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γ-Regioselective functionalization of 3-alkenylindoles via
extended alkylideneindolenine intermediates
Lucia Lenti
Instituto Superior Técnico, Universidade Técnica de Lisboa
December 2017
____________________________________________________________________
Abstract. Heterocyclic aromatic systems, particularly those containing an indole moiety are
known to be of wide interest. They are found in several biologically active compounds and this is
the reason why they are largely studied nowadays, in particular in the field of pharmaceuticals. In
this thesis work alkylideneindolenine ions have been taken into consideration as intermediates for
the appropriate C-3 indole functionalization. These reactive systems can be generated by acid
catalysed elimination of a suitable leaving group located at the benzylic position of the indole
substrate. Reaction of these vinylogous iminium ions with various nucleophiles allows the
appropriate functionalization of the C-3 side chain. The aim of this thesis work was to exploit the
reactivity of 3-indolyl allylic alcohols as precursors of poly-conjugated iminium ions evaluating the
regioselectivity achievable in their reaction with different nucleophiles. After extensive studies, a
complete γ-regioselectivity has been obtained for the reaction of differently functionalized 3-indolyl
allylic alcohols with indoles and pyrroles. The reaction conditions entail the utilization of 1 mol%
of zinc(II) triflate as catalyst in acetonitrile at room temperature. The obtained adducts retaining the
conjugated vinyl moiety would be of some practical interest since they are pivotal intermediates in
the synthesis of polycyclic derivatives through Diels-Alder reactions.
Keywords. 3-vinylindoles, alkylideneindoleninium ion, alkylideneindolenine, reactive
intermediates, regioselectivity, protocol optimization.
____________________________________________________________________
Introduction
Heterocyclic aromatic structures are known to
be of paramount importance, in fact they
represent one of the most varied family of
organic compounds. They are particularly
interesting in the important field of
pharmaceutical products but they are also
present in fields such as veterinary products,
agrochemicals of materials.1
One of the most important and studied
structure in this class of compounds is indole
1 (Figure 1). It has been identified in a huge
number of biologically active compounds and
this explain the deep interest in the synthetic
processes concerning this important moiety.2
Figure 1. Indole
One example that proves the relevance of the
indolyl moiety is Tryptophan 2, an essential
α-amino acid used as an important building
block in protein biosynthesis (Figure 2). It is
2
also a precursor for a lot of different
compounds such as Auxin 3 and Serotonin 4.
The first is a hormone with an important role
in the coordination of a lot processes in some
plant’s life cycle,3 the second is a well-known
neurotransmitter thought to be at the base of
happiness (Figure 2).4
Figure 2. Examples of important indole derivatives.
It is easy to understand why some Serotonin
analogues are used a synthetic drugs. In fact
they are able to interact with some Serotonin
receptors, producing the same biological
response.5
C3- functionalization of Indoles
From the examples shown it is easy to
observe that they are all C3-alkylated indole
derivatives. They are of great interest in
medicinal research due to their role in the
construction of biologically active
compounds.
These indole derivatives are easily obtained
through simple electrophilic aromatic
substitutions since this results to be the most
reactive one toward these reactions, for
electronic reasons.6
Starting from simple indole, a lot of different
reactions are known in literature in order to
obtain 3-substituted derivatives. One of the
most exploited is the Friedel-Crafts (F-C)
alkylation of acylation catalysed by the
presence of Brønsted or Lewis acids (Scheme
1, eq. 1).7
Another example is the Michael addition of
indoles to α,β-unsaturated systems to obtain
the corresponding products (Scheme 1, eq. 2).
Scheme 1. Examples of reaction for C3-
functionalization of indoles.
Functionalization of Indoles via
Alkylideneindolenine Intermediates
The previous examples are representative for
the synthesis of C3-funcionalised indoles in
which the indole is the nucleophilic reagent.
Taking into consideration indole derivatives
of type 5, coming from a preliminary
functionalization base on an electrophilic
substitution (Scheme 2), they present an
electrophilic character due to the presence of
a leaving group (HZ).8
Scheme 2. Alternative C-3 functionalization of indoles.
3
This is widely used for further functionalise
the benzylic position of these systems. In fact,
the indole derivative 5 containing the leaving
group, can be converted, under proper
reaction conditions, into the
alkylideneindoleninium ion I or into the
alkylideneindolenine II intermediates
(Scheme 3).
Scheme 3. Elimination and nucleophilic attack.
The two different reactive intermediates that
can be obtained depend on the nature of the
leaving group and on the consequent reaction
conditions needed for the elimination step. As
it can be deduced these systems are analogues
of α,β-unsaturated systems involved in the so
called conjugated additions. The difference is
that this time the electron withdrawing group
is the nitrogen contained in the indolyl moiety
and that is essential for the stabilization but
also reactivity of the intermediates.
The success of this strategy depends on a lot
of factors; the ease for the formation of the
reactive intermediate is the first, followed by
the stability of the intermediate and the
aptitude of the leaving group to be eliminated
under mild and controlled conditions.9 Many
leaving groups can be exploited for the
obtainment of C3-alkylated indoles like
substituted amines, arylsulfonyls, hydroxyl
groups, sulphonamides and halides. They are
prone to elimination under Lewis od Brønsted
acidic or Brønsted basic conditions. Some can
be also eliminated under different protocols
offering a great flexibility.
One class of the most studied leaving groups
are arylsulfonyls.
Sulfonyl indoles are useful substrates in
asymmetric synthesis and a lot of reactions
are known in literature involving this leaving
group. One example is the alkylination of
aldehydes catalysed by L-proline and
affording the corresponding 3-indolyl
derivatives in good yields, diastereo- and
enantio- selectivity (Scheme 4).10
The basic
promoter is able to bring the formation of the
relative neutral intermediate
alkylideneindolenine II that interacts with the
nucleophilic reagent.
Scheme 4. α-alkylation of aldehydes with
arylsulfonylindoles catalysed by L-proline.
In this case, the reaction is catalysed by a
basic promoter, but arylsulfonyls can be
eliminated also under acidic conditions
(Scheme 5). In fact, this was exploited in
reaction involving acid such as the Lewis one
AlEtCl2, confirming the versatility of this
important leaving group.11
4
Scheme 5. Alkylation of sulfonyl indoles promoted by
AlEtCl2.
Lewis acids, but also Brønsted ones can be
widely used in the elimination of the hydroxyl
group as well.
Its elimination brings to the formation of the
corresponding alkylideneindoleninium ion I,
followed by reaction with a nucleophile.
Brønsted acids have been also studied for this
kind of reactions. One example is the
cooperative systems involving the Jørgensen
chiral catalyst 6 and trifluoromethansulfonic
acid (TfOH) for the reaction of hydroxyl
indoles with aldehydes (Scheme 6).12
The elimination of an hydroxyl can be
catalysed also by the presence of a Lewis
acid. In fact the very similar cooperative
system was developed using InBr3 as the
promoter, able to catalyse a high
enantioselective intermolecular α-alkylation
of propanal to produce the corresponding
product in high yields and enantioselectivity
(Scheme 7).13
Scope of this thesis work
Introducing an additional double bond in the
alkyl framework of C3-substituted indoles
containing a leaving group, brings to the
formation of extended vinylogous systems.
Scheme 6. Conjugated addition of chiral enamines to
vinylogous imine interemediate catalysed by the
Jørgensen catalyst.
Scheme 7. Enantioselective intermolecular α-alkylation
of aldehydes catalysed by cooperative systems.
5
Starting from two different substrates, the
regioisomers containing the leaving group in
α or γ position (7 and 8), the same
intermediates IV or V can be obtained under
acidic or basic conditions respectively
(Scheme 8).
Scheme 8. Reactivity of vinyl indole derivatives,
bearing a leaving group in α or γ position.
In fact, once the substrates are treated with an
acid or a base the obtained intermediate is the
same, showing the same reactivity.
Occasional examples can be found in
literature demonstrating that the
functionalization of indole derivatives of type
7 led to the substitution in the benzylic
position.
For example, Huang et al. in a recent paper
used oxindoles as the nucleophilic reagent in
a highly enantioselective organocatalytic
substitution of 3-(1-tosylalkyl) functionalized
indoles. The reaction is catalysed by the
presence of the chiral thiourea 9 and a total α
regio-selectivity was observed (Scheme 9).14
Concerning the hydroxyl as the
leaving group, the study conducted by
Repuing and co-workers in 2008 with the aim
of the first catalytic asymmetric reaction of 3-
indolylethanoles in the presence of chiral
phosphoric acids was notable.
One example is the one that gave the product
11.
Scheme 9. Asymmetric substitution of 3-(1-
tosylalkyl)indoles with oxindoles.
It was obtained in moderate value of ee but it
also represented the basis for the catalytic
asymmetric reactions of this class of indole
derivatives (Scheme 10).15
Scheme 10. Catalytic Asymmetric Substitution of 3-
Indolylmethanol with N-methylindole.
Taking into consideration the examples
shown, it has been decided to carry out a
6
study with the aim of driving the nucleophilic
attack at the γ position, starting from
substrates of type 7 or 8 (Scheme 8).
Hence, the scope was to optimize a protocol
able to afford a high level of γ-regioselectivity
for the obtainment of compounds of type 12
(Figure 3).
Figure 3. Aim of this thesis work.
In order to do that the already known
literature for the benzylic functionalization of
C-3 alkylated indoles has been taken into
consideration.
The interest in the vinylindoles that could be
obtained, 12, stands in the fact the they still
retain a conjugated unsaturation making them
useful substrates for e. g. Diels-Alder (D-A)
reactions.
In the past, vinyl indole systems able to give
D-A reaction have been studied a lot. The
approach was pioneered by Pindur and co-
workers in 1987, showing the reactivity of 3-
vinyl indoles toward unsaturated ketones,
catalysed by aluminium trichloride (Scheme
11).16
Results and Discussion
The work was focused on the γ-
functionalization of vinyl indole derivatives,
particularly of type 8 with different
nucleophiles. Both basic and acidic conditions
were investigated using tosyl and hydroxyl
leaving groups respectively.
Scheme 11. Pindur’s studies on [4+2] cycloaddition
reactions of 3-vinylindoles.
Synthesis of the substrates
Following the retrosynthetic analysis, the
tosyl derivatives 14 can be obtained from the
corresponding alcohol, hence at first the allyl
alcohol 13 was synthetized (Scheme 12).
Scheme 12. Retrosynthetic analysis.
The initial Wittig reaction was performed
following a literature procedure, affording the
α-β-unsaturated ketone 15 in 75% yield
(Scheme 13).17
The allyl alcohol 16 was successfully
obtained by the selective reduction of the
C=O moiety. It was performed by the use of
NaBH4 as the reducing agent and the
7
Scheme 13. Wittig reaction.
quantitative conversion of the α-β-unsaturated
ketone into the alcohol was observed (Scheme
14).
Scheme 14. Selective reduction of α,β-unsaturated
ketone double bond.
The alcohol showed to be very sensitive to
acid, air, light and heat and it needed to be
store under N2 and at -20°C.
The corresponding tosyl 17 for the
basic catalysis was obtained as a
regioisomeric mixture using a procedure
found in literature that involved the use of p-
TSA and of sodium p-toluenesulfinate
(Scheme 15).18
It was not possible to separate the two
regioisomers 17 and 18 through column
chromatography, so it was kept as a mixture,
since the reactive intermediate formed under
basic catalysis would be the same.
Scheme 15. Synthesis of allyl tosylate.
Preliminary tests
A preliminary test for the basic catalysis was
performed on the allyl tosyl, following a
literature’s procedure, involving the presence
of K3PO4 as the base, the Takemoto catalyst
19 and malononitrile as the nucleophilic
reagent (Scheme 16).19
Scheme 16. Catalysis under basic conditions.
Unfortunately, the reaction showed a univocal
selectivity for the benzylic position, bringing
only to the formation of product 20, fully
characterised.
8
Successively the acidic catalysis was
investigated, using diphenyl phosphoric acid
21 as the promoter for the reaction (Scheme
17). A first reaction was performed using
indole 1 as the nucleophile. Using a catalytic
amount of 10 mol%, after 30 minutes the
desired product 22 was observed. In this case
the regioselectivity was not univocal for the γ-
functionalised product, showing the presence
of the benzylic functionalised one 23, as the
major product (Table 1, entry 1).
Scheme 17. Catalysis under acidic conditions.
Since the desired product was observed, even
though in a very small amount, a screening of
different nucleophiles was performed under
the same reaction conditions (Table 1). In
general, a regioisomeric mixture of α and γ
functionalization was observed (ratios from
80:20 to 90:10) and the major product was, in
all the cases, the benzylic functionalized one
23.
Anyway the best ratio α : γ was obtained with
2-substituted indole derivatives, indicating
that probably a substituent in this position
could play an important role in the regio-
chemistry of the reaction. A first purification
through column chromatography was also
performed on the products but they showed,
as the allyl alcohol 16 a very high sensitivity
toward acid environment, in fact they went
through degradation when in contact with
silica gel.
Table 1. Screening of different nucleophiles.
Entry Nucleophile Ratio α : γ
1 Indole 90 : 10
2 N-Methylindole 85 : 15
3 2-Methylindole 50 : 50
4 2-Phenylindole 50 : 50
5 2-Vinylindole 66 : 34
6 3-Methylindole Decomposition
7 Ethyl indole-2-
carboxylate Decomposition
8 β-Naphthol Decomposition
Substrate optimization to reach γ-
regioselectivity
After the obtained results for both catalysis
we spotted that steric or electronic factors
could probably influence a lot the reactivity of
our substrates toward this reaction. For this
reason, we performed an optimization in the
substrate, deciding to substitute the phenyl
ring with a methyl moiety and to test the new
substrate.
The new allyl alcohol 24 was obtained using
the same procedure used for the previous one
16 and was obtained in 85% yield. It showed
a very high sensitivity, hence it was stored
under N2 and at -20°C as the previous one.
The corresponding allyl tosyl 25 was
synthetized using the same procedure used
before and this time it was obtained together
with the by-product coming from the double
tosylation in α and γ position 26. (Scheme
18).
9
Scheme 18. New allyl alcohol and the synthesis of
allyl tosylate.
They were easily separated through column
chromatography obtaining only the desired
compound 25.
Study of the new substrate reactivity:
Preliminary tests
The reactivity of the new substrates was
studied. The basic catalysis was performed
with the same reaction conditions used before.
Unfortunately, even in this case the
regioselectivity gave as a result the total α-
functionalization of the allyl tosyl. For this
reason the attention was successively focused
only on the acidic catalysis, being the most
promising.
Concerning the acidic catalytic test, the
reaction conditions used at first were the same
used before (Scheme 17). The first
nucleophile tested was 2-methyindole, since,
as observed with the previous alcohol, C2-
substituted indoles gave the best results.
Effectively a 100% of regio-selectivity toward
the desired product was observed. The
product was successfully obtained and
consequently a screening of nucleophiles was
again performed, in order to have a more
complete view on the reactivity of the new
allyl alcohol (Table 2).
At the end 2-methylindoles and thiols (entries
1,5 and 6) gave the best results, that means a
100% of regio-selectivity toward the desired
γ-functionalised product even though thiols
showed a lower reactivity. Some of the
nucleophiles gave decomposition reactions,
while simple indole (entry 2) did not show a
univocal regio-selectivity.
We concluded that the structural
changes performed on the substrate made a
dramatic difference in the reactivity of the
alkylideneindolenine intermediate.
Table 2. Screening of different nucleophiles.
Entry Nucleophile Ratio
α : γ
1 2-Methylindole 0:100
2 Indole 30 : 70
3 9H-carbazole Decomposition
4 (E)-N-
phenylformimidic acid Decomposition
5 Thiolphenol 0:100
6 Benzylthiol 0:100
7 Triphenylmethanethiol Decomposition
Even in this case the isolation of the products
was compromised by their high sensitivity
toward the silica gel, showing degradation.
Lewis acid investigations and final
optimizations
Since the α : γ ratio for the reaction conducted
with indole 1 was unsatisfactory, the attention
was focused on the optimization of the
reaction with this nucleophile. Furthermore it
was also a very challenging nucleophile since
it has not substituent and its optimization
could avoid the limitations of C2-substituted
indoles.
The reaction was tested with longer reaction
times, with the presence of dehydrating agents
such as MgSO4 and molecular sieves (in order
to see if the water could play a role in the low
ratio) but no improvements were observed.
Consequently all the reaction conditions were
taken into consideration for the optimization
of the reaction protocol.
10
At first a screening of different acids was
performed comprising both Brønsted but also
of Lewis ones (Scheme 19 and Table 3).
Scheme 19. Screening of different acidic catalysts.
Table 3. Screening of different Brønsted and Lewis
acids.
Entry Acid Notes and ratio α : γ
1 (PhO) 2PO2H 30 : 70
2 CH3CO2H No reaction
3 CH3SO3H No reaction
4 CF3SO3H Decomposition
5 CF3CO2H Decomposition
6 BF3·Et2O Low conversion
100 : 1
7 Sc(OTf)3 Low conversion
50 : 50
8 Yb(OTf)3 Low conversion
10 : 90
9 ZrCl4 Low conversion
70 : 30
10 Pd(TFA)2 Decomposition
Brønsted acid catalysis gave all negative
responses (entry 2-5), while some Lewis
acids, even if with low conversions, were able
to improve the regioselectivity and to produce
the desired γ-functionalized product 27 (entry
7-9). Particularly Yb(OTf)3 showed not only
the best regioselectivity toward the desired
product, but also a cleaner reaction profile and
the further optimizations were performed
using this Lewis acid as the catalyst.
Dehydrating agents, different catalyst loading
(20, 10 and 5 mol%), different reaction
temperatures and different reaction times
were tested. New reaction conditions were set
(Scheme 20) obtaining cleaner NMR spectra
of the crude but also a still unsatisfactory ratio
between the two regioisomers. For this reason
a new screening of Lewis acid triflates was
performed (Table 4).
Scheme 20. New reaction conditions for the screening
of Lewis acid triflates.
The reactions were monitored at different
times (40 minutes 2.5 h and 6 h) and, as
before, the reactions were all analysed using
the NMR spectra of the crudes obtained.
The reactions showed in general good regio-
selectivities toward the desired product 27.
They were all performed in excess of alcohol
and, since the indole was still present in the
crudes of the reactions, Zn(II) and Eu(III)
triflates (entrie 3 and 4) were selected for
further optimizations aimed to improve the
11
conversion and also the γ : α ratios, being still
unsatisfactory.
Table 4. Screening of different Lewis acid triflates.
Entry Acid Ratio
α : γ
Conversion
(%)
Yield
(%)
1 Yb(III) 1:2 66 42
2 Sc(III) Dec - -
3 Zn(II) 1:14 52 43
4 Eu(II) 1:10 56 44
5 In(III) - - -
6 La(III) 1:7 44 32
7a Al(III) 1:6 53 35
8 Mg(II) 1:100 13 8
9a Ce(III) 1:6 46 33
10a Ag(I) 1:12 42 24
The values shown are referred to a reaction time 6 hours. aThese values are referred to 2.5 h of reaction time since at
this time no more alcohol was detected and the reaction was
considered finished or the values at 6h were not defined.
Different solvents were taken into
consideration for this purpose: toluene,
acetonitrile and THF that came from three
different class of organic compounds (Scheme
21, Table 5).
Scheme 21. Screening of different Lewis acid catalysts
and solvents.
The reaction were monitored again at
different reaction times (40 minutes, 3 h and
6h) and at the end Zn(II)triflate and
acetonitrile were set as the optimal catalyst
and solvent for the reaction.
Table 5. Screening of solvents.
Solvent
Ratio
α : γ
Conversion
(%)
Yield
(%)
Eu
Toluene 1 : 5 59 56
CH3CN - - -
THFa 1 : 2 70 79
Zn
Toluene 1 : 5 54 47
CH3CNa 1 : 17 67 54
THFa 1 : 2,5 77 72
Only the most representative results for every solvent are
shown. They are referred to 6 hours reaction time. aThese
values are referred to 2.5 hours as reaction time.
Even in this case indole, the limiting reagent,
was still present at the end of the reaction,
confirming that the allyl alcohol 24 went
through degradation during the reaction. For
this reason the protocol was further optimized
performing progressive addition of it during
the reaction. This was tested with 5 mol% and
1 mol% of catalytic amount (Scheme 22).
Only the desired product 27 was detected in
the NMR spectra with a 100% of the regio-
selectivity toward the γ-position. Only little
signals of decomposition were observed and
at the end the 1 mol% of catalytic amount was
kept for the final protocol.
For the isolation of the product a stabilization
was necessary. Following a literature
procedure (that required considerable
optimizations) the one-pot tosylation of the
nitrogens was performed (Scheme 23).20
The
desired product 29 was successfully obtained
and isolated in 69% yield and consequently a
scope on the alcohol 24 with different indole
derivatives was performed under the
optimized protocol (Scheme 23, Table 6).
12
Scheme 22. Tests of different reaction conditions
adding the substrate in small portions.
Scheme 23. Reactions with different indole
nucleophiles under the optimized reaction conditions.
Satisfactory yields ranging from 35 to 72%
were obtained, depending on the substituent
present in the indole ring. In fact the
nucleophile 5-chloroindole gave a low yield
(35%) of the product 32 since it is an
electron-withdrawing group. This means that
position C3 of indole results to be less
electron rich, compared to simple indole,
hence, less nucleophilic. On the other hand, a
reagent containing an electron-donating
group, such as 5-methoxyindole, gave the
product 33 with a higher yield, confirming the
important role of substituents in the reactivity
of the nucleophile. It is interesting to note also
that some products, 34 and 35, were obtained
as mono-tosylated, due to steric hindrance of
substituents in position C7.
After the successful results obtained with a
variety of substituted indole, N-methylpyrrole
was tested in order to see if the optimized
reaction conditions could be applied to other
nucleophiles (Scheme 24).
Scheme 24. N-methylpyrrole as nucleophilic reagent.
The reaction gave as result, the dimer 36,
isolated through column chromatography
after tosylation. This is a gratifying result,
since the reaction showed the desired
regioselectivity even though the nucleophile
used was different from an indole derivatives.
Furthermore, the NMR spectrum showed the
presence of two diastereoisomers (in a 2:1
ratio): the meso and the racemic isomers.
This could be a good starting point to obtain
building blocks useful for the construction of
more sophisticated systems, with the proper
optimizations that depend on the nucleophile.
13
Table 6. Reaction with different indole derivatives.
Products and relative yields
Preliminary test for synthetic elaboration
A first preliminary test for synthetic
elaboration toward D-A reaction was tested
while working with the diphenyl phosphoric
acid and with 3-methyindole are nucleophile.
As already introduced, substrate of type 12
could be theoretically good candidate for
cycloaddition reactions. Its reactivity as a
diene was tested using the commercially
available N-phenylmaleimide 37 as the
dienophile (Scheme 25).
The reaction was at first performed in a one-
pot protocol and then optimized with a three-
component one.
The cycloadduct 38 was successfully obtained
and isolated in 50% yield. This preliminary
test confirmed that this kind of products are
actually reactive toward [4+2] cycloadditions,
as expected. This protocol could be used in
order to obtain structurally sophisticated
compounds with the proper optimizations.
Conclusions and outlook
In this research paper a protocol for the
regioselective γ-functionalization of 3-
vinylindole derivatives is described. The
reaction is based on the presence on the
substrate of a good leaving group able to be
removed under suitable reaction conditions.
The consequent formation of a very reactive
intermediate makes the substrate able to
interact with a nucleophile. Sulfonyl and
14
Scheme 25. Three component reaction for D-A
cycloaddition.
hydroxyl have been used which activation can
be carried out under basic and acidic catalysis
respectively.
After the first unsatisfactory results different
aspect of the reaction have been studied,
starting from the substrate structure to the
final tosylation of the products for their
purification. After obtaining the proper
protocol, the reaction was performed with
different nucleophiles, indole derivatives and
N-pyrrole.
The future work will be focused on the study
of the optimized reaction conditions using
other nucleophiles but also allyl alcohols
containing different substituent on the
aromatic indolyl ring.
As far as the synthetic elaborations are
concerned, the D-A reaction will be attempted
under Zn(OTf)2 catalysis and with different
electrophiles.
Acknowledgement
I would like to thank Prof. Marino Petrini,
from University of Camerino, for supervising
me and for giving me the possibility to spend
my thesis period at the University of Bologna
(Industrial Chemistry department). I would
like also to thank my co-supervisors from
Bologna, Prof. Luca Bernardi and Dott.
Giulio Bertuzzi.
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