Synthetic Approaches to 3-(2-Nitroalkyl) Indoles and Their Use to

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Synthetic Approaches to 3‑(2-Nitroalkyl) Indoles and Their Use to Access Tryptamines and Related Bioactive Compounds Stefano Lancianesi, Alessandro Palmieri, and Marino Petrini* School of Science and Technology, Chemistry Division, Università di Camerino, via S. Agostino, 1, I-62032 Camerino, Italy motif in the whole molecular structure. Tryptamines are 3(aminoalkyl) indole derivatives showing a significant pharmacological profile and additionally, usable as starting materials for the preparation of carbolines and other polynitrogenated compounds.2 The flourishing chemistry of indole functionalization enjoys of the enhanced reactivity pertaining to this heterocyclic system that is particularly prone to electrophilic substitution reactions. Indoles react with electrophiles in a high CONTENTS regioselective fashion through the well-known Friedel−Crafts 1. Introduction 7108 (FC) reaction leading to C3 substituted compounds unlike to 2. Reaction of Indoles with Nitroalkenes 7109 what observed with pyrroles which in the same process afford 2.1. Uncatalyzed FC Reactions 7109 2-substituted derivatives. Concerning tryptamines, direct 2.2. Brønsted Acid Catalyzed FC Reactions 7110 installation of the aminoalkyl moiety onto a proper position 2.3. Lewis Acid Catalyzed FC Reactions 7112 at the indole ring is poorly documented because of the lack of 2.4. Organocatalyzed FC Reactions 7117 suitable electrophilic reactants that include a free or protected 2.5. FC Reactions Included in Tandem, Cascade, amino groups.3 Alternatively, it is possible to devise a de novo and One-Pot Processes 7119 synthesis of the indole system from benzene derivatives so that 2.6. Base Promoted Conjugate Additions of the aminoalkyl unit is correctly embedded in the proper Indoles to Nitroalkenes 7123 position after ring closure.4 Utilization of reactants bearing high 3. Reaction of Indolenine Derivatives 7124 oxidation state nitrogen atoms (e.g., nitroalkanes or nitro3.1. Reaction of Nitroalkanes with Gramines 7124 alkenes) having appropriate electronic features may be pursued 3.2. Reaction of Nitroalkanes with Sulfonyl in the reaction with indoles. A subsequent reduction of the Indoles 7124 nitro group after the addition reaction ensures an efficient entry 3.3. Reaction of Nitroalkanes with Other Derivto tryptamine derivatives. This strategy is presently the most atives 7126 exploited one to prepare functionalized tryptamines and 4. Nitroaldol Reaction on Indolyl-3-carbaldehydes 7126 involves three distinct approaches, the first of which is based 5. Direct Synthesis of Nitro Indoles by the Fischer on the catalyzed or promoted FC reaction of indoles 1 with Reaction 7129 nitroalkenes 2 with subsequent reduction of the nitroalkyl 6. Synthetic Applications of Nitro Indoles 7129 derivative 3 to tryptamine 4 (Scheme 1, route A).5 The second 6.1. Synthesis of Tryptophans 7129 approach entails a preliminary functionalization of the indole by 6.2. Synthesis of Polycyclic Compounds 7130 a three-component coupling using an aldehyde and a suitable 6.2.1. Ergot Alkaloids and Related Derivatives 7130 nucleophilic reagent LgH (Scheme 1, route B).6 The obtained 6.2.2. Other Polycyclic Compounds 7132 indolyl adduct 5 upon treatment with a base delivers, by Lg 6.3. Synthesis of β-Carbolines 7135 elimination, an alkylideneindolenine intermediate 7 which 6.4. Synthesis of Other Tryptamine Derivatives 7141 behaves as an actual vinylogous imine that by adding a suitable 7. Conclusion 7143 nitroalkane 6 generates the nitroindolyl compound 3. Finally, Author Information 7143 the third approach is based on a preliminary formylation of the Corresponding Author 7143 indole ring with formation of the corresponding aldehyde 8 Notes 7143 (Scheme 1, route C). The indolylcarbaldehyde undergoes a Biographies 7143 nitroaldol (Henry) reaction with rapid elimination of water Acknowledgments 7144 thus generating nitroalkene 9. This unsaturated compound can Abbreviations 7144 be partially reduced at the double bond giving nitro indole 10 References 7144 or, using a suitable reducing agent, totally reduced to tryptamine 4.7 A more profitable way to utilize indolyl 1. INTRODUCTION nitroalkene 9 lies in the possibility of implementing its carbon structure by a conjugate addition to the electron-poor olefin The assembly of architecturally complex alkaloids embedding using organometallic reagents or other carbanionic systems. the indole nucleus is of paramount importance for the target 1 oriented synthesis of biologically active molecules. A careful inspection of a notable array of indole-containing compounds Received: November 27, 2013 evidences the tryptamine backbone as a common recognizable Published: June 6, 2014 © 2014 American Chemical Society

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dx.doi.org/10.1021/cr400676v | Chem. Rev. 2014, 114, 7108−7149

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Scheme 1. General Synthetic Approaches to 3-(2-Nitroalkyl) Indoles and Their Tryptamine Derivatives

aromatic character. Although the final result is identical, these two main processes will be separately discussed.

These complementary strategies are all effective in producing the expected 3-(2-nitroalkyl) indole derivatives 3. However, it should be observed that the utilization of nitroalkenes 2 in route A is often made troublesome by the toxicity and instability of these strong electrophilic reactants, especially when they carry short alkyl chains (2, R2 = alkyl, R3 = H).8 Although route B involves a two-step procedure to afford compounds 3, it allows a more efficient tuning of the substituents to be included in the alkyl framework and also permits the access to tertiary nitroindolyl derivatives which are impossible to obtain using route A (vide infra). Concerning route C, in principle it would be of wide applicability but the examples available in literature are restricted to the utilization of nitromethane, nitroethane and nitroacetate esters. This review article aims to provide a comprehensive overview of synthetic methods currently available to obtain 3-(2-nitroalkyl) indole derivatives and outlines the utilization of these nitro indoles in the preparation of indole compounds having an enhanced biological activity.

2.1. Uncatalyzed FC Reactions

The powerful electron-withdrawing effect exerted by the nitro group makes nitroalkenes strong electrophilic reactants.9 This high reactivity usually requires only a moderate activation in their reaction with indoles as evidenced by the catalytic effect exerted by n-tetrabutylammonium bromide in this process.10 Physical activation by ultrasound irradiation or simple heating of the reaction mixture is often enough to provide a successful reaction of indoles with nitroalkenes. As a matter of fact, indoles and nitroalkenes can be made to react under solventfree conditions when heated at 100 °C (Scheme 2).11 The temperature required for the process can be lowered to 65 °C by sonication of the reaction mixture at moderate frequency (40 kHz, 600 W).12 Polar protic solvents such as water or butanol are able to provide the needed environment for a proper reaction.13 These simple reaction conditions are Scheme 2. Uncatalyzed FC Reaction of Indoles to Nitroalkenes

2. REACTION OF INDOLES WITH NITROALKENES Acid catalyzed reactions of indoles with nitroalkenes can be considered as FC processes. A plethora of acidic agents, working under homogeneous or heterogeneous conditions, may be employed in these reactions, while the use of chiral acid catalysts allows the asymmetric synthesis of 3-(2-nitroalkyl) indoles. Activation of the indole ring toward the reaction with nitroalkenes can also be achieved by removal of the acidic proton on the nitrogen atom under basic conditions. This process involves the generation of a stabilized indolyl anion, which reacts with a nitroalkene through a conjugate addition reaction followed by a tautomerization that restores the indole 7109


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as proton source. Unsymmetrical bisindolyl derivatives 21 can be readily obtained by reaction of indoles with 3-indolylnitroalkene 20 in the presence of silica gel (Scheme 5).18,19

particularly effective for multigram scale preparations as demonstrated by the synthesis of β-carboline 16 which starts from the FC reaction of indole 12 with nitroalkene 13 in nbutanol at reflux (Scheme 3).14

Scheme 5. Synthesis of Unsymmetrical Bisindoles 21

Scheme 3. Large Scale Preparation of β-Carboline 16

The reaction is carried out under solvent-free conditions at room temperature.20 Microwave activation of the reaction mixture is effective in reducing the reaction time to a few minutes and has a variable effect on the chemical yields.21 Sulfuric acid adsorbed on silica gel can be used as catalyst for the FC reaction in DCE at room temperature.22 Other heterogeneous acid agents, such as montmorillonite K-10,23 heteropolyacids,24 zeolites, and mesopoporous 3D aluminosilicate,25 are also able to promote the FC reaction of indoles with nitroalkenes. Montmorillonite K-10 acts under solventfree conditions at room temperature and therefore is more efficient than the aluminosilicate which requires reflux conditions in DCE. Sulfamic acid is an effective catalyst for the solvent-free reaction of indoles with nitroalkenes at moderate temperature. The bis adduct 23 can be obtained using 1,4-dinitrostyrene 22 as substrate in the reaction with indole 12 (Scheme 6).26

After cooling, nitro indole 14 is recovered by simple filtration from the reaction mixture and is reduced to tryptamine 15 after which a Pictet-Spengler and Pd-catalyzed dehydrogenation affords β-carboline 16.15 Direct utilization of nitroalkenes can often be avoided by generating them in situ via a nitroaldoldehydration process. Reaction of ethyl nitroacetate and paraformaldehyde gives nitroacrylate 17 which reacts with a large variety of indoles leading to the synthesis of nitroesters 18 (Scheme 4).16 Zinc mediated reduction of the nitro group Scheme 4. FC Reaction of Indoles to in Situ Generated 2Nitroacrylate 17.

Scheme 6. Double FC Reaction of Indole to Bisnitroalkene 22.

An interesting procedure for the preparation of 3,3′bisindolyl derivatives 27 starts with the sulfamic acid catalyzed FC addition of indoles to nitroalkenes bearing a supplementary ortho nitro group (Scheme 7).27 The obtained adducts 24 upon reaction with iron powder in AcOH are initially reduced to the corresponding anilines 25 and then undergo to an intramolecular ring closure. Sequential elimination of water and nitroxyl (HNO) from intermediates 26 completes the formation of the second indole system leading to the formation of 3,3′-bisindoles 27. Acids of moderate strength such as boric acid and alkali metal bisulfates both supported on silica gel or under aqueous conditions are also able to catalyze the reaction of indoles with

under acidic conditions affords the corresponding tryptophan derivative, which is then cyclized to the tetrahydrocarboline 19. Nitroethylene is seldom used in reactions with indoles because it easily polymerizes under alkaline or acidic conditions. This is in contrast with the behavior of 2-nitro-1-alkenes that can be profitably used in such reactions since they are more stable than nitroethylene but mantain a good reactivity when heated with indoles in benzene at reflux.17 2.2. Brønsted Acid Catalyzed FC Reactions

Protonation of the nitro group at oxygen provides a notable enhancement of the electrophilic character of nitroalkenes. This allows an effective FC reaction to occur even using weak acids 7110


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As previously stated, direct manipulation of toxic nitroalkenes can be circumvented generating them in situ from the parent nitro alcohols by a dehydration process. Water elimination from nitro alcohols or their esters can be obtained under mild acidic conditions at high temperature.32 In a study directed toward the preparation of agonists of benzodiazepine receptors, nitro alcohol 31 was made to react with 5(benzyloxy)-1H-indole 30 in toluene-acetic acid (9:1) at reflux (Scheme 9).33,34 Finally, the nitroester 32 was directly reduced to the tryptophan derivative 33 and then converted into the corresponding β-carboline.35

Scheme 7. Synthesis of 3,3′-Bisindoles 27

Scheme 9. Synthesis of Tryptophan Derivative 33.

nitroalkenes.28,29 Potassium bisulfate can be employed as catalyst in the reaction of indoles with polyfunctionalized nitroalkenes containing an alkyne moiety (Scheme 8).30 The obtained adducts 28 upon conversion into the parent nitrile oxides by reaction with Boc anhydride undergo a spontaneous 1,3-dipolar cycloaddition leading to isoxazolobenzoxepanes 29. The same activating procedure of the nitro group can be adopted for the preparation of isoxazoline derivatives by reaction of nitro indoles with acrylates.31

Chiral phosphoric acids are known to catalyze a number of asymmetric processes with outstanding enantioselectivity.36 Application of these chiral Brønsted acids to the reaction of indoles with nitroalkenes has been introduced only few years ago allowing the preparation of the corresponding adducts 11 in good yields and satisfactory enantioselections (Scheme 10).37,38 Scheme 10. Enantioselective FC Reaction Catalyzed by Chiral Phosphoric Acid 34.

Scheme 8. Synthesis of Isoxazolobenzoxepanes 29.

The presence of water, even in negligible amount, is detrimental both for yields and ee values. For this reason, addition of 3 Å molecular sieves is instrumental for a successful enantioselective reaction. A plausible transition state leading to adducts 11 entails the activation of the nitroalkene by hydrogen bonding with the acidic proton of the catalyst while interaction of the indole NH with the oxygen of the PO bond (Lewis base activation) enforces the required reactants closeness. A further elaboration of the prepared compound 35 can be done 7111


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derivative 38 (Scheme 12).45,46 Reduction of the nitro group in adduct 42 is possible without affecting the conjugated double bond thus leading to the hydrochloride salt of aminoester 43.

by usual reduction to tryptamine 36 and conversion to the optically active β-tetrahydrocarboline 37 (Scheme 11).37 All these synthetic operations occur with complete retention of the original stereocenter configuration and with good diastereoselection.

Scheme 12. Synthesis of Unsaturated Tryptophan Derivative 43.

Scheme 11. Synthesis of Optically Active βTetrahydrocarboline 37.

2.3. Lewis Acid Catalyzed FC Reactions

Interaction of nitroalkenes with Lewis acids is by far the most exploited way of activation in their reaction with indoles. A suitable tuning of the Lewis acidity of the catalyst is possible so that a large variety of reaction conditions can be adopted for a successful FC process (Table 2).47−56 Among these catalysts, lanthanide salts have been proved to be rather efficient in promoting this reaction since their “hard” acidity make them particularly effective in the interaction with the negatively charged oxygen atoms of nitroalkenes. Interestingly, CeCl3 alone is poorly efficient as a catalyst for the reaction of indoles with nitroalkenes. Conversely, the CeCl3/NaI couple supported on silica gel gives outstanding results with many different nitroalkenes including 1-nitrocyclohexene (Table 2, entry 14).47 Similarly, ytterbium(III) salts are effective catalysts for the synthesis of indolylnitroester derivatives (Table 2, entries 17−20).54,55 Water compatible

The TFA promoted FC reaction of indoles to 2dimethylamino-1-nitroethylene 38 results in the formation of 2-indolyl-1-nitroethylene derivatives via an addition−elimination process (Table 1).39−44 The obtained nitroalkene 39 can be selectively reduced at the double bond using NaBH4 thus generating the nitro indole which is further reduced to tryptamine 40 by catalytic hydrogenation (Table 1, entries 1,9). Alternatively, compound 39 can be totally reduced to the corresponding tryptamine 40 using LiAlH4 or the Hantzsch ester (Table 1, entries 2−7). The α-nitroacrylate system can be introduced by reaction of 6-methylindole with nitroalkene 41 without any added promoter, highlighting its superior reactivity over the amino

Table 1. FC Reaction of Indoles to 2-Dimethylamino-1-nitroethylene Followed by Reduction to Tryptamine Derivative

entry

R1

R2

R3

39 yield (%)

methoda

1 2 3 4 5 6 7 8 9 10

5-OMe H H H H H H H H 6-Br

H c-C5H9 Bn (CH2)2OMe i-Pr CH2−4-tolyl H H H H

CO2Me H H H H H CH2CO2Me Me CH(Me)CO2Me H

52 80 71 81 98 91 91 80 65 96

A B B B B B C D E F

40 yield (%)b 48 58 58 60 53 85 56 98 74 91

(98)

(95) (93) (94)

ref 39 40 40 40 40 40 41 42 43 44

Method A: NaBH4 then H2−Ni/Raney; method B: LiAlH4; method C: Hantzsch ester; method D: H2-(PPh3)3RhCl then H2−Pd/C; method E: NaBH4 then H2−PtO2; method F: NaBH4 then Zn/2 N HCl, MeOH, reflux. bYields in parentheses refer to the intermediate nitro indole.

a

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Table 2. Lewis Acid Catalyzed FC Reaction of Indoles to Nitroalkenes

entry

R1

R2

R3

R4

R5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

H H H H H H 7-Et 5-CN H 5-OMe H 5-OH H H H H 4-CO2Me H 5-Br 6-F H 4-OH

H H H H H H H H H H H H H H H H H H H H H H

H H H H H H H H Me H H H H H H Me H Ph H H H H

Ph Ph Ph Ph Ph Ph Ph 2-NO2Ph Ph Ph Ph CO2Me Ph −(CH2)4− H 4-ClPh 4-MeOPh 4-ClPh CO2Me CO2Me n-Bu Ph

H H H H H H H H H H Me H Me CO2Me H CO2Et CO2Et H H H H

catalysta

44 yield (%)

ref

CeCl3/NaI SmI3 TiO2 I2 InBr3 Zn(OAc)2 Zn(OAc)2 Zn(OAc)2 InBr3 InBr3 CeCl3/NaI CeCl3/NaI CeCl3/NaI CeCl3/NaI CeCl3/NaI TiO2 Yb(OTf)3 Yb(OTf)3 Yb(OTf)3 Yb(OTf)3 NBS NBS

96 95 79 99 60 98 94 82 93 88 88 86 88 87 79 87 73 89 68 70 70 70

47 48 49 50 51 52 53 54 51 51 47 47 47 47 47 49 54 54 54 54 54 54

CeCl3·7H2O−NaI (30 mol %) on silica gel, MeCN, overnight, rt. SmI3 (10 mol %), MeCN, 1−12 h, reflux. Nano-TiO2 (10 mol %), CH2Cl2, 4 h, rt. I2 (30 mol %), Et2O, 0.3−0.6 h, rt. InBr3 (5 mol %), THF/H2O (1:9), 2 h, rt. Zn(OAc)2 (5 mol %), EtOH, 0.3−1.5 h, rt. Yb(OTf)3 (5 mol %), Et2O, 4−30 h, rt. NBS (10 mol %), CH2Cl2, 4−36 h, rt.

a

currently predominate in the domain of catalyzed enantioselective reactions of indoles with nitroalkenes. Most of the chiral bisoxazolines tested give best results when Zn(OTf)2 is used as complexing metal (Table 3).67−70 Chiral bisimidazoline L2 is equally effective than its oxazoline analogue L1 in the preparation of nitro indoles 45. Satisfactory results may also be obtained using oxazoline-imidazoline ligand L3 featuring two different heterocyclic systems. The absolute configuration of the stereocenters in L1 seems to play a role in the stereoselectivity of the process since the (R,S)-L1 featuring a cis relationship between the phenyl groups gives slightly worse results.68 An immobilized version of the ligand L1 using a Fréchet-type dendrimeric system is also available for this process.71 The ee values recorded using the immobilized catalyst are slightly lower than those obtained with the original organometallic complex, but a reduced catalyst charge is required (1 mol % of immobilized ligand) and recyclability up to four times is evidenced. Preparation of trifluoromethylated nitro indoles bearing quaternary stereocenters is possible using β-trifluoromethylnitroalkenes in the presence of a complex of Ni(ClO4)2 with bisoxazoline L4 (Table 3, entries 10−12).72 This reaction is particularly significant since, differently from the zinc(II) catalyzed reactions, the process occurs at 60 °C. The origin of enantiofacial preference for the reaction of indoles with nitroalkenes catalyzed by bisoxazoline L1 can be rationalized considering a preliminary coordination of the nitro group oxygen atoms with the metal as depicted in TS1. The indole

Lewis acids such as InBr3 allow the process to be carried out in aqueous media. Surprisingly, the latter reagent gives only a modest result with the benchmark test reaction of indole with nitrostyrene (Table 2, entry 5).51 Better yields can be obtained for the same reaction using 2.5 mol % of scandium(III) dodecyl sulfate57 or Sc(OTf)3 in water at 30 °C for 10 h.58 Scandium can be replaced by aluminum using the same anionic system and under the same aqueous conditions leading to similar results.59 Zinc(II) acetate is effective for the FC reaction when used in ethanol (Table 2, entries 6−8) or cyclohexane at reflux,52,53 while utilization of Zn(ClO4)2 requires a bulky thiourea ligand to properly catalyze the reactions of indoles with nitroalkenes and seems therefore less appealing.60 Other metal salts, such as CoCl2·6H2O,61 BiOClO4 hydrate,62 FeCl3· 6H2O,63 and nickel(II) N-heterocyclic carbene complexes,64 can also be employed for this FC reaction with satisfactory results. Finally, the enhanced activity of copper(II) triflate in ionic liquids has been reported but only for the reaction of indole with nitrostyrene.65 The complexing ability of selected metal cations with optically active organic molecules containing nitrogen and oxygen atoms allows the preparation of chiral organometallic species that can be used as catalysts in asymmetric synthesis. One of the first attempts to use organometallic complexes for the enantioselective reaction of indoles with nitroalkenes employed chiral SalenAlCl complex and pyridine though the level of asymmetric induction was quite low (ee 99:1 97:3 99:1 99:1 98:2

>99 >99 >99 >99 >99 >99 >99 >99 >99 >99

The results obtained in this reaction evidence an excellent level of diastereoselection in favor of the anti isomer 125 combined with an outstanding enantioselectivity. The chemical yield is very high for straight chain aldehydes but less than modest (27%) when 2-methylpropanal is made to react with Ntosyl-2-indolyl nitroalkene. The presence of two versatile functional groups such as the nitro and the formyl in adducts 125 opens interesting opportunities to access structurally useful tryptamine derivatives. Apart from the expected reduction of these two functions leading to amino alcohols, a more attractive transformation entails the preparation of cyclic tryptamine derivatives 126 from nitro aldehydes 125 (Scheme 51).

Scheme 50. Enantioselective Addition of Arylboronic Acids to Nitroalkenes

Scheme 51. Conversion of γ-Nitro Aldehyde 125 into Cyclic Tryptamine 126

This procedure nicely complements the direct enantioselective FC reaction of nitrostyrenes to indoles described in section 2.3. Conjugate addition of easily enolizable reactants to nitroalkenes is of widespread utilization for the preparation of functionalized nitro derivatives. In this context 3-(2-nitro-1ethenyl) indole and its N-protected derivatives have often been used, among other nitroalkenes, to prove the effectiveness of the devised synthetic procedures.155 Enantioselective catalyzed addition of 5-methyl-2-phenyloxazol-4-one,156 2-oxobutanoic acid esters,157 enals,158 diethyl malonate,159 and diphenyl

Catalytic reduction of the nitro group is followed by the 1pyrroline formation which is further reduced to the pyrrolidine ring and then tosylated by a usual procedure. The adopted reaction conditions are mild enough to ensure only a negligible loss in the diastereomeric purity of the cyclic tryptamine 126 while the major stereoisomer obtained is enantiomerically pure. Conjugate addition of unsaturated metal alkoxides to indolyl nitroalkenes allows to use the obtained adducts in intramolecular 1,3-dipolar cycloadditions. Reaction of homopropar7128


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gylic alcohol 128 with indolyl nitroalkene 127 affords in high yield the β-alkoxy derivative which in the presence of phenyl isocyanate gives isoxazole 129 via the corresponding nitrile oxide intermediate (Scheme 52).162

Scheme 54. Synthesis of Nitro Indoles 133 by the Fischer Reaction

Scheme 52. Synthesis of Isoxazole 129 by Intramolecular 1,3-Dipolar Cycloaddition

6. SYNTHETIC APPLICATIONS OF NITRO INDOLES Utilization of nitro indoles other than those presented in the previous sections are discussed in this part of the review. Tryptophan derivatives, β-carbolines and other polycyclic compounds obtainable from tryptamine precursors are synthetic targets involving 3-(2-nitroalkyl) indoles as pivotal intermediates.2c Besides these important targets, other bioactive compounds featured by the indole ring, that can be accessed starting from nitro indoles, are presented.

The same result can be obtained upon deprotonation of the β-alkoxy nitro indole and quenching with acetic anhydride but the process is far less efficient leading to several coproducts. Conjugate addition of malonates to indolyl nitroalkenes followed by reduction of the nitro group can also be used in the early stages of a multistep synthesis aimed to the preparation of chiral 3-amino-4-indolyl-2-piperidones.163 Surprisingly, the complementary strategy for the synthesis of 3-(2-nitroalkyl) indoles involving addition of nitroalkanes to 3indolyl-α,β-unsaturated carbonyl derivatives seems quite neglected. A single example is up to date available reporting addition of nitromethane to 3-indolyl acrylate ester 130 leading to indolyl nitroester 131 (Scheme 53).164 The nitromethane is

6.1. Synthesis of Tryptophans

The two main approaches which are commonly exploited to install the α-amino acid moiety into the indole system involve the FC reaction with 2-nitroacrylates or reaction of nitroacetate esters with alkylideneindolenine precursors 5. In both cases reduction of the nitro group to the primary amine completes the synthesis of the requested α-amino acid framework.167 Earlier examples concerning the utilization of gramines in the reaction with nitroacetic acid esters dates back to the forties of the last century, but this strategy is still used to obtain tryptophan derivatives embedding particular functional groups in the indole ring such as 2-trifloromethyl or 2-phenyl tryptophan.168,169 The synthetic approach followed for the preparation of the photoaffinity labeling reagent 5-azido tryptophan 138 nicely illustrates the general procedure used for this purpose (Scheme 55).170

Scheme 53. Conjugate Addition of Nitromethane to 3Indolylacrylate Ester 130

Scheme 55. Synthesis of the Photoaffinity Labelling Agent 138 used as a solvent (40 mL for 3 mmol of substrate) and the procedure is ineffective on N-unprotected 130 since a preliminary deprotonation by DBU deeply affects the acrylate electrophilicity compromising the conjugate addition. The enantioselective version of this process is carried out starting from 3-(1-benzyl-3-indolyl)propanal which is oxidized with DDQ and then made to react with nitromethane under iminium ion catalysis in a one-pot process (yield 70%, ee 92%).165

5. DIRECT SYNTHESIS OF NITRO INDOLES BY THE FISCHER REACTION The direct assembly of the nitro indole system using common indole syntheses starting from benzene compounds and nitro carbonyl derivatives is poorly practiced. In the example reported in Scheme 54, fluorinated hydrazine 132 is made to react with nitro aldehydes in formic acid as a solvent exploiting a classical Fischer indole synthesis. The yields of the obtained nitro indoles 133 are not particularly high but are better than those recorded starting from preformed hydrazones using the same reactants.166 7129


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6.2. Synthesis of Polycyclic Compounds

Conversion of nitro indole 134 to gramine 135 by a Mannich reaction is followed by a high yielding substitution process using ethyl nitroacetate. Reduction of both nitro groups of indolylnitroester 136 is best accomplished by catalytic transfer hydrogenation using formic acid and the obtained diamino derivative 137 is hydrolyzed and finally converted into 5azidoindole 138 via the corresponding diazonium salt. Stereochemical control at the carbon bearing the nitro group in indolylnitroesters is particularly difficult because of the enhanced acidity of the corresponding hydrogen atom. This feature can be suitably exploited in order to carry out a crystallization-induced diastereomer transformation, which through an equilibration process allows the more thermodynamically stable isomer to be obtained in crystalline pure form.171 This strategy is illustrated for the following process in which a multigram-scale preparation of the antidiabete drug candidate 144 is obtained for biological tests purpose (Scheme 56).172

6.2.1. Ergot Alkaloids and Related Derivatives. Ergot alkaloids are fungi metabolites produced by the genus Claviceps and are featured by a polycyclic structure embedding the indole ring.173 This class of substances includes the group of clavines, ergopeptides and lysergic acid derivatives. Ergot alkaloids are poisonous substances currently under study for treatment of migraines and gynecologic diseases. A synthetic route to the preparation of clavicipitic acids which belong to this family of alkaloids, employs functionalized gramine 145 as starting material (Scheme 57).174 Scheme 57. Synthesis of Claviciptic Acid Derivatives 148

Scheme 56. Diastereoselective Synthesis of Nitroester 140 and its Conversion into Antidiabete Drug 144

A selective reaction on the dimethylaminomethyl group with methyl nitroacetate can be pursued activating the system by ntributylphosphine thus generating the corresponding adduct 146.130 Reduction of the nitro group is followed by the intramolecular ring closure with the allylic framework and is best realized using Zn(Hg) amalgam under acidic conditions. The stereoisomeric couple of N-hydroxy derivatives 147 can be separated and further reduced to clavicipitic acid esters 148 using aqueous TiCl3. This approach is of general application and can be used to prepare other ergot alkaloids such as aurantioclavine which is the decarboxylated analogue of compound 148.175 Amidation of tryptamine derivatives with suitable functional groups located at C4 in the indole ring can also be fruitfully exploited for the preparation of various tetrahydroazepino indoles.176 Intramolecular condensation of 4-cyanotryptamines 149 with BnMe3NOH (Triton B) affords indolyllactams 150 (Scheme 58).177 Even under optimized conditions, the condensation is incomplete and a large amount

Reaction of gramine 139 with ethyl nitroacetate is poorly diastereoselective leading to a 6:4 mixture of the corresponding stereoisomers. Crystallization of the crude product in a mixture of ethanol/n-heptane is effective in giving indolyl nitroester 140 as a single diastereomer by a rapid equilibration during the crystallization process. A crucial step in the devised synthetic plan is represented by the nitro reduction which must be carried out with zinc dust in the presence of acetic acid in order to ensure a complete retention of the relative configuration in β-methyl tryptophan 141. The racemic mixture can be successfully resolved using chiral acid 142 and the optically active amino acid, isolated as methanesulfonate salt 143, is finally converted into the target compound 144 by two sequential amidation reactions.

Scheme 58. Base Induced Ring Closure of Amino Nitriles 149

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sulfone 156 to arylsulfinate ester 157 in order to generate a good nucleofuge at the allylic position (Scheme 61).182

(up to 38%) of starting tryptamine 149 is recovered after the reaction. The same result can be achieved starting from the methyl 4-carboxylate tryptamine in slightly better yield (81%).178 Other tricyclic compounds featured by a tetrahydropyrroloquinoline skeleton can be prepared by related strategies involving intramolecular nucleophilic displacements by the tryptamine amino group at C4 of the indole ring.179 Fully carbacyclic structures related to ergot alkaloids can be obtained exploiting the carbanionic nature of the nitronate anion generated from the nitro indole. The nitroaldol reaction can be profitably used to install the nitroethyl moiety in compound 151 starting from the corresponding 3-formyl derivative in 53% overall yield (Scheme 59).180 Reduction of the cyano group in

Scheme 61. Synthetic Approach to 6,7-Secoagroclavine 159

Scheme 59. Synthesis of Tricyclic Amine 153 by Intramolecular Nitroaldol Reaction/Reduction

Ring closure to tricyclic nitro derivative 158 is carried out under basic conditions (SN2′ reaction) that also provide cleavage of the tosyl group at the indole nitrogen atom. Compound 158 is then converted into the desired alkaloid 159 by simple synthetic manipulations. The ring closure in nitro indoles structurally related to compound 157 bearing a free hydroxy group instead of the phenylsulfinate moiety can also be carried out under different conditions including Brønsted acid catalysis (HCl).183 Other synthetic plans aimed to prepare the same alkaloid 159 as well as related congeners involve intramolecular conjugate addition of the 3-nitroethyl appendage to α,β-unsaturated systems located at C4 of the indole ring.184 Condensed cyclohexane rings are present in several ergot alkaloids such as lysergic acid which amido derivatives are widely known for their psychotropic activity. Nitro indole 160 obtained from the corresponding gramine is employed as pivotal intermediate for the preparation of racemic lysergic acid 163 (Scheme 62).185

151 with DIBALH results in the formation of the 4formylindole derivative which undergoes a tandem intramolecular nitroaldol reaction-dehydration to the tricyclic nitroalkene 152. The nitroalkene moiety can be totally reduced in situ by a two-step procedure involving double bond reduction with NaBH4 and nitro to amino conversion using metal zinc in aqueous HCl. In the Pd(0)-catalyzed intramolecular allylation of indolylnitro derivatives 154, cyclization occurs through the formation of a Pd-π-allylic cation complex intermediate and requires preliminary deprotonation to the corresponding nitronate anion (Scheme 60).181

Scheme 62. Synthetic Approach to Lysergic Acid 163

Scheme 60. Palladium-Catalyzed Intramolecular Allylation of Nitro Indoles 154

Simple indolylnitro compound 154a can be deprotonated using KF on alumina while nitroester 154b being much more easily enolizable than 154a does not require any added base to cyclize. A synthetic route to the alkaloid 6,7-secoagroclavine 159 employs an interesting Lewis acid promoted 1,3-shift of the 7131


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A reductive nitro to carbonyl conversion (Nef reaction) is carried out on the nitroethyl moiety leading to the Omethyloxime derivative 161.186 This compound contains a latent acrylate moiety embedded in the norbornene system which upon heating undergoes a tandem retro/imino Diels− Alder process leading to the installation of the cyclohexene unit in compound 162. From this intermediate, lysergic acid 163 can be obtained in few synthetic steps. Intramolecular 1,3dipolar cycloadditions can be suitably used for the stereocontrolled assembling of key intermediates in the synthesis of ergot alkaloids such as chanoclavine I 168. Functionalized nitro indole 164, obtained from the corresponding gramine, is converted into nitrile oxide 165 which spontaneously undergoes a [3 + 2] cycloaddition to tetracyclic derivative 166 (Scheme 63).187 The ring closure occurs with excellent

Scheme 64. Synthesis of Indolactam V 173

Scheme 63. Synthesis of Chanoclavine I by the [3 + 2] Cycloaddition Route

V based on nitro indole formation and starting from 5aminoindole is available but lacks of any diastereocontrol leading to an equimolar mixture of 173 and its epimer.191 6.2.2. Other Polycyclic Compounds. The total synthesis of structurally complex polycyclic compounds mainly isolated from plants or of marine origin is a great challenge that has involved many scientists all over the years. In several of these compounds the tryptamine backbone is more or less easily recognizable and therefore its utilization in convergent synthetic approaches has been obviously devised.192 The aspidospermine alkaloid aspidophytine 179 is a component of the extract of the leaves of Haplophyton cimicidum having insecticidal properties. The total synthesis of this alkaloid involves as a central step, reaction of tryptamine 174 with chiral dialdehyde 175 (Scheme 65).193 An amazing stereoselective cascade process including a preliminary formation of dihydropyridinium ion 176 followed by a double cyclization process leading to iminium ion 177 is operating. Reduction of the iminium ion by in situ reaction with NaBH3CN gives as stable intermediate 178 which is then converted into aspidophytine 179 after seven synthetic steps. The alkaloid psychotrimine 183 is active as anticancer drug and shows an interesting structural feature based on the presence of three indole rings in which two of them are tryptamines connected to a central pyrroloindoline framework through the indole nitrogen atom (Scheme 66).194 In the first enantioselective synthesis of this alkaloid, the FC reaction with nitroethylene is carried out on polycyclic indolyl derivative 180. The obtained nitro compound 181 is reduced and protected at the amino group before the introduction of a second tryptamine unit by Cu(I)-catalyzed coupling. In a recent synthetic approach, the tricyclic central core of psychotrimine is generated starting from tryptamine 184 (Scheme 67).195 Reaction of 2-iodoaniline 185 with NIS generates a reactive 2-iodophenylnitrenium ion which adds to

diastereoselectivity which unfortunately is not observed in the subsequent N-methylation-reduction reactions of the iminium moiety leading to compound 167. At any event, the latter intermediate can be employed for the synthesis of racemic chanoclavine I 168, while using a similar approach based on the nitrile oxide 1,3-dipolar cycloaddition another ergot alkaloid, namely paliclavine can be prepared.188 Indolactam V 173 is a protein kinase C modulator structurally related to other phorboids of the teleocidin family. For its preparation dinitro compound 110, obtained from the corresponding gramine derivative, is selectively reduced at the aromatic nitro group (Scheme 64).189 The amino acid moiety on the benzene ring is introduced by a reductive alkylation using 2-ketoacid 170 and then made to react with Nhydroxysuccinimide. The obtained activated ester 171 upon reduction of the nitro goup with Nickel-Raney undergoes to a spontaneous lactamization leading to tricyclic compound 172 albeit with modest diastereoselectivity. Epimerization under basic conditions (K2CO3, EtOH) allows equilibration of the cis isomer to the desired trans-172 which is further reduced to the amino alcohol and then N-methylated to racemic indolactam V 173. Structurally related derivatives such as 13-O-indolactam V can be obtained following the same general approach.190 An alternative synthetic strategy for the preparation of indolactam 7132


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Scheme 65. Synthesis of Aspidophytine 179

Scheme 67. Synthesis of the Anticancer Drug Psychotrimine by Baran et al.

amidoalkyne 188. Finally, a second tryptamine moiety is installed into intermediate 189 by Cu(I)-catalyzed reaction followed by carbamate reduction to afford psychotrimine 183. Starting from an intermediate structurally related to compound 187 the preparation of the indole containing macrocycles kapakahine B and F has been reported.195 A very efficient procedure for the asymmetric synthesis of the tetrahydropyrrolo-[2,3-b]indole moiety 193 featuring psychotrimine as well as many other alkaloids, involves bromocyclization of tryptamines 190 by DABCO-derived bromine salt 191 in the presence of chiral phosphoric acid 192 (Scheme 68).196 The bromocyclization occurs with high enantioselectivity on a large variety of substrates and the procedure can be applied to the synthesis of (−)-chimonanthine, a cyclotryptamine alkaloid of natural origin. To this goal, bromocyclized compound 194 is homodimerized under Co(I)-catalyzed conditions and then, after N-Boc deprotection, the obtained product is reductively N-methylated to the target alkaloid 195. Other important applications of the prepared bromocyclotryptamines 193 entail the stereospecific substitution of the bromide anion by allylmetals and azide anions as well as the FC reaction with electron-rich aromatic systems. A tandem intramolecular [4 + 2]/[3 + 2] cycloaddition reaction represents the crucial step in the preparation of the naturally occurring alkaloid vindoline 204 the half portion of the anticancer drug vinblastine (Scheme 69).197 The synthesis starts from tryptamine 196 which is converted into compound 197 upon activation with CDI and reaction with methyl oxalylhydrazide. A Paal−Knorr type reaction allows to install the oxadiazole appendage in compound 198, and a subsequent amidation of the tryptamine nitrogen atom using acid 199 leads to the polyfunctionalized derivative 200. Upon heating in 1,3,5-triisopropylbenzene at 230 °C the latter compound is converted into 203 exploiting a series of processes involving a preliminary inverse electron demand Diels−Alder reaction leading to intermediate 201. Upon loss of a nitrogen molecule intermediate 201 generates the 1,3-dipole 202 that finally undergoes to a cycloaddition reaction. The Z stereochemistry of the dienophilic portion in substrate 200 and the endo 1,3-dipolar cycloaddition are responsible for the high diastereoselectivity of the process which affords a single diastereoisomer of the polycyclic compound 203. At this

Scheme 66. First Synthesis of the Anticancer Drug Psychotrimine 183

tryptamine 184 leading to intermediate 186 which rapidly undergoes to a ring closure to afford stable pyrroloindoline 187. The upper tryptamine unit is then cleverly built up on the iodoaniline moiety exploiting a Pd(II)-catalyzed reaction with 7133


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Scheme 68. Enantioselective Bromocyclization of Tryptamines

Scheme 69. Synthesis of Vindoline 204

stage, resolution of the racemic mixture of compound 203 allows to obtain enough optically active material to prepare (−)-vindoline 204 as well as its (+)-enantiomer. Using the same core strategy, structurally related alkaloids such as (−)-aspidospermine and (+)-spegazzinine can be obtained starting from 1-benzyl-7-benzyloxytryptamine.198 Several members of the kopsane alkaloid family are endowed of a complex polycyclic structure as illustrated by 11-methoxykopsilongine 211 (Scheme 70).199 The synthetic strategy devised for its preparation employs as starting material tryptamine 205 which upon condensation and subsequent amidation with ketodiacid monoester 206 affords tetracyclic derivative 207. Chemoselective reduction of the lactam function over the ester group can be realized upon oxygen−sulfur exchange using Belleau’s reagent 208 followed by reductive desulfurization to indolylazepine 209. The latter compound suffers an azepine ring cleavage by phenylchloroformate leading to 210 in 47% isolated yield with a 33% recovery of starting material. The total synthesis of 11-methoxykopsilongine 211 requires seven further steps including diene formation, Diels−Alder reaction and other functional group transformations. Aspidosperma alkaloids are featured by a pentacyclic structure as represented by 3-oxovincadifformine ethyl ester 216 (Scheme 71).43 Tryptamine 212, obtained by total

reduction of the corresponding nitroalkene (c.f. Table 1, entry 9), is made to react with 4-formyl ester 213 thus generating the lactam derivative 214. Lewis acid-assisted intramolecular cyclization provides formation of tetracyclic derivative 215 which in few synthetic steps involving ring reopening, bond rearrangement and a Diels−Alder cyclization, affords alkaloid compound 216. Staurosporinone 220 is a polycyclic derivative of natural origin containing two indole rings and a lactam moiety (Scheme 72).200 As other members of its family, staurosporinone is known for its inhibitory activity toward protein kinase C. The bisindolyl core system is preliminarily generated by conjugate addition of the lithium enolate of methylindoleacetate 217 to 3-(2-nitro-1ethenyl) indole 20. The disappointing yield (10%) recorded for the formation of adduct 218 is probably the result of a mistake in designing the addition reaction. As a matter of fact, when generating the lithium enolate of ester 217, two equivalents of the base are correctly used to account for the presence of the acidic hydrogen on the nitrogen atom. However, the efficiency in the subsequent addition of lithium dianion of 217 to N7134


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Scheme 70. Synthetic Approach to the Alkaloid 11Methoxykopsilongine 211

Scheme 72. Synthesis of the Polycyclic Alkaloid Stauroporinone 220

β-carbolines display an interesting pharmacological profile and are known for their sedative, anxiolytic, antitumor and antimicrobial properties. Some isolated aspects in the chemistry of these alkaloids have been faced in the previous sections, where a general strategy to build the β-carboline skeleton starting from tryptamine or tryptophan precursors has been illustrated. The Pictet−Spengler condensation of tryptamines with aldehydes, or their dimethyl acetals, can be greatly accelerated by microwave irradiation (150 °C, 3−20 min). The same physical activation is also beneficial in the subsequent conversion of β-tetrahydrocarbolines into β-carbolines using palladium on carbon in ethanol.202 Lavendamycin 225 is an antitumor antibiotic of natural origin consisting of a β-carboline unit linked to a quinoline-5,8dione system (Scheme 73).203 The convergent synthesis devised for compound 225 consists in the preliminary condensation of β-methyltryptophane 221, obtained as mixture of diastereomers from gramine 139 (c.f. Scheme 56), with quinolinecarboxylic acid 222, followed by the intramolecular ring closure to the β-carboline ring 224. Differently from related procedures in which a separated dehydrogenative aromatization step is required to generate the carboline unit, in this instance a spontaneous oxidation to the fully conjugated polycyclic system occurs with direct formation of the second pyridine ring. The amino group and the dione system are inserted in a later stage of the process to afford lavendamycin 225. The Pictet−Spengler condensation of tryptophan derivatives 226, with 2-formylquinoline-5,8diones 227 can also be employed to prepare a series of lavendamicyn antitumor derivatives 228 (Scheme 74).204 This synthetic approach displays a high convergent character since the quinone fragments 227 used have the required functionalities already embedded and formation of the lavendamicyn analogues 228 are obtained in a single step. The marine alkaloid eudistalbin A 232 shows in vitro cytotoxic activity against the growth of KB human buccal carinoma cells. Its synthesis starts from 6-bromotryptamine 229

Scheme 71. Synthetic Approach to Aspidosperma Alkaloid 216

unprotected nitroalkene 20 is very likely jeopardized by the deprotonation at the nitrogen atom with consequent dramatic reduction of the electrophilic character of the nitroalkene system. Reduction and cyclization of compound 218 affords 3,4-bisindolyl lactam 219 which upon oxidation with DDQ leads to the formation of the target compound 220. 6.3. Synthesis of β-Carbolines

β-Carbolines are alkaloids of natural origin featured by a tricyclic structure and largely present in plants, insects, marine organisms, and mammalians. These derivatives show a broad spectrum of biological activity being able to intercalate DNA, interact with several enzymatic systems (topoisomerase, monoamineoxidase, etc.) and various receptors.201 In addition, 7135


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Scheme 73. Synthesis of Lavendamycin 225

Scheme 75. Synthesis of the Marine Alkaloid Eudistalbin A 232

to the corresponding tryptophan derivative 235 (Scheme 76).207 Scheme 76. Synthesis of the Benzodiazepine Receptor Antagonist 237

Scheme 74. Highly Convergent Synthesis of Lavendamicyn Analogues 228

Acidic cleavage of the acetal system in aminoester 235 directly affords lactone 236 albeit in modest yield. The Pictet− Spengler reaction on lactone 236 occurs in good yield (71% yield), but the final aromatization to β-carboline 237, carried out using elemental sulfur in DMSO, is a rather unsatisfactory process leading to the target product in only 11% yield. Carboline 237 represents the first example of a high-affinity antagonist of the benzodiazepine receptor possessing a stereogenic center. Similarly to β-carbolines, their tetrahydro precursors often show a significant biological activity and for their synthesis the same general strategy, excluding the final aromatization step, can be followed.208 Tetrahydrocarbolin-1ones 241 are active as protein kinase 2 (MK2) inhibitors and can be prepared from a common tryptophan derivative 239 readily obtained from 3-formylindole 238 (Scheme 77).209 The ring closure leading to the lactam system in compound 240 is

which is condensed with N-Boc-L-leucinal 230 to give tetrahydrocarboline 231 (Scheme 75).205 Aromatization to the β-carboline system is realized using DDQ as oxidizing agent while nitrogen deprotection finally generates the natural product 232. A related procedure is effective for the preparation of the marine alkaloid hyrtiosulawesine featured by an indolecarbonyl appendage at C1.206 β-Carbolines having stereocenters of definite configuration in their structure can be synthesized starting from gramines obtained by Mannich reaction of indoles with optically active aldehydes. Thus, gramine 233, prepared by reaction of indole with (R)-2,3-O-isopropylideneglyceraldehyde and isopropylamine, can be made to react with ethyl nitroacetate leading to adduct 234 which in turn is reduced 7136


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noline skeleton as illustrated for the synthesis of eudistomin K 250 (Scheme 79).213

Scheme 77. Synthesis of Protein Kinase 2 Inhibitors 241

Scheme 79. Synthesis of Eudistomin K 250

realized exploiting a one-pot process involving formation of the isocyanate by treatment with triphosgene and then cyclization with HBr in acetic acid. Carbolinone 240 acts as a central intermediate for the preparation of various derivatives 241 showing different inhibitory activities. Ketones are seldom used in Pictet−Spengler processes because of their reduced reactivity compared to aldehydes. Notwithstanding, isatins are particularly reactive toward tryptamines in condensation reactions.210 As an example 5chloroisatin 243 reacts with tryptamines 242 leading to spiro derivatives 244 (Scheme 78).211

Partial reduction of nitro indole 245 with Al(Hg) amalgam is effective in giving the corresponding hydroxylamine 246, which upon reaction with N-Boc-S-methylcysteinal 247 gives nitrone 248.214 The subsequent Pictet−Spengler cyclization is strongly affected by the reaction conditions so that at low temperature (−78 °C), in the presence of TFA, nitrone 248 is stereoselectively converted into tetrahydroisoquinoline derivative 249. Conversely, the same process carried out at room temperature affords as main product a tetracyclic derivative arising from attack of the azomethine carbon at the indole C3 followed by further ring closure involving the N-Boc amino group at C2 of the indole ring.215 At any event compound 249 is easily converted into eudistomin K 250 by further ring closure and nitrogen deprotection.216 Other members of the eudistomin family can be prepared starting from tryptamines exploiting the usual amidation/Pictet−Spengler ring closure sequence as in the case of eudistomidin A and eudistomidins G, H, and I.217,218 Nitrones obtained by reaction of Nhydroxytryptamine with various arylaldehydes can undergo an enantioselective ring closure to the corresponding chiral tetrahydrocarboline.219 However, this process requires a 2fold excess of a boron-containing Lewis acid acting as a chiral promoter and the values of ee recorded are rather modest. Indolobenzazecine derivatives belong to a novel class of dopamine receptor antagonists showing affinity for all dopamine receptors. The general synthetic strategy, as illustrated for the preparation of compound 255, involves a preliminary condensation of tryptamine 251 with bromoarylaldehyde 252 which results in the formation of pentacyclic derivative 253 (Scheme 80).220 The ten-membered ring is conveniently generated by ring enlargement obtained upon nitrogen methylation to the ammonium iodide 254 and its reduction with sodium in liquid ammonia. The presence of a chiral tolylsulfinyl stereodirecting group linked on the tryptamine nitrogen atom such as in compound 256 allows a diastereoselective Pictet−Spengler process in the reaction with different aliphatic aldehydes (Scheme 81).221 The observed diastereoselection is not particularly high, but the

Scheme 78. Synthesis of Spiro Derivatives 244

The reaction is featured by a surprisingly high distereoselectivity and each enantiomer, after resolution of the racemic mixture, has been tested in order to evaluate its antiplasmodial activity for the treatment of malaria. Partial reduction of 3-(2-nitroalkyl) indoles affords the corresponding hydroxylamine derivatives which can be profitably used in the reaction with aldehydes to produce nitrones. These compounds are well-known 1,3-dipoles, but are also reactive electrophiles that can be involved in intramolecular reactions with indoles.212 Several procedures aimed to the preparation of the antiviral marine alkaloids eudistomins employ the nitrone approach to build up the tetrahydroisoqui7137


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Scheme 80. Synthesis of Indolobenzazecine 255

Scheme 82. Enantioselective Synthesis of the Alkaloid (+)-Deplancheine 262

Scheme 81. Diastereoselective Pictet−Spengler Reaction on Chiral Sulfinylamine 256

The asymmetric organocatalyzed version of the Pictet− Spengler reaction can be achieved by reaction of tryptamines 263 with aldehydes in the presence of chiral thiourea 264 (Scheme 83).223 The catalytic cycle would involve a preliminary Scheme 83. Enantioselective Pictet−Spengler Reaction Catalyzed by Chiral Thiourea 265

major stereoisomer in compounds 257 can be easily recovered in pure form by a simple crystallization. After removal of the sulfinyl group by acid hydrolysis, the correspondding βtetrahydrocarbolines 258 are finally obtained in good yield and in enantiopure form. The enantioselective reduction of β-dihydrocarbolines obtained by Pictet−Spengler reaction of N-acyltryptamines represents a profitable way to prepare optically active βtetrahydrocarbolines. This process is nicely illustrated for the synthesis of the naturally occurring alkaloid (+)-deplancheine starting from tryptamine derivative 259 obtained by reaction of tryptamine with glutaric anhydride and subsequent methyl esterification (Scheme 82).222 The intramolecular Pictet− Spengler condensation readily provides the corresponding βdihydrocarboline 260 which is reduced using triethylsilane in the presence of the host/guest complex between β-cyclodextrin (β-CD) and PdCl2. The enantioselective reduction is followed by a spontaneous lactamization ultimately leading to tetracyclic derivative 261 with satisfactory enantioselection (ee 90%). The target compound 262 is then obtained after few synthetic steps including α-ethylenation and selective lactam reduction. A major drawback in the utilization of the β-CD/PdCl2/Et3SiH system concerns the high Pd(II) catalyst charge (30 mol %) and the large excess (4 equivs) of silane reducing agent required for the reduction.

imine formation between the tryptamine and the aldehyde. Upon protonation of the imine by the acid additive, a tight ion pair is then generated between the iminium cation and the benzoate anion which is linked to the thiourea catalyst through hydrogen bonding. This catalytic system provides a notable enantiofacial discrimination in the subsequent electrophilic substitution of the iminium ion to the indole ring as evidenced by the high ee values recorded for the final tetrahydrocarboline 265. In a preliminary version of the same process the iminium ion was generated by acetylation of the preformed imine at low temperature in the presence of a chiral thiourea catalyst structurally related to 264 and applied to the enantioselective total synthesis of the alkaloid (+)-yohimbine.224 The acid additive required for the Pictet−Spengler reaction can also be embedded in the side arm of the chiral thiourea catalyst thus providing an enhanced catalytic effect in the enantioselective synthesis of tetrahydrocarbolines.225 The asymmetric Pictet−Spengler reaction has been successfully employed for the total synthesis of the alkaloid (−)-mitragynine 272, a plant extract with powerful analgesic properties (Scheme 84).226 7138


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Scheme 85. Enantioselective Synthesis of β-Carboline Derivatives 277 by a Tandem Process

Scheme 84. Enantioselective Synthesis of the Plant Alkaloid (−)-Mitragynine 272

The enantioselective reaction is carried out on functionalized tryptamine 268 obtained by alkylation of tryptamine 266 with allyl bromide 267. The monoalkylation is ensured by preliminary nosylation of the primary amine and after alkylation with bromide 267 the N-nosyl group is removed by reaction with thiophenol under basic conditions. The previously devised thiourea catalyst 264 is poorly effective in the reaction of 268 with aldehyde 269 (ee 53%) while cinchona derived thiourea 270 gives satisfactory results even in the absence of any acid additive. The obtained β-tetrahydrocarboline 271 can be easily converted into (−)-mitragynine 272 in few synthetic steps. A tandem conjugate addition/enantioselective Pictet−Spengler cyclization is evidenced the reaction of tryptamine derivative 273 with enones (Scheme 85).227 The base employed for the Michael addition leading to intermediate 275 is a polystyrene bound diazaphosphorine 274 which coexists in the reaction mixture with chiral phosphoric acid 34 (Scheme 10) required for the subsequent enantioselective cyclization. The reduced size of the resin’s pores prevents from any reaction between the basic sites of 274 and the bulky phosphoric acid avoiding any catalyst quenching. The Pictet−Spengler reaction on intermediate 275 entails the preliminary formation of a highly reactive N-acyliminium species 276 by reaction of the carbonyl group with the amido group and is followed by a second ring closure involving the indole ring. The independent action of the catalytic couple is really effective in promoting the tandem process leading to the synthesis of the tetracyclic carboline derivative 277, albeit the ee values recorded are generally modest. A related example is reported in Scheme 86 in which the N-acyliminium ion required for the Pictet−Spengler cyclization is formed in a cascade process starting with the reaction of tryptamine 263 with butenolide 278.228 The intermediate 1,4-dicarbonyl derivative 279 undergoes to an intramolecular acid catalyzed condensation leading to the

Scheme 86. Enantioselective Cascade Process for the Synthesis of Tetrahydrocarboline Derivative 281

cyclic N-acyliminium ion 280. The final step is the enantioselective electrophilic substitution into the indole ring catalyzed by the chiral phosphoric acid 34 affording tetracyclic indole derivatives 281. Since butenolides 278 can be obtained by gold(I)-catalyzed ring closure of 3-alkynoic acids, a one-pot synthesis of compounds 281 starting from tryptamines and 7139


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these unsaturated acid derivatives can be also envisaged.229 Nacyliminium ion intermediates 280 can also be prepared by partial reduction of the corresponding cyclic imides and subsequent elimination of water under acidic conditions.230 This procedure has been used for the synthesis of (+)-harmicine exploiting a ring closure under chiral thiourea catalysis.231 A very general procedure widely used to generate Nacyliminium ion intermediates involves a Lewis acid promoted elimination of alcohols from the corresponding N,O-acetals.232 This strategy has been applied to the total synthesis of the antianoxia agent vincantril 286 (Scheme 87).233

Scheme 88. Synthesis of the Alkaloid Borrerine 291

Scheme 87. Synthesis of Vincantril 286

potentially useful drugs for the treatment of obesity, Alzheimer’s disease and schizophrenia (Scheme 89).237 Tryptamine 292 is involved in a Ugi-azide process by reaction with an aldehyde, an isonitrile and trimethylsilyl azide. The obtained tetrazolyl intermediate is then converted into xantate 293 by amidation with chloroacetyl chloride followed by chlorine substitution with potassium ethylxantogenate. The azepinone ring is built-up by a radical intramolecular ring Scheme 89. Synthesis of Tetrazolylazepinoindolones 297

Nosylated tryptamine derivative 282 undergoes to a Pdcatalyzed amidation with benzyloxyallene 283 to afford the corresponding N,O-acetal 284. The latter compound is then treated with a catalytic amount of tin(II) triflate in order to generate a vinylogous N-acyliminium ion which regioselectively cyclizes to the β-tetrahydrocarboline 285. Installation of the fourth condensed cycle which completes the synthesis of vincantril 286 can be realized exploiting a cross-metathesis reaction with methyl acrylate followed by a double bond reduction and a final amidation reaction. Finally, N-acyliminium ions can be formed upon double bond isomerization of N-acylN-allyltryptamines catalyzed by RuHCl(PPh 3 ) 3 and (PhO)2PO2H. As usual, a rapid ring closure follows leading to N-acyl-β-tetrahydrocarbolines.234 An interesting approach to β-tetrahydrocarbolines, other than the common Pictet− Spengler condensation, entails a procedure already proved effective in the preparation of ergot alkaloids. It consists in the intramolecular nucleophilic substitution of the primary amine, obtained by the nitro reduction, with a suitable group preinstalled at C2 of the indole ring and is properly illustrated for the synthesis of the alkaloid borrerine 291, a plant roots growth factor (Scheme 88).235,236 2-Bromo-3-formylindole 287, readily obtained from 2oxindole, is sequentially subjected to a Stille coupling with tin derivative 288 and a nitroaldol-reduction process to afford disubstituted nitro indole 289. Upon reduction of the nitro group with zinc powder under acidic conditions a cyclization involving a SN2′ process occurs generating tetrahydrocarboline 290 which is selectively N-methylated to afford borrerine 291. The tetrazole unit and the azepinoindol-4-one framework are known pharmacophoric entities commonly found in many compounds interacting with the 5-hydroxytryptamine 6 receptor (5-Ht6). For this reason, compounds 297 are 7140


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closure in which dilauryl peroxide is used as radical initiator. The electrophilic radical 294 undergoes to a favored 7-endotrig closure with the indole ring resulting in the formation of benzylic radical 295 which is likely oxidized to carbocation 296 by the lauryl radical. The final tetrazolylazepinoindolone 297 is obtained by proton removal from carbocation 296. Recently, various synthetic plans have been devised for the preparation of trigonoliimines, a family of natural alkaloids extracts from plants displaying promising anti-HIV activity. Particularly, trigonoliimine C 301 can be obtained exploiting a convergent synthesis involving the Au(I)-catalyzed reaction of N-phthaloyltryptamine 298 with nitrone 299, easily prepared from commercially available materials in two steps (Scheme 90).238

Scheme 91. Stille Cross-Coupling Approach to the Synthesis of Trigonoliimine C 301

Scheme 90. Nitrone Approach to the Synthesis of Trigonoliimine C 301

curtailed by the poor regioselectivity (2.2:1) observed in the oxidative step carried out using an optically active oxaziridine. 6.4. Synthesis of Other Tryptamine Derivatives

Reduction of the nitro group in 3-(2-nitroalkyl) indoles is the most straighforward way to prepare tryptamines. As previously stated, when 3-formyl indoles are involved in a nitroaldol process, the corresponding indolyl nitroalkene is directly produced and a subsequent total reduction to the tryptamine derivative is possible.241 Using this strategy, several tryptamines and their N-acyl derivatives particularly active on serotonine and melatonine receptors and with antioxidant or antibiotic properties can be efficiently prepared.242−245 Protein inhibitors including the tryptamine unit can also be prepared following this synthetic route.246 Interestingly, N-hydroxylamines obtained by partial reduction of 3-(2-nitroalkyl) indole derivatives with Na(Hg) amalgam, still retain a notable biological activity providing that the free hydroxy group is not methylated.247 A selective reduction of the pyrrole ring over the nitro group is possible and provides an interesting entry to indolines which upon further reduction afford dihydro analogues of tryptamines. This chemoselective reaction can be carried out with NaBH3CN in acetic acid on nitro indole 307 leading to indoline 308 (Scheme 92).248 Unexpectedly, the subsequent reduction of the nitro group to the dihydrotryptamine 308 is a poor yielding process compared to those usually occurring on nitro indole derivatives. At any event indoline compounds of type 309 are powerful cholinesterase inhibitors that can be used for the treatment of Alzheimer’s disease. Structural modifications concerning tryptamines may involve the indole core, the amino group or both of them. Rotationally restricted analogues of 5-hydroxytryptamines with potential serotonergic activity, can be prepared from propargyl derivative 310 which through a cascade Claisen rearrangements affords tricyclic derivative 311 (Scheme 93).249 Catalytic hydrogenation of nitro indole 311 to tryptamine 312 also provides reduction of the dihydropyran moiety and the final reductive amination with ketones 313 finally affords 5-

Cleavage of both N-protecting groups on pseudodimer 300 is followed by intramolecular imine formation and nitrogen formylation by N-formylbenzotriazole (NFB) and finally leads to the preparation of the natural alkaloid 301. A different approach for the pseudodimer formation, en route to the synthesis of same alkaloid, is based on a Stille cross-coupling between bromotryptamine 302 and stannane 303 (Scheme 91).239 The first crucial step in this synthesis is the regioselective oxidation of dimer 304 at the proper indole ring which can be suitably performed using phenyliodonium trifluoroacetate (regioisomeric ratio 13:1). In the second crucial step the correct molecular skeleton is cleverly obtained by a Wagner− Meerwein [1,2]-shift on compound 305 which also allows to install the required carbonyl group in intermediate 306. Trigonoliimine 301 is finally obtained by selective cleavage of the phthaloyl group and intramolecular imine formation. A related strategy has been used for the enantioselective synthesis of the same alkaloid as well as of trigonoliimines A and B.240 In the latter approach, the efficiency of the overall process is 7141


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The yield of the obtained compounds is rather poor, however compound 316 (n = 8) is particularly effective in activating two high-affinity G-protein coupled receptors (MT1 and MT2), localized in the central nervous system and in peripheral tissues. The search for more potent analogues of indolmycin, a selective competitive inhibitor of the bacterial tryptophanyl enzyme, involved the substitution of the α-methyl group with the more polar aminomethyl acetate salt. The preparation of this compound involves a preliminary reaction of nitroalkene 317 with lithium enolate 318 (Scheme 95).251 Indole deprotection,

Scheme 92. Synthesis of Indoline 309 by Partial Reduction of the Indole Ring

Scheme 95. Synthesis of Indolmycin Analogue 320

Scheme 93. Synthesis of Rotationally Restricted Analogues of Hydroxytryptamines

transamination at the oxazolone ring and reduction of nitro group are the three synthetic steps required to obtain the indolmicyn analogue 320 from compound 319. Antinociceptive agents targeting the adenosine receptor are known for their sedative and antispasmodic activity. Adenosine analogues embedding known pharmacophores such as the indole ring can be obtained, as illustrated for the preparation of compound 323, by reaction of tryptamine 321 with adenosine derivative 322 (Scheme 96).40 Indole containing adenosine 323, among several related analogues, is the more effective in binding to A1 and A2 adenosine receptors in a specific manner. Indole analogues of labetalol, a known antihypertensive drug, can be prepared by reaction of suitable tryptamine derivatives 325 with epoxides 326 (Scheme 97).252,253 The required

HT2 receptor agonists 314. The same rearrangements sequence can also be carried out directly on N-Cbz-tryptamine precursors with variable results.250 A series of melatonin dimers 316 can be generated by coupling tryptamine derivative 315 with α,ω-diols through a diester functionality (Scheme 94).39

Scheme 96. Synthesis of the Antinociceptive Agent 323 Scheme 94. Synthesis of Melatonin Dimers 316

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AUTHOR INFORMATION

Scheme 97. Synthesis of Labetalol Analogues 327

Corresponding Author

*Fax: +39 0737 402297. E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies

tryptamines 325 are obtained by reaction of gramines 324 with excess of 2-nitropropane in the presence of KOH followed by reduction of the intermediate nitro indoles with hydrazine hydrate/Nickel-Raney. The regioselective ring-opening of epoxides 326 to the final amino alcohol derivatives 327 is efficiently carried out under solvent-free conditions, although ethanol at reflux can also be be used as a solvent. Other available synthetic approaches to related biologically active amino alcohol derivatives are based on the amidation of tryptamines with 2-hydroxy carboxylic acids and subsequent reduction.254

Stefano Lancianesi was born in 1986 and received his Laurea degree cum laude in 2011 at the University of Camerino. During the same year he started his Ph.D. under the supervision of Professor Marino Petrini and he is currently attending his third year. His research interests include the study of new methodologies for the synthesis and functionalization of heteroaromatic compounds and their application

7. CONCLUSION Different synthetic approaches are currently available for the preparation of 3-(2-nitroalkyl) indoles starting from various functionalized indole derivatives. The FC reaction of indoles with nitroalkenes is still the most exploited process employed to generate such nitro indole compounds. A plethora of catalysts and promoters are available to carry out this reaction under heterogeneous as well as homogeneous conditions. The asymmetric version of the FC reaction has been also developed and involves the utilization of chiral organometallic catalysts and more recently purely organic catalysts. Beside this approach, 3-substituted indole derivatives bearing a suitable leaving group at benzylic position can be employed in a process involving an elimination reaction followed by the addition of a nitronate anion, generated under basic conditions, to the corresponding indolenine intermediate. The most popular derivatives of this kind are gramines but the recently discovered sulfonyl indoles are gaining increasing attention because of their superior reactivity which makes them amenable to be used in asymmetric synthesis. Knoevenagel-type reactions involving 3formylindoles and nitroalkanes can also be applied to introduce the nitroalkenyl moiety into the indole ring. This strategy is less common than those previously described, even though it seems rather versatile because of the possible functionalization of the indolyl nitroalkene system through an alkylative conjugate addition. All these synthetic opportunities offered for the preparation of 3-(2-nitroalkyl) indoles can be used to prepare tryptamines and tryptophan derivatives which are pivotal intermediates for the preparation of indole-containing biologically active compounds.

in the synthesis of potentially bioactive targets.

Alessandro Palmieri began his studies in Chemistry in 1997 at the University of Camerino, where he received his Laurea degree cum laude in 2002. In May 2007 he received a Ph.D. degree in Chemical Sciences. For three years (2007−2010), Dr. Palmieri held a postdoctoral fellowship in the same laboratory and, since November 2010, he is assistant professor at the University of Camerino. His research interests concern the use of nitro compounds in new synthetic methodologies, the synthesis of heterocyclic compounds, the exploitation of solid supported reagents, the development of new sustainable processes, and the investigation of new flow chemical protocols. 7143


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MOM MS NBS NFB NIS Ni−Ra NMO Ns PCL Phth Piv PMP Red-Al SEM TES Tf TFA TFAA THF THP TIPB TMG TMS Tol Ts

Marino Petrini obtained the Laurea degree in Chemistry in 1980 (University of Camerino). In 1983 he became Research Associate at the University of Camerino and during the period 1987−88 he has been visiting scientist at the University of Montreal (Prof. S. Hanessian). In 1992 he was appointed Associate Professor and then Full Professor in Organic Chemistry at the University of Camerino. Currently he is Dean of the School of Science and Technology at the University of Camerino. His research interests mainly deal with the following topics: synthesis and reactivity of aliphatic and aromatic nitrocompounds; synthesis of natural products featured of enhanced biological activity; synthesis and reactivity of imino derivatives.

methoxymethyl molecular sieves N-bromosuccinimide N-formylbenzotriazole N-iodosuccinimide nickel Raney N-methylmorpholine 4-nitrobenzenesulfonyl (nosyl) Pseudomonas cepacia lipase phthaloyl t-butylcarbonyl (pivaloyl) p-methoxyphenyl sodium bis(2-methoxyethoxy)aluminumhydride 2-(trimethylsilyl) ethoxymethyl triethylsilyl trifluoromethanesulfonyl trifluoroacetic acid trifluoroacetic anhydride tetrahydrofuran tetrahydropyranyl 1,3,5-triisopropylbenzene 1,1,3,3-tetramethylguanidine trimethylsilyl 4-methylphenyl (tolyl) 4-toluenesulfonyl (tosyl)

REFERENCES

ACKNOWLEDGMENTS The authors warmly thank all co-workers who over all these last years have contributed to the development of the nitro indole chemistry in our lab. Special thanks are due to our colleague Prof. Roberto Ballini for helpful discussions. Financial support has been provided by the University of Camerino and MIUR (FIRB National Project “Metodologie di nuova generazione nella formazione di legami carbonio-carbonio e carbonioeteroatomo in condizioni eco-sostenibili”).

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ABBREVIATIONS Ac acetyl Bn benzyl Boc t-butoxycarbonyl Cbz benzyloxycarbonyl β-CD β-cyclodextrin CDI 1,1-carbonyldiimidazole CSA 10-camphorsulfonic acid DABCO 1,4-diazabicyclo[2.2.2]octane DBU 1,5-diazabicyclo[5.4.0]undec-5-ene DCC dicyclohexylcarbodiimide DCE 1,2-dichloroethane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DLP dilauryl peroxide DMA N,N-dimethylacetamide dr diastereomeric ratio dppe 1,2-bis(diphenylphosphino)ethane dppp 1,3- bis(diphenylphosphino)propane DIBALH diisobutylaluminum hydride DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EDCI 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide ee enantiomeric excess HFIP hexafluoroisopropanol LDA lithium diisopropylamide 7144


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