ϒ-REGIOSELECTIVE FUNCTIONALIZATION

OF 3-ALKENYILINDOLES VIA EXTENDED

ALKYLIDENEINDOLENINE INTERMEDIATES

Lucia Lenti

Thesis to obtain the Master of Science Degree in

Chemistry

Supervisors: Profª.Pedro Paulo de Lacerda Oliveira Santos

Prof.Marino Petrini

Examination Commitee

Chairperson: Profª. Isabel Maria Marrucho

Supervisor: Profª. Pedro Paulo de Lacerda Oliveira Santos Members of the Committee: Profª. Dulce Elisabete Bornes Teixeira Pereira Simão

December 2017

Resumo

Os sistemas aterocíclicos aromáticos, particularmente, aqueles que contêm um indol, são conhecidos

por serem de particular interesse. Eles são encontrados em varios compostos biologicamente ativos e

essa é a razão pela qual eles são amplamente estudados hoje em dia, em particular no campo dos

produtos farmacêuticos. Neste tese os iões de alquilideno-indolenina foram levados em consideração,

como intermediários, para a funcionalização apropriada de C-3 indole.

Estes sistemas reativos podem ser gerados da eliminação ácido-catalisada de um “leaving group”

adequado, localizato na posição benziática do substrato de indol..

As reações desses “vinylogous iminium” ions com vários nucleófilos permitem a funcionalização

apropriada da C-3 cadeia lateral.

O objetivo deste trabalho de tese foi explorar a reatividade dos álcoois 3-indolil alílicos como

precursores de iões de iminium poli-conjugados, avaliando a regioselectividade possível na sua

reação com diferentes nucleófilos.

Depois de extensos estudos, foi obtida uma completa γ regioselectividade para a reação de álcoois

3-indolilalílicos diferencialmente funcionalizados, com indoles e pirroles.

As condições de reação implicam a utilização de 1 mol% do Zn(II)triflate como catalisador em

acetonitrile à temperatura ambiente.

Os aductos obtidos que retém o radical vinilico conjugado seriam de algum interesse pratico, pois são

intermediários fundamentais na síntese de derivados policíclicos através de reações de Diels-Alder.

Palavras-chave

3-vinylindoles, ion de alquilideno-indolenínio, alquilidenoindolenina, intermediários reativos,

regioselectividade, otimização de protocolo.

Abstract

Heterocyclic aromatic systems, particularly the ones containing an indole moiety are known to be very

important. They are found in a lot of biologically active compounds and this is the reason why they are

widely studied nowadays, in particular in the field of pharmaceuticals. C3-substituted indole derivatives

are known to be very interesting in medicinal research and they are at the base for the construction of

various biologically active molecules. In this thesis work alkylideneindolenine systems has been taken

into consideration. They are widely used for the functionalization of C3-alkenyl indoles in the benzylic

position, exploiting the presence of a leaving group. The reactive alkylideneindolenine intermediate

formed after the elimination of the leaving group can interact with different nucleophiles, bringing to the

formation of more sophisticated systems. The aim of this thesis work was to optimized a protocol in

order to bring the nucleophilic attack in the γ position in 3-vinlyl indole derivatives that differ from the

previous well known studied systems for the presence of one more double bond in the alkenyl

substituent and, consequently, in the conjugated reactive intermediates. The class of compounds

obtained would be very interesting and sophisticated since they retain the exocyclic double bond, that

could be further functionalized.

Key-words

Indole, C3-substituted indole derivatives, 3-vinylindoles, alkylideneindoleninium ion,

alkylideneindolenine, reactive intermediates, regioselectivity, protocol optimization.

INDEX

1. Introduction……………………………………………………………..…………..…………….…...1

1.1 The importance of the Indole core……………………………………………..……….…..……1

1.2 C-3 functionalization of Indoles: State of the Art……………………………………………….6

1.3 Functionalization of Indoles via Alkylideneindolenine Intermediates………….…..…...….11

1.4 Addition of indole nucleophiles to stabilized carbocationic electrophiles……..….…...….19

2. Scope of the Thesis work …………………………….……………………………………………24

3. Results and Discussion……………………………………………………………………….……29

3.1 Synthesis of the substrates………………………………………………………….…...……..29

3.2 Preliminary tests…………………….………………….…………………….……………..……32

3.2.1 Catalytic tests under basic reaction conditions…………………..……………..…..32

3.2.2 Catalytic tests under acidic conditions…………………………………….……..…..32

3.3 Substrate optimization to reach γ-regioselectivity………………………….…………….…..35

3.4 Study of the new substrate reactivity: Preliminary tests………………..…….………….….38

3.4.1 Catalytic tests under basic reaction conditions …………………..………...…..…..38

3.4.2 Catalytic tests under acidic conditions…………………………….………………....39

3.5 Lewis acid investigations and final optimizations……………………..……………………...42

4. Preliminary test for synthetic elaboration………….….………………………..………………53

5. Conclusions and outlook……………………………..………………………..….…….…………55

6. Experimental part……………………………………………………………….…………...………57

6.1 General………………………………………………………………………………………..…..57

6.2 General procedure for the synthesis of Phosphonium salts………………………….…….58

6.3 General procedure for the synthesis of Ylides………………………………………..………59

6.4 General procedure for the synthesis of α,β-unsaturated ketones: Wittig reaction….......60

6.5 General procedure for the reduction of α,β-unsaturated ketones: Synthesis of allyl

alcohols……………………………………………………………………………………….......61

6.6 General procedure for the synthesis of allyl sulfonyls from allyl alcohols…………….....62

6.7 General procedure for γ-functionalization: catalytic tests under basic

conditions……………………………………………………………….......................…….….63

6.8 General procedure for γ-functionalization: catalytic tests with phosphoric acid……........64

6.9 General procedure for γ-functionalization: Lewis acid catalysis……………………….…...66

6.10 General optimized procedure for γ-functionalization under Lewis acid

catalysis …………………………………………………………………………………..…..67

6.11 General procedure for three component reactions……………………….…………...…71

7. References……………………………………………………………..........................................72

Index of Figures

Figure 1.Tryptophan …………………………………………………………………………………………….2

Figure 2. Bioactive indole containing compounds……………………………….…………………………...2

Figure 3. Examples of synthetic indole based drugs…………………………………………………...…….3

Figure 4. Conversion of Serotonin to Melatonin………………………………………………………...…….3

Figure 5. Tryptamine..……………………………………………………………………………………………3

Figure 6. Camalexin………………………………………………………………………………….…….…….4

Figure 7.Vinblastine……………………………………………………………………………………………...4

Figure 8. Examples of indole alkaloids from marine organisms………………………………………........5

Figure 9. Methylaplysinopsin…………………………………………………………………………………....5

Figure 10.Gramine………………………………………………………………………………………….…..13

Figure 11. Tested nucleophiles and examples of biologically active compounds…………………….....19

Figure 12. General benzyl alcohol structure……………………………………………………………..…..20

Figure 13. (+)-Trigolutes B………………………………………………………………………………...…..25

Figure 14. General structure of a vinyl indole derivative ………………………….………………………29

Index of Schemes

Scheme 1. Examples of application fields for indole core…………………………………….………...…..1

Scheme 2. Comparison between C-2 and C-3 electrophilic substitution……………………..……………6

Scheme 3. F-C acylation of indole with acyl chlorides………………………………………………….……7

Scheme 4. Indole C-3 Michael additions to nitroalkenes…………………………………………………….7

Scheme 5. Michael addition reaction to α,β-unsaturated ketones……………………………………..…...8

Scheme 6. Enantioselective Friedel–Crafts reaction of indoles to in situ generated N-Boc-imines…....8

Scheme 7. Mechanism of 3-vinyl indoles nucleophilic attack………………………………………….……9

Scheme 8. Reaction of 3-vinylindole with N-acylimine………………………………..……………………10

Scheme 9. In situ formation mechanism for N-Boc aminal………………………….……….…………….10

Scheme 10. Indole C-3 functionalization……………………………………………………………………..11

Scheme 11. Elimination and nucleophilic attack…………………………………………………………….12

Scheme 12. Michael (conjugated) addition to α,β-unsaturated carbonyl systems………………………12

Scheme 13. Synthesis of gramine derivatives by Mannich reaction…………………………………..….13

Scheme 14. General mechanism for the nucleophilic substitution reactions of gramines and their

salts…………………………………………………………………………………………………………...….14

Scheme 15. Synthesis of sulfonyl indoles by three component reaction…………………………………14

Scheme 16. α-alkylation of aldehydes with arylsulfonylindoles catalysed by L-proline…………………15

Scheme 17. Catalytic asymmetric addition of nitroalkane to alkylideneindolenine……………….……..16

Scheme 18. Alkylation of sulfonyl indoles promoted by AlEtCl2..........................………………..……..17

Scheme 19. Conjugate addition of chiral enamines to vinylogous imine intermediates catalysed by the

Jørgensen catalyst……………………………….………………………………………………………….….18

Scheme 20. Enantioselective intermolecular α-alkylation of aldehydes catalysed by cooperative

systems……………………………………………………………………..……………………………….…..18

Scheme 21. Nucleophilic substitution reaction of benzyl alcohol in water……………………………….20

Scheme 22. Resonance structures after water loss in benzyl alcohols…………….…………………….20

Scheme 23. Nucleophilic attack of indole to the benzyl alcohol, performed on water……………….….21

Scheme 24. Reactivity of vinyl indole derivatives, bearing a leaving group in α or γ position……..….24

Scheme 25. Asymmetric substitution of 3-(1-tosylalkyl)indoles with oxindoles……………….…………25

Scheme 26. Catalytic Asymmetric Substitution of 3-Indolylmethanol with N-methylindole……….……26

Scheme 27. Aim of the thesis………………………………………………………………...……………….27

Scheme 28. Pindur’s studies on [4+2] cycloaddition reactions of 3-vinylindoles………………………..27

Scheme 29. Asymmetric alkelynation of arylglyoxals with 3-vinyl indoles………………….…………….28

Scheme 30. Retrosynthetic analysis for the synthesis of allyl alcohols…………………………..………29

Scheme 31. Wittig reaction…………………………………………………………………………………….30

Scheme 32. Selective reduction of α,β-unsaturated ketone double bond…………………………..……30

Scheme 33. Synthesis of allyl tosylate………………………………………………...……………………..31

Scheme 34. Catalysis under basic conditions…………………………………………….…………………32

Scheme 35. Catalysis under acidic conditions……………………………...……………………………….33

Scheme 36. Screening of different nucleophiles under acidic catalysis…………………...……………..33

Scheme 37. Wittig reaction…………………………………………………………..………………………..35

Scheme 38. Synthesis of a new substrate through Grignard reaction……………………………………35

Scheme 39. Wittig reaction……………………………………………………………….……………………36

Scheme 40. Selective reduction of α,β-unsaturated ketone C=O………………..……………………….37

Scheme 41. Synthesis of allyl tosylate……………………………………………..………………………..37

Scheme 42. Catalysis under basic conditions……………………….………………………………………38

Scheme 43. Screening of different nucleophiles under acidic catalysis………………………………….39

Scheme 44. Screening of different acidic catalysts…………………………………………………………42

Scheme 45. Screening of different metal triflates………………………………..………………………….44

Scheme 46. Screening of different Lewis acid catalysts and solvents……………………………………46

Scheme 47. Tests of different reaction conditions adding the substrate in small portions……………..48

Scheme 48. Tosylation of the catalytic product……………………………………………………….…….49

Scheme 49. Reactions with different indole nucleophiles under the optimized reaction conditions…..50

Scheme 50. N-methylpyrrole as nucleophilic reagent………………………………………………………52

Scheme 51. Cycloaddition reaction………………………………………………………………………..…53

Scheme 52. Three component reaction………………………………………….……..……………………54

Scheme 53. General procedure for the synthesis of Phophonium salts………………………………….58

Scheme 54. General procedure for the synthesis of Ylides………………………………………………..59

Scheme 55. General procedure for the synthesis of α-β-unsaturated ketones: Wittig reaction…….….60

Scheme 56. General procedure for the reduction of α,β-unsaturated ketones: Synthesis of allyl

alcohols……………………………61

Scheme 57. General procedure for the synthesis of allyl sulfonyl from allyl alcohols…………………..62

Scheme 58. General procedure for γ-functionalization: catalytic tests under basic conditions………..63

Scheme 59. General procedure for γ-functionalization: catalytic tests with phosphoric acid………..…64

Scheme 60. General optimized procedure for γ-functionalization under Lewis acid catalysis…………67

Scheme 61. General procedure for three component reactions…………………………………………..71

Index of Tables

Table 1. Examples of alkylation of indoles with alcohols…………………………………….……………..22

Table 2. Screening of different nucleophiles………………………………………………….……………..34

Table 3. Screening of different nucleophiles…………………………………………………………..….....40

Table 4. Screening of different Brønsted and Lewis acids…………………………………………….…...43

Table 5. Screening of different Lewis acids triflates at different reaction times………………………….45

Table 6. Screening of different solvents……………………………………………………….................…47

Table 7. Reaction with different indole derivatives…………………………………….……………...…..51

1

1. Introduction

1.1 The importance of the Indole core

Heterocyclic aromatic structures are in general known to be of paramount importance, since they

represent one of the most varied families of organic compounds. In fact, more than 50% of the

available chemical literature describe these kind of compounds and 70% of all pharmaceutical

products possess heterocyclic structural subunits.1 This is due to their favourable drug-like properties,

that are at the base of the interaction of drugs with living organisms.

Heterocyclic structures are not only important as pharmaceuticals but they are also present in

structures from different fields such as veterinary products, agrochemicals or materials.2

One of the most important heterocyclic aromatic structures is indole 1. Indole consists of a

bicyclic structure in which a benzene ring is fused to a five-membered nitrogen-containing aromatic

ring. It has been identified in over than ten thousand biologically active compounds and it makes it

easy to understand the reason under the deep interest in synthetic processes concerning this moiety

(Scheme 1).3

Scheme 1. Examples of application fields for indole core.

1

2

One of the most important examples that proves the relevance of the indole structure is Tryptophan 2

(Figure 1).

2

Figure 1. Tryptophan.

This is an α-amino acid involved in the synthesis of proteins and it belongs to the group of the

essential amino acids. This amino acid is not produced directly by the human body; therefore it has to

be obtained through the diet. It is an important building block in protein biosynthesis, whose absence,

like the absence of the other essential amino acids, can lead to serious illnesses. Tryptophan is also a

biochemical precursor for a wide range of different compounds. Auxin 3, a hormone with an important

role in the coordination of many growth and behavioural processes in plant's life cycle, represents an

essential feature for the plant body development.4 Serotonin 4 (or 5-hydroxytryptamine, 5-HT) is an

important neurotransmitter, popularly thought to be a contributor to feelings of well-being and

happiness (Figure 2).5

Figure 2. Bioactive indole containing compounds.

It is easy to understand why some analogues of serotonin are used as potent psychedelic drugs. In

fact, molecules such as: Psilocin 5, its phosphorylated counterpart Psilocybin 6 (both found in some

kind of mushrooms), DMT 7 (found in some plants) and LSD 8 (synthetized from the natural

lisergamides) are all agonists of the serotonin receptors (Figure 3).6,7

This means that they are able to

bind to some kind of HT receptors producing the same biological response of serotonin.

3

Figure 3. Examples of synthetic indole based drugs.

Serotonin can also be converted to Melatonin 9 (Figure 4), a neurohormone that, as a drug, is used for

the treatment of insomnia. It can be found not only in humans but also in animals and some kind of

plants.8,9

Figure 4. Conversion of Serotonin to Melatonin.

As it can be observed, most of the examples shown above, such as psychedelic drugs and also

Melatonin, present a basic and repetitive structure called tryptamine.

Tryptamine 10 (Figure 5) can be found in plants, animals and fungi. It has been detected also

in mammalian’s brains where it constitutes a very important neurotransmitter and neuromodulator.10

10

Figure 5. Tryptamine.

4

This is the backbone of the class of compounds called tryptamines, biologically very active and widely

used as drugs. They are 3-(aminoalkyl)indole derivatives, showing a broad pharmaceutical profile and

offering the possibility to be employed, as starting materials, for the preparation of carbolines and

other polynitrogenated compounds.11

Hence, the indole core can be found in a large class of naturally occurring molecules called

alkaloids, as they present basic nitrogen moieties. Several alkaloids have been studied during the

years, from their activity to their synthesis and use as potential medicines. For example, Xu and et al.

in 2014 focused their attention on the synthesis of fungal indole alkaloids.12

Indole alkaloids can, however, be very different from one to the other. In fact, while some of

them are structurally very simple, others present very large and complex structures. One example of a

simple indole alkaloid is Camalexin 11 (Figure 6), or 3-thiazol-2-yl-indole, a molecule contained in the

plant Arabidopsis thaliana and whose metabolites are used to fight fungal and bacterial infections.13

11

Figure 6. Camalexin.

On the other hand, one example of a very complex indole alkaloid structure is Vinblastine 12 (Figure

7), that is a dimeric alkaloid used in chemotherapic medication.14

12

Figure 7. Vinblastine.

This molecule is used to treat different types of cancer, including Hodgkin’s lymphoma, lung cancer,

melanoma, brain cancer and testicular cancer. Vinblastine can be isolated from Catharanthus roseus

but this is usually a very expensive way to obtain it; therefore, nowadays, its enantioselective

synthesis has been studied and improved in order to obtain cheaper sources of this alkaloid.15

Other important examples are indole alkaloids that are being reported from various marine

organisms. The structural similarity of these isolated compounds to endogenous amines and

5

neurotransmitters has led researchers to postulate the possible neurological activity of these

molecules. For example, some of them have been reported to possess affinity towards different

serotonin receptors: Barettin 13 and tris-indole alkaloids Gelliusine A 14 (Figure 8).16

Figure 8. Examples of indole alkaloids from marine organisms.

Methylaplysinopsin 15 (Figure 9), isolated from Aplysinopsis reticulata by Baird-Lambert et al. was

reported to displace serotonin from its receptors.

15

Figure 9. Methylaplysinopsin

Furthermore, several naturally occurring indole alkaloids have not been tested for neurological activity

yet. Their structures, however, indicate a possible affinity to serotonin, dopamine, or adrenergic

receptors.17

6

7

1.2 C-3 functionalization of Indoles: State of the Art

From the various examples previously shown, it is very easy to understand the interest of researchers

in studying different approaches to the synthesis of functionalized indoles. In particular C3-alkylated

indole derivatives are of great interest in medicinal research because of their importance for the

construction of various biologically active molecules.

In general, the position C-3 of indole is easy to functionalize in order to obtain more complex

structures or starting substrates for further functionalization and reactions. In fact, this position results

to be the most reactive towards electrophilic aromatic substitutions. Comparing the resonance

structures coming from attack in position C-2 and C-3, this can be easily explained (Scheme 2).

Scheme 2. Comparison between C-2 and C-3 electrophilic substitution.

As it can be observed, the intermediates deriving from an electrophilic substitution at position C-3

result to be more stable with respect to the ones from a C-2 substitution. In fact, intermediate II is

stabilized by the lone pair of the nitrogen without the disruption of the benzenoid resonance, that

occurs instead in the case of a C-2 electrophilic substitution, with the consequent formation of the less

stable intermediate I.18

Starting from simple indoles, a notable number of different reactions are known in literature in

order to obtain C-3 functionalized indoles. One of the most exploited and used in organic chemistry is

the Friedel-Crafts (F-C) alkylation or acylation. This reaction is used, in general, to introduce an

electrophilic substituent in the aromatic ring, in the presence of a Brønsted or Lewis acid as catalyst.19

The Scheme below represents the reaction conditions by which C-3 acylated indoles 16 can be

easily obtained (Scheme 3).20

8

Scheme 3. F-C acylation of indole with acyl chlorides.

Another example of C-3 functionalization is the Michael addition of indoles 17 to nitro alkenes 18 to

obtain the corresponding products 19. (Scheme 4).

Scheme 4. Indole C-3 Michael additions to nitroalkenes.

Lewis acid catalysed Michael addition to electron-deficient alkenes is an important reaction, widely

used to produce 3-substituted indoles. In can be performed also on α,β-unsaturated ketones 21

producing 3-(3-oxoalkyl)indole derivatives 22 in good yields. (Scheme 5).21

9

Scheme 5. Michael addition reaction to α,β-unsaturated ketones.

Even though a large variety of electrophilic systems are available for F-C reactions, some notable

ones, as for example α,β-unsaturated esters are poorly reactive with indoles in whatever conditions.22

This make the F-C reaction presenting some limitations in the nature of the functional groups that can

be present in the electrophilic reactant. Additional limitations derive from the low tolerance of, acid-

sensitive groups under the usual conditions required for the process.

Very recently, Kim et al. reported another interesting example for the C-3 functionalization of

indoles. It involves the use of a cooperative cation-binding catalysis for the enantioselective Friedel–

Crafts reaction of indoles 23 with the in situ generated N-Boc-imines 25 to afford the respective

enantio-enriched products 26 (Scheme 6).23

Scheme 6. Enantioselective Friedel–Crafts reaction of indoles to in situ generated N-Boc-imines.

10

3-Functionalized indoles are very useful for the synthesis of many chiral 3-substituted indoles that,

otherwise, would be difficult to synthetize from unfunctionalized ones. The search for new 3-

functionalized indoles in the synthesis of structurally diverse chiral 3-substituted systems brought

recent interest on 3-vinyl indoles.

It is interesting to note that the centre of reactivity for the nucleophilic attack shifts its position on

the exocyclic carbon as it can be observed in the Scheme 7. This is due to the presence of a

conjugated system, able to extend the reactivity of the substrate in a vinylogous fashion.

Scheme 7. Mechanism of 3-vinyl indoles nucleophilic attack.

The nucleophilic exocyclic carbon is, in fact, able to attack an electrophilic species, leading to the

formation of intermediate III, stabilized by the nitrogen lone pair. The following loss of a proton is

essential in order to restore the neutrality and aromaticity of the system.

This reaction permits to obtain more complex C-3 substituted indole systems in which the exocyclic

double bond is still present after the attachment of the electrophilic substituent, making them

sophisticated building blocks for further functionalization.

In general, both electron-rich and -deficient substituted 3-vinyl indoles are able to produce the

corresponding products in excellent yields, E/Z ratios and enantioselectivities under mild reaction

conditions, making this kind of systems very interesting from the synthetic point of view. Xue and co-

workers in 2016 reported a work in which subsequent optimizations of a three components reaction

brought to the final substrate scope shown in Scheme 8.

11

Scheme 8. Reaction of 3-vinylindole with N-acylimines.

The reaction involves the use of 3-vinyl indoles 27 bearing various substituents on the phenyl ring in

the presence of a chiral phosphoric acid 29, benzaldehyde and tert-butyl carbamate. The last two

reagents are able to produce in situ the N-Boc aminal 28 which is converted into the electrophilic N-

acylimine by acidic catalysis (Scheme 9). Either electron-rich and or -deficient substituents were

introduced in the phenyl ring and the desired products 30 were always obtained in good yields and

excellent enantiomeric excesses (from 83% to 95 %).24

Scheme 9. In situ formation mechanism for N-Boc aminal.

12

1.3 Functionalization of Indoles via Alkylideneindolenine Intermediates

All the previous examples are representative for indolyl systems able to behave as nucleophilic

reagents. By contrary, indole derivatives of type 33, coming from a preliminary functionalization based

on an electrophilic substitution at C-3, present an electrophilic character that is widely used for further

functionalization at the benzylic position of indole derivatives.

This is a versatile approach to overcome the limitations displayed by the C-3 functionalization of

indoles and it combines two different processes. The first step involves a Friedel-Crafts reaction with

an unsaturated electrophilic reagents of type 32 in order to obtain an electrophilic adduct 33, which

features a good leaving group ZH in the benzylic position (Scheme 10).25

The second step involves

the displacement of the leaving group with another functionality.

Scheme 10. Indole C-3 functionalization.

In general, this strategy involves the formation of intermediate alkylideneindoleninium ion IV or

alkylideneindolenine V, which can be considered as a vinylogous iminium ion or imine, respectively

(Scheme 11). Elimination of the leaving group Lg under acidic conditions affords the ionic intermediate

IV which can be reacted with weak (neutral) nucleophiles leading to the final substituted product.

Alternatively, the elimination can be carried out under basic condition generating a neutral species V

which may undergo an addition reaction using strong (anionic) nucleophilic reagents.

This strategy constitutes a valid option and complements the venerable F-C reaction, offering

to organic chemists more synthetic flexibility for the preparation of indole derivatives.26

13

Scheme 11. Elimination and nucleophilic attack.

As it can be deduced from Scheme 11, this kind of systems are analogues of α,β-unsaturated systems

involved in the so called conjugated additions. Conjugated additions are widely used and are at the

base of a lot of different synthetic strategies in organic chemistry, in which a nucleophile is able to

attack the β position of an α,β-unsaturated carbonyl system (Scheme 12).

Scheme 12. Michael (conjugated) addition to α,β-unsaturated carbonyl systems.

The presence of an electron-withdrawing group, for example a carbonyl moiety, in a conjugated

system is able to enhance the electrophilicity of the carbon in the conjugated position leading, after the

attack of a nucleophile, to the formation of intermediates VI. This intermediate is an anionic specie

prone to accept a proton form the environment in order to restore the neutrality. This brings about the

formation of the corresponding enol intermediate VII in equilibrium with its ketone in the keto-enol

tautomerism in which the keto form, in most of the cases, predominates.

The success of the addition of nucleophiles to alkylideneindoleinines depends on a series of factors.

The most important are the ease for the formation of the reactive indolenine intermediate, the stability

of this intermediate and the aptitude of the leaving group to be eliminated under mild and controlled

conditions.27

Many leaving groups can be used for the α-functionalization of C3-alkylated indoles, for

example, substituted amines, arylsulfonyls, hydroxyl groups, sulphonamides and halide groups. They

are prone to be removed under Lewis or Brønsted acidic conditions or by Brønsted bases. Most of the

14

leaving groups can be eliminated under different protocols entailing the utilization of catalysts or

promoters and offering a great flexibility concerning the selection of the leaving group and the proper

reaction conditions.

The first precursors of C-3 substituted indoles employed for the formation of the vinylogous

iminium ion IV are derivatives of Gramine 34, a naturally occurring alkaloid present in several plant

species (Figure 10). The main pathway for gramines 37 synthesis is based on the Mannich reaction,

using imino derivatives of type 36 (Scheme 13).

34

Figure 10. Gramine

Scheme 13. Synthesis of gramine derivatives by Mannich reaction.

Nucleophilic substitution reactions on gramines can be achieved through alkylideneinolenine

intermediate as shown in Scheme 14. Considering that secondary amines are poor leaving groups in

elimination reactions, it is often advisable to preliminarily convert gramines into their quaternary

ammonium salts. Thus, as exemplified for Gramine 34, the corresponding ammonium salt 38 obtained

by methylation, can be easily eliminated under thermal conditions to give the reactive vinylogous imino

intermediate VIII which can accept a wide range of nucleophiles to give the desired products 39

(Scheme 14).

15

Scheme 14. General mechanism for the nucleophilic substitution reactions of gramines and their salts.

The strategy is particularly used in organic chemistry for the synthesis of tryptophan derivatives. Even

though different types of reactions involving gramines were published,28

they require in general troublesome protection and de-protection steps. Furthermore, the elimination of

the dialkylamino group is usually performed under harsh thermal conditions (boiling toluene or

xylenes). This aspect reduces the field of applicability of these derivatives, especially for what

concerns the sustainability of the process and the utilization in asymmetric synthesis.

Alternatively, the arylsulfonyl moiety is a well-known leaving group in elimination reactions,

that makes the corresponding indolyl derivatives excellent precursors of alkylideneindolenines.27

Furthermore, in general, it does not need harsh conditions for the elimination step and starting

materials bearing the sulfonyl group are usually stable and not prone to decomposition.

Sulfonyl indoles are relatively easy to synthetize. One pathway, for example, involves the use

of a three component coupling as shown in Scheme 15, where the products of type 42 can be

obtained with yields up to 95%.29

Scheme 15. Synthesis of sulfonyl indoles by three component reaction.

16

The mild reaction conditions needed for the elimination of the arylsulfonyl group makes

sulfonyl indoles particularly useful substrates in asymmetric synthesis which usually requires strictly

controlled reaction conditions. For example, L-proline 45 has been successfully used to catalyse the

alkylation of aldehydes 44 with arylsulfonyl-alkylindoles 43 to access 3-indolyl derivatives 46 with high

diastereo- and enantio- selectivity (Scheme 16).30

Scheme 16. α-alkylation of aldehydes with arylsulfonylindoles catalysed by L-proline.

The stereoselectivity of this reaction is governed by steric hindrance between the chiral catalyst and

the substituent at position C-2 of 43, essential to obtain a good enantioselectivity.

Later on, nitroalkanes have been used as nucleophiles for the asymmetric synthesis of 3-(2-nitroalkyl)

indoles which are precursors of tryptamine derivatives. One example is the solvent-free non-covalent

organocatalytic protocol disclosed in 2012, in which the enantioselective addition of nitroethane 48 to

alkylideneindolenines V was exploited to obtain optically active tryptamine derivatives 50 (Scheme

17).

17

Scheme 17. Catalytic asymmetric addition of nitroalkane to alkylideneindolenine.

The reaction is catalysed by the bifunctional urea 49, affording the products 50 with yields up to 98%

and enantiomeric excesses up to 99%.31

Elimination of the arylsulfonyl group can also be carried out under acidic conditions as evidenced for

the reaction of sulfonyl indoles 51 with different nucleophiles promoted by Lewis acids such as AlEtCl2,

to afford the corresponding products 52 (Scheme 18). The reaction showed yields up to 86%,

confirming the versatility of this leaving group.32

18

Scheme 18. Alkylation of sulfonyl indoles promoted by AlEtCl2.

The use of Lewis or Brønsted acids is also possible in the elimination of other groups, such as the

hydroxyl, followed by the coupling with a nucleophile. In both cases the hydroxyl is converted to a

better leaving group with subsequent formation of a cationic species of type IV stabilized by

resonance.

Brønsted acids have been particularly studied for this kind of reactions. One example is the

cooperative system of Jørgensen catalyst 55 and trifluoromethansulfonic acid (TfOH). The acid is able

to give the first dehydration step for the formation of the vinylogous iminium ion IV and it also

facilitates the formation of the chiral enamine IX from aldehyde 54 and Jørgensen catalyst 55, to

afford adducts 56 (Scheme 19).33

19

Scheme 19. Conjugate addition of chiral enamines to vinylogous imine intermediates

catalysed by the Jørgensen catalyst.

The elimination of an hydroxyl group and the subsequent coupling with a nucleophile can also be

facilitated by the presence of Lewis acids. In fact, a very similar cooperative system involving again

the Jørgensen catalyst 55 was developed using InBr3 as Lewis acid, instead of a Brønsted acid, to

catalyse a high enantioselective intermolecular α-alkylation of propanal 54 to produce the desired

functionalized products 58 in high yields and enantioselectivities, starting from 3-indolylmethanol 57

(Scheme 20).34

Scheme 20. Enantioselective intermolecular α-alkylation of aldehydes catalysed by

cooperative systems.

20

1.4 Addition of indole nucleophiles to stabilized carbocationic electrophiles

Substitutions following this mechanism can be found even in other systems not involving the indole

core. For example, the dehydration of benzyl alcohols was widely studied in the past. Shirakawa and

Kobayashi reported, for example, a study in which DBSA (dodecylbenzenesulfonic acid) is able to

catalyse the reaction between alcohols 59 and different nucleophiles in aqueous media (Figure 11).

Initially, they focused their attention on selected benzhydrol derivatives 59 as substrates because the

resulting products 60-63 contain motifs that are integral part of a number of biologically-active and

pharmaceutical compounds.

Figure 11. Tested nucleophiles and examples of biologically active compounds.

They then examined the substrate generality testing a variety of benzyl alcohols. It was found that

primary, secondary and tertiary alcohols could be applied to this reaction and that the desired C-3

substituted indoles were obtained in moderate to good yields using indoles as nucleophilic partners.

21

For example, the reaction performed with alcohol 64 in the presence of N-methylindole 65 gave a yield

of product 66 up to 96% (Scheme 21).35

Scheme 21. Nucleophilic substitution reaction of benzyl alcohol in water.

Such type of reaction was subsequently further developed by Cozzi and Zoli.36

Systems in which a

benzyl alcohol is functionalized by the presence of an amino group at the para position with respect to

the hydroxymethyl group 67 (Figure 12) were object of their investigation.

67

Figure 12. General benzyl alcohol structure.

The hydroxyl group is activated by the presence of acids, and, after its elimination, the formation the

benzylic carbocation is further stabilized by the presence of the amino group allowing an additional

resonance structure X (Scheme 22).

Scheme 22. Resonance structures after water loss in benzyl alcohols.

It has been demonstrated that the direct substitution of alcohols on water, without addition

Brønsted or Lewis acid was also possible because of the additional stabilization of the carbocationic

intermediate in the polar medium. As a matter of fact, the best result was obtained using 68 as

substrate and indole 1 as nucleophile “on water”, affording product 69 in 96% yield (Scheme 23).37

22

Scheme 23. Nucleophilic attack of indole to the benzyl alcohol, performed on water.

It is interesting to note that indole 1 behaves as the nucleophile, while reagent 68 as the electrophile

and the systems results to be very similar to the ones previously shown in which the indolyl system

was instead the electrophilic species.

Several examples are present in literature regarding benzylic and allylic alcohols wherein the

hydroxyl moiety acts as leaving group. Many reactions involve the use of indole or indole derivatives

as nucleophilic partners. Some relevant examples are shown in Table 1. The reactions are all

performed under acidic catalysis using Brønsted or Lewis acids, since the versatility of this reaction

permit to use both.

23

Table 1. Examples of alkylation of indoles with alcohols.

Entry Substrate Nucleophile

(Nu) Product

Yield

(%)

Ratio

α : γ

1

92 -

2

72 1 : 100

3

91 -

4

55 55 : 45

5

93 -

6

71 53 : 47

7

83 100 : 1

Concerning Entry 3, for example, the substrate is a simple benzyl alcohol, that in the presence of a

good nucleophile such as 5-methoxyindole is able to produce the product with a yield up to 91% under

the catalysis of PdCl2(MeCN)2.38

Taking into consideration the benzyl alcohols already discussed in which a para exocyclic

amine is able to enhance the reactivity of the substrate, it is important to underline that electro-

24

donating groups are, in general, able to participate in the stabilization of the carbocation formed by the

loss of water. In fact, substrates containing groups such as methoxy have been exploited for this

purpose (Entries 1 and 2) and, when an extended conjugated system was used as represented in

Entry 2, the nucleophile showed to be more reactive toward the less hindered position, giving a 100%

selectivity for the γ-carbon. Both substrates showed activation by FeCl3, an inexpensive and

environmentally friendly Lewis acid.39

Considering again substrates that present an extended conjugated system, we can observe

very different yields, and hence reactivity, towards nucleophilic substitutions (Entries 4-7). The

reaction of Entry 4, for example, was catalysed by monohydrated p-toluenesulfonic acid as Brønsted

catalyst and showed a low yield and α : γ ratio.40

A similar regioselectivity is shown in Entry 6, where

the reaction between the two reagents was catalysed by Pd-Sn heterobimetallic catalyst, and resulted

in a higher yield (71%).41

The products shown in entries 5 and 7 were obtain in good yields and, for entry 7, good

regioselectivity. The reactions were catalysed by different systems, since entry 5 exploited the use of

InBr3 Lewis acid,42

while entry 7 the already mentioned PdCl2(MeCN)2 catalyst.

All the previous examples make it even easier to understand the interest in this kind of

systems and the dramatic contribution that a conjugated resonance structure is able to give to the

substrate reactivity.

25

2. Scope of the Thesis work

The introduction of an additional double bond in the alkyl framework of 3-substituted indoles bearing a

leaving group LG, generates an extended vinylogous system endowed of electrophilic character upon

acid or base-assisted elimination. The two different regioisomers 70 and 71 can both generate the

neutral alkylideneindolenine XI or the corresponding cation XII depending on the activation mode

(Scheme 24). It is interesting to note that even though the substrates contain the leaving group at

different positions, once they are treated with acidic o basic promoters/catalysts, the obtained

intermediate is the same. This means that the systems presents the same reactivity and can be

attacked by a nucleophile in position α or γ, since both positions potentially present an electrophilic

character, given by the conjugation.

Scheme 24. Reactivity of vinyl indole derivatives, bearing a leaving group in α or γ position.

Occasional examples available in the literature have shown that functionalization of systems of type

70 invariably led to a substitution at the α position. In a recent paper, Huang et al. used oxindoles 72

as nucleophiles in a highly enantioselective organocatalytic substitution of 3-(1-tosylalkyl)

functionalized indoles 73, in the presence of the chiral bifunctional thiourea 74 (Scheme 25). A

complete α-selectivity was observed in the formation of adduct 75. A specific derivative 75 was used

as an advanced intermediate for the total synthesis of (+)-Trigolutes B 76 (Figure 13).43

26

Scheme 25. Asymmetric substitution of 3-(1-tosylalkyl)indoles with oxindoles.

76

Figure 13. (+)-Trigolutes B.

Concerning instead the hydroxyl as leaving group and, consequently, the use of Brønsted acids,

another example is a study by Rueping and co-workers reported in 2008 for the first catalytic

asymmetric reaction of 3-indolylmethanols in the presence of a chiral phosphoric acid 78. Indole 77

underwent a first dehydration followed by the nucleophilic attack of N-methylindole, affording 79 as the

result of an α-substitution (Scheme 26).

27

Scheme 26. Catalytic Asymmetric Substitution of 3-Indolylmethanol with N-methylindole.

The ion pair formed by the carbocation (resulting from the elimination of water) and the corresponding

anion of 78 was proposed to contribute to the control of the enantioselectivity. Even though only a

moderate value of ee was obtained, this work represented the basis for the catalytic asymmetric

reactions of 3-indolylmethanols, providing also access to enantio-enriched atropisomers.44

Taking into consideration the examples shown above it has been decided to carry out a study

aimed at driving the nucleophilic attack at the γ-position, starting from substrates of type 70 or 71. The

obtained vinylindoles 80 still retains a conjugated unsaturation making them useful substrates for e.g.

Diels–Alder (D-A) reactions (Scheme 27).

The scope of the thesis was to develop an optimized protocol in order to obtain a high level of

γ-regioselectivity, obtaining compounds of type 80 as products. We took into considerations the

already known literature for benzylic functionalization of C-3 alkylated indoles and we decided to use

vinyl indoles derivatives containing sulfonyls or hydroxyl as leaving groups. This was performed in

order to generate the reactive intermediates both under acidic or basic conditions and to study the

relative reactivity

We tried to exploit the fact that an extended conjugated system could enhance, under the

suitable conditions, the electrophilicity of the γ carbon. This was performed through optimizations

varying the different reaction parameters, from the intrinsic structure of the substrate to the reactions

conditions.

28

Scheme 27. Aim of the thesis

Vinyl indol systems able to give D-A reactions have been extensively studied.45

This approach has

been pioneered by Pindur and co-workers in 1987 showing the reactivity of 3- and 2-vinyl indoles

towards [4+2] cycloadditions.46

Reactions of 3-vinyl indoles 81 with α,β-unsaturated ketones 82 were

catalysed by aluminium trichloride, providing the corresponding tetrahydrocarbazoles 83, and followed

by a [1,3] hydrogen shift in order to restore the aromaticity of the ring and affording the final

cycloadducts 84 (Scheme 28).

Scheme 28. Pindur’s studies on [4+2] cycloaddition reactions of 3-vinylindoles.

Up to date, only few works can be found in literature for the synthesis of system containing

potentially good leaving group in γ position 71. In a very recent paper Guo and co-workers exploited

the nucleophilic reactivity of electron rich vinyl indoles towards the reaction with arylglyoxal compound

86 to produce the corresponding allyl alcohols 88. The reaction was catalysed by chiral calcium

phosphoric 87 obtaining the product not only in good yields but also with excellent enantiomeric

excess (Scheme 29).47

29

Scheme 29. Asymmetric alkelynation of arylglyoxals with 3-vinyl indoles.

30

3. Results and Discussion

3.1 Synthesis of the substrates

As already anticipated, in this thesis work we decided to focus on the γ- functionalization of vinyl

indole derivatives of type 71 (Figure 14) with different nucleophiles. We decided to investigate both

basic and acidic reaction conditions and, for this reason, we took into consideration leaving groups

such as tosyl (for basic catalysis) and hydroxyl (for acidic catalysis).

71

Figure 14.

Tosyls can be obtained from alcohols through one synthetic step. The first aim was thus the synthesis

of allylic alcohols 89, which was performed after studying a proper retrosynthetic analysis (Scheme

30).

Scheme 30. Retrosynthetic analysis for the synthesis of allyl alcohols.

As it can be observed from Scheme 30, allyl alcohol 89 can be synthetized by the selective C=O bond

reduction on an α-β-unsaturated ketone of type 90. In turn, the ketone can be obtained by the

construction of a new C-C double bond between an aldehyde 91 and a phosphorane of type 92. This

is one of the most important and known pathway in order to synthetize a new C-C double bond, known

31

as the Wittig olefination.48

In general, it involves the reaction between a carbonyl compound (mostly an

aldehyde) and a triphenyl phosphonium ylide (called the Wittig reagent).

We therefore decided to use indole-3-carboxadehyde 91 and 2-(triphenylphosphoranylidene)-

acetophenone 93 as reagents for the first synthetic step in order to obtain product 94, following a

literature procedure (Scheme 31).49

Scheme 31. Wittig reaction

The reaction was stirred at reflux in toluene for 48 hours and the product 94 was obtained in 75% yield

after purification by column chromatography.

The next step involved the selective reduction of the carbonyl moiety in order to obtain the

corresponding allyl alcohol. We performed this process using NaBH4 as reducing agent and a mixture

of THF and MeOH as reaction media in order to dissolve completely the reagents. Furthermore, we

decided to perform progressive additions of NaBH4 at 0 °C (Scheme 32). In order to see if the reaction

was complete, we monitored it through NMR analysis and we observed that sequential additions of the

reducing agent, up to 5 equivalents, were necessary.

For the purification step, the procedure involved the use of an aqueous work up with a saturated

NH4Cl solution, extraction and a final separation through column chromatography. We performed the

chromatography purification but we found out that product 95 was very unstable and very sensitive to

acids, so it decomposed during the purification because of the acidity of the silica gel. Hence, the

purification process was successfully modified through a simple basic Na2CO3 aqueous-work up and

extraction in diethyl ether. At the end the product was obtained in quantitative yield and under the form

of a green/yellow powder. Allyl alcohol 95 resulted to be very sensitive to acid, air, light and heat, so it

needed to be stored at -20 °C, under nitrogen and away from light sources.

Scheme 32. Selective reduction of α,β-unsaturated ketone double bond.

32

As already anticipated, the corresponding tosyl 96, selected for the basic catalytic tests, could be

obtained starting from the allyl alcohol. Hence, the previously synthetized product 95 was employed to

obtain allyl sulfone as shown in Scheme 33. At first, the reaction was performed with p-TSA in the

presence of sodium p-toluenesulfinate dissolved in ethyl acetate and at room temperature, following a

procedure found in literature.50

Scheme 33. Synthesis of allyl tosylate.

The salt and the acid reagents were stirred until their complete dissolution and then the substrate was

added. The reaction was stirred for 30 minutes at 0°C, then is was quenched with water and extracted

in dichloromethane. NMR analysis of the obtained crude mixture showed also the formation of product

97 derived by sulfonation at indole benzylic position. (ca. 75:25 ratio in favour of product 96). The two

isomers were not separable through column chromatography, hence the regioisomeric mixture was

kept for the successive basic catalytic tests. On the other hand, both product afford the same

alkylideneindolenine intermediate under basic reaction conditions (see Scheme 24).

33

3.2 Preliminary tests

3.2.1 Catalytic tests under basic reaction conditions

A preliminary reactivity test was performed on the allyl sulfone regioimeric mixture, following a

procedure found in literature that involved the use of K3PO4 as a base, combined with a suitable

catalyst, able to deprotonate the -NH moiety and to allow the formation of the already mentioned

electrophilic vinylogous imine intermediate V, prone to react with a nucleophilic species (Scheme

34).51

Scheme 34. Catalysis under basic conditions.

The reaction procedure involved the use of a chiral thiourea (Takemoto catalyst 99, 20 mol%) to

promote the asymmetric transformation, the use of malononitrile 98 as nucleophile and toluene as

solvent, at 30 °C. We decided to perform the reaction at room temperature and after 3 hours it was

quenched using a aqueous work up and then the crude obtained was purified through column

chromatography. Unfortunately, the reaction converged to only one product, showing a complete α-

regioselectivity, with the formation of product 100.

The product was fully characterized and its structure confirmed by means of 1H,

13C, DEPT, HMBC,

HSQC and NOESY NMR.

3.2.2 Catalytic tests under acidic conditions

The first catalytic tests under acidic conditions were all performed using diphenyl phosphoric acid 101

in order to study the reactivity of these kind of allyl alcohols under Brønsted acidic catalysis. This acid

was chosen because of the good results found in literature, obtained with phosphoric acids, chiral or

34

not, towards this kind of reactions. The first test was performed using indole 1 as nucleophile in the

presence of different amounts of the phosphoric acid 101, (1 and 10 mol%) in dichloromethane as

solvent and at a low temperature, -30 °C, to avoid decomposition of the very sensitive allyl alcohol 95

(Scheme 35).

Scheme 35. Catalysis under acidic conditions.

Using the acidic catalyst at 10 mol% loading the reaction proceeded in 30 minutes, while using it at 1

mol% proceeded in 1 hour; for this reason 10 mol% was kept as the optimal catalytic amount. The

desired product 102 was observed and isolated, even though the product 103 resulting from the α

nucleophilic attack was still formed as the major adduct.

After the initial reaction conditions were set (Scheme 36), different nucleophiles were

investigated in order to gain some information about the reactivity of the extended

alkylidenenindoleninium resulting from allyl alcohol 95. (Table 2).

35

Scheme 36. Screening of different nucleophiles under acidic catalysis.

Table 2. 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

As it can be observed from Table 2, in general, a regioisomeric mixture of α and γ functionalization

was observed (ratios from 50:50 to 90:10) in which the major product was, as expected from the first

results with indole, the undesired one, deriving from the functionalization at the indole benzylic

position, while in all the other tested systems (entry 6 to 8), including also the indole derivative 3-

methylindole, the starting alcohol 95 decomposed.

The best regioselectivity was obtained for 2-methyl and 2-phenylindole, indicating that

substitution on position C-2 of the indole nucleophile could play an important role in the regiochemistry

of the present process.

However, 2-vinylindole gave a different result, a higher α : γ ratio (entry 5), probably due to

the fact that in this case the substituent can participate in the extended conjugated system, altering its

reactivity.

From the results obtained at this stage it was not easy to determine if electronic or steric

factors were at the base of the regioselectivity shown by the reaction; however, unlike the catalytic

approach under basic conditions, the acidic one showed that the desired γ-regioisomeric products

could form, even though accompanied by substantial amounts of the undesired α-regioisomers.

Hence, this represented a good starting point for further optimization in order to reach the scope of this

thesis work.

36

3.3 Substrate optimization to reach γ-regioselectivity

Taking into consideration the steric factor, we speculated that a strategy to shift the reactivity of the

substrate to the desired γ-position was to make the indole benzylic carbon more hindered, synthetizing

a new allyl alcohol, and subsequently the respective allyl sulfone, carrying a substituent at the α

carbon. Two ways were investigated in order to obtain new substrates in which the only difference with

the previously tested ones was the presence of a methyl group at the benzylic position.

The first synthetic attempt in order to obtain the new allyl alcohol was again the Wittig reaction,

involving the same Wittig reagent 93 used before and moving from indole-3-carboxaldehyde to 3-

acetylindole 104 (Scheme 37).

Scheme 37. Wittig reaction.

The reaction was performed using the same procedure already tested and optimized, but

unfortunately it did not give the desired product 105. The presence of an acetyl group is able to

change drastically the reactivity of the carbonyl reagent; in fact, ketones are known to be much less

reactive compared to aldehydes towards Wittig reactions.

The second pathway was the one for the synthesis of substrate 108, carrying even in this case

a methyl group for steric hindrance at benzylic position (Scheme 38).

Scheme 38. Synthesis of a new substrate through Grignard reaction.

37

Substrate 108 was different from the one that we wanted to obtain with the previous Wittig reaction,

bearing the hydroxyl leaving group at the indole benzylic position. Anyway, the reactive intermediated

XII formed under acidic conditions, after the loss of a water molecule, would be the same showing

consequently the same reactivity.

The first synthetic step was the one for the obtainment of styryl magnesium bromide 107, the

Grignard reagent. It was successfully performed using a procedure already known in literature, starting

from the commercially available (E)-(2-bromovinyl)benzene 106 (Scheme 38, Step 1).

For the successive Step 2, the Grignard reaction, a solution of 3-acetylindole 104 and THF

was cooled to 0 °C and then the previously synthetized styryl magnesium bromide 107 was added

under N2 atmosphere. The reaction mixture was then left at room temperature overnight.

Unfortunately, this second step did not give the product desired 108 but, instead, the reaction

led only to decomposition products. The idea of installing a methyl group at the indole benzylic

position was therefore discarded.

In parallel, another substrate 110 was taken into consideration. The difference between the

allyl alcohol 95 and the sulfone 96 tested before was the presence of a methyl group instead of an

aromatic ring at the γ position.

The methyl and the phenyl groups are very different one to the other, concerning both steric

hindrance and the electronic features. The presence of an aromatic structure, in fact, can give a

different reactivity to the substrate and to the reactive intermediates XI or XII formed, because it is

able to participate to the whole conjugated system, while the methyl group does not, changing

drastically the behaviour of the substrates.

The new allyl alcohol 110 was thus synthetized using again a Wittig reaction between indole-

3-carboxaldehyde 91 and ylide 109 as Wittig reagent, following the previously reported procedure

(Scheme 39).

Scheme 39. Wittig reaction.

The product 110 was finally purified by column chromatography and it was successfully obtained in

85% yield, according to the literature.49

The next step was to reduce selectively the carbonyl moiety in order to obtain the final allyl

alcohol 111 (Scheme 40).

38

Scheme 40. Selective reduction of α,β-unsaturated ketone C=O.

Even in this case we followed the procedure previously performed: NMR analysis on the crude mixture

showed that the ketone was totally consumed and the allyl alcohol was the only product obtained after

1 hour and only 2 equivalent of NaBH4. The reaction was then quenched and extracted in Et2O

affording the desired alcohol 111 in quantitative yield.

Even in this case the product showed to be very unstable and prone to decomposition when in

contact with air, light, acids and heat. For this reason it was stored at -20 °C, under nitrogen and away

from light sources.

In order to take into consideration also the basic catalysis, we synthetizes the corresponding

tosyl derivative 112 from the alcohol, following the procedure previously employed. Hence, we

performed again the reaction involving p-TSA in the presence of sodium p-toluenesulfinate in ethyl

acetate, at 0 °C (Scheme 41).

Scheme 41. Synthesis of allyl tosylate.

This time the sulfonyl group was installed selectively at the γ position and the only by-product 113 was

the one coming from a double sulfonation. However, the two products could be separated through

column chromatography, enabling the obtainment of the new allyl sulfone 112 as a single product and

not as a regioisomeric mixture.

39

3.4 Study of the new substrate reactivity: Preliminary tests

3.4.1 Catalytic tests under basic conditions

The reaction conditions to test the new substrate 112 under the influence of a basic catalysis were the

same used on the substrate 96, that means the use of Takemoto catalyst 99, malononitrile 98 as

nucleophilic reagent, K3PO4 as base and toluene as reaction media (Scheme 42).

Scheme 42. Catalysis under basic conditions.

Compound 112 showed however a lower reactivity compared to 96 and for this reason the formation

of some product was observed only after heating the reaction mixture to 60 ° C overnight. We

observed the formation of a single product 114 that was isolated after column chromatography and

completely characterized. Even in this case it showed to be the one coming from the α-

functionalization of the substrate.

In the case of basic catalysis, the change in the substrate did not alter the high bias of these

substrates to react at the indole benzylic position.

40

3.4.2 Catalytic tests under acidic conditions

The allyl alcohol 111 was then tested under acidic conditions using again the phosphoric acid 101 and

the reaction conditions previously set for compound 95, in order to see if the structural change was

able to enhance the reactivity of the substrate at the desired position, promoting the attack of the

nucleophile towards a selective γ-functionalization.

Based on the results previously obtained, the first nucleophile tested was a C-2 functionalized

derivative of indole 1. In fact these derivatives were able to give a regioisomeric ratio up to 50:50 with

compound 95. 2-Methylindole was thus the first nucleophile investigated.

After 1 hour the reaction mixture showed by NMR analysis the presence of the desired product

115 with 100% of the desired regioselectivity (Table 3, Entry 1) which was isolated by column

chromatography (purification of this product proved to be in fact quite difficult, given its poor stability

over silica gel).

After this first successful result, a screening of different nucleophiles (Scheme 43) was performed in

order to study the reactivity of the allyl alcohol 111 and very different results were obtained based on

the nature of nucleophile used (Table 3).

Scheme 43. Screening of different nucleophiles under acidic catalysis.

41

Table 3. Screening of different nucleophiles.

Entry Nucleophile Product 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

As shown in Table 3, 2-methylindole (entry 1) and thiols (entries 5 and 6) were the nucleophiles able

to give the best results and the corresponding products were all isolated after purification through

column chromatography, showing poor stability over silica gel. The only difference between the two

42

classes of reagents was that phenyl and benzyl thiols were less reactive and only small amounts of

product could be obtained even after prolonged reaction times. Entries 3, 4 and 7 showed to go

towards decomposition, while simple indole (entry 2) did not give full regioselectivity for the γ-

functionalization; however, the major product was anyway found to be the desired one and not the α

product.

In can be concluded that, in general, switching from an aromatic substituent to a small alkyl

one, could make a dramatic difference in the reactivity of the alkylideneindolenine intermediate, if

acidic conditions are employed.

43

3.5 Lewis acid investigations and final optimizations

Since with simple indole 1, as it can be seen in Table 3, entry 2, it was not possible to reach a

satisfactory value of γ-regioselectivity we decided to investigate the process in more detail. Therefore,

indole 1, a more general, yet more challenging, substrate was taken as model nucleophilic partner, in

order to avoid the limitation of C-2 substituted indoles.

We decided to perform the reaction under acidic catalysis again, under the same conditions,

but for a longer time (Scheme 44). This was made in order to see if the nucleophilic attack was

reversible and if more time was necessary to force indole at the γ-position. The result was again a

mixture of the two regioisomers 116 and 119 both isolated and characterized through NMR analysis

(Table 4, entry 1).

We performed the reaction using dehydrating agents, such as MgSO4 or molecular sieves, to

see if the presence of water, both from the environment and produced as the only co-product of the

reaction, could be at the base of the not satisfactory result (ratio 70:30 γ:α). Under these new

conditions no improvements were observed.

After the negative results obtained we decided to focus on the other reaction conditions and

we started taking into consideration the choice of the acid. Diphenyl phosphoric acid 101 was probably

not the most suitable one for the reaction and consequently a screening of other acids was performed,

starting an investigation not only of Brønsted but also of Lewis acids (Scheme 44, Table 4).

Scheme 44. Screening of different acidic catalysts.

44

Table 4. Screening of different Brønsted and Lewis acids.

Entry Acid Notes and ratio α : γ

1 Diphenylphosphoric acid

(PhO) 2PO2H 30 : 70

2 Acetic acid

CH3CO2H No reaction

3 Metansulfonic acid

CH3SO3H No reaction

4 Trifluoromehansulfonic acid

CF3SO3H Decomposition

5 Trifluoroacetic acid

CF3CO2H Decomposition

6 Boron trifluoride diethyl etherate

BF3·Et2O

Low conversion

100 : 1

7 Scandium(III)triflate

Sc(OTf)3

Low conversion

50 : 50

8 Yitterbium(III)triflate

Yb(OTf)3

Low conversion

10 : 90

9 Zirconium tetrachloride

ZrCl4

Low conversion

70 : 30

10 Palladium(II)trifluoroacetate

Pd(TFA)2 Decomposition

It can be deduced that tests conducted under Brønsted acid catalysis had 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 116 (entry 7-9). In particular, Yb(OTf)3 (entry 8)

showed a cleaner reaction profile and it was chosen for the optimization of other reaction parameters,

such as the presence or absence of dehydrating agents, different catalyst loadings (20, 10 and 5

mol%), different temperatures and different reaction times.

We observed that the reaction was extremely slow at -30 °C and, instead, very fast at room

temperature; furthermore, an amount of 5 mol% of Yb(OTf)3 was found to be sufficient to promote the

reaction.

Under these new reaction conditions the process displayed a better regioselectivity, when

compared with phosphoric acid catalysis. Anyway, neither a 100% γ-selectivity nor a satisfactory

45

conversion value, was yet reached. For this reason, a new screening of different Lewis acids was

performed and the attention was set on metal triflates. The previously optimised reaction conditions,

found for Yb(OTf)3, were maintained for this new screening (Table 5).

We chose also to monitor the reactions, at different times (40 minutes, 2.5 hour and 6 hours),

by analysing the crudes through NMR spectroscopy, taking into consideration the conversion (taking

indole as the limiting reagent), the yield (using bibenzyl as internal standard) and the regioselectivity

values (Scheme 45).

Scheme 45. Screening of different metal triflates.

46

Table 5. Screening of different Lewis acids triflates at different reaction times.

Triflate Reaction time Ratio α : γ Conversion (%) Yield (%)

Yitterbium(III)

40 min 1 : 6 42 33

2.5 h ND ND ND

6 h 1 : 2 66 42

Scandium(III)

40 min ND - -

2.5 h ND - -

6 h Decomposition - -

Zinc(II)

40 min 1 : 15 46 36

2.5 h ND 52 43

6 h 1 : 14 52 43

Europium(II)

40 min 1 : 100 16 18

2.5 h 1 : 5 46 52

6 h 1 : 10 56 44

Indium(III)

40 min 1 : 100 53 38

2.5 h ND ND ND

6 h - - -

Lanthanum(III)

40 min 1 : 100 13 10

2.5 h 1 : 6 39 34

6 h 1 : 7 44 32

Alluminium(III)

40 min 1 : 5 55 36

2.5 h 1 : 6 53 35

6 h No more alcohol - -

Magnesium(II)

40 min No reaction - -

2.5 h 1 : 100 16 11

6 h 1 : 100 13 8

Cerium(III)

40 min 1 : 6 45 35

2.5 h 1 : 6 46 33

6 h - - -

Silver(I)

40 min 1 : 7 49 36

2.5 h 1 : 12 42 24

6 h ND ND ND

47

The spectra obtained were not very clean, hence in some cases it was not easy to interpret them and

to define a precise response. Anyway, it can be affirmed that, in general, the reactions showed good

regioselectivities for the γ-functionalization. Under these reaction conditions the product seemed to be

stable enough and the various decomposition signals observed in the NMR spectra came from the

degradation of the allyl alcohol 111 predominantly. We could confirm it because we worked in excess

of alcohol (1.5 equivalent with respect to the indole) and, at the end of the reaction, while the

nucleophile (indole) was still present, the signals of the alcohol, in most of the cases, were no longer

detected.

In order to improve the conversion and the yield values, the reaction conditions required

further optimization. For this aim Zn(II) and Eu(III) triflates were selected because of their cleaner

reaction profiles and general better results. In fact, they gave the best values not only in terms of

conversion but also of yields and γ : α ratios.

We performed a screening of different solvents, choosing toluene, acetonitrile and THF

(Scheme 46). The choice was made on the basis of their very different features. Toluene is an

aromatic apolar solvent, acetonitrile is very polar an miscible with water and THF is a less polar

solvent that stand on the class of ethereal compounds. Again, the reactions were monitored at

different times (40 minutes, 3 and 6 hours) through NMR analysis. (Table 6).

Scheme 46. Screening of different Lewis acid catalysts and solvents.

48

Table 6. Screening of different solvents.

Solvent Reaction time Alcohol

remained Ratio α : γ Conversion (%) Yield (%)

E U R O P I U M

Toluene

40 min Abundant 1 : 100 32 27

3 h Few 1 : 6 65 46

6 h Few 1 : 5 59 56

CH3CN

40 min Unclear

spectrum - - -

3 h - - - -

6 h - - - -

THF

40 min Few 1 : 2.5 69 73

3 h - 1 : 2 70 79

6 h - - - -

Z I N C

Toluene

40 min Abundant 1 : 100 17 12

3 h Few 1 : 3 52 37

6 h Few 1 : 5 54 47

CH3CN

40 min Few 1 : 17 70 60

3 h - 1 : 17 67 54

6 h - - - -

THF

40 min Few 1 : 5 74 67

3 h - 1 : 2.5 77 72

6 h - - - -

The reaction was considered complete when no more indole was observed. Concerning Eu(OTf)3 in

toluene, a 100% γ-selectivity was showed at the beginning of the reaction (40 minutes) but, after 3

hours, the product coming from the α-functionalization was detected, hence a consequent lowering in

the γ:α ratio was obtained. The reaction performed in THF gave a higher yield, but at the same time, a

lower regioselectivity.

The reaction of Zn(II) triflate in toluene gave almost the same results of Europium, with an

initial univocal selectivity for the nucleophilic attack at the γ-position, and a subsequent formation of

the α-functionalized product. The reaction in THF provided high yields but poor α:γ ratios, while the

reaction performed in acetonitrile gave, after 2.5 hours, only the desired product, even if in lower yield.

We therefore decided to choose Zn(OTf)2 as catalyst and acetonitrile as solvent to continue

the protocol optimization, since the yield value was improved compared to dicholoromethane The

spectrum obtained was furthermore much cleaner with respect to all the others, showing less

decomposition signals.

49

As already mentioned, allyl alcohol 111 was found to be unstable and sensitive to acids,

leading to several decomposition by-products. We decided to proceed with the protocol optimization

trying to perform progressive additions of this substrate during the reaction. In this way the little

amount added was able to react very quickly and had no time to go toward decomposition pathways.

Additions of 0.5 eq. were performed every 30 minutes, until reaching 2 equivalents of alcohol and

therefore the reaction proceeded for 2 hours (Scheme 47).

At the end of the reaction, the conversion resulted to be practically complete, in fact no more

indole 1 was observed in the NMR spectrum of the crude product obtained. After this successful

result, we performed the reaction again, this time using an amount of just 1 mol% of catalyst. This

change produced a lowering of the reaction rate. Consequently, the additions of 0.5 equivalents were

performed again until reaching 2 final equivalents, but every hour and not every 30 minutes, in order to

give the catalyst enough time to promote the conversion of the alcohol into product 116 (Scheme 47).

Scheme 47. Tests of different reaction conditions adding the substrate in small portions.

Even this time the reaction showed an almost complete conversion of alcohol 111 to de desired

product 116 with 100% γ-regioselectivity. No benzylic functionalized product was detected and the

NMR spectrum showed only little signals of decomposition.

It is interesting to notice that even if the change in the catalytic amount was considerable, it produced

only a slight change in the obtained result. For this reason we decided to keep 1 mol% as the optimal

catalytic amount. A further experiment performed with 0.1 mol% catalyst loading showed no

conversion after 6 h.

As already discussed, the products obtained by the nucleophilic attack at the γ-positions, are

very sensitive and could not be readily isolated directly through column chromatography, since they

partly decompose in contact with silica gel. For this reason, a stabilization strategy was taken into

consideration. We decided to try the functionalization of the nitrogen atoms through tosylation,

adapting a literature procedure. In this way, the product should be less electron rich, thus more stable

under acidic (i.e. silica gel) conditions. Even if the reaction could be performed in a one-pot manner, it

required considerable optimization, as described in the following paragraphs (Scheme 48).52

50

Scheme 48. Tosylation of the catalytic product.

The reaction involved the use of tosyl chloride as tosylating agent, a solution of KOH (50% w/w) as the

base, able to deprotonate the NH hydrogen, and the use of a phase transfer catalyst (tetra-n-

butylammonium hydrogen sulfate) in toluene. Hence, at the end of the catalytic reaction, acetonitrile

was evaporated and the crude product was directly tosylated under the described conditions. The

crude product was purified by column chromatography, affording the desired, stable, tosylated product

120 in 25% yield.

Unfortunately, the NMR spectrum of the crude mixture showed several signals due to the

presence of by-products. This was assumed as the reason of the low yield obtained. We thus modified

the protocol, trying to perform the reaction using the same solvent used for the first step of the

reaction, acetonitrile, in order to avoid the concentration of the unstable product 116. We decided also

to lower the temperature for the tosylation step, from room temperature to 0°C, in order to minimize

the formation of by-products. The reaction was also monitored using TLC analysis until no more

starting materials were detected. Then, to avoid the aqueous work up, the crude mixture was simply

filtered over celite. The NMR spectrum of the crude obtained resulted to be much more clean than

before. Product 120 was subsequently successfully purified through column chromatography and

isolated in 69% yield.

After this positive result, the reaction was performed again under the same optimized

conditions with different nucleophiles (Scheme 49). Indole derivatives carrying substituents of different

nature and at different positions were taken into consideration (Table 7).

51

Scheme 49. Reactions with different indole nucleophiles under the optimized reaction conditions.

52

Table 7. Reaction with different indole derivatives.

Products and relative yields

Different yields, ranging from 35 to 72%, were obtained. This can be easily explained by the nature but

also the position of the substituents on the indole ring. In general, electron rich indole derivatives

containing electron-donating groups, such as methoxy (compounds 124 and 126) have a more

nucleophilic character and thus are more reactive towards this kind of reactions. On the other hand,

electron withdrawing substituents such as chlorine, make position C-3 of indole less electron rich, that

means less nucleophilic, bringing to lower yields (compound 123). Substituents such as methyl groups

were in general able to give results similar to the one reported for unsubstituted indole 1, as 2-methyl

and 7-methyl indoles gave the same 66% yield (compounds 122 and 125).

53

It is also interesting to note the behaviour of the products towards the tosylation step, since, in

some cases, only a mono-tosylated product was obtained. Monotosylation occurred with 2-methyl-, 7-

substituted indoles (compounds 122, 125 and 126) probably because of the steric hindrance in

proximity to the nitrogen atom.

After the good results obtained with a variety of substituted indoles, we decided to test the

reaction taking N-methylpyrrole as the nucleophilic partner (Scheme 50). It was taken into

consideration in order to see if the optimized reaction conditions could be applied to other

nucleophiles, since indole and pyrrole present similar features but they are not identical. In fact, one

difference is the fact that pyrrole tends to attack an electrophilic species with its C-2 and not C-3

carbon.

Scheme 50. N-methylpyrrole as nucleophilic reagent.

The obtained crude was analysed by NMR showing that the reaction gave dimer 127 as major

product, that was then isolated via column chromatography after tosylation. This compound arises

from the attack of the nucleophile at both its C-2 positions, since both are free and reactive. After the

first attack the adduct obtained results to be still reactive enough to give a nucleophilic attack on a

second electrophile and in both cases the nucleophilic attack was obtained at the γ position. The NMR

spectrum showed the presence of two diastereoisomers (in a 2:1 ratio): the meso and the racemic

isomers, both symmetrical: the first for the presence of a plane and the second of a C2 axis of

symmetry.

This can be considered a gratifying result, since the reaction showed the desired regioselectivity even

though the nucleophile used was different from an indole derivative. Although the reaction conditions

would need optimization depending on the nucleophile and on its reactivity, it can be affirmed that, in

general, this protocol could be expanded on other systems. This could be a good starting point to

obtain building blocks useful for the construction of more sophisticated systems.

54

4. Preliminary test for synthetic elaborations

As already discussed, the desired product of type 80, that is a substituted 3-vinyl indole, is very

interesting since it still retains the exocyclic double bond, that could be further functionalised. This kind

of substrates can be considered as dienes and hence are able to give D-A cycloaddition reactions. In

literature various examples of these reactions involving 3-vinyl indoles derivatives can be found.

We tested the reactivity of our substrate toward cycloadditions using product 115, obtained by the

reaction between allyl alcohol 111, 2-methylindole as nucleophile under Brønsted acid catalysis.

Because of the difficulty of isolating the product of the first reaction step, we performed the reaction in

a one-pot protocol.

The dienophile that we chose to perform the reaction with was the commercially available N-

phenylmaleimide 128 (Scheme 51).

Scheme 51. Cycloaddition reaction.

When the first step was complete, N-phenylmaleimide was added to the reaction mixture, maintaining

the temperature at -30 °C. The mixture was continuously monitored using TLC analysis until no more

intermediate (the γ-functionalized product) was observed. The adduct obtained through this second

55

step is cycloadduct 129 in which the indole has lost its aromaticity. For this reason, a shift of the newly

formed exocyclic double bond was performed under acidic conditions.

A column chromatography purification was performed in order to purify the product 130 that

was successfully obtained as a single diastereoisomer.

The reactivity of the substrate was then studied, more in detail, trying to perform this reaction

through a three component pathway. This means that the allyl alcohol 111, the nucleophile and the

dienophile 128 were placed together in the reaction flask, at the very beginning of the reaction

(Scheme 52).

Scheme 52. Three component reaction.

After adding all the reagents in the flask, the reaction mixture was cooled to -30 °C and then

phosphoric acid 101 was added to start the reaction. The mixture was stirred for two days and then

the double bond shift was performed. The formation of product 130 was observed together with some

impurities coming from decomposition pathways. Product 130 was purified through column

chromatography and obtained in 50% yield.

This is only a preliminary test, but demonstrates that this kind of products are actually reactive

toward [4+2] cycloadditions, as expected. This feature renders the products obtainable with the

disclosed vinylogous reaction very interesting from the synthetic point of view. In fact, they are

probably amenable to other cycloadditions present in the literature. This protocol could be used in

order to obtain structurally sophisticated compounds.

56

5. Conclusions and outlook

In this thesis, 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

made the substrate able to interact with a nucleophile.

Two different leaving groups, sulfonyl and hydroxyl have been used which activation can be carried

out under basic and acidic catalysis respectively. After synthetizing the proper substrates 95 and 96,

some preliminary tests have been performed. We observed that under basic catalysis, using

sulfonylated substrates 96, the α-functionalized product was exclusively obtained. Conversely, the

Brønsted acidic activation carried out on hydroxy derivatives was able to afford the desired γ-products

even if with low regioselectivity.

In order to increase the regioselectivity of the process, different aspects of the reaction have been

studied. First of all, an optimization of the starting substrate was necessary to force the nucleophilic

attack towards the desired γ-position. In particular, we decided to change the substituent attached to

the carbon that brought the leaving group. A phenyl ring was replaced by a methyl, and, as it can be

deduced by the very different features between the two, different results were obtained in the tests

performed on the new substrates 111 and 112.

Concerning the basic catalysis we observed that the new allyl sulfonyl substrate was, as before, totally

selective for the α functionalization, hence we abandoned this compound as substrate. On the other

hand, the use of the substrate 111 under acidic catalysis was able to produce the desired product with

100% γ-selectivity, using 2-methylindole, benzylthiol and tiophenol as nucleophiles.

Concerning simple indole as nucleophile, it proved to be a more challenging one, affording the

corresponding product in a 70 : 30 γ:α ratio. In order to optimize the reaction we took into

consideration different acids, different catalyst amounts, different reaction temperature and solvents.

We performed an extensive screening and, ultimately, we selected the Lewis acid Zn(OTf)2 in 1 mol%

as new acidic catalyst and acetonitrile as reaction medium. We observed that the reaction was very

fast at room temperature and that portion-wise additions of the allyl alcohol were necessary. Since the

product obtained resulted unstable we performed the tosylation of the indole nitrogens in order to

stabilize it, obtaining the corresponding product in 69% yield after chromatography on silica gel. After

this thorough optimization, the reaction was performed with different nucleophiles, focusing on indole

derivatives and N-methylpyrrole. The obtained results confirmed that the protocol is versatile and able

to give the desired products with full regioselectivity.

Finally we decided to test the reactivity of the product toward D-A reaction, since 3-vinyl indole

derivative can be considered as dienes. We performed it using the product obtained with allyl alcohol

and indole under Brønsted catalysis and N-phenylmaleimide as dienophile. The desired adduct was

obtained confirming the expected possibility of further functionalization of the product for the

construction of structurally diverse compounds.

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. This

57

will be useful to confirm if the protocol can be extended not only to different nucleophilic species but

even to different electrophilic ones, since we observed drastic changes in the reactivity by small

variations in the structure of the substrate.

As far as the synthetic elaborations are concerned, the D-A reaction will be attempted under Zn(OTf)2

catalysis and with different electrophiles, in order to expand the range of products obtainable through

the disclosed process.

58

6. Experimental section

6.1 General

1H and

13C NMR spectra were recorded on a Varian Inova 300, Mercury 400 or Inova 600

spectrometer. Chemical shifts (δ) are reported in ppm relative to residual solvents signals for 1H and

13C NMR.

13C NMR were acquired with

1H broad-band decoupled mode. Chromatographic

purifications were performed using 70-230 mesh silica. Mass spectra were recorded on a Waters Xevo

Q-TOF spectrometer.

Analytical grade solvents and commercially available reagents were acquired from common

commercial sources and used as received, unless otherwise stated.

59

6.2 General procedure for the synthesis of Phophonium salts

Scheme 53.

A solution of triphenyl phosphine (50 mmol), α-haloketone (50 mmol) in toluene (50 mL) was refluxed

under stirring for 3 h. The mixture was then cooled to room temperature and the resulting precipitate

was filtered and washed several times with Et2O to afford pure phosphonium salts as white crystals.

(2-oxo-2-phenylethyl)triphenylphosphonium bromide

Following the general procedure and using α-bromoacetophenone, product

131 was obtained as a white powder in quantitative yield (23 g). MW:

461.33 g/mol.

(2-oxopropyl)triphenylphosphonium chloride

Following the general procedure and using α-chloroacetone, product 132 was

obtained as a white powder in quantitative yield (17.74 g). MW: 354.81 g/mol.

60

6.3 General procedure for the synthesis of Ylides

Scheme 54.

In a round bottom flask equipped with a magnetic stirring bar, the desired phosphonium salt (20 mmol)

and dichloromethane (70 ml) were added, followed by the addition of a 2M NaOH aqueous solution

(35 ml). The reaction mixture was stirred at room temperature for 30 minutes and poured in a

separatory funnel. The organic layer was separated, the aqueous phase is extracted with

dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, filtered

and evaporated in vacuo to afford a crude product directly employed in the next Wittig reaction.

1-phenyl-2-(triphenyl-l5-phosphaneylidene)ethan-1-one

Following the general procedure and using (2-oxo-2-phenylethyl)triphenyl

phosphonium bromide as salt, product 93 was obtained in quantitative yield

as a white powder. 1H NMR (300 MHz, Chloroform-d): δ 6.40 (d, J= 12, 2H),

7.51 (t, J = 7.7, 2H), 7.64–7.69 (m, 7H), 7.75–7.78 (m, 3H), 7.93–7.98 (m,

6H), 8.39 (d, J =7.7, 2H).

1-(triphenyl-l5-phosphaneylidene)propan-2-one

Following the general procedure and using (2-oxopropyl)triphenyl phosphonium

chloride as salt, product 109 was obtained in quantitative yield as a white

powder. 1H NMR (300 MHz, Chloroform-d): δ 2.12 (s, 3H), 3.72 (bs, 1H), 7.45–

7.50 (m, 6H), 7.54–7.58 (m, 3H), 7.65–7.70 (m, 6H).

61

6.4 General procedure for the synthesis of α-β-unsaturated ketones: Wittig reaction

Scheme 55.

In a round bottom flask equipped with a magnetic stirring bar and a reflux condenser , the indole-3-

carboxyaldehyde (10 mmol) and toluene (20 ml) were added followed by the addition of the ylide (12

mmol). The reaction mixture was stirred at reflux for 24 hours and then 5 mmol of ylide were added.

After 24 hours the reaction mixture was cooled at room temperature and the obtained crude oil was

directly purified by column chromatography on silica gel (n-hexane/EtOAc mixtures) to afford the

desired products.

(E)-3-(1H-indol-3-yl)-1-phenylprop-2-en-1-one

Following the general procedure from indole-3carboxaldehyde and 1-

phenyl-2-(triphenyl-l5-phosphaneylidene)ethan-1-one the product 94

was obtained in 75 % yield (1.95 g) as a yellow powder. MW: 247

g/mol. 1

H NMR (300 MHz, Chloroform-d) δ 8.72 (bs, 1H), 8.12 (d, J =

15.6 Hz, 1H), 8.09 – 8.00 (m, 3H), 7.68 – 7.42 (m, 6H), 7.37 – 7.28 (m,

2H).

(E)-4-(1H-indol-3-yl)but-3-en-2-one

Following the general procedure from indole-3-carboxaldehyde and 1-

(triphenyl-l5-phosphaneylidene)propan-2-one the product 110 was obtained

in 85% yield (1.57 g) as a yellow powder and after purification through column

chromatography (eluent: 6:4-hexane:ethyl acetate). MW: 185 g/mol. 1H NMR

(400 MHz, Chloroform-d) δ 9.19 (bs, 1H), 7.96 – 7.89 (d, 1H), 7.82 (d, J = 15.6

Hz, 1H), 7.54 (d, J = 2.8 Hz, 1H), 7.47 – 7.42 (d, 1H), 7.32 – 7.23 (dd, 2H),

6.82 (d, J = 16.1 Hz, 1H), 2.41 (s, 3H). 13

C NMR (101 MHz, cdcl3) δ 199.1, 137.8, 137.3, 129.7, 125.3,

123.5, 123.0, 121.6, 120.4, 113.5, 112.0, 27.3.

62

6.5 General procedure for the reduction of α,β-unsaturated ketones: Synthesis of allyl alcohols

Scheme 56.

In a round bottom flask equipped with a magnetic stirring bar, the desired α,β-unsaturated ketone (6

mmol) was dissolved in a mixture of THF and MeOH (20 mL and 30 mL). The reaction was cooled to 0

°C and then NaBH4 (12 mmol or 30 mmol) was added in portions. The reaction mixture was stirred at

0 °C for 1 hour or 3 hours and then the solvent was evaporated in vacuo. The obtained crude oil was

dissolved in Et2O and treated with a saturated Na2CO3 aqueous solution. The organic layer was

separated and the aqueous phase was extracted with Et2O. The combined organic layers were dried

over MgSO4, filtered and evaporated in vacuo.

NOTE: The product is extremely acid sensitive and must be stored under nitrogen in a dark

refrigerated (-20 °C) environment. It can be although weighted in air if immediately stored back under

the previous conditions.

(E)-3-(1H-indol-3-yl)-1-phenylprop-2-en-1-ol

Following the general procedure product 95 was obtained as a

green/yellow powder in quantitative yield after 3 hours and after 3 hourly

additions of NaBH4 (2 eq., 2 eq. and 1 eq.), starting from (E)-3-(1H-indol-

3-yl)-1-phenylprop-2-en-1-one 94 as substrate. MW: 249 g/mol. 1H NMR

(300 MHz, Chloroform-d) δ 8.17 (bs, 1H), 7.85 (ddt, J = 7.6, 1.6, 0.8 Hz,

1H), 7.53 – 7.46 (m, 2H), 7.43 – 7.35 (m, 3H), 7.34 – 7.21 (m, 3H), 7.21

– 7.14 (m, 1H), 6.88 (ddd, J = 15.9, 1.2, 0.6 Hz, 1H), 6.41 (dd, J = 15.9, 6.9 Hz, 1H), 5.42 (dd, J = 7.1,

2.9 Hz, 1H), 2.05 (d, J = 3.4 Hz, 1H).

(E)-4-(1H-indol-3-yl)but-3-en-2-ol

Following the general procedure product 111 was obtained in quantitative yield

as a white solid after 1 hour and with 2 eq. of NaBH4, from (E)-4-(1H-indol-3-

yl)but-3-en-2-one 110 as substrate. MW: 187 g/mol. 1H NMR (400 MHz,

Chloroform-d) δ 8.25 (bs, 1H), 7.90 – 7.85 (m, 1H), 7.37 (ddd, J = 8.0, 1.4, 0.8

Hz, 1H), 7.26 – 7.11 (m, 3H), 6.76 (d, J = 16.0, 1.1, 0.6 Hz, 1H), 6.27 (dd, J =

16.0, 6.8 Hz, 1H), 4.57 – 4.46 (m, 1H), 1.42 (d, J = 6.3 Hz, 3 H). 13

C NMR (101

MHz, cdcl3) δ 136.8, 130.3, 125.6, 123.6, 122.61, 122.55, 120.3, 120.0, 114.4,

111.4, 70.0, 23.7.

63

6.6 General procedure for the synthesis of allyl sulfonyl from allyl alcohols

Scheme 57.

In a round bottom flask equipped with a magnetic stirring bar, p-toluenesulfonic acid (0.1 mmol) and

sodium p-toluene sulfinate (0.1 mmol) were dissolved in ethyl acetate (2 ml) at room temperature. The

reaction mixture was cooled to 0 °C and then the allyl alcohol (0.1 mmol) was added. The reaction

mixture was stirred at 0 °C for 1 hour and then quenched with water. The organic layer was separated

and the aqueous phase was extracted with dichloromethane. The combined organic layers were dried

over MgSO4, filtered and evaporated in vacuo to afford the desired product.

(E)-3-(3-tosylbut-1-en-1-yl)-1H-indole

Following the general procedure, product 112 was obtained in 75% yield as a

pink solid, from (E)-4-(1H-indol-3-yl)but-3-en-2-ol 111 as substrate. MW: 325

g/mol. 1H NMR (300 MHz, Chloroform-d) δ 8.27 (bs, 1H), 7.79 – 7.69 (m, 3H),

7.38 (dt, J = 8.1, 1.0 Hz, 1H), 7.30 (s, 1H), 7.25 – 7.13 (m, 4H), 6.52 (d, J =

16.0 Hz, 1H), 6.01 (dd, J = 16.0, 8.3 Hz, 1H), 3.86 (m, J = 7.5, 6.6 Hz, 1H), 2.42

(s, 3H), 1.57 (d, J = 6.9 Hz, 3H).

64

6.7 General procedure for γ-functionalization: catalytic tests under basic conditions

Scheme 58.

In a test tube equipped with a magnetic stirring bar, the allyl sulfone (0.11 mmol) , malonitrile (0.1

mmol), Takemoto catalyst (20 mol%, 0.02 mmol), K3PO4 (0.11 mmol) and toluene (1 ml) were added.

The reaction mixture was stirred for 4 hours and then the obtained crude oil was directly purified by

column chromatography on silica gel (n-hexane/EtOAc mixtures) to afford the desired products.

65

6.8 General procedure for γ-functionalization: catalytic tests with phosphoric acid

Scheme 59.

In a test tube equipped with a magnetic stirring bar, the allyl alcohol (0.1 mmol), the nucleophile (0.1

mmol) and dichloromethane (250 µl) were added. The reaction mixture was cooled at -30 °C and then

the phosphoric acid catalyst (10 mol%, 0.01 mmol) was added. The reaction mixture was stirred for 4

hours and then quenched with water. The organic layer was separated and the aqueous layer

extracted with dichloromethane. The combined organic layers were dried over MgSO4, filtered and the

solvent was evaporated in vacuo. The crude product obtained was purified by column chromatography

on silica gel (n-hexane/EtOAc mixtures) to afford the desired products.

Only α products characterizations are shown below since γ products will be subsequently

characterized after the appropriate stabilization and isolation. Instead, only the phenyl tiol γ product is

here reported because it was not used in the next section for the Lewis acid tests.

(E)-3,3'-(3-phenylprop-2-ene-1,1-diyl)bis(1H-indole)

Following the general procedure the product 103 was obtain in 83%

yield as an off-white solid from (E)-3-(1H-indol-3-yl)-1-phenylprop-2-en-1-

ol as substrate and indole as nucleophile. MW: 348 g/mol. 1H NMR (300

MHz, Chloroform-d) δ 7.93 (bs, 2H), 7.61 (ddt, J = 7.9, 1.3, 0.7 Hz, 2H),

7.37 (dt, J = 8.1, 1.0 Hz, 4H), 7.34 – 7.22 (m, 2H), 7.19 (ddd, J = 8.2, 7.1,

1.2 Hz, 3H), 7.06 (ddd, J = 8.1, 7.0, 1.0 Hz, 2H), 6.94 (dd, J = 2.4, 0.9

Hz, 2H), 6.81 (dd, J = 15.8, 7.0 Hz, 1H), 6.55 (dd, J = 15.8, 1.2 Hz, 1H),

5.42 (d, J = 7.0, 1.1 Hz, 1H).

(E)-3,3'-(but-2-ene-1,1-diyl)bis(1H-indole)

Following the general procedure product 119 was obtained as an off-white

solid, from (E)-4-(1H-indol-3-yl)but-3-en-2-ol as substrate and indole as

nucleophile. MW: 286 g/mol. 1H NMR (400 MHz, Chloroform-d) δ 7.92 (s, 2H),

7.59 – 7.53 (m, 2H), 7.35 (dt, J = 8.1, 0.9 Hz, 2H), 7.17 (ddd, J = 8.3, 7.0, 1.2

Hz, 2H), 7.04 (ddd, J = 8.1, 7.0, 1.0 Hz, 2H), 6.91 (dd, J = 2.4, 0.9 Hz, 2H), 6.09

– 5.98 (ddq, 1H), 5.71 – 5.58 (m, 1H), 5.22 – 5.15 (m, 1H), 1.72 (ddd, J = 6.5,

1.7, 1.0 Hz, 3H).

66

(E)-3-(3-(phenylthio)but-1-en-1-yl)-1H-indole

Following the general procedure, product 117 was obtained as an oil,

from (E)-4-(1H-indol-3-yl)but-3-en-2-ol as substrate and phenyl tiol as

nucleophile. MW: 279 g/mol. 1H NMR (300 MHz, Chloroform-d) δ 8.06

(bs, 1H), 7.84 – 7.73 (m, 1H), 7.49 – 7.43 (m, 2H), 7.38 – 7.33 (m, 1H),

7.30 – 7.26 (m, 1H), 7.25 – 7.12 (m, 5H), 6.44 (d, J = 15.9 Hz, 1H), 6.16

(dd, J = 15.9, 8.2 Hz, 1H), 4.04 – 3.88 (m, 1H), 1.52 (d, J = 6.8 Hz, 3H).

67

6.9 General procedure for γ-functionalization: Lewis acid catalysis

In a test tube equipped with a stir bar, indole (0.1 mmol), allyl alcohol 111 (X mmol), bibenzyl (internal

standard) and solvent (X ml) are added. The mixture is cooled to 0 °C and then the proper Lewis acid

is added (x mol% ). The reaction mixture is then warmed at r.t and controlled periodically using TLC

and NMR to check the conversion, the yield (by means of the internal standard) and the α:γ ratio. The

mixture is filtered over celite every time and the solvent is evaporated in vacuo.

68

6.10 General optimized procedure for γ-functionalization under Lewis acid catalysis

Scheme 60.

In a test tube equipped with a stir bar, the desired substituted indole (0.1 mmol), the allyl alcohol 111

(0.05 mmol) and acetonitrile (2 ml) were added. The mixture was cooled to 0 °C and then Zn(OTf)2

was added (1 mol% 0.001 mmol). Then 0.05 mmol of alcohol 111 were added hourly until, after 4

hours, 0.2 mmol were reached. Then, tosyl chloride (0.24 mmol), tetra-n-butylammonium hydrogen

sulfate (0.01 mmol) and a 50% aqueous potassium hydroxide solution (100 µL) were added to the

reaction flask and the mixture was vigorously stirred for 1 hour at 0 °C. The mixture was filtered over

celite and the solvent was evaporated in vacuo. The crude product was then dissolved in toluene and

a little quantity of dichloromethane and purified by column chromatography, using the proper eluent.

(E)-3,3'-(but-1-ene-1,3-diyl)bis(1-tosyl-1H-indole)

Following the general procedure the product 120 was obtained in 69%

yield (40.9 mg) as a white powder, from indole as nucleophile. MW:

594 g/mol. 1H NMR (400 MHz, Chloroform-d) δ 7.98 (tt, J = 8.1, 0.9

Hz, 2H), 7.79 – 7.73 (m, 4H), 7.58 (dddd, J = 23.5, 7.9, 1.3, 0.8 Hz,

2H), 7.49 (s, 1H), 7.40 (d, J = 1.1 Hz, 1H), 7.31 (ddt, J = 8.5, 7.2, 1.5

Hz, 2H), 7.25 – 7.17 (m, 6H), 6.47 – 6.36 (m, 2H), 3.83 (tt, J = 7.1, 6.1

Hz, 1H), 2.33 (d, J = 1.9 Hz, 6H), 1.55 (d, J = 7.0 Hz, 3H). 13

C NMR

(101 MHz, cdcl3) δ 144.9, 144.8, 135.5, 135.4, 135.3, 135.1, 134.9,

130.3, 129.88, 129.86, 129.8, 129.1, 126.82, 126.77, 126.4, 124.8, 124.6, 123.3, 123.2, 123.0, 122.3,

120.31, 120.26, 120.1, 119.8, 113.8, 113.7, 34.4, 21.5, 20.2.

69

(E)-1-methyl-3-(4-(1-tosyl-1H-indol-3-yl)but-3-en-2-yl)-1H-indole

Following the general procedure the product 121 was obtained in 56%

yield (25.4 mg) as a white powder, from N-methylindole as nucleophile.

MW: 454 g/mol. 1H NMR (600 MHz, Chloroform-d) δ 7.97 (dt, J = 8.3,

0.9 Hz, 1H), 7.77 – 7.71 (m, 2H), 7.68 (ddt, J = 14.2, 7.9, 0.9 Hz, 2H),

7.51 (s, 1H), 7.33 – 7.27 (m, 2H), 7.22 (tdd, J = 8.1, 2.6, 1.1 Hz, 2H),

7.19 (d, J = 8.1 Hz, 2H), 7.08 (ddd, J = 8.1, 7.0, 1.0 Hz, 1H), 6.89 (s,

1H), 6.56 – 6.49 (m, 2H), 4.02 – 3.89 (m, 1H), 3.76 (s, 3H), 2.32 (s, 3H),

1.57 (d, J = 7.1 Hz, 3H). 13

C NMR (151 MHz, cdcl3) δ 144.8, 137.2, 137.1, 135.5, 135.2, 129.8, 129.3,

127.1, 126.8, 125.3, 124.7, 123.3, 122.9, 121.6, 120.9, 120.4, 119.6, 118.7, 118.6, 118.5, 113.7,

109.2, 34.6, 32.7, 21.5, 20.9.

(E)-2-methyl-3-(4-(1-tosyl-1H-indol-3-yl)but-3-en-2-yl)-1H-indole

Following the general procedure the product 122 was obtained in 66%

yield (29.9 mg) as a white powder, from 2-methylindole as nucleophile.

The product was afforded as monotosylate. MW: 454 g/mol. 1H NMR

(400 MHz, Chloroform-d) δ 7.97 (dt, J = 8.3, 0.9 Hz, 1H), 7.74 (dd, J =

8.5, 6.6 Hz, 3H), 7.64 (ddt, J = 23.2, 7.9, 0.9 Hz, 2H), 7.49 (s, 1H), 7.34

– 7.25 (m, 2H), 7.26 – 7.15 (m, 3H), 7.11 (ddd, J = 8.0, 7.1, 1.2 Hz, 1H),

7.04 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 6.66 (dd, J = 16.2, 5.6 Hz, 1H),

6.47 (ddd, J = 16.2, 1.9, 0.7 Hz, 1H), 3.99 – 3.87 (m, 1H), 2.43 (s, 3H), 2.32 (s, 3H), 1.59 (d, J = 7.2

Hz, 3H). 13

C NMR (101 MHz, cdcl3) δ 144.8, 136.6, 135.5, 135.3, 135.2, 130.3, 129.8, 129.3, 127.5,

126.8, 124.7, 123.3, 122.8, 121.0, 120.8, 120.4, 119.2, 119.0, 118.3, 114.5, 113.7, 110.3, 34.0, 21.5,

20.3, 12.2.

(E)-5-chloro-1-tosyl-3-(4-(1-tosyl-1H-indol-3-yl)but-3-en-2-yl)-1H-indole

Following the general procedure the product 123 was obtained in 35%

yield (21.9 mg) as a white powder, from 5-chloroindole as nucleophile.

MW: 628 g/mol. 1H NMR (400 MHz, Chloroform-d) δ 7.97 (dt, J = 8.3,

1.0 Hz, 1H), 7.91 (dd, J = 8.8, 0.6 Hz, 1H), 7.78 – 7.72 (m, 4H), 7.61

(ddd, J = 7.9, 1.3, 0.8 Hz, 1H), 7.50 (s, 1H), 7.49 (d, J = 0.5 Hz, 1H),

7.41 (d, J = 1.0 Hz, 1H), 7.31 (ddd, J = 8.4, 7.2, 1.3 Hz, 1H), 7.27 (dd,

J = 2.1, 0.4 Hz, 1H), 7.25 – 7.19 (m, 5H), 6.52 – 6.28 (m, 2H), 3.77 (p,

J = 6.9 Hz, 1H), 2.35 (s, 3H), 2.33 (s, 4H), 1.53 (d, J = 7.0 Hz, 4H). 13

C

NMR (101 MHz, cdcl3) δ 145.1, 145.0, 135.4, 135.1, 135.0, 134.4, 133.9, 131.5, 129.93, 129.89,

129.0, 128.9, 126.8, 126.7, 126.0, 124.9, 124.87, 123.6, 123.4, 120.2, 120.2, 119.8, 114.8, 113.7,

34.3, 21.6, 21.6, 20.2.

70

(E)-5-methoxy-1-tosyl-3-(4-(1-tosyl-1H-indol-3-yl)but-3-en-2-yl)-1H-indole

Following the general procedure the product 124 was obtained in 72%

yield (44.9 mg) as a white powder, from 5-methoxyindole as

nucleophile. MW: 624 g/mol. 1H NMR (400 MHz, Chloroform-d), 8.01 –

7.93 (m, 1H), 7.88 (dd, J = 9.0, 0.6 Hz, 1H), 7.78 – 7.69 (m, 4H), 7.60

(dt, J = 7.7, 1.0 Hz, 1H), 7.48 (s, 1H),δ 7.35 (d, J = 1.0 Hz, 1H), 7.31

(ddd, J = 8.3, 7.3, 1.2 Hz, 1H), 7.25 – 7.17 (m, 5H), 6.96 (d, J = 2.5

Hz, 1H), 6.91 (dd, J = 9.0, 2.5 Hz, 1H), 6.47 – 6.32 (m, 2H), 3.78 (dd, J

= 12.3, 5.8 Hz, 1H), 3.75 (s, 3H), 2.33 (s, 6H), 1.53 (d, J = 7.0 Hz, 3H).

13C NMR (101 MHz, cdcl3) δ 156.1, 145.0, 144.7, 135.4, 135.2, 135.1,

134.8, 131.3, 130.2, 129.9, 129.8, 129.1, 126.8, 126.7, 126.5, 124.8, 123.3, 123.22, 123.18, 120.3,

120.2, 119.9, 114.7, 113.7, 113.3, 102.9, 55.6, 34.3, 21.6, 21.5, 20.1.

(E)-7-methyl-3-(4-(1-tosyl-1H-indol-3-yl)but-3-en-2-yl)-1H-indole

Following the general procedure the product 125 was obtained in

66% yield (29.9 mg) as a white powder, from 7-methylindole as

nucleophile. The product was afforded as monotosylate. MW: 454

g/mol. 1

H NMR (400 MHz, Chloroform-d) δ 7.97 (dt, J = 8.4, 0.9 Hz,

1H), 7.93 (bs, 1H), 7.77 – 7.71 (m, 2H), 7.68 (dt, J = 7.8, 1.0 Hz,

1H), 7.57 – 7.51 (m, 1H), 7.50 (s, 1H), 7.29 (ddd, J = 8.4, 7.2, 1.3

Hz, 1H), 7.24 – 7.16 (m, 3H), 7.07 – 6.98 (m, 3H), 6.57 – 6.49 (m,

2H), 4.03 – 3.86 (m, 1H), 2.50 (s, 3H), 2.32 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H). 13

C NMR (101 MHz,

cdcl3) δ 144.8, 137.0, 136.1, 135.5, 135.2, 129.8, 129.3, 126.8, 126.2, 124.7, 123.2, 122.9, 122.6,

120.9, 120.8, 120.4, 120.3, 120.1, 119.5, 118.6, 117.3, 113.7, 34.8, 21.5, 20.8, 16.6.

(E)-7-methoxy-3-(4-(1-tosyl-1H-indol-3-yl)but-3-en-2-yl)-1H-indol

Following the general procedure the product 126 was obtained in

55% yield (25.8 mg) as a white powder, from 7-methoxylindole as

nucleophile. The product was afforded as monotosylate. MW: 470

g/mol. 1

H NMR (400 MHz, Chloroform-d) δ 8.21 (bs, 1H), 7.97 (dt,

J = 8.3, 0.9 Hz, 1H), 7.78 – 7.71 (m, 2H), 7.71 – 7.66 (m, 1H),

7.51 (s, 1H), 7.33 – 7.27 (m, 2H), 7.25 – 7.16 (m, 3H), 7.05 – 6.99

(m, 2H), 6.68 – 6.60 (m, 1H), 6.58 – 6.48 (m, 2H), 3.96 (s, 3H),

3.95 – 3.87 (m, 1H), 2.32 (s, 3H), 1.58 (d, J = 7.0 Hz, 3H). 13

C

NMR (101 MHz, cdcl3) δ 146.2, 144.8, 137.0, 135.5, 135.2, 129.8, 129.3, 128.0, 127.1, 126.8, 124.7,

123.3, 122.9, 120.9, 120.6, 120.4, 120.0, 119.7, 118.6, 113.7, 112.3, 101.8, 55.3, 34.8, 21.5, 20.8.

71

3,3'-((1E,1'E)-(1-methyl-1H-pyrrole-2,5-diyl)bis(but-1-ene-3,1-diyl))bis(1-tosyl-1H-indole)

Following the general procedure the product 127 was obtained in 45% yield (33 mg) as a white

powder, from N-methylpyrrole as nucleophile. The product was afforded as bitosylate. MW: 739 g/mol.

1H NMR (400 MHz, Chloroform-d) δ 7.98 (dt, J = 8.3,

0.9 Hz, 2H, M), 7.94 (dt, J = 8.3, 0.9 Hz, 2H, m), 7.78 –

7.73 (m, 4H, M), 7.73 – 7.69 (m, 4H, m), 7.67 (dt, J =

7.9, 1.3, 0.7 Hz, 2H, M), 7.59 (dt, J = 7.8, 1.0 Hz, 2H,

m), 7.51 (s, 2H, M), 7.49 (s, 2H, m), 7.31 (ddd, J = 8.3,

7.2, 1.2 Hz, 2H, M), 7.25 – 7.18 (m, 6H M overlapped

with 2H m), 7.17 – 7.13 (m, 4H, m), 7.07 (ddd, J = 8.1,

7.2, 1.0 Hz, 2H, m ), 6.41 – 6.27 (m, 4H M overlapped with 4H m), 6.01 (s, 1H, m), 6.00 (s, 1H, M),

3.63 (m, J = 7.1, 5.9 Hz, 2H, M), 3.54 – 3.50 (m, 2H, m), 3.47 (s, 3H, m), 3.46 (s, 3H, M), 2.33 (s, 6H,

M), 2.29 (s, 6H, m), 1.48 (d, 6H M overlapped with 6H m). 13

C NMR (101 MHz, cdcl3) δ 144.9 (M

overlapped with m), 135.9, 135.8, 135.6, 135.5, 135.4, 135.3, 135.2, 135.1, 129.9, 129.8, 129.09,

129.06, 126.83, 126.78, 124.81, 124.78, 123.310, 123.28, 123.1, 123.0, 120.5, 120.4, 120.3, 120.2,

119.2, 119.1, 113.7, 113.6, 103.6, 103.5.

72

6.11 General procedure for three component reactions

Scheme 61.

In a test tube equipped with a magnetic stirring bar, the allyl alcohol ( 0.1 mmol), the desired

nucleophile (0.1 mmol) the desired diene (0.1 mmol), the phosphoric acid 101 (10 mol%, 0.01 mmol)

and the dichloromethane ( 500 µl) were added. The reaction mixture was stirred at -30 °C for 2 days

and then acetone ( 3.2 mL) and a 9% (w/w) aqueous solution of acidic chloride ( 120 µL ) were added

and the mixture is stirred for 2 hours at room temperature. The reaction mixture was then quenched

with a NaHCO3 saturated aqueous solution and the organic layer was separated. The aqueous layer

was extracted with dichloromethane and then the organic combined was dried over MgSO4. The

solvent was evaporated in vacuo and the product was purified by column chromatography on silica gel

(n-hexane/EtOAc mixtures) to afford the desired products.

4-(1-(2-methyl-1H-indol-3-yl)ethyl)-2-phenyl-4,5,10,10b-tetrahydropyrrolo[3,4-a]carbazole-

1,3(2H,3aH)-dione

Following the general procedure, product 130 was obtained in 50% yield as

a solid, from (E)-4-(1H-indol-3-yl)but-3-en-2-ol and 2-methylindole as

nucleophile. MW: 472 g/mol. 1H NMR (600 MHz, Chloroform-d) δ 8.31 (s,

1H), 7.78 (s, 1H), 7.63 – 7.57 (m, 2H), 7.38 – 7.32 (m, 2H), 7.35 – 7.26 (m,

3H), 7.25 – 7.18 (m, 1H), 7.16 (ddd, J = 8.1, 7.2, 1.1 Hz, 1H), 7.11 (ddd, J =

8.0, 7.0, 1.1 Hz, 1H), 7.08 – 6.99 (m, 3H),4.10-4.04 (m, 1H) overlapped with

4.08 (dt, J = 7.7, 1.7 Hz, 1H), 3.44 (ddd, J = 7.5, 3.4, 1.0 Hz, 1H), 3.38 (dd, J

= 15.5, 4.2 Hz, 1H), 3.00 – 2.76 (m, 1H), 2.71 (ddd, J = 14.7, 11.9, 2.4 Hz,

1H), 2.47 (s, 3H), 1.56 (d, J = 7.1 Hz, 3H).

73

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