A simple, direct synthesis of 3-vinylindoles from the carbocation-catalysed dehydrative cross-coupling of ketones and indoles. A combined experimental and computational study

Article abstract of DOI:10.1016/j.tet.2018.11.073

A straightforward synthesis of a library of largely new 3-vinylindoles via a clean dehydrative coupling reaction between ketones and indoles has been developed. Highly stable, non-nucleophilic aryl(2-methylindol-3-yl)methylium salts have been used as effi

Full text of DOI:10.1016/j.tet.2018.11.073

Accepted Manuscript
A simple, direct synthesis of 3-vinylindoles from the carbocation-catalysed
dehydrative cross-coupling of ketones and indoles. A combined experimental and
computational study
Margherita Barbero, Stefano Dughera, Sara Alberti, Giovanni Ghigo
PII:
S0040-4020(18)31463-7
https://doi.org/10.1016/j.tet.2018.11.073
TET 29984
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 8 November 2018
Revised Date: 29 November 2018
Accepted Date: 30 November 2018
Please cite this article as: Barbero M, Dughera S, Alberti S, Ghigo G, A simple, direct synthesis of
3-vinylindoles from the carbocation-catalysed dehydrative cross-coupling of ketones and indoles. A
combined experimental and computational study, Tetrahedron (2019), doi: https://doi.org/10.1016/
j.tet.2018.11.073.
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ACCEPTED MANUSCRIPT
A simple, direct synthesis of 3-vinylindoles from the carbocation-catalysed
dehydrative cross-coupling of ketones and indoles. A combined experimental
and computational study.
Margherita Barbero,* Stefano Dughera, Sara Alberti, Giovanni Ghigo*
Dipartimento di Chimica, Università di Torino, Via P. Giuria 7, 10125 Turin, Italy
Corresponding authors: tel. +39-011-6707645, e-mail margherita.barbero@unito.it; tel. +39-
011-6707872, e-mail giovanni.ghigo@unito.it
Graphical abstract:
Abstract: A straightforward synthesis of a library of largely new 3-vinylindoles via a clean
dehydrative coupling reaction between ketones and indoles has been developed. Highly stable, non-
nucleophilic aryl(2-methylindol-3-yl)methylium salts have been used as efficient Lewis acid
catalysts. The advantages of the reaction are the use of equimolar amounts of inexpensive and easily
available reagents, the low catalyst amount, high atom efficiency, the production of only one
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molecule of water as a by-product and the mild reaction conditions. Computational studies of two
specific reaction mechanism instances show that both steric and electronic effects heavely influence
the nature of the final products, whether a methyl group in position 2 of the indole is present or
absent.
Keywords: Stable carbocations, Lewis acid catalysis, Dehydrative coupling, 3-Vinylindoles, DFT
calculations
1. Introduction
Indoles are one of the most widespread heterocycles to be found in natural products and are often
endowed with biological activity.1-5 The synthesis and functionalization of indole derivatives are
still challenging goals with these species being referred to as “privileged structures”,6 in a large
number of drugs.7-17 One of these structure groups, 3-(α-aryl)vinylindoles, features the 1-aryl-1-
heteroarylethene scaffold, which is often found in molecules that show strong biological
activity.18,19 Furthermore, 3-vinylindole and its derivatives have been used as elaborate building
blocks in the asymmetric synthesis of substituted indoles.20
Most of the methods for the synthesis of 1-aryl-1-(indol-3-yl)ethenes involve expensive reagents or
metal-catalysed procedures and preformed 3-acylindoles or 3-bromoindoles (Scheme 1). The most
recent metal-involving methods include the alkenylation of 3-bromoindoles with proper
organostannanes,21 indole gold- or indium-catalysed alkenylation with alkynes,22,23 the nickel-
catalysed addition of arylboron reagents to ketones,24 the use of Nysted reagent and the Peterson
olefination of indolyl ketones,25 and the Suzuki–Miyaura coupling of 1-indolylvinyl phosphates,26
while the most general protocols are based on the addition of Grignard reagents to ketones,
followed by dehydration, or on Wittig olefination by methyl triphenylphosponium ylide.27 On the
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contrary, metal-free procedures comprehend the dehydrative coupling of indoles with ketones
catalysed by Brønsted acid28 or Brønsted acidic ionic liquids29 and the metal-free formal C(sp2)–
C(sp2) cross-coupling of indoles with nitrimines.30 3-Vinylindoles have also been formed as key
intermediates in multicomponent reactions between indoles, ketones and a nucleophile,31-34 and in
multistep reactions.35,36
Scheme 1: Previous procedures for the synthesis of 3-(α-aryl)vinylindoles.
Our research interest in indole37-39 and carbocation chemistry40-43 has driven us to explore the
synthetic potential of highly stabilised benzhydrylic cations, which we have recently reported
on,41,40 as Lewis acid catalysts in indole functionalisation. Like all other Lewis acids, carbocations
have a low-lying empty pC orbital, that can accept electrons and therefore activate an electrophile
towards nucleophilic attack.
Mukaiyama and co-workers reported the very first carbocation-catalysed reactions,44 and stable
carbocations, such as tritylium ions, have been frequently investigated for use as organic Lewis acid
catalysts eversince. The most recent applications of this type of catalysts are: intramolecular
carbonyl-ene cyclization and [2+2]cycloaddition,45 the hydrothiolations of di- and trisubstituted
olefins,46 the three component redox-neutral α-arylation of amines,47 the Michael-type Friedel–
Crafts reaction of indoles with α,β-unsaturated carbonyl compounds,48 the chiral anion directed
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asymmetric Diels–Alder reaction,49 asymmetric latent carbocation catalysis in Friedel−Crafts
alkylation, hetero-Diels−Alder and carbonyl-ene reactions,50 the Povarov reaction,51 carbonyl/olefin
oxo-metathesis,52 oxa-Diels−Alder reactions,53 and heterocycle synthesis.54,55 Comprehensive
reviews on earlier works have been published by Franzen,56,57 who mentioned the use of tritylium
salts as Lewis acids in Mukaiyama aldol and Sakurai allylation reactions, as well in Diels–Alder,
aza Diels−Alder and Michael reactions.
Tritylium salts were either used as commercially available reagents or generated in situ in the
above-mentioned reports. As an alternative to these options, we have decided to test our air-stable
aryl (2-methylindol-3-yl)methylium salts, which can be easily prepared in high yields and stored for
significant amounts of time without decomposition (some months at 5°C) (Scheme 2). The
diarylcarbenium ion can be stabilized by positive charge resonance delocalization both onto the
phenyl and the indole rings, as reported for salt 1a in Scheme 2. Bond distances obtained by X-ray
analysis of 1a clearly agree with the resonance structure III. The resonance structure II is however
responsible of the reactivity of these species, as previously reported by us in an organocatalysed
asymmetric α−alkylation of aldehyde43 and in a diastereoselective alkylation of cyclic silyl enol
ethers.42
Scheme 2: Synthetic procedure for preparing salts 1 and resonance structures of salt 1a.
The great stability of these indolyl-stabilised carbocations has also been confirmed by their
electrophilicity values, as tabulated by Mayr.58
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Indole alkyation normally occurs via electrophilic aromatic substitution and predominantly affords
3-alkyl derivatives. We have previously reported on a triarylmethane synthesis that was performed
via a Brønsted acid-catalysed bisarylation (or bisheteroarylation) of activated aryl aldehydes. The
reaction followed a multistep Friedel–Crafts type hydroxyalkylation in which the diarylmethanol
intermediate immediately reacted with another equivalent of the arene, giving rise to a bisarylation
product.37 We herein report a new synthesis of 3-(α-aryl)vinylindoles that is based on a clean
dehydrative coupling reaction between simple, cheap ketones 2 and nucleophilic aromatics 3 in the
presence of catalytic amounts of either (4-methoxyphenyl) or (4-nitrophenyl)(2-methyl-3-
indolyl)methylium tetrafluoroborate as Lewis acid catalysts (1a and 1b, respectively, Scheme 3).40
This direct coupling approach has only been reported once in the literature, giving excellent results
in the presence of catalytic amounts of Brønsted acid ionic liquids that contained a sulfonic group.29
Scheme 3: Dehydrative coupling reaction of ketones 2 with nucleophiles 3
The dehydrative coupling products 4 were isolated in good yields in most cases. The reaction also
benefits from high atom efficiency and produces only one molecule of water as a by-product.
2. Results and discussion
We decided that the reference reaction would be the coupling of 4-nitroacetophenone (2a) and 2-
methylindole (3a) in a 1:1 molar ratio, in the presence of catalytic amounts of the above salts (1a or
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1b) and varying experimental conditions (Table 1). The variables taken into consideration are
solvent, temperature, reaction time, and catalyst type and amount.
Neat conditions were initially tested and were found to be quite advantageous, although the
formation of a very thick reaction mixture led to incomplete reactions both at rt (even after
prolonged reaction times) and under heating (Table 1, entries 1−6). Furthermore, the catalyst
amount was varied from 3 to 5 mol% (entries 2 and 3); no significant differences in the use of salts
1a (entries 1−3) and 1b (entries 4−6) were observed. Neat conditions were then extended to the
reactions of 3a with some representative acetophenones, namely 2b, 2f and 2g (entries 7−10).
While the results were unsatisfactory, except for the reaction of 2b (entry 7), they highlighted the
strong substituent effect and confirmed that, in the reaction of unactivated 2g, the two catalysts
showed identical performance (entries 9 and 10).
Then, the reference reaction was run in a solvent. Only traces of product were detected in
dichloromethane under reflux in the presence of 10 mol% of salt 1b (Table 1, entry 11). Finally, the
model reaction was performed in MeOH in order to achieve reaction completion, as it is well-
known that protic solvents stabilize carbocations. The reaction went to completion in 6 h at room
temperature and furnished product 4a under milder conditions and in better yield than previous
reactions (entry 12).
A pilot run in methanol without catalyst did not give reaction (entry 13).
Table 1: Optimisation conditions of the dehydrative coupling reaction of ketones 2 with 2-
methylindole (3a)a :
O
1a or 1b cat
R
R
+
NH
N
H
3a
2a, R=4-NO2
2b, R=4-CN
2f, R=H
4a, R=4-NO2
4b, R=4-CN
4h, R=H
2g, R= 4-Me
4i, R= 4-Me
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Entry Ketone
Catalyst
(mol%)
1a (3)
1a (3)
1a (5)
1b (3)
1b (3)
1b (3)
1a (3)
1a (5)
1a (3)
1b (3)
1b (10)
1a (5)
-
solvent
t(h)
T(°C)
Yield (%)b
4a; 60c
neat
neat
neat
neat
neat
neat
neat
neat
neat
neat
DCM
24
rt
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2b
2f
1
1
90
110
rt
4a; 70c
4a; 51
4a; 70c
4a; 58
4a; 74c
4b; 74
4h; traces
4i; 30
24
1
60
90
90
90
60
60
reflux
rt
1
1
7
24
24
10
6
9
2g
2g
2a
2a
2a
4i; 30
10
11
12
13
4a; traces
4a; 76
-
anhydrous MeOH
anhydrous MeOH
24
rt
a Reaction conditions: 2:3 =1:1, on a 2 mmol scale.
b Yields refer to isolated products purified by column chromatography (eluent PE/acetone 85:15)
c Incomplete reaction.
The optimised reaction conditions (catalyst 1a, 5 mol%, anhydrous methanol as solvent) were then
applied to a number of acetophenones (substituted and not) and other representative ketones.
The list of tested acetophenones 2a−i, and cyclic ketone 2j, is reported in Chart 1, while that of
aromatic and heteroaromatic compounds that reacted as nucleophiles can be found in Chart 2.
Finally, Table 2 reports the results of the tested reactions, purified products 4a−4l, reaction
conditions and isolated yields.
Chart 1: Ketones 2a−j tested in the dehydrative coupling reaction.
Chart 2: Aromatic and heteroaromatic compounds 3a−g tested as nucleophiles in the
dehydrative coupling reaction with ketones 2.
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As observed in the trial runs, the reactions with 2-methylindole (3a) proceeded under milder
reaction conditions in the presence of electron-withdrawing subtituents than when electron-donating
groups were present. The effect that substituents have on the activation of the carbonyl group
towards nucleophilic attack is noticeable. In fact, products 4a−d were obtained in good yields at rt
(yield range 70−85%; Table 2, entries 1−4), whereas the reactions of the less activated ketones 2f−g
needed to be heated at reflux and gave modest yields of 4h and 4i (59 and 54%, respectively; entries
8−9). The reaction of ketone 2g was also carried out in the presence of salt 1b, although no yield
improvements were observed. In addition to the low reactivity shown by ketone 2g, the nucleophilic
solvent was observed to have attacked the catalyst 1b (entry 9; see further in the discussion).
Table 2: Dehydrative coupling reaction of ketones 2 with nucleophiles 3 in the synthesis of 3-
(α-aryl)vinylindoles 4.
Entry Ketones 2 Nucleophiles 3 T °(C) T (h) Products 4 and yields (%)a
1
rt
6
2a
3a
4a; 76%
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2
3
4
5
6
7
rt
4.5
2b
2c
2d
2a
2d
2e
3a
3a
3a
3b
3b
3a
NC
N
H
4b; 85%
4c; 78%
4d; 70%
4e; 85%b
4f; 65%b
rt
4
F3C
N
H
rt
6.5
4.5
4
rt
rt
65
30
4g; 65%c
8
9
65
65
5.5
4
2f
3a
3a
4h; 59%
2g
4i; 54%d
e
10
11
65
rt
24
-
2h
2i
3a
3a
H
2.5
N
O
4j; 65%f
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12
13
rt
24
2i
2j
3a
3a
4k; 34%g
65
8
4l; 68%
e
h
e
-
14
15
16
17
18
rt
6
2a
2a
2a
2a
2a
3e
3e
3f
3f
3g
-
65
rt
4
3
-
-
-
e
e
65
rt
6
20
a Reactions were performed on a 2 mmol scale in a molar ratio 2:3 =1:1 in the presence of catalyst 1a (5% mol with
respect to 2, unless otherwise stated), in anhydrous methanol (5 mL), without the exclusion of air or moisture. Reaction
conditions (time, temperature and yield) for each vinylindole 4 are reported. Yields refer to products purified by column
chromatography. See experimental section for details.
b Product separated from the reaction mixture. The solid washed thoroughly with PE was virtually pure.
c Reaction was carried out at rt but with less satisfactory results.
d Reaction was carried out at a molar ratio 2:3 = 1:1.2. Furthermore, the reaction was run in the presence of 1b as the
catalyst, but without giving a better yield; furthermore, the nucleophilic solvent was observed to have attacked the
catalyst 1b; see text for details.
e No products 4 were obtained. GC-MS analyses showed the formation of 4-nitroacetophenone dimethylacetal.
f The molar ratio was 2:3=2:1. Traces of 4k were also isolated.
g The molar ratio was 2:3=1:3 and the catalyst 10% mol. Product 4j was also isolated along with 4k (54% yield).
h GC-MS analyses of the reaction mixture showed a complex mixture of products among which expected product MS
(EI): m/z 228 (M+) in traces and 4-nitroacetophenone dimethylacetal (5) MS (EI): m/z 196 (M+) were detected.
The scope of the reaction was then evaluated by reacting 2a and 2d with 1,2-dimethylindole (3b);
products 4e and 4f were isolated in yields that are comparable with those of 4a and 4d (entries 5−6).
The steric effect was investigated by reacting ortho-substituted ketone 2e with 3a; 4g was obtained,
although after prolonged heating and in a lower yield than the para-substituted product (entry 7).
Highly unactivated ketone 2h did not even give traces of the expected product (entry 10).
1,4-Diacetylbenzene (2i), a ketone that is potentially interesting for dehydrative coupling, was then
reacted under the optimised reaction conditions. The presence of two carbonyl groups meant that
the number of nucleophile equivalents was changed in order to give the monovinyl (4j) and the
divinyl (4k) adducts (molar ratio 2i:3a=2:1 or 1:3, respectively, catalyst loading was 10 mol% in
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the latter case). Unfortunately, the concomitant formation of both compounds was observed in both
reactions. After chromatographic purification, 4j was isolated as the predominant product at the first
molar ratio (65% yield, accompanied by only traces of 4k), whilst a mixture of 4j and 4k was
obtained at the second molar ratio (54% and 34% yields, respectively; entries 11−12).
Finally, a cyclic ketone was tested. Bulky 1-tetralone (2j) was reacted with 2-methylindole (3a); the
corresponding product 4l was obtained in quite good yield (entry 13).
We attempted to extend the scope of the reaction by including nucleophiles that are not indoles.
Several trial reactions were carried out using ketone 2a with 1-methylpyrrole (3e), 1,2,4-
trimethoxybenzene (3f) and 3-methoxyphenol (3g) as the nucleophiles, while reaction temperature
and time were varied (entries 14−18). Unfortunately, only 4-nitroacetophenone dimethylacetal (5)
was detected by GC-MS analyses.
Intrigued by the finding of entry 9, where a nucleophilic solvent attack on the catalyst 1b was
observed, we decided to analyse the respective stabilities of salts 1a and 1b in our reaction
conditions and a significant difference in stability was observed. Whilst salt 1a seemed to remain
unaltered in the unsuccessful reactions, salt 1b quickly disappeared, even at room temperature. TLC
analyses of the reaction mixture showed a spot that we believe to be a product of the solvent’s
nucleophilic attack on catalyst 1b (more electrophilic than 1a). This product’s formation was
confirmed, first by monitoring the stability of salts 1a and 1b in CD3OD in NMR tubes, and then by
stirring 1a and 1b in methanol at room temperature (see details in the experimental section). After 6
h, the first of the salts was almost completely recovered unaltered, whereas in the latter case, the
reaction was stopped after 20 min (disappearance of the salt); reaction work-up and
chromatographic purification furnished adduct 6 in a 76% yield (Scheme 4). This finding could
open up new synthetic opportunities for our salts with other nucleophilic partners.
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Scheme 4: Formation of product 6
The stability of 1a was further tested by running reaction between 2a and 3a four months after its
preparation; product 4a was obtained in the same reaction conditions with the same yield, clearly
showing no loss of catalytic efficiency. Furthermore, the scalability of the proposed synthetic
method was tested in the same reaction on a 10 mmol scale; the reaction was complete after 6 h at
rt, product 4a was obtained in 77% yield.
After the screening of the above nucleophiles, several trials were performed on unsubstituted indole
(3c) and 1-methylindole (3d). Reaction with ketone 2a did not give the expected dehydrative
coupling products under the usual reaction conditions. The only isolated products were the
dimethylacetal of 2a (namely 5) and adducts 7a and 7b, which were produced by the reaction of 2a
with two equivalents of indole. Under these non-optimised conditions, the isolated yields were 76%
and 86% for 7a and 7b, respectively (Scheme 5; for details, see experimental section).
Scheme 5: Reactions of 2a with indoles 3c and 3d.
O2N
R'
N
O
1a cat
rt, 24 h
O2N
+
O
O
O2N
+
N
R'
N
R'
2a
3c, R'=H; 3d, R'=Me
5
7a, R'=H; 76% yield.
7b, R'=Me; 86% yield
A comparison with the literature59-62 suggests that these findings can be explained by a lack of steric
hindrance at C-2, which favours a second reaction with the nucleophile, after the first
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hydroxyalkylation step, rather than the dehydration step. A competing reaction mechanism can
therefore be proposed when indole (or 1-methylindole) is the nucleophile; the reaction pathway
relies on the absence of either steric hindrance59-62 or the stabilising effect of a substituent,63 in the
C-2 position of the indole, as illustrated in Scheme 3 (Scheme 6; Path B).
Scheme 6: Competitive mechanisms in the dehydrative coupling of ketones 2 with indoles 3.
The reaction follows a well-known Lewis-acid-catalysed Friedel−Crafts type hydroxyalkylation
reaction. In order to better rationalise the experimental findings, a computational method was used
to study the reaction mechanism, as reported in Scheme 6, for the reactions of 2a with 3a (the
energy profiles are shown in Figure 1a, and the reaction mechanism in Scheme 1a in the
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Supplementary Data) and with 3c (Figure 1b, and Scheme 1b in the Supplementary Data) in the
presence of 1a, used as the catalyst. The predictable products of paths A and B are shown in
Scheme 7. All energy values and pictures of the structures are reported in the Supplementary Data.
Scheme 7: Predictable products of the reaction of 2a with 3a (4a and 7c) and with 3c (4m and
7a) using 1a as the catalyst.
In both cases, the rate-determining step is the Friedel−Crafts electrophilic attack of the ketone,
activated by the catalyst, on the indole to form intermediates A. Throughout a proton transfer
+
mediated by the solvent (MeOH/MeOH2 ), intermediates B break into catalyst 1a forming
intermediates C. The alternative breakings from B (reported only in Figures 1a and 1b) to D plus
the hydroxylated catalyst (1a−OH) are thermodynamically unfavoured. The generation of cations D
+
requires the protonation of intermediates C by the solvent. MeOH2 is generated by the following,
almost isoergic, equilibrium (eq. 1):
Two pathways open up once carbeniums D have been irreversibly generated. Path A sees prompt
deprotonation generate alkenes 4a, when the indole is 3a, and 4m, when the indole is 3c. Path B
sees the electrophilic attack on a second indole molecule generate intermediates E whose
deprotonation finally generates adducts 7c, when the indole is 3a, and 7a, when the indole is 3c.
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All the kinetic rate constants for all the reactions in paths A and B are in the order of min-1 or
higher. This means that, due to the long reaction times (hours), the reactions that generate alkenes 4
and adducts 7 are subjected to thermodynamic control.
In the reaction of 2a with indole 3a, alkene 4a is 4.3 kcal mol-1 more stable than the reactants in
terms of energy and 1.5 kcal mol-1 in terms of free energy, while adduct 7c is 14.0 kcal mol-1 more
stable than the reactants in terms of energy but 1.6 kcal mol-1 less stable than the reactants in terms
of free energy. This means that the alkene 4a is thermodynamically favoured, as was observed
experimentally. The rate of the estimated equilibrium constants, K4a/K6c, is 184; only traces of 7c
are expected to be formed.
When the indole is 3c, alkene 4m is 3.8 kcal mol-1 more stable than the reactants in terms of energy
and 1.7 kcal mol-1 in terms of free energy while the adduct 7a is 20.1 kcal mol-1 more stable than
the reactants in term of energy and 5.1 kcal mol-1 in term of free energy. This means that, although
both products are thermodynamically possible, adduct 7a is favoured, as is coherent with
experimental findings. The rate of the estimated equilibrium constants, K6a/K4m , is 295; now it is
4m that is only estimated to be formed in traces.
The protonated solvent generated in the deprotonations of D or E reacts with 1a‒OMe regenerating
the catalyst.
We provide a detailed comparison and discussion of the two energy profiles in the Supplementary
Data. On the basis of the data, we propose an explanation of the different energies of the final
products and, therefore, of the different outcomes shown by the reactions of 2a with 3a and 3c.
Herein, we only report that both the steric and the stabilising electronic effects shown by the methyl
group, which is present in position 2 of indole 3a and absent in 3c, must be taken into account, and
that the electronic effect plays a predominant role.
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Figure 1a: Energy (∆E = ∆Eel+∆ZPE)a and free energy (∆G at room temperature)b profilesc
for the reaction of 2a with 3a, with 1a as the catalyst.d
a Dashed lines. b Thick solid lines. c All energies are referred to that of the reactants. d See Scheme 3 or Scheme 1a in the
Supplementary Data for the labels.
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Figure 1b: Energy (∆E = ∆Eel+∆ZPE)a and free energy (∆G at room temperature)b profilesc
for the reaction of 2a with 3c, with 1a as the catalyst.d
a Dashed lines. b Thick solid lines. c All energies are referred to that of the reactants. d See Scheme 3 or Scheme 1b in the
Supplementary Data for the labels.
3. Conclusions
In this paper, we have reported the first application of highly stable, non-nucleophilic aryl(indol-3-
yl)methylium salts for use as Lewis acid catalysts in a clean dehydrative coupling reaction between
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selected ketones and indoles to give 3-vinylindoles. The advantages of this reaction are the use of
equimolar amounts of inexpensive and easily available reagents, the low amounts of the stable and
efficient catalyst used, the high atom efficiency, the production of only one molecule of water as a
by-product and the mild reaction conditions. This simple and mild procedure has produced a library
of largely new 3-(α-aryl)vinylindoles in modest to good yields. The formation of unexpected
products has been explained. The explanation for the different outcomes that are observed in the
reactions of 2a with 3a (and presumably 3b) and with 3c (and presumably 3d) is based on the fact
that the methyl group, which is present in position 2 of indole 3a and absent from 3c, acts both with
steric effect in all intermediates and with stabilizing electronic effect on carbeniums only. The
presence (or lack) and the relative relevance of these two factors are responsible for the formation
of alkene 4a, when 2a reacts with 3a, and that of adduct 7a, when 2a reacts with 3c. Further
detailed research into the synthetic applicability of these salts, both as Lewis acid catalysts and as
electrophilic reagents, is currently underway.
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.
1H NMR and 13C NMR spectra were recorded in CDCl3 on a spectrometer at 200 MHz and 50
MHz, respectively. 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), coupling constants (Hz), and
integration. TLC were performed on silica gel TLCPET foils GF 254, 2–25 ꢀm, layer thickness 0.2
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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. Catalysts 1a and 1b
were prepared as reported in literature.40 Room temperature (20−25 °C) is abbreviated as rt. Yields
1
for pure (GC, GC-MS, TLC, H NMR) isolated products are listed in Table 2. The structure and
purity of all new products were determined by elemental analyses, ESI, 1H and 13C NMR and DEPT
spectra. The structure and purity of known products were confirmed by comparing their physical
and spectral data (MS, 1H and 13C NMR) with those reported in the literature.
4.2. Dehydrative Coupling: representative procedure for the synthesis of products 4.
Catalyst 1 (5 mol%) was added to a solution of ketone 2 (2.0 mmol) and aromatic compound 3 (2.0
mmol) in anhydrous methanol (5 mL) under stirring. The reaction mixture was then stirred in an air
atmosphere, at either room temperature or reflux (65 °C), as reported in Table 4. Upon completion,
the reaction mixture was treated with H2O/ DCM (1:1, 30 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-(4-nitrophenyl)ethenyl]-1H-indole (4a).
Chromatographic purification (PE/Acetone 85:15) gave 4a as a yellow solid; 0.42 g, (76% yield);
1
mp 106.5−107.5 °C (DCM/PE); H NMR (200 MHz, CDCl3) δ 2.25 (s, 3H), 5.47 (d, J = 1.4 Hz,
1H), 5.82 (d, J = 1.0 Hz, 1H), 6.91–7.16 (m, 3H), 7.27 (d, J = 7.8 Hz, 1H), 7.49 (d, J = 11.0 Hz,
2H), 8.10 (d, J = 11.2 Hz, 2H) overlapped with 8.08 (br s, 1H); 13C NMR (50 MHz, CDCl3): δ 12.6
(CH3), 110.2 (CH), 112.6 (C), 118.2 (CH2), 119.0 (CH), 119.8 (CH), 121.4 (CH), 123.4 (2 x CH),
127.7 (C), 127.9 (2 x CH), 133.3 (C), 135.0 (C), 140.8 (C), 146.9 (C), 148.3 (C); IR ν (cm-1) 3381,
19

ACCEPTED MANUSCRIPT
1587, 1510, 1343, 858, 748; MS m/z (%) 278 [M+](100), 231 (65), 217(90); Anal. Calcd for
C17H14N2O2: C, 73.37; H, 5.07; N, 10.07. Found C, 73.32; H, 5.10; N,10.11.
4.2.2. 3-[1-(4-Cyanophenyl)ethenyl]-2-methyl-1H-indole (4b).
Chromatographic purification (PE/Acetone 90:10) gave 4b as a pale grey solid; 0.44 g (85% yield):
1
mp 185−186 °C (DCM/PE); H NMR (200 MHz, CDCl3) δ 2.38 (s, 3H), 5.42 (d, J = 1.4 Hz, 1H),
5.77 (d, J = 1.4 Hz, 1H), 6.94–7.12 (m, 3H), 7.24–7.29 (m, 1H), 7.43 (d, J = 8.8 Hz, 2H), 7.53 (d, J
13
= 9.8 Hz, 2H), 8.03 (br s, 1H); C NMR (50 MHz, CDCl3) δ 12.6 (CH3), 110.2 (CH), 112.6 (C),
112.6 (C), 117.5 (CH2), 118.9 (C), 119.1 (CH), 119.7 (CH), 121.4 (CH), 127.7 (2 x CH), 131.9 (2 x
CH), 133.3 (C), 135.0 (C), 141.0 (C), 141.4 (C) , 146.3 (C); IR ν (cm-1) 3327, 2238, 1502, 1457,
899, 846, 738, 572; MS m/z (%) 258 [M+](85), 243 (100); Anal. Calcd for C18H14N2: C, 83.69;
H, 5.46; N, 10.84. Found C, 83.60; H, 5.40; N, 10.87.
4.2.3. 3-[1-(4-Trifluoromethylphenyl)ethenyl]-2-methyl-1H-indole (4c).29
Chromatographic purification (PE/Acetone 90:10) gave 4c as a white solid; 0.47 g (78% yield): mp
83.5−84.5 °C (DCM/PE); 1H NMR (200 MHz, CDCl3) δ 2.24 (s, 3H), 5.42 (d, J = 1.6 Hz, 1H), 5.78
(d, J = 1.6 Hz, 1H), 6.95–7.20 (m, 3H), 7.24−7.29 (m, 1H), 7.47 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.6
13
Hz, 2H), 7.89 (br s, 1H); C NMR (50 MHz, CDCl3) δ 12.6 (CH3), 110.2 (CH), 113.1 (C), 116.7
(CH2), 119.3 (CH), 119.7 (CH), 121.3 (CH), 124.2 (C, q, J1 = 270 Hz), 125.0 (CH, q, J3 =3.8 Hz),
127.4 (CH), 127.9 (C), 129.6 (C, q, J2= 33.0 Hz), 133.2 (C), 135.0 (C), 141.3 (C), 145.3 (C); MS
m/z (%) 301 [M+](100), 286 (75), 217 (50).
4.2.4. 3-[1-(4-Chlorophenyl)ethenyl]-2-methyl-1H-indole (4d).29
Chromatographic purification (PE/Acetone 85:15) gave 4d as a white solid; 0.37 g (70% yield): mp
1
127.5−128.5 °C (DCM/PE); H NMR (200 MHz, CDCl3) δ 2.24 (s, 3H), 5.30 (d, J = 1.9 Hz, 1H),
20

ACCEPTED MANUSCRIPT
5.68 (d, J = 1.9 Hz, 1H), 6.97–7.09 (m, 1H), 7.13−7.32 (m, 3 H) overlapped with 7.22 (d, J = 8.4,
2H) and 7.29 (d, J = 8.6 Hz, 2H), 7.87 (br s, 1H); 13C NMR (50 MHz, CDCl3) δ 12.7 (CH3), 110.1
(CH), 113.4 (C), 115.2 (CH2), 119.4 (CH), 119.6 (CH), 121.2 (CH), 128.0 (C), 128.2 (2 x CH),
128.5 (2 x CH), 133.1 (2 x C), 134.9 (C), 140.2 (C), 141.2 (C); MS m/z (%) 267 [M+](75), 231
(55), 217 (100).
4.2.5. 1,2-Dimethyl-3-[1-(4-nitrophenyl)ethenyl]indole (4e).
The product separated from the reaction mixture, it was collected under vacuum and washed
thoroughly with PE to give virtually pure 4e as a pale yellow solid; 0.50 g (85% yield): mp
1
144.0−144.8 °C (DCM/PE); H NMR (200 MHz, CDCl3) δ 2.24 (s, 3H), 3.68 (s, 3H), 5.44 (br s,
1H), 5.83 (br s, 1H), 6.91–6.98 (m, 1H), 7.05−7.16 (m, 2H), 7.24−7.28 (m, 1H), 7.48 (d, J = 8.6 Hz,
2H), 8.09 (d, J = 8.6 Hz, 2H); 13C NMR (50 MHz, CDCl3) δ 11.3 (CH3), 29.6 (CH3), 108.7 (CH),
112.0 (CH2), 118.2 (C), 119.0 (CH), 119.5 (CH), 121.0 (CH), 123.4 (2 x CH), 126.9 (C), 127.8 (2 x
CH), 135.1 (C), 136.5 (C), 141.1 (C), 146.9 (C), 148.5 (C); IR ν (cm-1) 1593, 1507, 1343, 864, 736;
MS m/z (%) 292 [M+](100), 245 (70), 231 (78); Anal. Calcd for C18H16N2O2: C, 73.95; H, 5.52;
N, 9.58. Found C, 73.89; H, 5.49; N, 9.51.
4.2.6. 3-[1-(4-Chlorophenyl)ethenyl]-1,2-dimethylindole (4f).64
The product separated from the reaction mixture, it was collected under vacuum and washed
thoroughly with PE to give virtually pure 4f as a white solid; 0.36 g (65% yield): mp 102.0−102.5
°C (DCM/PE); 1H NMR (200 MHz, CDCl3) δ 2.24 (s, 3H), 3.67 (s, 3H), 5.27 (br s, 1H), 5.69 (br s,
1H), 6.92–6.99 (m, 1H), 7.13−7.31 (m, 3 H) overlapped with 7.20 (d, J = 8.6, 2H) and 7.29 (d, J =
8.6 Hz, 2H); 13C NMR (50 MHz, CDCl3) δ 11.3 (CH3), 29.5 (CH3), 108.5 (CH), 112.8 (C), 115.1
(CH2), 119.3 (CH), 120.8 (CH), 127.2 (C), 128.1 (2 x CH), 128.4 (2 x CH), 128.7 (CH), 133.0 (C),
21

ACCEPTED MANUSCRIPT
134.9 (C), 136.5 (C), 140.4 (C), 141.6 (C); MS m/z (%) 281 [M+](100), 266 (40), 245 (90), 231
(100).
4.2.7. 2-Methyl-3-[1-(2-nitrophenyl)ethenyl]-1H-indole (4g).
Chromatographic purification (PE/Acetone 85:15) gave 4g as a yellow solid; 0.36 g (65% yield) :
1
mp 177.0−177.9 °C (DCM/PE); H NMR (200 MHz, CDCl3) δ 2.17 (s, 3H), 5.45 (s, 1H), 5.48 (s,
1H), 6.86–7.06 (m, 3H), 7.14−7.20 (m, 1H), 7.34−7.42 (m, 1H), 7.50−7.55 (m, 2H), 7.67 (d, J = 7.8
Hz, 1H), 7.91 (br s, 1H); 13C NMR (50 MHz, CDCl3) δ 12.5 (CH3), 110.2 (CH), 112.1 (CH2),
116.4 (C), 118.7 (CH), 119.8 (CH), 121.2 (CH), 123.7 (CH), 127.4 (C), 128.1 (CH), 131.4 (CH),
132.1 (CH), 133.6 (C), 134.8 (C), 138.1 (C), 139.5 (C), 149.3 (C); IR ν (cm-1) 3422, 1522, 1456,
1353, 890, 742, 498; MS m/z (%) 278 [M+](65), 219 (100); Anal. Calcd for C17H14N2O2: C,
73.37; H, 5.07; N, 10.07. Found C, 73.30; H, 5.02; N,10.12.
4.2.8. 2-Methyl-3-(1-phenyl)ethenyl)-1H-indole (4h).23,30,29,22
1
Chromatographic purification (PE/Acetone 90:10) gave 4h as an oil; 0.27 g (59% yield); H NMR
(200 MHz, CDCl3) δ 2.23 (s, 3H), 5.28 (d, J = 2.0 Hz, 1H), 5.68 (d, J = 1.8 Hz, 1H), 6.93–6.97 (m,
1H), 7.02–7.12 (m, 1H), 7.12–7.18 (m, 1H), 7.22–7.27 (m, 4H), 7.33−7.37 (m, 2H), 7.88 (br s, 1H);
13C NMR (50 MHz, CDCl3) δ 12.6 (CH3), 110.0 (CH), 113.8 (C), 114.8 (CH2), 119.4 (CH), 119.5
(CH), 121.0 (CH), 127.2 (2 x CH), 127.4 (CH), 128.0 (2 x CH), 128.2 (C), 132.9 (C), 135.0 (C),
141.7 (C), 142.3 (C); MS m/z (%) 233 [M+](95), 218 (100), 217 (100).
4.2.9. 2-Methyl-3-[(p-tolyl)ethenyl)-1H-indole (4i).23,29
1
Chromatographic purification (PE/Acetone 80:20) gave 4i as an oil; 0.27 g (54% yield); H NMR
(200 MHz, CDCl3) δ 2.24 (s, 3H), 2.34 (s, 3H), 5.27 (d, J = 1.8 Hz, 1H), 5.71 (d, J = 1.8 Hz, 1H),
6.95–7.02 (m, 1H), 7.07−7.14 (m, 3H), 7.22−7.31 (m, 4H), 7.80 (br s, 1H); 13C NMR (50 MHz,
22

ACCEPTED MANUSCRIPT
CDCl3) δ 12.6 (CH3), 21.0 (CH3), 110.0 (CH), 113.0 (C), 114.0 (CH2), 119.4 (CH), 119.6 (CH),
121.0 (CH), 127.0 (2 x CH), 128.3 (C), 128.8 (2 x CH), 133.0 (C), 135.0 (C), 137.1 (C), 138.8 (C),
142.1 (C); MS m/z (%) 247 [M+](90), 232 (100), 217 (75).
4.2.10. 3-[1-(4-Acetylphenyl)ethenyl]-2-methyl-1H-indole (4j).
The compound was synthesised as described in general procedure, from 1,4-diacetylbenzene (2i, 4.0
mmol, 0.65 g) and 2-methylindole (3a, 2.0 mmol, 0.26 g) in the presence of 1a (5 mol%, 0.068 g).
1
Chromatographic purification (PE/Acetone 80:20) gave 4j (oil); 0.36 g (65% yield); H NMR (200
MHz, CDCl3) δ 2.22 (s, 3H), 2.56 (s, 3H), 5.40 (d, J = 1.6 Hz, 1H), 5.78 (d, J = 1.6 Hz, 1H), 6.91–
6.98 (m, 1H), 7.04−7.14 (m, 2H), 7.20−7.27 (m, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.4 Hz,
1H), 8.15 (br s, 1H); 13C NMR (50 MHz, CDCl3) δ 12.6 (CH3), 26.5 (CH3), 110.2 (CH), 113.0 (C),
116.8 (CH2), 119.2 (CH), 119.6 (CH), 121.2 (CH), 127.3 (2 x CH), 127.9 (C), 128.2 (2 x CH),
133.2 (C), 135.0 (C), 135.9 (C), 141.6 (C), 146.6 (C), 197.9 (CO); IR ν (cm-1) 3393, 3334, 1667,
1593, 1462, 1260, 739; MS m/z (%) 275 [M+](100), 232 (65), 217 (80); Anal. Calcd for
C19H17NO: C, 82.88; H, 6.22; N, 5.09. Found C, 82.80; H, 6.24; N, 5.02.
4.2.11. 1,4-Bis[1-(indol-3-yl)ethenyl)]lbenzene (4k).
The compound was synthesised as described in general procedure, from 1,4-diacetylbenzene (2i, 2.0
mmol, 0.32 g) and 2-methylindole (3a, 6.0 mmol, 0.79 g) in the presence of 1a (10 mol%, 0.068 g).
Chromatographic purification (PE/Acetone 80:20) gave 4j (oil); 0.30 g (54% yield) and 4k (solid);
0.26 g (34% yield); mp 184−185.5 °C (DCM/PE); 1H NMR (200 MHz, CDCl3) δ 2.23 (s, 6H), 5.28
(d, J = 1.8 Hz, 2H), 5.71 (d, J = 2.0 Hz, 2H), 6.90–7.12 (m, 4H), 7.20−7.26 (m, 4H), 7.29 (s, 4H),
13
7.84 (br s, 2H); C NMR (50 MHz, CDCl3) δ 12.7 (CH3), 110.0 (CH), 113.8 (C), 114.4 (CH2),
119.4 (CH), 119.5 (CH), 121.0 (CH), 127.0 (CH), 128.2 (C), 132.9 (C), 135.0 (C), 140.8 (C), 142.0
23

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(C); IR ν (cm-1) 3381, 1605, 1459, 1215, 846, 748; Anal. Calcd for C28H24N2: C, 86.56; H, 6.23;
N, 7.21. Found C, 86.60; H, 6.19; N, 7.18.
4.2.12. 4-(2-Methylindol-3-yl)-1,2-dihydronaphthalene (4l).29
1
Chromatographic purification (PE/Acetone 90:10) gave 4l (oil); 0.35 g (68% yield); H NMR (200
MHz, CDCl3) δ 2.28 (s, 3H), 2.40−2.50 (m, 2H), 2.84−2.94 (m, 2H), 6.07 (t, J = 4.6 Hz, 1H),
13
6.89−7.15 (m, 6H), 7.22−7.25 (m, 2H), 7.84 (br s, 1H); C NMR (50 MHz, CDCl3) δ 12.4 (CH3),
23.5 (CH2), 28.3 (CH2), 110.2 (CH), 112.5 (C), 119.3 (CH), 119.4 (CH), 121.0 (CH), 125.5 (CH),
126.2 (CH), 126.6 (CH), 127.4 (CH), 128.7 (C), 129.2 (CH), 131.8 (C), 132.4 (C), 135.1 (C), 135.3
(C), 136.2 (C); MS m/z (%) 259 [M+](100), 244 (65).
4.3. Reaction of 1b with methanol:
1-Methoxy-1-(2-methylindol-3-yl)-1-(4-nitrophenyl)methane (6).
Salt 1b (1 mmol, 0.35 g) was suspended in methanol (5 mL) at rt; the reaction was stopped after 20
minutes (disappearance of the coloured salt). Usual work-up of the reaction and chromatographic
purification (PE/acetone, 9:1) gave 6 as a pale yellow solid; 0.22 g (76% yield): mp 154.1−154.8 °C
1
(DCM/PE). H NMR (200 MHz, CDCl3) δ 2.40 (s, 3H), 3.34 (s, 3H), 5.63 (s, 1H), 6.92−7.10 (m,
2H), 7.23 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 9.0 Hz, 2H), 8.01 (br s, 1H),
8.08 (d, J = 8.8 Hz, 2H); 13C NMR (50 MHz, CDCl3) δ 12.0 (CH3), 56.3 (OCH3), 77.0 (CH), 109.9
(C), 110.3 (CH), 118.8 (CH), 119.7 (CH), 121.4 (CH), 123.2 (2 x CH), 126.7 (C), 126.9 (2 x CH),
133.5 (C), 135.2 (C), 146.5 (C), 150.1 (C); IR ν (cm-1) 3375, 2940, 1599, 1512, 1456, 1346, 1087,
840, 748, 727; Anal. Calcd for C17H16N2O3: C, 68.91; H, 5.44; N, 9.45. Found C, 68.85; H, 5.40;
N, 9.40.
4.4. Dehydrative Coupling: gram-scale procedure for the synthesis of product 4a.
24

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Catalyst 1 (5 mol%, 0.167 g) was added to a solution of ketone 2a (10.0 mmol, 1.65 g) and 2-
methylindole 3a (10.0 mmol, 1.31 g) in anhydrous methanol (5 mL) under stirring. The reaction
mixture was then stirred in an air atmosphere at room temperature for 6 hours. Then the reaction
mixture was treated with H2O/ DCM (1:1, 100 mL). The organic phase was dried over Na2SO4, the
solvent was removed under reduced pressure and the crude product was purified by column
chromatography (PE/acetone 85/15) to give pure 4a (2.15 g, 77% yield).
4.5. Reactions of ketone 2a with indoles 3c and 3d. Representative procedure.
The reactions were performed as reported in the general procedure by reacting 4-nitroacetophenone
(2a, 2.0 mmol, 0.33 g) and either indole (3c, 2.0 mmol, 0.23 g) or 1-methylindole (3d, 2.0 mmol,
0.26 g) in the presence of 1a (5 mol%, 0.034 g) at room temperature. The reaction were monitored
by TLC an GC analyses, and no traces of the expected products were detected. The reactions were
stopped after running at rt for 24 hours, although no completion was observed. Yellow solid 7b
separated from the reaction mixture, was isolated by filtration and purified by gentle washings with
cold methanol. Chromatographic purification (PE/Acetone 85:15) led to the recovery of acetal 5 and
products 7a and 7b, which were quantified and characterised as reported below.
4.5.1. 1,1-Dimethoxy-1-(4-nitrophenyl)ethane (5):65
Oil; 0.08 g, 20%; 1H NMR (200 MHz, CDCl3) δ 1.47 (s, 3H), 3.12 (s, 6H), 7.60 (d, J = 9.0 Hz, 2H),
8.13 (d, J = 9.0 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ 25.6 (CH3), 48.9 (OCH3), 101.0 (C), 123.2
(2 x CH), 127.2 (2 x CH), 147.2 (C), 150.0 (C); MS m/z (%) 196 [M+-15](30), 180 [M+-31](
(100).
4.5.2. 1,1-Bis(indol-3-yl)-1-(4-nitrophenyl)ethane (7a):66,67
25

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1
Yellow solid; 0.29 g (76% yield) : mp 246.8−248 °C (DCM); H NMR (200 MHz, CD3COCD3) δ
2.32 (s, 3H), 6.74–6.81 (m, 4H), 6.94–7.03 (m, 2H), 7.11−7.16 (m, 2H), 7.33−7.39 (m, 2H), 7.61 (d,
J = 9.2 Hz, 2H), 8.07 (d, J = 9.0 Hz, 2H), 10.06 (br s, 2H); 13C NMR (50 MHz, CD3COCD3) δ 43.9
(C), 111.4 (2 x CH), 118.3 (2 x CH), 120.9 (4 x CH), 122.1 (2 x C), 122.5 (2 x CH), 123.5 2 (2 x
C), 126.0 (2 x CH), 129.1 (2 x CH), 137.5 (2 x C), 145.9 (C), 156.3 (C); the product is much less
13
soluble in chloform, but C NMR (50 MHz, CDCl3) evidenced signal of the methyl group on the
quaternary carbon at 28.6 ppm.
4.5.3. 1,1-Bis(1-methylindol-3-yl)-1-(4-nitrophenyl)ethane (7b):
Pale yellow solid; 0.35 g (86% yield): mp 214.0−215.5 °C (DCM/PE); 1H NMR (200 MHz, CDCl3)
δ 2.30 (s, 3H), 3.64(s, 6H), 6.48 (s, 2H), 6.89 (t, J = Hz, 7.8 Hz, 2H), 7.10−7.20 (m, 6H), 7.22-7.28
(m, 2H), 7.52 (d, J = 9.0 Hz, 2H), 8.03 (d, J = 9.0 Hz, 2H); 13C NMR (50 MHz, CDCl3) δ 29.0
(CH3), 32.5 (N-CH3), 43.9 (C), 109.3 (2 x CH), 118.6 (2 x CH), 121.2 (2 x CH), 121.5 (2 x CH),
122.9 (2 x CH), 126.2 (2 x C), 127.8 (2 x C), 127.9 (2 x CH), 128.9 (2 x CH), 137.6 (2 x C), 145.9
(C), 156.0 (C); IR ν (cm-1) 2926, 1590, 1509, 1465, 1343, 733, 705; Anal. Calcd for C26H23N3O2:
C, 76.26; H, 5.66; N, 10.26. Found C, 76.20; H, 5.62; N, 10.22.
5. Computational Method
The structures of reactants, intermediate adducts and transition states were optimized using the
density functional method (DFT),68 with the functional M06-2X69,70 with the cc-pVDZ basis set.71
The nature of the critical points was characterized by using vibrational analysis72,73 which also
furnished the Zero Point Energyes (ZPE) and entropies for the calculations of the Free Energies.
These have been converted from the gas phase to the 1M standard state at 1 atm and 298.15 K.74
The geometries have been refined by optimizing them with the larger basis set cc-pVTZ71 and their
energy calculated with even large basis set aug-cc-pVTZ.71 The latter have been combined with the
thermodinamic corrections calculated with the smallest basis set to get the final E+ZPE and Free
energies. These are used to calculate the rate constant with the Eyring equation.75 Solvent effects
26

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were introduced in all using the polarized continuum method (IEF-PCM)76-80 within the universal
solvation model density (SMD).81,82
Calculations were performed by the quantum package Gaussian 09-A.02.83 Figures in the
Supplementary Information were obtained using the graphical program Molden.84
Supporting Data
Supplementary data to this article can be found online at ……….
Supplementary data for this article include copies of the 1H and 13C NMR spectra, tables of
calculated relative energies, discussion on steric and electronic effects, pictures of calculated
structures, calculated absolute energies and cartesian coordinates.
ACKNOWLEDGMENTS
The authors thank the Italian MIUR and Università degli Studi di Torino for financial support.
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