Reaction Mechanism of Iodine-Catalyzed Michael Additions

Article abstract of DOI:10.1021/acs.joc.7b00445

Molecular iodine, an easy to handle solid, has been successfully employed as a catalyst in different organic transformations for more than 100 years. Despite being active even in very small amounts, the origin of this remarkable catalytic effect is still unknown. Both a halogen bond mechanism as well as hidden Br?nsted acid catalysis are frequently discussed as possible explanations. Our kinetic analyses reveal a reaction order of 1 in iodine, indicating that higher iodine species are not involved in the rate-limiting transition state. Our experimental investigations rule out hidden Br?nsted acid catalysis by partial decomposition of I₂ to HI and suggest a halogen bond activation instead. Finally, molecular iodine turned out to be a similar if not superior catalyst for Michael additions compared with typical Lewis acids.

Full text of DOI:10.1021/acs.joc.7b00445

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Reaction Mechanism of Iodine-Catalyzed Michael Additions
Daniel von der Heiden, Seyma Bozkus, Martin Klussmann, and Martin Breugst
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00445 • Publication Date (Web): 28 Mar 2017
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Reaction Mechanism of IodineꢀCatalyzed Michael
Additions
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Daniel von der Heiden,‡ Seyma Bozkus,‡ Martin Klussmann,† and Martin Breugst‡*
‡ Universität zu Köln, Department für Chemie, Greinstraße 4, 50939 Köln, Germany.
† MaxꢀPlanckꢀInstitut für Kohlenforschung, KaiserꢀWilhelmꢀPlatz 1, 45470 Mülheim an der
Ruhr, Germany.
Keywords: Halogen Bonding – Iodine – Kinetics – PhysicalꢀOrganic Chemistry – Reaction
Mechanism
Abstract. Molecular iodine –an easy to handle solid– is successfully employed as a catalyst in
different organic transformations for more than 100 years. Despite being active even in very
small amounts, the origin of this remarkable catalytic effect is still unknown. Both a halogenꢀ
bond mechanism as well as hidden Brønstedꢀacid catalysis are frequently discussed as possible
explanations. Our kinetic analyses reveal a reaction order of one in iodine indicating that higher
iodine species are not involved in the rateꢀlimiting transition state. Our experimental
investigations rule out hidden Brønstedꢀacid catalysis by partial decomposition of I2 to HI and
suggest a halogenꢀbond activation instead. Finally, molecular iodine turned out to be a similar if
not superior catalyst for Michael additions compared with typical Lewis acids.
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Introduction
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For more than 100 years, molecular iodine (I2) is known to effectively catalyze various
transformations.1 Hibbert reported as one of the first in 1915 that tiny amounts of I2 (0.01 mol%)
catalyze the conversion of diacetone alcohol (1) into mesityl oxide (2).2 Over the next decades,
many reactions have been published in which molecular iodine acts as the sole catalyst (Scheme
1).1
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Scheme 1. Examples of iodineꢀcatalyzed reactions.2ꢀ3
Iodineꢀcatalyzed reactions have gained more importance over the last years due to the recent
success of halogenꢀbond donors in organic catalysis.4 However, the analysis of the origin of
iodine catalysis is further complicated by a potential side reaction of molecular iodine. In the
presence of protic solvents, iodine is known to slowly decompose to yield Brønsted acids like HI
(Scheme 2, top).5 Cruickshank and Benson reported the formation of HI and CO from methanol
and iodine in the gas phase.5a In aqueous, alkaline solution, iodine readily disproportionates to
yield iodide and different HIOn species.5c Comparable reactions are also proposed for reactions
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of iodine with alcohols, and the intermediate organic hypoiodites are oxidized to the
corresponding aldehydes.5dꢀf Accordingly, two modes of activation are often proposed for iodineꢀ
catalyzed reactions: Halogenꢀbond activation and a hidden Brønstedꢀacid catalysis6 (Scheme 2,
bottom).
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Scheme 2. Proposed pathways for HI generation from iodine5 and proposed modes of activation
for iodine catalysis.
So far, only few mechanistic studies have been performed and Jereb and coꢀworkers summarized
those previous investigations on different classes of iodineꢀcatalyzed reactions: “There is an
open debate about the nature of the actual catalyst in I2-catalyzed reactions, particularly when
conducted in protic solvents. There are a plethora of papers, but very little mechanistic
explanation is given.”1d Most experimental studies relied on a simple comparison of yields
indicating that iodine is more reactive than its decomposition products.3a,7 In one of the very few
detailed mechanistic studies, Katsuko and Takeshi identified chargeꢀtransfer complexes between
I2 and alcohols in iodineꢀcatalyzed alkoxyꢀalkoxy exchange reactions of alkylalkoxysilanes,8 and
suggested heterolytic cleavage of iodine in the transition state. As a consequence, the reaction
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mechanism and, therefore, the mode of activation of iodineꢀcatalyzed reactions remained
unclear.1b,1d,1f
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A recent computational investigation revealed that halogen bonding is strong enough to be
catalytically relevant, lowering the activation energies for a subsequent nucleophilic attack by up
to 30 kJ mol–1 (e.g., for the reaction of 3 and 4, Scheme 1),9 which prompted us to investigate
these reactions in more detail experimentally. We now report on a thorough experimental study
on iodineꢀcatalyzed Michael additions to distinguish between halogenꢀbond activation and
Brønstedꢀacid catalysis. The experimental data presented below clearly support the picture of
halogenꢀbond catalysis and rule out a significant contribution from Brønsted acids in these
reactions.
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Results and Discussion
Solvent Effects. We started our analysis of iodineꢀcatalyzed reactions by analyzing the
influence of the solvent in these transformations. The reaction between transꢀcrotonophenone (3)
and indole (4) using 5 mol% of I2 was deactivated after 3 minutes by filtration through a mixture
of Na2S2O3 and Na2CO3 on silica, and the reaction progress was monitored by HPLC (Scheme 3,
see the Supporting Information for more details). We chose the reaction between 3 and 4 for this
analysis as no product can be detected in the absence of any catalyst even after prolonged
reaction times and previous computational data indicated that this reaction is extremely
susceptible to iodine catalysis.3a,9 Most aprotic solvents resulted in acceptable to high yields and
only for DMSO and DMF no product formation could be observed even after extended reaction
times.
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Scheme 3. Solventꢀdependency of the HPLCꢀyields of the iodineꢀcatalyzed Michael addition
between transꢀcrotonophenone (3) and indole (4).
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As DMSO (and similarly DMF) can form strong halogenꢀbonded complexes with molecular
iodine itself,10 it is likely that this competing complexation reaction deactivates the catalyst for
the Michael addition. This interpretation is supported by the comprehensive Lewisꢀbasicity scale
based on reactions with molecular iodine:11 DMSO ( G = –8.9 kJ mol–1) and DMF (ꢀG = –4.6
ꢀ
kJ mol–1) bind significantly stronger to iodine than other solvents (Et2O: +0.3, CH3CN: +0.4,
benzene: +3.5 kJ mol–1). These findings are also in agreement with the previous analysis of
solvent effects of different halogenꢀbonded complexes.12 This effect could also explain the low
yields observed for protic (and Lewis basic) solvents MeOH and iPrOH. Another plausible
explanation is the decomposition of I2 (Scheme 2). However, in this case the decomposition
product has to be a less active catalyst compared to molecular iodine.
Kinetic Analysis. To get a better understanding of the role of iodine in these reactions, we
monitored the kinetics of two iodineꢀcatalyzed Michael additions in various solvents by IR
spectroscopy and reaction calorimetry (Figure 1). transꢀChalcone (9) was employed as
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Figure 1. Determining the reaction order in iodine for the reaction between indole (4) and
chalcone (9) in 1,4ꢀdioxane (top, IR analysis, ([4] = [9] = 0.5 mol L–1; [xylene] = 90 mmol L–1
(internal standard) 23 °C) and 5ꢀmethoxy indole (11) and chalcone (9) in acetonitrile (bottom,
reaction calorimetry, [9] = 100 mmol L–1, [11] = 80 mmol L–1, [xylene] = 23 mmol L–1 (internal
standard), 23 °C) plotting the initial rates versus the iodine concentration.
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electrophile for the kinetic investigations [instead of transꢀcrotonophenone (3)] to ensure suitable
extended reaction times for the kinetic measurements. While the reaction between the
electrophile 9 and indole (4) was studied by IR spectroscopy, 5ꢀmethoxy indole (11) was chosen
as nucleophile for the calorimetric experiments. The reaction is more exergonic in the case of 11
which leads to a better signalꢀtoꢀnoise ratio in the kinetic runs. All reactions proceed with high
yields and no side products could be detected under the reaction conditions. As shown in the
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1
Supporting Information, conversions determined by H NMR spectroscopy at different points of
the reaction perfectly fit to those determined by reaction calorimetry, indicating that this method
1
is suitable for reaction monitoring. In all cases, conversions were determined by H NMR
spectroscopy at the end of the kinetic experiments with respect to an internal standard (xylene;
see the Supporting Information for details). To determine the reaction order in iodine, series of
kinetic experiments with variable iodine concentrations under otherwise identical conditions
were studied in different solvents.
Plotting the initial rate13 versus the concentration of iodine (Figure 1) resulted in linear
correlations indicating a reaction order of 1 for iodine (see the Supporting Information for more
details). Similar conclusions can also be obtained from doubleꢀlogarithmic plots or the reaction
progress kinetic analysis method.14 The results exclude the participation of higher iodine species
+
–
(e.g., I3 or I3 ) in the rateꢀlimiting step of these transformations. In combination with the
effective deactivation of iodine by iodide (see below), the experimentally observed first order in
iodine also argues against mechanistic proposals involving a heterolytic cleavage of I2 (→ I+ and
I–)15 as the latter should recombine with molecular iodine and form the triiodide anion.
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Halogen-Bond vs. Brønsted-Acid Catalysis. Next, we had to distinguish between halogenꢀ
bond activation or an activation by Brønsted acids formed under the reaction conditions (Scheme
2). As both pathways are in agreement with a reaction order of 1 in iodine, we started this
analysis with a comparison of the reactivities of both species in different solvents for the reaction
shown in Scheme 3. Both catalysts (I2 and HI) were used in 5 mol% loadings in acetonitrile and
the reactions were deactivated by addition of an aqueous alkaline Na2S2O3ꢀsolution.
Commercially available, aqueous HI (57 wt%) was used for acetonitrile solutions which turned
out to be unsuitable for the less polar solvents CH2Cl2 and toluene because it formed
inhomogeneous mixtures. Therefore, anhydrous HI freshly prepared from KI and H4P2O7 was
used for these solvents (see the Supporting Information for details).16 As the solubility of HI is
limited in these solvents, slightly smaller catalyst loadings (3 and 2 mol%) were used for CH2Cl2
and toluene and the results are summarized in Table 1. A potential side reaction, the addition of
HI to transꢀcrotonophenone (3),17 was not observed under the reaction conditions. However,
small amounts of the addition product (< 15 %, see the Supporting Information for details) were
formed in a slow reaction when 3 was mixed with HI in a stoichiometric ratio. As this conjugate
addition product was not observed in the catalyzed reaction, we have to conclude that this
process does not take place during catalysis or that the product is formed in a reversible reaction.
In all cases, significantly higher yields have been obtained for iodine compared to the Brønsted
acid HI. Similar results have also been observed in the reactions of 5ꢀmethoxy (11) and 5ꢀ
cyanoindole (12) with both Michael acceptors 3 and 9 (Table 2). The use of
trifluoromethanesulfonic acid as another strong Brønsted acid gave essentially the same results in
acetonitrile. These comparisons indicate that iodine seems to be the more active catalyst system
compared to simple Brønsted acids.
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Table 1. HPLC Yields (Yields in Parentheses) for the I2ꢀ and HIꢀCatalyzed Reaction between
transꢀCrotonophenone (3) and Indole (4) in Different Solvents (23 °C, 3 min).
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Solvent
CH3CN
Catalyst
Loading
5 mol%
Yield
(Iodine)
Yield
(HI)
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93 %[a]
(73 %)[a]
72 %
58 %[a]
(40 %)[a]
34 %
CH2Cl2
toluene
3 mol%
2 mol%
60 %
17 %
[a] average of 4 experiments; standard deviation 3 %.
Table 2. Yields for the I2ꢀ and HIꢀCatalyzed Reaction between Substituted Indoles and Several
Michael Acceptors (CH3CN, 23 °C).
R1
H
R2 Product Time
[min] (Iodine) (HI)
Yield
Yield
Me
3
3
73 %
78 %
72 %
47 %
51 %
23 %
40 %
45 %
31 %
16 %
17 %
14 %
5
OMe Me
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15
10
12
16
CN
H
Me
Ph
3
20
20
20
OMe Ph
CN Ph
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As the different yields in Table 1 and 2 indicate that different mechanisms might be
responsible for I2 and HI catalysis, we set out to experimentally distinguish between these
pathways (Table 3). Acetonitrile was used as the solvent for these experiments to assure
homogeneous reactions and we employed aqueous HI (57 wt%) as Brønsted acid. In the absence
of any catalyst, no product could be detected by HPLC (Table 3, entry 1). We initially analyzed
the influence of traces of water in the reaction mixture on the catalytic activity of molecular
iodine. Addition of 28 mol% water (the amount of water present in the experiments with HI)
resulted in an almost identical yield (Table 3, entry 3), indicating that small amounts of water do
not affect the reactivity of molecular iodine. The catalytic activity of molecular iodine can be
completely suppressed by addition of KI (approx. 1 equiv.) while the reactivity of the Brønsted
acid remains unchanged upon addition of KI (Table 3, entries 4 and 7). This is most likely
caused by the formation of triiodide ions (eq. 1).18 This assumption is further supported by strong
UV bands at 290 and 360 that were observed when KI was added to an iodine solution in CH3CN
(see the Supporting Information for details).19 Furthermore, no product could be detected by
HPLC when NBu4I3 was employed as the sole catalyst in a control reaction.
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–
I2 + I– → I3
(1)
To selectively deactivate the Brønsted acid, a variety of Brønsted bases were tested. However,
as strong Brønsted bases are also excellent halogenꢀbond acceptors, usually a deactivation of
both pathways was observed. Instead, we found that the addition of molecular sieve (3 Å,
between 50 and 200 wt%) resulted in a significant decrease in HIꢀreactivity (19 %, Table 3, entry
8) while the corresponding yield with I2 remained constant (entry 5). When HI was mixed with
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molecular sieve (25 mg), the solution changed to a light brown colour which could indicate the
formation of I2 under the reaction conditions. This assumption is further supported by the fact
that the yield dropped to 0 % upon the addition of KI (Table 3, entry 9). Decomposition of HI in
the presence of porous additives (presumably due to traces of oxygen) has been reported
before.20
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Table 3. Yields for the I2ꢀ and HIꢀCatalyzed Reaction between transꢀCrotonophenone (3) and
Indole (4) in the Presence of Additives (CH3CN, 23 °C, 3 min)
Entry
Catalytic
System
Yield
Entry
Catalytic
System
Yield
1
2
3
4
5
no catalyst 0 %
I2 73 %
I2 + H2O[a] 71 %
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9
HI
40 %
40 %
19 %
0 %
HI + KI
HI + MS
HI + MS + KI
I2 + KI
0 %
I2 + MS
78 %
[a] The water content (28 mol%) is identical to those reactions that employ aqueous HI as
catalyst.
As iodine could also decompose during the reaction and HI is only present at late stages of the
reactions, we further investigated the stability of the iodine catalyst in the absence (green bars in
Figure 2) and in the presence of KI (addition of KI after run 2, blue bars in Figure 2). Without
any additives, repeated additions of aliquots of a stock solution of the reactants to the reaction
mixture (1 equiv. of 3 and 4 every 20 min) resulted in similar HPLC yields for each addition
step. This suggests that the activity of molecular iodine remains almost constant over several
catalytic cycles even when the actual concentration of I2 is reduced by dilution in every addition
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step. The deactivation of iodine by KI not only works in the beginning of the reaction, but is also
highly effective after several catalytic cycles as indicated by the blue bars in Figure 2 (see the
Supporting Information for additional information). This further indicates that iodine is still
available after the reaction has been completed and that a potential background reaction by HI
formed from I2 is negligible.
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Figure 2. HPLC yields for the reaction of transꢀcrotonophenone (3) and indole (4). After each
run, an aliquot of a stock solution containing 1 equiv. of 3 and 4 was added (green bars). KI (1
equiv.) was added after the 2nd run (blue bars).
In summary, the different behavior of both putative catalysts upon the addition of additives
clearly shows that iodine catalysis is not caused by a hidden Brønstedꢀacid catalysis.
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Comparison to other Lewis Acids. As the experimental investigations discussed above and
previous computational studies9 clearly support a halogenꢀbondꢀbased activation as the origin of
the catalytic activity of molecular iodine, we wanted to compare its activity in these reactions to
those of other Lewis acids of different reactivity.21
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Table 3. Comparison of HPLC Yields Obtained for Different LewisꢀAcid Catalysts in the
Reaction between transꢀCrotonophenone (3) and Indole (4).
Entry
Catalyst
TiCl4
I2
mol%
HPLC Yield
96 %
1
2
3
4
5
6
7
8
9
5
5
5
5
5
5
1
1
1
93 %
AlCl3
CuBr2
FeCl3
InCl3
TiCl4
I2
90 %
47 %
19 %
8 %
33 %
41 %
AlCl3
28 %
Under otherwise identical conditions, highly Lewis acidic complexes (TiCl4, AlCl3) resulted in
similar yields compared to iodine in the reaction between 3 and 4 and almost quantitative yield
can be obtained within minutes (Table 3, entries 1 and 3). On the other hand, other Lewis acids
that were classified as moderately active in benzylation reactions (FeCl3, InCl3, CuBr2, Table 3,
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entries 4–6)21a were inferior to molecular iodine. When the catalyst loading is further reduced to
1 mol%, the catalytic potential of molecular iodine is even more striking (entries 7–9). After 3
minutes, 41 % yield was determined for iodine while only 33 % (TiCl4) and 28 % (AlCl3) were
observed for the other highly active catalysts. As Lewis acids are usually deactivated by water,
iodine is –at the same or even higher catalytic activity– much easier to handle experimentally.
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Conclusions
In summary, the experimental investigations discussed above completely support a halogenꢀ
bondꢀbased activation of the Michael acceptors by molecular iodine. A reaction order of 1
excludes the participation of higher iodine species in the rateꢀdetermining step and the selective
deactivation of either I2 or HI as a competing Brønsted acid rule out hidden Brønstedꢀacid
catalysis. Therefore, this investigation not only confirms that molecular iodine is one of the
simplest halogenꢀbondꢀbased catalysts but could also help in the development of more active
catalysts in the field of halogen bonding. Furthermore, the presented approach to distinguish
between iodine and Brønstedꢀacid catalysis could turn out to be useful for the investigation of
other iodineꢀcatalyzed reactions and related ones, respectively, in order to differentiate between
halogenꢀbond and Brønstedꢀacid catalysis.
Experimental Details
General Remarks. Commercially available HPLCꢀgrade solvents (e.g., CH3CN, CH2Cl2,
toluene, and THF, MeOH) were used without further purification, while all other solvents were
dried prior to use. KarlꢀFischer titrations indicated a water content of less than 30 ppm for all
aprotic solvents. For the experiments involving HI, all solvents have been degassed to avoid
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partial oxidation of HI. All reactions have been performed under argon and with dried glassware.
5
6
7
1
Chemical shifts are given in ppm and refer to tetramethylsilane (
δ
H = 0.00) for H NMR spectra
13
and CD2Cl2, (δC = 53.8) or CDCl3 (δC = 77.2) for C NMR spectra.22 Signal assignments are
based on additional COSY, gHSQC, or gHMBC experiments (see the Supporting Information for
more details). Infrared spectra were recorded on an SHIMADZU IR Affinity I spectrometer
using attenuated total reflectance (ATR). For mass spectrometry, a THERMO Scientific LTQ
Oribitrap XL using electrospray ionization (ESI) and FTMS analyzer was employed. HPLC
analysis has been performed on a Hitachi Chromaster System using a Chiralcel ODꢀH
8
9
10
11
12
13
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(ø = 0.46 cm, length = 25 cm, nꢀhexane:isoꢀpropanol = 90:10, flow = 1.0 mL min–1, 18 °C,
λ
= 223 nm). Conductivity measurements for the titration of HI have been performed with an
InLab731 ISM conductivity cell with a measuring range of 0.01–1000 mS cm–1 and a
multiparameter station by Mettler Toledo.
Synthesis of trans-1-Phenylbut-2-en-1-one (3). The title compound was prepared by a
modified procedure reported by Moody and coworkers:23 trans-Crotonyl chlorid (6.50 g,
62.2 mmol, 1.0 equiv.) was suspended in benzene (18.0 mL, 202 mmol, 3.2 equiv.), and AlCl3
(13.6 g, 101 mmol, 1.6 equiv.) was added while cooling. The mixture stirred overnight and was
deactivated by pouring into a mixture of 1
M
HCl (300 mL) and ice (200 mL). Extraction with
NaOH (20 mL) and drying over
dichloromethane (3 × 50 mL) followed by washing with 1
M
Na2SO4 yielded the crude product after removal of the solvent. The product was purified by
column chromatography (SiO2; EtOAc/cyclohexane, 1:13, Rf = 0.44) to give the pure product as
1
3
a colorless oil (5.72 g, 39.1 mmol, 63 %). H NMR (300 MHz, CD2Cl2)
δ = 1.99 (dd, J = 6.6
4
3
3
Hz, J = 1.2 Hz, 3 H), 6.94 (m, 1 H), 7.07 (dq, J = 15.2 Hz, J = 6.6 Hz, 1 H), 7.48 (m, 2 H),
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7.57 (m, 1 H), 7.90–7.99 (m, 2 H). 13C{1H} NMR (75.5 MHz, CD2Cl2)
δ = 18.7, 127.7,
5
6
7
8
128.8, 128.9, 132.9, 138.4, 145.2, 190.5. IR (neat, ATR) ꢀꢁ [cm–1] = 3057 (w), 2970 (w), 2913
(w), 2361 (w), 1668 (m), 1651 (m), 1622 (s), 1447 (m), 1331 (w), 1294 (s), 1217 (s), 962 (m),
916 (m), 813 (w), 756 (m), 691 (s), 662 (m). HRꢀMS (ESI) [M+H]+: m/z calcd for C10H11O+:
147.0804 found 147.0804. The recorded analytical data matched with those reported
previously.23
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General Procedure for Preparative Reactions. A substrate solution with equimolar amounts
of the indole and the α,βꢀunsaturated ketone in dry acetonitrile was added to the same volume of
the catalyst solution (I2 or HI). In the reaction mixture, concentrations of both reactants were
approx. 0.5
stirring for either 20 minutes (for 9) or 3 minutes (for 3), the reaction was deactivated with a 1:1
mixture of saturated, aqueous Na2S2O3 and 1 aqueous NaOH. The mixture was extracted with
M each, whereas the catalyst concentration was approx. 25 mM (5 mol%). After
M
ethyl acetate and the combined organic layers were dried over MgSO4 or Na2SO4. After
removing the solvent under reduced pressure, the crude product was purified by column
chromatography (silica, EtOAc/cꢀhex) to obtain the pure Michael adducts.
3-(1H-Indol-3-yl)-1-phenylbutan-1-one (5). According to the general procedure, 5 (76.4 mg,
290 µmol, 73 %) was obtained from indole (46.9 mg, 400 µmol) and transꢀcrotonophenone (3)
(58.4 mg, 399 µmol) in the presence of iodine (20 µmol in the reaction mixture, 5.0 mol%). 5
(42.1 mg, 160 µmol, 40 %) was also obtained from the same substrate concentrations in the
presence of HI (20 µmol in the reaction mixture, 5.0 mol%). The average yield determined from
4 experiments for each iodine and HI catalysis resulted in 73 ± 3 % for I2 and 40 ± 3 % for HI
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(Table 1, see the Supporting Information for more details). Melting point: 103–104 °C (Lit:24
3
4
5
6
7
8
103−105 °C). 1H NMR (CD2Cl2, 300 MHz)
δ
= 1.42 (d, 3J = 6.9 Hz, 3 H), 3.23 (dd, 3J = 8.5 Hz,
3
2
2J = 16.5 Hz, 1 H), 3.44 (dd, J = 5.4 Hz, J = 16.4 Hz, 1 H), 3.73−3.84 (m, 1 H), 6.97 (d,
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3
3J = 2.2 Hz, 1 H), 7.04−7.16 (m, 2 H), 7.31 (d, J = 8.0 Hz, 1 H), 7.41 (t, 3J = 7.5 Hz, 2 H), 7.52
(t, J = 7.4 Hz 1 H), 7.63 (d, J = 7.8 Hz, 1 H), 7.91–7.93 (m, 2 H), 8.12 (br s, 1 H). 13C{1H}
3
3
NMR (CD2Cl2, 75.5 MHz) = 21.4, 27.5, 46.8, 111.7, 119.5, 119.5, 120.7, 121.7, 122.2, 126.8,
δ
128.4, 128.9, 133.3, 137.0, 137.8, 200.0. IR (neat, ATR) ꢂꢁ [cm−1] = 3352 (m), 3057 (w), 2982
(w), 2961(w), 2872(w), 1667 (s), 1618 (w), 1593 (w), 1489 (w), 1445 (m), 1339 (m) 1215 (s),
999 (m), 745 (s), 660 (m). HRꢀMS (ESI) [M+H]+: m/z calcd for C18H18NO+: 264.1383 found
264.1384. The recorded analytical data matched with those reported previously.25
3-(5-Methoxy-1H-indol-3-yl)-1-phenylbutan-1-one (14). According to the general
procedure, 14 (112 mg, 382 µmol, 78 %) was obtained from 5ꢀmethoxyindole (11) (74.1 mg,
503 µmol) and transꢀcrotonophenone (3) (71.7 mg, 490 µmol) in the presence of iodine
(25.7 ꢁmol in reaction mixture, 5.2 mol%) as a viscous oil. 14 (65.0 mg, 222 µmol, 45 %) was
1
also obtained from the same substrates in the presence of HI (25.1 ꢁmol, 5.1 mol%). H NMR
3
(CDCl3, 300 MHz)
δ
= 1.44 (d, 3J = 6.9 Hz, 3 H), 3.22 (dd, J = 8.9 Hz, 2J = 16.4 Hz, 1 H), 3.44
(dd, 3J = 4.9 Hz, 2J = 16.3 Hz, 1 H), 3.72−3.84 (m, 4 H), 6.85 (dd, 3J = 8.8 Hz, 4J = 2.4 Hz, 1 H),
6.99 (d, 4J = 2.2 Hz, 1 H), 7.09 (d, J = 2.3 Hz, 1 H), 7.23 (d, J = 8.8 Hz, 1 H), 7.41–7.45 (m, 2
4
3
H), 7.54 (tt, J = 7.3 Hz, J = 1.5 Hz, 1 H), 7.93–7.96 (m, 3 H). 13C{1H} NMR (CDCl3,
3
4
75.5 MHz) = 21.2, 27.2, 46.6, 56.2, 101.4, 112.2, 112.3, 121.2, 121.4, 126.9, 128.3, 128.8,
δ
131.9, 133.2, 137.5, 154.0, 200.1. IR (neat, ATR) ꢀꢁ [cm−1] = 3422 (m), 3061 (w), 2951 (w),
2922 (w), 1674 (s), 1483 (s) 1439 (m), 1277 (m), 1213 (s), 1001 (m), 924 (m), 760 (s), 689 (s).
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HRꢀMS (ESI) [M+Na]+: m/z calcd for C19H19O2NNa+: 316.1308 found 316.1308. The recorded
3
4
5
6
analytical data matched with those reported previously.26
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3-(5-Cyano-1H-indol-3-yl)-1-phenylbutan-1-one (15). According to the general procedure,
15 (105 mg, 364 µmol, 72 %) was obtained from 5ꢀcyanoindole (71.5 mg, 503 µmol) and transꢀ
crotonophenone (3) (74.6 mg, 510 µmol) in the presence of iodine (25.9 ꢁmol in the reaction
mixture, 5.1 mol%). 15 (45.1 mg, 156 µmol, 31 %) was also obtained from the same substrates
in the presence of HI (25.1 ꢁmol in the reaction mixture, 5.0 mol%). Melting point: 137–138 °C
1
3
(Lit:26 136−139 °C). H NMR (CDCl3, 400 MHz)
δ
= 1.46 (d, J = 6.9 Hz, 3 H), 3.28 (dd,
3
2
3
2J = 16.5 Hz, J = 7.8 Hz, 1 H), 3.42 (dd, J = 16.5 Hz, J = 6.0 Hz, 1 H), 3.82 (sextet,
3
3J = 6.9 Hz, 1 H), 7.14 (d, J = 1.6 Hz, 1 H), 7.36−7.41 (m, 2 H), 7.36–7.41 (m, 2 H), 7.56 (t,
3J = 7.4 Hz, 1 H), 7.92–7.94 (m, 2 H), 8.00 (s, 1 H), 8.42 (br s, 1 H). 13C{1H} NMR (CDCl3, 100
MHz)
δ = 21.6, 27.2, 46.5, 102.5, 112.4, 121.1, 122.6, 122.7, 125.1, 125.2, 126.5, 128.3, 128.9,
133.4, 137.3, 138.4, 199.4. IR (neat, ATR) ꢂꢁ [cm−1] = 3368 (m), 3136 (w), 2959 (m), 2924 (m),
2853 (w), 2214 (s), 1674 (s), 1449 (m), 1215 (s), 1005 (s), 881 (m), 802 (s), 754 (s), 687 (s). HRꢀ
MS (ESI) [M+H]+: m/z calcd for C19H17N2O+: 289.1335 found 289.1337. The recorded analytical
data matched with those reported previously.27
3-(1H-Indol-3-yl)-1,3-diphenylpropan-1-one (10). According to the general procedure, 10
(76.1 mg, 234 ꢁmol, 47 %) was obtained from indole (4) (58.5 mg, 499 ꢁmol) and
transꢀchalcone (9) (104 mg, 499 ꢁmol) in the presence of iodine (24.7 ꢁmol in reaction mixture,
5.0 mol%). 10 (25.5 mg, 78.4 ꢁmol, 16 %) was also obtained from the same substrates in the
presence of aqueous HI (24.9 ꢁmol in reaction mixture, 5.0 mol%). Melting point: 138–139 °C
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(Lit:28 138–139 °C). H NMR (CDCl3, 400 MHz)
δ
= 3.71 (d, J = 16.7 Hz, 1 H), 3.80 (dd,
5
6
7
8
3
3
4
2J = 16.7 Hz, J = 6.8 Hz, 1 H), 5.06 (t, J = 7.2 Hz, 1 H), 6.95 (d, J = 1.8 Hz, 1 H), 6.98–7.35
3
3
(m, 8 H), 7.39–7.43 (m, 3 H), 7.52 (t, J = 7.4 Hz, 1 H), 7.91 (d, J = 8.4 Hz, 2 H), 7.95 (br s,
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1 H). 13C{1H} NMR (CDCl3, 100 MHz)
δ
= 38.4, 45.4, 111.3, 119.4, 119.5, 119.7, 121.6, 122.3,
126.4, 126.8, 128.0, 128.2, 128.6, 128.7, 133.1, 136.8, 137.3, 144.4, 198.7. IR (neat,
ATR) ꢀꢁ [cm−1] = 3422 (m), 3401 (w), 3080 (w), 3055 (w), 3024 (w), 1661 (s), 1597 (m),
1449 (m), 1337 (m), 1267 (m), 1209 (m) 1098 (m), 737 (s), 685 (s). HR–MS (ESI) [M+Na]+: m/z
calcd for C23H19ONNa+ = 348.1359 found 348.1362. The recorded analytical data matched with
those reported previously.25
3-(5-Methoxy-1H-indol-3-yl)-1,3-diphenylpropan-1-one (12). According to the general
procedure, 12 (91.1 mg, 256 µmol, 51 %) was obtained from 5ꢀmethoxyindole (11) (74.5 mg,
506 µmol) and transꢀchalcone (9) (106 mg, 509 µmol) in the presence of iodine (24.9 ꢁmol in
reaction mixture, 4.9 mol%). 12 (30.3 mg, 85.2 ꢁmol, 17 %) was also obtained using the same
substrate concentrations in the presence of HI (24.9 ꢁmol in reaction mixture, 4.9 mol%).
Melting point: 156–158 °C (Lit:28 157−159 °C). 1H NMR (CDCl3, 300 MHz)
δ = 3.65−3.82 (m,
3
5 H), 5.01 (t, J = 7.1 Hz, 1 H), 6.77−6.80 (m, 1 H), 6.83 (s, 1 H), 6.91 (s, 1 H), 7.12–7.16 (m,
3
3
2 H), 7.24 (7, J = 7.1 Hz, 2 H), 7.33–7.43 (m, 4 H), 7.52 (t, J = 7.1 Hz, 1 H), 7.90–7.93 (m,
13
3 H). C{1H} NMR (CDCl3, 75.5 MHz)
δ = 38.3, 45.3, 55.9, 101.6, 111.9, 112.3, 119.1, 122.3,
126.4, 127.2, 128.0, 128.2, 128.6, 128.7, 131.9, 133.2, 137.2, 144.3, 153.9, 198.8. IR (neat,
ATR) ꢀꢁ [cm−1] = 3362 (m), 3065 (w), 2994 (w), 2928 (w), 2891 (w), 2359 (m), 2342 (m),
1676 (s), 1485 (s), 1304 (m), 1213 (s), 1169 (m), 829 (s), 800 (s), 723 (s). HR–MS (ESI)
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[M+Na]+: m/z calcd for C24H21O2NNa+ = 378.1465 found 378.1468. The recorded analytical data
3
4
5
6
matched with those reported previously.28
7
8
9
10
11
12
13
14
15
16
17
18
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3-(5-Cyano-1H-indol-3-yl)-1,3-diphenylpropan-1-one (16). According to the general
procedure, 16 (39.7 mg, 113 ꢁmol, 23 %) was obtained from 5ꢀcyanoindole (71.1 mg, 500 µmol)
and transꢀchalcone (9) (104 mg, 499 µmol) in the presence of iodine (24.7 ꢁmol in the reaction
mixture, 4.9 mol%). 16 (24.6 mg, 70.2 ꢁmol, 14 %) was also obtained using the same substrate
concentrations in the presence of HI (25.1 ꢁmol in reaction mixture, 5.0 mol%). Melting point:
163–164 °C. 1H NMR (CDCl3, 300 MHz)
δ
= 3.69 (dd, 2J = 16.8 Hz, 3J = 6.6 Hz, 1 H), 3.84 (dd,
3
3
2J = 16.8 Hz, J = 6.6 Hz 1 H), 5.04 (t, J = 7.2 Hz, 1 H), 7.15–7.35 (m, 8 H), 7.45 (t,
3J = 7.2 Hz, 2 H), 7.56 (tt, 3J = 7.4 Hz, 4J = 1.2 Hz, 1 H), 7.73 (s, 1 H), 7.92–7.95 (m, 2 H), 8.32
(br s, 1 H). 13C{1H} NMR (CDCl3, 75.5 MHz)
δ = 38.1, 45.2, 102.7, 112.1, 120.3, 120.9, 123.5,
125.3, 125.5, 126.7, 126.9, 127.8, 128.2, 128.8, 128.9, 133.4, 137.0, 138.4, 143.6, 198.2. IR
(neat, ATR) ꢀꢁ [cm−1] = 3281 (br), 2961 (w), 2920 (w), 2361 (w), 2224 (w), 1670, (m), 1261 (m),
808 (s), 689 (s). HRꢀMS (ESI) [M+Na]+: m/z calcd for C24H18ON2Na+ = 373.1311 found
373.1316. The recorded analytical data matched with those reported previously.29
General Procedure for HPLC Analysis. For these experiments, a deactivating agent has been
prepared by stirring approx. 2.7 g of a mixing containing silica (80 wt%), Na2S2O3 (10 wt%), and
Na2CO3 (10 wt%) in 25 mL water. After removal of water under reduced pressure and elevated
temperatures, a highly reactive deactivation agent was obtained which effectively decolorizes
iodine solutions during filtration and neutralizes acidic solutions. For the Michael additions,
electrophile 3 was dissolved in the desired solvent and a solution of indole (4) and Ph2O in the
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chosen solvent was added at 23 °C. The reaction was started by addition of an iodine solution. In
5
6
the reaction mixture, concentrations of both reactants were approx. 0.5
M each whereas the
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9
catalyst concentration was approx. 25 m (5 mol%). After 3 minutes, a small sample (~20–50
M
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µL) is diluted with isoꢀpropanol (2 mL) and transferred onto a small column charged with cotton
and the deactivation agent described above. After elution with isoꢀpropanol (8 mL) the filtrate
was used for HPLC measurements. The fraction of product 5 was determined in relation to the
internal standard Ph2O.
Corresponding Author
*mbreugst@uniꢀkoeln.de
Acknowledgment
Financial support from the Fonds der chemischen Industrie (Liebig scholarship to M.B. and
Ph.D. scholarship to D.v.d.H.) and the DFG (Heisenberg scholarship to M.K., KL 2221/4ꢀ2) is
gratefully acknowledged. We thank Prof. Dr. Albrecht Berkessel and his group for support.
Supporting Information.
The following files are available free of charge.
Details of the experimental procedures, copies of NMR spectra
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References
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6
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8
(1)
(a) Banerjee, A. K.; Vera, W.; Mora, H.; Laya, M. S.; Bedoya, L.; Cabrera, E. V. J Sci
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S.; Borah, R.; Devi, R. R.; Thakur, A. J. Synlett 2008, 2741–2762; (d) Jereb, M.; Vražič,
D.; Zupan, M. Tetrahedron 2011, 67, 1355–1387; (e) Parvatkar, P. T.; Parameswaran, P.
S.; Tilve, S. G. Chem. Eur. J. 2012, 18, 5460–5489; (f) Ren, Y.ꢀM.; Cai, C.; Yang, R.ꢀC.
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(3)
Hibbert, H. J. Am. Chem. Soc. 1915, 37, 1748–1763.
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Lin, C.; Hsu, J.; Sastry, M. N. V.; Fang, H.; Tu, Z.; Liu, J.ꢀT.; ChingꢀFa, Y. Tetrahedron
2005, 61, 11751–11757.
(4)
for selected reviews, see: (a) Halogen Bonding I; Metrangolo, P.; Resnati, G., Eds.;
Springer, 2015; (b) Halogen Bonding II; Metrangolo, P.; Resnati, G., Eds.; Springer,
2015; (c) Cavallo, G.; Metrangolo, P.; Milani, R.; Pilati, T.; Priimagi, A.; Resnati, G.;
Terraneo, G. Chem. Rev. 2016, 116, 2478–2601; (d) Bulfield, D.; Huber, S. M. Chem.
Eur. J. 2016, 22, 14434–14450; for selected examples, see: (e) Walter, S. M.; Kniep, F.;
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Mode of Activation in Iodine Catalysis
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HalogenꢀBond Activation
BrønstedꢀAcid Activation
ꢀ
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R‘
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