1

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.

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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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