This journal is c The Royal Society of Chemistry 2010 Chem. Soc. Rev., 2010, 39, 4449–4465 4449

Organocatalytic strategies for the asymmetric functionalization of

indolesw

Giuseppe Bartoli,*a Giorgio Bencivennia and Renato Dalpozzob

Received 3rd March 2010

DOI: 10.1039/b923063g

The desire for new synthetic methodologies for the rapid construction of enantiomerically pure

substituted indole has been a fruitful driving force for chemical research in the last few years.

This research line has produced a stunning array of enantioselective technologies either metal or

organocatalyzed. This critical review documents the development of organocatalytic indole

alkylation strategies, until the end of 2009 (127 references).

1. Introduction

The synthesis of relevant organic compounds is a main topic in

academic and industrial chemistry and one particular molecular

scaffold of interest is the indole. In fact the indole ring system

is the most widely distributed heterocycle found in nature.

Substituted indoles have been referred to as ‘‘privileged

structures’’ owing to their excellent binding ability to many

receptors with high affinity and a number of approved drugs

has this core in their structures. A plethora of indole-based

biologically active natural products and indole-derived drugs

spans over an enormous range of biological activity. The

essential amino acid tryptophan, the neurotransmitter serotonin

and several groups of important alkaloids are indole derivatives.

Indole core is also an important component in many of

today’s drugs for the treatment of chemotherapy-induced

nausea and vomiting, cluster headache, or as antihypertensive,

antineoplastic and antimitotic agents. Hence, it is not surprising

that this structural motif has been the object of research from

the first preparation of indoles dated from 1866. Reviews on

this topic continuously appear in literature.1–12

The Friedel–Crafts (F–C) alkylation is one of the

archetypical acid catalyzed C–C bond-forming reactions to

introduce side-chains onto an aromatic compounds via electro-

philic compounds.13 The most reactive position on indole for

electrophilic aromatic substitution is C-3 (Fig. 1, eqn (1)),

which is 1013 times more reactive than benzene positions.

Moreover, electrophilic substitution of the 2-position can

occur only if the pyrrole core is electronically isolated: i.e.

on 4,7-dihydroderivatives (Fig. 1, eqn (2)). Finally the reduced

nucleophilicity of the N–H functionality allows N-substitution

only when the N–H proton of indoles is removed to generate a

strong charged nucleophile (Fig. 1, eqn (3)). Electrophilic

aUniversita di Bologna, Dipartimento di Chimica Organica‘‘A. Mangini’’, viale Risorgimento 4, I-40136 Bologna, Italy.E-mail: giuseppe.bartoli@unibo.it; Fax: +39-051-20-93654;Tel: +39-051-20-93617

bUniversita della Calabria, Dipartimento di Chimica,Ponte Bucci cubo 12/c, I-87030 Arcavacata di Rende (Cs), Italy.E-mail: dalpozzo@unical.it; Fax: +39-0984-49-3077;Tel: +39-0984-49-2055

w Dedicated to Prof. L. Lunazzi in University of Bologna on theoccasion of his 70th birthday.

Giuseppe Bartoli

Giuseppe Bartoli graduatedfrom the University ofBologna in 1967 with a Laureain Industrial Chemistry. Since1968, he has been an AssistantProfessor at the University ofBari (Italy), then AssociateProfessor at the University ofBologna (Italy) and, in 1986,Full Professor of OrganicChemistry at the Universityof Camerino. In 1993 hereturned in Bologna. Head ofthe Department of OrganicChemistry ‘‘A. Mangini’’(2001–2006) and now

Chairman of the Industrial Chemistry degree course. Hisresearch interests include studies on the reactivity of organo-metallic compounds with aromatic systems, the use ofenaminones dianions, the stereoselective reduction of ketones,the development of new Lewis acid systems, and the enantio-selective organocatalysis.

Giorgio Bencivenni

Giorgio Bencivenni was bornin 1978. He graduated in2003 with a Laurea in Indus-trial Chemistry. After hisdegree he started a fellowshipwith Prof. Spagnolo’s researchgroup and in 2005 he startedhis doctoral studies in Chem-istry under the supervision ofProf. D. Nanni working on theradical reactivity of new metalhydrides with organic azides.In 2007, he spent six months atthe University of St. Andrews(Prof. John C. Walton)studying radical reaction

mechanisms of organic azides by ESR spectroscopy. In 2008he obtained his PhD degree and he joined Prof. G. Bartoli’sgroup as a postdoctoral associate, studying new organocatalyticasymmetric reactions.

CRITICAL REVIEW www.rsc.org/csr | Chemical Society Reviews

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4450 Chem. Soc. Rev., 2010, 39, 4449–4465 This journal is c The Royal Society of Chemistry 2010

substitution of the carbocyclic ring can take place only after

N-1, C-2, and C-3 positions are substituted and, owing to this

difficulty, benzene-ring functionalization is generally obtained

by de novo ring syntheses.14

Many electrophiles can be employed for the F–C alkylation

of indoles and it is noteworthy that although organohalides

were used early on in F–C reactions, they are nowadays only

employed in very few catalytic processes owing to many

drawbacks connected to their use. Therefore, chemists are

prompted to find alternatives to organohalides.

Moreover, biologically active indoles often carry stereo-

centres in the a- or b-positions of the ring side chains and to

form optically active compounds, one can either employ an

optically active catalyst/mediator or perform diastereo-

selective reactions using chiral substrates followed by cleavage

of the auxiliary. Both methods are not compatible with the use

of halides as electrophiles owing to the generation of a planar

carbocation.

Nowadays, asymmetric organocatalysis has seen a tremendous

rise in popularity when measured in publications and hence

in references.15–31 The use of purely organic molecules as

chiral catalysts fills a gap between metal- and enzyme-catalysis

complementing these approaches to asymmetric catalysis.

In addition, it offers some attractive benefits: the organic

catalysts are generally readily available, and stable, therefore

with simple handling and storage, so allowing most reactions

to be performed in non-inert reaction conditions such as wet

solvent and in air. Furthermore, the commercial availability of

many catalysts hopefully and broadly stimulates the application

of organocatalysis for stereoselective synthesis.

Epoxides/aziridines, activated alcohols, and allylic acetates/

carbonates can be considered as electrophilic saturated

reagents for catalytic asymmetric F–C alkylations. However,

until now only addition of epoxides has been reported under

organocatalytic conditions, but not enantioselectively.32

This review aims to give a panoramic and critical survey of

the literature about organocatalytic enantioselective functio-

nalization of the pyrrole moiety of indole core nucleus,

compared with the most important metal-catalyzed analogous

reactions. Chiral organocatalysis applied to F–C alkylation

appears, in fact, a valuable development of this reaction, since

most of the metal catalysts are traditionally associated with

strictly anhydrous conditions, being generally water-unstable

Lewis or Brønsted acids, whereas, as reported above,

organocatalysts do not require these conditions. Moreover,

it will show how difficult or elusive metal catalyzed asymmetric

transformations may now be performed using chiral organo-

catalysts.

1.1 General mechanistic overview

Since its origin organocatalytic mechanism has been designed

on two main strategies: the covalent and non-covalent ones.

The former is limited to the use of unsaturated aldehydes

and ketones and is termed ‘‘Iminium Ion Catalysis’’.16,18,23–26

The indole 1 (or more generally a nucleophile) attacks the

b-position of a,b-unsaturated aldehydes and ketones activated

by the reversible formation of a reactive iminium ion inter-

mediate (2) with a high level of geometry control (Scheme 1).

The catalyst is therefore a chiral primary or secondary amine,

Fig. 1 Electrophilic attacks to C3 (1), C2 followed by oxidation (2),

deprotonated N1 (3).

Scheme 1 Asymmetric ‘‘Iminium Ion Catalysis’’ applied to indole.

Renato Dalpozzo

Renato Dalpozzo graduatedfrom the University of Bolognain 1981 with a Laurea inIndustrial Chemistry under thesupervision of professor Bartoli.He was Researcher of OrganicChemistry at University ofBologna (Italy) since 1983. In1992, he moved to theUniversity of Calabria (Italy)as Associate Professor and nowas Full Professor of Environ-mental and Cultural HeritageChemistry. His research inter-ests include studies on thereactivity of organometallic

compounds with aromatic systems, the use of dianions derived fromenamino carbonyl compounds, the stereoselective reduction ofvarious classes of ketones, the development of new Lewis acidsystems, and the chemistry of mimicry of social insects.

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This journal is c The Royal Society of Chemistry 2010 Chem. Soc. Rev., 2010, 39, 4449–4465 4451

derived from natural products, whose geometry allows selective

p-facial coverage of one reactive face of the iminium ion

species over another. The formation of the covalent bond

maintains the asymmetric centre very close to the reactive

moiety. As the two reactive iminium faces lead to opposite

enantiomers of the product, only the availability of the

two enantiomers of the amine allows the synthesis of both

enantiomers of the product.

The ‘‘Non-Covalent Organocatalysis’’ is based on small

organic molecules designed as catalysts capable primarily

of hydrogen bonding interactions with oxygen or nitrogen

lone-pair electrons in the reagent, thereby increasing its

electrophilic character and making it more prone to react

with the nucleophilic aromatic substrate (Scheme 2). Chiral

phosphoric acid and urea derivatives are the typical catalyst

working by this mechanism. This strategy is more general

and finds application also to every electrophile possessing

accessible lone pairs, but the catalyst is less close to the

reactive site and the shielding of a face may be less

effective.15,17,27–31,33–35

A variant of this strategy is the so-called ‘‘Asymmetric

Counteranion-Directed Catalysis’’.36 This is a well-known

general strategy that takes advantage of the close proximity

of a chiral counterion to a carbocation, very often a

species which has captured the acidic hydrogen of the chiral

catalyst.

A further organocatalytic enantioselective variant was

named by Jacobsen: ‘‘Anion Binding Catalysis’’.37 In this

mechanism, catalysis and enantio-induction may result from

abstraction of a leaving anion in an SN1-type rate determining

step, promoted by the anion-binding properties of ureas and

thioureas. This model suffers pronounced halide counterion

and solvent effects on enantioselectivity. In Scheme 3 the

mechanistic differences between the similar Anion Binding

Catalysis and Asymmetric Counteranion-Directed Catalysis

are shown.

2. Functionalization at C-3

As mentioned above, unsaturated compounds, such as activated

alkenes or carbonyl compounds and imines, found large

application as suitable electrophilic reagents for F–C alkylation

under organocatalysis, and in this section the functionalization

of the 3-position of the indole nucleus will be considered.

2.1 Conjugate addition of a,b-unsaturated carbonyl

compounds

The catalytic asymmetric F–C alkylation of indoles with

a,b-unsaturated carbonyl compounds is an elegant method

for the synthesis of chiral indole derivatives.

The first organocatalytic contribution was presented by

MacMillan in 2002, who developed the enantioselective F–C

alkylation of indoles with a,b-unsaturated aldehydes, but not

ketones, in the presence of a chiral imidazolidinone (7, Fig. 2)

with enantioselectivities >90% ee for the R stereoisomer.38

The catalyst selectively forms the iminium ion (Scheme 1) in

which the E-olefin orients itself in order to avoid nonbonding

interactions with the tert-butyl group and the benzyl group

shields the si-enantioface of the substrate. Moreover, the

energy of the LUMO of the C–C double bond on the carbonyl

compound is lowered, increasing its inherent b-eletrophilicity.The product 5 can be hydrolyzed to yield the enantioenriched

product with R configuration, regenerating the chiral amine

catalyst. The transition structures are confirmed with B3LYP/

6-31G(d) density functional theory for the alkylations of

N-methylpyrrole, but they can be easily extended to indoles.

The theoretical geometries provide a rationale for the sense of

asymmetric induction observed.39

It should be noted that 7 is found effective also for

unsubstituted acrolein. No stereogenic carbon atom is

obviously formed, but MacMillan amine catalysts allow

homotryptamines to be synthesized in 14–37% yield after

two steps, while simpler achiral secondary amines such as

Scheme 2 Asymmetric ‘‘Non-Covalent Organocatalysis’’ applied to

indole.

Scheme 3 Anion Binding Catalysis (ABC, top) and Asymmetric

Counteranion-Directed Catalysis (ACDC, bottom) asymmetric

mechanisms.

Fig. 2 MacMillan catalyst (7) Transition state model: addition from

bottom.

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pyrrolidine and diisopropylamine were ineffective in catalyzing

the desired Michael reaction.40

Catalyst 7 is also efficient for the synthesis of tetra-

hydropyrano[3,4-b]indoles (9, X = O) (Scheme 4), a common

structural component of naturally occurring and biologically

active molecules.41 The reaction can be extended to the

synthesis of piperidino[3,4-b]indole (b-carboline) (9, X = NTs)

in 90% ee and 78% isolated yield. When X was a methylene

group instead, 8 cannot be isolated from its preparation

reaction system and the ring-closing alkylation occurs

spontaneously.

Moreover MacMillan’s catalyst (7) trifluoroacetate salt

(20 mol%) performs asymmetric Friedel–Crafts alkylation

of substituted indoles with (E)-dialkyl-3-oxoprop-1-

enylphosphonates (11) in 48–82% yield and 73–96% ee

(Scheme 5). The optimal enantiocontrol was achieved in

dichloromethane at �78 1C.42

However MacMillan’s methodology is limited to the use of

indoles without strong electron withdrawing groups, as well as

a,b-unsaturated aldehydes that have no a-substituents. In fact,

in all the cited examples, the lowest yields are obtained with

electron-deficient indoles. King partially has overcome this

drawback introducing the modified catalyst 15 that allows the

efficient alkylation of 5-iodoindole (13) by cyclopentene-

1-carbaldehyde (14) in 83% yield and 84% ee of the S,S-

stereoisomer with 20 mol% of 15-trifluoroacetate

(Scheme 6).43 The opposite stereochemistry with respect

to MacMillan’s reaction is explained by significant steric

interactions to the cyclopentene group with the imidazolidinone

benzyl group compared to the minimal steric obstacle presented

by 5-methylfuryl group.

An alternative to imidazolinones is the diphenylprolinol

silyl ether (17, Fig. 3), independently developed by Jørgensen’s

and Hayashi’s groups,44,45 which has been revealed as

an efficient organocatalyst for many asymmetric reactions

proceeding under iminium ion and enamine mechanisms.16,46

The steric hindrance of the C-2 substituent shifts the iminium

equilibrium toward the E-isomer (Fig. 3, right) and shields of

the upper face of the C–C double bond forcing the nucleophile

to attack from bottom with final absolute configuration of the

major enantiomer as in MacMillan’s catalysis. The enantio-

selectivity is higher, the more the equilibrium is shifted.

Very recently, two applications of prolinols to catalytic

enantioselective Friedel–Crafts alkylation of indoles by

a,b-unsaturated aldehydes have appeared in the literature.47,48

Both procedures worked well with 20 mol% catalyst loading,

but the a priori approach is different. Starting from the

observation that, under the traditional catalytic conditions,

the formation of the iminium ion has been always improved by

adding acids, they both try to overcome this feature, which is a

disadvantage with acid-sensitive substrates. In fact,47 Bao

does not use any acid co-catalyst, but a polar solvent as

methanol. However, his reaction is restricted to substituted

cinnamaldehydes (56–87% yield, 86–96% ee), and long

reaction times (4 days). So if Bao’s neutral conditions appear

surprising, the particularly reactive substrate and the reaction

conditions can justify the observed results.

On the other hand,48 Wang tested a Lewis base-Lewis base

bifunctional catalysis, where prolinol and triethylamine activated

the a,b-unsaturated aldehyde to induce the chirality and the

nucleophilic indole by hydrogen-bonding interaction, respectively

(Fig. 4). Under these conditions, he obtained similar results

(67–95% yield, 92–98% ee), at lower temperatures, shorter

reaction times and with a larger substrate range than Bao.

Scheme 4

Scheme 5

Scheme 6 King’s reaction (top) with catalyst 15 and envisaged

transition state (bottom, right).

Fig. 3 Jørgensen-Hayashi’s catalyst and envisaged transition state.

Fig. 4 Lewis base–Lewis base bifunctional catalysis supposed by

Wang.

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As reported above, both Jørgensen-Hayashi’s andMacMillan’s

catalysts led after addition of simple a,b-unsaturated aldehyde

to 3-substituted indoles with the same absolute configuration.

To the best of our knowledge reaction with the opposite

enantiomer of these catalysts are not reported, so only two

examples are reported for the F–C alkylation of indole with

simple a,b-unsaturated aldehydes that led to the opposite

enantiomer. In particular the camphor sulfonyl hydrazine

(CaSH, 18, Fig. 5)49 as trifluoroacetic salt is an enantio-

selective organocatalyst (30 mol%) (49–71% yield, 81–88% ee),

where the further nitrogen atom and the sulfonyl group

attached to the amino functionality, enhanced the amino

nitrogen atom nucleophilicity, the so-called a-heteroatomeffect. No hypothesis on the transition state has been made

but with larger alkyl substituent on the b-position of the

unsaturated aldehydes, the reactions were slower with lower

yields but higher ee, perhaps due to the steric effect.

Moreover, a rigid resin-bound peptide framework, that

shields the re-face leading to the same enantiomer as CaSH,

allows the asymmetric F–C alkylation in aqueous media.50 For

the best reaction efficiency and enantioselectivity, the peptide

should be tailored with a N-terminal proline, a b-turn inducing

D-Pro-2-methylalanine unit and a polyleucine tether. A high

degree of asymmetric induction (52–90% ee) was realized at

room temperature along with 44–88% yield. The resin-bound

peptide catalyst could be reused at least for five times without

lack of selectivity.

The addition of indoles to a,b-unsaturated ketones is a more

difficult reaction. Asymmetric metal-catalyzed reactions often

overcame this problem adding a further chelating group to the

metal catalyst. These reactions have been extensively

reviewed,51–53 but only ‘‘SALEN’’ and ‘‘BINOL’’ type catalysts

were applied to simple enones.

However, the asymmetric addition of simple unsaturated

ketones in high ee is more challenging and it can be achieved

only with organocatalysis. However, the first attempts, using

chiral secondary amines such as L-proline and the MacMillan’s

imidazolidinone catalysts, have been found with very low

ee.54,55 Actually, the relative bulkiness of secondary amines

is unfavourable for the generation of iminium ions from

a,b-unsaturated ketones. The first really enantioselective

example with simple a,b-unsaturated ketones was developed

by Chen in 2007 introducing a chiral primary amine derived

from natural cinchonine (19, Fig. 6), that afforded, in partner-

ship with an achiral acid, chiral indole derivatives in 16–99%

yields and 47–89% ee, when used in 10 mol%.56 Actually,

Chen’s report was also the first enantioselective alkylation

with non-chelating ketones, since the Zr(O-t-Bu)2BINOL

catalyzed reaction appeared somewhat later.57

Further improvements in the Friedel–Crafts alkylation with

a,b-enones appeared few weeks later in the literature, when

Melchiorre used 20 mol% of catalytic salt 20 (Fig. 6), in which

both partners are optically active.58–60 This catalytic system

gave the highest enantioselectivity achieved until now (up to

96% ee) of the optically active 3-substituted indole.58 It should

be noted that both Chen and Melchiorre’s reaction conditions

led to the opposite enantiomers using the two pseudo-

enantiomeric forms of the cinchona catalyst.

All the reactions reported until now operate through the

covalent bond strategy described in Scheme 1, but addition of

a,b-unsaturated ketones can be achieved also with Brønsted

acid catalysis, i.e. via hydrogen-bonding mechanism

(Scheme 2). The most important class of these compounds is

represented by phosphoric acids derived from BINOL (21 or 22)

and their modifications (for example 23) (Fig. 7).

An example of such reactions is the 1,4-addition of

N-methylindoles with b,g-unsaturated a-ketoesters catalyzed

(5 mol%) by N-triflylphosphoramides (23). The differently

substituted a-ketoesters were isolated in 55–88% yields and

up to 92% ee.61

Simple chiral phosphoric acids such as 21 and 22 were found

to give moderate enantioselectivity in the addition to indoles

to chalcones. In particular 21 (R = 4-ClPh) gave a maximum

56% ee and 63–92% yield when used in 2 mol% at room

temperature.62 Catalyst 22 (R = 4-NO2Ph), under the same

reaction conditions but with longer reaction times (48 h vs.

24 h) and higher catalyst loading (10 mol%), gave comparable

results (34–98% yield, 41–54% ee).63 Ee’s can be increased by

crystallization with detriment of the yield. Obviously, since 21

Fig. 5 A CaSH catalyst and its iminium ion.

Fig. 6 Cinchona derived catalysts for F–C of a,b-unsaturatedketones.

Fig. 7 Optically active phosphoric acid derivatives.

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4454 Chem. Soc. Rev., 2010, 39, 4449–4465 This journal is c The Royal Society of Chemistry 2010

and 22 have opposite stereochemistry they led to opposite

enantiomers.

Very recently, You et al. reported the ketone-variation of

the reaction described in Scheme 4, using 21 (R=9-phenanthryl)

as the catalyst (5 mol%) with better results with respect to the

intermolecular reaction. In fact they obtained ee up to 98%

and almost quantitative yields.64

A particular borderline approach used allo-threonine-

derived oxazaborolidinone 24 (Fig. 8) that is a Lewis acid

capable to activate carbonyl compounds toward addition. In a

double Lewis acid-Lewis base catalysis, 24 (10 mol%) and

N,N-dimethylaniline (2.5 mol%) allowed the Friedel–Crafts

alkylation of indoles with acyclic a,b-unsaturated ketones to

give products with 52–93% yield and 37–94% ee.65

2.2 Cascade reactions

Enantioselective functionalization of a,b-unsaturated carbonyl

compounds dramatically grew up its importance when it was

realized that some intermediates of the catalytic cycle

(Scheme 1) can undergo further manipulations, the so-called

cascade reactions.

One of the first examples was introduced by MacMillan

when envisioned that the presence of pendant nucleophilic

substituents on a 3-substituted indole should address reaction

pathway toward a 5-exo-heterocyclization of intermediate 5.

In fact, the C(3)-quaternary carbon-substituted ion 28

(a particular example of 5) cannot undergo rearomatization,

generating the tricyclic system 29 (Scheme 7).66 The three

stereogenic centres were forged with high levels of enantio-

(82–99% ee) and diastereo-control (13–50 : 1 dr) by using

20 mol% of indolyl catalyst 27 (R = H). The reaction was

applied to the total synthesis of marine bryozoan alkaloids

(�)-flustramine B and (�)-debromoflustramine B. Actually

every nucleophilic pendant can undergo cyclization so the

reaction also allowed the formation of furanoindoline.

A quite different approach was then suggested by MacMillan

for the key step of a synthesis of minfiensine.67 Actually, the

reaction is a cascade reaction that would incorporate an

organocatalytic Diels–Alder cycloaddition, enamine to iminium

isomerization, and an amine cyclization sequence. A modified

MacMillan catalyst (30, Scheme 8) condensed with propynal

to generate an activated iminium ion with the acetylenic group

being away from the bulky tert-butyl substituent. This

conformation shields the top face of the reactive alkyne

facilitating an endo-selectivity (32-TS) to produce the tricycle

32. Protonation of the enamine moiety with tribromoacetic

acid then gives rise to an iminium ion (33), allowing the same a

5-exo-heterocyclization as in 28 to deliver the tetracycle 34,

which then is converted into minfiensine in further five steps.Intermediate 35 (another particular example of 5) would

enter a second catalytic cycle being in equilibrium with the

enamine activated intermediate 36 that would enable

highly diastereoselective additions of electrophiles. Through

this cascade reaction MacMillan prepared 2-chloro-3-

(N-protected-indol-3-yl)aldehydes in 67–83% yield, 9 : 1 to

12 : 1 diastereomeric ratio and almost exclusively with (2R,3S)

configuration using modified catalyst 27 (R = Bn, 20 mol%,

Scheme 9).68Fig. 8 Oxazaborolidinone catalyst.

Scheme 7

Scheme 8

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2.3 Addition of nitroenes

As well as a,b-unsaturated ketones, nitroalkenes are activated

alkenes suitable for organocatalytic enantioselective Friedel–

Crafts alkylation with indoles. The nitro moiety is very flexible

and can be conveniently transformed into numerous molecular

motifs. Despite this fact, until 2005 only rare reports have been

published. In fact, the high electrophilicity of a,b-unsaturatednitro derivatives promotes uncatalyzed background reactions.

Moreover the highly coordinating oxygen atoms of the nitro

group can often compete with the metal ligand thus be lacking

of a geometrical rigidity and inhibiting the chiral organo-

metallic catalytic loop, leading to moderate levels of stereo-

selection.

In Table 1 are summarized the enantioselective, metal-

catalyzed addition of nitroenes to indoles, where the combination

zinc and bisoxazoline appears to give the best results.

The absence of carbonyl compounds do not evidently allow

the iminium ion mechanism, therefore asymmetric organo-

catalysis is only exploited by the hydrogen bonding mechanism

(Scheme 2), owing to the presence of two Lewis-basic oxygen

atoms potentially allowing for activation of the olefin by the

acceptance of hydrogen bonds from a suitably designed catalyst

(Scheme 10). The pioneer Ricci’s paper used a simple chiral

thiourea catalyst (40, Fig. 9), which gave up to 89% ee when

used in 20 mol%.77 The catalyst can be easily accessed in both

enantiomeric forms.

Then structural modifications of 40 were evaluated, for

example replacing the 3,5-bis-trifluoromethylphenyl group

with a protonated 2-pyridine,78 or building (thio)urea

moieties on a bis-N-aryl structural motif (i.e. a 2,20-

bis-naphthylamine).79 From this screening, thioamide 41

emerged as a very powerful catalyst (5 mol%), increasing ee

up to 98% with 80–96% yield, results that are competitive

with the best metal-catalyzed reactions.78 The reasons of this

success may arise from the free alcoholic function in the

indanine moiety of these catalysts which can interact with

the indolic proton through a weak hydrogen bond, directing

the attack of the incoming nucleophile on the Si face of the

nitroolefin as depicted in Fig. 9 for catalyst 41.

Moreover, Jørgensen proposed vicinal diamine derivatives

as the chiral hydrogen bond donors. In particular chiral

bis-sulfonamide catalyst 38 promoted the Michael addition

only in 2 mol%, but with moderate stereochemical outcome

(20–87% yield and up to 63% ee).80 In particular, alkyl

b-substituted nitroalkenes dramatically decreased enantio-

selectivity. The coordination of nitroalkene occurs with only

one hydrogen bond (Fig. 10), the Re-face of the alkene is

shielded by the substituents in the chiral catalyst, leaving the

Si-face available for approach of the indole.

Chiral phosphoric acid (i.e. the enantiomer of 22,

R = SiPh3, 10 mol%) in the presence of 3 A molecular sieves

demonstrated to be highly yielding (80–96%) and selective

(90–98% ee).81 Catalysis was exploited by double hydrogen

bonding interactions: catalyst acidic hydrogen atom—one

nitro group oxygen atom and indole NH–phosphoric acid

PQO (Fig. 11). The easy synthesis of the catalyst with respect

to the other tested organocatalyst renders it the best choice

until now available.

2.4 Additions to carbonyl derivatives

Other important F–C alkylation processes of indoles are

the addition of indole derivatives to imines, aldehydes and

a-ketoesters, which provide easy access to the synthesis of

Scheme 9

Table 1 Best metal-catalyzed conditions for additions of nitroalkenes to indoles

Catalyst (10 mol%) Yield range (%) ee range (%) Ref.

Cu(OTf)2-imidazoline-aminophenol 29–90 87–99a 69Zn(OTf)2-Ph-bisoxazoline 62–98 21–90 70Cu(OTf)2-diPh-bisoxazoline Up to 95 Up to 86 71, 72Zn(OTf)2-diphenylaminebisoxazolineb Up to 99 Up to 98 73, 74Al(salen)Cl 38–76 28–60 75Zn(OTf)2-(R)-BINAM 23–90 9–67 76

a Yields and ee on a three-component reaction between indole, nitroalkenes and aldehyde. b 5 mol% of catalyst.

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enantiopure 3-indolylmethanamine or methanol derivatives,

other pivotal structural motifs embedded in numerous natural

and unnatural products with significant biological activities.

The presence of a carbonyl function on some of these substrates

allowed both organocatalytic pathways (covalent and non-

covalent bonding, Schemes 1 and 2).

The main drawback of these reactions, especially in the

synthesis of indolylmethanols, arises from the formation of

bis(indolyl)methane derivatives, deriving from a spontaneous

release of the hydroxyl group, often good leaving group under

the employed reaction conditions. The dehydration step leads

to a novel electrophilic intermediate (the azafulvenium ion 45)

that can undergo further indole addition. The presence of two

identical substituents obviously falls down stereochemical

efforts.

An interesting exception was found during the investigation

of conjugate addition of N-methylindole to the b,g-unsaturated

a-keto esters already described above.61 In fact the bisindoles

46 display atropisomerism, so a screening of some chiral

N-triflylphosphoramides was performed and an atropisomeric

ratio of 81 : 19 when 5 mol% of 44 was used (Scheme 11).

However in the presence of nucleophiles other than indole

the reaction can be exploited to functionalize the 3-position by

the Asymmetric Counteranion-Directed Catalysis (Scheme 3).

By this way, the double Friedel–Crafts reaction of substituted

indoles with 2-formylbiphenyls (47) provided the 9-(3-indolyl)-

fluorene derivatives (50) with up to 96% ee and 66–96%

yield,82 through enantiocontrol of the chiral phosporic acid

22 (Scheme 12).

Recently, also intermolecular examples appeared in

literature. For example, the phosphoric acid 21 (R = Ph,

10 mol%) enabled the a-alkylation of enamides (51) with

indolyl methanols (52) to give b-aryl 3-(3-indolyl) propanones(53) in high yields (up to 96%) and with enantioselectivities up

to 96% ee (Scheme 13).83

A new challenging strategy is founded upon the use of a

3-substituted indole, where the presence of a suitable leaving

group can generate the azafulvenium ion that can readily

intercept the transient enamine intermediate from an aldehyde

and the chiral catalyst. The synthesis used easily available

3-(1-arylsulfonylalkyl)indoles (54),84 as suitable electrophilic

precursors, and L-proline (20 mol%), as the chiral catalyst for

the synthesis of the transient chiral nucleophile (Scheme 14).85

The method proved to be successful for a wide range of

aliphatic aldehyde substituents (77–92% yield, d.r. > 4.5 : 1,

86–90% ee), but the lack of a 2-substituent on the indole

scaffold drastically lowered the stereoselectivity. The relative

and absolute configuration of major compound was determined

to be 2R,3S.

In this reaction both classical enantioselective mechanisms

are operative. The proline nitrogen atom easily condenses with

the aldehydic carbonyl, leading to the iminium ion formation,

which then tautomerize to enamine, and the acid hydrogen

Scheme 10 (Thio)urea activation mechanism for nitro-olefins.

Fig. 9 Urea catalyst for nitroalkenes addition to indoles and

proposed transition state.

Fig. 10 Sulfonamide catalyst for nitroalkene addition to indoles and

proposed transition state.

Fig. 11 Envisioned transition state for chiral BINOL phosphoric acid.

Scheme 11

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atom of the same amino acid hydrogen-bonds to the indole

nitrogen atom.

Owing to the difficulties in the isolation of indolylmethanol

derivatives, described in this preamble it is not surprising that

very rare papers report the enantioselective condensation of

indoles to aldehydes or ketones. A potent electron-withdrawing

substituent must be present both to enhance the reactivity

of substrates and to prevent water elimination from the

indolylmethanol. For example trifluoromethylaryl ketones

gave trifluoromethyl-substituted tertiary alcohols with up to

99% ee when a chiral phosphoric acid catalyst like 22 was

employed.86

Analogously, the 1,2-addition of indoles to a-ketoesters wasperformed (52–97% yield, 81–99% ee) in the presence of the

bifunctional cinchona alkaloid 56 (Fig. 12).87 The process was

extended to simple aromatic aldehydes (60–96% yield,

82–93% ee), and less than 5% of bisindole derivative was

recovered as a by product. Both enantiomers can be obtained

varying the catalyst (56a or 56b).

The corresponding reaction under metal catalysis (10 mol%

BINOL/Ti(OiPr)4 complex) is reported to proceed with very

high enantioselectivity (up to 96% ee); but the method

appeared to be limited to glyoxylate.88

Also 3,3,3-trifluoromethylpyruvate gave corresponding

trifluoromethylated indolylalkane carboxylic acid derivatives

in almost quantitative yields and up to 95% ee, regardless of

the substitution pattern of the indole nucleus by using 5 mol%

cinchonidine or cinchonine as the chiral catalysts for the

opposite enantiomer synthesis.89 The corresponding reaction

catalyzed by bisoxazoline–copper(II) complexes gave comparably

the products up to 93% yield and 94% ee.90

In contrast to 3-indolylmethanols, indolylmethanamines are

stable enough to be isolated. Moreover 3-indolylglycines are

interesting non-proteinogenic amino acids in drug development,

natural product synthesis and in peptide mimetic.

In general, N-activated imines with electron-withdrawing

groups are employed, thereby enabling mild reaction conditions

to be used. However, only very recently the scope, stereo-

selectivity, and catalyst loading were successfully addressed

in organocatalysis. The most important results are reported in

Table 2.

The chiral catalyst should be effective in activating the

weakly electrophilic imines to iminium ions (60), but still

compatible with the acid-sensitive 3-indolylmethanamines

(58), to avoid its reaction with indoles to form bisindole

compounds. Urea and BINOL phosphoric acids were found

to be the best choice. Under acidic conditions alkyl imines

readily tautomerize to the corresponding enamine (59), but

Terada’s results on pure E and Z-enecarbamates suggested

that both reactions proceeded through the common inter-

mediate 60.93 On the other hand, bifunctional catalysis on

indole, in particular by the Lewis basic sites of phosphoric

acid, can be ruled out since some examples regarded

N-substituted indoles (Fig. 13).92,100

Brønsted acid catalysts with unusual alkylating substrates

such as a-aryl enamide91 and enecarbamate92 (that are

reported in Table 2 as the imine tautomer: the true reactive

species) overcame the poor reactivity and difficult stereo-

discrimination of keto derivatives as well as the poor stability

and difficult handling of aliphatic aldimines respectively. The

corresponding metal catalyzed reaction seemed to be less

studied.101

A particular type of activated imines are the N-acyl iminium

ions (63). Recently, a highly enantioselective addition of

Scheme 12

Scheme 13

Scheme 14

Fig. 12 Cinchona alkaloids for addition of aldehydes to indoles.

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indoles to cyclic N-acyl iminium ions was developed with a

chiral thiourea catalyst (62, 10 mol%). Both electron-rich

(60–93% yield and 80–93% ee) and electron-poor indole

nucleophiles (12–87% yield and 85–97% ee) can be used as

substrates, but TMSCl/H2O and BCl3 had to be added

respectively (Scheme 15).102 The same reaction was exploited

to g,g0-disubstituted g-lactams starting from acyl iminium ions

from hemiaminals by succinimide and indoles with 5 mol%

of Rueping’s N-triflylphosphoramide 44.103 These two

reactions are wonderful examples of Anion Binding Catalysis

(Scheme 3).

Finally, chiral BINOL-phosphoric acids were also

efficiently adopted in a three-component indole alkylation

(up to 98% ee), by indole, aniline, and trifluoroacetaldehyde

hemiacetal.104

3. Functionalization at C-2

2-Substituted indoles are potential intermediates for many

alkaloids and pharmacologically important substances and

the development of novel and efficient catalytic asymmetric

syntheses of these compounds appear to be of great importance.

If indole undergoes electrophilic substitution preferentially at

C3-position, pyrrole gives reaction at C2-position, as well

explained by the stability of the Wheland intermediates for

electrophilic substitution. On the basis of these features,

4,7-dihydroindoles are good intermediates to synthesize

2-substituted indoles. In fact, they are pyrroles in nature, but

they can easily be converted into indoles by oxidation. Therefore

great efforts and progress have been made in the enantio-

selective Friedel–Crafts alkylation of 4,7-dihydroindoles that

provides direct and useful access to such valuable scaffolds.

Other interesting indole derivatives are compounds containing

the tetrahydro-b-carboline core, because of their inherent

biological activity. These compounds are generally obtained

via the Pictet–Spengler reaction105 that allows cyclization on

the C2-position of the indole core of tryptamine (67) with a

Table 2 Organocatalytic synthesis of 3-indolylmethanamines (58)

57 Catalyst Yield (%) ee (%) Ref.

22 [R = 2,4,6(i-Pr)3Ph] 10 mol%, toluene, 4 A MS 95–99 73–97 91

22 [R = 3,5(Ph)2Ph] 2�10 mol%, TCE 16–91 82–98 92

22 [R = 2,4,6(i-Pr)3Ph] 5 mol%, MeCN 63–98 90–96 93

22 [R = 1-naphthyl] 10 mol%, toluene 56–93 58–99 949-Thiourea quinidine 10 mol%, AcOEt 53–98 86–96 95

Supported 9-thiourea epi-quinine 1 mol%, AcOEt 66–80 89–99 96, 97

22 (R = SiPh3) 2 mol (%) >85 86 98

21 [R = CH(Ph)2] 2 mol (%) 88

22 (R = 9-phenanthryl) 10 mol% toluene 5 A MS 85–93 51–87 99

22 (R = SiPh3) 5 mol%, CH2Cl2, 4 A MS 89–99 64–97 100

Fig. 13 Envisioned mechanism for indolemethanamine synthesis on

the basis of the experimental evidences.

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variety of aromatic and aliphatic aldehydes in the presence of

a Brønsted acid (Scheme 16). Due to the importance of

asymmetric generation of the new stereogenic centre in C-2

side chain, organocatalysis often answered this demand.

This section will be devoted and scheduled to discuss these

two topics.

3.1 F–C of 4,7-dihydroindoles

Taking advantage of chiral catalysis, the Friedel–Crafts

reaction of 4,7-dihydroindoles (69) was recently realized with

all the electrophiles already described in the previous sections

(Table 3). Simple unsaturated aldehydes and ketones exploited

iminium ion catalysis as well as chiral Brønsted acids were

used for ketoesters, nitroalkenes and imines, while saturated

aldehydes are up to date unexplored.

The addition to nitroalkene was also used for the synthesis

of a tetrahydro-g-carboline (72, Scheme 17), an example of

biologically important compounds not-readily accessible by

known methods in enantiopure forms.108

A quite different approach was proposed by McMillan,111

who exploited the ability of fluoborates to enable aryl moieties

to readily undergo intermolecular 1,4-addition to iminium

ions. Using his catalyst 28, the site-specific alkylation of

N-Boc indole 73 at the 2-position was accomplished (Scheme 18).

It should be noted at the end of this paragraph that the

corresponding metal catalyzed reactions worked moderately

with BINOL zirconium(IV) tert-butoxide (up to 78% ee)112

and well with bis(oxazolinyl)pyridinescandium(III) triflate

(up to 97% ee).113

3.2 Pictet–Spengler reaction

Chiral Lewis acids have not proven to be generally useful

for the Pictet–Spengler reaction, a likely result of catalyst

inhibition by the Lewis basic product. Greater success has

been instead achieved with Brønsted acid or hydrogen bond

donor catalysts.

Since tryptamines are the starting material of the

Pictet–Spengler reaction, the adducts from enantioselective

addition of indoles to nitroenes are valuable precursors, if

the stereochemistry of the newly formed stereogenic centre is

controlled by the original chirality. Actually, in order to

demonstrate the high synthetic value of their protocols,

Ricci,77 Jørgensen,80 and Akiyama81 all reported Pictet–Spengler

examples. Nitro compounds were reduced to the corresponding

tryptamine and then allowed to react with aldehydes. All

reactions occurred without any loss in the enantiomeric

enrichment of the products, and the relative stereochemistry

of 1,2,3,4-tetrahydro-b-carboline derivative was 1,4-trans.

The challenge of developing an asymmetric catalytic variant

of the Pictet–Spengler reaction starting from unsubstituted

tryptamines appears to be associated with the low reactivity of

the imine substrate. So more reactive iminium ion are prepared

in situ, but these reactions suffer from the disadvantage that

the N-group is difficult to remove. However, asymmetric

catalysis of Pictet–Spengler-type reactions has been firstly

reported with N-acyliminium ions and thiourea catalyst 74

(R= i-Bu, Scheme 19) (5–10 mol%, 65–81% yield, 85–95% ee

of the isomer with R out of the plane);114 another example of

Anion Binding Catalysis.

The N-substituent became an advantage if complex

polycyclic molecules had to be prepared. For example, acyl

iminium ions (like 63, section 2.3)102,103 were recently reported

by Jacobsen affording highly enantio-enriched indolizidinones

75, when the reaction was catalyzed by thiourea 74.37 The

reaction was carried out with many substituted indoles and

five and six-membered cyclic hemiaminals with 52–94% yields

Scheme 15 Reaction mechanism for the addition of N-acyl iminium

ions (63) to indoles with TMSCl. (BCl3 mechanism is almost super-

imposable).

Scheme 16 Overview of the Pictet–Spengler reaction.

Scheme 18

Scheme 17

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4460 Chem. Soc. Rev., 2010, 39, 4449–4465 This journal is c The Royal Society of Chemistry 2010

and 81–99% ee. The reaction was then applied to the synthesis

of (+)-harmicine (Scheme 20).

Envisaging for this reaction an Asymmetric Counteranion-

Directed Catalysis, the authors extended the reaction to

electronically and sterically diverse imines protonated by

benzoic acid and with asymmetric benzoate-thiourea (76,

Scheme 21) counterion providing unprotected carbolines in

39–94% yield and 85–99% ee. 115 It should be noted that

attempts to carry out acid catalysis of the Pictet–Spengler

reaction of unsubstituted tryptamines are often unfruitful

owing to competing homo-aldol pathways and imine

formation. The Asymmetric Counteranion-Directed Catalysis

provide a valuable solution to this problem, since the medium

acidity is very low.

BINOL-phosphoric acid (22) catalyzed asymmetric

Pictet–Spengler reaction of N-substituted tryptamines. In

particular (R)- and (S)-22 afford 68, whose configuration has

R-substituent out of or into the plane, respectively.

N-sulfenyl derivatives and chiral phosphoric acid [22,

R = 3,5(CF3)2Ph] (5 mol%) provided carbolines, (77–90%

yield, 30–87% ee),116 whereas N-benzyl derivatives gave

N-benzyl carbolines in yields ranging from 77% to 97% and

with ee values up to 87% (Scheme 22).117 In the latter reaction

the triphenylsilyl-substituted and the 3,5-bistrifluoromethyl-

phenyl-substituted BINOL phosphoric acid (2 mol%) proved

to be the catalyst of choice for the aromatic and aliphatic

aldehydes, respectively.

Table 3 Asymmetrical F–C addition of electrophiles to 4,7-dihydroindoles

Electrophile Catalyst Yield (%)a ee (%)a Ref.

43 44 [R = 2,4,6(i-Pr)3Ph] mol%, Et2O, �60 1C 59–96 87–98 (+) 106

22 (R = SiPh3) 10 mol%, toluene, �40 1C 80–97 86–>99 (+) 107

Nitroalkenes 22 (R = 9-anthryl) 0.5 mol%, CH2Cl2–benzene (1 : 1), 4 A MS, rt 93–97 24–97 (R)b 10826 17 [R = 3,5(CF3)Ph]/NEt3 20 mol%, MTBE 61–93 92–99 (R)b 109

3 75–97 66–97 (S)b 110

a Calculated on 70, Many papers show some representative example also after oxidation to 71. We direct the reader to references for these

data. b Priority: Indole, CH2, R.

Scheme 19

Scheme 20

Scheme 21

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The N-substitution can be obviously and cleverly used for

the synthesis of more complex molecules. As well as (+)-

harmicine (Scheme 20) was prepared by thiourea catalyst, the

tetracyclic indole alkaloid (�)-arboricine has been prepared

using an asymmetric organocatalytic Pictet–Spengler reaction

as the key step catalyzed by (R)-21 (R = SiPh3, 1 mol%).118

The key intermediate was obtained in 92% and 78% ee

(Scheme 23). The unnatural compound can be obviously

obtained starting from (S)-21.

In order to overcome the competing homo-aldol pathways,

substrates biased toward cyclization by gem-disubstitution

adjacent to the reactive imine were prepared and allowed to

react with aldehydes. The requirement of a geminal disubstitution

constitutes a current limitation, but the use of functionality for

further transformations by diastereoselective functional group

differentiation can partially overcome this drawback.

For example various geminal diester-substituted tryptamines

and both aromatic and aliphatic aldehydes if treated with

chiral Brønsted acid [(S)-22 R = 2,4,6-(i-Pr)3Ph, 20 mol%]

furnished enantio-enriched products 77 in 40–98% yield and

92–96% ee.119 Then their treatment with NaBH4/InCl3provided mono-alcohol by highly diastereoselective reduction

of the ester function trans to the substituent (Scheme 24).

At the top of this section we affirmed that chiral Lewis acids

are ineffective in the Pictet–Spengler reaction. Actually this

statement is true for metal-centred chiral Lewis acid. Very

recently, in fact, an organic Lewis acid has been found effective

for a highly enantioselective Pictet–Spengler reaction with

ketimines derived from a-ketoamides.120 The chiral silane

Lewis acid (S,S)-78 (Scheme 25) is simple to prepare and

inexpensive, and the method did not require any modification

or derivatization of the tryptamine precursor, since the Lewis

acid did not promote competing homo-aldol pathways. On

the other hand 78 had to be used in super-stoichiometric

amounts (1.3–1.5 equiv.), so it cannot be considered a catalyst.

However, compounds 79 are recovered in 50–94% yield and

81–94% ee.

Finally, a quite different approach has been proposed by

Franzen. The reaction took, once more, an advantage by

N-substituent and exploited a cascade reaction. The first step

involved an enantioselective Michael addition catalyzed by

Jørgensen-Hayashi’s organocatalyst 17, through iminium ion

catalytic cycle, of an unsaturated aldehyde onto a 1,3-dicarbonyl

moiety built on the amino group of the tryptamine (80). The

induced chirality allowed then an asymmetric acyliminium-ion

cyclization to form indolequinolizines (81, Scheme 26).121

The reaction proceeds well for various a,b-unsaturatedaldehydes 26 (56–71% yield, 3/1–9/1 dr, 87–95% ee of the

major isomer 81).

4. Functionalization at N-1

In sharp contrast to the progress in enantioselective alkylation

at the C-3 or C-2 positions of indoles, the asymmetric

N-alkylation has been underdeveloped: probably because the

NH proton of indoles must be removed to generate the

nucleophile. Direct organocatalytic methods based on amines

Scheme 22

Scheme 23

Scheme 24

Scheme 25

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are unable to deprotonate unsubstituted indole, since they

have a functional pKa barrier for nucleophile activation very

close to indole (pKa value of 16.97).122 This problem can be

overtaken by introducing an electron-withdrawing substituent

that may reduce the pKa value of the NH proton, (for example

3-formylindole has pKa = 12.36)122 eventually reinforced by

intramolecular reactions, where deprotonation leads to the

subsequent formation of tight and conformationally rigid

ion pairs. Moreover, such a substituent tempers the

nucleophilicity at C-3, and can be used either for additional

transformations or removed after reaction at the nitrogen

centre.

For example, the introduction of a formyl group on the C-2

position of the indole nucleus allowed a domino reaction

between indole-2-carbaldehyde (82) and a,b-unsaturatedaldehydes (26) with 17 as the catalyst following an iminium/

enamine activation mode (Scheme 27). The synthesis has been

carried out under two different reaction conditions (MTBE,123

or in toluene and 4 A MS)124 and provided an efficient and

asymmetric entry to synthetically useful and potentially

bioactive (R)-3-substituted 3H-pyrrolo[1,2-a]indoles (83) in

40–71% yields and 85 to >99% ee or 57–81% yields and

71–96% ee, respectively. Both reactions worked at room

temperature, with 20 mol% of 17, in comparable reaction

times (24–96 h or 72 h respectively) and aliphatic enals

afforded only traces of 83. Moreover, 2-furyl enal led to the

isomeric achiral 84 as the major product. On the other hand,

the notable features of the process are the use of easily

accessible and cheap building blocks and the capability to

obtain optically active tricyclic ring structures in a single step.

Bandini exploited the enantioselective intramolecular

version of this reaction with tethered indole-2-carboxylates

under chiral phase-transfer catalysis with cinchona-

based ammonium salt 86 (10 mol%). The increased acidity

of the N–H proton in 85 enhanced the reactivity of the

1-position under basic conditions. High enantio-control

and regioselectivity was obtained (55–93% yield, 75–96% ee)

(Scheme 28).125

A quite different approach was set up for the chemoselective

N-allylic alkylation of indoles with Morita–Baylis–Hillman

carbonates (87).126 A modified cinchona alkaloid (88) nucleo-

philically added to 87, leading to the asymmetric reagent and

tert-butoxy anion that achieved the deprotonation of the

acidic NH group of the indole (Scheme 29). Either electron-

rich or electron-deficient indoles could be employed and

62–93% ee was achieved, while 7-substituted indoles suffered

from steric crowding. Also the choice of solvent was found to

have effect on enantio-control of the reaction.

It should be noted that chiral metal catalysis is much more

underdeveloped, and only recently a method with high

branched-to-linear selectivity for N-allylation of indoles with

allylic carbonates appeared in literature. Enantioselectivity are

higher (close 99% ee) than Chen’s ones for the absolute

configuration as in 89.127

Scheme 26

Scheme 27

Scheme 28

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This journal is c The Royal Society of Chemistry 2010 Chem. Soc. Rev., 2010, 39, 4449–4465 4463

5. Conclusion

It is our hope that this review article serves to highlight the

unique synthetic challenges associated with organocatalytic

alkylation of indoles and in turn to inspire further development

in this area, especially employing those electrophiles now

underused (epoxides and aziridines over all).

In fact, the functionalization of the indole nucleus is a

fascinating area that still has a tremendous impact on organic

synthesis. These new methods kept to a minimum all those

ancillary reactions such as functional group manipulation,

preactivation of the aromatic ring and protecting–deprotecting

group derivatizations, increasing sustainability and efficiency

of the syntheses.

In the future, there remains room and need for improvement

of these synthetic methods. In particular, the implementation

of cascade reactions will enable multiple bond-forming and

bond-cleaving events to occur in a single synthetic operation,

thus circumventing the waste associated with traditional

stepwise synthesis.

6. Abbreviations

Ac Acetyl

BHT Butylated Hydroxytoluene

BINAM N-(2,3-Dichlorobenzylidene)-1,1 0-binaphthyl-

2,20-diamine

BINOL 2,2-bisnaphtholate

Bn Benzyl (PhCH2)

Boc t-Butoxycarbonyl

CaSH Camphor sulfonyl hydrazine

DCE Dichloroethane

MS Molecular sieves

MTBE Methyl t-butyl ether

PMB p-Methoxybenzyl

PMP p-Methoxyphenyl

SALEN N,N0-Ethylenebis(salicylimine)

TCE 1,1,2,2-Tetrachloroethane

TFA Trifluoroacetic acid

Tol p-Tolyl (4-MeC6H4)

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