Simple iodoalkyne-based organocatalysts for the activation of carbonyl compounds

Article abstract of DOI:10.1039/c9ob02688f

A novel approach for the formation of bisindolylmethane derivatives (BIMs) is described as a proof of concept to evaluate the catalytic capacity of iodoalkynes. The use of these derivatives is reported as an example of simple halogen bond-based organocatalyst. This kind of activation has not been used before for the synthesis of bisindolylmethane derivatives 3. Interestingly, the preparation of 3-(1H-indol-3-yl)-1-phenylbutan-1-one (8) has been also achieved for the first time with an iodoalkyne derivative. We prove the efficiency of this family of new catalysts by developing a simple and easy operational methodology, opening the door to the development of alternative catalysts in the area of halogen bond-based organocatalysts.

Full text of DOI:10.1039/c9ob02688f

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Simple iodoalkyne-based organocatalysts for the
activation of carbonyl compounds†
Cite this: DOI: 10.1039/c9ob02688f
a
Juan V. Alegre-Requena, a Alberto Valero-Tena,a,b Isaac G. Sonsona,
a
Santiago Uriel b and Raquel P. Herrera
*
A novel approach for the formation of bisindolylmethane derivatives (BIMs) is described as a proof of
concept to evaluate the catalytic capacity of iodoalkynes. The use of these derivatives is reported as an
example of simple halogen bond-based organocatalyst. This kind of activation has not been used before for
the synthesis of bisindolylmethane derivatives 3. Interestingly, the preparation of 3-(1H-indol-3-yl)-1-phe-
nylbutan-1-one (8) has been also achieved for the first time with an iodoalkyne derivative. We prove the
efficiency of this family of new catalysts by developing a simple and easy operational methodology, opening
the door to the development of alternative catalysts in the area of halogen bond-based organocatalysts.
Received 18th December 2019,
Accepted 3rd January 2020
DOI: 10.1039/c9ob02688f
rsc.li/obc
that interacts with Lewis bases by halogen bonding.14
Moreover, halogen atoms can be activated to participate in
Introduction
Along the years, the search for new kinds of interactions or halogen bonding by introducing electron-withdrawing groups
modes of activation has fascinated chemists and has been the into the molecular backbone.
focus of research of many scientific groups. Among the variety
Haloalkynes have a well-established role in synthetic
of non-covalent interactions, where normally hydrogen bonds organic chemistry15 but their application as halogen bond
occupy a privileged place,1 more recently halogen bond (XB) donors is less well developed despite their long history.16
interactions have been making space as an alternative tool.2 Theoretical, statistical and crystallographic studies demon-
Their use as Lewis acid activating Lewis bases has been strate that the sp hybridization of the carbon atom adjacent to
recently explored in the literature.3 In contrast, during the past the halogen allows the ethynyl-based iodine atom to display a
two decades, many applications of halogen bonding in fields polar σ-hole.17 The maximum positive value of calculated
as diverse as crystal engineering, enantiomer separation, electrostatic potential (Vs,max) of 1,4-bis(iodoethynyl)benzene is
biology, and supramolecular architectures have been reported 25.2 kcal mol−1 and is similar to those of strong XB donors
and reviewed.4–6
such as 1,4-diiodo-tetrafluorobenzene (25.9 kcal mol−1), which
In comparison, the use of XB in organocatalysis remains is one of the most widely used halogen bonding donors.
underexplored. Since 2008 when Bolm reported an example of Therefore, haloalkynes can form strong, directional and selec-
perfluoroiodoalkanes as an XB catalyst,7 positively charged tive halogen bonds, which makes them suitable for being used
iodo heterocycles such as imidazolium,8 1,2,3-triazolium8e,9 as organocatalysts.18,19 Moreover, iodoalkynes are stable
and pyridinium9a,10 or neutral halogen bond donors have been towards nucleophiles and elevated temperatures and easily
used as catalysts in a variety of organic transformations. The accessible from terminal alkynes,20 which allows to modify the
most common neutral XB-donor scaffolds typically contain number and arrangement of halogen bond donors, their solu-
iodopolyfluoroaromatic moieties,11 although N-iodosuccinimide, bility and their rigidity or flexibility among other character-
N-iodosaccharin,12 and tetrabromomethane,13 have also been used. istics. However, to the best of our knowledge, there is only one
Halogen atoms bound to carbon, nitrogen or halide atoms example where a perfluorinated iodoethynyl compound has
show a positive electrostatic potential end-cap, i.e., a σ-hole, been used as a catalyst.20 Therefore, more contributions in this
new field could be of great interest.
Indole is a privileged structural core present in many
natural products and biological systems21 and its use in drug
discovery has grown over the past decades.22 Consequently,
considerable attention has been focused on the development
of new synthetic23 and catalytic24 methods, leading to more
complex indole structures. Moreover, indole is the structural
unit of bisindolylmethane derivatives (BIMs), many of them
aLaboratorio de Organocatálisis Asimétrica. Dpto de Química Orgánica. Instituto de
Síntesis Química y Catálisis Homogénea (ISQCH) CSIC-Universidad de Zaragoza.
C/Pedro Cerbuna 12, 50009 Zaragoza, Spain. E-mail: raquelph@unizar.es
bDpto. de Química Orgánica, Escuela de Ingeniería y Arquitectura,
Universidad de Zaragoza, 50018 Zaragoza, Spain
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9ob02688f
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Table 1 Screening of catalysts I–IVa
isolated from marine natural sources.25 This family of indoles
discloses a range of biological properties such as antibacterial,
antifungal, antimicrobial, anti-inflammatory or antitumor,
among others.26
Inspired in our own experience in the field of organocataly-
sis27 using hydrogen bond-based catalysts, we focused our
attention on the activation of aldehydes for the production of
bisindoles28 using iodoalkyne derivatives (non-perfluorinated)
as promising catalysts for the first time in the literature.
Entry
Catalyst
Time (days)
Yieldb (%)
1
2
3
4
I
2
3
5
2
98
89
92
54
II
III
IV
Results and discussion
a Experimental conditions: To a mixture of catalyst I–IV (0.03 mmol)
and aldehyde 1a (0.1 mmol) in toluene (250 μL), indole (2a) (0.4 mmol,
2 equiv.) was further added at room temperature. After the reaction
time, adduct 3aa was isolated by column chromatography
(hexane : AcOEt 8 : 2). b Isolated yield.
Recently, several mild and convenient methods have been
developed to prepare haloalkynes, most of them from terminal
alkynes.9a,15 Among them, we have used the electrophilic ioda-
tion of terminal alkynes with N-iodosuccinimide (NIS) and an
Ag(I) catalyst29 due to the mild reaction conditions required,
high efficiency, and simple manipulation. Organocatalysts I–IV
were obtained with yields in the range of 63 to 82% from the
corresponding terminal alkynes (Scheme 1).18 The precursors
to synthesise I to III are commercially available and the precur-
sor for IV was directly prepared through esterification reaction
of 1,3,5-benzenecarbonyl trichloride with 2-propyn-1-ol.30
In order to further evaluate the viability of our work hypoth-
esis, the efficiency of halogen bond-based organocatalysts I–IV
was first tested in the model reaction between indole (2a) and
3-nitrobenzaldehyde (1a). Interestingly, the synthesis of bisin-
dole 3aa was successful in all cases. First, the activity of cata-
lysts I–IV was evaluated in CH2Cl2. Although the reaction
worked well in all cases (Table S1,† entries 1–4), it was noted
that small loss of solvent through evaporation could be acceler-
ating the reaction and the results could be misleading.
Therefore, in order to prevent this problem, toluene was tested
as a solvent. In this case, catalyst I successfully activated bisin-
dole 3aa formation better than the other three catalysts
(Table 1, entry 1).
Table 2 Screening of the best reaction conditions using catalyst Ia
Entry I (mol%) Indole 2a (mmol)/equiv. Time (days) Yieldb (%)
1
2
3
4
5
6
7
8
9
30
30
0.4/2
0.3/1.5
0.2/1
0.2/1
0.4/2
0.4/2
0.3/1.5
0.2/1
0.4/2
0.4/2
2
2
2
2
2
2
2
2
5
2
98
98
47
74
98
98
98
35
77
n.r.d
30
30c
20
20c
20c
20c
10
10
—
a Experimental conditions: to a mixture of catalyst I (30–0 mol%) and
aldehyde 1a (0.1 mmol) in toluene (0.5–0.25 mL), indole (2a)
(0.4–0.2 mmol) was further added at room temperature. After the reac-
tion time, adduct 3aa was isolated by column chromatography
(hexane : AcOEt 8 : 2). b Isolated yield. c 0.25 mL of toluene. d No reac-
tion observed.
Although other more polar solvents were also tested, such
as acetonitrile, THF, dioxane and ethyl acetate (Table S1,†
entries 5–8), they led to reaction quenching or lower yields.
This finding is not surprising since polar solvents typically
disrupt the activating catalyst⋯substrate XB interactions easier
than nonpolar solvents such as toluene. Using toluene and
catalyst I in the model reaction, an optimization of different
reaction conditions was carried out (Table 2).
Reactions were stopped after two days to allow for a better
comparison of the yields obtained; however, reactions using 2
and 1.5 equivalents of indole 2a (0.4 mmol or 0.3 mmol) with
20–30 mol% of catalyst were probably completed before the
reaction time employed (Table 2, entries 1, 2, 5, 6 and 7). The
results showed that 20 and 30 mol% of catalyst lead to similar
yields while 10 mol% of catalyst affords lower yields. Also,
Scheme 1 Synthesis of iodoalkynes I–IV.
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Table 3 Scope of the reaction for the synthesis of bisindoles 3a
Entry
Aldehyde
Indole
Product
Yieldb (%)
1
4-NO2Ph (1b)
4-CNPh (1c)
4-ClPh (1d)
4-BrPh (1e)
3-ClPh (1f)
3-BrPh (1g)
Ph (1h)
4-MePh (1i)
2-Phenylethyl (1j)
2-Furyl (1k)
Ph (1h)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
H (2a)
2-Me (2b)
5-OMe (2c)
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
98
95
95
85
89
90
98
85
95
81
98
54
2
3c
4c
5
6
7d
8d
9
3ja
10d
11d
12d
3ka
3hb
3hc
Ph (1h)
Scheme 2 Plausible reaction mechanism.
a Experimental conditions: to a mixture of catalyst I (20 mol%) and
aldehyde 1b–k (0.1 mmol) in toluene (250 μL), indole 2a–c (0.3 mmol)
was further added at room temperature. After two days of reaction
Lewis acid (Scheme 2).28 Hence, catalyst I would activate the
first addition of one molecule of indole 2 to aldehyde 1
through halogen bonding (4).31 Unstable intermediate 5 would
promote the elimination of a molecule of H2O to give azaful-
vene derivative 6.32 Finally, intermediate 6 would undergo a
further addition of a second molecule of indole 2 to produce
the final observed product 3.
In order to expand the utility of catalyst I, an additional
model reaction between trans-1-pheny-2-buten-1-one (7)
and indole (2a) has been also explored as described in
Table 4.8c,33
time, adducts
3
were isolated by column chromatography
(hexane : AcOEt 8 : 2). b Isolated yield. c After
3 days of reaction.
d 30 mol% of I.
raising the amount of indole 2a from one to two equivalents
(Table 2, entries 6 and 8) and increasing concentration (Table 2,
entries 3 and 4) have great positive impacts on the yields
obtained. The best conditions found included 1.5 equivalents
of indole 2a and 20 mol% of catalyst in 250 μL of toluene
(Table 2, entry 7). It is worth noting that in the absence of
catalyst I the reaction did not work (Table 2, entry 10), which
supports the role of I as the catalyst of this process. In all cases,
the crudes of the reactions are very clean and only the excess of
indole and the final product appear in the NMR spectra.
Using the best reaction conditions, the scope of this meth-
odology was evaluated employing diverse commercially avail-
able aldehydes and indoles. This methodology was success-
fully applied to produce a great number of substituted bisin-
doles 3 with very good results (Table 3).
Interestingly, we have also observed reactivity using catalyst
I in the Michael addition reaction depicted in Table 4 with
MeOH as solvent at room temperature (entries 4 and 5). It is
remarkable that the process did not work in other less polar
Table 4 Screening of the Michael addition between indole (2a) and
trans-1-pheny-2-buten-1-one (7)a
As reported in Table 3, high yields were achieved in a
reasonable reaction time using a representative spectrum of
aldehydes 1b–k. Non-activated aldehydes 1h,i (without an elec-
tron withdrawing group in their skeleton, entries 7 and 8) or
heteroaromatic aldehyde 1k (entry 10) showed a lower reactiv-
ity and a 30 mol% of catalyst I was necessary to achieve high
yields in the same reaction time. In contrast, activated alde-
hydes 1b–g (entries 1–6) or aliphatic 1j (entry 9) afforded good
levels of reactivity in all cases. Surprisingly, aldehydes 1d,e
(entries 3 and 4) required longer reaction times (72 h),
although with good yields. Activated indole 2b (entry 11)
showed high reactivity with aldehyde 1h while indole 2c only
led to a moderate yield (entry 12).
Entry
I (mol%)
Solvent
Yieldb (%)
1
2
3
4
5
—
10
10
10
20
MeOH
CH3CN
Toluene
MeOH
MeOH
n.r.c
n.r.c
n.r.c
37
82
a Experimental conditions: to a mixture of catalyst I (0–20 mol%) and
trans-crotonophenone (7) (0.1 mmol) in the corresponding solvent
(0.25 mL), indole 2a (0.2 mmol) was further added at room tempera-
ture. After 48 h of reaction, product 8 was isolated by column chrom-
atography (hexane : AcOEt 8 : 2). b Isolated yield. c No reaction observed.
A plausible mechanism is proposed assuming the same
route as that previously reported by us when using AgOTf as a
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Table 5 EPN values of benzaldehyde (1h) and complexes IH⋯1h and
I⋯1h
solvents such as toluene or in polar aprotic solvents such as
acetonitrile (entries 2 and 3, respectively). Since it is remark-
able that even with the presence of protic solvents, such as
MeOH, the halogen–bond interaction is formed, in order to
be sure that the reaction was not promoted by MeOH itself,
the background of this Michael addition was also examined.
In the absence of catalyst, the formation of the final product
8 was not observed at the same reaction time (entry 1). This
reaction shows the importance of our catalyst promoting also
this benchmark reaction with a simpler iodine-based catalyst
in comparison with those catalysts previously used to
promote this reaction.8c,33 Moreover, Breugst and co-workers
found that an iodoalkyne-based catalyst did not promote the
latter reaction.33d Therefore, this proves that structural vari-
ations in the aromatic ring could be pivotal to promote the
Relative EPN
Experimental
yield (%)
Entry
System
(kcal mol−1
)
1
2
3
1h
IH⋯1h
I⋯1h
0.0
4.5
11.1
0
0
98
towards a subsequent indole attack. In order to verify this, we
calculated the electrostatic potentials at nuclei (EPN) of the
carbonyl C atom of benzaldehyde and complexes I⋯1h and
IH⋯1h (Table 5).
EPN values have previously been correlated to the reactivity
of different functional groups, including carbonyl groups.36 As
the EPN value of the carbonyl C atom becomes higher, the
electrophilicity and reactivity of the carbonyl group increases.
As seen in Table 5, benzaldehyde 1h shows the lowest EPN
value of the three values calculated (Table 5, entry 1) and
suggests that the carbonyl group of benzaldehyde is the least
reactive carbonyl group of the carbonyl groups studied. The
results also indicate that the I⋯O interaction created by cata-
lyst I (Table 5, entry 3) activates the carbonyl group in a greater
extent than the H⋯O interaction created by its hydrogenated
analogous IH (Table 5, entry 2). As expected, the reaction was
performed experimentally using catalyst IH and no reaction
was observed after two days, while catalyst I showed a 98%
yield after two days under the same reaction conditions
(Table 3, entry 7).
Furthermore, in order to ensure that the I⋯O interaction
was generated, NCIPLOT37 was employed to analyse the nonco-
valent interactions (NCI) generated in the I⋯1h complex
(Fig. 2). The results suggest that the I⋯O halogen is the only
relevant intermolecular NCI created in the I⋯1h complex and,
therefore, the only NCI that activates the carbonyl group
towards the nucleophilic attack of indole.
process. The efficiency of catalyst
I to activate other
α,β-unsaturated ketone derivatives is being explored in this
moment in our lab.
Computational study of the I⋯O halogen bond
We have computationally analysed the impact that the I⋯O
halogen bond created between catalyst I and the initial
aldehydes has on the reaction. Initially, the I⋯O interaction is
compared with the H⋯O interaction created by an analogous
hydrogenated catalyst (IH) that does not contain iodine atoms
(Fig. 1).34
The distance and angle of the calculated halogen bonding
are in accordance with those determined in the crystal struc-
ture of II⋯acetone halogen bonding complex.18 The results
suggest that iodine atoms create stronger interactions with the
O atom of benzaldehyde compared to H atoms (more negative
BE when catalyst I is used). Analogous to the electron flow in
hydrogen bonds, iodine atoms take electron density from O
atoms in halogen bonds.2 Therefore, this I⋯O interaction
could activate the carbonyl group of the aldehyde molecule
Preliminary kinetic studies performed with the aim of
knowing the order of reaction of the aldehyde seem to provide
a more complex mechanism of reaction. These studies suggest
that more than one molecule of aldehyde is involved in the
process. Since at this stage the role of more than one molecule
of aldehyde could not be clear, more computational calcu-
lations and experimental studies are ongoing in our lab in
order to understand this interesting aspect.
Fig. 1 Optimised complexes of benzaldehyde (1h) with catalyst I (I⋯1h)
or IH (H⋯1h) along with the bonding energies (BE) created by the I⋯O
and H⋯O interactions. Negative values in the BE values correspond to
attractive interactions. Calculated at the ωB97X-D/Def2-QZVPP(SMD)//
ωB97X-D/Def2-TZVP(SMD) level of theory.35
Fig. 2 I⋯O halogen bond created between catalyst I and benzaldehyde
(1h). Only attractive NCI are shown.
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132.3, 123.9, 93.7, 77.2, 9.1. HRMS calcd for C10H4I2 377.8397;
found [M] 377.8410.
Conclusions
A novel approach for the formation of bisindolylmethane
1,3-Bis(iodoethynyl)benzene (II).18 Following the general
1
derivatives (BIMs) is described as a proof of concept to evalu- procedure, compound II was obtained in 82% yield. H NMR
ate the catalytic ability of iodoalkyne organocatalysts. The use (300 MHz, CDCl3): δ 7.49 (t, J = 1.4 Hz, 1H), 7.41–7.33 (m, 2H),
of these derivatives is reported as an example of simple 7.29–7.20 (m, 1H). 13C NMR (75 MHz, CDCl3): δ 212.3, 136.2,
halogen bond-based organocatalyst. This kind of activation 132.6, 128.4, 123.8, 93.2, 7.8. HRMS calcd for C10H4I2
has not been used before for the synthesis of bisindolyl- 377.8397; found [M] 377.8395.
methane derivatives. We prove the efficiency of this family of
1,3,5-Tris(iodoethynyl)benzene (III).9a Following the general
1
new catalysts by developing a simple and easy operational procedure, compound III was obtained in 63% yield. H NMR
methodology, opening the door to the development of alterna- (300 MHz, CDCl3): δ 7.44 (s). 13C NMR (75 MHz, CDCl3): δ
tive catalysts in the area of halogen bond-based catalysts. 135.9, 124.1, 92.3, 9.1. HRMS calcd for C12H3I3 522.7363;
Additional kinetic studies and computational calculations are found [M] 527.7369.
ongoing in our lab in order to shed light to the mechanism of
this process.
Tris(prop-2-ynyl)benzene-1,3,5-tricarboxylate (IV). Following
the general procedure, compound IV was obtained in 76%
1
yield. H NMR (300 MHz, CD3CN): δ 8.73 (s, 3H), 5.10 (s, 6H).
13C-APT NMR (75 MHz, CD3CN): δ 164.7, 135.3, 132.1, 88.5,
55.5, 8.9. HRMS (ESI+) calcd for C18H9I3NaO6 724.7425; found
[M + Na] 724.7401.
Experimental section
General experimental methods and instrumentation
Purification of reaction products was carried out either by
flash chromatography using silical-gel (0.063–0.200 mm).
Analytical thin layer chromatography was performed on
0.25 mm silica-gel 60-F plates. ESI ionization method and
mass analyser type MicroTof-Q were used for the ESI measure-
ments. 1H and 13C{1H}-APT NMR were recorded at room temp-
erature on a BRUKER AVANCE 400 spectrometer (1H, 300 or
400 MHz; 13C, 75 or 100.6 MHz) in CDCl3, CD3COCD3 or
CD3CN as solvent. Chemical shifts were reported in the δ scale
relative to residual CHCl3 (7.28 ppm), CH3COCH3 (2.05 ppm)
Representative procedure for synthesis of bis(indolyl)
methanes (3)
To a mixture of catalyst I (20 mol%, 7.6 mg) and aldehyde 1a–k
(0.1 mmol) in toluene (250 μL), indole 2a–c (0.3 mmol) was
further added in a test tube at room temperature. After two days
of reaction time, adducts 3 was isolated by column chromato-
graphy (hexane : AcOEt 8 : 2). The yields are given in Table 3.
3,3′-((3-Nitrophenyl)methylene)bis(1H-indole) (3aa).38
Following the general procedure, compound 3aa was obtained
after 2 days of reaction at room temperature in 98% yield, as a
1
and CH3CN (1.94 ppm) for H NMR and to the central line of
1
red solid. H NMR (400 MHz, CDCl3) δ 8.22 (t, J = 2.0 Hz, 1H,
CHCl3 (77.16 ppm), CH3COCH3 (29.84 ppm) and CH3CN
(1.32 ppm) for 13C{1H}-APT NMR. Tri(Prop-2-ynyl)benzene-
1,3,5-tricarboxylate was synthesized according to the literature
procedure.30 All other reagents were obtained from commer-
cial sources and used without prior purification.
Ar–H), 8.08 (ddd, J = 8.2, 2.3, 1.0 Hz, 1H, Ar–H), 7.96 (br s, 2H,
N–H), 7.69 (d, J = 7.7 Hz, 1H, Ar–H), 7.43 (d, J = 7.9 Hz, 1H, Ar–
H), 7.40–7.34 (m, 4H, Ar–H), 7.23–7.18 (m, 2H, Ar–H), 7.04
(ddd, J = 8.1, 5.9, 0.9 Hz, 2H, Ar–H), 6.64 (d, J = 1.4 Hz, 2H,
Ar–H), 6.00 (s, 1H, CH).
All commercially available solvents and reagents were used
3,3′-((4-Nitrophenyl)methylene)bis(1H-indole) (3ba).39
Following the general procedure, compound 3ba was obtained
after 2 days of reaction at room temperature in 98% yield, as a
1
as received. H- and 13C{1H}-APT NMR spectra for compounds
3aa,38 3ba,39 3ca,40 3da,41 3ea,40 3fa,38 3ha,38 3ia,38 3ka,42
3hb,43 3hc44 and 833d are consistent with values previously
reported in the literature.
1
red solid. H NMR (400 MHz, CDCl3) δ 8.16–8.12 (m, 2H, Ar–
H), 8.01 (br s, 2H, N–H), 7.52–7.49 (m, 2H, Ar–H), 7.40–7.33
(m, 4H, Ar–H), 7.20 (ddd, J = 8.2, 7.1, 1.0 Hz, 2H, Ar–H), 7.03
General procedure for electrophilic iodation of terminal alkynes
2 mmol of the corresponding ethynyl derivative was dissolved (ddd, J = 8.0, 7.1, 1.0 Hz, 2H, Ar–H), 6.69 (d, J = 2.4, 0.8 Hz, 2H,
in acetone (30 mL) followed by the addition of AgNO3 (0.1 mol/ Ar–H), 5.99 (s, 1H, CH).
mol CuC–H). The reaction was kept for 30 min in an ice bath,
4-(Di(1H-indol-3-yl)methyl)benzonitrile (3ca).40 Following
in the dark, then N-iodosuccinimide (1.2 mol/mol CuC–H) the general procedure, compound 3ca was obtained after
was added slowly. The reaction was stirred overnight at room 2 days of reaction at room temperature in 95% yield, as a red
temperature. The crude was filtered over Celite, the solvent solid. 1H NMR (400 MHz, CDCl3) δ 8.02 (br s, 2H, N–H),
was removed in vacuo, and the residue was dissolved in CH2Cl2 7.58–7.55 (m, 2H, Ar–H), 7.46–7.44 (m, 2H, Ar–H), 7.39–7.32
(30 mL) and washed with NaHCO3 (10%) (3 × 20 mL). The (m, 4H, Ar–H), 7.20 (ddd, J = 8.2, 7.1, 1.1 Hz, 2H, Ar–H), 7.03
organic fraction was dried over MgSO4, filtered and the solvent (ddd, J = 8.0, 7.1, 1.0 Hz, 2H, Ar–H), 6.66 (d, J = 2.4, 0.8 Hz, 2H,
was evaporated. The pure products were recovered as yellow Ar–H), 5.94 (s, 1H, CH).
solids (63–82%).
3,3′-((4-Chlorophenyl)methylene)bis(1H-indole) (3da).41
1,4-Bis(iodoethynyl)benzene (I).18 Following the general pro- Following the general procedure, compound 3da was obtained
cedure, compound I was obtained in 80% yield. 1H NMR after 3 days of reaction at room temperature in 95% yield, as a
(300 MHz, CDCl3): δ 7.36 (s). 13C NMR (75 MHz, CDCl3) δ ppm: red solid. 1H NMR (400 MHz, CD3COCD3) δ 10.04 (br s, 2H,
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N–H), 7.40 (d, J = 8.3 Hz, 4H, Ar–H), 7.36–7.29 (m, 4H, Ar–H),
3,3′-(Furan-2-ylmethylene)bis(1H-indole) (3ka).42 Following
7.08 (t, J = 7.6 Hz, 2H, Ar–H), 6.91 (t, J = 7.5 Hz, 2H, Ar–H), the general procedure, compound 3ka was obtained after
6.83 (s, 2H, Ar–H), 5.94 (s, 1H, CH). 2 days of reaction at room temperature in 81% yield, as a red
1
3,3′-((4-Bromophenyl)methylene)bis(1H-indole) (3ea).40 solid. H NMR (400 MHz, CDCl3) δ 7.96 (br s, 2H, N–H), 7.48
Following the general procedure, compound 3ea was obtained (dd, J = 4.2, 3.7 Hz, 2H, Ar–H), 7.38–7.34 (m, 3H, Ar–H), 7.18
after 3 days of reaction at room temperature in 85% yield, as a (ddd, J = 8.1, 7.1, 1.1 Hz, 2H, Ar–H), 7.04 (ddd, J = 8.0, 7.1,
red solid. 1H-NMR (300 MHz, CDCl3) δ 7.89 (br s, 2H, N–H), 1.0 Hz, 2H, Ar–H), 6.88 (dd, J = 2.4, 0.8 Hz, 2H, Ar–H), 6.30
7.42–7.34 (m, 6H, Ar–H), 7.24–7.16 (m, 4H, Ar–H), 7.02 (ddd, (dd, J = 3.0, 1.9 Hz, 1H, Ar–H), 6.06 (dt, J = 3.2, 0.8 Hz, 1H,
J = 7.9, 7.1, 1.0 Hz, 2H, Ar–H), 6.63 (dd, J = 2.4, 0.9 Hz, 2H, Ar–H), 5.95 (s, 1H, CH).
Ar–H), 5.85 (s, 1H, CH).
3,3′-(Phenylmethylene)bis(2-methyl-1H-indole) (3hb).43
3,3′-((3-Chlorophenyl)methylene)bis(1H-indole) (3fa).38 Following the general procedure, compound 3hb was obtained
Following the general procedure, compound 3fa was obtained after 2 days of reaction at room temperature in 98% yield, as a
after 2 days of reaction at room temperature in 89% yield, as a red solid. 1H NMR (400 MHz, CD3COCD3) δ 9.85 (br s, 2H,
red solid. 1H NMR (400 MHz, CD3COCD3) δ 10.06 (br s, 2H, N–H), 7.30–7.18 (m, 7H, Ar–H), 6.95–6.90 (m, 4H, Ar–H), 6.71
N–H), 7.42–7.21 (m, 8H, Ar–H), 7.08 (t, J = 7.6 Hz, 2H, Ar–H), 6.92 (ddd, J = 8.1, 7.2, 1.0 Hz, 2H, Ar–H), 6.05 (s, 1H, CH), 2.11 (s,
(t, J = 7.5 Hz, 2H, Ar–H), 6.86 (s, 2H, Ar–H), 5.97 (s, 1H, CH).
3,3′-((3-Bromophenyl)methylene)bis(1H-indole) (3ga).
6H, 2 × CH3).
3,3′-(Phenylmethylene)bis(5-methoxy-1H-indole) (3hc).44
Following the general procedure, compound 3ga was obtained Following the general procedure, compound 3hc was obtained
after 2 days of reaction at room temperature in 90% yield, as a after 2 days of reaction at room temperature in 54% yield, as a
red solid. 1H-NMR (400 MHz, CD3COCD3): δ 10.05 (br s, 2H, red solid. 1H NMR (400 MHz, CD3COCD3) δ 9.84 (br s, 2H, N–H),
N–H), 7.58 (t, J = 1.8 Hz, 1H, Ar–H), 7.42–7.36 (m, 6H, Ar–H), 7.43–7.40 (m, 2H, Ar–H), 7.30–7.26 (m, 4H, Ar–H), 7.20–7.16 (m,
7.23 (t, J = 7.8 Hz, 1H, Ar–H), 7.09 (ddd, J = 8.1, 7.1, 1.1 Hz, 2H, 1H, Ar–H), 6.83 (dd, J = 8.2, 2.3 Hz, 4H, Ar–H), 6.73 (dd, J = 8.8,
Ar–H), 6.93 (ddd, J = 8.0, 7.1, 1.0 Hz, 2H, Ar–H), 6.86 (dd, J = 2.5 Hz, 2H, Ar–H), 5.83 (s, 1H, CH), 3.62 (s, 6H, 2 × OCH3).
2.4, 0.8 Hz, 2H, Ar–H), 5.97 (s, 1H). 13C NMR (100.6 MHz,
Representative procedure for synthesis of 3-(1H-indol-3-yl)-
1-phenylbutan-1-one (8)
CD3COCD3) δ 148.9, 138.1, 132.3, 130.9, 129.8, 128.5, 127.9,
124.7, 122.7, 122.3, 120.2, 119.5, 119.1, 112.3, 40.8.
HRMS (ESI−) calcd for C23H16BrN2 399.0491; found 399.0508
[M − H].
To a mixture of catalyst I (20 mol%, 7.6 mg) and ketone 7
(0.1 mmol) in MeOH (250 μL), indole 2a (0.2 mmol) was
further added in a test tube at room temperature. After two
days of reaction time, adduct 8 was isolated by chromato-
graphy (hexane : AcOEt 9 : 1).
3,3′-(Phenylmethylene)bis(1H-indole) (3ha).38 Following the
general procedure, compound 3ha was obtained after 2 days of
1
reaction at room temperature in 98% yield, as a red solid. H
3-(1H-indol-3-yl)-1-phenylbutan-1-one (8).33d Following the
general procedure, compound 8 was obtained after 2 days of
reaction at room temperature in 82% yield, as a yellow solid.
1H NMR (400 MHz, CDCl3) δ 8.03–7.90 (m, 3H, 2Ar–H and
N–H), 7.72–7.66 (m, 1H, Ar–H), 7.59–7.52 (m, 1H, Ar–H),
7.49–7.41 (m, 2H, Ar–H), 7.36–7.33 (m, 1H, Ar–H), 7.20 (ddd,
J = 8.0, 7.1, 1.1 Hz, 1H, Ar–H), 7.13 (ddd, J = 8.0, 7.1, 1.1 Hz,
1H, Ar–H), 7.03 (d, J = 2.0 Hz, 1H, NHCH), 3.91–3.77 (m, 1H,
CH3CH), 3.49 (dd, J = 16.0, 4.0 Hz, 1H, CHH), 3.25 (dd, J =
16.0, 8.0 Hz, 1H, CHH), 1.46 (d, J = 6.9 Hz, 3H, CH3).
NMR (400 MHz, CD3COCD3) δ 9.98 (br s, 2H, N–H), 7.43–7.36
(m, 6H, Ar–H), 7.29–7.26 (m, 2H, Ar–H), 7.20–7.18 (m, 1H, Ar–
H), 7.07 (ddd, J = 8.1, 7.1, 1.1 Hz, 2H, Ar–H), 6.90 (ddd, J = 8.0,
7.1, 1.0 Hz, 2H, Ar–H), 6.82 (dd, J = 2.3, 0.8 Hz, 2H, Ar–H), 5.93
(s, 1H, CH).
3,3′-(p-Tolylmethylene)bis(1H-indole) (3ia).38 Following the
general procedure, compound 3ia was obtained after 2 days of
1
reaction at room temperature in 85% yield, as a red solid. H
NMR (400 MHz, CDCl3) δ 7.88 (br s, 2H, N–H), 7.40 (dd, J =
7.9, 1.0 Hz, 2H, Ar–H), 7.34 (dt, J = 8.2, 0.8 Hz, 2H, Ar–H), 7.24
(d, J = 8.1 Hz, 2H, Ar–H), 7.17 (ddd, J = 8.1, 7.1, 1.0 Hz, 2H,
Ar–H), 7.09 (d, J = 7.8 Hz, 2H, Ar–H), 7.01 (ddd, J = 8.0, 7.1, 1.0
Hz, 2H, Ar–H), 6.65 (dd, J = 2.4, 1.0 Hz, 1H, Ar–H), 5.86 (s, 1H,
CH), 2.33 5.86 (s, 3H, CH3).
Conflicts of interest
3,3′-(3-Phenylpropane-1,1-diyl)bis(1H-indole) (3ja).
Following the general procedure, compound 3ja was obtained
after 2 days of reaction at room temperature in 95% yield, as a
red solid. 1H NMR (400 MHz, CDCl3) δ 7.90 (br s, 2H, N–H),
7.56 (d, J = 8.0 Hz, 2H, Ar–H), 7.34 (dt, J = 8.1, 0.9 Hz, 2H,
There are no conflicts to declare.
Acknowledgements
Ar–H), 7.31–7.12 (m, 7H, Ar–H), 7.08–6.98 (m, 4H, Ar–H), 4.52 This work was supported by
a 2018 Leonardo Grant
(t, J = 7.4 Hz, 1H, CH), 2.74 (dd, J = 9.2, 6.3 Hz, 2H, CH2), for Researchers and Cultural Creators, BBVA Foundation.
2.60–2.49 (m, 2H, CH2). 13C-APT NMR (100.6 MHz, CDCl3) Authors also thank the Ministerio de Economía, Industria y
δ 142.7, 136.7, 128.7, 128.4, 127.2, 125.8, 121.9, 121.6, 120.2, Competitividad (MINECO/FEDER CTQ2017-88091-P and
119.8, 119.2, 111.2, 37.5, 34.6, 33.6. HRMS (ESI−) calcd for PGC2018-093761-B-C31), and DGA-FSE (E7_17R and E47_17R)
C25H21N2 349.1699; found 349.1692 [M − H].
for financial support of this research. All the calculations were
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performed in the Trueno cluster facility of SGAI-CSIC and the
Extreme Science and Engineering Discovery Environment
(XSEDE) through allocation CHE190111. J.V.A.-R. thanks
Dr Robert S. Paton (Colorado State University) for his support
with NCIPLOT and PyMOL. We acknowledge support of the
publication fee by the CSIC Open Access Publication Support
Initiative through its Unit of Information Resources for
Research (URICI).
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