148.8

8

10.1002/ejoc.202000957

European Journal of Organic Chemistry

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δ/ppm 177.3 (C), 158.1 (C), 152.6 (C), 146.4 (C), 138.5 (CH), 131.5 (CH),

128.0 (CH), 121.0 (CH), 120.1 (C), 119.4 (CH), 118.7 (CH), 116.8 (CH),

109.3 (CH), 14.1 (CH₃). IR (neat) ν/cm^-1: 3339 (m), 3224 (m), 1638 (s),

1587 (s), 1511 (s), 1345 (s), 1246 (m), 1203 (m), 1038 (m), 1024 (m), 803

(m), 747 (s). HR-MS (TOF ES): calculated for C₁₄H₁₄NO₂228.1019, found

228.1021 (M+H+).

J = 8.4 Hz, 1H), 7.43 – 7.37 (m, 1H), 7.21 – 7.15 (m, 2H). ¹³C-NMR (125

MHz, CDCl₃) δ/ppm 187.2 (C), 138.0 (C), 137.6 (C), 134.4 (C), 132.4 (CH),

129.2 (2CH), 128.5 (2CH), 127.8 (C), 126.5 (CH), 123.3 (CH), 121.1 (CH),

112.8 (CH), 112.2 (CH). IR (neat) ν/cm^-1: 3316 (s), 3060 (w), 1618 (s),

1572 (m), 1519 (s), 1342 (m), 1261 (m), 1127 (m), 728 (m). HR-MS (TOF

ES): calculated for C₁₅H₁₂NO 222.0919, found 222.0912 (M+H⁺).

(E)-3-(2-Aminophenyl)-1-(benzo[d][1,3]dioxol-5-yl)prop-2-en-1-one,

(3l): yellow powder. Yield: 81% (1.07 g, 4.0 mmol). ¹H-NMR (400 MHz,

CDCl₃) δ/ppm 7.94 (d, J = 15.3 Hz, 1H), 7.63 (dd, J = 8.2, 1.7 Hz, 1H),

7.51 (d, J = 1.6 Hz, 1H), 7.49 (dd, J = 7.8, 1.6 Hz, 1H), 7.41 (d, J = 15.3

Hz, 1H), 7.17 (ddd, J = 8.6, 7.3, 1.5 Hz, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.77

(td, J = 7.6, 1.1 Hz, 1H), 6.70 (dd, J = 8.1, 1.2 Hz, 1H), 6.04 (s, 2H), 4.06

(s, 2H). ¹³C-NMR (100 MHz, CDCl₃) δ/ppm 188.1 (C), 151.6 (C), 148.3 (C),

146.2 (C), 139.6 (CH), 133.1 (C), 131.5 (CH), 128.0 (CH), 124.6 (CH),

121.5 (CH), 120.4 (C), 118.8 (CH), 116.7 (CH), 108.4 (CH), 107.9 (CH),

101.8 (CH₂). IR (neat) ν/cm^-1: 3348 (w), 2901 (w), 1639 (m), 1601 (m),

1566 (s), 1486 (s), 1441 (s), 1335 (m), 1245 (s), 1110 (m), 1036 (m), 807

(m), 748 (s). HR-MS (TOF ES): calculated for C₁₆H₁₄NO₃268.0968, found

268.0969 (M+H+).

(5H-[1,3]Dioxolo[4,5-f]indol-6-yl)(phenyl)methanone

(7o):

yellow

powder. Yield: 6% (21 mg, 0.08 mmol; side-product). ¹H-NMR (400 MHz,

CDCl₃) δ/ppm 9.29 (s, 1H), 7.97 – 7.90 (m, 2H), 7.61 – 7.56 (m, 1H), 7.53

– 7.47 (m, 2H), 7.02 (d, J = 3.5 Hz, 1H), 6.98 (s, 1H), 6.86 (s, 1H), 5.98 (s,

2H). ¹³C-NMR (100 MHz, CDCl₃) δ/ppm 185.9 (C), 149.0 (C), 144.4 (C),

138.2 (C), 134.0 (C), 133.7 (C), 132.0 (CH), 129.0 (2CH), 128.4 (2CH),

122.1 (C), 113.3 (CH), 101.2 (CH₂), 100.0 (CH), 91.8 (CH). IR (neat) ν/cm^-

¹: 3284 (s), 2904 (w), 1602 (s), 1573 (m), 1497 (s), 1485 (s), 1365 (m),

1290 (s), 1251 (m), 12223 (s), 1175 (m). HR-MS (TOF ES): calculated for

C₁₆H₁₂NO₃266.0817, found 266.0818 (M+H⁺).

(1E,4E)-1-(2-Aminophenyl)-5-(benzo[d][1,3]dioxol-5-yl)penta-1,4-

dien-3-one, (10): orange powder. Melting range 175-177 °C. Yield: 86%

(2.08 g, 7.1 mmol). ¹H-NMR (400 MHz, DMSO-d₆) δ/ppm 7.94 (d, J = 15.8

Hz, 1H), 7.59 (d, J = 15.8 Hz, 1H), 7.50 (dd, J = 7.9, 1.5 Hz, 1H), 7.45 (d,

J = 1.6 Hz, 1H), 7.33 (d, J = 15.8 Hz, 1H), 7.23 (dd, J = 7.9, 1.7 Hz, 1H),

7.09 – 7.03 (m, 1H), 6.98 – 6.89 (m, 2H), 6.68 (d, J = 7.9 Hz, 1H), 6.53 (t,

J = 7.4 Hz, 1H), 6.06 (s, 2H), 5.74 (s, 2H). ¹³C-NMR (100 MHz, DMSO-d₆)

δ/ppm 188.7 (C), 149.7 (C), 149.2 (C), 148.5 (C), 142.1 (CH), 139.0 (CH),

132.0 (CH), 129.8 (C), 127.5 (CH), 125.6 (CH), 124.9 (CH), 123.5 (CH),

118.2 (C), 116.8 (CH), 116.7 (CH), 109.0 (CH), 107.1 (CH), 102.0 (CH₂).

IR (neat) ν/cm^-1: 3332 (m), 3222 (m), 3020 (w), 1634 (s), 1600 (m), 1566

(s), 1493 (s), 1450 (s), 1346 (s), 1257 (s), 1185 (s), 1031 (s), 921 (s), 736

(s). HR-MS (TOF ES): calculated for C₁₈H₁₆NO₃294.1125, found 294.1126

(M+H+).

(E)-3-(2-Amino-5-morpholinophenyl)-1-(4-methoxyphenyl)prop-2-en-

1-one (3m): red powder. Yield: 77% (1.04 g, 3.1 mmol). ¹H-NMR (400 MHz,

CDCl₃) δ/ppm 8.02 (d, J = 9.0 Hz, 2H), 7.93 (d, J = 15.4 Hz, 1H), 7.44 (d,

J = 15.4 Hz, 1H), 7.05 (d, J = 2.7 Hz, 1H), 6.97 (d, J = 9.0 Hz, 2H), 6.89

(dd, J = 8.6, 2.7 Hz, 1H), 6.69 (d, J = 8.7 Hz, 1H), 3.87 (s, 3H), 3.86 (app.

s, 4H), 3.81 (br s, 2H), 3.07 – 3.02 (m, 4H). ¹³C-NMR (100 MHz, CDCl₃)

δ/ppm 188.5 (C), 163.4 (C), 144.5 (C), 140.6 (C), 139.7 (CH), 131.2 (C),

130.8 (2CH), 121.9 (CH), 121.7 (CH), 121.2 (C), 118.1 (CH), 115.8 (CH),

113.8 (2CH), 67.0 (2CH₂), 55.5 (CH₃), 51.0 (2CH₂). IR (neat) ν/cm^-1: 3353

(m), 2960 (m), 2837 (m), 1650 (m), 1598 (s), 1498 (s), 1311 (m), 1258 (s),

1230 (s), 1164 (s), 1114 (s), 1021 (m), 981 (m), 902 (m), 831 (s), 727 (s).

HR-MS (TOF ES): calculated for C₂₀H₂₃N₂O₃339.1709, found 339.1706

(M+H⁺).

General procedure for the preparation of quinolines 1a-o: A solution

of amine 3 (typically 100 mM EtOH) was prepared and pumped through

the UV LED unit (10 min residence time, ~30 °C, 75 W power). After

evaporating the solvent and silica column chromatography (10%

hexanes/EtOAc) the desired quinoline products were isolated in pure form.

(E)-3-(2-Amino-5-(2,2,2-trifluoroethoxy)phenyl)-1-(2-fluoro-4-

methoxyphenyl)prop-2-en-1-one (3n): orange powder. Yield: 75% (1.10

g, 3.0 mmol). ¹H-NMR (400 MHz, CDCl₃) δ/ppm 7.90 – 7.83 (m, 2H), 7.33

(dd, J = 15.4, 3.0 Hz, 1H), 7.06 (d, J = 3.0 Hz, 1H), 6.85 (dd, J = 8.8, 2.9

Hz, 1H), 6.77 (dd, J = 8.8, 2.4 Hz, 1H), 6.66 (d, J = 8.9 Hz, 1H), 6.63 (dd,

J = 13.1, 2.4 Hz, 1H), 4.29 (q, J = 8.2 Hz, 2H), 3.90 (br s, 2H), 3.85 (s, 3H).

¹³C-NMR (100 MHz, CDCl₃) δ/ppm 186.8 (d, J = 4 Hz, C), 164.6 (d, J = 12

Hz, C), 163.1 (d, J = 254 Hz, CF), 150.5 (C), 141.9 (C), 138.4 (CH), 132.6

(d, J = 5 Hz, CH), 126.1 (d, J = 9 Hz, CH), 123.4 (q, J = 279 Hz, CF₃),

121.2 (C), 119.8 (CH), 119.6 (d, J = 13 Hz, C), 118.1 (CH), 114.1 (CH),

110.9 (d, J = 3 Hz, CH), 101.8 (d, J = 28 Hz, CH), 67.1 (q, J = 35 Hz, CH₂),

55.8 (CH₃). ¹⁹F-NMR (376 MHz, CDCl₃) δ/ppm -74.1 (t, J = 8.3 Hz), -106.5

(ddt, J = 13.7, 9.0, 2.7 Hz). IR (neat) ν/cm^-1: 3372 (w), 2944 (w), 1614 (s),

1585 (m), 1498 (m), 1289 (m), 1238 (s), 1160 (s), 976 (m), 854 (m). HR-

MS (TOF ES): calculated for C₁₈H₁₆NO₃F₄370.1066, found 370.1052

(M+H⁺).

2-Methylquinoline, (1a):³⁷red oil. Yield: 91% (2.7 g, 18.9 mmol). ¹H-NMR

(400 MHz, CDCl₃) δ/ppm 8.03 (m, 2H), 7.77 (dd, J = 8.1, 1.2 Hz, 1H), 7.68

(ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.48 (ddd, J = 8.0, 7.0, 1.1 Hz, 1H), 7.28 (d,

J = 8.4 Hz, 1H), 2.75 (s, 3H). ¹³C-NMR (100 MHz, CDCl₃) δ/ppm 159.0 (C),

147.8 (C), 136.2 (CH), 129.4 (CH), 128.5 (CH), 127.5 (CH), 126.5 (C),

125.7 (CH), 122.0 (CH), 25.3 (CH₃). IR (neat) ν/cm^-1: 3055 (w), 1600 (m),

1504 (m), 1423 (m), 1311 (m), 1220 (m), 1117 (m), 950 (w), 817 (s), 745

(s), 619 (m), 474 (m). HR-MS (TOF ES): calculated for C₁₀H₁₀N 144.0808,

found 144.0809 (M+H+).

2-(tert-Butyl)quinoline, (1b):³⁷pale yellow oil. Yield: 85% (66 mg, 0.36

mmol). ¹H-NMR (500 MHz, CDCl₃) /ppm 8.07 (d, J = 8.3 Hz, 1H), 8.06 (d,

J = 8.0 Hz, 1H), 7.76 (dd, J = 8.1, 1.3 Hz, 1H), 7.66 (ddd, J = 8.4, 6.9, 1.5

Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.47 (ddd, J = 8.1, 6.9, 1.2 Hz, 1H), 1.47

(s, 9H). ¹³C-NMR (125 MHz, CDCl₃) /ppm 169.2 (C), 147.4 (C), 135.8

(CH), 129.4 (CH), 128.9 (CH), 127.2 (CH), 126.4 (C), 125.6 (CH), 118.2

(1H-Indol-2-yl)(phenyl)methanone, (7c):⁴⁰off-white solid. Melting range

143-146 °C. Yield: 3% (35 mg, 0.16 mmol; side-product). ¹H-NMR (500

MHz, CDCl₃) δ/ppm 9.48 (s, 1H), 8.02 (dd, J = 8.3, 1.2 Hz, 2H), 7.74 (d, J

= 8.1 Hz, 1H), 7.67 – 7.62 (m, 1H), 7.56 (dd, J = 8.3, 6.9 Hz, 2H), 7.51 (d,

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(CH), 38.1 (C), 30.1 (3CH₃).IR (neat) ν/cm^-1: 2957 (m), 1619 (m), 1600 (s),

1502 (s), 1363 (m), 1138 (s), 1102 (w), 829 (s), 756 (s), 478 (w). HR-MS

(TOF ES): calculated for C₁₃H₁₆N 186.1277, found 186.1280 (M+H+).

2-(1H-Indol-3-yl)quinoline, (1g):³⁹light yellow solid. Yield: 71% (30 mg,

1

0.12 mmol). H-NMR (400 MHz, CDCl₃) δ/ppm 8.77 (m, 1H), 8.67 (br. s,

1H), 8.19 (d, J = 10.7 Hz, 1H), 8.14 (d, J = 11.6 Hz, 1H), 7.81 (m, 3H), 7.72

(ddd, J = 11.2, 9.2, 2.0 Hz, 1H), 7.49 (ddd, J = 10.8, 9.3, 1.6 Hz, 1H), 7.41

(m, 1H), 7.33 (m, 2H). ¹³C-NMR (100 MHz, CDCl₃) δ/ppm 155.1 (C), 148.5

(C), 137.0 (C), 136.0 (CH), 129.4 (CH), 129.1 (CH), 127.4 (CH), 126.5 (C),

125.8 (C), 125.4 (CH), 125.2 (CH), 122.9 (CH), 122.1 (CH), 121.2 (CH),

119.5 (CH), 117.7 (C), 111.3 (CH). IR (neat) ν/cm^-1: 3037 (w), 1598 (m),

1539 (s), 1431 (s), 1290 (w), 1238 (m), 1152 (w), 1117 (m), 983 (w), 932

(w), 815 (s), 742 (s), 562 (m), 496 (m), 427 (m). HR-MS (TOF ES):

calculated for C₁₇H₁₃N₂245.1073, found 245.1078 (M+H+).

2-Phenylquinoline, (1c):³⁷off-white solid. Melting range 85-87 °C. Yield:

1

91% (374 mg, 1.8 mmol). H-NMR (300 MHz, CDCl₃) /ppm 8.25 (d, J =

8.7 Hz, 1H), 8.22 – 8.16 (m, 3H), 7.91 (d, J = 8.6 Hz, 1H), 7.85 (dd, J = 8.1,

1.0 Hz, 1H), 7.75 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.60 – 7.46 (m, 4H). ¹³C-

NMR (125 MHz, CDCl₃) δ/ppm 157.4 (C), 148.3 (C), 139.7 (C), 136.8 (CH),

129.8 (CH), 129.6 (CH), 129.3 (CH), 128.8 (2CH), 127.6 (CH), 127.5 (CH),

127.2 (C), 126.3 (2CH), 119.0 (CH). IR (neat) ν/cm^-1: 2922 (m), 1595 (m),

1486 (m), 1318 (w), 1123 (w), 1074 (w), 827 (s), 762 (s), 688 (s), 481 (m).

HR-MS (TOF ES): calculated for C₁₅H₁₂N 206.0970, found 206.0962

(M+H+). X-ray data (CCDC2013438): for C₁₅H₁₁N; Pna21, α = 90, β = 90,

γ = 90, a = 16.5745(5), b = 11.1553(4), c = 5.8522(4).

2-(2,4-Dimethoxyphenyl)quinoline, (1h): colourless oil. Yield: 90% (713

mg, 2.7 mmol). ¹H-NMR (400 MHz, CDCl₃) δ/ppm 8.14 (dd, J = 8.6, 1.0 Hz,

1H), 8.08 (d, J = 8.7 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H), 7.88 (d, J = 8.5 Hz,

1H), 7.78 (dd, J = 8.0, 1.5 Hz, 1H), 7.67 (ddd, J = 8.6, 6.8, 1.5 Hz, 1H),

7.51 – 7.45 (m, 1H), 6.66 (dd, J = 8.5, 2.4 Hz, 1H), 6.58 (d, J = 2.3 Hz, 1H),

3.85 (s, 3H), 3.83 (s, 3H). ¹³C-NMR (100 MHz, CDCl₃) δ/ppm 161.7 (C),

158.4 (C), 156.8 (C), 148.3 (C), 135.0 (CH), 132.4 (CH), 129.5 (CH), 129.1

(CH), 127.3 (CH), 126.9 (C), 125.9 (CH), 123.4 (CH), 122.6 (C), 105.4

(CH), 98.9 (CH), 55.6 (CH₃), 55.5 (CH₃). IR (neat) ν/cm^-1: 2937 (w), 2835

(w), 1606 (s), 1497 (s), 1456 (s), 1427 (m), 1299 (s), 1277 (s), 1207 (s),

1160 (s), 1060 (m), 1030 (s), 834 (m), 759 (m). HR-MS (TOF ES):

calculated for C₁₇H₁₆NO₂265.1097, found 265.1088 (M+H+).

2-(2-Fluorophenyl)quinoline, (1d): off-white solid. Melting range 120-

123 °C. Yield: 88% (196 mg, 0.88 mmol). ¹H-NMR (400 MHz, CDCl₃)

δ/ppm 8.20 (d, J = 8.7 Hz, 1H), 8.17 (d, J = 8.6 Hz, 1H), 8.09 (td, J = 7.8,

1.8 Hz, 1H), 7.88 (dd, J = 8.6, 2.7 Hz, 1H), 7.84 (dd, J = 8.0, 1.4 Hz, 1H),

7.76 – 7.69 (m, 1H), 7.57 – 7.51 (m, 1H), 7.46 – 7.39 (m, 1H), 7.35 – 7.28

(m, 1H), 7.19 (ddd, J = 11.2, 8.2, 1.4 Hz, 1H). ¹³C-NMR (100 MHz, CDCl₃)

δ/ppm 160.8 (d, J = 251 Hz, CF), 154.0 (C), 148.3 (C), 136.1 (CH), 131.5

(d, J = 3 Hz, CH), 130.8 (d, J = 8 Hz, CH), 129.7 (CH), 129.6 (CH), 128.0

(d, J = 12 Hz, C), 127.5 (CH), 127.2 (C), 126.6 (CH), 124.7 (d, J = 4 Hz,

CH), 122.4 (d, J = 8 Hz, CH), 116.2 (d, J = 23 Hz, CH). ¹⁹F-NMR (376 MHz,

CDCl₃) δ/ppm -117.3. IR (neat) ν/cm^-1: 3059 (w), 1598 (m), 1505 (m), 1489

(m), 1452 (m), 1206 (m), 831 (m), 761 (s). HR-MS (TOF ES): calculated

for C₁₅H₁₁FN 224.0870, found 224.0875 (M+H+).

2-(Thiophen-2-yl)quinoline, (1i):³⁷white solid. Melting range 133-135 °C.

Yield: 92% (43 mg, 0.2 mmol). ¹H-NMR (500 MHz, CDCl₃) /ppm 8.14 (d,

J = 8.6 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.78 (dd,

J = 8.1, 1.2 Hz, 1H), 7.75 (dd, J = 3.7, 1.1 Hz, 1H), 7.71 (ddd, J = 8.4, 6.9,

1.4 Hz, 1H), 7.52 – 7.46 (m, 2H), 7.17 (dd, J = 5.0, 3.7 Hz, 1H).¹³C-NMR

(125 MHz, CDCl₃) /ppm 152.3 (C), 148.1 (C), 145.4 (C), 136.6 (CH),

129.8 (CH), 129.3 (CH), 128.6 (CH), 128.0 (CH), 127.5 (CH), 127.2 (C),

126.1 (CH), 125.8 (CH), 117.7 (CH). IR (neat) ν/cm^-1: 2916 (w), 1592 (m),

1497 (m), 1424 (m), 1315 (m), 1057 (w), 821 (s), 756 (s), 707 (s), 618 (m),

470 (m). HR-MS (TOF ES): calculated for C₁₃H₁₀NS 212.0528, found

212.0533 (M+H+).

2-(2,4-Difluorophenyl)quinoline, (1e):³⁸white solid. Melting range 94-

95 °C. Yield: 95% (42 mg, 0.17 mmol). ¹H-NMR (400 MHz, CDCl₃) /ppm

8.17 – 8.10 (m, 3H), 7.83 – 7.79 (m, 2H), 7.71 (ddd, J = 8.4, 6.9, 1.4 Hz,

1H), 7.52 (ddd, J = 8.1, 6.9, 1.1 Hz, 1H), 7.03 (dddd, J = 8.8, 8.0, 2.5, 0.9

Hz, 1H), 6.93 (ddd, J = 11.2, 8.8, 2.5 Hz, 1H). ¹³C-NMR (100 MHz, CDCl₃)

/ppm 163.4 (dd, J = 250, 12 Hz, CF), 160.9 (dd, J = 251, 12 Hz, CF),

153.1 (d, J = 2 Hz, C), 148.3 (C), 136.4 (CH), 132.7 (dd, J = 10, 5 Hz, CH),

129.7 (CH), 129.6 (CH), 127.5 (CH), 127.2 (C), 126.7 (CH), 124.3 (dd, J =

12, 4 Hz, C), 122.1 (d, J = 9 Hz, CH), 112.1 (dd, J = 21, 4 Hz, CH), 104.4

(app. t, J = 26, CH). ¹⁹F-NMR (376 MHz, CDCl₃) /ppm -108.7, -112.8. IR

(neat) ν/cm^-1: 2921 (w), 1595 (m), 1496 (m), 1416 (m), 1263 (m), 1133 (m),

1095 (m), 968 (m), 833 (s), 755 (s), 468 (m). HR-MS (TOF ES): calculated

for C₁₅H₁₀F₂N 242.0776, found 242.0781 (M+H+). X-ray data

(CCDC2013437): for C₁₅H₉NF₂; 21/n, α = 90, β = 99.775(2), γ = 90, a =

15.5081(3), b = 3.81884(9), c = 18.2055(4).

2-(4-Fluoro-3-(trifluoromethyl)phenyl)quinoline, (1j): off-white solid.

Melting range 104-106 °C. Yield: 84% (244 mg, 0.84 mmol). ¹H-NMR (400

MHz, CDCl₃) δ/ppm 8.45 (dd, J = 6.9, 2.3 Hz, 1H), 8.33 (ddd, J = 8.6, 4.8,

2.3 Hz, 1H), 8.22 (d, J = 8.6 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 7.82 (d, J =

8.0 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.74 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H),

7.54 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 7.35 – 7.28 (m, 1H). ¹³C-NMR (100

MHz, CDCl₃) δ/ppm 160.5 (dq, J = 257, 2 Hz, CF), 154.5 (C), 148.2 (C),

137.2 (CH), 136.0 (d, J = 4 Hz, C), 132.8 (d, J = 9 Hz, CH), 130.1 (CH),

129.7 (CH), 127.5 (CH), 127.2 (C), 126.8 (CH), 126.5 – 126.2 (m, CH),

122.6 (qd, J = 272, 2 Hz, CF₃), 118.8 (qd, J = 33, 13 Hz, C), 118.1 (CH),

117.3 (d, J = 21 Hz, CH). ¹⁹F-NMR (376 MHz, CDCl₃) δ/ppm -61.4 (d, J =

12 Hz, CF₃), -114 (m). IR (neat) ν/cm^-1: 3080 (w), 1597 (m), 1499 (m), 1290

(m), 1260 (m), 1242 (m), 1111 (s), 1050 (m), 812 (s), 767 (m), 682 (m).

HR-MS (TOF ES): calculated for C₁₆H₁₀F₄N 292.0744, found 292.0745

(M+H+). X-ray data (CCDC2013441): for C₁₆H₉NF₄; P21/n, α = 90, β =

101.674(2), γ = 90, a = 7.0848(1), b = 11.7942(2), c = 14.9556(2).

2-(4-Methoxyphenyl)quinoline, (1f):³⁷white solid. Melting range 126-

130 °C. Yield: 89% (139 mg, 0.53 mmol). ¹H-NMR (500 MHz, CDCl₃)

/ppm 8.24 – 8.13 (m, 4H), 7.85 (d, J = 8.6 Hz, 1H), 7.82 (dd, J = 8.1, 1.1

Hz, 1H), 7.73 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.09

– 7.05 (m, 2H), 3.90 (s, 3H). ¹³C-NMR (125 MHz, CDCl₃) /ppm 160.9 (C),

156.9 (C), 148.2 (C), 136.8 (C), 132.1 (C), 129.7 (C), 129.4 (C), 129.0

(2CH), 127.4 (CH), 126.9 (CH), 126.0 (CH), 118.6 (CH), 114.3 (2CH), 55.4

(CH₃). IR (neat) ν/cm^-1: 2917 (w), 1594 (m), 1496 (m), 1429 (m), 1288 (w),

1248 (m), 1174 (m), 1027 (m), 815 (s), 788 (m), 745 (m), 482 (w). HR-MS

(TOF ES): calculated for C₁₆H₁₄NO 236.1070, found 236.1074 (M+H+).

2-(5-Methylfuran-2-yl)quinoline, (1k): off-white solid. Melting range 119-

122 °C. Yield: 90% (188 mg, 0.90 mmol). ¹H-NMR (400 MHz, CDCl₃)

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δ/ppm 8.06 – 8.12 (m, 2H), 7.70- 7.80 (m, 2H), 7.66 (ddd, J = 8.6, 6.9, 1.4

Hz, 1H), 7.47 – 7.42 (m, 1H), 7.10 (d, J = 3.3 Hz, 1H), 6.18 – 6.15 (m, 1H),

2.44 (s, 3H). ¹³C-NMR (100 MHz, CDCl₃) δ/ppm 154.5 (C), 152.1 (C),

149.2 (C), 148.1 (C), 136.4 (CH), 129.7 (CH), 129.3 (CH), 127.5 (CH),

126.9 (C), 125.8 (CH), 117.3 (CH), 111.5 (CH), 108.6 (CH), 14.0 (CH₃). IR

(neat) ν/cm^-1: 3061 (w), 1593 (m), 1540 (m), 1422 (m), 1201 (m), 1131 (m),

1080 (m), 1014 (s), 832 (s), 795 (s), 766 (s). HR-MS (TOF ES): calculated

for C₁₄H₁₂NO 210.0913, found 210.0915 (M+H+).

(100 MHz, CDCl₃) δ/ppm 155.3 (C), 150.8 (C), 147.7 (C), 146.5 (C), 139.8

(C), 135.5 (CH), 128.9 (CH), 128.7 (2CH), 127.2 (2CH), 124.1 (C), 117.2

(CH), 106.2 (CH), 102.5 (CH), 101.6 (CH₂). IR (neat) ν/cm^-1: 2904 (w),

1618 (w), 1489 (m), 1464 (s), 1230 (s), 1174 (m), 1038 (m), 956 (m), 860

(m), 756 (m). HR-MS (TOF ES): calculated for C₁₆H₁₂NO₂250.0868, found

250.0862 (M+H⁺).

6-(Thiophen-2-yl)-[1,3]dioxolo[4,5-g]quinoline (1p):⁴¹colourless solid.

Melting range 120-124 °C. Yield: 91% (230 mg, 0.91 mmol). ¹H-NMR (400

MHz, CDCl₃) δ/ppm 7.91 (d, J = 8.6 Hz, 1H), 7.64 – 7.63 (m, 1H), 7.62 (d,

J = 8.7 Hz, 1H), 7.40 (dd, J = 5.1, 1.2 Hz, 1H), 7.36 (s, 1H), 7.11 (dd, J =

5.1, 3.6 Hz, 1H), 7.00 (s, 1H), 6.08 (s, 2H). ¹³C-NMR (100 MHz, CDCl₃)

δ/ppm 150.9 (C), 150.4 (C), 147.6 (C), 146.3 (C), 145.5 (C), 135.3 (CH),

127.9 (CH), 127.7 (CH), 124.9 (CH), 124.0 (C), 115.8 (CH), 105.8 (CH),

102.7 (CH), 101.6 (CH2). IR (neat) ν/cm^-1: 3068 (w), 2902 (w), 1617 (w),

1581 (w), 1499 (m), 1466 (s), 1439 (s), 1258 (m), 1240 (m), 1218 (m), 1173

(m), 1037 (m), 852 (m), 706 (m). HR-MS (TOF ES): calculated for

C₁₄H₁₀NO₂S 256.0427, found 256.0429 (M+H+).

2-(Benzo[d][1,3]dioxol-5-yl)quinoline, (1l): off-white solid. Melting range

91-93 °C. Yield: 93% (231 mg, 0.93 mmol). ¹H-NMR (400 MHz, CDCl₃)

δ/ppm 8.15 – 8.10 (m, 2H), 7.77 (dd, J = 8.0, 1.5 Hz, 1H), 7.76 (d, J = 8.6

Hz, 1H), 7.74 (d, J = 1.8 Hz, 1H), 7.69 (ddd, J = 8.5, 6.9, 1.5 Hz, 1H), 7.64

(dd, J = 8.1, 1.8 Hz, 1H), 7.48 (ddd, J = 7.9, 6.7, 1.2 Hz, 1H), 6.93 (d, J =

8.2 Hz, 1H), 6.02 (s, 2H). ¹³C-NMR (100 MHz, CDCl₃) δ/ppm 156.6 (C),

148.8 (C), 148.4 (C), 148.2 (C), 136.6 (CH), 134.1 (C), 129.6 (CH), 129.5

(CH), 127.4 (CH), 127.0 (C), 126.0 (CH), 121.7 (CH), 118.6 (CH), 108.4

(CH), 107.9 (CH), 101.3 (CH₂). IR (neat) ν/cm^-1: 2893 (m), 1594 (s), 1556

(m), 1486 (s), 1443 (s), 1354 (m), 1290 (m), 1251 (s), 1034 (s), 930 (s),

799 (s), 742 (s). HR-MS (TOF ES): calculated for C₁₆H₁₂NO₂250.0863,

found 250.0867 (M+H+).

General procedure for the preparation of tetrahydroquinolines 8a-c:

The flow stream exiting the photochemical reactor (1, 100 mM EtOH, 1

mL/min) was continuously diluted by adding a with a stream of EtOAc (4

mL/min) via a T-piece. The resulting mixture was directed into a holding

reservoir and pumped from this into an H-Cube™ Mini (1 mL/min)

equipped with a catalyst cartridge containing 10% Pd/C (70 mm length,

maintained at 50 °C). Upon evaporation of the volatile products 8a-c were

isolated and purified on silica (10% EtOAc/hexanes).

4-(2-(4-Methoxyphenyl)quinolin-6-yl)morpholine (1m): light brown

powder. Yield: 87% (279 mg, 0.87 mmol). ¹H-NMR (600 MHz, CDCl₃)

δ/ppm 8.09 (d, J = 8.6 Hz, 2H), 8.03 (app. dd, J = 8.9, 4.1 Hz, 2H), 7.76 (d,

J = 8.7 Hz, 1H), 7.47 (dd, J = 9.3, 2.8 Hz, 1H), 7.05 – 7.01 (m, 3H), 3.93 –

3.90 (m, 4H), 3.87 (s, 3H), 3.30 – 3.28 (m, 4H). ¹³C-NMR (150 MHz, CDCl₃)

δ/ppm 160.5 (C), 154.5 (C), 148.9 (C), 143.9 (C), 135.4 (CH), 132.5 (C),

130.3 (CH), 128.5 (2CH), 127.9 (C), 122.1 (CH), 118.9 (CH), 114.2 (2CH),

108.9 (CH), 66.9 (2CH₂), 55.4 (CH₃), 49.5 (2CH₂). IR (neat) ν/cm^-1: 2956

(w), 2855 (m), 1669 (m), 1595 (s), 1512 (m), 1495 (m), 1449 (m), 1247 (s),

1226 (s), 1167 (s), 1116 (s), 1024 (s), 826 (s), 810 (s). HR-MS (TOF ES+)

calculated for C₂₀H₂₁N₂O₂321.1603, found 321.1601 (M+H⁺).

2-(tert-Butyl)-1,2,3,4-tetrahydroquinoline, (8a):⁴²colourless oil. Yield:

1

77% (73 mg, 0.38 mmol). H-NMR (400 MHz, CDCl₃) δ/ppm 6.90 – 6.99

(m, 2H), 6.57 (td, J = 7.4, 1.2 Hz, 1H), 6.48 (dd, J = 7.8, 1.2 Hz, 1H), 3.79

(s, 1H), 2.95 (dd, J = 10.9, 2.6 Hz, 1H), 2.86 – 2.76 (m, 1H), 2.72 (ddd, J

= 16.1, 5.3, 2.7 Hz, 1H), 1.96 (ddt, J = 12.7, 5.4, 2.7 Hz, 1H), 1.64 – 1.54

(m, 1H), 0.96 (s, 9H). ¹³C-NMR (100 MHz,) δ/ppm 145.4 (C), 128.9 (CH),

126.7 (CH), 121.5 (C), 116.7 (CH), 114.0 (CH), 60.9 (CH), 33.4 (C), 27.4

(CH₂), 26.0 (3CH₃), 23.1 (CH₂). IR (neat) ν/cm^-1: 3420 (m), 2960 (s), 2868

(m), 1607 (m), 1504 (m), 1486 (s), 1311 (m), 1261 (m), 1116 (m), 744 (s).

HR-MS (TOF ES): calculated for C₁₃H₂₀N 190.1590, found 190.1590

(M+H+).

2-(2-Fluoro-4-methoxyphenyl)-6-(2,2,2-trifluoroethoxy)quinoline (1n):

colourless solid. Melting range 113-115 °C. Yield: 84% (295 mg, 0.84

mmol). ¹H-NMR (400 MHz, CDCl₃) δ/ppm 8.10 – 8.04 (m, 3H), 7.85 (dd, J

= 8.7, 2.5 Hz, 1H), 7.42 (dd, J = 9.2, 2.9 Hz, 1H), 7.11 (d, J = 3.0 Hz, 1H),

6.86 (dd, J = 8.7, 2.5 Hz, 1H), 6.72 (dd, J = 13.1, 2.5 Hz, 1H), 4.48 (q, J =

8.1 Hz, 2H), 3.86 (s, 3H). ¹³C-NMR (100 MHz, CDCl₃) δ/ppm 161.7 (d, J =

11 Hz, C), 161.5 (d, J = 249 Hz, CF), 155.2 (C), 152.5 (C), 144.9 (C), 135.0

(CH), 131.9 (d, J = 5 Hz, CH), 131.6 (CH), 127.5 (C), 123.2 (q, J = 277 Hz,

CF₃), 122.8 (d, J = 9 Hz, CH), 121.7 (CH), 120.1 (d, J = 12 Hz, C), 110.8

(d, J = 3 Hz, CH), 106.9 (CH), 101.9 (d, J = 27 Hz, CH), 65.9 (q, J = 36 Hz,

CH₂), 55.7 (CH₃). ¹⁹F-NMR (376 MHz, CDCl₃) δ/ppm -73.8 (t, J = 8.1 Hz),

-114.6 (ddd, J = 12.7, 9.4, 2.7 Hz). IR (neat) ν/cm^-1: 2946 (w), 1625 (m),

1497 (m), 1284 (s), 1253 (m), 1225 (m), 1159 (s), 975 (m), 835 (s). HR-

MS (TOF ES): calculated for C₁₈H₁₄NO₂F₄352.0961, found 352.0947

(M+H⁺). X-ray data (CCDC2013439): for C₁₈H₁₃NO₂F₄; P-1, α = 86.5843(8),

β = 79.7431(8), γ = 74.8033(8), a = 11.5995(1), b = 12.3325(1), c =

17.0643(2).

2-Phenyl-1,2,3,4-tetrahydroquinoline, (8b):⁴²colourless oil. Yield: 86%

(90 mg, 0.43 mmol). ¹H-NMR (400 MHz, CDCl₃) δ/ppm 7.43 – 7.34 (m,

4H), 7.33 – 7.27 (m, 1H), 7.00 – 7.09 (m, 2H), 6.70 – 6.64 (m, 1H), 6.58 –

6.53 (m, 1H), 4.45 (dd, J = 9.4, 3.4 Hz, 1H), 4.04 (s, 1H), 2.94 (ddd, J =

16.2, 10.6, 5.5 Hz, 1H), 2.75 (dt, J = 16.3, 4.8 Hz, 1H), 2.19 – 2.09 (m, 1H),

2.07 – 1.96 (m, 1H). ¹³C-NMR (100 MHz, CDCl₃) δ/ppm 144.8 (C), 144.7

(C), 129.3 (CH), 128.6 (2CH), 127.4 (CH), 126.9 (CH), 126.5 (2CH), 120.9

(C), 117.2 (CH), 114.0 (CH), 56.3 (CH), 31.0 (CH₂), 26.4 (CH₂). IR (neat)

ν/cm^-1: 3400 (w), 3024 (w), 2921 (w), 2840 (w), 1606 (m), 1478 (s), 1308

(m), 1272 (m), 1251 (m), 1111 (m), 743 (s), 714 (s). HR-MS (TOF ES):

calculated for C₁₅H₁₆N 210.1277, found 210.1279 (M+H+).

6-Phenyl-[1,3]dioxolo[4,5-g]quinoline (1o):⁴¹colourless solid. Yield:

88% (218 mg, 0.88 mmol). ¹H-NMR (400 MHz, CDCl₃) δ/ppm 8.12 – 8.07

(m, 2H), 8.01 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 8.5 Hz, 1H), 7.52 – 7.46 (m,

2H), 7.44 (s, 1H), 7.44 – 7.39 (m, 1H), 7.05 (s, 1H), 6.10 (s, 2H). ¹³C-NMR

2-(2-Fluorophenyl)-1,2,3,4-tetrahydroquinoline, (8c):⁴³colourless oil.

Yield: 90% (163 mg, 0.72 mmol). ¹H-NMR (400 MHz, CDCl₃) δ/ppm 7.46

(td, J = 7.7, 1.8 Hz, 1H), 7.26 – 7.20 (m, 1H), 7.10 (td, J = 7.4, 1.3 Hz, 1H),

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7.06 – 6.97 (m, 3H), 6.65 (td, J = 7.4, 1.3 Hz, 1H), 6.56 (dd, J = 7.9, 1.3

Hz, 1H), 4.84 (dd, J = 8.1, 3.6 Hz, 1H), 3.98 (s, 1H), 2.88 (ddd, J = 15.4,

9.4, 5.3 Hz, 1H), 2.68 (dt, J = 16.4, 5.4 Hz, 1H), 2.16 (dtd, J = 12.9, 5.5,

3.4 Hz, 1H), 2.07 – 1.94 (m, 1H). ¹³C-NMR (100 MHz, CDCl₃) δ/ppm 160.0

(d, J = 246 Hz, CF), 144.5 (C), 131.6 (d, J = 14 Hz, C), 129.3 (CH), 128.6

(d, J = 8 Hz, CH), 127.8 (d, J = 5 Hz, CH), 126.9 (CH), 124.2 (d, J = 4 Hz,

CH), 120.8 (C), 117.3 (CH), 115.3 (d, J = 23 Hz, CH), 114.0 (CH), 48.7 (d,

J = 3 Hz, CH), 28.8 (CH₂), 25.7 (CH₂). ¹⁹F-NMR (376 MHz, CDCl₃) δ/ppm

-120.3. IR (neat) ν/cm^-1: 3407 (w), 3017 (w), 2927 (w), 1607 (m), 1585 (m),

1483 (s), 1311 (m), 1273 (m), 1230 (m), 750 (s). HR-MS (TOF ES):

calculated for C₁₅H₁₅FN 228.1183, found 228.1182 (M+H+).

to 70 °C rendered racemic galipinine 14, which was isolated in pure form

after silica chromatography (5% EtOAc/hexanes).

2-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-1,2,3,4-tetrahydroquinoline,

(13):⁴²colourless oil. Yield: 77% (215 mg, 0.77 mmol). ¹H-NMR (400 MHz,

CDCl₃) δ/ppm 6.99 – 6.90 (m, 2H), 6.72 (d, J = 7.9 Hz, 1H), 6.68 (d, J =

1.7 Hz, 1H), 6.64 (dd, J = 7.9, 1.8 Hz, 1H), 6.58 (td, J = 7.4, 1.2 Hz, 1H),

6.46 – 6.41 (m, 1H), 5.91 (s, 2H), 3.74 (s, 1H), 3.27 (dtd, J = 9.4, 6.3, 3.0

Hz, 1H), 2.75 (tp, J = 16.5, 5.2 Hz, 2H), 2.67 – 2.60 (m, 2H), 1.97 (dddd, J

= 12.9, 5.5, 4.4, 3.0 Hz, 1H), 1.81 – 1.72 (m, 2H), 1.64 (dddd, J = 12.8,

10.4, 9.2, 5.6 Hz, 1H). ¹³C-NMR (100 MHz, CDCl₃) δ/ppm 147.6 (C), 145.7

(C), 144.5 (C), 135.6 (C), 129.2 (CH), 126.7 (CH), 121.3 (C), 121.0 (CH),

117.0 (CH), 114.1 (CH), 108.7 (CH), 108.2 (CH), 100.8 (CH₂), 50.9 (CH),

38.5 (CH₂), 31.8 (CH₂), 27.9 (CH₂), 26.2 (CH₂). IR (neat) ν/cm^-1: 3390 (w),

2922 (m), 1606 (m), 1488 (s), 1444 (m), 1246 (s), 1038 (s), 928 (m), 810

(m), 749 (m). HR-MS (TOF ES): calculated for C₁₈H₂₀NO₂282.1489, found

282.1489 (M+H+).

Procedures for the preparation of galipinine 11-14: A solution of amine

10 (100 mM EtOH) was prepared and pumped through the UV LED unit

(15 min residence time, ~30 °C, 75 W power) producing quinoline 11 as a

~7:1 mixture of alkene isomers.

2-(2-(Benzo[d][1,3]dioxol-5-yl)vinyl)quinoline, (alkene mixture, 11

(major isomer)): yellow oil. Yield: 90% (246 mg, 0.9 mmol). ¹H-NMR (400

MHz, CDCl₃) δ/ppm 8.04 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.73

(dd, J = 8.0, 1.5 Hz, 1H), 7.68 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.48 (ddd, J

= 8.2, 6.8, 1.2 Hz, 1H), 7.30 (d, J = 8.6 Hz, 1H), 6.87 – 6.78 (m, 3H), 6.76

(d, J = 12.5 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 5.92 (s, 2H). ¹³C-NMR (100

MHz, CDCl₃) δ/ppm 157.0 (C), 148.2 (C), 147.5 (C), 147.4 (C), 135.3 (CH),

134.1 (CH), 130.5 (C), 129.7 (CH), 129.5 (CH), 129.1 (CH), 127.5 (CH),

126.9 (C), 126.3 (CH), 123.6 (CH), 122.2 (CH), 109.2 (CH), 108.2 (CH),

101.0 (CH₂). HR-MS (TOF ES): calculated for C₁₈H₁₄NO₂276.1019, found

276.1021 (M+H+).

Galipinine (rac), (14):⁴⁴colourless oil. Yield: 72% (105 mg, 0.36 mmol).

¹H-NMR (400 MHz, CDCl₃) δ/ppm 7.06 (t, J = 8.2 Hz, 1H), 6.96 (d, J = 7.6

Hz, 1H), 6.70 (d, J = 7.9 Hz, 1H), 6.66 (d, J = 1.7 Hz, 1H), 6.61 (dd, J =

7.9, 1.8 Hz, 1H), 6.60 – 6.54 (m, 1H), 6.51 (d, J = 8.1 Hz, 1H), 5.90 (s, 2H),

3.25 (dq, J = 8.5, 4.2 Hz, 1H), 2.89 (s, 3H), 2.82 (ddd, J = 17.6, 11.6, 6.7

Hz, 1H), 2.67 (dt, J = 15.1, 3.6 Hz, 1H), 2.64 – 2.57 (m, 1H), 2.48 (ddd, J

= 13.9, 10.0, 6.6 Hz, 1H), 1.95 – 1.81 (m, 3H), 1.74 – 1.62 (m, 1H). ¹³C-

NMR (100 MHz, CDCl₃) δ/ppm 147.6 (C), 145.6 (C), 145.3 (C), 135.8 (C),

128.6 (CH), 127.1 (CH), 121.7 (C), 120.9 (CH), 115.4 (CH), 110.6 (CH),

108.7 (CH), 108.1 (CH), 100.7 (CH₂), 58.2 (CH), 38.0 (CH₃), 33.1 (CH₂),

32.0 (CH₂), 24.3 (CH₂), 23.5 (CH₂). IR (neat) ν/cm^-1: 2937 (m), 2889 (m),

1602 (m), 1501 (s), 1442 (m), 1245 (s), 1040 (m), 937 (m), 809 (m), 746

(m). HR-MS (TOF ES): calculated for C₁₉H₂₂NO₂296.1645, found

296.1635 (M+H+).

After continuously diluting the above reaction mixture (11, 100 mM EtOH,

1 mL/min) with a stream of EtOAc (4 mL/min) the resulting mixture was

directed into a holding reservoir and pumped from this into an H-Cube™

Mini (1 mL/min) equipped with a catalyst cartridge containing 10% Pd/C

(maintained at 50 °C). Upon evaporation of the volatiles product 12 was

isolated and purified on silica (10% EtOAc/hexanes).

Acknowledgements

We gratefully acknowledge the School of Chemistry for providing

a PhD-Scholarship (MDF). Dr Helge Müller-Bunz is thanked for

solving all X-ray structures reported. We are furthermore thankful

to Duncan Guthrie (Vapourtec) for support and helpful

discussions. We acknowledge generous support of our research

through Science Foundation Ireland (Infrastructure Call 2018

18/RI/5702 and European Regional Development Fund

12/RC2275_P2).

2-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)quinoline, (12):⁴¹colourless oil.

Yield: 88% (244 mg, 0.88 mmol). ¹H-NMR (400 MHz, CDCl₃) δ/ppm 8.07

– 8.00 (m, 2H), 7.76 (dd, J = 8.0, 1.5 Hz, 1H), 7.68 (ddd, J = 8.6, 7.2, 1.7

Hz, 1H), 7.48 (ddd, J = 8.2, 6.8, 1.3 Hz, 1H), 7.20 (d, J = 8.3 Hz, 1H), 6.74

(d, J = 1.7 Hz, 1H), 6.70 (d, J = 7.9 Hz, 1H), 6.66 (dd, J = 8.0, 1.6 Hz, 1H),

5.90 (s, 2H), 3.23 (dd, J = 9.5, 6.3 Hz, 2H), 3.07 (dd, J = 9.5, 6.5 Hz, 2H).

¹³C-NMR (100 MHz, CDCl₃) δ/ppm 161.7 (C), 148.0 (C), 147.5 (C), 145.7

(C), 136.2 (CH), 135.3 (C), 129.4 (CH), 128.9 (CH), 127.5 (CH), 126.8 (C),

125.8 (CH), 121.5 (CH), 121.3 (CH), 109.0 (CH), 108.1 (CH), 100.7 (CH₂),

41.2 (CH₂), 35.6 (CH₂). IR (neat) ν/cm^-1: 3042 (w), 2893 (m), 1600 (m),

1502 (s), 1488 (s), 1442 (m), 1244 (s), 1039 (s), 929 (m), 815 (m). HR-MS

(TOF ES): calculated for C₁₈H₁₆NO₂278.1176, found 278.1176 (M+H+).

Keywords: quinoline • tetrahydroquinoline • flow chemistry •

photochemistry • galipinine alkaloid

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Entry for the Table of Contents

✓

Light-driven and green solvent

✓

High throughput and purity

✓ Antimalarial drug synthesis

Continuous photochemistry: A continuous flow process exploiting a light-driven method for generating a series of drug-like

quinolines is reported and applied to the synthesis of the alkaloid natural product galipinine.

Institute and/or researcher Twitter usernames: @ucdchemistry

.

14

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Continuous Flow Synthesis of Quinolines via a Scalable Tandem Photoisomerization-Cyclization Process

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