Cite this: RSC Advances, 2013, 3, 19135 Organocatalyzed coupling of indoles with dehydroalanine esters: synthesis of bis(indolyl)propanoates and indolacrylates Received 12th June 2013, Accepted 8th August 2013 DOI: 10.1039/c3ra42922a www.rsc.org/advances Simone Lucarini, Michele Mari, Giovanni Piersanti* and Gilberto Spadoni Functionalized and substituted bis(indolyl)alkanes were synthesized from indoles and dehydroalanine esters in the presence of catalytic amounts of Brønsted acid. When 2- or 4-bulky substituted indoles were used, unusual elimination occurred to yield interesting indolyl acrylates. Introduction The bis(indolyl)methane scaffold is frequently found in natural products isolated from terrestrial and marine sources 1 and the range of biological activities possessed by individual members of this series includes anticancer (against several common cancer cell lines), 2 antibacterial, 3 anti-oxidant, 4 and anti-inflammatory activities 5 as well as coronary dilatory and genotoxic properties. 6 Some of these natural products, for example vibrindole A, have been used to treat fibromyalgia, chronic fatigue, and irritable bowel syndrome. 7 Recently, bis(indolyl)maleimides and compounds with a bis(indolyl)- methane moiety linked with hydroxamic acids have been identified as NAD + -dependent histone deacetylase (HDAC) inhibitors (Fig. 1). 8 In addition, some substituted bis(indolyl) alkane derivatives have been investigated as contrast agents in diagnostic applications for the identification and visualization of tissues and organs, more specifically those involved in necrosis as well as myocardial and cerebral infarction. 9 Synthetic bis(indolyl)methanes are not only useful in biologi- cal applications, but they also have been used in materials chemistry 10 as dyes 11 (the oxidized form) as well as colori- metric sensors. 12 Considering their importance, there has been growing interest in the development of efficient synthetic protocols for the preparation of this type of molecule. The most widely used approach to synthesize symmetrical bis(indolyl)alkane derivatives involves the condensation of two equivalents of an (un)substituted indole with one equivalent of an aldehyde or ketone in the presence of protic or Lewis acids. 13 Echavarren 14 and others 15 have recently published an interesting metal-catalyzed synthesis of bis(indolyl)alkane derivatives by reacting alkynes and indoles (Scheme 1). Although these methods allow the synthesis of bis(indolyl)alk- ane derivatives in good yields, they are limited in terms of the scope of substrate allowed. In particular, the electrophilic partners employed (alkynes and carbonyl compounds) do not permit the introduction of useful functional groups for possible derivatization. Thus, we became interested in devel- oping an alternative and efficient catalytic synthetic protocol to generate highly functionalized a,a-di-substituted bis(indo- lyl)alkanes that can also be used as suitable building blocks for further elaboration or derivatization. N-acyl-dehydroaminoesters are rather unique structures containing both an acylamino and an ester group on the same carbon of the double bond. They can promote nucleophilic attack at the a- and b-positions of the double bond, affording easy and practical access to unnatural aminoacids. The synthetic utility of dehydroamino acids is extensive, and new chemo-, regio-, stereo- and positionally selective transformations have been developed over the past 10 years. 16 We have recently reported the regioselective hydro- indolization of methyl N-acetamido acrylate, in which a single molecule of indole is added to the internal carbon of the double bond via N-acyliminium intermediates. 17 During the optimization of this reaction, we also observed the formation of methyl 2,2-bis(1H-indol-3-yl)propanoate. The amounts of Department of Biomolecular Sciences, University of Urbino, Piazza Rinascimento 6, 61029 Urbino (PU), Italy. E-mail: [email protected]; Fax: +390722303313; Tel: +390722303320 Fig. 1 Examples of interesting bis(indolyl)alkanes. RSC Advances PAPER This journal is ß The Royal Society of Chemistry 2013 RSC Adv., 2013, 3, 19135–19143 | 19135 Published on 08 August 2013. Downloaded by Portland State University on 05/10/2013 08:38:18. View Article Online View Journal | View Issue
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Cite this: RSC Advances, 2013, 3,19135
Organocatalyzed coupling of indoles withdehydroalanine esters: synthesis ofbis(indolyl)propanoates and indolacrylates
Received 12th June 2013,Accepted 8th August 2013
DOI: 10.1039/c3ra42922a
www.rsc.org/advances
Simone Lucarini, Michele Mari, Giovanni Piersanti* and Gilberto Spadoni
Functionalized and substituted bis(indolyl)alkanes were synthesized from indoles and dehydroalanine
esters in the presence of catalytic amounts of Brønsted acid. When 2- or 4-bulky substituted indoles were
used, unusual elimination occurred to yield interesting indolyl acrylates.
Introduction
The bis(indolyl)methane scaffold is frequently found innatural products isolated from terrestrial and marine sources1
and the range of biological activities possessed by individualmembers of this series includes anticancer (against severalcommon cancer cell lines),2 antibacterial,3 anti-oxidant,4 andanti-inflammatory activities5 as well as coronary dilatory andgenotoxic properties.6 Some of these natural products, forexample vibrindole A, have been used to treat fibromyalgia,chronic fatigue, and irritable bowel syndrome.7 Recently,bis(indolyl)maleimides and compounds with a bis(indolyl)-methane moiety linked with hydroxamic acids have beenidentified as NAD+-dependent histone deacetylase (HDAC)inhibitors (Fig. 1).8 In addition, some substituted bis(indolyl)alkane derivatives have been investigated as contrast agents indiagnostic applications for the identification and visualizationof tissues and organs, more specifically those involved innecrosis as well as myocardial and cerebral infarction.9
Synthetic bis(indolyl)methanes are not only useful in biologi-cal applications, but they also have been used in materialschemistry10 as dyes11 (the oxidized form) as well as colori-metric sensors.12 Considering their importance, there hasbeen growing interest in the development of efficient syntheticprotocols for the preparation of this type of molecule.
The most widely used approach to synthesize symmetricalbis(indolyl)alkane derivatives involves the condensation of twoequivalents of an (un)substituted indole with one equivalent ofan aldehyde or ketone in the presence of protic or Lewisacids.13 Echavarren14 and others15 have recently published aninteresting metal-catalyzed synthesis of bis(indolyl)alkanederivatives by reacting alkynes and indoles (Scheme 1).Although these methods allow the synthesis of bis(indolyl)alk-ane derivatives in good yields, they are limited in terms of the
scope of substrate allowed. In particular, the electrophilicpartners employed (alkynes and carbonyl compounds) do notpermit the introduction of useful functional groups forpossible derivatization. Thus, we became interested in devel-oping an alternative and efficient catalytic synthetic protocolto generate highly functionalized a,a-di-substituted bis(indo-lyl)alkanes that can also be used as suitable building blocks forfurther elaboration or derivatization.
N-acyl-dehydroaminoesters are rather unique structurescontaining both an acylamino and an ester group on thesame carbon of the double bond. They can promotenucleophilic attack at the a- and b-positions of the doublebond, affording easy and practical access to unnaturalaminoacids. The synthetic utility of dehydroamino acids isextensive, and new chemo-, regio-, stereo- and positionallyselective transformations have been developed over the past 10years.16 We have recently reported the regioselective hydro-indolization of methyl N-acetamido acrylate, in which a singlemolecule of indole is added to the internal carbon of thedouble bond via N-acyliminium intermediates.17 During theoptimization of this reaction, we also observed the formationof methyl 2,2-bis(1H-indol-3-yl)propanoate. The amounts of
Department of Biomolecular Sciences, University of Urbino, Piazza Rinascimento 6,
this product depended on the experimental conditions andacid catalyst used. Based on this observation, in this paper, wereport an efficient and organocatalyzed synthesis of severalbis(indolyl)alkane derivatives with very broad structuraldiversity and versatility via a cascade aza-Friedel–Craftsalkylation reaction of a suitable indole with N-acetyl a,b-dide-hydroalanine methyl ester (1), followed by acetamido elimina-tion and subsequent addition of the second indole.18
Results and discussion
We first examined the reaction using a 2 : 1 molar ratio ofindole (2a) and 1 along with a catalytic amount of variousBrønsted acids in refluxing toluene (Table 1).
To our great delight, most of the tested acids catalyzed thetransformation smoothly. As shown in Table 1, p-toluenesul-fonic acid (PTSA) was the best catalyst to provide the desiredproduct 3a (93% yield, entry 1). Prolonging the reaction timeslightly decreased the yield of 3a, probably due to instability ofthe product at high temperature under acidic conditions.19
The efficacy of some other acid catalysts, such as L-camphorsulfonic acid (L-CSA), 2,4-(NO2)2-C6H3SO3H, triflicacid, trifluoroacetic acid (TFA), HBF4 and diphenylphosphoricacid (DPP) in bis(indolyl)methane derivative formation isoutlined in entries 2–7, Table 1. Trichloroacetic acid andtrifluoromethansulfonamide were ineffective as catalysts ofthis reaction, likely due to their relatively weak acidities(entries 8 and 9, Table 1). Using 10 mol% PTSA as the catalyst,various solvents were then screened to further optimize thereaction conditions, (Table 1). Among these tested solvents,only toluene and benzene afforded the maximum yield of 3a(93% yield, entries 1 and 10, Table 1). Reactions in THF,CHCl3, CH3CN, and dioxane afforded relatively lower yields(entries 11–14, Table 1). Furthermore, use of Et2O, CCl4,ethanol, or water as the solvent caused the reaction to proceedmuch less efficiently (entries 15–18 Table 1). We also examinedthe loadings of catalyst. With 5 mol% of the catalyst intoluene, the reaction proceeded smoothly but with a slightlyincrease of the reaction time (entry 19, Table 1).20
Under the optimal reaction conditions (5 mol% PTSA as thecatalyst, 2 equiv. indole, toluene, reflux), various substitutedindoles were investigated to test the generality of the reaction(Table 2). In general, most of the tested substrates weretransformed to the corresponding substituted bis(indolyl)pro-panoates 3 in good to excellent yields, emphasizing the wideapplicability and usefulness of this procedure. This methodwas effective for indoles that are substituted in position 5, 6, or7 with either an electron-donating or -withdrawing substitu-ent, although the reactions with electron donating-substitutedindoles required longer reaction times and provided loweryields than those of their electron-deficient counterparts(entries 3–14, Table 2), as well as for N-methyl indole (entry2, Table 2). It should be noted that various halogens and etherswere tolerated in different positions, and the products were allobtained in good to excellent yields (entries 4–7, 12, and 14,Table 2). Remarkably, the proposed bisindolization alsotolerated the presence of a boronate ester in the indole ring,offering unique, site-specific handles that can be utilized incross-coupling methodology for further functionalization ofthe bisindole moiety (entry 11, Table 2).
Encouraged by these results, we applied the reactionconditions to more challenging sterically hindered substrates,such as 2- and 4-substituted indoles.21 However, formation ofthe desired bisindole derivative seemed to be adverselyaffected by steric hindrance of the C-2 and C-4 indole
substituents, and the reaction evolved in another way. In fact,when the reaction was performed using 2-methylindole thecorresponding bis(indolyl)alkane derivative 3o was formed in60% yield together with a 40% yield of methyl 2-methyl-indol-3-yl-acrylate 4o. Interestingly, when a bulky group such asphenyl (entry 17, Table 2) was introduced to the C-2 position ofthe indole, or other substituents such as Br or Bpin (entries 18and 19 respectively, Table 2) were introduced to the C4-indoleposition, only the corresponding unsaturated products 4 wereisolated in good yields. Even by inserting a strong electron-withdrawing substituent at C2, which can temper thenucleophilicity at C3 and increase the acidity of the N–Hbond, the formation of 3-vinylindole derivatives was notprecluded.22
Unsaturated esters of type 4 are rather uncommon, butaccording to their structural features they are possiblecandidates for conjugate additions with external nucleophilesor, after hydrogenation, they can afford pharmacologicallyinteresting methyl-3-indolylacetic acid derivatives bearing astereogenic center alpha to the C-3 indole position;23 they canalso be used as diene equivalents for the synthesis ofpolyfunctional indole derivatives.24
This methodology is also compatible with pyrrole nucleo-philes. For example, under the optimized reaction conditions,pyrrole provided the expected bis(pyrrol-2-yl)methane deriva-tive 5 in good yields (Scheme 2). Importantly, we did not detect
any di- or polysubstituted products. Furan and thiophene werenot suitable nucleophiles, as their reactions resulted in eitherdecomposition or no reaction, respectively.
Although rationalization of the catalytic system is compli-cated at the moment by the presence of numerous steps, acrucial role of the acid may be envisaged when considering thelikely formation of cationic alkylideneindoleninium25 aftertautomerization of N-acetylamidoacrylate (step A), the indoleaza-Friedel–Crafts reaction (step B) and loss of the amideleaving group (step C) (Fig. 2). Protonation of this vinylogousimino derivative by the sulfonic group of the catalyst wouldstrongly activate the system toward indole nucleophilic attack,resembling iminium ion activation. When the indole isparticularly sterically demanding close to the nucleophilicC3-center, an easier beta elimination is supposed to occur togive the alkenylated products 4o–s. However, formation of the
Table 2 PTSA-catalyzed reactions of indoles with N-acetyldehydroalanine methyl ester
Entry Comp. R1 R2 R3 Time (h)
Product (yield%)a
3 4
1 a H H H 2.5 93 —2 b CH3 H H 20 72 —3 c H H 5-CH3 3 71 —4 d H H 5-OCH3 5 40 —5 e H H 5-F 3 96 —6 f H H 5-Cl 3 83 —7 g H H 5-Br 4 98 —8 h H H 5-CN 2 68 —9 i H H 5-COOCH3 5 83 —10 j H H 5-NO2 4 89 —11 k H H 5-Bpin 2 51 —12 l H H 6-Br 2 88 —13 m H H 7-CH3 3 80 —14 n H H 7-Br 2 47 —15 o H CH3 H 2 60 4016 p H COOCH3 H 20 — 4617 q H Ph H 1 — 9018 r H H 4-Br 2 — 4519 s H H 4-Bpin 6 — 67
a Isolated yields.
Scheme 2 Reaction of N-Methylpyrrole with dehydroalanine esters.
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carbocation, which would preserve the aromaticity of theindolic core, and its involvement in the C–C bond-formingevent or in the double bond formation may also be envisaged.The possible involvement of vinylindoles 4 as intermediates inthe formation of bis-indole derivatives 3 has been investigatedand found unlikely. No bisindole derivatives (trace amounts)were isolated by reacting indole with the 3-vinylindolederivative 4q in the presence of a catalytic amount of PTSA.
With functionalized bis(indolyl)methane and indol-3-yl-acrylate in hand, selective functionalization of the ester orthe olefinic moiety could be successfully performed(Scheme 3). Thus, the hydrolysis and reduction of 3a furnishedacid 726 and alcohol 6 in almost quantitative yield. Theunusual vinyl indole 4q was treated with indole under aFriedel–Crafts Michael-type addition reaction16g to give thebis(indolyl)ethane derivative (¡)-9 in moderate yields.Interestingly, simple catalytic hydrogenation of 4q affordedthe racemic a-methyl indolacetic ester (¡)-8 in high yield.Studies towards enantioselective Rh- or Ir-catalyzed reductionsare in progress.
Conclusion
In summary, we have developed a simple and highly efficientapproach to synthesize pharmaceutically interesting 3,3-bis(indolyl)propanoates through PTSA-catalyzed Markovnikovaddition and cleavage of C–N bonds of indoles with N-acetyldehydroaminoesters. The advantages of this method overprevious reports include its simplicity, clean reactions, highyields, readily available starting materials, short reactiontimes, and inexpensive catalyst. When a bulky substituent isintroduced at C-2 or C-4 indole position, the attack of thesecond indole molecule is hampered and unusual methylindol-3-yl-acrylates are surprisingly formed via an unprece-dented elimination reaction. This novel methodology not onlyprovides a valid way to construct novel functionalizedbisindoles and 3-vinylindole derivatives but also opens a newway to construct more complex molecules bearing indole andbisindole fragments. Further studies in this area are beingactively pursued in our laboratory.
Experimental
Material and methods
All reactions were run in air unless otherwise noted. Columnchromatography purifications were performed in flash condi-tions using Merck 230–400 mesh silica gel. Analytical thinlayer chromatography (TLC) was carried out on Merck silicagel plates (silica gel 60 F254), that were visualized by exposureto ultraviolet light and an aqueous solution of ceriumammonium molybdate (CAM) or p-anisaldehyde. 1H-NMRand 13C-NMR spectra were recorded on a Bruker Avance 200spectrometer, using CDCl3 or DMSO-d6 as solvent. Chemicalshifts (d scale) are reported in parts per million (ppm) relativeto the central peak of the solvent. Coupling constants (J values)are given in Hertz (Hz). ESI-MS spectra were taken on a WatersMicromass ZQ instrument, only molecular ions (M + 1 or M 2
1) are given. IR spectra were obtained on a Nicolet Avatar 360FT-IR spectrometer, absorbance values are reported in cm21.Melting points were determined on a Buchi SMP-510 capillarymelting point apparatus and are uncorrected. Elementalanalyses were performed on a Carlo Erba analyzer and theresults are within ¡0.3 of the theoretical values (C,H,N).Microwave assisted reactions were carried out in a CEMDiscover SP microwave reactor. Indoles 2a–j, 2l–r, 1-methyl-1H-pyrrole, methyl 2-acetamidoacrylate and 2-acetami-doacrylic acid are commercially available; indoles 2k and 2swere prepared as previously described.27
p-Toluenesulfonic acid catalyzed coupling of indoles withmethyl 2-acetamidoacrylate: general procedure for thesynthesis of methyl 2,2-bis(substituted-1H-indol-3-yl)propanoates 3a–o
p-Toluenesulfonic acid (0.05 mmol) was added to a solution ofthe appropriate indole 2a–o (2 mmol) and methyl 2-acetami-doacrylate (1) (1 mmol) in toluene (5 ml), and the resultingmixture was stirred at 110 uC for 2–20 h monitoring theprogress of the reaction by TLC and HPLC-MS. After cooling to
Scheme 3 Reaction conditions: a) LiAlH4 (1 equiv.), THF, 0 uC to RT, 2 h; b) KOH,H2O, reflux 4.5 h; c) H2 (1 atm), Pd/C, MeOH, 3 h; d) Indole, EtAlCl2 (2 equiv.),CH2Cl2, 0 uC to RT 16 h.
19138 | RSC Adv., 2013, 3, 19135–19143 This journal is � The Royal Society of Chemistry 2013
room temperature, water (15 ml) was added and the aqueousphase was extracted with ethyl acetate (3 6 15 ml). After dryingover dry Na2SO4, the combined organic phases were concen-trated in vacuo and the resulting crude product was purified bycolumn flash chromatography on silica gel (cyclohexane–ethylacetate 8 : 2, or CH2Cl2 for 3a, as eluent) and/or crystallization.
Methyl 2,2-di(1H-indol-3-yl)propanoate (3a)
White solid, (294 mg, 93%). The chemical-physical data are inagreement to those described in literature.18
p-Toluenesulfonic acid catalyzed alkenylation of 2- or4-substituted indoles with methyl 2-acetamidoacrylate: generalprocedure for the synthesis of methyl 2-(indol-3-yl)acrylates4o–s
p-Toluenesulfonic acid (0.05 mmol) was added to a solution ofthe appropriate indole 2o–s (2 mmol) and methyl 2-acetami-doacrylate (1) (1 mmol) in toluene (5 ml), and the resultingmixture was stirred at 110 uC for 1–20 h monitoring theprogress of the reaction by TLC and HPLC-MS. After cooling toroom temperature, water (15 ml) was added and the aqueousphase was extracted with ethyl acetate (3 6 15 ml). After dryingover dry Na2SO4, the combined organic phases were concen-trated in vacuo and the resulting crude product was purified bycolumn flash chromatography on silica gel (cyclohexane–ethylacetate 8 : 2, or CH2Cl2 for 4p, as eluent) and/or crystallization.
A solution of 1-methyl-1H-pyrrole (35.5 ml, 0.4 mmol), methyl2-acetamidoacrylate (1) (29 mg, 0.2 mmol) and p-toluenesul-fonic acid (0.05 equiv.) in acetonitrile (1 ml) was charged in aPyrex microwave vial and the resulting mixture was stirred in amicrowave reactor at 110 uC (300 W) for 10 min. After coolingto room temperature, water (5 ml) was added and the aqueous
phase was extracted with ethyl acetate (3 6 5 ml). Thecombined organic phases were dried over anhydrous sodiumsulphate, and the solvent was removed by distillation underreduced pressure, obtaining a crude residue that was purifiedby flash chromatography on silica gel (cyclohexane–CH2Cl2
To a solution of methyl 2,2-di(1H-indol-3-yl)propanoate 3a (32mg, 0.1 mmol) in THF (1 ml) at 0 uC was added LiAlH4 (4 mg,0.1 mmol) and the reaction mixture was stirred at roomtemperature for 2 h. The solution was diluted with CH2Cl2 (5ml), quenched by addition of distilled water (5 ml) and theresulting mixture was filtered on Celite. The aqueous phasewas extracted with further CH2Cl2 (2 6 5 ml). The combinedorganic phases were dried over anhydrous sodium sulphateand the solvent was removed by distillation under reducedpressure, obtaining a crude residue that was purified by flashchromatography on silica gel (ciclohexane–ethyl acetate 6 : 4).White solid (24 mg, 83%). mp 92–93 uC (from CH3OH); 1HNMR (CDCl3): d 1.93 (s, 3H), 4.33 (s, 2H), 6.92 (dd, J1 = 7.0 Hz,J2 = 8.0 Hz, 2H), 7.12 (s, 2H), 7.13 (dd, J1 = 7.0 Hz, J2 = 8.0 Hz,2H), 7.37 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 8.08 (bs,2H); 13C NMR (CDCl3) d 24.8, 41.6, 69.7, 111.2, 119.1, 120.4,121.1, 121.7, 122.3, 126.1, 137.0; IR (nujol, cm21): 3408; MS ESI(m/z): 289 [M 2 H]2; Anal. found: C, 78.51; H, 6.19; N, 9.74.Calc. for C19H18N2O: C, 78.59; H, 6.25; N, 9.65%.
2,2-di(1H-indol-3-yl)propanoic acid (7)
Method A from 3a. A solution of KOH (10 mg, 0.2 mmol) inH2O (1 ml) was added to a solution of methyl 2,2-di(1H-indol-3-yl)propanoate 3a (64 mg, 0.2 mmol) in CH3OH (2 ml) and theresulting mixture was stirred at 70 uC for 4.5 h. After cooling toroom temperature, the solution is acidified with HCl and theaqueous phase was extracted with CH2Cl2 (3 6 8 ml). Thecombined organic phases were dried over anhydrous sodiumsulphate and the solvent was removed by distillation underreduced pressure, obtaining a crude residue that was purifiedby flash chromatography on silica gel (cyclohexane–ethylacetate 1 : 1). Orange solid (58 mg, 95%).
Method B from 2a with 2-acetamidoacrylic acid26. A solutionof 1H-indole (2a) (47 mg, 0.4 mmol), 2-acetamidoacrylic acid(26 mg, 0.2 mmol) and p-toluenesulfonic acid (0.05 equiv.) inacetonitrile (1 ml) was charged in a Pyrex microwave vial andthe resulting mixture was stirred in a microwave reactor at 110uC (300W) for 1 h. After cooling to room temperature, water (3ml) was added and the aqueous phase was extracted with ethylacetate (3 6 5 ml). The combined organic phases were driedover anhydrous sodium sulphate and the solvent was removedby distillation under reduced pressure, obtaining a cruderesidue that was purified by flash chromatography on silica gel(cyclohexane–ethyl acetate 1 : 1). Orange solid (45 mg, 74%).
This journal is � The Royal Society of Chemistry 2013 RSC Adv., 2013, 3, 19135–19143 | 19141
A solution of methyl 2-(2-phenyl-1H-indol-3-yl)acrylate 4q (40mg, 0.14 mmol) in CH3OH (2 ml) was hydrogenated overpalladium on carbon (10%, 5 mg) at 1 atm of H2 for 3 h atroom temperature. The catalyst was filtered on Celite, thefiltrate was concentrated under reduced pressure to give acrude residue that was purified by flash chromatography onsilica gel (cyclohexane–ethyl acetate 8 : 2). White solid (35 mg,90%). The chemical-physical data are in agreement to thosedescribed in literature.30
A 1M solution of EtAlCl2 in hexane (0.4 ml, 0.4 mmol) wasadded to an ice-cooled solution of 4q (55 mg, 0.2 mmol) and1H-indole (2a) (26 mg, 0.22 mmol) in dry CH2Cl2 (1 ml) underargon, and the resulting mixture was stirred at roomtemperature for 16 h. The mixture was diluted with CH2Cl2
(5 ml), neutralized with a saturated aqueous solution ofNaHCO3 (5 ml) and filtered through Celite pad. The two layerswere separated and the aqueous phase was extracted withfurther CH2Cl2 (2 6 5 ml). The combined organic phases weredried over anhydrous sodium sulphate and the solvent wasremoved by distillation under reduced pressure, obtaining acrude residue that was purified by flash chromatography onsilica gel (cyclohexane–ethyl acetate 6 : 4). White solid (25 mg,32%). mp 71–72 uC (from CH3OH); 1H NMR (CDCl3): d 3.21(dd, J1 = 7.0 Hz, J2 = 14.5 Hz, 1H), 3.55 (s, 3H), 3.75 (dd, J1 = 8.0Hz, J2 = 14.5 Hz, 1H), 4.31 (dd, J1 = 7.0, J2 = 8.0, 1H), 6.63 (d, J =2.0 Hz, 1H), 6.84 (ddd, J1 = 1.0 Hz, J2 = J3 = 8.0 Hz, 1H), 7.02(ddd, J1 = 1.0 Hz, J2 = J3 = 8.0 Hz, 1H), 7.08–7.32 (m, 10H), 7.70(bs, 1H), 7.90–7.95 (m, 1H), 7.96 (bs, 1H); 13C NMR (CDCl3) d
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19142 | RSC Adv., 2013, 3, 19135–19143 This journal is � The Royal Society of Chemistry 2013
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19 Notably, heating 3a under the reaction conditions led todecomposition. On the contrary, 3a was stable and inert inthe presence of a stoichiometric amount of acetamide.
20 We subsequently found that PTSA was extremely active as itprovided 3a in 86% yield in acetonitrile with microwaveirradiation in only 7 min.
21 The ability to access C4-substituted indoles is of impor-tance for natural product synthesis and drug discovery. AScifinder search indicated that more than 600 C4-sub-stituted indole-containing natural products exist andnearly 10 000 bioactive C4-substituted indoles have beenreported.
22 The formation of indolacrylates under these conditions isquite surprising, since these products have a high tendencyto polymerize under acidic conditions, see: T. P. Pathak, J.G. Osiak, R. M. Vaden, B. E. Welm and M. S. Sigman,Tetrahedron, 2012, 68, 5203. Probably, the side productacetamide is Lewis basic enough to temper/reduce theacidity in solution.
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