Diastereoselective synthesis of 3-(α-aryl)alkenylindoles from the direct dehydrative coupling of indoles and ketones: A synthetic and theoretical study

Article abstract of DOI:10.1016/j.tet.2020.131498

A representative library of 3-(α-aryl)alkenylindoles has been prepared via a Br?nsted-acid catalysed dehydrative coupling reaction between alkyl aryl ketones and some indoles. An interesting diastereoselectivity has been observed and has been explained from a mechanistic point of view.

Full text of DOI:10.1016/j.tet.2020.131498

Journal Pre-proof
Diastereoselective synthesis of 3-(α-aryl)alkenylindoles from the direct dehydrative
coupling of indoles and ketones: A synthetic and theoretical study
Margherita Barbero, Domenica Marabello, Stefano Dughera, Tiziana Sicari, Achille
Antenucci, Giovanni Ghigo
PII:
S0040-4020(20)30682-7
https://doi.org/10.1016/j.tet.2020.131498
TET 131498
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 June 2020
Revised Date: 4 August 2020
Accepted Date: 10 August 2020
Please cite this article as: Barbero M, Marabello D, Dughera S, Sicari T, Antenucci A, Ghigo G,
Diastereoselective synthesis of 3-(α-aryl)alkenylindoles from the direct dehydrative coupling of indoles
and ketones: A synthetic and theoretical study, Tetrahedron (2020), doi: https://doi.org/10.1016/
j.tet.2020.131498.
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R'
cat
O
R
+
- H2O
N
H
HN
R'
R
1
3
2
R'
R'
+ MeOH+
- MeOH2
HN
HN
R
R
E-4
Z-4
reaction diastereoselectivity depends on C-2 substitution of indole!

DIASTEREOSELECTIVE SYNTHESIS OF 3-(α-ARYL)ALKENYLINDOLES FROM THE
DIRECT DEHYDRATIVE COUPLING OF INDOLES AND KETONES: A SYNTHETIC
AND THEORETICAL STUDY
Margherita Barbero,a* Domenica Marabello,a,b Stefano Dughera,a Tiziana Sicari,a Achille
Antenucci,a Giovanni Ghigoa*
a Dipartimento di Chimica, Università di Torino, Via P. Giuria 7, 10125 Turin, Italy
b CrisDi − Interdepartmental Centre for Crystallography, Università di Torino, Turin, Italy
Corresponding authors: tel. +39-011-6707645, e-mail margherita.barbero@unito.it; tel. +39-
011-6707872, e-mail giovanni.ghigo@unito.it
Tel: +39-011-6707645
Graphical abstract:
Abstract:
A representative library of 3-(α-aryl)alkenylindoles has been prepared via a Brønsted-acid catalysed
dehydrative coupling reaction between alkyl aryl ketones and some indoles. An interesting
diastereoselectivity has been observed and has been explained from a mechanistic point of view.
Keywords:
1

3-(α-aryl)alkenylindoles; diastereoselective reaction; dehydrative coupling; DFT calculations;
indole functionalisation
1. Introduction
Indole is one of the most widespread heterocycles to be found in natural products, often endowed
with biological activity;1-7 therefore the synthesis and functionalisation of indole and its derivatives
are fundamental processes and still challenging goals in synthetic studies. Limiting our references to
even just the most recent reviews, indole alkaloids, carbazole and other indole-based heterocycles
syntheses have been reported starting from 2- or 3-vinylindoles,8, 9 as isolated or in situ formed
intermediates. Furthermore, 3-vinylindole derivatives display interesting biological activities.10-12
The alkenyl group can be introduced on the indole ring using indirect or direct approaches, the
former requiring and the second avoiding a previous indole functionalisation. Oxidative
alkenylation, however, is the most commonly exploited synthetic procedure to introduce the α-
unsubstituted alkenyl group directly on heterocycle rings.13-15 Conversely, few reports deal with the
synthesis of α-aryl substituted 3-alkenylindoles through the direct functionalisation of indole. These
include hydroarylations of alkynoates which have been catalysed by palladium,16, 17 platinum,18
gold complexes in ionic liquids,19 or hydroarylation of alkynes catalysed by indium bromide.20
Other procedures involve a dehydrative coupling of 3-indolylmethanols,21 an indole alkenylation
with 1,3-dicarbonyl compounds in DES,22 a metal-free cross-coupling with nitrimines,23 and a
Brønsted acid catalysed reaction with tertiary propargylic alcohols on 2-substituted indoles.24-26
2

Scheme 1: Previous synthetic approaches to the synthesis of 3-(α-aryl)alkenylindoles
Dehydrative coupling of indoles with ketones (or aldehydes) is a simple method for direct C-3
alkenylation, although it can exploit subsequent intramolecular cyclisations.14, 27-30 To the best of
our knowledge, the papers most relevant to our research described the dehydrative coupling of
indoles with ketones catalysed by Brø
nsted acidic ionic liquids,31 or with benzyl aryl ketones under
conventional and microwave conditions,32 and, finally, the above-mentioned metal-free coupling of
indoles with ketone derived nitrimines.23 In those works, the authors tested some aryl alkyl ketones
and, when the alkyl was the ethyl or benzyl group, they normally obtained the expected dehydrative
coupling products as predominant or exclusive E diastereomers.31
Recently, we described a carbocation catalysed direct dehydrative coupling reaction between
methyl aryl ketones (or cyclic ketones) and indoles,33 a simple and straightforward way of
achieving a 3-(α-aryl)vinylindole scaffold which is a versatile building block for the construction of
complex structures. With the aim of extending our research to a 3-(α-aryl)alkenylindole synthesis,
we decided to expand the above synthetic procedure to the reaction of indoles with some
representative alkyl aryl ketones in the presence of different acid catalysts.
2. Results and discussion
3

As a model reaction, we decided to begin the study by reacting 2-methylindole (1a) with
propiophenone (2a) to afford dehydrative coupling product 3a in the presence of different catalysts,
at variable temperatures and solvents (Scheme 2). We started our screening conditions using
commercially available protic acid catalysts, namely methanesulfonic acid and p-toluenesulfonic
acid, later moving on to the Lewis acid catalyst previously employed (Table 1).33
Scheme 2: Model reaction between 2-methylindole (1a) with propiophenone (2a)
Table 1: trial reactions
entry 1a:2a solvent
Cat
(mol %)
T (°C)
t (h)
Yield % (dr)a
1
2
1:1
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeCN
MeCN
-
CH3SO3H (5)
CH3SO3H (5)
p-TosOH (5)
p-TosOH (5)
p-TosOH (5)
p-TosOH (5)
p-TosOH (5)
p-TosOH (5)
p-TosOH (5)
p-TosOH (5)
p-TosOH (0.5)
4 (5)
rt
65
65
65
65
rt
3
2
slow incomplete reaction
1:1
81 (92:8)
b
3
1:1
5
4
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1.1
1:1
1
89 (92:8)
93 (92:8)c
86 (92:8)
85 (90:10)
89 (90:10)
79 (95:5)
5
1
6
5
7
rt
24
10
10
1d
30
24
2
8
65
rt
9
10
11
12
13
14
15
16
-
65
rt
55 (92:8)
e
-
MeOH
rt
Incomplete reaction
83 (88:12)
1:1.1
1:1.1
1:1.1
1:1
4 (5)
65
65
rt
MeOH
-
48
24
24
Only traces
e
-
-
-
-
90
Minimal traces
a
The reactions were run on a 2 mmol scale. Yields refer to pure isolated product. Diastereomeric ratio (dr) calculated
from 1H NMR spectra of isolated 3a.
b Unreacted indole present in not negligible amount.
4

c The reaction was run on a 10 mmol scale.
d The reaction was stopped in the absence of indole 1a.
e No traces of product were detected.
The progress of the reaction was monitored by TLC, GC and GC-MS analyses. When using
methanesulfonic acid as the catalyst, the GC and GC-MS analyses clearly showed the immediate
formation of two diastereomeric products (M+ 247; Table 1, entries 1 and 2). The first eluting
product became rapidly predominant with respect to the second one, which prevailed at the
beginning of the reaction but readily converted into the other. An attempt was made to stop the
observed diastereomers conversion by varying the catalyst amount, reaction time and temperature,
but this was unsuccessful. Even stopping the reaction at its onset, when the GC analysis revealed
that the second diastereomer was slightly predominant (in the presence of the majority of unreacted
reagents), the reaction work-up furnished only the first eluting diastereomer in low yield. With the
reaction completed, product 3a was isolated in 81% yield in 92:8 diastereomeric ratio (Table 1,
entry 2).
Subsequently, p-toluenesulfonic acid was tested by screening different solvent and solvent-less
conditions, catalyst amount and reaction temperature (Table 1, entries 3−11). The same evolution in
product formation was observed as for methanesulfonic acid. The reagent ratio was optimised to
1a:2a = 1:1.1, the better conversion was observed by heating to 65°C in methanol and in the
presence of 5 mol% of catalyst (Table 1, entry 4); product 3a was isolated in 85% yield (dr 92:8).
Furthermore, the scale-up of the reaction was confirmed on a 10 mmol scale (Table 1, entry 5).
Unsatisfactory results were obtained when using acetonitrile as the solvent (Table 1, entries 7 and 8)
and in neat conditions (Table 1, entries 9−11), both at room temperature and under reflux heating.
Finally, we decided to evaluate the Lewis acid 4 used in our previous work dealing with
dehydrative coupling between indoles and acetophenones (Table 1, entries 12 and 13).33 The
reaction required heating conditions with respect to the above Brønsted acids, but the same trend in
5

product formation/isomerisation and the same unsuccessful efforts to stop the reaction as the first
diastereomer were unfortunately confirmed.
Figure 1: (4-Methoxyphenyl)(2-methylindol-3-yl)methylium tetrafluoroborate (4).
A blank reaction was eventually run in the absence of any catalyst in methanol and in neat
conditions; no reaction was observed (Table 1, entries 14-15); furthermore, only traces of products
were detected by heating to 90°C neat reagents for 24 hours (Table 1, entry 16).
In all reaction conditions, we isolated product 3a in the virtually identical diastereomeric ratio. In
order to establish the configuration of the prevalent diastereomer, spectral analyses were initially
1
completed. Quite unexpectedly, H NMR spectrum of 3a showed a diastereomer ratio of 92:8, in
favour of the Z isomer, by unambiguous comparison with NMR spectra reported in literature.
Alkene 3a was obtained by Mattson in a diastereomeric ratio E:Z = 6:1,23 along with another three
diastereomeric indole derivatives in predominant E configuration. The most distinctive signals are
the vinylic proton quadruplet and the olefinic methyl doublet, which are centred at 6.35 ppm and
1.70 ppm, respectively, for the Z diastereomer, and centred at 5.94 ppm and 1.94 ppm for the E.
In order to rationalise this outcome, the reaction mechanism was studied via the computational
method (the details are reported in the Supplementary Data). As the reaction mechanism is
assumed to be the same as that previously studied for a similar system,33 only the last step of the
reaction was analysed (Scheme 3). The catalysed addition of 2a to 1a and dehydration generates
the cation 5a. This intermediate is deprotonated by the solvent methanol, yielding the final product
3a. The structures of the transition states and the product complexes (3a and the protonated
methanol) were optimised for the two diastereomers. For both of them, 12 conformations were
found (see Tables 5aS and 5bS in the Supplementary Data). The free energy barriers for the
deprotonation range from 14.6 and 18.2 kcal mol-1 for the generation of the E diastereomer and
6

from 17.0 and 19.4 kcal mol-1 for the generation of the Z diastereomer. As one of the reactants is the
solvent, the application of the Eyring equation is questionable; therefore, we cannot confidently
calculate the absolute values of the reaction rate constants kE and kZ. However, here, we are only
interested in the comparison between the two pathways so that we can calculate the rate between kE
and kZ which is found to be 26. The formation of the E diastereomer is faster. However, the most
stable complex of the diastereomer Z of 3a is more stable than that of the E diastereomer by 1.5 kcal
mol-1. Moreover, the formation of both products is only slightly thermodynamically favoured (-1.9
and -0.4 kcal mol-1, respectively). Therefore, we can hypothesise that, due to the long reaction time
(at least 2 hours), the thermodynamic controls the final outgoing. From the reaction free energies
reported above we can calculate a diastereomeric ratio of 83:17 in favour of the Z product, in
agreement with the experimental findings.
Scheme 3: Key steps in the reaction mechanism of 1a and 2a yielding the E and Z
diastereomers of 3a.
Furthermore, in order to confirm the predominant configuration of 3a, NOE experiments were
performed (see Figure 1 in the Supplementary Data). Different selective excitations of methyl
protons in position 2 of the indole, of the methyl protons on the double bond and of the vinylic
proton made it possible for the Z configuration to be assigned to 3a. Selective excitation of methyl
protons in 2 of the indole ring showed an NOE effect on phenyl protons in ortho position and on
proton bound to indole nitrogen. Selective excitation of methyl protons bound to the double bond
showed an NOE effect with the vinylic proton and the indole proton in 4 position. Finally, selective
7

excitation of vinylic proton showed an NOE on methyl protons in 2 and on phenyl protons in ortho
position. A weak NOE effect was, moreover, observed between protons of the two methyl groups,
and between phenyl protons in ortho position with indole proton in 4 position, which can
presumably be ascribed to conformational equilibriums between anti and syn conformers (Figure 2).
Calculations (see Table 6S in the Supplementary Data) confirm this hypothesis: the conformer syn
is less stable than the anti by only 0.3 kcal mol-1 in terms of free energy and the rotational barrier
along the styryl sp2–sp2 single bond is 5.0 kcal mol-1, so the interconversion is expected to be very
fast even at room temperature.
Figure 2: conformational equilibrium between 3a conformers.
In effect, because of the steric hindrance, the two conformations of 3a are not fully planar so they
both present an axially chiral styrene motif, where fairly large substituents could prevent rotation
about the styryl sp2–sp2 single bond.34-39 Immediately, optical rotatory power was tested in different
solvents and concentrations: however, no significant value was observed. This is coherent with Free
energy barriers were calculated for the R/S interconversion in the two conformers, which are 15 and
16 kcal mol-1 for conformers anti and syn, respectively (see Table 6S in the Supplementary Data).
From these values we can estimate the interconversion rate constants of 8•102 and 3•102 sec-1,
which are fast enough to prevent the isolation of the enantiomers.
Finally, 3a configuration was examined by X-ray analysis. Crystals suitable for X-ray diffraction
were obtained for three specimens of 3a; these were obtained directly after chromatographic
purification the first by using 4 as the catalyst and the second by using p-TosOH, and the third after
re-crystallisation from dichloromethane/petroleum ether (using p-TosOH as the catalyst). The three
collected structures are the same and confirm the Z configuration of compound 3a. In this paper, the
8

data for the second specimen were reported. The asymmetric unit contains the whole molecule
(Figure 3). The molecule is composed of two planar fragments, one containing the atoms C1 and the
indole moiety (rmsd = 0.011 Å) and the second containing the atoms from C10 to C18 (rmsd =
0.102 Å). The two planes form a twist angle of 77 degrees around the C3-C12 bond, as expected
due to the steric hindrance of the aromatic moieties. Thus, the molecule in the solid state is chiral
(with an S configuration) and, since it crystallises in the acentric space group P21, the single crystal
should show optical rotatory power. The structure determined for the three data collections show
the same enantiomer for the molecule, so we can suspect that this one alone is formed during
crystallisation. Thus, the molecule in the solid state is chiral (with an S configuration) and it
crystallises in the acentric space group P21; furthermore, the structure determined for the three data
collections show the same enantiomer for the molecule.
Figure 3. Asymmetric unit of compound 3a.
In order to exclude any hypothesis that the powder of the compound 3a is a mixture of crystals with
E and Z configurations, the powder pattern was collected and compared to the one calculated from
the crystal structure (Figure 4): only the presence of the Z diastereomer was found, since the
9

structure with E configuration must show a completely different position and relative intensities of
the peaks.
Figure 4. X-ray powder pattern of compound 3a compared with the one calculated from the
crystal structure.
With the optimised reaction conditions in our hands, we decided to explore the scope of the reaction
to some other activated nucleophiles and alkyl aryl ketones; they are reported in reagent Chart 1.
Chart 1: Nucleophiles 1a-h and alkyl aryl ketones 2a-d.
10

All the products we were able to prepare are listed in Table 2 along with all experimental details,
product yields and diastereomeric ratios.
Table 2: reaction details and scope
Entry Reagents
products
and Reagents
t
Products 3; Yield %a
dr
Lit.
dr
(h)
(Z:E)
R1
R2
R3
R4
1
2
(E:Z)
1
2
3
4
H
Me Me
H
1
3a;
92:8
6:123
1a 2a
1a 2b
1a 2c
1a 2d
85
H
H
H
Me Pr
H
2
1
2
3b;
90:10
80
Me Me Cl
3c; 87 98:2
20:123
Me Ph
H
3d;
92:8
Z32
79
6:9420
5:123
E31 (by
comparison
with ref.30 )
5
Me Me Me
H
2
3e; 82 94:6
1b 2a
11

6
7
Me Me Pr
H
H
3
3f; 80 92:8
1b 2b
H
H
Ph
Ph
Me
Ph
48
3g;
99:1
96:4
1c 2a
73b
8
H
48
3h;
Z>9920
1c 2d
24c
9
Me Ph
Me
Me
H
H
24
7
3i; 80 95:5
3j; 58 37:63
E (dr not
reported)31
1d 2a
10
H
H
H
H
No data16
1e 2a
11
12
H
Me Cl
7
3k;
35:65
E (but dr
not done) or
Z23
1e 2c
43
Me
Ph
H
24
3l; 78 40:60
90:1020
1f
2d
a The reactions were run on a 2 mmol scale, in a molar ratio 1:2=1:1.1, in anhydrous methanol (5 mL), without
exclusion of air or moisture, at 65 °C. Reaction details (time and yield) are reported for each product. Yields refer to
pure isolated products. Diastereomeric ratios (dr) were calculated from 1H NMR spectra or GC analyses of isolated
products. See experimental section for details.
b Reaction was carried out in the presence of 10 mol% cat
c Reaction was carried out in the presence of 15 mol% cat
First of all, 2-methylindole (1a) was reacted with valerophenone (2b); product 3b was isolated in
80% yield and a dr Z:E = 90:10, on the grounds of chemical shifts of the diastereomer vinylic
12

proton (Table 2, entry 2). By reaction with m-chloropropiophenone (2c), product 3c was obtained in
a dr Z:E = 98:2 based on a comparison with literature spectral data (Table 2, entry 3).23
Reaction with benzyl phenyl ketone (2d) afforded product 3d (Table 2, entry 4) in 87% yield, which
was assigned the Z configuration by Perumal,20 and the E configuration by Mattson23 and Gu.31 The
assignment of Gu is made by comparison with Srinivasan’s work; in this work, however, the
authors reported the X-ray structure of the product condensation between 2-methylindole (1a) with
benzyl p-tolyl ketone and this structure had a Z configuration.32 Furthermore Perumal’s paper on
hydroarylation of alkynes with indoles demonstrated that the E/Z ratio of the products was a result
of the substitution of indole in position 2: unsubstituted indoles chiefly afforded E diastereomers,
whilst 2-substituted indoles, on the contrary, gave mainly Z diastereomers. This statement was
confirmed by an X-ray diffraction analysis of 3d (obtained form 2-substituted indole 1a; isolated in
a 94:6 Z/E diastereomeric ratio) and of 3l (obtained from 2-unsubstituted indole 1f; isolated in a Z/E
diastereomeric ratio 10:90). These findings were rationalised based on the thermodynamic stability
of the final products; the proposed mechanism involved an isomerisation of a carbocationic
intermediate. In our conditions, product 3d was obtained in a dr Z:E = 92:8, as confirmed by
comparison with literature data.
Subsequently, 1,2-dimethylindole (1b) was reacted with ketones 2a and 2b (Table 2, entries 5 and
6): products 3e and 3f were obtained in good yields in a diastereomeric ratio in favour of Z based on
vinylic proton chemical shifts with respect to similar products 3a and 3b.
Reactions of 2-phenylindole (1c) with ketones 2a and 2d (Table 2, entry 7 and 8) turned out to be
much slower than the above reactions: a strong steric effect can be ascribed to the phenyl
substituent in 2, enhanced by the additional phenyl group in ketone 2d. Nevertheless, products 3g
and 3h were obtained and the diastereomeric ratio was in favour of the Z diastereomer by
comparing literature findings and chemical shifts of their vinylic proton with that of known
compounds 3a and 3c.20, 23 Thereafter, 1-methyl-2-phenylindole (1d) was tested in the reaction with
propiophenone (2a); as expected, the reaction took more time than less hindered indoles, but the
13

1
yield was good. The dr of product 3i by H NMR spectroscopy is in favour of the Z isomer, as
assigned above (Table 2, entry 9).
Incidentally, the optical rotatory power of both 3h and 3i was tested, as for 3a; however, although
the steric hindrance should reasonably be higher and prevent racemisation, no significant values
were observed.
Thereafter, 2-unsubstituted indoles 1e and 1f were tested in dehydrative coupling reactions with 2a,
2c and 2d. The reaction of indole 1e with ketones 2a and 2c gave products 3j and 3k, respectively,
in low yields and with longer reaction times (Table 2, entries 10 and 11). The unsatisfactory yields
could be explained, although only in part, by the well-known acid-catalysed indole trimerisation.40-
42 Indole 1f and ketone 2d gave product 3l in good yield, but in the same diastereomeric ratio as the
above reactions with indole 1e. Reacting 2-unsubstituted indoles, the diastereomeric ratios were
slightly in favour of the E diastereomer, as evidenced by the comparison of their NMR spectra with
those of authentic specimens, when available,20, 23 or with those of similar compounds reported
here; this assignment accords with Perumal’s claims.20
Finally, we tried to expand the scope of the reaction to activated nucleophiles other than indoles,
namely 1-methylpyrrole (1g) and 1,2,3-trimethoxybenzene (1h); in our conditions, however, the
corresponding dehydrative coupling products were not obtained.
3. Conclusions
In conclusion, we studied a Brønsted-acid catalysed direct dehydrative coupling reaction between
alkyl aryl ketones and some indoles from a synthetic and mechanistic point of view. The results
obtained are interesting also when compared with the few known literature reports. A representative
library of 3-(α-aryl)alkenylindoles has been prepared; currently, our research interest is focused on
the functionalisation of these reactive useful intermediates for the synthesis of complex scaffolds
present in natural products endowed with biological activity.
14

4. Experimental
4.1. General Information
All reactions were conducted in open air vials using analytical grade reagents, and were monitored
by TLC and GC analyses, GC-MS spectrometry and NMR spectroscopy. GC-MS spectra were
recorded on a mass selective detector connected to a GC with a cross-linked methyl silicone
capillary column. Mass spectra were recorded on a mass spectrometer equipped with an
ElectroSpray Ionization source (ESI). IR spectra were recorded on an IR PerkinElmer UATR Two.
13
1H NMR and C NMR spectra were recorded in CDCl3 on a JEOL ECZR600 spectrometer at 600
MHz and 150 MHz, respectively. The data are reported as follows: chemical shifts in ppm from
TMS with the solvent resonance as the internal standard (deuterochloroform: δ = 7.27 ppm),
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad signal),
1
coupling constants (Hz), and integration. In H NMR spectra, distinctive signals for Z and E
diastereomers are reported; signals are however often indistinguishable in the aromatic region. TLC
were performed on silica gel TLCPET foils GF 254, 2–25 μm, layer thickness 0.2 mm, medium
pore diameter 60 Å. Plates were visualised using UV light (254 nm). Column chromatography was
carried out using SiO2 (pore size 70 Å, 70–230 mesh). Petroleum ether refers to the fraction boiling
in the 40–60 °C range and is abbreviated as PE. Commercially available reagents and solvents were
used without purification or distillation prior to use. Room temperature (20–25 °C) is abbreviated as
1
rt. Yields for pure (GC, GC-MS, TLC, H NMR) isolated products are listed in Table 2.
Diastereomeric ratio (dr) were calculated from 1H NMR spectra when feasible or from GC analyses
of purified products. The structure and purity of all new products were determined by elemental
1
13
analyses, ESI, H and C NMR and DEPT spectra. The structure and purity of known products
1
13
were confirmed by comparing their physical and spectral data (MS, H and C NMR) with those
reported in the literature.
Single crystal X-ray diffraction (XRD). X-ray diffraction data for 3a were collected at room
temperature using an Oxford Diffraction Gemini R Ultra diffractometer equipped with AtlasS2
15

detector. Data were collected with mirror monochromatized Cu-Kα radiation (1.5418 Å). The
CrysAlisPro43 package was used for data collection and integration, SHELXT44 for resolution,
SHELXL44 for refinement and Olex245 for graphics.
Crystal Data: M = 247.32 g/mol, monoclinic, space group P21 (no. 4), a = 8.0148(1) Å, b =
9.7768(1) Å, c = 9.7130(2) Å, β = 114.121(2)°, V = 694.65(2) Å3, Z = 2, T = 298.7(3) K, μ(Cu-Kα)
= 0.519 mm-1, Dcalc = 1.182 g/cm3, 11071 reflections measured (9.978 ≤ 2Θ ≤ 133.966), 2460
unique (Rint = 0.0231, Rsigma = 0.0199) which were used in all calculations. The final R1 was 0.0389
(I > 2σ(I)) and wR2 was 0.0906 (all data).
The interested reader can find further details of crystal data, data collection, least-squares
refinements and bond lengths and angles in the Supporting Information (Tables S1, S2). CIF file
was deposited in the Cambridge Crystallographic Database (CCDC 2003357).
4.2. Dehydrative Coupling: representative procedure for the synthesis of products 4.
To a solution of indole 1 (2.0 mmol) and alkyl aryl ketone 2 (2.2 mmol) in anhydrous methanol (5
mL), p-toluenesulfonic acid was added as the catalyst (0.019 g, 5 mol%) under stirring. The
reaction mixture was then stirred in an air atmosphere, at reflux temperature (65 °C), as reported in
Table 2. Upon completion, the reaction mixture was treated with H2O/DCM (1:1, 40 mL). The
organic phase was dried over Na2SO4, the solvent was removed under reduced pressure and the
crude product was purified by column chromatography.
4.2.1. 2-Methyl-3-[1-phenylprop-1-enyl]-1H-indole (3a).23
Chromatographic purification (PE/Acetone 90:10) gave 3a as a pale yellow solid; 0.42 g (85%
1
yield); dr Z:E = 92:8; mp 114.0−115.0 °C (DCM/PE); H NMR (600 MHz, CDCl3) predominant Z
diastereomer δ 1.70 (d, J = 6.9 Hz, 3H), 2.22 (s, 3H), 6.35 (q, J = 6.9 Hz, 1H), 6.98 (td, J = 7.5, 0.9
Hz, 1H), 7.10 (td, J = 7.3, 0.8 Hz, 2H), 7.17 (tt, J=7.1, 1.3 Hz, 1H), 7.20-7.24 (m, 2H), 7.27-7.32
16

(m, 3H), 7.96 (br s, 1H); distinctive signals for the E diastereomer δ 1.94 (d, J = 6.8 Hz, 3H), 2.19
13
(s, 3H), 5.94 (q, J = 7.2 Hz, 1H). C NMR (150 MHz, CDCl3) δ 12.6 (CH3), 16.2 (CH3), 110.2
(CH), 111.8 (C), 119.5 (CH), 119.7 (CH), 121.1 (CH), 126.0 (CH), 126.6 (CH), 126.7 (2 x CH),
128.2 (2 x CH), 128.8 (C), 132.9 (C), 134.7 (C), 135.5 (C), 142.8 (C). IR ν (cm-1) 3424, 2909,
1591, 1214, 746, 700. MS m/z (%) 247 [M+](100), 232 (25), 218 (85).
4.2.2. 2-Methyl-3-[1-phenylpent-1-enyl]-1H-indole (3b).
Chromatographic purification (PE/Acetone 90:10) gave 3b as a yellow solid; 0.44 g, (80% yield);dr
1
Z:E = 90:10; mp 89.7−90.9 °C (DCM/PE); H NMR (600 MHz, CDCl3) predominant Z
diastereomer δ 0.85 (t, J = 7.4 Hz, 3H), 1.40−1.46 (m, 2H), 2.00−2.05 (m. 2H), 2.22 (s, 3H), 6.28 (t,
J = 7.2 Hz, 1H), 6.97−7.00 (m, 1H), 7.08−7.12 (m, 1H), 7.15−7.18 (m, 2H), 7.20−7.24 (m, 2H),
7.29−7.31 (m, 3H), 7.95 (br s, 1H); distinctive signals for the E diastereomer δ 0.96 (t, J = 7.4 Hz,
3H), 2.20 (s, 3H), 5.85 (t, J = 7.4 Hz, 1H). 13C NMR (150 MHz, CDCl3) δ 12.5 (CH3), 14.0 (CH3),
22.9 (CH2), 32.3 (CH2), 110.1 (CH), 112.3 (C), 119.5 (CH), 119.6 (CH), 121.1 (CH), 126.6 (CH),
126.7 (CH), 128.2 (CH), 129.0 (C), 132.2 (CH), 132.7 (C), 133.6 (C), 135.5 (C), 142.8 (C). IR
ν (cm-1) 3376, 2957, 1458, 1214, 748, 694. MS m/z (%) 275 [M+](100), 260 (85), 246 (88). Anal.
Calcd for C20H21N: C, 87.23; H, 7.69; N, 5.09. Found C, 87.18; H, 7.62; N, 5.03.
4.2.3. 2-Methyl-3-[1-(3-chlorophenyl)prop-1-enyl]-1H-indole (3c).23
Chromatographic purification (PE/Acetone 90:10) gave 3c as an oil; 0.49 g, (87% yield); dr Z:E =
1
98:2; H NMR (600 MHz, CDCl3) predominant Z diastereomer δ 1.71 (d, J = 6.9 Hz, 3H), 2.21 (s,
3H), 6.37 (q, J = 6.9 Hz, 1H), 6.98−7.03 (m, 1H), 7.11−7.17 (m, 5H), 7.32 (d, J=8.1 Hz, 2H), 8.07
(br s, 1H); distinctive signals for the E diastereomer δ 1.95 (d, J = 7.1 Hz, 3H), 2.19 (s, 3H), 5.98 (q,
13
J = 7.1 Hz, 1H). C NMR (150 MHz, CDCl3) δ 12.6 (CH3), 16.3 (CH3), 110.4 (CH), 111.07 (C),
119.5 (CH), 119.6 (CH), 121.2 (CH), 125.0 (CH), 126.6 (CH), 126.7 (CH), 127.4 (CH), 128.6 (C),
17

129.4 (CH), 133.1 (C), 133.8 (C), 134.1 (C), 135.6 (C), 144.9 (C). IR ν (cm-1) 3399, 2910, 1589,
1214, 740, 695. MS m/z (%) 281 [M+](100), 266 (30), 252 (35), 230 (33), 217 (50).
4.2.4. 2-Methyl-3-[1,2-diphenyleth-1-enyl]-1H-indole (3d).23, 31, 32
Chromatographic purification (PE/Acetone 90:10) gave 3d as a white solid; 0.49 g, (79% yield); dr
1
Z:E = 92:8; mp 158−159 °C (DCM/PE); H NMR (600 MHz, CDCl3) predominant Z diastereomer
δ 1.97 (s, 3H), 6.97 (t, J = 7.4 Hz, 1H), 7.07−7.10 (m, 2H), 7.11−7.16 (m, 6H), 7.30−7.34 (m, 4H),
13
7.45−7.47 (m 2H), 7.85 (br s, 1H). C NMR (150 MHz, CDCl3) δ 12.6 (CH3), 110.3 (CH), 111.9
(C), 119.7 (CH), 120.1 (CH), 121.3 (CH), 126.5 (CH), 127.4 (CH), 127.5 (CH), 128.2 (CH), 128.4
(CH), 128.6 (C), 128.8 (CH), 129.6 (CH), 133.2 (C), 135.2 (C), 135.8 (C), 138.7 (C), 143.2 (C). IR
ν (cm-1) 3408, 3051, 1594, 1218, 742, 693. MS m/z (%) 309 [M+](100), 294 (50), 217(45).
4.2.5. 1,2-Dimethyl-3-[1-phenylprop-1-enyl]indole (3e).
Chromatographic purification (PE/EE 99:1) gave 3e as a white solid; 0.43 g, (82% yield); dr Z:E =
1
94:6; mp 94.7−96.0 °C (DCM/PE); H NMR (600 MHz, CDCl3) predominant Z diastereomer δ
1.71 (d, J = 7.2 Hz, 3H), 2.23 (s, 3H), 3.74 (s, 3H), 6.38 (q, J = 7.2 Hz, 1H), 6.99−7.02 (m, 1H),
7.15−7.18 (m, 2), 7.18−7.21 (m, 2H), 7.23−7.26 (m, 2H), 7.30−7.33 (m, 3H); distinctive signals for
the E diastereomer δ 1.99 (d, J = 7.2 Hz, 3H), 2.44 (s, 3H), 3.67 (s, 3H), 5.94 (q, J = 7.1 Hz, 1H).
13C NMR (150 MHz, CDCl3) δ 11.3 (CH3), 16.3 (CH3), 29.8 (CH3), 108.6 (CH), 111.0 (C), 119.1
(CH), 119.7 (CH), 120.6 (CH), 125.9 (CH), 126.6 (CH), 126.8 (2XCH), 127.8 (C), 128.2 (2XCH),
134.7 (C), 135.2 (C), 136.9 (C), 143.1 (C). IR ν (cm-1) 3017, 1552, 1233, 750, 697. MS m/z (%)
261 [M+](100), 246 (30), 232 (70). Anal. Calcd for C19H19N: C, 87.31; H, 7.33; N, 5.36. Found C,
87.27; H, 7.29; N, 5.30.
4.2.6. 1,2-Dimethyl-3-[1-phenylpent-1-enyl]indole (3f).
18

Chromatographic purification (PE/EE 95:5) gave 3f as a white solid; 0.46 g, (80% yield); dr Z:E =
92:8; mp 73.8−74.2 °C (DCM/PE); 1H NMR (600 MHz, CDCl3) predominant Z diastereomer δ 0.93
(t, J = 7.2 Hz, 3H), 1.47−1.54 (m, 2H), 2.06−2.11 (m, 2H), 2.27 (s, 3H), 3.76 (s, 3H), 6.35 (t, J =
7.2 Hz, 1H), 7.06 (t, J = 7.4, 1H), 7.20−7.24 (m, 3H), 7.29−7.25 (m, 2H), 7.34−7.38 (m, 3H);
distinctive signals for the E diastereomer δ 1.04 (t, J = 7.5 Hz, 3H), 1.58−1.64 (m, 2H), 2.40−2.44
13
(m, 2H), 2.47 (s, 3H), 3.69 (s, 3H), 5.89 (t, J = 7.3 Hz, 1H). C NMR (150 MHz, CDCl3) δ 11.3
(CH3), 14.1 (CH3), 23.0 (CH2), 29.8 (CH3), 32.4 (CH2), 108.6 (CH), 111.5 (C), 119.2 (CH), 119.6
(CH), 120.7 (CH), 126.6 (CH), 126.8 (2XCH), 128.1 (C), 128.2 (2XCH), 132.2 (CH), 134.1 (C),
134.6 (C), 136.7 (C), 143.1 (C). IR ν (cm-1) 2952, 1540, 1233, 759, 697. MS m/z (%) 289
[M+](100), 274 (40), 260 (75). Anal. Calcd for C21H23N: C, 87.15; H, 8.01; N, 4.84. Found C,
87.10; H, 7.93; N, 4.80.
4.2.7. 2-Phenyl-3-[1-phenylprop-1-enyl]-1H-indole (3g).
Chromatographic purification (PE/Acetone 90:10) gave 3g as a yellow waxy solid; 0.45 g, (73%
1
yield); dr Z:E = 99:1; mp 65.0−68.0 °C (DCM/PE); H NMR (600 MHz, CDCl3) predominant Z
diastereomer δ 1.51 (d, J = 6.6 Hz, 3H), 6.40 (q, J = 6.6 Hz, 1H), 7.03−7.06 (m, 1H), 7.18−7.26 (m,
6H), 7.32−7.35 (m, 2H), 7.39−7.43 (m, 3H), 7.61 (d, J = 7.1 Hz, 2H), 8.32 (br s, 1H); distinctive
signals for the E diastereomer δ 1.91 (d, J = 7.2 Hz, 3H), 5.93 (q, J = 7.1 Hz, 1H). 13C NMR (150
MHz, CDCl3) δ 15.9 (CH3), 110.8 (CH), 112.2 (C), 120.1 (CH), 120.5 (CH), 122.6 (CH), 126.5
(CH), 126.6 (CH), 126.8 (CH), 126.9 (CH), 127.6 (CH), 128.3 (CH), 128.9 (CH), 129.1 (CH),
129.6 (C), 133.1 (C), 134.9 (C), 136.2 (C), 142.2 (C). IR ν (cm-1) 3406, 3053, 1601, 1227, 739, 691.
MS m/z (%) 309 [M+](100), 294 (75). Anal. Calcd for C23H19N: C, 89.28; H, 6.19; N, 4.53. Found
C, 89.22; H, 6.15; N, 4.49.
4.2.8. 2-Phenyl-3-[1,2-diphenyleth-1-enyl]-1H-indole (3h).20
19

Chromatographic purification (PE/Acetone 90:10) gave 3h as a yellow waxy solid; 0.18 g, (24%
1
yield); dr Z:E = 96:4; mp 65.0−68.0 °C (DCM/PE); H NMR (600 MHz, CDCl3) predominant Z
diastereomer δ 6.93−7.00 (m, 5H), 7.00−7.04 (m, 1H), 7.15−7.20 (m, 5H), 7.20−7.23 (m, 5H),
7.40−7.44 (m, 3H), 7.50−7.52 (m, 2H), 8.30 (br s, 1H); distinctive signal for the E diastereomer δ
13
8.23 (br s, 1H). C NMR (150 MHz, CDCl3) δ 110.9 (CH), 112.5 (C), 120.3 (CH), 120.6 (CH),
122.7 (CH), 126.5 (CH), 126.9 (CH), 127.1 (CH), 127.5 (CH), 127.6 (CH), 127.9 (CH), 128.4
(CH), 128.5 (CH), 128.7 (CH), 129.1 (C), 130.9 (CH), 132.5 (C), 135.0 (C), 135.1 (C), 136.4 (C),
138.1 (C), 142.89. IR ν (cm-1) 3460, 3025, 1598, 1217, 761, 695. MS m/z (%) 371 [M+](100), 294
(35).
4.2.9. 1-Methyl-2-phenyl-3-[1-phenylprop-1-enyl]indole (3i).31
Chromatographic purification (PE/EE 99:1) gave 3i as a white solid; 0.51 g, (80% yield); dr Z:E =
1
95:5; mp 153.2−153.7 °C (DCM/PE; lit. mp 79-81 °C for E diastereomer); H NMR (600 MHz,
CDCl3) predominant Z diastereomer δ 1.43 (d, J = 6.8 Hz, 3H), 3.78 (s, 3H), 6.20 (q, J = 6.9 Hz,
1H), 7.08 (t, J = 7.4, 1H), 7.16−7.19 (m, 1H), 7.21−7.25 (m, 3H), 7.28 (t, J = 7.2 Hz, 1H),
7.31−7.33 (m, 1H), 7.35−7.37 (m, 6H), 7.43 (d, J = 8.2 Hz, 1H); distinctive signals for the E
diastereomer δ 1.78 (d, J = 7.1 Hz, 3H), 3.63 (s, 3H), 5.80 (q, J = 6.9 Hz, 1H). 13C NMR (150 MHz,
CDCl3) δ 16.1 (CH3), 31.4 (CH3), 109.5 (CH), 112.4 (C), 119.7 (CH), 120.6 (CH), 121.9 (CH),
126.4 (CH), 126.5 (CH), 126.7 (2xCH), 127.8 (CH), 128.0 (C), 128.1 (2xCH), 128.3 (2xCH), 130.1
(2xCH), 132.4 (C), 134.7 (C), 137.8 (C), 139.3 (C), 143.2 (C). IR ν (cm-1) 3052, 1603, 1238, 740,
696. MS m/z (%) 323 [M+](100), 308 (40).
4.2.10. 3-[1-Phenylprop-1-enyl]-1H-indole (3j).16
Chromatographic purification (PE/Acetone 80:20) gave 3j as an oil; 0.27 g, (58% yield); dr Z:E =
37:63; 1H NMR (600 MHz, CDCl3) predominant E diastereomer δ 1.87 (d, J = 7.0 Hz, 3H), 6.28 (q,
20

J = 7.0 Hz, 1H), 6.81 (d, J = 2.5 Hz, 1H), 7.03−7.06 (m, 1H), 7.10−7.12 (m, 2H), 7.18−7.22 (m,
3H), 7.24−7.29 (m, 3H), 7.31−7.38 (m, 5H), 7.40−7.42 (m, 2H), 7.48−7.51 (m, 1H), 7.59−7.61 (m,
1H), 8.23 (br s, 1H); distinctive signals for the Z diastereomer δ 1.85 (d, J = 7.0 Hz, 3H), 6.32 (q, J
13
= 7.0 Hz, 1H), 8.02 (br s, 1H). C NMR (150 MHz, CDCl3) δ 15.4 (and 16.3, CH3), 111.2 (CH),
111.4 (CH), 114.9 (C), 118.9 (CH), 119.7 (CH), 120.0 (C), 120.2 (CH), 120.8 (C), 121.2 (CH),
121.5 (CH), 122.0 (CH), 122.2 (CH), 123.7 (CH), 124.4 (CH), 125.4 (C), 126.7 (CH), 126.8 (CH),
127.2 (CH), 127.5 (C), 127.7 (CH), 128.2 (CH), 128.5 (CH), 128.7 (CH), 128.9 (CH), 130.0 (CH),
135.2 (C), 136.1 (C), 136.5 (C), 136.8 (C), 141.0 (C), 143.5 (C). IR ν (cm-1) 3408, 3054, 1596,
1206, 741, 698. MS m/z (%) 233 [M+](100), 217 (30).
4.2.11. 3-[1-(3-Chlorophenyl)prop-1-enyl]-1H-indole (3k).23
Chromatographic purification (PE/Acetone 80:20) gave 3j as an oil; 0.23 g, (43% yield); dr Z:E =
35:65; 1H NMR (600 MHz, CDCl3) predominant E diastereomer δ 1.81 (d, J = 7.1 Hz, 3H), 6.29 (q,
J = 7.1 Hz, 1H), 6.81 (br s, 1H), 7.02−7.05 (m, 1H), 7.09−7.11 (m, 1H), 7.12 (br s 1H), 7.14−7.16
(m, 2), 7.17−7.21 (m, 4H), 7.29−7.31 (m, 2H), 7.40 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H),
8.07 (br s, 1H); distinctive signals for the Z diastereomer δ 1.83 (d, J = 6.9 Hz, 3H), 6.25 (q, J = 6.9
13
Hz, 1H), 8.26 (br s, 1H). C NMR (150 MHz, CDCl3) δ 15.3 (and 16.3, CH3), 111.2 (CH), 111.4
(CH), 114.3 (C), 119.7 (C), 119.8 (CH), 120.2 (CH), 120.6 (CH), 122.1 (CH), 122.2 (CH), 122.3
(CH), 123.6 (CH), 124.3 (CH), 125.4 (CH), 125.7 (C), 126.6 (CH), 126.7(CH), 127.0 (CH), 127.1
(CH), 127.3 (C), 128.2 (CH), 129.3 (CH), 129.4 (CH), 129.9 (CH), 133.9 (C), 134.0 (C), 134.1 (C),
135.2 (C), 136.1 (C), 136.7 (C), 142.9 (C), 145.4 (C). IR ν (cm-1) 3403, 3055, 1590, 1201, 740, 694.
MS m/z (%) 267 [M+](100), 230 (30).
4.2.12. 3-[1,2-Diphenyleth-1-enyl]-1-methylindole (3l).20
21

Chromatographic purification (PE/EE 895:5) gave 3l as a white solid; 0.48 g, (78% yield); dr Z:E =
40:60; mp 178-182 °C (DCM/PE); 1H NMR (600 MHz, CDCl3) predominant E diastereomer δ 3.73
(s, 3H) 6.77 (s, 1H), 6.89−6.96 (m, 2H), 7.02−7.14 (m, 9H), 7.17−7.21 (m, 2H), 7.24−7.35 (m,
10H), 7.42−7.44 (m, 1H), 7.71 (d, J = 8.0 Hz, 1H); distinctive signal for the Z diastereomer δ 3.77
13
(s, 3H). C NMR (150 MHz, CDCl3) δ 32.9 (and 33.0, CH3), 109.2 (CH), 109.6 (CH), 113.9 (C),
119.3 (C), 119.4 (CH), 120.0 (CH), 121.1 (CH), 121.3 (CH), 121.7 (CH), 122.1 (CH), 124.4 (CH),
125.9 (CH), 126.2 (C), 126.4 (CH), 127.4 (CH), 127.5 (CH), 127.9 (CH), 128.0 (CH), 128.1 (CH),
128.3 (CH), 128.6 (CH), 129.2 (CH), 129.3 (CH), 129.7 (CH), 129.8 (CH), 130.3 (CH), 135.4 (C),
137.1 (C), 137.8 (C), 138.1 (C), 138.5 (C), 141.4 (C), 144.3 (C). IR ν (cm-1) 3025, 1532, 1206, 734,
694. MS m/z (%) 309 [M+](100), 293 (45).
Supporting Data
Supplementary data for this article can be found online and include copies of the 1H and 13C NMR
spectra, crystal data, X-ray data collection and structure refinement, bond lengths and angles from
X-ray diffraction, tables of calculated relative energies, discussion on steric and electronic effects,
pictures of calculated structures, calculated absolute energies and Cartesian coordinates.
ACKNOWLEDGMENTS
The authors would like to thank the Italian MIUR and the Università degli Studi di Torino for their
financial support.
References and notes
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24

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•
•
3-(α-Aryl)alkenylindoles can be easily prepared via a direct dehydrative coupling
reaction between alkyl aryl ketones and some indoles, in the presence of a Brønsted-acid
catalyst.
The observed good diastereoselectivity depending on indole substitution has been
explained by a computational method.
The synthesized compounds are reactive intermediates, useful for the synthesis of indole
alkaloids, carbazole and other indole-based heterocycles.

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: