Heumann indole flow chemistry process

Article abstract of DOI:10.1021/acs.joc.9b01516

Continuous flow chemistry has improved efficiency in the Heumann indole process. 3-Substituted indoles were prepared by three flow steps performed in succession in better overall yield and shorter reaction times relative to their batch counterparts. Novel

Full text of DOI:10.1021/acs.joc.9b01516

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Article
Heumann Indole Flow Chemistry Process
Cynthia Crifar, Fenja Leena Dücker, Sacha Nguyen Thanh, Vanessa Kairouz, and William D. Lubell
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01516 • Publication Date (Web): 17 Jul 2019
Downloaded from pubs.acs.org on July 18, 2019
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Heumann Indole Flow Chemistry Process
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Cynthia Crifar, Fenja L. Dücker, Sacha Nguyen Thanh, Vanessa Kairouz and William D. Lubell*
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Department of Chemistry, Université de Montréal, C.P. 6128, Succursale Centre-Ville, Montreal,
Quebec H3C 3J7
william.lubell@umontreal.ca
Supporting Information Placeholder
ABSTRACT: Continuous flow chemistry has improved efficiency in the Heumann indole process. 3-
Substituted indoles were prepared by three flow steps performed in succession in better overall yield and
shorter reaction times relative to their batch counterparts. Novel 3-alkyl and 3-methoxyindoles were
synthesized from their corresponding amino ketone and ester precursors by flow sequences featuring base-
free alkylation with methyl bromoacetate in DMF, saponification, and cyclization with acetic anhydride
and Et3N.
INTRODUCTION
Indole is ubiquitous among heterocycle ring systems in natural products, agrochemicals, medicines,
dyes and materials.1 Indoles are frequently used as pharmaceutical components, and found in anti-
inflammatory, antihypertensive, anti-tumour, anti-HIV, and antimigraine agents.2-3 Intense worldwide use
of indoles, particularly 3-substituted derivatives (e.g., tryptophan), dictates need for effective synthetic
methods.
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Strategies for indole synthesis are usually categorized according to the aromatic precursors.4-5 For
example, the Fisher protocol employs aryl hydrazine derivatives and is a mainstay for indole synthesis in
spite issues of regiocontrol,6-8 which have been addressed by alternative methods which use o-iodo
aniline9-10 and o-nitro toluene precursors.11 The spectrum of indole products impels continued search for
safe cost-effective methods employing alternative starting materials and mild conditions with minimal
waste.1, 12-15
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Figure 1. Heumann indole process general reaction sequence and representative products.
Lessons in the challenges of indole derivative synthesis are epitomized in research towards an industrial
process to make the important dyestuff, indigo. In spite the harsh conditions of heating N-phenylglycine
and sodium amide at ca. 200 °C,16 the Heumann–Pfleger process supplanted a relatively milder reaction
sequence from anthranilic acid and remains viable today. The discarded process, the so-called Heumann
indole process consisted of heating N-(2-carboxyphenyl)glycine III with acetic anhydride and sodium
acetate to provide indoxyl after work-up and hydrolysis of acetate IV (RAr = H, R3 = OAc).17-18 Nearly
forgotten, due likely in part to challenges in preparing N-arylglycine precursors (e.g., II and III), the
Heumann indole process has been occasionally used to prepare substituted indoles (e.g., IVa-g) with
regiocontrol (Figure 1).4, 19-24 For example, employing 2-acyl arylglycines III, indoles with 2-, 4-, and 6-
position substituents were synthesized in 50-78% yields.4, 22, 25
In our research oriented on homologues of tryptophan,26-27 3-(but-3’-enyl)indole (5a) was considered as
a versatile precursor from which different analogs could be obtained from olefin diversification chemistry.
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Substituted 3-(but-3’-enyl)indoles have been used in carbazole synthesis, and prepared by conjugate
additions of indole onto vinyl ketones and subsequent Wittig reaction with methyl triphenylphosphonium
bromide.28 The parent 3-(but-3’-enyl)indole has also been obtained from indole precursors. For example,
treatment of indole with methyl magnesium chloride and 4-bromobutene in benzene gave 5a in 41%
yield.29 Moreover, indole-3-carbaldehyde reacted in an indium-mediated allylation with allyl bromide in
the presence of Hantzsch’s ester to provide 5a in 77% yield.30 Notably, 3-(but-3’-enyl)indole has been
employed as substrate in cross-metathesis chemistry,31 as well as starting material for the synthesis of 3-
substituted indole fluoroalkanes,32 pyrroloindolines,33 a pentacyclic strychons alkaloid skeleton,34 and
hexahydrocarbazole alanine.29 To the best of our knowledge, 3-(but-3’-enyl)indole has however never
been synthesized from an aromatic precursor. Previously, 1-2-aminophenylpent-4-en-1-one (1a, RAr =
H, R3 = CH2CH2CH=CH2) has been prepared quantitatively from methyl anthranilate using a copper
catalyzed cascade addition of vinyl Grignard reagent,35 and used as an effective starting material for
syntheses of pyrroles,36 quinazolinones,36 quinolines,35 benzodia- and triazepinones,37-39 and
pyrrolobenzodi- and trizepinones.40 The Heumann indole process from amino ketone 1a was thus pursued
to effectively prepare 3-(but-3’-enyl)indole (5a).
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In exploring the Heumann indole process to make 1-acetyl-3-(but-3’-enyl)indole (4a), the use of flow
chemistry was found to give significant enhancements in reaction rates and yields relative to the
corresponding batch processes. Continuous flow chemistry is known to improve specific synthetic
processes through controlled reagent mixing, enabling safer and more reliable scale-up.41 Moreover,
effective Fisher and Hemetsberger-Knittel syntheses have been adapted to flow processes to give
convenient access to certain indole products.42-49 In the flow Heumann indole process, the yields of the
aniline alkylation and Heumann cyclization steps, both were significantly augmented compared to the
batch counterparts likely due to better substrate mixing. Examining the flow method on a set of other
substrates, certain 3-substituted indoles as well as 3-methoxy indole were effectively synthesized.
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RESULTS AND DISCUSSION
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In the Heumann indole process,18 the construction of the arylglycine component has been a traditional
challenge, often plagued by low yields, and pursued using various protocols: e.g., alkylation of
anthranilate with haloacetates,25 reductive amination with ethylglyoxalate,21 copper-catalyzed cross-
couplings of halobenzoates (e.g., V) with glycine derivatives,20, 50 as well as ipso-displacement of
fluorobenzonitrile with glycinates.51 In our hands, attempts at N-alkylation of aniline 1a using
bromoacetic acid caused product degradation as detected by thin-layer chromatography. On the contrary,
methyl bromoacetate reacted with 1a at 110°C under various conditions (Table 1).4, 52 In the presence of
potassium carbonate in DMF, alkylation with methyl bromoacetate (6 eq.) gave arylglycine 2a in only
20% yield (entry 1).4 In the absence of base, the reaction improved to 57% yield (entry 2), which was also
obtained using stoichiometric amounts of alkyl halide (entry 3). Alternative solvents (MeCN and MePh)
were less effective (entries 4 and 5), and use of Hünig’s base gave no improvement in yield (entry 6).
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BrCH2CO2Me Yield
Entry
Solvent
Base
(eq)
6
(% )
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DMF
DMF
DMF
K2CO3
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None
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1.1
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1.1
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Acetonitrile None
no rxn
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Toluene
DMF
None
DIPEA
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Table 1. Alkylation of aniline 1a in batch
Saponification gave quantitatively arylglycine 3a from heating N-arylglycinate 2a in 4N NaOH at 40C
for 1h (Scheme 1). The Heumann cyclization performed best in batch using acetic anhydride (100 eq.)
and triethylamine at 130°C for 30 min to afford indole 4a in 74% yield.4 Increasing the amount of acetic
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anhydride in the batch cyclization process from 1 to 10 to 100 equivalents improved the yield from 33 to
41 to 74%.
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Scheme 1. Batch synthesis of N-acetyl-3-(but-3-enyl)indole (4a)
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The synthesis of 1-acetyl-3-(but-3-enyl)indole (4a) from aniline 1a gave 42% overall yield using a route
featuring three batch reactions: amine alkylation with methyl bromoacetate, saponification and annulation
(Scheme 1). In batch, the alkylation and cyclization steps gave moderate yields, and required relatively
long reaction times, high temperature and purification of the reaction mixture using column
chromatography. To overcome these obstacles, we reasoned that efficient heat transfer and rapid mixing
in a continuous flow microreactor may enable shorter residence times to improve product purity and
yields.
Initially, the alkylation of aniline 1a was examined by adopting the batch conditions. Aniline 1a and
methyl bromoacetate were safely mixed in DMF at room temperature, introduced into a Vapourtec system
through an injection loop and flowed through and heated in a perfluoroalkoxy alkane (PFA, 110 C)
reactor equipped with a back-pressure regulator. After 90 min, glycine 2a was obtained quantitatively
without chromatography (Table 2). Lower conversion was obtained using a shorter residence time. A
longer residence time gave poorer yields of 2a due in part to formation of dialkylated and degradation
products. Poorer yields were also obtained in attempts to replace DMF with more environmentally benign
solvents such as ethyl acetate and tert-butyl methyl ether (Table 2, entries 4 and 5).
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Residence
Time (min)
% Yield
(% )
Entry
Solvent
Temp.
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DMF
DMF
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90
60
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DMF
EtOAc
t-BuOMe
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Table 2. Alkylation of aniline 1a in flow
Saponification of ester 2a was accomplished quantitatively using both the batch and flow conditions;
however, the latter were more expedient. N-Arylglycinate 2a was dissolved in methanol and treated with
sodium hydroxide (10 N) at rt, introduced into the injection loop and heated in the PFA reactor at 60C
for a residence time of 15 min. Acid 3a was quantitatively afforded as a white solid by quenching the
excess of NaOH with 2N HCl (4.1 eq.) followed by extraction into DCM, and evaporation of the volatiles
under vacuum (Scheme 2).
The Heumann cyclization was performed in flow by passing the reaction mixture through a 5-mL
stainless-steel reactor. The relatively viscous acetic anhydride was diluted with ethyl acetate to avoid
reactor clogging. Indole 4a was obtained in 90% yield by reacting N-arylglycine 3a with excess acetic
anhydride and triethylamine in ethyl acetate for 15 min at 130C in the stainless-steel reactor. The final
indole was isolated as a yellow oil after co-evaporation of the excess acetic anhydride with methanol.
Compared to the batch reaction sequence, the three flow-step synthesis of indole 4a was achieved in
shorter reaction times with more than twofold improvement in overall yield.
The best flow conditions for the Heumann indole flow chemistry process to synthesize 3-(but-3’-
enyl)indole 4a were subsequently examined on the corresponding o-aminophenyl methyl and phenyl
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ketones 1b and 1c, and provided the corresponding 3-methyl and 3-phenyl indoles 4b and 4c in 59% and
33% overall yields (Scheme 2, isolated individual yields are shown for glycinates 2 and 3, and indole 4).
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Scheme 2. Heumann indole flow chemistry process.
The influence of aromatic ring substituents in the flow protocol for Heumann indole synthesis was
examined using 1-2-amino-5-bromophenylpent-4-en-1-one (1d) and methyl 2-amino-5-(p-
methoxyphenyl)phenyl ketone (1e). The latter was synthesized from 1-(2-amino-5-bromophenyl)ethan-
1-one in 62% yield by Suzuki cross-coupling with methoxyphenylboronate using catalytic Pd(PPh3)4 and
sodium carbonate in 4:1 toluene/methanol at 120°C.53
Attempts to use continuous flow chemistry to alkylate 5-bromo-aniline 1d gave only 32% yield of
bromophenylglycinate 2d, likely due to diminished aniline nucleophilicity from the electron withdrawing
bromide. Improved access to ester 2d resulted on bromination of N-arylgycinate 2a using potassium
bromide (1 eq.) hydrogen peroxide (2 eq.) and ammonium molybdate tetrahydrate (0.01 eq.) which gave
2d in 60% yield (Scheme 3).
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Scheme 3. Synthesis of 4-bromophenyl)glycinate 2d
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Saponification of bromophenylglycinate 2d and Heumann cyclization under flow conditions gave 1-
acetyl-5-bromo-3-(but-3-enyl)indole (4d) in 70% yield over two steps. Employing conditions optimized
for the flow synthesis of 4a, alkylation of aniline 1e (65%), saponification of ester 2e (65%) and Heumann
cyclization of acid 3e (60%) provided 3,5-disubstituted indole 4e. Notably, Suzuki cross-coupling of 5-
bromoindole 4d with p-methoxyphenylboronate using the same conditions mentioned above gave N-
acetyl 3-(but-3-en-1-yl)-5-(4-methoxyphenyl)-1H-indole 4g in 76% yield.
The flow process gave consistently better yields than the batch counterpart likely due to multiple factors.
For example, the small dimensions of the flow reactor have been shown to enhance heat transfer and to
accelerate mixing, diminishing diffusion times and variations in temperature, which may avoid side
reactions encountered in batch chemistry.41 A set of experiments were performed to analyze further the
differences between the flow and batch processes in the alkylation and indole synthesis steps. The yields
for the synthesis of glycinates 2b and 2c in batch and flow were respectively 70% and 63% vs 99% and
77%. The batch alkylation failed to go to completion after 16 h, such that chromatography was essential
to obtain pure glycinate 2b. Notably, batch mixing influenced the rate at which starting aniline 1b was
consumed, which varied from 70% to 90% to 99% after 1.5 h as the stirring speed changed from 0 to ca.
750 rpm to 1500 rpm. In the batch alkylation reaction to 2b, a molecular ion corresponding to a dimer
(m/z = 368) was observed to increase in aliquots removed over time and analyzed by mass spectrometry.54
After the batch reaction, glycinate 2b was separated from decomposition products by elution on a
medium-pressure liquid chromatography column using a gradient of 0-100% ethyl acetate in hexanes.
Glycinate 2b was shown however to be unstable to the purification conditions on silica gel by reinjection
of pure sample, which was recovered in 60% yield. In the corresponding flow reaction, enhanced heat
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transfer and rapid mixing accelerate likely the alkylation reaction, such that after a shorter reaction time,
pure sample was obtained after aqueous work-up without chromatography.
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Although consumption of starting material was observed and pure indole 4 was isolated from the flow
Heumann cyclization after aqueous work-up, the mass balance was not 100%. After the flow reaction and
elution of indole 4b, washing of the stainless-steel reactor using methanol acidified with 1% concentrated
HCl eluded a colored impurity, which exhibited a molecular ion (m/z = 392) consistent with the bis-
sodium salt of a dimer of the starting glycine 3b in the mass spectrometric analysis.54 Slow elution of this
impurity may account for the high purity of the indole products. Notably, attempts failed to prepare indole
4b by cyclization of glycinate 3b in batch; instead, a colored residue was obtained likely due to the
formation of similar bi-products. In addition, attempts to perform the Heumann cyclization in batch failed
to provide indoles 4c and 4f, but gave 4d using a 1 h reaction time in 70% yield after chromatography.
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3-Methoxyindole 4f was synthesized by employing methyl anthranilate 1f in the 3-step flow Heumann
synthesis. Alkylation of 1f was significantly more effective using flow compared to batch conditions (72%
vs 6% yield). Saponification of glycinate 2f gave selectively acid 3f, which was difficult to isolate due to
its aqueous solubility (40%). Although longer reactions times were necessary, Heumann cyclization of
acid 3f under the flow conditions gave 3-methoxyindole 4f in 66% yield (vs 26% in batch, Scheme 2). 3-
Alkoxy indoles have previously been pursued due to their wide range of biological activities; however,
their synthesis has generally required multiple steps and expensive metal catalysis.55-57 The ability to
obtain 3-alkoxy indoles directly from the corresponding anthranilates enriches the utility of the flow
Heumann chemistry.
In addition to arylation of indole bromide 4d, the utility of 3-(but-3’-enyl)indoles 4a, 4d and 4g was
demonstrated by modification of the amine and olefin groups (Scheme 4). Liberation of the indole
nitrogen by acetamide removal was achieved by flowing 4a together with sodium hydroxide in acetonitrile
for 20 min at 80C to afford 3-(but-3’-enyl)indole (5a) in 70% yield; similar yield was obtained in batch
in 1h. Olefin oxidation was examined to provide the corresponding aldehyde 6 and ketone 7. Aldehyde
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6a was obtained quantitatively by treating olefin 4a with ozone in DCM. Ketones 7 were respectively
obtained in 72-93% yields by Wacker oxidation of indoles 4a, 4d and 4g using palladium dichloride and
copper chloride under 1 atm of oxygen in DCM/water. Applications of aldehyde 6a and ketones 7 in
syntheses of other 3-substituted indole products are under investigation and will be presented in due time.
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Scheme 4. Diversification of 3-(but-3’enyl)indoles 4
Flow chemistry has enhanced the utility of the Heumann indole process. A set of 3-substituted indoles
were synthesized by three successive flow steps in typically higher yields and shorter reaction times
compared to the corresponding batch processes. Products were obtained in high purity without silica gel
purification. Novel 3-alkyl and 3-methoxyindoles were prepared effectively for the first time. Considering
the need for effective means to prepare substituted indoles and the potential to diversify groups such as
the bromide and olefin of 3-(but-3’enyl)indoles 4, this novel flow method offers interesting utility for
procuring this important class of heterocycle structures.
EXPERIMENTAL SECTION
General Methods. Anhydrous conditions refer to reactions performed in flame-dried glassware under
a positive pressure of argon using dry solvent transferred by syringe. Methyl bromoacetate was purchased
from Sigma- Aldrich and filtered on a silica plug prior to use. 1-2-Aminophenylpent-4-en-1-one (1a)
was synthesized according to the literature.35 Anhydrous THF and DMF were obtained by passage through
solvent filtration systems (GlassContour, Irvine, CA). Flash column chromatography was performed
using 230-400 mesh silica gel.58 Thin layer chromatography (TLC) was performed on silica gel-coated
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glass-backed plates (Merck 60 F254). Batch processes were performed on an IKA RCT Basic stirring
plate with a speed range from 50 to 1500 rpm. The stir bar sized was 12.7 x 8mm.
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1H and 13C{1H} NMR spectra were measured in CDCl3 (7.27 and 77.2 ppm) at 400 MHz and 75 MHz,
respectively. The Mass Spectrometry Facility at the Université de Montréal performed HRMS
measurements on a LC-MSD TOF (Agilent) mass analyzer.
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Methyl (2-(pent-4-enoyl)phenyl)glycinate (2a). In a 20 mL-vial, aminoketone 1a (175.3 mg, 1.0
mmol) and methyl bromoacetate (0.1 mL, 1.1 mmol) were premixed in DMF (1.4 mL, 0.71M). The
mixture was injected into a 2 mL-loop that flowed into a 10 mL PFA reactor preheated at 110°C with a
back-pressure regulator at 8 bar. The reaction was run with a residence time of 90 min (flow rate of 111
L/min) and DMF was used as the elution solvent. The crude mixture was collected in an opened flask
and co-evaporated with toluene. The reduced volume was partitioned between water (5 mL) and DCM (5
mL). The aqueous layer was extracted with DCM (4 × 5 mL). The combined organic layers were washed
with water (3 × 5 mL) and brine, dried over MgSO4, filtered, evaporated and dried under vacuum to afford
glycinate 2a as yellow oil (247 mg, 99%); 1H NMR (400 MHz, CDCl3) δ 9.29 (s, 1H), 7.82 (dd, J = 6.3,
1.4 Hz, 1H), 7.36 (td, J = 6.3, 1.4 Hz, 1H), 6.67 (t, J = 7.7 Hz, 1H), 6.55 (d, J = 8.4 Hz, 1H), 5.95- 5.89
(m, 1H), 5.11 (m, 1H), 5.06 (m, 1H), 4.02 (d, J = 5.6 Hz, 2H), 3.78 (s, 3H), 3.07 (t, J = 7.5 Hz, 2H), 2.49
(q, J = 6.6 Hz, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ 202.2, 170.9, 150.1, 137.8, 135.1, 131.9, 118.2,
115.3, 111.8, 52.5, 44.9, 38.5, 29.8, 28.8; HRMS (ESI) Calcd m/z for C14H18NO3 [M+H+] 248.1280, found
248.1272.
Methyl (2-acetylphenyl)glycinate (2b). Glycinate 2b was synthesized from 2’-aminoacetophenone
(1b, 500 mg, 3.7 mmol) following the protocol for the synthesis of ester 2a, which afforded a yellow oil
(767 mg, 99%): 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 1H), 7.37 (t, J = 7.8 Hz 1H), 6.68 (t,
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J = 8.1 Hz, 1H), 6.55 (d, J = 8.5 Hz, 1H), 4.03 (d, J = 5.6 Hz, 2H), 3.79 (s, 3H), 2.60 (s, 3H); C{1H}
NMR (75 MHz, CDCl3) δ 201.1, 170.8, 150.0, 135.2, 132.9, 118.6, 115.3, 111.6, 52.5, 44.8, 28.1; HRMS
(ESI) Calcd m/z for C11H13NO3 [M+H+] 208.0968, found 208.0972.
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Methyl (2-benzoylphenyl)glycinate (2c). Glycinate 2c was synthesized from 2’-aminobenzophenone
(1c, 546.5 mg, 2.8 mmol) following the protocol for the synthesis of ester 2a, which afforded an orange
oil (574.4 mg, 77%): 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 7.67- 7.61 (m, 2H), 7.56- 7.50 (m, 2H),
7.49- 7.38 (m, 3H), 6.67- 6.60 (m, 2H), 4.09 (d, J = 3.2 Hz, 2H), 3.82 (s, 3H); 13C{1H} NMR (75 MHz,
CDCl3) δ 199.5, 170.8, 150.6, 140.3, 135.6, 135.1, 131.1, 129.3, 128.2, 118.3, 115.1, 111.6, 52.5, 45.0;
HRMS (ESI) Calcd m/z for C16H16NO3 [M+H+] 270.1125, found 270.1121.
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Methyl (4-bromo-2-(pent-4-enoyl)phenyl)glycinate (2d). Glycinate 2d was synthesized from 1-(2-
amino-5-bromophenyl)pent-4-en-1-one (1d, 384.0 mg, 1.51 mmol) following the protocol for the
synthesis of ester 2a, which afforded a dark brown oil (147.0 mg, 32%): 1H NMR (400 MHz, CDCl3) δ
9.27 (s, 1H), 7.91 (d, J = 2.3 Hz, 1H), 7.43 (dd, J = 9.0, 2.3 Hz, 1H), 6.46 (d, J = 9.0 Hz, 1H), 5.91 (m,
1H), 5.10 (m, 1H), 5.03 (m, 1H), 4.01 (d, J = 5.6 Hz, 2H), 3.80 (s, 3H), 3.05 (dt, J = 8.6, 6.3 Hz, 2H),
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2.56-2.42 (dt, 2H); C{1H} NMR (75 MHz, CDCl3) δ 201.1, 170.4, 148.9, 137.5, 137.4, 134.1, 119.5,
115.5, 113.7, 106.7, 52.6, 44.8, 38.5, 28.5; HRMS (ESI) Calcd m/z for C14H17BrNO3 [M+H+] 326.0386,
found 326.0396.
Methyl (3-acetyl-4'-methoxy-1,1'-biphen-4-yl)glycinate (2e). Glycinate 2e was synthesized from 1-
(4-amino-4'-methoxy-1,1'-biphen-3-yl)ethan-1-one (1e, 173.3 mg, 0.72 mmol) following the protocol for
the synthesis of ester 2a, which afforded a dark brown oil (146.6 mg, 65%); δ 9.23 (br s, 1H), 7.95 (d, J
= 2.2 Hz, 1H), 7.59 (dd, J = 8.7, 2.2 Hz, 1H), 7.46 (d, J = 8.9 Hz, 2H), 6.98 (d, J = 8.9 Hz, 2H) , 6.63 (d,
J = 8.8 Hz, 1H), 4.08 (d, J = 5.1 Hz, 2H), 3.86 (s, 3H), 3.81 (s, 3H), 2.67 (s, 3H); 13C{1H} NMR (75 MHz,
CDCl3) δ 201.2, 170.8, 158.8, 148.9, 133.7, 133.2, 130.8, 128.3, 127.5, 118.7, 114.4, 112.1, 55.5, 52.5,
44.9, 28.1; HRMS (ESI) Calcd m/z for C18H20NO4 [M+H+] 314.1387, found 314.1395.
Methyl 2-((2-methoxy-2-oxoethyl)amino)benzoate (2f). Glycinate 2f was synthesized from methyl
2-aminobenzoate (1f, 1 g, 6.61 mmol) following the protocol for the synthesis of ester 2a, which afforded
a yellow solid (1.06 g, 72%); 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.0 Hz, 1H), 7.36 (t, J = 8.8 Hz,
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1H), 6.66 (t, J = 8.1 Hz, 1H), 6.52 (d, J = 8.5, 0.7 Hz, 1H), 4.02 (s, 2H), 3.87 (s, 3H), 2.79 (s, 3H); 13C{1H}
NMR (75 MHz, CDCl3) δ 171.0, 168.9, 149.9, 134.7, 131.8, 115.7, 111.2, 111.0, 52.4, 51.7, 44.9; HRMS
(ESI) Calcd m/z for C11H14NO4 [M+H+] 224.0917, found 224.0923.
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(2-(Pent-4-enoyl)phenyl)glycine (3a). In a 20 mL-vial, glycinate 2a (500 mg, 2.02 mmol) and a 10N
aqueous NaOH (0.8 mL, 8.09 mmol) solution were mixed in MeOH (9 mL, 0.22M). The reaction mixture
was injected into a 10 mL-loop and flowed into a 10 mL PFA reactor preheated at 60°C maintaining a
regulated back-pressure of 8 bar. The reaction was run with a residence time of 15 min (flow rate of 667
L/min) using MeOH as elution solvent. The mixture was collected in an opened flask, acidified with 2M
HCl (4.1 mL, 8.3 mmol) and extracted with DCM. The combined organic layers were washed with brine,
dried over MgSO4, filtered and evaporated to afford the carboxylic acid 3a as yellow solid (466.6 mg,
99%), which was employed in the next step without further purification: HRMS (ESI) Calcd m/z for
C13H15NO3 [M+H+] 234.1125, found 234.1122.
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1-Acetyl-3-(but-3’-enyl)indole (4a). In a 20 mL-vial, glycine 3a (150 mg, 0.64 mmol), acetic
anhydride (6 mL, 64.3 mmol) and triethylamine (1 mL, 7.04 mmol) were premixed in EtOAc (3 mL, 0.21
M). The reaction mixture was injected into a 10 mL-loop and flowed through a 5 mL-stainless steel reactor
preheated at 130°C maintaining a back-pressure regulated at 8 bar. The reaction was run with a residence
time of 15 min (flow rate of 333 L/min) using EtOAc as the elution solvent. The mixture was collected
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in an opened flask and co-evaporated with MeOH to afford 4a as yellow oil (123 mg, 90%): H NMR
(400 MHz, CDCl3) δ 8.43 (brs, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.37 (t, J = 7.9, Hz, 1H), 7.30 (t, J = 7.6,
1.1 Hz, 1H), 7.21 (s, 1H), 5.99-5.87 (m, 1H), 5.11 (m, 1H), 5.05 (m, 1H), 2.82 (t, J = 7.6 Hz, 2H), 2.62
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(s, 3H), 2.50 (dt, J = 14.0, 7.0 Hz, 2H); C{1H} NMR (75 MHz, CDCl3) δ 168.3, 137.9, 136.0, 130.7,
125.2, 123.4, 122.5, 121.8, 118.9, 116.7, 115.3, 33.1, 24.4, 24.0; HRMS (ESI) Calcd m/z for C14H16NO
[M+H+] 214.1235, found 214.1226.
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1-Acetyl-3-(methyl)indole (4b). Indole 4b was synthesized from glycinate 2b (767 mg, 3.67 mmol)
following the protocols for the saponification to prepare glycine 3a (99% yield of 3b) and the Heumann
reaction to prepare 4a (60% yield of 4b), which afforded a dark brown oil (39 mg, 59% from glycine 2b);
1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 7.7 Hz, 1H), 7.52 (d, J = 8.3 Hz,1H), 7.37 (t, J = 9.5 Hz, 1H),
7.30 (t, J = 7.4Hz 1H), 7.20 (s, 1H), 2.61 (s, 3H), 2.30 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 168.4,
136.0, 131.6, 125.3,123.5, 122.3, 119.0, 118.5, 116.7, 24.1, 9.8; HRMS (ESI) Calcd m/z for C11H12NO
[M+H+] 174.0913, found 174.0920.
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1-Acetyl-3-(phenyl)indole (4c). Indole 4c was synthesized from glycinate 2c (574.4 mg, 2.2 mmol)
following the protocols for the saponification to prepare glycine 3a (88% yield of 3c) and the Heumann
reaction to prepare 4a (48% yield of 4c), which afforded a dark brown oil (28 mg, 42% from glycine 2c);
1H NMR (400 MHz, CDCl3) δ 8.53 (d, J = 8.3 Hz, 1H), 7.66 (d, J = 7.0 Hz 2H), 7.44-7.32 (m, 6H), 2.71
(s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 168.6, 136.3, 133.3, 129.0, 128.9, 128.0, 127.6, 125.5, 124.1,
123.9, 122.0, 119.9, 116.8, 24.1; HRMS (ESI) Calcd m/z for C16H16NO3 [M+H+] 270.1125, found
270.1121.
1-Acetyl-3-(but-3’-enyl)-5-bromoindole (4d). Indole 4d was synthesized from glycinate 2d (147.0
mg, 0.48 mmol) following the protocols for the saponification to prepare glycine 3a (99% yield of 3d)
and the Heumann reaction to prepare 4a (70% yield of 4d), which afforded a light yellow oil (110 mg,
69% from glycine 2d): 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 1.8 Hz, 1H),
7.44 (dd, J = 8.8, 1.9 Hz, 1H), 7.19 (s, 1H), 5.97- 5.83 (m, 1H), 5.11 (m, 1H), 5.05 (m, 1H), 2.76 (d, J =
7.8 Hz, 2H), 2.61 (s, 3H), 2.47 (dt, J = 13.9, 6.8 Hz, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ 168.4, 137.7,
134.7, 132.6, 128.1, 123.0, 121.9, 121.8, 118.2, 116.9, 115.7, 33.1, 24.4, 24.0; HRMS (ESI) Calcd m/z
for C14H15BrNO [M+H+] 292.0332, found 292.0319.
1-Acetyl-3-methyl-5-(4-methoxy)phenylindole (4e). Indole 4e was synthesized from glycinate 2e
(146.6 mg, 0.47 mmol) following the protocols for the saponification to prepare glycine 3a (65% yield of
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3e) and the Heumann reaction to prepare 4a (60% yield of 4e). Indole 4e was obtained as a yellow oil
(20 mg, 40% from glycine 2e); 1H NMR (400 MHz, CDCl3) δ 8.44 (br s, 1H), 7.64 (d, J = 1.3 Hz, 1H),
7.60 (d, J = 8.8 Hz, 2H), 7.56 (dd, J = 8.5, 1.7 Hz, 1H), 7.22 (br s, 1H), 7.01 (d, J = 8.8 Hz, 2H), 3.88 (s,
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C18H17NO2 [M+H+] 280.1332, found 280.1329
1-Acetyl-3-methoxyindole (4f). Indole 4f was synthesized from glycinate 2f (1.06 g, 4.76 mmol)
following the protocols for the saponification to prepare glycine 3a (40% yield of 3f) and the Heumann
reaction to prepare 4a (66% yield of 4f) with residence time of 30 min. Indole 4f was obtained as light
translucent oil (60 mg, 26% from glycine 2f): 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 7.9 Hz, 1H),
7.73 (s, 1H), 7.55 (d, J = 7.0 Hz, 1H), 7.44-7.38 (t, 1H), 7.36-7.28 (t, 1H), 2.62 (s, 3H), 2.40 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 168.9, 168.0, 134.8, 133.0 126.4, 123.9, 117.6, 116.8, 113.4, 24.1,
21.2. HRMS (ESI) Calcd m/z for C11H12NO2 [M+H+] 190.0863, found 190.0869.
3-(But-3’-enyl)indole (5a). In a 20 mL vial, NaOH pellets (56.4 mg, 1.41 mmol) were dissolved in 1
mL of water and treated with indole 4a (100 mg, 0.47 mmol) in MeCN (1.6 mL, 0.88M). The heterogenous
reaction mixture was injected into a 2 mL-loop and flowed into a 10 mL PFA reactor preheated at 80°C
maintaining a back-pressure regulated at 8 bar. The reaction was run with a residence time of 20 min
(flow rate of 500 L/min) using MeCN as the elution solvent. The mixture was collected in an opened
flask, treated with 1M NaH2PO4 (5 mL,) and extracted with EtOAc. The combined organic layers were
washed with brine, dried over MgSO4, filtered and evaporated to afford the indole 5a as a yellow oil (57.1
mg, 71%); 1H NMR (400 MHz, CDCl3) δ 7.92 (br s, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 8.1 Hz,
1H), 7.20 (t, J = 7.5 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.01 (s, 1H), 6.01-5.91 (m, 1H), 5.10 (m, 1H), 5.01
(m, 1H), 2.88 (t, J = 5.9 Hz, 2H), 2.50 (dt, J = 14.9, 7.1 Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3)
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138.9, 136.4, 122.0, 121.3, 119.3, 119.1, 116.4, 114.8, 111.2, 34.4, 29.8, 24.9. HRMS (ESI) Calcd
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1-(2-Amino-5-bromophenyl)pent-4-en-1-one (1d). Aniline 1d was synthesized according to the
procedure used to make bromide 2d described below using 1-(2-aminophenyl)pent-4-en-1-one 1a (1 g,
7.4 mmol). After silica gel column chromatography (5% EtOAc/hexanes), 1d was isolated as orange oil
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(1.33 g, 71%); H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 2.3 Hz, 1H), 7.32 (dd, J = 8.8, 2.3 Hz, 1H),
6.56 (d, J = 8.8 Hz, 1H), 6.30 (s, 2H), 5.90 (m, 1H), 5.10 (m, 1H), 5.03 (m, 1H), 3.02 (t, J = 5.6 Hz, 2H),
2.48 (dt, J = 6.6, 1.2 Hz, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ 200.9, 149.3, 137.4, 137.0, 133.3, 119.3,
119.2, 115.5, 106.9, 38.4, 28.5. HRMS (ESI) Calcd m/z for C11H13BrNO [M+H+] 254.0175, found
254.0167.
1-(2-Amino-5-bromophenyl)ethan-1-one (1h). Aniline 1h was synthesized according to the
procedure used to make bromide 2d described below using 1-(2-aminophenyl)ethan-1-one (1b, 1 g, 7.4
mmol). After silica gel column chromatography (30% EtOAc/hexanes), 1h was isolated as brown solid
(1.31 g, 83%); 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.3 Hz, 1H), 7.27 (t, J = 7.7 Hz, 1H), 6.72- 6.60
(m, 2H), 2.58 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 200.9, 150.4, 134.5, 132.2, 118.4, 117.3, 115.9,
28.0. The spectral corresponded to that previously reported.59
1-(2-Amino-5-(4-methoxyphenyl)phenyl)ethan-1-one (1e). In a 25-mL round bottom flask, a
solution of 4-methoxyphenylboronic acid (297.4 mg, 1.96 mmol) in dry MeOH (1.1 mL) was added to a
suspension of aniline 1h (300 mg, 1.40 mmol), Pd(PPh3)4 (48.5 mg, 42 mol) and Na2CO3 (sat.) (1.6 mL)
in toluene (4.3 mL). The reaction mixture was heated to reflux for 4 h, cooled to room temperature and
diluted with water (5 mL). The aqueous layer was extracted with EtOAc (3 × 5 mL). The combined
organic layers were washed with water, sodium carbonate and brine, dried over MgSO4, filtered and
concentrated to a residue, which was purified on silica gel column chromatography (40%
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EtOAc/hexanes). Aniline 1e was obtained as orange solid (207 mg, 61%): 1H NMR (400 MHz, CDCl3) δ
7.87 (d, J = 2.1 Hz, 1H), 7.51 (dd, J = 5.2, 2.6 Hz, 2H), 7.46 (d, J = 9 Hz, 1H), 6.98 (d, J = 8.9 Hz, 2H),
6.73 (d, J = 8.6 Hz, 1H), 6.28 (s, 2H), 3.86 (s, 3H), 2.65 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 201.0,
158.8, 149.3, 133.3, 133.2, 130.0, 128.9, 127.5, 118.5, 117.9, 114.4, 55.5, 28.1; HRMS (ESI) Calcd m/z
for C15H16NO2 [M+H+] 242.1176, found 242.1180.
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Methyl (2-(pent-4-enoyl)phenyl)glycinate (2a). Aminoketone 1a (500 mg, 2.85 mmol) and methyl
bromoacetate (300 L, 3.14 mmol) were heated in DMF (1 mL, 2.85M) at 110°C overnight, in a 20-mL
sealed vial. After cooling to room temperature, DMF was co-evaporated three times with toluene and the
reduced volume was partitioned between water (5 mL) and DCM (5 mL). The aqueous layer was extracted
with DCM (4 × 5 mL). The combined organic layers were washed with water (3 × 5 mL) and brine, dried
over MgSO4, filtered and evaporated to a residue, that was purified by silica gel column chromatography
(10-20% EtOAc/hexanes) to afford 2a as yellow oil (409 mg, 57%), which exhibited identical physical
and spectral characterization as material that was obtained from the corresponding flow chemistry
protocol above.
Methyl (2-acetylphenyl)glycinate (2b). Employing 2-aminoacetophenone (500 mg, 3.7 mmol) and
methyl bromoacetate (390 L, 4.07 mmol) in DMF (2 mL, 1.85M) in the batch protocol described above
for 2a, followed by silica gel column chromatography (10-20% EtOAc/hexanes), glycinate 2b was
obtained as brown oil (537 mg, 70%), which exhibited identical physical and spectral characterization as
material that was obtained from the corresponding flow chemistry protocol above.
Methyl (2-benzoylphenyl)glycinate (2c). Employing 2-aminobenzophenone (200 mg, 1.01 mmol)
and methyl bromoacetate (110 L, 1.12 mmol) in DMF (2 mL, 0.51 M) in the batch protocol described
above for 2a followed by silica gel column chromatography (10-20% EtOAc/hexanes), glycinate 2c was
obtained as a pale yellow oil (173 mg, 63%), which exhibited identical physical and spectral
characterization as material that was obtained from the corresponding flow chemistry protocol above.
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Methyl (2-(pent-4-enoyl)-4-bromophenyl)glycinate (2d). In a 50-mL round bottom flask, potassium
bromide (341 mg, 2.87 mmol) and (NH4)6Mo7O24•4 H2O (36 mg, 28.7 mol) were added to a solution of
homo-allylic ketone 2a (500 mg, 2.87 mmol) in acetic acid (8 mL), followed dropwise with 30% hydrogen
peroxide (440 L, 4.31 mmol) at room temperature. The solution was stirred overnight, treated with
saturated sodium carbonate, and extracted with EtOAc. The organic layer was washed with Na2CO3 (sat.)
and dried over MgSO4. After chromatography (95:5 hexane:EtOAc), bromide 2d was obtained as orange
oil (439 mg, 60%); 1H NMR (400 MHz, CDCl3) δ 9.27 (s, 1H), 7.91 (s, 1H), 7.43 (dd, J = 9.0, 2.3 Hz,
1H), 6.46 (d, J = 9.0 Hz, 1H), 5.91 (m, 1H), 5.07 (m, 2H), 4.01 (d, J = 5.6 Hz, 2H), 3.80 (s, 3H), 3.05 (dd,
J = 8.6, 6.3 Hz, 2H), 2.54- 2.43 (m, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ 201.1, 170.4, 148.9, 137.5,
137.4, 134.1, 119.5, 115.5, 113.7, 106.7, 52.6, 44.8, 38.5, 28.5; HRMS (ESI) Calcd m/z for C14H17BrNO3
[M+H+] 326.0386, found 326.0396.
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(2-(Pent-4-enoyl)phenyl)glycine (3a). To a solution of glycinate 2a (200 mg, 0.81 mmol) in MeOH
(5 mL, 0.16M), 4M aqueous NaOH (0.81 mL, 3.24 mmol) was added. The mixture was stirred at 40°C
for an hour, in a 20-mL sealed vial. The resulting solution was acidified with 2M HCl (1.66 mL, 3.32
mmol) and extracted with DCM. The combined organic layers were washed with brine, dried over
MgSO4, filtered and evaporated to afford the crude carboxylic acid as a yellow solid (189 mg, 100%),
which exhibited identical physical and spectral characterization as material that was obtained from the
corresponding flow chemistry protocol above, and was used without further purification.
1-Acetyl-3-(but-3’-enyl)indole (4a). Carboxylic acid 3a (200 mg, 0.85 mmol) was added to a solution
of acetic anhydride (8.02 mL, 85 mmol) and triethylamine (1.30 mL, 9.35 mmol), and heated to 130°C
for 30 min, in a 20-mL sealed vial. The mixture was co-evaporated with MeOH to a residue, that was
partitioned between EtOAc (2 mL) and 1M NaH2PO4 (2 mL). The aqueous layer was extracted with
EtOAc (3 × 5 mL). The combined organic layers were washed with water (3 × 5 mL) and brine, dried
over MgSO4, filtered and evaporated to a residue, that was purified by silica gel column chromatography
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(10% EtOAc/hexanes) to afford 4a as yellow oil (134 mg, 74%), which exhibited identical physical and
spectral characterization as material that was obtained from the corresponding flow chemistry protocol
above.
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1-Acetyl-3-(but-3’-enyl)-5-bromoindole (4d). Carboxylic acid 3d (167 mg, 0.54 mmol) was
dissolved in acetic anhydride (3 mL) and triethylamine (1.3 mL, 0.59 mmol), in a 20-mL sealed vial, and
the solution was heated at reflux (130C bath temperature) for 1 h. The reaction mixture was cooled to
room temperature, the volatiles were evaporated and the residue was purified by silica gel column
chromatography (10% EtOAc/hexanes) to afford 4d as light-yellow oil (110 mg, 70%), which exhibited
identical physical and spectral characterization as material that was obtained from the corresponding flow
chemistry protocol above.
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1-Acetyl-3-methoxyindole (4f). Indole 4f was synthesized from glycinate 2f (100 mg, 0.48 mmol)
following the batch protocols for the saponification to prepare glycine 3a and the Heumann reaction to
prepare 4a. Indole 4f was obtained as light translucent oil (24 mg, 26% from the glycine 2f): 1H NMR
(400 MHz, CDCl3) δ 8.47 (d, J = 7.9 Hz, 1H), 7.73 (s, 1H), 7.55 (d, J = 7.0 Hz, 1H), 7.44-7.38 (t, 1H),
7.36-7.28 (t, 1H), 2.62 (s, 3H), 2.40 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 168.9, 168.0, 134.8, 133.0
126.4, 123.9, 117.6, 116.8, 113.4, 24.1, 21.2. HRMS (ESI) Calcd m/z for C11H12NO2 [M+H+] 189.0790,
found 189.0767.
1-Acetyl-3-(but-3’-enyl)-5-(4-methoxy)phenylindole (4g). Indole 4g was synthesized according to
the cross-coupling procedure used to make biphenyl 1e using 1-acetyl-3-(but-3’-enyl)-5-bromoindole (4d,
40 mg, 0.14 mmol), and obtained after purification by silica gel column chromatography (5 to 10%
EtOAc/hexanes) as yellow oil (33 mg, 76%). In the proton-NMR spectrum, a mixture of amide isomers
was observed. The signals of the major isomers are as follows. 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J
= 7.6 Hz, 1H), 7.67 (d, J = 1.3 Hz, 1H), 7.59 (d, J = 8.8 Hz, 3H), 7.40 (d, J = 1.2 Hz, 1H), 7.23 (s, 1H),
7.01 (d, J = 8.8 Hz, 2H), 6.01- 5.87 (m, 1H), 5.16- 5.00 (m, 2H), 3.87 (s, 3H), 2.85 (t, J = 8.0 Hz, 2H),
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2.63 (s, 3H), 2.52 (dt, J = 13.9, 6.9 Hz, 2H); C{1H} NMR (75 MHz, CDCl3) δ 159.1, 138.0, 136.6,
134.3, 128.5, 124.5, 122.9, 122.5, 122.0, 121.8, 117.0, 115.5, 114.4, 114.2, 55.5, 44.8, 34.4, 33.3, 24.6,
24.1; HRMS (ESI) Calcd m/z for C21H22NO2 [M+H+] 320.1645, found 320.1646.
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3-(1-Acetyl-1H-indol-3-yl)propanal (6a). A solution of indole 4a (84.3mg, 0.39 mmol) in DCM (4
mL) in a 20-mL sealed vial was treated with ozone bubbles at –78°C until a blue color persisted, purged
with a stream of argon bubbles, treated with dimethyl sulfide (144 L, 1.95 mmol), and stirred overnight,
after which time, the bath had warmed to room temperature. Removal of the volatiles by rotary
evaporation gave a residue, which was purified by column chromatography on silica gel (2%
MeOH/DCM) to provide aldehyde 6a as yellow oil (84 mg, 100%); 1H NMR (400 MHz, CDCl3) δ 9.87
(s, 1H), 8.43 (d, J = 1.2 Hz, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.38 (t, J = 1.5 Hz, 1H), 7.31 (t, J = 1.5 Hz,
1H), 7.22 (s, 1H), 3.06 (t, J = 7.1 Hz, 2H), 2.89 (t, J = 7.1 Hz, 2H), 2.62 (s, 3H); 13C{1H} NMR (75 MHz,
CDCl3) δ 210.2, 168.3, 135.9, 130.1, 125.4, 123.5, 122.2, 121.1 118.6, 116.8, 43.0, 24.0, 17.4; HRMS
(ESI) Calcd m/z for C13H14NO2 [M+H+] 216.1019, found 216.1024.
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4-(1-Acetyl-1H-indol-3-yl)butan-2-one (7a). In a 25-mL round bottom flask containing 2 mL of a
7:1 DMF/H2O solution, PdCl2 (24.8 mg, 0.14 mmol) and CuCl (71.3 mg, 0.72 mmol) were dissolved.
The vessel was evacuated and filled three times with oxygen before stirring under O2 (1 atm) for 1 h.
Indole 4a (102.4 mg, 0.48 mmol) in 2 mL of a 7:1 DMF/H2O solution was then added to the reaction
mixture and stirred under oxygen atmosphere overnight at room temperature. The vessel was purged with
nitrogen and treated with a solution of 10% aq. HCl (4 mL). The aqueous layer was separated and
extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with water and brine, filtered
over Celite™, dried over MgSO4, filtered and evaporated to a residue, that was purified by silica gel
column chromatography (40% EtOAc/hexanes) to afford ketone 7a as a dark oil (79 mg, 72%): 1H NMR
(400 MHz, CDCl3) δ 8.43 (br d, J = 8.0 Hz, 1H), 7.53 (d, J = 7.2 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.31
(t, J = 7.1 Hz, 1H), 7.22 (s, 1H), 3.00 (t, J = 7.6 Hz, 2H), 2.88 (t, J = 7.6 Hz, 2H), 2.62 (s, 3H), 2.18 (s,
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3H); C{1H} NMR (75 MHz, CDCl3) δ 207.8, 168.5, 136.1, 130.4, 125.5, 123.6, 122.4, 121.8, 118.8,
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116.9, 43.0, 30.2, 24.2, 19.0; HRMS (ESI) Calcd m/z for C14H16NO2 [M+H+] 230.117, found 230.1176.
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4-(1-Acetyl-5-bromo-1H-indol-3-yl)butan-2-one (7d). Bromoindole 7d was synthesized according
to the protocol described to prepare ketone 7a using 1-(5-bromo-3-(but-3-en-1-yl)-1H-indol-1-yl)ethan-
1-one 4d (85 mg, 0.29 mmol). After purification by silica gel column chromatography (50%
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EtOAc/hexanes), ketone 7d was isolated as white solid (83 mg, 93%): mp 118-125°C; H NMR (400
MHz, CDCl3) δ 8.32 (d, J = 8.9 Hz, 1H), 7.64 (d, J = 1.9 Hz, 1H), 7.45 (dd, J = 8.8, 1.9 Hz, 1H), 7.22 (s,
1H), 2.95 (t, J = 7.0 Hz, 2H), 2.84 (t, J = 7.0 Hz, 2H), 2.60 (s, 3H), 2.18 (s, 3H); 13C{1H} NMR (75 MHz,
CDCl3) δ 207.4, 168.4, 132.2, 128.3, 123.6, 121.6, 121.0, 117.0, 104.0, 42.8, 30.2, 24.0, 18.7; HRMS
(ESI) Calcd m/z for C14H15BrNO2 [M+H+] 308.0281, found 308.0275.
4-(1-acetyl-5-(4-methoxyphenyl)-1H-indol-3-yl)butan-2-one (7g). Indole 7g was synthesized
according to the protocol described to prepare ketone 7a using 1-(3-(but-3-en-1-yl)-5-(4-methoxyphenyl)-
1H-indol-1-yl)ethan-1-one 4g (40 mg, 0.13 mmol). After purification by silica gel column
chromatography (50% EtOAc/hexanes) ketone 7g was isolated as white oil (33 mg, 75%); 1H NMR (400
MHz, CDCl3) δ 8.44 (br d, J = 7.9 Hz, 1H), 7.65 (m, 4H), 7.24 (s, 1H), 7.02 (d, J = 8.0 Hz, 2H), 3.88 (s,
3H), 3.88 (t, J = 7.2 Hz, 2H), 2.89 (t, J = 7.0 Hz, 2H), 2.63 (s, 3H), 2.19 (s, 3H); 13C{1H} NMR (75 MHz,
CDCl3) δ 207.8, 168.4,159.2, 136.7, 135.1, 134.1, 131.0, 128.5, 127.8, 124.6, 122.9, 121.9, 116.7, 114.4,
55.5, 43.0, 30.2, 24.1, 18.9; HRMS (ESI) Calcd m/z for C21H22NO3 [M+H+] 336.1594, found 336.1597.
ASSOCIATED CONTENT
The Supporting Information is available free of charge on the ACS Publications website.
Characterization data and copies of NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
* E-mail: lubell@chimie.umontreal.ca
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Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENT
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We are grateful for support from the Natural Sciences and Engineering Research Council of Canada
(NSERC) for Discovery Grant #04079, the NSERC Collaborative Research and Training Experience
Program in flow science (#449307), and the Fonds de recherche nature et technologie Quebec for the
Centre in Green Chemistry and Catalysis (FRQNT-2020-RS4-265155-CCVC). We thank the Université
de Montreal, and staff members of its regional centers for Mass Spectrometry (Dr. Alexandra Furtos-
Matei, Marie-Christine Tang, Louiza Mahrouche and Karine Gilbert) and Dr Pedro M. Aguiar for NMR
Spectroscopy. Dr. Eric Lesveque is thanked for images of flow chemistry apparatus schemes in the
supporting information.
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