Synthesis of Indole Derivatives with Biological Activity by Reactions ...

Current Organic Chemistry, 2010, 14, 2409-2441

2409

Synthesis of Indole Derivatives with Biological Activity by Reactions Between Unsaturated Hydrocarbons and N-Aromatic Precursors Giovanni Palmisanoa, Andrea Penonia*, Massimo Sistia, Francesco Tibilettia, Stefano Tollaria and Kenneth M. Nicholasb a

Dipartimento di Scienze Chimiche ed Ambientali, Università degli Studi dell’Insubria, via Valleggio 11, 22100, Como – Italy

b

Department of Chemistry and Biochemistry, University of Oklahoma, 620 Parrington Oval, 73019, Norman, Oklahoma – USA Abstract: The present review is devoted to illustrate the state of the art of the syntheses of indoles, focusing particularly on the most recent developments of new synthetic approaches. Emphasis is given to the preparation of natural products or bioactive compounds containing the indole unit. We present a historical perspective of indole synthesis showing the strategies by choosing the nitrogen precursors. The review is organized sharing the indole synthetic approaches by using different nitrogen-containing functional groups in aromatic substrates used as source of the nitrogen of the indole moiety. Some functional groups and some typical reactions are particularly stressed and highlighted because of the limited coverage given in previous reviews published on this topic. Other synthetic approaches more used and discussed in recent, complete and excellent reviews on the topic are summarized but the most recent published results are highlighted. Our interest is particularly focused on the indolization procedures and on the different methods used for the ring closure and no attention is given to modification of indole structures starting from molecules with a preformed indole unit. Intriguing indole syntheses are continually discovered and the importance that the scientific community gives to these new developments is connected with the strategic role of molecules containing the indole unit. Indoles are the class of heterocycles with more applications and extensive interest due to their biological and pharmacological activity.

Keywords: Indoles, natural products, bioactive compounds, heterocyclic synthesis, annulations, nitrogen-containing functional groups, named reactions, alkaloids. 1. INTRODUCTION The name indole is a portmanteau of the words indigo and oleum, since indole was first isolated by treatment of the indigo dye with oleum. The indole ring system is probably one of the most ubiquitous heterocycles in nature that occurs in many biologically natural and synthetic compounds. Indole is a popular component of fragrances and the precursor to many pharmaceuticals. Indoles are among the most abundant and important classes of N-heterocycles. Fagnou recently reported that a Beilstein search yielded more than 45000 results for indoles with biological activity [1]. Both naturally occurring and synthetic indole containing molecules produced by many synthetic approaches have important uses and potential as drugs with a broad spectrum of applications in many therapeutic categories, including non-steroidic anti-inflammatory, antimigrain, antidepressant, antineoplastic, anticancer and many others [2]. Libraries based on the indole scaffold have been developed to address the need for novel drugs with increased and enhanced potency [3]. Accordingly, chemists have long sought methods for the preparation of indoles and numerous approaches continue to be reported toward this end [4]. Indoles are currently prepared by numerous and varied synthetic approaches, both intramolecularly and intermolecularly. Stoichiometric procedures and catalytic reactions were used so far to afford molecules with the indole framework. The presence of the indole unit in numerous biologically active compounds, including the widespread indole alkaloids, has stimulated the development of transition metal-catalyzed methods [5]. These latter methods offer neutral conditions, better functional

group compatibility, and (potentially) more ready access to particular substitution patterns. Many excellent and complete reviews were published so far, [4] but the ongoing research studies and novel synthetic approaches continuously appear in the recent literature giving extraordinary opportunities to develop this topic. Many of these strategies utilized to design and synthesize the indole unit were classified as named reactions [6]. This review is finalized to cover and update the synthetic strategies to indoles starting from various nitrogen sources from arylhydrazines via the universally known Fischer indole synthesis [7], to more recent developments by using catalytic reactions with anilines [5]. Indigo was one of the first compounds isolated with an indole-type skeleton and from ancient times was used as dye for textile purposes. Other related compounds are used as colorants for nylon, surgical sutures, foods and ingested drugs. Other applications for indigo family substances are as a reagent for renal functional tests, for detection of nitrates, chlorates and in testing milk (Fig. 1). O R' R

H N

N H

R

R' O

Indigo (R = R' = H) Tyrian Purple (R = Br, R' = H) Indigo Carmine (R = H, R' = SO3- Na+) Fig. (1). Indigo and related compounds.

*Address correspondence to this author at the Università degli Studi dell’Insubria, Dipartimento di Scienze Chimiche ed Ambientali, Via Valleggio 11, 22100 – Como – Italy; Tel: +39-031-2386440; Fax: +39-031-2386449; E-mail: [email protected] 1385-2728/10 $55.00+.00

Among the structures with biological activity many have been known for a long time such as tryptophan (an essential aminoacid used in therapy of depressive states and sleep disorders), tryptamines © 2010 Bentham Science Publishers Ltd.

2410 Current Organic Chemistry, 2010, Vol. 14, No. 20

Palmisano et al.

functional groups showing a wide range of oxidation states reacting with unactivated hydrocarbons like alkanes, alkenes, alkynes and other compounds. Some different disconnection strategies involving one or more bonds were studied and realized. We present here some chapters and each of them is dedicated to indole synthesis by starting from a different class of nitrogen containing substances.

such as serotonin (an important neurotransmitter), melatonin (a regulator of the circadian cycle), indole-3-acetic and indole-3-butyric acids, known as growth factors in plants (Fig. 2). More complex molecules showing the indole unit are present in naturally occurring alkaloids and synthetic products derived by modification of natural structures [8]. Strychnine is a strong central nervous system (CNS) stimulant, LSD is a potent allucinogen and reserpine has been used as antihypertensive agent (Fig. 3). This review is organized, as described before, accordingly to the nitrogen sources that generates the indole ring by cyclization in the key step.

2.1. Indoles from Anilines-Amines, Anilides-Amides o-Aminobenzaldehydes and ketones by simple intramolecular condensation with loss of water cyclize to indoles. Many different precursors can be used for this process and both the carbonyl and the amino group can be generated by other functional group interconversions. This means that many synthetic routes can give the right intermediates. The prototype for this reaction is the Reissert synthesis [10]. A development uses an intermediate in

2. INDOLE SYNTHESIS FROM DIFFERENT NITROGEN PRECURSORS AND HYDROCARBONS Indolization procedures [9] are very intriguing and fascinating reactions, most of them starting from different nitrogen containing

CH3 HO COOH NH2 N H

N H

Tryptamine

N

S O

NH2

N H Sumatriptan

Indol acetic acid

H3CO

COOH

CH3

N CH3

HN

N H

NH2

N H Melatonine

Gramine

CH3

O

N H

Serotonin CH3

CH3

HN

N H Skatole

O

N H L-Trypthophan O

H3CO

CH3

OH

COOH

N N

P O

CH3

O

CH3 COOH N H

N H

O Indomethacin

HO

Cl

N H Psilocybin

Indol butyric acid

Psilocin

Fig. (2). Bioactive molecules containing the indole framework. O Et2N N N H N

H

O H

O N H LSD

Strychnine

N

H3CO N H

H

O

H O

H H3COOC

OCH3 Reserpine

Fig. (3). More complex indole compounds.

OCH3 OCH3 OCH3

CH3

CH3 H N CH 3

Synthesis of Indole Derivatives with Biological Activity

Current Organic Chemistry, 2010, Vol. 14, No. 20 2411

which the nitrogen is at the level of a Boc-protected amine. Lithiation causes deprotonation of an o-methyl group that promptly reacts with oxalate and then, after nitrogen deprotection, the indole is produced [11]. o-Aminobenzyl carbanion equivalents are used as useful intermediates for cyclization to indoles. Generally, these anions undergo acylation that is normally followed by an in situ cyclization and aromatization. With this last protocol the isolation of the intermediates is not involved [12]. o-Alkylanilides are another class of substrates that give indole formation through base-catalyzed cyclo-condensation. The first reaction in this category of compounds employed very harsh conditions and was not very tolerant of many functional groups. This protocol is known as the Madelung synthesis [13]. With the use of alkyllithium reagents this condensation can be carried out under milder conditions [14]. A modification of the Madelung protocol was introduced generating a phosphonium ylide and then an intramolecular Wittig-like reaction involving the amide carbonyl [15]. Kraus and co-workers reported an interesting one-pot synthesis through a Wittig-like procedure starting from (2-aminobenzyl) triphenylphosphonium bromides with aromatic aldehydes. This procedure constitutes an excellent starting point for the preparation of advanced intermediates for an easy access to rutaecarpines and analogue derivatives. Rutaecarpine is an indolpyridoquinazolinone alkaloid isolated from Evodia rutaecarpa which has shown antithrombotic, anticancer, anti-inflammatory, analgesic and antiobesity activity (Scheme 1). The method presented by Kraus et al. is an easy and successful route to 2-substituted indoles by way of a novel six-electron electrocyclic closure of the imine intermediate derived from commercially available phosphonium salts. This procedure is a mild and high yield electrocyclic annulation strategy for the synthesis of 2,3-disubstituted indoles. The formation of the imine intermediate is the relevant step of the process. This was carried out by efficient procedure both in conventional thermal method and by the assisted heating in microwave reactor. The latter conditions are dramatically more efficient, shortening reaction times. The imine intermediates are not isolated and immediately used in a second step for the preparation of 2,3-disubstituted indoles [16]. Another modification employed amino-silanes as starting materials [17]. In a complementary approach to the Madelung synthesis, o-acylanilines can be used as starting materials [18]. One of the most complex indole alkaloids, (-)-penitrem, was synthesized by Smith and co-authors by using a modification of the Madelung protocol [19]. A solid-phase version of the Madelung indole

synthesis was developed by Wacker et al. for the preparation of 2,3disubstituted indoles [20]. The aniline is anchored to a Bal resin by a reductive amination (Scheme 2). Working with -arylaminocarbonyl compounds, the cyclization occurs via an electrophilic attack onto the aromatic ring. The reactants are easily prepared by reactions between anilines and 2haloketones. This reaction can give a mixture of regioisomers [21]. N-Acylated derivatives can cyclize in mild conditions, producing unsubstituted indoles [22]. By using N-diacylanilines, Fürstner synthesized indoles by a McMurry-type reaction with TiCl3 as reductant [23]. -Anilino aldehydes and -anilino ketones are involved in cyclization processes in the presence of protic or Lewis acids. Julia and coworkers firstly reported this kind of reaction that is formerly an intramolecular Friedel-Crafts reaction [24]. Two other named reactions in which indoles are produced starting from anilines are known as the Gassman synthesis and Sugasawa synthesis. The Gassman synthesis produces sulfurcontaining indoles, but these can be easily hydrogenated if required [25]. N-Chloroanilines and -thiomethylketones or anilines and chlorosulfonium salts are used to prepare anilinosulfonium ylides. A [2,3]-sigmatropic rearrangement occurs to generate indoles and oxindoles. Sulfonium ylides are generally treated with Et3N. Sulfurcontaining indoles can be treated with Raney Nickel to induce desulfurization [26]. Other desulfurization methods are carried out with LiAlH4 [27]. Arylamines without any protecting group undergo FriedelCrafts acylation regioselectively ortho to the nitrogen by using nitriles and BCl3 as Lewis acid. This step generally produces (ochloroacetyl)arylamines that give cyclization to indole after reduction of the carbonyl group [28]. The reduction is usually effected by NaBH4. Sometimes, an additional catalyst as TiCl4 , AlCl3 or ZnCl2 is used. As summarized in the introduction, the Fischer indole synthesis is probably the most popular and deeply investigated approach to indole derivatives. In the last decades, concomitant with the study and rapid development of the chemistry of organometallic compounds and particularly with the extraordinary interest in transitionmetal complexes, new synthetic tools have been introduced. Novel indolization methods starting from the amino group became extremely important and many research groups are actively involved in this topic. New catalysts are continuously discovered in a sort of never ending landscape. The first seminal reports displayed the use of o-aminophenylacetylenes and N-protected derivatives in the cyclization to indoles

P+Ph3BrR2

R2 O +

R1

1) 0.4 equiv. AcOH, heating MeOH R1 H

2) 1.6 equiv t-BuOK, THF, 25° C, 1h

NH2

R3

N H

R3

Scheme 1.

N

(i-Pr)2NEt

+

Cl

NH O

Scheme 2.

CN

CN

CN

r.t., 16 h

KOt-Bu

O N

N

NMP reflux, 24 h

CN N

N

TFA N

Et3SiH

N H


Palmisano et al.

in less than one hour [32]. Slight variants of this kind of reaction by using NaAuCl4·2H2O in EtOH or EtOH-water mixtures at room temperature and InBr3 were respectively introduced by Marinelli [33] and by Sakai [34]. The indole Larock synthesis was used as a step in the total synthesis of (-)-fuchsiaefoline by Cook and coworkers [35] and various 3-iodoindoles [36]. Many azaindoles were produced by this kind of reaction [37]. 7-Azaindole derivatives from 2-amino-3-iodopyridines were produced in excellent yields [38]. Other cyclizations starting from o-haloanilines or o-haloanilides with carbonyl compounds were carried out achieving indoles as major products and by using different palladium catalyzed procedures [39] or uncatalyzed processes under microwaves as a solid state reaction [40]. Cacchi and co-workers synthesized 3-(-trifluoroacetamidoaryl)-1-propargylic esters, common intermediates for the Pdcatalyzed indolization. By this synthetic approach, 2-aminomethyl-, 2-vinyl- and 2-alkylindoles were prepared. These intermediates have been prepared by a Sonogashira-type reaction and the indole precursors (2-alkynyl-trifluoracetanilides) were isolated in good yields. Treatment of these anilides with substituted piperazines in the presence of Pd catalysts lead to the formation of 2-substituted indoles (Scheme 4) [41]. In a similar procedure o-bromotrifluoroacetanilide heated with terminal alkynes in the presence of CuI/L-Proline leads to the formation of the corresponding indoles [42]. The same group performed the synthesis of 2,3-disubstituted indoles with a CuI/L-Proline-catalyzed cross-coupling of 2halotrifluoroacetanilides with -keto esters [43]. Another coppercatalyzed reaction was successfully carried out on 2-ethynylaniline

and most of the catalytic methodologies are based on Pd-complexes [4r-s]. Many synthetic approaches that used an amino/amide group to cyclize show the use of metal-mediated or catalyzed reactions to open new ways to form the precursor and led to work in mild conditions. This topic was thoroughly reviewed in an excellent report by Beller and co-workers [4d]. After an initial historical perspective we will show a few very recent reports, published after Beller’s paper, that illustrate this kind of reactivity. 2-Alkynylarylamines or N-protected derivatives can be cyclized to indoles by an addition that is generally catalyzed by Pd-based complexes. Aminoarylacetylenes can be prepared as stable and isolable intermediates or even generated in situ in a one-pot reaction that leads directly to indoles. Many named procedures were registered on this topic. The most popular are known as Castro’s, Larock’s and Cacchi’s variants indole syntheses. The preparation of the intermediates is generally carried out via classic cross-coupling approach to 2-haloanilines and related N-protected compounds by using Stille procedure with stannylacetylenes or Sonogashira-type reactions by the means of silylacetylenes [29]. A direct cyclization of o-alkynylanilines can be effected simply by treatment with tetrabutylammonium fluoride [30]. Palladium catalysts can act the final ring-closure [31]. Larock very recently presented a one-pot three-component coupling reaction for the synthesis of indoles by the assistance of microwaves (Scheme 3). Working in standard Sonogashira coupling conditions polysubstituted indoles have been prepared in moderate to excellent yields. All the reactions were dramatically accelerated and the complete conversion of the substrates occurred R1

N

3 mol % PdCl2(PPh3)2 2 mol % CuI, Et3N MW (300 W), 60°C

R2

R1

N

R2

Ar R4

ArI R3

I + R4 R3

CH3CN MW (300 W), 90°C

R3

R1

Scheme 3.

R2 R1

R2

I

R3

+ NHCOCF3

PdCl2(PPh3)2, CuI (i-Pr)2NH

R1

R3 OH

DMF, r.t.

OH

NHCOCF3 ClCO2Et, DMAP CH2Cl2 -30 °C to 0 °C

R1

R2 or R3 = H Pd(PPh3)4 N H

N

THF H N

N R

N R Scheme 4.

R2 R1

R3 OCO2Et

NHCOCF3

R4 N



derivatives in aqueous media and a catalyst recycling reaction was established by using 1-ethylpiperidine [44]. Cacchi’s protocol was used in a practical one-pot, regiospecific three-component process for the synthesis of 2,3-disubstituted indoles by a Pd-catalyzed domino indolization procedure [45]. Anilines were used even in Zn(OTf)2-catalyzed cyclization reactions with propargyl alcohols without additives to give indole products with different structures [46]. Willis and co-workers have recently demonstrated that tandem palladium-catalyzed amination reactions – one intramolecular, one intermolecular – can be used for an easy access to 1-functionalized indoles from acyclic non-nitrogen containing precursors [47]. By using this procedure, the same group reported a protocol to access 1-functionalized-7-azaindoles (Scheme 5) [48]. This method shows a tandem approach with alkenyl- and arylC-N bond formation. Utilizing Pd catalysts a cascade N-annulation is successfully achieved. In a similar procedure Lautens and coworkers obtained 2-substituted indoles by Pd-catalyzed reactions in excellent yields [49]. Envisioning this chemical mechanism, Ackermann and coworkers showed the synthesis of indole compounds starting from oalkynylhaloarenes (Scheme 6). The reaction is formally a palladium-catalyzed N-arylation/hydroamination sequence. The privileged and superior catalyst for this kind of sequence was a palladium-complex derived from a bulky N-heterocyclic carbene ligand [4q]. The same group reported a multi-component approach to indoles by starting from o-diahaloarenes in a multicatalytic system obtaining the target molecules as single regioisomers [50]. o-Chloroarylamines were used as privileged substrates to elaborate a novel one-pot process to N-alkylindoles and N-alkylazaindoles via copper-free Sonogashira alkynylation followed by a base-mediated indolization [51]. Similarly, Alper reported a tandem palladium-catalyzed N,Ccoupling/carbonylation sequence for the synthesis of 2-carb-

R2 R1

RNH2

+

X N

oxyindoles. The first step of this procedure is a cyclization reaction mediated by Pd complexes starting from 2-(2,2-dibromovinyl) phenylamines [52]. o-Halo-N-arylenamines, o-halo-N-vinylamines, N-propargylamines and N-allylamines are typically used as building blocks giving indoles by transition metal catalyzed cyclization. Palladiumcomplexes are surely the privileged catalysts for this kind of ring closure. 2-Halo-N-allylanilines are cyclized to indoles by an intramolecular Heck-type reaction. The pioneering work on this topic was presented by Hegedus and co-workers, who reported an heating on N-allyl-o-iodoaniline with Pd(OAc)2 and Et3N in CH3CN [53]. The reaction presumably involves a Pd(0) species which undergoes oxidative addition with aryl iodide. After cyclization and reductive elimination, Pd(0) is regenerated. More recently, a ruthenium catalyst was developed achieving indoles in excellent yields [54]. N-Protected o-aminostyrenes were used as starting materials to achieve indole compounds by reactions with alkyllithiums [55]. Related N-propargylamines give similar reaction [56]. N-Vinyl-o-haloanilines cyclize via intramolecular Pd-catalyzed reactions. As in the Heck reaction, electron-withdrawing substituents on the vinyl group facilitate the reaction, stabilizing the enamine intermediates. N-Vinyl anilines can be cyclized by photochemical reactions [57]. Similar reactivity is shown by -anilino-acrylonitriles and -anilino-ketoesters. N-Propargylanilines are useful building blocks and their use in indole synthesis was recently verified by Saito et al. via a Rh(I) catalyzed amino-Claisen rearrangement. 2Substituted and 2,3-disubstituted indoles have been produced in mild conditions. The formation of indoles was proved to be derived from an o-allenylamine intermediate [58]. Substituted 7-azaindoles were afforded from nicotinic acid derivatives or 2,6-dichloropyridine respectively by microwave heating that dramatically accelerates the penultimate reaction step, an epoxide-opening-cyclizationdehydration sequence [59]. R2

Pd(OAc)2, ligand Cs2CO3

R1

toluene, 110 °C

Y

N

N

R

Scheme 5. R2

+

R1

R3

5 % mol Pd(OAc)2 5 % mol ligand NH2

R1

R2 N

KOt-Bu, PhMe 105-120 °C, 14 h

Cl

R3

Scheme 6.

Ac N 5 % cat + N Ac

Toluene, 80°C

N Ac N Ac

Scheme 7.


Palmisano et al.

Ring-closing metathesis reaction is a powerful tool for the generation of carbocyclic and heterocyclic derivatives. Some groups reported the indole synthetic approach starting from enamines and ynamines. Alkene ring closing metathesis and even alkyne metathesis were tested furnishing indole compounds [60]. The first example of indole synthesis through a metathetical process was discovered by Söderberg and co-workers by heating the Narylamino-substituted chromium carbine [61]. Using Grubbs' second generation catalyst, Nishida [62] and Benassar [63] independently performed an isomerization of allylic amine to the enamine, and the final step of ring closing metathesis provided excellent yields. By using enyne metathesis, Perez-Castells synthesized protected indoles obtaining a mixture of vinyl indoles with two regioisomeric approaches (Scheme 7) [64]. By enyne metathesis, N-tosyl-2-vinyl pyrroles were synthesized as useful starting materials to produce indoles by further cycloaddition procedures (see 2.9). An interesting development of indole synthesis via rhodium catalyzed oxidative coupling of acetanilides and internal alkynes was reported by Fagnou and co-workers who discovered the extraordinary catalytic activity of cyclopentadienyl Rh-complexes in the activation of unfunctionalized C-H arylic bonds. This reaction leads to heteroannulation through the formation of C-C and C-N bonds (Scheme 8) [1]. A similar discovery on the indole synthesis from anilines and alkynes via palladium-catalyzed C-H activation was reported by Jiao and co-workers by using dioxygen as the oxidant [65]. An intriguing new indole synthesis with a metal-free procedure was recently reported by Wang and co-workers that first introduced a single-step formation of functionalized indoles from readily available anilides and ethyl diazoacetate with a domino approach. The combined use of Tf2O and a mixture of 2-chloropyridine and 2,6-dichloropyridine promoted the reaction with the formation of indoles in moderate to good yields (Scheme 9) [66].

One of the first indolization reactions that used arylhydrazines as indole precursors was performed by Fischer and Jourdan in 1883 [67] and after more than one century this popular procedure is one of the most used and important methods for the preparation of indole derivatives [7, 68]. From a mechanistic point of view, the reaction involves a condensation step of an arylhydrazine with a carbonyl group followed by a [3,3]-sigmatropic rearrangement and rearomatization with loss of ammonia. The reaction is successfully catalyzed by strong and weak protic acids and even by Lewis acids. The arylhydrazone is not generally isolated and the indolization is performed in one-pot reaction. Unsymmetric carbonyl compounds generally gave a mixture of regioisomers. Some of the recent papers that reported the use of Fischer indole synthesis afforded bioactive molecules. Bonjoch applied a regioselective version of the Fischer indole synthesis in one step of the preparation of deethylibophyllidine (Scheme 10) [69]. The arylhydrazones, important intermediates in the Fischer indole synthesis, are not only available by the classic condensation reactions between arylhydrazines and carbonyl compounds. An interesting variant was introduced by the procedure known as the Japp-Klingemann modification [70] in which an arylhydrazone is obtained by a reaction of aryldiazonium salt and 1,3-dicarbonyl compounds. This procedure has been used by many research groups to provide an alternative route to arylhydrazones easily convertible in indoles by Fischer conditions. By following this variant, Cook and co-workers reported the enantioselective total synthesis of tryprostatin A via Japp-Klingemann procedure using diazonium salts derived from m-anisidine and the anion of ethyl ethylacetoacetate (Scheme 11) [71]. One preparation of the serotonin relies on a Fischer’s protocol, the requisite arylhydrazone was constructed by Japp-Klingemann reaction [72]. Me

[Cp*RhCl2]2 (2.5 mol %) AgSbF6 (10 mol%)

Me O R

2.2. Indoles from Arylhydrazines, Diazocompounds and Diazonium Salts

Ph

R

+ N H

Ph

Cu(OAc).2 H2O 2.1 eq. t-AmOH (0.2 M) 120° C, 1h

N Ac

Scheme 8.

R2 +

R1

CO2Et

2-ClPy (1.2 equiv) 2,6-Cl2Py (0.2 equiv)

O

H N

OEt

O N2

R1

Tf2O (1.2 equiv), CH2Cl2 -78°C - -30°C, 20 min

N H

Scheme 9. O NHNH2

Ph

S

S

N O

AcOH

N

Ph

+ 120° C, 1,5 h O Scheme 10.

R2

N H


O

CH3

MeO

O

+ MeO


1) NaNO2, HCl, 0° C

EtOH / HCl

MeO

NH

OEt

2) KOH, pH 5-6, 0° C, 4 h

NH2

N

CO2Et

N H

70° C, 12 h

EtO O

Scheme 11.

The authors show a wide survey of epoxides and arylhydrazines affording indoles in moderate to very good yields. An alternative, novel and very recent approach to the preparation of arylhydrazone was presented by Takamura et al. which provided the precursors for the Fischer indolization starting from -diazoesters (Scheme 14) [78]. -Diazoesters react with aryllithium reagents by a nucleophilic attack on the terminal nitrogen of the diazo group providing arylhydrazones that in acidic conditions gave the indolization in good to excellent yields. Similarly, magnesium reagents were used as nucleophiles instead of lithium reactants. The Fischer reaction is a typical two components reaction. Recently, this procedure was re-engineered into a three-component process by the Ganem research group. For this purpose the hydrazone was generated in situ in a one-pot procedure after the nucleophilic attack of an organometallic reagent (organolithium or Grignard reagents) to nitriles or carboxylic acids and subsequent reaction with arylhydrazine hydrochloride salts (Scheme 15) [79]. This three-component condensation can be successfully implemented as a one-pot process. The extension to substituted arylhydrazine hydrochloride salts leads to 4, 5, 6 and 7-substituted indoles. The same group recently described a one-pot synthesis or a two-stage procedure to indoles working with arylhydrazines and aliphatic nitrocompounds, avoiding the strong acidic conditions, typically used and usually associated with Nef reaction, thus achieving the target molecules in moderate to good yields. Nitroalkanes may be converted to indoles via the corresponding nitronates using mild H2SO4 treatment. Under these conditions acinitro, ketones and oximes are all transformed into the arylhydrazone that undergoes the Fischer indolization [80]. Both primary and secondary nitroalkanes are readily transformed into polysubstituted

Fischer indole synthesis was even performed in combinatorial chemistry [73] by using a solid-supported synthesis with resinbound arylketones treated with arylhydrazone and ZnCl2 in glacial acetic acid at 70 °C for 18-20h [74]. A survey of resins revealed that polystyrene was superior to polyethylene glycol (PEG) polystyrene (PEG-PS) minimizing impurities. Both electron-rich and electron-deficient hydrazines could be used in this solid phase synthesis. The Fischer indole synthesis is probably the most important and versatile reaction that led to the introduction of almost all the substitutions both in the benzene and in the pyrrole nuclei. An interesting extension to the Fischer indolization is the preparation of arylhydrazones by palladium-catalyzed coupling of benzophenone hydrazone with aromatic halides (Scheme 12) [75]. A wider range of arylhydrazines was prepared. Benzophenone hydrazone can be used for a ketone exchange reaction giving a substrate that readily cyclizes in Fischer conditions. The entire process starting from aryl halide to indole was carried out in onepot without isolation of intermediates. A special case of the Fischer indolization process was reported by Grandberg and developed by other groups for the synthesis of tryptamines [56]. Taylor and co-workers reported recently a tandem Sc(OTf)3mediated Meinwald epoxide rearrangement/Fischer indole synthesis (Scheme 13) [77]. Many different epoxides through a known rearrangement process gave an aldehyde or a ketone intermediate that promptly reacted with arylhydrazines and protected aromatic hydrazines furnishing highly substituted indoles. Different Lewis acids were tested and used to favour the epoxide ring opening, and Sc(OTf)3 was found to be the superior catalyst. Other main-group and transition metal triflates successfully induced the reaction. Ph2C=NNH2, Pd(OAc)2 BINAP, NaOt-Bu

Me

Me

Ph

n-C5H11

n-C6H13COMe, TsOH Ph

PhMe, 100° C

Br

N H

aq. EtOH, reflux

N

Me

N H

Scheme 12.

NHNH2 O

Ph

Sc(OTf)3

+ THF, 100° C, 1 h

N H

Scheme 13.

X

Ph X Ph

CO2Et

+ N2

Scheme 14.

BuLi

CO2Et

X

Br

THF, - 68° C

N H

N

Ph SOCl2, EtOH 80° C, sealed tube

N H

CO2Et


R1CN

Palmisano et al.

R2CH2Met

+ or

R2CH2CN

R1COOH

R2

R2

R1Met

+

R2CH2Met

or

LiO R1

Met N

+

R1

LiO

R3C6H4NHNH2 HCl

R2CH2COOH +

R1Met

R3C6H4NHNH2 HCl

AcOH

AcOH

R2 R1

R3 N H Scheme 15.

indoles and o-, m- and p-substituted arylhydrazines were successfully tested. Eilbracht applied the Fischer indolization by using this reaction as the last step inside a very fascinating pathway passing through an Ir(I)-catalyzed asymmetric allylic substitution followed by a Rhcatalyzed hydroformylation for the synthesis of tryptamines and analogues (Scheme 16) [81]. This tandem process is carried out by using Rh catalyst for the hydroformylation step and then acidic conditions to cyclize the hydrazone intermediate. While the allylic substitution proceeds with high enantiomeric excess, the stereocenter may epimerize during tandem hydroformylation–Fischer indolization via reversible double bond isomerization, either caused by the transition metal catalyst or the acid. The tryptamines afforded by this method from enantiomerically pure allylic amines revealed complete retention of enantiopurity. This technique is a valid method for the achievement of tryptamines and tryptophan derivatives and even homotryptophans were obtained. The number of required steps is reduced to a minimum since simple functional group conversions are not required. Again in the ambit of the Fischer indolization, a novel and intriguing way to prepare the arylhydrazones was introduced by Odom et al. through the hydrazination of alkynes catalyzed by titanium complexes (Scheme 17) [82]. This new procedure could provide many hydrazones that cyclized in the presence of Lewis acids such as ZnCl2 affording indoles in a one-pot procedure. By

1 mol % Rh(acac)(CO)2 1 mol % Xantphos 1 eq phenylhydrazine

Ph N

CO2Et

Ph

10 bar CO, 10 bar H2 THF, 5d, 80° C

R1

this novel procedure, hydrazones were generated with perfect atom economy. 1,1-Dialkyl hydrazines were used as privileged substrates in a non-catalytic direct addition to unactivated alkynes. More recently, the same group reported a complete study with the first use of mono-substituted hydrazines. A deep analysis of the properties of the catalyst and a titanium catalyst design study was carried out together with a regioselective addition of hydrazines to carbon-carbon triple bond [83]. Beller and co-workers introduced the employment of different catalysts and particularly Cp complexes of titanium for the addition of arylhydrazines to the carbon-carbon triple bond, achieving regioselectively both Markovnikov and anti-Markovnikov hydrazone adducts [84]. A discrete number of terminal alkynes was screened for the titanium catalyzed hydroamination with hydrazines. Except for phenylacetylene, all reactions occurred with high Markovnikov selectivity leading to 2-methyl-3-alkyl-substituted indoles. Working with phenylacetylene both regioisomers were isolated. This straightforward and efficient route for the synthesis of arylhydrazones is one of the topic that received a particular attention and development in the recent years [85]. The synthesis of interesting bioactive molecules such as tryptamine, tryptophol and related compounds, useful precursors of potential drugs, was accomplished using the titanium-catalyzed hydrazination of alkynes as a relevant step. Very recently, Beller et al. performed the hydrazination reaction avoiding the use of any H2N

Ph N

CO2Et

COOEt 4 wt% H2SO4

Ph

R1

R1

3 h, 80° C Ph

N H

N N H

R1 = Ph, Et

Scheme 16.

R3 NH2 R1

R2

+

R4

N

N R4

Scheme 17.

Ti(NMe2)2(dap)2 or R3

Ti(NMe2)2(SC6F5)2(NHMe2)

R1

N

R1

R2

R3 = aryl

N R4

R2



One of the indole synthetic approaches that is a popular name reaction is the Nenitzescu indole synthesis, an easy way to indole compounds starting from enamines and quinines [92]. This procedure is particularly useful as an easy access to 5-hydroxy indoles. During the 1950s the reaction was particularly investigated and employed for the preparation of melatonin related compounds. Nenitzescu’s protocol was used for the preparation of one of the most important selective secretory phospholipase A2 (s-PLA2 ) inhibitor LY311727. Martinelli and co-workers obtained this target in high yield (Scheme 21) [93]. Nenitzescu’s synthesis can be re-engineered as a threecomponent process by using -ketoesters, primary amines and pbenzoquinones. This modification led Ketcha and co-workers to develop the solid-phase synthesis of 5-hydroxyindole-3-carboxamides [94]. Another variant was introduced using benzoquinone mono- and bis-imides as starting material [95]. N-Alkoxyindoles are interesting compounds for their biological activity. A new method for their synthesis was provided by Zhao and co-workers (Scheme 22) [96]. This group reported the preparation of N-alkoxyindole-3-carbonitrile derivatives under mild conditions by a FeCl3-mediated intramolecular heterocyclization. This process shows a wide functional group tolerance both for electron-withdrawing and electron-donating aromatic substituents. m-Substituents have the possibiity to produce two regioisomeric products. The cyano group has a potential implication in further functionalizatons due to a broad versatility. Zhao and co-workers reported more recently a novel synthesis of 3-indolecarbonitriles, analogue compounds of the previous paper, by a PIDA (Ph(IOAc)2)- and PIFA (PhI(O2CCF3)2)-mediated oxidative carbon-carbon bond formation on N-arylenamines [97].

transition metal complex and achieving indole-2,3-dicarboxylates and in regioselective fashion 2-arylindole-3-carboxylates (Scheme 18) [86]. Beller and co-workers obtained a domino hydroamination/ Fischer indole cyclization by using acetylene dicarboxylates and phenyl propiolates as substrates. Similar results were reported before in an analogous transformation by Acheson [87] and Miki [88]. Karchava very recently presented a research work on the synthesis of indole molecules by starting from arylhydrazines but not involved in a Fischer indolization (Scheme 19) [89]. By using the same approach reported with amines [90] but working with hydrazines, this research group studied the copper(I)-catalyzed intramolecular amination of aryl bromides. The reaction occurred on 2-(2-bromophenyl)-3-phenylacetates with various hydrazines, affording the corresponding enehydrazines in excellent yields. These products were used as substrates in intramolecular ringclosure by amination of bromides catalyzed by CuI and achieving N-aminoindoles-3-carboxylates in very good yields. Substituted hydrazines were used and gave good results. The use of monosubstituted hydrazines leads only to the formation of tars. By using O-benzylhydroxylamines instead of arylhydrazones, 1-alkoxy derivatives were prepared by copper-catalyzed intramolecular ring closure on the intermediate adducts (benzyloxyamino acrylates), which are known as pharmaceutical precursors, but not so easily available. 2.3. Indoles from Imines and Enamines Some recent reports provided the access to the indole ring using aromatic imines or enamines as starting materials by intramolecular addition to arynes (Scheme 20) [91].

CO2Et

N

CO2Et

1) toluene, 100° C, 24 h

+

NH2

2) ZnCl2, 100° C, 24 h

N

R = Ph, CO2Et

Me

R

Me

R

Scheme 18.

Br

Br

CO2Me

R +

OH

CO2Me

CO2Me

MeOH

CuI (5 mol %)

N H2N

X

r.t. or reflux

HN

R'

R N

R'

N

K3PO4 (2 equiv.) DMF, 85° C

R' N

X

X

Scheme 19.

Cl MeO

MeO

NaNH2, NaOtBu THF, 0° C - r.t.

N

MeO

N

N H

Scheme 20.

MeO2C O

O

CH3NO2

+ HN Bn

Scheme 21.

CO2Me HO

20° C, 48 h

N Bn

R


Palmisano et al.

CN R1

CN

R1

R2

FeCl3

N

R2 N

CH2Cl2 r.t.

OR3

OR3

Scheme 22.

This new method is particularly relevant for the use of environmental benign conditions via transition-metal free procedure. Many different research groups are involved in the synthesis of complex organic molecules with indole skeleton or heterocyclic skeleton containing the indole framework. Carbodiimides were used as building blocks for the preparation of polycyclic derivatives showing the indole moiety. Saito [98] and Molina [99] independently studied intramolecular Diels-Alder reaction of conjugated carbodiimides. Saito’s group studied the effect of the addition of Lewis Acids and optimized reaction condition by working in the presence of AlCl3, achieving selectively -carbolines. Indolo [2,3b]quinolines that display strong cytostatic antitumour activity were afforded by Molina and co-workers by thermal reactions. More recently, Wang produced in situ benzannulated enyne-isocyanates and iminophosphoranes [100]. These compounds were used for the formation, by cycloaddition processes, of pyrido[1’,2’:1,2]pyrimido[4,5-b]indoles and related compounds, potential DNA-binding agents. Mukai reported the use of alkyne carbodiimides for the preparation of indole alkaloids by following an aza-Pauson-Khand reaction catalyzed by Co2(CO)8 [101]. Larock and co-workers reported a palladium-catalyzed annulation of internal alkynes affording isoindolo[2,1-a]indoles (Scheme 23) [102]. These target molecules have been prepared via annulations of internal alkynes by imines derived from o-iodoanilines in the presence of a palladium catalyst. This method provides an efficient

route for the synthesis of these tetracyclic heterocycles. The mechanism of this interesting annulation process appears to involve: 1) oxidative addition of the aryl iodide to Pd(0), 2) alkyne insertion, 3) addition of the resulting vinylic palladium intermediate to the C-N double bond of the imine, 4) electrophilic palladation of the resulting -palladium intermediate onto the adjacent aromatic ring, 5) reduction of the tetracyclic product and Pd(0). Many internal alkynes were employed with a very broad survey. Yamamoto recently described an intramolecular cyclization of alkynes and imines catalyzed by Pd-complexes (Scheme 24) [103]. This group, in the same paper, reported even the in situ formation of imine by condensation of 2-alkynylaniline and cyclohexanecarboxaldehyde. Indole and carbazole derivatives were prepared even from 2-fluorophenyl imines [104]. Barluenga and Valdes presented a new Pd-catalyzed cascade process for the preparation of indoles starting by o-dihaloarenes or o-halobenzene sulfonates and imines (Scheme 25) [105]. This method proceeds through the -arylation of an imine followed by an intramolecular ring closing. This approach is definitely a very efficient Pd-catalyzed cascade of carbon-carbon/ carbon-nitrogen bond formation and presents a very general, truly reliable and highly convergent synthesis of substituted indoles with high structural diversity. Interestingly better results in terms of yields and reaction times were generally obtained for indoles bearing secondary or tertiary substituents at the nitrogen. The authors experimented even a worthly scale up of the reaction Ph

N

Ph +

Ph

2

Ph

5% Pd(OAc)2, LiCl Na2CO3, DMF

N

100° C, 8h

I

Ph Scheme 23.

R1

R1 Pd(OAc)2 n-Bu3P

R2

R2 R3

THF, 100° C N H

R3

N Scheme 24.

Z

R3 X

R2

Pd2(dba)3 (2 mol %) XPhos (4 mol%)

R1

NaOtBu 2.8 eq. dioxane, 110° C

+ Y

Scheme 25.

N

R3

Z

R2 N R1



affording the target product on a multigram scale. An interesting chemoselectivity and regioselectivity for highly substituted odihaloarenes can be introduced using different halogens on the aromatic ring. N-H indoles were produced by using t-butyl imines for the cyclization procedure followed by a “deprotective” treatment of the products with TFA or AlCl3 by thermal heating or under microwave that reduced dramatically the reaction time. The authors developed even an interesting expansion of this methodology to o-chlorotriflate though the product yields were sometimes moderate. Much more better results were obtained by using o-chlorononaflates (Ar-ONf = Ar-OSO2CF2CF2CF2CF3). Cross-coupling reactions are among the most powerful transformations in synthetic organic chemistry. Barluenga and coworkers conducted competitive reactions for the alkenyl- and the aryl-amination promoted by palladium catalyst. In all the cases, the alkenyl amination is faster than the corresponding aryl process. This gives the initial formation of an enamine that is in tautomeric equilibrium with the more stable imine. The imines undergo a Heck reaction catalyzed by the same Pd system producing indoles [106]. The overall transformation represents a new approach for the synthesis of polysubstituted indoles in a single step from very simple starting materials. Other groups developed cross-coupling approach for the synthesis of indoles and indolines by using tandem Suzuki-Miyaura coupling/5-endo-trig cyclization strategy. 2Substituted indoles and indolines were produced from imidederived enol phosphates, readily available from commercial ohaloanilides. Different palladium complexes were used for this purpose [107]. Other palladium-catalyzed C-H activations were proposed by Doi et al., who performed an intramolecular amination of an aromatic C-H bond by using enamine compounds with Pd(OAc)2 (10 mol%)/Cu(OAc)2 (100 mol %) in DMSO. N-Tosyl-3substituted indoles were produced in moderate to good yields [108]. The same catalytic system was employed by Glorius et al. starting from methyl (Z)-3-(phenylamino)-but-2-enoate affording indole-3carboxylates [109]. A recent report on the indole synthesis catalyzed by copper(I) complexes via intramolecular amination of aryl bromides was presented by Karchava. 1-Substituted-indole-3carboxylates were synthesized efficiently via Ullmann-type intramolecular aryl amination (Scheme 26) [110].

OMe O

2.4. Indoles from Azo Derivatives In the first pioneering reports by Kisch and co-workers, CoCl(PPh3)3 was reported to catalyze the formation of 1:1 adducts from PhCCPh and substituted diaryldiazenes [111]. The research group directed by Kisch firstly introduced the synthesis of indole and N-arylaminoindoles derivatives starting from azobenzene and disubstituted alkynes through the C-H arylic activation of the oposition in the diariyldiazene and by the intermediacy of cyclometallated compounds. First experiments were carried out using cobalt-phosphine catalysts. CoCl(PPh3)3 induces formation of 1:1 adducts (indoles and N-arylaminoindoles) while Co(N2)(PPh3)3 gives rise to 2:1 adducts. N-Arylamino indoles were isolated as the major products by working with internal alkynes and various azobenzene derivatives with electron-donating groups. Terminal acetylene derivatives gave lower yields and formation of mixtures of byproducts. Kisch and co-authors experimented with some different transition-metal catalysts such as cyclopentadienyl carbonyl complexes based on metals like Fe, Mo and Ru. A preliminary study irradiating or heating easily accessible iron and molybdenum compounds in the presence of aromatic diazenes afforded the o-metalated species [112]. The formation of an ometalated compound was carried out by a photochemical process in a subsequent study by the same research group [113]. Other metal complexes, tipically cyclopentadienyl complexes of Ru, Fe and Mo, were tried in reactions with azoarenes affording o-metalated intermediate azo-compounds able to release indoles by thermal reactions with internal alkynes. All these complexes were detected and characterized by X-ray diffraction. The following thermal or photochemical reaction of the intermediate metal complexes with diphenylacetylene afforded 2,3-diphenylindole derivatives as the major products. Contemporarily, the same result was achieved by using CpRu(PPh3)2Cl in the presence of azobenzene and diphenylacetylene heating at 200 °C. Under optimized reaction conditions, using RhI(PPh3)3/SiO2[114] and RhCl(PPh3)3 (Wilkinson's catalyst) in refluxing solvent, N-arylaminoindole derivatives were obtained as major products with small amounts of indoles (Scheme 27). Optimization of the reaction conditions using the Wilkinson’s catalyst and a complete kinetic study was presented by the same group [115]. An easy conversion of N-anilinoindoles into indoles was carried out with Zn/HCl. O

1) O , NaH O 2) RNH2, MeOH, rt, 6h

OMe

3) 5mol% CuI, K3PO4, DMF, 75°C

Br

N R

Scheme 26.

R3

R3

R2

R2

R3

110° C

N R6

N

N

+ RhCl(PPh3)3 R1

H

R1

Scheme 27.

N H

R4 R5

+ R6

N

R2

R4 R5

R1


Bu3SnH

I N

Palmisano et al.

N N

Ar

H N

Ar

I +

N

AIBN

H N

Ar

H Scheme 28.

The addition of weak acids or silica gel accelerates the reaction inducing an almost complete conversion to the major product. Other rhodium(I) complexes are less active than the Wilkinson’s catalyst, while rhodium(III) complexes inhibit completely the reaction. A mechanistic study was proposed with ab initio calculations that supported and substained the structure of two key intermediates. Electron withdrawing groups in the alkyne induces a decrease of the turnover rate. The substitution on the azoderivative show a minor influence. Using unsymmetrical substituted alkynes a mixture of regioisomers was obtained, except in the case of very large substituents. Steric alterations in the diazene gave significant effects. The reaction reveals a first-order dependence on the catalyst and azobenzene. The key step is the o-metalation of the diazene followed by insertion of the alkyne in Rh-H bond and reductive elimination. A final step of an acid catalyzed reaction leads to the N-(arylamino)indole derivatives. A SiO2 supported catalyst with trisulfonated phosphines was found to catalyze the reaction in aqueous media showing good parameters as turnover number and turnover frequency and a partial recyclability [116]. By using CoH3(PPh3)3 to catalyze additions between azobenzenes and internal alkynes the major products 2-stilbenylazobenzenes and isomeric 2,3-dihydrocinnolines were isolated. These compounds were determined to have a role as intermediates in the rhodium catalyzed formation of N-anilindoles from the same substrates [117]. Some carbazole derivatives were obtained by intramolecular reactions between azoarenes and tributyltin hydride. With osubstituted azoarenes, mixtures of hydrazo derivatives and Nheterocycles or cyclic products were obtained. Stannyl radicals may be involved as reaction intermediates when a radical initiator such as 2,2’-azobisisobutyronitrile (AIBN) which on its own is inert toward azo compounds, is used. As a mechanistic probe, Zanardi and co-workers examined the reduction of 2-iodo-2’-(4tolylazo)biphenyl since the corresponding aryl radical formed by homolysis of the iodine-aryl bond is known to attack intramolecularly the azo group, affording a cyclic hydrazyl radical (Scheme 28).

2.5. Indoles from Isocyanides and Isocyanates Isocyanides are a class of stable organic compounds that show interesting reactivity and application in organic synthesis through a multiplicity of reactions and are particularly interesting and versatile for their role in multicomponent reactions. As fully and completely summarized by excellent reviews published by the Garcìa-Valverde [118] and Beller groups, [4d] isocyanides were used in the synthesis of indoles through the typical distinguished reactions by -additions, -metallations and subsequent radical reactions. The versatility of isocyanides as starting materials in heterocyclic chemistry is fully highlighted by Garcìa-Valverde showing all the types of reactivity cited above. Three major approaches were used to synthesize indoles starting from isocyanides: i) lithiation of o-alkylisocyanobenzenes, ii) radical cyclization of 2-alkenylphenylisocyanide and iii) transition-metal catalyzed or mediated processes [119]. The activity of isocyanides as precursors of indoles started with the seminal work by Saegusa and co-workers that reported for the first time the use of isocyanides en-route to indole units [120]. Benzylic anions from ortho-isocyanotoluenes are the active and simplest form of this approach (Scheme 29). Using benzylic anions with alkylating agents like halides and epoxides, 3-substituted indoles were afforded. CH3 N+

1) LDA, diglyme - 78° C - r.t. N H

2) H2O

C-

Scheme 29.

Peculiar in this topic is the Fukuyama approach to the indole synthesis in which o-isocyanostyrenes, prepared by dehydration of the corresponding formamides, undergo a tin-promoted radical cyclization giving unstable intermediate structures, that can be furtherly hydrolyzed to afford 2-unsubstituted indoles or used in coupling reaction with aryl halides by Pd(0)-catalysis achieving 2arylindole derivatives (Scheme 30) [121]. H3O+

CO2Me N H

CO2Me N+

MeCN, 100° C C-

CO2Me

n-Bu3SnH, AIBN N H

Sn-n-Bu PhBr, Pd(PPh3)4 Et3N, 100° C

CO2Me N H

Scheme 30.

Ph



available 2-iodobenzoic acid into indole derivatives by a one-pot Curtius rearrangement/palladium-catalyzed indolization process. Using this strategy, 2-iodoanilines and all the other intermediates and byproducts of Curtius rearrangement are not isolated. Only few examples were reported so far of an intermolecular and intramolecular palladium-catalyzed indolization in which a carbamate was used as a substrate [128]. By working with 2iodobenzoic acid, Lebel et al. achieved its direct conversion into carbamate and urea derivatives that undergo a palladium-catalyzed indolization reaction. This method led the authors to discover the first indole-N-carboxamide derivatives, extensively studied as pharmacophores, through a heteroannulation procedure.

Multicomponent coupling reactions for the synthesis of Ncyanoindoles starting from isocyanides were introduced by Yamamoto and co-workers (Scheme 31) [122]. The indole preparation by isocyanides precursors following Fukuyama’s method was used in a step of a tin-mediated new route to kenpaullone a potential cyclin dependent kinase (CDK) inhibitor [123]. For the total synthesis of the target molecules the Fukuyama indole synthesis was followed by a Stille reaction. Mironov disclosed a procedure for the synthesis of 3iminoindole derivatives by the reaction of aromatic isocyanides with excess N,N-dialkylbenzylamines [124] in benzene at reflux. 2Dialkylamino-3-aryliminoindoles are interesting compounds because of the role of precursors of 3-aminoindoles that exhibit antibacterial activity or CNS drugs. The reaction of 2-alkynylisocyanobenzenes, allyl methyl carbonate and trimethylsilyl azide in the presence of Pd2(dba)3·CHCl3 and tri(2-furyl)phosphine at high temperatures afforded N-cyanoindoles in good yields. Pd(PPh3)4 and Pd(acac)2 also showed catalytic activity and less polar solvents afforded the desired products in better yields. No particular effect was registered by the nature of the substituents on the phenylalkynylisocyanide ring. Another three component process in which isocyanides were used for the preparation of the indole framework was presented by Takahashi and co-workers (Scheme 32) [125]. A new route to 2,3disubstituted indoles was disclosed when a mixture of aryl iodide, o-alkenylphenylisocyanide and diethylamine were reacted at 40 °C in THF in the presence of Pd(OAc)2 as catalyst and dppp as ligand. Isocyanates are postulated as interesting and versatile intermediates in many reactions and their role in the synthesis of carbamates and ureas (e.g. by reductive carbonylation of nitrocompounds) was thoroughly reviewed [126]. Isocyanate intermediates were postulated even in one-pot multicomponent synthesis of indole compounds from 2-iodobenzoic acid (Scheme 33) [127]. Lebel and co-workers very recently presented a novel multicomponent process that allows the transformation of readily

2.6. Indoles from Aromatic Azides Aromatic azides were used as versatile reagents for the synthesis of many different organic compounds [129]. Their activation involves the loss of a molecule of dinitrogen that can be mediated by different activators like photochemical procedures, transition-metal complexes and cycloaddition reactions with the elusive formation of unstable triazole or triazoline rings that easily decompose giving rearrangement structures. Arylazides and conjugated vinylazides like -azido cinnamates, generally prepared by condensation of an aromatic aldehyde with an azidoacetate ester, are used as precursors for indole synthesis. The -azidocinnamates typically generate the formation of the azirine ring by thermolytic loss of nitrogen and by a subsequent rearrangement that leads to the cyclization with the aromatic ring, achieving the formation of indole-2-carboxylate esters in a process usually known as Hemetsberger indole synthesis (Scheme 34) [130]. Conditions developed by Moody [131] with the slow addition of the aldehyde to an excess of the azide in a cold solution of sodium ethoxide usually gave good yields. This process is a nitrene insertion reaction carried out generally in toluene or xylenes at reflux. This kind of reaction gives ring closure via the activation of an arylic C-H bond.

R3 R2 +

OCO2Me

+

TMSN3

2.5 mol Pd2(dba)3 CHCl3 10 mol% (2-furyl)3P

R3 N

octane, 100° C

NC

CN Scheme 31.

R

NEt2

Pd(OAc)2 (5 mol %) dppp (10 mol %) Y

X

HNEt2

+

+

Y

NC

THF, 40° C

N H

Scheme 32.

R2

O I

I

R1 +

COOH

N

R2

C

or

Nuc

N R1 O

O R2

Scheme 33.

R1 Nuc


Palmisano et al.

CO2R

CO2R

CO2R

N

N3

N H

Scheme 34.

The Hemetsberger-Knittel indole synthetic approach can be carried out under microwave activation [132]. A wide survey of different solvent and reaction conditions was operated. By using microwave irradiation, high conversion, lower reation times (about ten minutes) and elevate selectivities were registered. Many different groups reported this method for the formation of indoles by thermal reactions in good yields and more recently catalytic procedures involving the use of transition-metal complexes received more attention by some research teams particularly for the search of mild reaction conditions (Scheme 35) [133]. Rhodium catalysts are long known for the activation of C-H bonds with carbenoid and nitrenoid species affording respectively, the formation of new carbon-carbon [134] and new carbon-nitrogen bonds [135]. Valuable carbocycles and heterocycles are obtained efficiently and stereoselectively. As previously observed, nitrenes can be formed from azides by thermolysis, but high temperatures can mitigate the usefulness of this method. Rhodium(II) perfluorobutyrate-mediated decomposition of vinyl azides allows rapid access to a variety of indoles and other functionalized Nheterocycles in two steps from commercially available starting materials in mild reaction conditions and with high efficiency. Dirhodium(II) carboxylates are the privileged catalysts for the formation of indoles while other metal salts and complexes revealed unsuccessful results. The reaction tolerated substrates with both electron-donating and electron-withdrawing aryl substituents. This indolization approach was even employed for the total synthesis of many bioactive molecules like conophylline [136] a bisindole alkaloid with anti-cancer and anti-diabetic activities, new

Rh2(O2CC3F7)4 3 - 5 mol %

CO2Me R

high potent EGFR-tyrosine kinase inhibitors with excellent cytotoxic properties at different cell lines, [137] and a tetrahydropyridoindole scaffold studied for the properties as prostaglandin D2 receptor antagonists [138]. Other indole high valuable compounds are potential agents in pancreatic cancer therapy, [139] duocarmycin analogues, [140] selective NR1/2B N-methyl-D-aspartate receptor antagonists, [141] and lyngbyatoxin A [142]. Asymmetric total syntheses of (+)- and ent-(-)-yatakemycin and duocarmycin SA [143] and of a new water-soluble DNA-binding subunits for analogues of the cytotoxic antibiotic CC-1065 and their prodrugs [144] were achieved. Thermolysis of o-azidostyrenes gave nitrenes which insert into the side chain to form indoles [145]. The azide thermolysis can be used to prepare indole compounds not available by other methods [146]. A new, efficient and easily available method for the preparation of 2-aryl-4,6-dinitroindoles based on reductive cyclization of E-2azido-4,6-dinitrostilbenes under the action of FeCl3·6H2O-NaI system in the CH3CN media at room temperature was developed by Mezhnev and co-workers (Scheme 36) [147]. Feldman and co-workers reported the thermal reactions on 2(allenyl)phenyl azides to give annulated indoles (Scheme 37) [148]. The same group two years later reported that the irradiation of allenylazides in the presence of an excess of CuI furnished 2,3cyclopentenyl indoles in good yields [149]. 1,1’-Bisindolyl derivatives were prepared by thermally induced decomposition of ferrocenylazides by Molina et al. by refluxing the starting materials in toluene or xylene (Scheme 38) [150].

R

CO2Me

toluene 30 - 60° C, 16 h

N3

N H

Scheme 35.

CF3 CF3

NO2

FeCl3 6H2O - NaI

NO2

CH3CN, r. t. O2N

N3 N H

O2N Scheme 36.

R3

R2

R3 254 nm

R2 R1

R +

R1 N3

Scheme 37.

R

CH3CN 150 mol% CuI

N R1

R N H

R3

R2



O

N3

HN O

toluene / xylene

N3

Fe

Fe

O

reflux NH O Scheme 38.

By using a complementary strategy, arylazides having a tethered vinyl group like o-azidostyrenes, were used as useful reagents for the synthesis of indoles by vinyl C-H activation. Thermolysis of o-azidostyrenes gives nitrenes which promptly insert into the side chain to form indoles as reported by Sundberg and co-authors [151]. The azide thermolysis method can be used to prepare 2-nitroindoles as showed by Gribble [146]. Arylazides can be prepared by mild procedures and functional group tolerant routes. This procedure was used for the preparation of useful intermediates in the total synthesis of polycyclic indole-fused complex heterocyclic structures (Scheme 39). An intermediate process, in which a five-membered ring closure was obtained by cyclization with arylazides, was reported by Molina and coworkers. When this compound was heated at 160 °C in toluene in a sealed tube, 2-(2-azidoethyl)indole was obtained in 61% yield as the only reaction product and no decomposition products were detected. This product containing the indole unit was used for the preparation of -carbolines and pyrimido[3,4-a]indoles through multi-step reactions [152]. The same group reported few years before the intermediate role of o-allylphenyl azide as an entry to azirino[1,2-a]-indole by a

cascade epoxidation/Staudinger reaction [153]. Analogously working with biaryl azides, carbazoles were obtained in good yields [154]. Many other examples were reported in literature on the known photolytic and/or thermolytic reactions of azidobiphenyls for the formation of carbazole and phenanthridine by the nitrenoid insertion in arylic and/or benzylic C-H bonds [155]. Similar to the complementary intramolecular reactions with azidocinnamates, Driver and co-workers introduced and reported in 2008 the dirhodium(II)-catalyzed intramolecular C-H amination of aryl azides affording substituted indoles in excellent yields and in mild conditions working with o-azidostyrenes (Scheme 40) [156]. The decomposition of arylazides was developed as a mild functional group tolerant method for the synthesis of indoles. This methodology was tolerant of a variety of electronically different psubstituents to the azide. Different R1 and R2 substituents were shown to give 6- or 7-substituted indoles. A phenyl group as R 4 reduces the reactivity. The nature of the substituents R2 and R3 did not relevantly alterate and influence the yields in indole compounds. Changing the identity of the R5 substituent from an aryl group to an alkyl group reduced both conversion and yield.

S NH

N H N3 N3

toluene, 160° C sealed tube

N3

N H

N NH S Scheme 39.

R4 R3

R5 H

R2

N3 R1

Scheme 40.

Rh2(O2CC3F7)4 (5 mol %)

R4 R3 R5

4 Å molecular sieves PhMe, 60° C

N H

R2 R1


Palmisano et al.

Few methods are known for benzylic C-H activation and corresponding formation of new C-N bonds by the use of aromatic azides in intermolecular fashion. By photochemical reactions, the formation of a nitrene was observed as intermediate generated by 2(-phenylalkyl)phenyl azides affording indolines in a intramolecular fashion. The indolines were found in the products together with 3Hazepines that is the product of the ring expansion of phenylnitrene intermediate (Scheme 41) [157]. Tomioka and Murata reported even a complete and detailed mechanistic study with interesting results on isotope effect, configurational purity and radical clock studies. Transition-metal porphyrins were developed as potent catalysts for azide reactions and particular interest was invested in reactions using ruthenium and cobalt compexes. At the beginning of the recent millennium some of us firstly reported the use of aromatic azides as precursors for the catalytic benzylic amination of unactivated hydrocarbons in a intermolecular fashion using Co(II)porphyrinato complexes as privileged transfer of nitrogen source [158]. Cenini and Gallo continued to investigate this topic on the nitrogenation of hydrocarbons by transfer of a nitrene moiety [159]. Trying to applicate the same synthetic approach in an intramolecular version for the preparation of nitrogen heterocycles we synthesized a precursor for the generation of the amino group in the benzylic position by loss of nitrogen and subsequent C-N bond formation. The preparation of the right substrate is a multi-step strategy and the final ring closing procedure was achieved by a thermal process catalyzed by Co(TPP) in good yields as a mixture of indole (22% yield) and indoline (56%) (Scheme 42) [160]. 2.7. Indoles from Nitro- and Nitrosoarenes Ready availability of nitrocompounds and multiplicity of reducing agents makes the nitro group a powerful tool for the production of many functional groups easily convertible in cyclic structures with the formation of indole rings. Nitroaromatics could be used in some classical and typical indole syntheses after the conversion into other reduced groups that provided the final cyclization. Some of the most popular and largely known named indole syntheses started multi-step approaches using nitroaromatics as building blocks. In the Reissert synthesis the acidity of a methyl group ortho to a nitro fragment on a benzene ring is the means for condensations with oxalate [10]. In a variant, nitrocompounds react with silyl enolethers giving the intermediate formation of a nitronate that after oxidation with bromine furnished a 2-(onitroaryl)-ketone. The indole ring is generated after reduction of the nitro group [161]. o-Alkynylnitrobenzenes were used as useful precursors of indole frameworks. After reactions with alkoxides and formation of nitroacetals the reduction of the nitro group leads to Ph

the ring, closure [162]. In another variant of the Madelung indole synthesis, starting from nitroarenes, and after reduction and acylaton the final product is a compound that gives cyclization on a nucleophilic alkyl group in the o-position. An interesting procedure shows the generation of a phosphonium ylide followed by a Wittiglike reaction involving the amide carbonyl [15, 163]. Another very interesting method to afford indole molecules was presented by Fürstner that applied an intramolecular McMurry reaction on oacylanilides favouring a reductive cyclization by low valent titanium. Even in this case the anilides can be generated by nitroarenes [23b, 164]. Direct syntheses of indoles using nitrocompounds belong to other frequently used and developed procedures known even as named reactions like Leimgruber-Batcho and Cadogan-Sundberg indole preparation. All these cited procedures need the presence of a tethered alkene in the o-position regarding the nitro group. The Leimgruber-Batcho synthesis is a two-step method that afford indoles with 2 and 3 unsubstituted positions [165]. The two steps are respectively the formation of the enamine and the reduction of the nitro group that leads to the cyclization. Many reducing agents were used so far like TiCl3 [166], Fe/AcOH,[167] Pd-C [168] and Zn/NH4Cl [169]. This last reactive was particularly interesting for the purpose to provide N-hydroxyindoles as major products. Similarly to the Leimgruber-Batcho approach by using o-dinitrostyrenes the major products detected were indoles with only carbocyclic substituents [170]. Recent development of LeimgruberBatcho procedure were carried out with the assistance of microwave by using DMFDMA (dimethylformamide dimethyl acetal) and indoles, azaindoles and pyrrolquinolines were achieved in good yields. (Scheme 43) [171]. Utilizing nitropyridines in the Leimgruber-Batcho process some azaindoles were produced [172]. Azaindoles are particularly useful intermediates with a broad spectrum of activities like variolins isolated from marine sponge Kirkpatrickia varialosa. Variolin B has exhibited notable anti-cancer properties [173]. Pioneering research on the indole synthesis starting from nitroaromatics was reported for the intramolecular deoxygenation of nitro groups by trivalent phosphorus for the preparation of indoles from o-nitrostyrenes [174]. Nitrostyrenes are easily available by many routes as Wittig condensation, o-nitration of styrene and base catalyzed condensation of a methyl group ortho to an aromatic nitro group with an aldehyde. Nitrostyrenes and nitrostilbenes were used as privileged substrates by Cadogan and Sundberg who reported independently their complete deoxygenation and formation of nitrene passing through nitrosoaromatics and the ring closure with the tethered alkene group in the ortho position. After the first seminal papers and reports many other catalytic systems based on transition metal-complexes were introduced and revealed an interesting general validity. (Scheme 44) Pd(OAc)2 in Ph

h Ph Ar, 12 K

N3

+

N H

N

Scheme 41.

Ph Co(TPP) N3 Scheme 42.

benzene

N H

Ph

+ N H

Ph



Me

MeO

NMe2

MW Lewis acids

NMe2

+ OMe

NO2

R1

DMF

NO2

R1

[H] N H

R1 Scheme 43.

Br

Br

Pd(OAc)2, CO, (4 atm), PPh3 Et3N, DMF, MeOH, 60° C NO2

N H

Scheme 44.

CO atmosphere gave the one-pot ring closure to indoles and takes place in a very efficient way by Söderberg and co-authors [175]. Söderberg used the synthetic approach from nitro to 1,2-dihydro4(3H)carbazolones via Pd catalyzed reductive deoxygenation of nitroaromatics furnishing the products synthesized so far only by Fischer approach [176]. Other catalysts in reducing conditions were used and among them the most efficient are Se [177] Ru3(CO)12 [178] and a wide series of palladium complexes [179]. Russell and co-workers obtained indoles starting from -nitrostyrenes via an intramolecular arylic C-H activation by treatment with trialkylphosphites (Scheme 45) [180]. Ph X NO2

Ph

(EtO)3P 150° C 24 h

N H

X

X = H, PhS, tBuS Scheme 45.

In a very recent paper by Dong and co-workers indoles were prepared by palladium-catalyzed C-H amination via reduction of nitroalkenes with carbon monoxide. In a CO atmosphere the nitro group is generally reduced by Pd catalysis to nitroso and then the cyclization occurs via a C-H aromatic activation (Scheme 46) [181]. A different catalyst survey was tested giving different results in the preparation of 3-phenylindole. The catalyst with the best activity was found to be Pd(OAc)2/Phen in 1 atm CO. Among the

catalysts tried in this reduction/C-H arylic activation there are NiCl2, Ru2(CO)12, Rh6(CO)16, PtCl2(PPh3)2 and Fe3(CO)12 and most of them lead to the cyclization but in moderate yields. Analogously, in a similar procedure in the presence of -nitrostyrenes and dialkyl phosphites this reaction gave rise to 3-dialkoxyphosphoryl-1hydroxyindoles. Very recently, Tsoungas published a review illustrating the interesting applications of reductive cyclisation of nitro- and nitrosoarenes for the synthesis of N-heterocycles [4g] and more recently Ragaini reported in a different review [4f] a wide and complete summary on the reductive carbonylation of nitroarenes catalyzed by transition metal complexes. Both these reviews reported an excellent update of the state of the art on the indole synthesis by using nitrocompounds as precursors. Intramolecular process and intermolecular reactions are evaluated and deeply reviewed. We cited here some previous reports on the heterocyclization, just to give an historical perspective of the deoxygenation of nitroarenes in a intramolecular way. The most obvious and long known named reactions as Cadogan-Sundberg, Leimgruber-Batcho and other related approaches have a relevant and deep scope on this topic. The intermediacy formation of partially deoxygenated species in the reductive cyclization of nitrostyrenes and nitrostilbenes was theoretically predicted by a research group at Merck in collaboration with the Houk’s group and the experimental evidence of the formation of N-hydroxyindoles [182]. Some of us reported a reaction catalyzed by Pd(TMB)2 (TMB 2,4,6-trimethylbenzoate) in the presence of nitrogen ligands as TMPhen (3,4,7,8-Tetramethyl-1,10-phenanthroline) in which Nhydroxyindoles were formed as the major products [183]. NR

R

Pd(OAc)2, phen

R

R

CO, DMF NO2

Scheme 46.

N H


Palmisano et al.

TiCl3/NH4OAc reduction of nitro group in ethanol at room temperature in presence of a tethered electrophile carbonyl (Scheme 48) [193]. The reaction proceeds through the arylation of ketone enolates generating the nitroarylated ketones that led to achieve the indoles. In this report the authors reported furtherly the possibility to get 2,3-disubstituted indoles by introducing the appropriate alkyl group in the position of the carbonyl. The inclusion of a catalytic amount of phenol in the enolate arylation of o-halonitroarenes causes a remarkable increase in the efficiency of the transformation. One of the most interesting and valuable reactions for the synthesis of indoles starting from nitroarenes via intermolecular cyclization process is the Bartoli’s reaction. Substituted nitroarenes with vinyl Grignard reagents in excess (3 fold) at low temperature afford substituted indoles upon aqueous work-up (Scheme 49) [194].

Hydroxyindoles have received considerable attention in recent years particularly because their potential biological role that is under investigation. As reported by Kuethe biologically inactive compounds has been rendered biologically active when converted into their N-hydroxy analogues derivatives [184]. For this scope their syntheses are becoming an explored research area by many groups both from academy and industry. The first reports on this class of compounds were reported by Somei, [185] Acheson, [186] Loudon and Tennant [187]. Belley and co-authors afforded Nhydroxyindoles by Pd catalyzed cyclization of 2-nitrobenzyl aldehydes, ketones, nitriles and amides by hydrogenation using Pd/C as catalyst and Pd(PPh3)4 as cocatalyst [188]. Under water gas shift conditions Cho and Shim reported a synthesis of indoles starting from nitrobenzenes and trialkylamines via a ruthenium– catalyzed reductive heteroannulation [189]. Indoles were produced and isolated in moderate yields by this group that performed other synthetic approaches to indoles by using anilines as starting materials [190] Other intramolecular procedures that provide the formation of an indole ring and N-hydroxyindoles as target molecules were recently presented by Mkosza, [191] and Wong [184b]. Nicolaou and co-workers reported very recently some papers on the approach to the total synthesis of nocathiacin I an interesting bioactive compound recently discovered as an antibiotic isolated from Nocardia sp. and the fungus Amicolaptosis sp. An intermediate generated by an indolization procedure was afforded by a tin(II) chloride mediated reduction of a nitroketoester by using the trapping of unsaturated nitrones with the assistance of oxygen, sulfur and nitrogen nucleophiles (1,5-nucleophilic addition) (Scheme 47) [192]. Small amounts of indoles found by the nitrene formation and following attack on the carbon-carbon double bond were detected. Buchwald recently reported an innovative annulative approach to highly substituted indoles realizing the ring closure by the use of

The reaction mechanism was studied in detail to clarify the observed results [195]. Three equivalents of vinylmagnesium halides are necessary for the reaction to occur. Superior substrates are substituted nitroarene that furnished very good yields in the indole products; m- and p-substituted nitroaromatics gave lower yields. The fate of the Grignard reagent was clarified: the first equivalent is incorporated in the indole nucleus, the second reduces the nitro group and the third reacts in an acid-base fashion. The mechanistic studies evidenced the intermediate formation of nitroso compounds. Nitroso arenes react with two equivalents of Grignard reagent to give almost the same product distribution. A sigmatropic rearrangement leads to the ring closure through the intermediacy formation of N-aryl-O-vinylhydroxylamino magnesium salt. 7Substituted indoles were afforded as the major products by reactions with o-substituted nitroarenes. The formation of indole-7carbaldehyde through the Gilmore’s modification was performed [196]. By the same procedure 7-alkyl- [197] and 7-aminoindoles O

CO2Me R1

O

SnCl2 H2O (2.2 equiv) NuH (5.0 equiv)

Nu R1

CO2Me

DME 4Å molecular sieves

NO2

CO2Me +

R1

N

N

OH

OH

Scheme 47.

Pd2(dba)3, K3PO4 NMe2

O

Br/Cl NO2

R2

O

Cy2P

+ R2

NO2

Me

TiCl3, NH4OAc

R2

EtOH, rt

R1

Phenol, 35-80° C 15-27 h

R1

R1

Scheme 48.

R' R + NO2 X Scheme 49.

1) THF, - 40° C

R

R' MgBr

N

2) NH4Cl X

H

N H



both starting from 7-bromoindoles were prepared respectively passing through the Heck and Suzuki cross-coupling reactions and formation of the 7-azidoindoles after lithiation. Dobbs introduced a straightforward improvement realizing the important goal to afford 7-unsubstituted indoles. The use of a radical debromination by means of tributyl tin hydride, promoted by azobisisobutyronitrile (AIBN) furnished an easy access to 7-unsubstituted indoles [198]. Some improvements were introduced by many organic and biological chemists interested in the application of this synthetic approach for the preparation of high valuable molecules and fine chemicals. The Bartoli indole synthesis has provided a powerful tool for the preparation of useful key intermediates for the synthesis of complex indoles. Trikentrin A and herbindole A [199], hippadine, [200] 7-hydroxyindole subunit of dragmacidin D and both indole nuclei of rebeccamycin [194b] were prepared by using the indolization step of the Bartoli indole synthesis. 4- and 6-azaindole from substituted nitropyridines based on the Bartoli indole synthesis was developed [201]. An interesting and useful improvement for this synthetic approach is based on carrying out the reaction on solid support as Merrifield resin. Nitrobenzene and other nitroarenes were linked to a resin through an ester linkage. Indoles were obtained in high purity and moderate overall yields [202]. Another indole synthetic approach by using nitroarenes as starting materials in intermolecular reactions is the reductive annulation of nitroaromatics with alkynes under carbon monoxide pressure and in the presence of transition metal complexes as cyclopentadieny carbonyl dimers of iron and ruthenium and related complexes [203]. Some years ago we reported a catalytic intermolecular version of the nitroarene reductive annulations with alkynes affording indoles in moderate to good yields and excellent regioselectivity. Anticipating a new route to propargyl- and/or allenylamines, we began to start our study examining the reactions between nitroaromatics and alkynes but have found, remarkably, that indoles were the major products of these reactions. Using Fe and Ru-cyclopentadienyl derivatives, 3-substituted indoles were provided as the final products (Scheme 50). No traces of the 2substituted regioisomers were detected in the reaction mixtures. This procedure involved even the arylic C-H activation of the oposition in the aromatic ring regarding the nitro group. Subsequently, Ragaini and co-workers reported a similar palladium-catalyzed reaction with a more efficient Pd catalytic system [204]. Carbonylative reduction of nitroarenes in CO atmosphere has been studied since long time and many heterocyclic X

molecules were afforded [4f-g, 126]. Some of us reported the allylic amination of alkenes by reductive carbonylation of nitroarenes in CO atmosphere catalyzed by Ru [205] and Fe [206] complexes. Given the precedented, metal-promoted deoxygenation of nitro compounds by carbon monoxide, it seemed likely that nitrosoarenes could be intermediates in the catalytic reductive annulation of nitroarenes to indoles. Examining the reactions of nitrosoarenes with alkynes under the above catalytic conditions, we reported even an uncatalyzed version of the process [207]. Differently from the reactions with nitroaromatics the major products of this annulation processes were N-hydroxyindoles produced regioselectively, in mild conditions, with functional group tolerance and with an excellent atom economy. Ragaini and co-workers introduced a new catalytic system with a good activity by using palladiumphenanthroline complexes (Scheme 51). Studying the optimization of the method the same group proposed the use of a mixed catalyst [Pd(Phen)2][BF4]2/Ru3(CO)12 in different proportions with the aim to achieve an improvement of the selectivities in indole derivatives by reduction of the corresponding N-hydroxyindoles. The addition of Ru3(CO)12 increases the indole selectivities by 8-11%. A different approach to improve the amount of indoles was the addition of a methylating agent like dimethyl carbonate and even in this case the detected improvement was about 9%. The combination of the two strategies gave a 36% increase in the amount of the obtained indole. The intermolecular cyclization of unfunctionalized nitroarenes and alkynes was proposed by Ragaini’s group for the application to an easy access to fluvastatin, a cholesterol-lowering agent [208]. As cited before nitrosoaromatics play a relevant role in the heterocyclization of nitroarenes. Many mechanistic investigation and computational studies revealed the intermediacy of nitrosocompounds. As easily predictable, nitrosoderivatives are intermediate of the process of the deoxygenation of nitrocompounds with olefins and they can react in a fast way and sometimes without the intervention of metal-catalysts. Nitrosoarenes, like their corresponding nitrocompounds are able to undergo an intramolecular and an intermolecular indolization in reactions with unsaturated carboncarbon bonds. Their rare commercial availability has limited the use of this class of compounds. As previously seen Sundberg [209] and more recently some of us [183] observed the formation of Nhydroxy and N-ethoxyindoles in the reduction of o-nitrostilbenes. Davies and Houk presented a theoretical evidence for a 6-electron 4-atom electrocyclization of nitroso-styrene, -stilbenes and byphenyls to nitronates. A downstream 1,5-shift and tautomerization

R

Z

CO

X

[Mp]2

Y

Z

R

+ Y

NO2

N

R'

R'

H

[Mp]2 = [(5-CpFe(CO)2]2, [(5-C5Me5Fe(CO)2]2, [(5-C5Me5Ru(CO)2]2 Scheme 50.

R1

R3

R3 [Pd(Phen)2][BF4]2 (0.33 mol %) X NO2 R2

Scheme 51.

R1 R4

+ + CO, - CO2 R4

X

N R2

H


Palmisano et al.

R

we postulate and envisioned the formation of nitrosoarenes as intermediates for the catalytic reductive heterocyclization of nitroarenes with alkynes and decided to test directly nitrosoaromatic compounds as precursors in indole ring formation providing a twostep procedure that furnished N-hydroxyidoles and indoles by hydogenolysis of the intermediate compound (Scheme 54) [207].

R THF +

N

r. t. NO

R = H, Br

Scheme 52.

leads to N-hydroxy heterocycles [182]. The first report showing the formation of a carbazole unit in moderate yields was presented by Steinhoff and Henry for reactions between nitrosobenzene or pbromonitrosobenzene with two equivalents of benzyne. The mechanism postulated by the authors passes through the formation by 1:1 addition of nitrosoaromatic with benzyne of an hydroxylamine intermediate. Then a subsequent reaction with another molecule of benzyne yields a N-oxide product that loses oxygen forming the N-phenylcarbazole derivative (Scheme 52) [210]. Another example of the potential role for nitrosoaromatics as indole precursors was presented by Tedder and co-workers some decades ago. By reaction of two molecules of nitrosobenzene with two molecules of phenylacetylene 1,3’-diepoxy-3,3’-diphenyl-2,2’bi-indolinyl products were produced even if in very low yields (Scheme 53) [211]. This dimeric compounds with the indoline skeleton were subsequently called “kabutanes” by Somei after his discovery of a novel dimerization process on 1-hydroxyindoles. These compounds were unaffected by catalytic hydrogenation at atmospheric pressure. Many years later the same group reported the X-ray characterization of the first example of a kabutane ring [212]. In parallel with our study of reductive annulations of nitroaromatics with alkynes [203] our interest was devoted to the investigation of nitrosoarenes. Investigating the reaction mechanism

Heating nitrosoarenes in a CO atmosphere in the presence of ruthenium and iron catalysts gave directly the N-H indoles as expected in very short reaction times. Kabutanes were found as by products in our indole synthesis procedure by cycloaddition of nitrosoaromatics with alkynes working in benzene at reflux and without any catalyst and/or carbon monoxide. The efficiency of the ArNO/alkyne cycloaddition can be improved significantly by alkylative trapping of the labile N-hydroxyindoles with K2CO3/ Me2SO4 [213], providing access to a variety of N-methoxyindoles from substituted nitrosoarenes and arylacetylenes. This last protecting process led us to avoid the formation of dimerization products like kabutanes. The reactions with methyl propiolate afforded a one-step preparation of phytoalexin analogues from Wasabi. Very recently other O-protected 1-hydroxyindoles were provided using this reaction [214]. We always carried out our indole ring formation by using an excess of alkyne and terminal conjugated alkynes as privileged substrates. Non-conjugated and internal alkynes gave minor selectivities in indole products. Although many reactions of nitrosocompounds with alkenes, carbonyl derivatives, dienes are known and deeply studied, the evaluation of the reactivity of nitrosoarenes with alkynes has been rarely and scarcely explored. Kinetic, experimental and computational studies finalizing to the determination of the reaction mechanism shows that the more plausible pathway for the nitrosoarene-alkyne cycloaddition is the formation of the C-N bond as a rate determining step followed by a rapid C-C bond formation. A diradical intermediate is the focus point of the mechanism [215].

O N

+

H

H reflux

N O

NO

Scheme 53.

R

X

X

R

CO + NO Y

Y

X

R

N Y Scheme 54.

N

[Cp*Ru(CO)2]2

R'

OH

R'

H2 Pd/C

H

R'



Working with phenylacetylene and only with o-carbomethoxynitrosobenzene we had the indirect proof of the formation of nitrone as intermediate because of the isolation of a tricyclic product. We very recently submitted our procedure for the synthesis of meridianins and related compound by annulations of nitrosoarenes with ethynylpyrimidine. Meridianins A-G are marine indole alkaloids and firstly isolated from the tunicate Aplidium meridianum (Ascidiae, Polyclinidae family) in the vicinity of the South Georgia Islands, South Atlantic [216]. Meridianins and their analogues are actually deeply studied as potent inhibitors of several protein kinases [217]. To the best of our knowledge this report is the first indolization process because all the previous papers on the preparation of meridianins started from preformed indole units. Only one example was reported by Palermo and co-workers for the Fischer indolization of isomeridianins [218]. For the first time we carried out our cycloadditions by using a molar ratio 1:1 alkyne/nitrosoarene with success. Our strategy was directed to an easy access to the meridianins and to define a shortcut for the preparation of bioactive molecules showing indole units. We firstly prepared 2-chloropyrimidine derivatives, easily convertible to the corresponding 2-aminopyrimidine meridianins by subsequent substitution of the chlorine with a NH2 group by reaction with NH3. We also demonstrated the direct access to meridianins and analogues by cycloaddition of nitroso compounds

with 2-amino-4-ethynylpyrimidine. Both indolization processes proceed efficiently. The substitution of the chlorine with an amino group worked fine on the indole compound (Scheme 55) [219]. As previously noted not many methods were presented on the solid-support synthesis of indoles [73]. Few reports on the Fischer procedure and Larock type reaction catalyzed by palladium complexes were published so far. One of the few methods involving nitrocompounds as indole precursors in indole synthetic approach was discovered by Zaragoza et al. who reported a solid phase synthesis of N-hydroxyindoles with polystyrene-bound aryl fluorides (Scheme 56) [220]. A Wang resin was used as privileged solid support and it proved definitely superior to other resins. Similarly Watanabe and co-workers produced indoles from 2aminophenetyl alcohols and 2-nitrophenetyl alcohols. This procedure shows the opportunity to produce in-situ indoles starting from o-nitrophenetyl alcohols with a catalyst of Rh/C and RuCl2 (PPh3)2 giving formation of water and molecular hydrogen [221]. By using o-nitrophenethyl alcohols intermediates and onitrostyrenes Kuethe and co-workers more recently reported the synthesis of indolecarbazole derivatives as relevant step in the total synthesis of tjiparazoles B, D, E and I [222]. Ring closures were carried out indifferently with P(OEt)3 and in the presence of Pd-catalysts. Indolocarbazoles are a very important Cl

Cl

R1

R2 N

+

N

N

N

toluene 80° C

R3 N

R4

H

R1 R2

NH3, 80° C R3

sealed tube

N R4

O NH2 NH2 +

N

N

R1

R2

N

N

toluene 80° C

R3 R4

N H

Scheme 55.

Z1

O O2N

O

Z2

10% DBU in DMF 20° C, 16 h

O2N Z1

Scheme 56.

O

1) SnCl2, NMP, 20° C, 10 h

N R1

2) TFA / CH2Cl2 1 : 1, 0,5 h

F Z1 = Z2 = COCH3 Z1 = COPh; Z2 = CONHPh Z1 = CN; Z2 = SO2CH3

HO

O

Z2

R1 = CH3 R1 = Ph R1 = NH2

Z2

CO2H


Palmisano et al.

242784, an osteoclast inhibitor, synthesized by a multi-step strategy. This total synthesis is an interesting strategy because of the easy availability of the reactants and is a low cost procedure suitable for large scale preparation [228].

class of compounds containing the indole framework and many substances of this class exhibit potent biological activities [4l]. Another intramolecular approach to indole synthesis by using nitroaromatics as privileged precursors was performed by some of us who studied the intramolecular cyclization of Baylis-Hillman (BH) alcoholic adducts derived from o-nitro benzaldehydes and acrylates. The Baylis-Hillman reaction is a powerful tool for carbon-carbon bond formation between an arylaldehyde and a Michael acceptor catalyzed by a non-nucleophilic base giving a 2functionalized allylic alcohol [223]. These Baylis-Hillman adducts reacted in reductive carbonylation conditions using Fp2 as catalyst (Fp2=[CpFe(CO)2]2) in CO atmosphere affording a mixture of indoles, 1-formylindolines and quinolines as products (Scheme 57) [224]. By working on acetylated BH adducts the same group reported the selective formation of quinoline derivatives in good yields by heating at 150 °C in dioxane with 10% of Fp2 under 750 psi CO without any traces of indoles and indolines [225]. Wong and co-workers at Merck carried out a similar reaction affording N-hydroxyindoles by reduction of o-nitrobenzylketones using Pb and TEAF (triethylammonium formate) as a reducing agent. A mechanistic pathway was proposed involving an arylhydroxyamine intermediate that is formed before the cyclization step. The reduction occurs via transfer hydrogenation [226]. The reduction of o-nitrobenzyl carbonyl compounds was studied for the preparation of N-hydroxyindoles using many reducing agents but these procedures were found to be generally intolerable to many functional groups. The Merck research team proposed a novel method that is suitable for many molecules carrying different functional groups. By this procedure in mild conditions the authors achieved the preparation of N-methoxy-3-indole carboxaldehyde, isolated from the Cruciferae and a typical building block for the synthesis of natural products in a two-step procedure with 89% overall yield. Some azaindoles were synthesized by using o-nitropyridinenitriles through hydrogenolysis and achieving 2-amino-4azaindoles identified as a new class of BKCa channel openers. The cyclization occurs after reduction of the nitro group to an amino group and even directly from nitropyridine derivatives by the reductive action of H2 and Pd/C in ethanol [227]. By the intermediacy reduction of nitrocarbonyl arenes using Fe/AcOH Conde and co-workers detected the formation of amines and the condensation with carbonyl groups producing indoles like SB-

2.8. Indoles from Arylhydroxylamines Arylhydroxylamines were postulated, but not isolated, as intermediates in the intramolecular synthesis of indoles by starting from nitroarenes in reductive processes. Some examples were reported above and even reactions with the formation of N-hydroxyindoles were particularly focused as already reported in Ch. 2.7. The intermolecular approach to indoles starting from aryhydroxylamines was a relatively unexplored topic. A paper by Huntress and co-workers more than fifty years ago reported an experiment with phenylhydroxylamine and dimethyl acetylenedicarboxylate providing a mixture of products among which there was an intermediate that could be easily converted into indole-2,3dicarboxylate [229]. Other studies involved in the indole synthetic strategies were conducted by many chemists that performed reactions by using aryl hydroxylamines with allenyl compounds and acetylene derivatives. Blechert reported that the reacton of oxygen-deprotonated N-phenyl hydroxylamines with monosubstitued allenyl reagents H2C=C=CHR2 (R2=CN, CO2Me, PO(OEt)2, POPh2, SO2Me, SO2Ph, SOMe, SOPh, 4-methylpyridyl, CO2Et) gave, via Michael addition and Cope rearrangement, a series of anilines that were easily converted into indoles. The authors showed that sulfoxides served as the equivalent of 2-vinylindoles and this last product can undergo the Diels-Alder reaction with 2-vinylindole and then an indolization process was observed affording isoquinuclidine derivatives (Scheme 58) [230]. In a different paper the same group studied the reactivity of allenes with nitrones. By reaction of N-phenylnitrones (structurally similar and connected with arylhydroxylamines) with substituted allenes carrying electron acceptor groups, various products were formed via an addition reaction and a subsequent [3,3]-sigmatropic rearrangement. 2-Substituted indoles, were finally used for the synthesis of tetrahydrobenzazepinone derivatives. Even in this case 2-vinylindoles were produced as useful intermediates for the total synthesis of highly complex molecules [231]. Blechert demonstrated the use of 2-vinylindoles as starting materials for further structural modification of the heterocyclic skeleton with the aim to prepare alkaloids. Similar results were reported by Blechert for the use of O

OH

O

X

X OMe

OMe

X

CO, Fp2 +

dioxane

NO2

O OMe

N H

N H

O

Scheme 57.

R2

R

CH2R2

R

+

Scheme 58.

O

NOH

NH

R1

R1

R2 = EWG

R CH2R2 N R1



N-phenylnitrone intermediates with electron-deficient allenes getting the stereoselective achievement of 2-vinylindoles in a simple one-pot reaction [232]. In this report Blechert and co-authors emphasized the techniques used for the synthesis of polycyclic indole alkaloids and related derivatives by using a domino-process for the preparation of 2-vinylindoles [233]. Cycloadditions with enamines intermediates leads to the successful synthesis of epidasycarpidone a natural alkaloid generally isolated from other sources or obtained by total synthesis [234]. Contemporarily and independently Martin studied the reactivity of vinyl N-phenylhydroxamates derivatives in hetero-Cope rearrangements accessing to structural subunits (containing the indole moiety) of the antitumor antibiotic CC-1065 as well as the phosphodiesterase inhibitors PDE-I and PDE-II [235]. By using a similar approach Martin achieved the synthesis of natural halogenated indoles obtaining 4-chloro-6-methoxyindole, a promutagen from Vicia fava, and some bromoindoles from Enteropneusta, were prepared. via the hetero-Cope rearrangement [236]. The synthesis of 2,3-unsubstituted N-acylindoles by sigmatropic [3,3]-rearrangement of the N-phenyl-O-vinylhydroxylamine derivatives was performed by the treatment of hydroxamic acids (R = Me, OEt, H, Ph, CH2=CH, ClCH2CH2, CH2Cl, R1 = H; R = Me, R1 = 2-, 4Cl, 2-, 3-, 4-Me; RR1=CH2CH2) with CH2=CHOAc in the presence of Li2PdCl4 (Scheme 59) [237]. The same catalytic system was employed by Martin for the synthesis of indoles starting by 3,5-dibromonitrobenzene as a fundamental step in the preparation of glossobalol and balanoglossol [238]. Some indole compounds were prepared from 3,5dinitrobenzene via a common intermediate. Catalytic hydrogenation of the nitroaromatics in the presence of DMSO and aq. NH3 followed by acetylation gave the formaton of an amide compound that after treatment with CH2=CHOAc in the presence of Li2PdCl4 gave an intermediate vinyl ether which underwent a spontaneous hetero-Cope rearrangement and a subsequent cyclization. Final hydrolysis of this intermediate with NaOH-MeOH gave indole derivatives. A mechanistic study provided evidence of the formation of a radical intermediate [239]. The same group reported even the synthesis of 2-substituted indoles from acyl Meldrum's acids and phenylhydroxylamine via [3,3]-sigmatropic rearrangement [240]. When PhN(OH)COCH2COR was treated with a second equivalent of the same acyl Meldrum's acid in refluxing toluene, a series of domino reactions (O-acylacetylation, 1-aza-1'-oxa[3,3]-

OAc

R' N O

OH

sigmatropic rearrangement, decarboxylation, dehydrative cyclization, and deacylation) occurred consecutively to give substituted indoles in fair yield. Fukumoto and co-authors developed a novel reaction based on a tandem Michael addition followed by a [3,3] sigmatropic rearrangement process. Starting from Cbz-protected arylhydroxylamine with methyl propiolate indoles were afforded in moderate to excellent yields. This research group reported this procedure for the construction of a fragment of an antitumor antibiotic CC-1065 (Scheme 60) [241]. CC-1065 is an antitumour antibiotic agent isolated in trace quantities from culture of Streptomyces zelensis. Saczewski and co-workers used this method to assemble the indole subunit for the preparation of 1-(4,5-dihydro-1H-imidazol-2yl)indole that was evaluated for their antiaggregatory activity in human platelets [242]. Hwu showed recently this method for the preparation of indole ring structures starting from arylhydroxylamines and activated acetylenes. The mechanistic study postulated by Hwu and co-workers hypothesized both the N-addition followed by the cyclization and another path through, respectively, the Naddition, O-addition and [3,3]-sigmatopic rearrangement that contributes to the ring closure and the indole formation [243]. This group reported this excellent and regioselective method for the preparation of indoles in very good yields. Only activated acetylenes were tried but successful experiments and good yields of products were found with esters (R=OMe), aldehydes (R=H) and ketone (R=Me)(Scheme 61). More recently some of us reported the synthesis of indoles from phenyl hydroxylamines through the intermediate formation of nitroso compounds by oxidation with FeIII(Pc) (iron-phthalocyanines). The use of FeIII(Pc) was found after a catalyst survey and observing the ineffectiveness of other redox-active complexes, including (dtc)2MoO2, (dipic)MoO2(HMPA), FeCl2/FeCl3, Cu(CH3CN)4PF 6 and CuCl2•2H2O, (dtc=N,N-diethyl dithiocarbamate; dipic= 2,6pyridinedicarboxylate, HMPA=hexamethyl phosphorotriamide). In the catalytic cycle proposed by the authors a specific role is attributed to FeIII(Pc) for the in situ oxidation of arylhydroxylamines to nitrosocompounds. Nitrosoarenes then cyclize with terminal alkynes producing the N-hydroxyindoles as the major product that can be reduced by the intervention of the reduced catalyst that converts the N-hydroxyindoles to N-H indoles with the concomitant reoxidation of FeII(Pc) to FeIII(Pc) (Scheme 62). In each reaction the addition of the nitrogen containing precursor was done gradually by a syringe-pump thereby working

Li2PdCl4

R' N

+ O

R

R

Scheme 59.

O

COOMe R

N

OH

Cbz Scheme 60.

COOMe

N Me

+ CH2Cl2, r.t.

R

N Cbz


Palmisano et al.

NMe2 R5

(0.1 equiv.) O

R4 OH

R3

R

N

O R

+ 4 Å molecular sieves THF, rt

N R2

R5 R4

R1

R3

N R2

R1

Scheme 61.

(Y)

Ar X

X

10% Fe(Pc)

Ar

+ Y

NHOH

Y

H

N H

Z

H

Z

Scheme 62.

in excess of the alkyne. This method was applied to the preparation of particularly interesting indoles (Ar = 4-pyridinyl and 3,4dimethoxyphenyl) which both possess interesting bioactivity and relatively limited synthetic approaches [244]. A scale-up of the reaction was tested achieving positive results. All these kinds of reactions belong to methods that produce indoles by annulations of easily available and inexpensive N-aromatic precursors 2.9. Indoles from Other Nitrogen and Oxygen Containing Heterocycles The synthesis of indoles starting from other aza-heterocycles like pyridines, pyrroles, benzotriazoles or oxa-heterocycles as furan is a relatively unexplored research field. A different approach to the indole ring was recently used by Vanderwal and co-workers through the ring opening of pyridinium salts (Scheme 63) [245]. The ring opening of pyridinium salts dates back over a century to the pioneering and independent work of Zincke [246] and König [247]. The appropriately activated pyridinium salts renders the heterocycle electrophilic at the 2- and 4-positions enabling the ring opening by nucleophiles tethered at C3 in pyridine ring. The reaction involves treatment of pyridinium salts with primary amines leading to new pyridinium salts followed by the possible formation

of N-cyanoimine intermediates. Indoles are afforded in good yields (63-80%). The method is quite general because a variety of R groups are tolerated, both EWG and EDG. Pyridinyl-anilines precursors were efficiently prepared by coupling methods. A significant and successful experiment was performed by using cyanogen bromide on a bipyridine derivative achieving a 7-azaindole skeleton. As reported above, the Hemetsberger indole synthesis shows the intermediacy formation of an azirine ring by thermal reaction of vinyl azides and loss of dinitrogen. By a different approach the azirine ring was synthesized by Teber and co-workers following the Neber reaction of the oximes derived from the -arylketones with hydroxylamine [248]. -Arylazirines undergo the same thermolytic rearrangement giving indoles (Scheme 64) as observed in the Hemetsberger indole approach [249]. The rearrangement occurrs at temperatures ranging from 40 °C up to 170 °C and the cyclization mechanism proceeds probably via a -participation of the aromatic ring followed by a reorganization of the skeleton of the molecule before the new C-N bond is formed. Du and Zhao have recently introduced the preparation of 2-aryl2H-azirine from a variety of enamine derivatives by the mediation

R O BrCN, EtOH

R

aq. NH4Cl NH2

N H

N

Scheme 63. R2 R3

R2 R3

O

R3 N

1) NH2OH

R2

2) - H2O R1

Scheme 64.

R1

R1

N H



nmycin [252]. In a typical cycloaddition example 1-methyl-2vinylpyrrole reacted promptly with acetylene dicarboxylate achieving in good yields 1-methyl-4,5-dicarboxylate indole (Scheme 66). As known for Diels-Alder reactions donor substituents on the vinyl group further enhance the reactivity towards electrophiles. Alternatively the reactions between vinylpyrroles and dienophiles having a carbon-carbon double bond gave tetrahydroindoles that can be readily oxidized by DDQ (2,3-dichloro-5,6-dicyanobenzoquinone) [253]. Another interesting approach to indole units by [3+3] annulations of 2-(benzotriazol-1-ylmethyl)-pyrroles with ,unsaturated aldehydes and ketones was achieved by Katritzky and co-workers in good yields (Scheme 67) [254]. This protocol was suggested by the authors as an easy access to poly-substituted 1-H indoles generally difficult to synthesize by other tested methods. This synthetic route might be used to introduce different substituents at 7 position. An alternative cycloaddition procedure was carried out on furan derivatives by the assistance of microwaves and this led to an interesting approach to 4-substituted indoles (Scheme 68). The reaction passes through the addition of an -lithiated alkylaminofuran to a carbonyl compound and a microwave accelerated DielsAlder cycloaddition occurred followed by an in situ double aromatization [255]. The success of the microwave conditions vs

of PIDA (phenyliodine (III) diacetate). With this interesting variant indole-3-carbonitriles were preferentially prepared in very good yields. This alternative route to azirines is a useful tool for the generation of substituted indoles obtained by the cited thermal rearrangement of azirine rings [250]. Other different general strategies are known and used for the construction of 2H-azirine skeleton like the Swern oxidation of aziridine derivatives, the ring expansion of isoxazoles and oxazaphosphazoles or the intermolecular reactions between nitriles and carbenes or nitrenes and acetylenes. A peculiar method for the synthesis of indoles starting from pyrroles passes through the construction of the six-membered benzene ring by different synthetic strategies. Indoles can be usually prepared by construction of an aromatic ring on pyrrole molecules via many disconnection approaches that can start from 2and/or 3-monosubstituted pyrroles followed by a cyclization or via a cycloaddition procedure generally starting from 2- or 3vinylpyrrole derivatives and a subsequent aromatization. One successful strategy implies the use of a pyrrole derivative bearing a side chain in the position according to Scheme 65 [251]. By following a procedure starting from the functionalization in position of the N-protected pyrrole, the synthesis of indole was achieved as a preliminary step in the total synthesis of chuangxiO

O

O

O

BrMg

H N O

H

Ts

O

2) MeMgBr

N OH

O

1) MnO2

Ts

Me

H2SO4 N

i-PrOH, reflux

N OH

Me

Ts

Ts

Scheme 65.

H3CO2C

CO2CH3

CO2CH3 +

N CH3

R

N CO2CH3

CH3

R

Scheme 66.

R4

R3

1) n-BuLi

R3

R5

Bt R2

R2 O

N 2)

R1 Bt = 1-benzotriazolyl

R5

N

R6 R4

R1

R6

Scheme 67.

R Li O

N Boc

Scheme 68.

R

+

O O

R

N Boc

OH

1) [4+2] 2) -2 H2O 3) - Boc

N H


Palmisano et al.

standard heating is a consequence of the much faster heating process and higher temperatures in the pressurized reaction vial accomplished by current MW reactors. Previously Padwa and co-workers introduced an intramolecular Diels-Alder furan cycloaddition reaction that provided substituted indolines from N-homoallylic-2-aminofurans [256]. This annulations strategy is quite tolerant of functional groups. Wipf and co-workers extended this method to the preparation of 3,4-disubstituted indoles derived from addition of lithium reagents to ,-unsaturated ketones [255]. Gelb and co-authors reported the total synthesis of a potent inhibitor of mammalian group X secreted phospholipase A 2 and the indolization step consists in the annulation of a substituted pyrrole derivative with the ring closure on the position (Scheme 69) [257]. A very recent paper reported the construction of fused rings via palladium-catalyzed oxidative coupling with alkynes. Many examples were given for the synthesis of carbazoles, but one experiment was conducted favouring the decarboxylative coupling of N-methyl-2-pyrrolecarboxylic acid with diphenylacetylene catalyzed by Pd(OAc)2/Cu(OAc)2·H2O affording 1-methyl-4,5,6,7tetraphenylindole in 61% yield (Scheme 70) [258]. Another study carried out by Nakamura focused the attention on the role of benzotriazole as precursor of indole ring molecules. In a palladium-catalyzed reaction the authors observed the denitrogenative indolization of N-aroylbenzotriazoles by reaction with internal alkynes affording polysubstituted indoles. The mechanistic hypothesis shows that the aroylbenzotriazole acts as a synthetic equivalent of a 2-haloanilide in Larock’s indole synthesis. A plausible intermediate in this reaction is a 2-iminobenzenediazonium specie obtained by thermal isomerization of Nacylbenzotriazoles. This intermediate is the initial step of a palladium-catalyzed cross-coupling reaction of diazonium salts. Polysubstituted indoles were obtained in moderate to very good yields (Scheme 71) [259].

The yields of indoles increased with the order of the electronwithdrawing ability of the arylcarbonyl group. All the reactions were carried out in a slight excess of alkynes. Mixtures of regioisomers were obtained by using unsymmetrical alkynes. Palladium-catalyzed denitrogenative [3+2] cycloaddition of benzotriazoles and internal alkynes is a free-base reaction that enables to get poly-substituted indoles in an efficient and atom economic way. A known reaction for the synthesis of indoles uses the oxidation of the corresponding indolines. Many oxidizing agents were developed so far for this purpose and many research groups reported the achievement of indoles in good to excellent yields. When 2-allylindolin-3-ones were treated with phosphonium ylides in refluxing toluene, domino Wittig reaction and reverse aromatic Cope rearrangement took place to give -allyl-3-indole acetate derivatives in good yields [260]. Some examples of the syntheses of indoles by oxidation of the corresponding indoline employ Hg(OAc)2 [261], Co(Salen)/O 2 [262], hypochlorite/dimethylsulfide [263], and MnO2 [264]. Other processes were described for the synthesis of indoles starting from oxindole, indoxyl and isatin derivatives. We do not focus particularly on this kind of reactions because our aim, as stated in the introduction, is to emphasize indolization procedures by ring closure. 3. CONCLUSION Our review was mainly focused on indolization processes from various nitrogen precursors rather than on disconnection approaches previously used. Many reactions have been developed using amines and particularly anilines and even nitroarenes. Other precursors like azoderivatives were scarcely used and roughly studied so far but even with the extraordinary result to obtain an indole structure. The rapid access to indoles as well as the selection of environmentally HO

O O

p-TsOH toluene

O O

HOCH2CH2OH reflux

N

N

Bos

Bos Scheme 69.

Ph

Ph

Pd(OAc)2 Ph +

COOH

N

Ph

Me

Cu(OAc)2 H2O Ph

LiOAc 4 A MS

N

DMAc, 120° C

Me

Ph

Scheme 70. R3 R2

N

10 mol % Pd(PPh3)4 N

N

R2 O Scheme 71.

+

R3

R3

R3 neat, 130° C

R1

R2 N

R2 O

R1


benign and chemoselective methods is one of the major goal in heterocyclic synthesis. The search for new annulations and heterocyclization procedures is a very competitive and ambitious research field. Writing on the indole synthesis and about the biologically active compounds containing the indole unit is surely a never ending work because almost daily new indole syntheses and reactions are discovered and optimized showing a very broad expansion of this research field that involves many groups both from academic world and industrial companies. The ongoing studies on this topic has led to the discovery of many stoichiometric and catalytic reactions. Many methods were presented involving the use of transition-metal complexes (especially palladium complexes, but many other transition- and main-group metals and their complexes are continuously studied and introduced in the chemistry of heterocycles), thermal reactions, photochemical procedures, solid-support synthesis for a combinatorial approach, green procedures with the auxiliary techniques of microwaves and ultrasound for environmental friendly reaction conditions. Parallelly with the refinement of the synthetic procedures the isolation of new molecules from natural sources bearing indole moieties is another ongoing and growing research field. The study of these new compounds and the investigation of their properties and potential application in the treatment of different diseases is another synergistic aspect of the importance of the organic synthesis of indoles.


[5] [6]

[7] [8] [9]

ACKNOWLEDGEMENTS We are grateful to all the people that are working and worked in our research groups, for the helpful discussions, the experimental results and the extraordinarily nice and fruitful time spent together.

[10]

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Received: 21 October, 2009

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Revised: 27 January, 2010

Accepted: 04 February, 2010