HETEROCYCLES

Paper | Regular issue | Vol. 83, No. 11, 2011, pp. 2535-2546
Received, 8th August, 2011, Accepted, 15th September, 2011, Published online, 27th September, 2011.
DOI: 10.3987/COM-11-12331

■ Synthesis of Novel Methylene Bridge Functionalized Bis(indolyl)methanes through a Double Michael Addition

Mojgan Kargar, Rahim Hekmatshoar,* and AbdolJalil Mostashari

Department of Chemistry, School of Sciences, Alzahra University, Vanak, Tehran, Iran

Abstract

A simple synthesis of a series of novel diethyl bis(indol-3-yl)methylmalonate is described. This involves domino Michael addition/ elimination/Michael addition of indoles to diethyl ethoxymethylenemalonate as double Michael acceptor.

INTRODUCTION
Diethyl ethoxymethylenemalonate (DEEM) and similar so-called "β-alkoxyacrylates" are utilized extensively as Michael acceptors and usually form Michael monoadducts with retention of the double bond. A broad range of their applications in the synthesis of chain, cyclic, heterocyclic and fused heterocyclic structures have been reported and reviewed.1 Michael addition of amine nucleophiles to "alkoxyacrylates" are most common. Syntheses of "floxacine" type anti-bacterials start with addition of anilines or 2-aminopyridines to DEEM.2 However, there are not many reports on the reactions of carbon nucleophiles with DEEM.1
The chemistry of indole is also one of the most active areas of research in heterocyclic chemistry.3 Medicinal chemists frequently turn to indole based compounds as target pharmacophores for the development of therapeutic agents.4 More recently simple 1,1-bis(3-indolyl)-1-(substituted phenyl)methanes have been introduced as anti-cancer drugs as they are cancer cell proliferation inhibitors and apoptosis inducers.5
Numerous methods have been reported for the synthesis of bis(indolyl)methanes. Among them, the acid catalyzed reaction of indoles with alkyl or arylaldehydes is a simple and straightforward approach.6 However, most bis(indolyl)methanes produced by these methods lack non-hydrocarbon functional groups on the methylene bridge of the products.
Exceptions are those prepared using oxazines,7 unsaturated α-ketoesters,8 glyoxylic acid,9 acetylene-carboxylates,10 α-oxoketenedithioacetals,12 2-hydroxy-(2-indolyl)acetamides13 and 1,3-dicarbonyls14 as starting materials. Most of the above protocols require rather expensive catalysts such as silylated N-triflylphosphoramides,8 (S)-BINOL/Ti(O-iPr)4,9a Sc(OTf)3,9b AuCl3,10a PtCl2,10b Pd(OAc)2,10c Dy(OTf)3,11 and TFA.12
We are pleased to report for the first time, a p-TsOH-catalyzed double Michael addition of 1- or 2-substituted indoles to DEEM. This simple protocol leads to the synthesis of novel bis(indolyl)methanes 3a-e (Scheme 1), having a malonate group on the methylene bridge. The protocol also presents novel examples of double Michael addition of carbon nucleophiles to “β-alkoxyacrylate” type push-pull olefins such as DEEM. It is noteworthy that unlike most previous reports, here both the reagents and the catalyst are easily available and of low cost.

RESULTS AND DISCUSSION
In our model experiment, p-TsOH catalyzed reaction of DEEM 1 with 2-methylindole 2a in a polar aprotic solvent such as CH2Cl2 at reflux within 6 hours, afforded diethyl bis(2-methylindolyl-3-yl)methylmalonate 3a, at 95% yield (Table 1 entry 1).
This interesting result, exhibiting a tandem Michael addition/elimination/Michael addition reaction sequence by DEEM is unprecedented. Extensive survey of literature showed no reports, either of the compounds presented in this paper, or of this new application of DEEM as a double Michael acceptor synthon.

In order to evaluate the scope of the process, 2-phenylindole 2d and some 2-(substituted phenyl)indoles 2b,c were synthesized and used in this protocol. These indoles afforded moderate yields of the corresponding bridge substituted bis(indolyl)methanes 3b-d. The higher yield and faster reaction rate of 2-methylindole 2a as compared to 2-phenylindole 2d and its derivatives 2b,c demonstrate the great influence of the steric effect of bulky 2-aryl groups in this reaction. Results of the experiments are summarized in Table 1.

A plausible mechanism for the synthesis of bis(indolyl)methanes 3a-e, has been shown in Scheme 2. The first step is the production of monoadducts [A] through a Michael addition of indole to DEEM followed by ethanol elimination. A second molecule of indole is then added to the monoadduct [A] to produce 3a-e.

In the case of 1-methylindole 2e (entry 5), in addition to the expected product 3e, we also isolated tris(1-methylindolyl)methane 415 in 50% yield. Apparently, 3e undergoes a facile elimination reaction, losing a diethyl malonate molecule, to produce the unisolated intermediate [B]. 4 is the product of the Michael addition of a third 1-methylindole to [B] (Scheme 3).

Structures assigned to 3a-e are fully consistent with spectral data. In the mass spectra of 3a-e, main peaks were assigned to corresponding fragments produced by loss of malonate moiety. The OCH2 protons of the ethyl groups in compounds 3a-e are not isochronous, and give rise to an ABX3. The IR spectra of 3b-d, show two ester C=O bands but the IR spectra of 3a and 3e show only one ester C=O band.
Curiously enough, contrary to the findings of previous reports of acid catalyzed reactions with aldehydes, 1H-indole 2f itself did not produce the corresponding bis(indolyl)methane, but instead furnished diethyl-2-[({2-[2,2-bis(1H-indol-3yl)ethyl]phenyl}amino)methylidene]propane-1,3-dioate 5 in moderate yield. Production of 5 was optimized for higher yield and purity, by performing the reaction under solvent free conditions at 80 ºC for 1 h (Scheme 4).

A plausible mechanism for this transformation is proposed in Schemes 5 and 6. Under acidic conditions, 1H-indole is in equilibrium with 3-(indolin-2-yl)indole (indole dimer) 6 (Scheme 5).16

Reaction of indoline "NH" group of dimer 6 with electrophile such as DEEM, causes drain of reaction equilibrium towards production of intermediate [C]. Addition of a third molecule of indole to [C] leads to the formation of novel substituted trimer 5 in almost quantitative yield.

In the mass spectrum, compound 5 shows a base peak at m/z 245, assignable to the bis(indolyl)methyl moiety. The IR spectrum shows two NH bands at 3430 and 3320 cm-1 and four carbonyl bands at 1693, 1651, 1620 and 1593 cm-1. The 1H NMR spectrum (500 MHz, DMSO-d6) shows a singlet ascribable to two indolic NH groups at δ 10.71, two doublets at 10.97 (J = 13.6 Hz, NHaniline) and 8.14 (J = 13.6 Hz, =CH-NH) and fourteen aromatic protons [set a (δ 6.78, 6.93 and 6.99), set b (7.14, 7.20 and 7.39)], together with a triplet at 4.79 (J = 7.8 Hz, CH2-CH) and a doublet at 3.55 (J = 7.8 Hz, CH2-CH). Methyl signals (CO2CH2CH3) of compound 5 in CDCl3 appeared at δ 1.27 and 1.31 and in DMSO-d6 as solvent; these signals were observed at δ 1.19 and 1.21. This indicates that these methyl groups are subject to different field anisotropic effects of the aromatic rings at different solvents.
3a was chosen as a model compound to further investigate the chemistry and reactivity of this type of bis(indolyl)methanes. Bis(indolyl)methane 3a, having a malonate leaving group, was found to be labile in basic conditions. Thus, treating 3a with NaOMe in refluxing MeOH afforded (2-methyl-3-indolyl)(2-methyl-3-indolinylidene)methane 7 (Urorosein type base)17 in very good yield (Scheme 7). 1H NMR spectrum of compound 7 shows an olefinic proton (Bridge CH) at δ 8.2 but no N-H signals were observed, which is probably due to the fast exchange of N-H single proton between two nitrogen atoms. The absence of an N-H signal of the similar type of structure has been previously reported.18

The structure of 7 was further confirmed by NaBH4 reduction producing the previously reported bis(2-methyl-indol-3-yl)methane 8.19
Attempts to add indole and various 2-substituted indoles to compound 7 in glacial acetic acid, with the aim of obtaining unsymmetrical tris-indoles, failed and spontaneous decomposition of the unstable compound 7, led to the production of tris(2-methylindolyl)methane 9 as the main product.
Oxidation of 3a, with DDQ in acetonitrile led to a novel alkenyl substituted bisindole 10, retaining the malonate moiety on the methane bridge (Scheme 8). This type of bisindole has been reported via the reaction of indoles with α-oxoketenedithioacetal.12

In conclusion, the present paper reports for the first time, the simple synthesis of the novel bis(indolyl)methylmalonates based on Michael addition-elimination-addition of the indole derivatives to double Michael acceptor DEEM. A particularly significant feature of this work is the introduction of diethylmalonate on the methylene bridge of bis(3-indolyl)methanes. These novel compounds and their derivatives may be directly used for screening as potential drugs or may further be built up and used as scaffolds in the synthesis of more complex molecules. Commercial availability and low cost of the DEEM and the catalyst used in this protocol, is an advantage that justifies pursuing further studies in this direction.

EXPERIMENTAL
General information
2-Phenylindole derivatives were synthesized according to reported procedures.20 All other chemicals were purchased from Kimia Exir Co. Tehran, Iran. Barnstead Electrothermal 9200 melting point apparatus was used for melting point determinations. GC/Mass analyses were performed using Agilent 6890 GC system Hp-5 capillary 30 m × 530 μm × 1.5 μm nominal. IR spectra were recorded as KBr disc on the FT-IR Bruker Tensor 27 spectrometer. 1H and 13C NMR spectra were recorded on a Bruker DRX-500-AVANCE spectrometer at 500 (1H) and 125 MHz (13C). Elemental analyses were carried out by a CHN-Rapid Heraeus elemental analyzer (Wellesley, MA).
Typical procedure for the synthesis of 3a-d
A 100 mL round bottom flask was charged with DEEM (25 mmol, 5.4 g) and a solution of indole derivative 2 (50 mmol) in CH2Cl2 (20 mL) was added. p-TsOH (5 mol%, 0.23 g) was added to the stirring solution. The mixture was refluxed for the appropriate time (Table1). The progress of the reaction was monitored by TLC using petroleum ether: EtOAc (4:1) as eluent. When the starting materials were no longer consumed, the solvent was removed by short path distillation. The resulting residue was dissolved in EtOAc and petroleum ether was added to precipitate the product. The produced solid was filtered, and dried under reduced pressure to yield the target bis(indolyl)methanes 3a-d. Further purification of the product was normally not needed.
Diethyl bis(2-methyl1H-indol-3-yl)methylmalonate 3a
Compound 3a was obtained as white powder, Mp 194-196 ºC; yield: (10.3g, 95%); IR (KBr) 3410, 3357, 3050, 2978, 1743, 1459, 1392, 1372, 1300, 1266, 1146, 1017, 742 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 0.89 (6H, t, J = 7.0 Hz, 2OCH2Me), 2.32 (6H, s, 2Meindole), 3.86-3.88 (2H, m, OCH2Me), 3.91-3.95 (2H, m, OCH2Me), 4.99 (1H, d, J = 12.5 Hz, CH-CH(CO2Et)2), 5.25 (1H, d, J = 12.5 Hz, CH(CO2Et)2), 6.94-7.00 (4H, m, ArH), 7.13 (2H, d, J = 7.7 Hz, ArH), 7.70 (2H, d, J = 7.7 Hz, ArH), 8.35 (2H, s, 2NH); 13C NMR (125.7 MHz, DMSO-d6) δ 12.9, 14.0, 35.1, 55.8, 61.5, 110.6, 111.7, 119.2, 119.5, 120.6, 128.1, 132.3 135.6, 168.9; MS m/z 432 (M+, 10), 273 (100), 257 (21), 216 (6), 158 (15), 130 (13), 81 (30), 69 (51), 55 (36), 43 (52%); Anal. Calcd for C26H28N2O4: C, 72.22; H, 6.53; N, 6.48%. Found: C, 72.26; H, 6.55; N, 6.43%.
Diethyl bis[2-(4-methylphenyl)-1H-indol-3-yl]methylmalonate 3b
Compound 3b was obtained as pinkish powder, Mp 199-200 ºC; yield: (10.5 g, 72%); IR (KBr) 3409, 3383, 977, 1731, 1710, 1457, 1271, 1184, 1153, 1033, 847, 737, 519 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 0.71 (6H, t, J = 7.0 Hz, 2OCH2Me), 2.38 (6H, s, 2CH3-Ar), 3.74-3.79 (2H, m, OCH2Me), 3.81-3.84 (2H, m, OCH2Me), 5.03 (1H, d, J = 12.0 Hz, CH-CH(CO2Et)2), 5.80 (1H, d, J = 12.1 Hz, CH-CH(CO2Et)2), 6.82 (2H, t, J = 7.4 Hz, ArH), 6.96 (2H, t, J = 7.5 Hz, ArH), 7.09 (4H, d, J = 7.8 Hz, ArH), 7.20 (6H, m, ArH), 7.55 (2H, d, J = 8.0 Hz, ArH), 10.88 (2H, s, 2NH); 13C NMR (125.7 MHz, DMSO-d6) δ 14.0, 35.1, 55.3, 61.7, 111.7, 112.6, 119.1, 120.9, 121.4, 128.0, 129.5, 129.9, 131.3, 136.2, 136.5, 137.7, 168.9; MS m/z 584 (M+, 87), 425 (100), 377 (21), 333 (27), 304 (22), 258 (73), 231 (53.9), 207 (34), 133 (40), 115 (53), 88 (38), 60 (16), 43 (62%); Anal. Calcd for C38H36N2O4: C, 78.06; H, 6.21; N, 4.79 %. Found: C, 78.04; H, 6.20; N, 4.82%.
Diethyl bis[2-(4-chlorophenyl)-1H-indol-3-yl]methylmalonate 3c
Compound 3c was obtained as yellow powder, Mp 137-139 ºC; yield: (10.9 g, 70%); IR (KBr) 3410, 3357, 3055, 2978, 1735, 1704, 1485, 1372, 1331, 1186, 1093, 1014, 833, 739, 518 cm-1; 1H NMR (500 MHz, DMSO-d6) δ = 0.73 (6H, t, J = 7.0 Hz, 2OCH2Me), 3.82-3.85 (2H, m, OCH2Me), 3.89-3.91 (2H, m, OCH2Me), 5.28 (1H, d, J = 12.2 Hz, CH-CH(CO2Et)2), 5.81 (1H, d, J = 12.2 Hz, CH-CH(CO2Et)2), 6.92 (2H, t, J = 7.6 Hz, ArH), 7.00 (2H, t, J = 7.6 Hz, ArH), 7.22 (2H, d, J = 7.9 Hz, ArH), 7.28 (8H, m, ArH), 7.82 (2H, d, J = 8.0 Hz, ArH), 11.03 (2H, s, 2NH); 13C NMR (125.7 MHz, DMSO-d6) δ 14.1, 34.6, 55.3, 61.7, 112.0, 113.0, 119.5, 121.1, 121.8, 127.4, 129.0, 131.3, 132.6, 133.6, 135.1, 136.8, 168.9; MS m/z 624 (M+-1, 3), 577 (51), 551 (71), 465 (100), 77 (6), 42 (3%); Anal. Calcd for C36H30N2O4Cl2: C, 69.12; H, 4.83; N, 4.48%, Found: C, 69.15; H, 4.85; N, 4.44%.
Diethyl bis[2-(phenyl)-1H-indol-3-yl]methylmalonate 3d
Compound 3d was obtained as pinkish powder, Mp 184-185 ºC; yield: (9.8 g, 71%); IR (KBr) 3396, 3346, 2983, 1742, 1697, 1453, 1288, 1224, 1026, 769, 734, 502 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 0.69 (6H, t, J = 7.0 Hz, 2OCH2Me), 3.70-3.75 (2H, m, OCH2Me), 3.79-3.81 (2H, m, OCH2Me), 4.91 (1H, d, J = 12.1 Hz, CH-CH(CO2Et)2), 5.75 (1H, d, J = 12.1 Hz, CH-CH(CO2Et)2 ), 6.78 (2H, t, J = 7.2 Hz, ArH), 6.96 (2H, t, J = 7.9 Hz, ArH), 7.19 (2H, d, J = 8.0 Hz, ArH), 7.31-7.39 (10H, m, ArH), 7.44 (2H, d, J = 8.0 Hz, ArH), 11.5 (2H, s, 2NH); 13C NMR (125.7 MHz, DMSO-d6) δ 14.0, 35.1, 55.3, 61.7, 111.7, 113, 119.2, 121, 121.7, 128.0, 129.5, 129.9, 131.3, 136.5, 137.7, 168.9; MS m/z 556 (M+, 8), 397 (16), 193 (100), 165 (27), 133 (38), 115 (51), 88 (18), 60 (11), 43 (35%); Anal. Calcd for C36H32N2O4: C, 77.68; H, 5.79; N, 5.03 %. Found: C, 77.60; H, 5.72; N, 5.07%.
Procedure for the synthesis of 3e and 4
In the case of 1-methylindole 2e, following the same procedure as the ones for 3a-d, after 12 h, product 4 precipitated from the reaction mixture, from which was separated by simple vac. filtration. The filtrate was evaporated and the residue was crystallized from light petroleum ether: toluene (7:3), to afford 3e.
Diethyl bis(1-methyl-1H-indol-3-yl)methylmalonate 3e
Compound 3e was obtained as yellow powder, Mp 140-142 ºC; yield: (4.3 g, 40%); IR (KBr) 3112, 2977, 2933, 1755, 1470, 1369, 1325, 1240, 1132, 1072, 1024, 859, 740 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 0.84 (6 H, t, J = 7.0 Hz , 2OCH2Me), 3.69 (6H, s, N-Me), 3.84-3.91 (4H, m, OCH2Me), 4.52 (1H, d, J = 11.9 Hz, CH-CH(CO2Et)2), 5.14 (1H, d, J = 11.9 Hz, CH(CO2Et)2, 6.92 (2H, t, J = 7.4 Hz, ArH), 7.04 (2H, t, J = 7.2 Hz, ArH), 7.28 (2H, d, J = 8.1 Hz, ArH), 7.38 (2H, s, ArH), 7.60 (2H, d, J = 7.9 Hz, ArH ); 13C NMR (125.7 MHz, DMSO-d6) δ 14.3, 33.2, 34.3, 58.0, 61.5, 110.3, 115.6, 119.2, 119.8 121.8, 127.5, 127.6, 137.3, 168.4; MS m/z 432 (M+, 8.5), 313 (4.7), 286 (5.5), 273 (100), 257 (12.6), 217 (3.9), 158 (10), 69 (8), 43 (9%); Anal. Calcd for C26H28N2O4: C, 72.20; H, 6.53; N, 6.48%. Found: C, 72.27; H, 6.55; N, 6.43%.

Tris(1-methylindol-3-yl)methane 4
This compound is previously reported; Mp 263-265 ºC (lit.,15a Mp 264-266 ºC).
Procedure for the production of Compound 5
A 50 mL round bottom flask was charged with indole (purity 97%) (60 mmol, 7.2 g), DEEM (20 mmol, 4.4 g) and p-TsOH (1 mmol, 0.2 g). The reaction mixture was heated at 80 ºC for 1 h. The reaction mixture was then cooled to room temperature and 30 mL CH2Cl2 was added and the mixture stirred for 15 min. The undissolved solid was filtered and dried to yield the product. Beautiful large crystals were obtained by recrystallization from MeNO2-MeOH (7:3).
Diethyl-2-[({2-[2,2-bis(1H-indol-3-yl)ethyl]phenyl}amino)methylidene]propane-1,3-dioate 5
Compound 5 was obtained as white powder, Mp 188 ºC; yield: (9.4 g, 90%); IR (KBr) 3414, 3324, 2977, 1693, 1650, 1619, 1592, 1184, 1494, 1263, 1220, 744, 672 cm-1; H NMR (500 MHz, DMSO-d6) δ 1.19 (3H, t, J = 7.0 Hz, OCH2Me), 1.22 (3H, t, J = 7.0 Hz , OCH2Me), 3.54 (2H, d, J = 7.8, CH-CH2), 4.09-4.16 (4H, m, 2OCH2Me), 4.78 (1H, t, J = 7.8 Hz, CH-CH2), 6.78 (2H, t, J = 7.6 Hz, ArH), 6.94 (2 H, t, J = 7.9 Hz, ArH ), 6.99 (1H, t, J = 7.2 Hz, ArH ), 7.14-7.25 (7H, m, ArH), 7.39 (2H, d, J = 7.9 Hz, ArH ), 8.14 (1H, d, J = 13.6 Hz, NH-CH), 10.71 (2 H, s, 2NH), 10.97 (1H, d, J = 13.6 Hz, NH-CH); 13C NMR (125.7 MHz, DMSO-d6) δ 15.0, 15.1, 34.7, 37.4, 60.1, 60.4, 93.5, 112.1, 118.5, 118.7, 119.6, 121.4, 123.1, 125.7, 127.3, 128.2, 131.8, 132.2, 137.1, 138.8, 153.8, 165.5, 168.8; MS m/z 521 (M+, 4), 313 (3), 245 (100), 217 (23), 189 (6), 158 (7), 130 (13), 91 (6), 45 (14%); Anal. Calcd for C32H31N3O4: C, 73.68; H, 5.99; N, 8.06 %. Found: C, 73.66; H, 5.96; N, 8.10 %.
Procedure for the synthesis of 7
In a 50 ml, round bottom flask, compound 3a (10 mmol, 4.3 g) was dissolved in MeOH (20 mL) and heated to a temperature of 40-45 ºC. A 30% solution of NaOMe in MeOH (1 mL) was added. The resulting solution was heated to reflux. After about 30 min TLC showed the 3a to have been consumed. The mixture was then cooled to 10 ºC and the red precipitate was filtered, washed with cold MeOH and dried to give 7 as an orange powder of low solubility in most organic solvents. This compound which is readily soluble in acids, has previously been reported only in various salt forms.17
(2-methyl-3-indolyl)(2-methyl-3-indolinylidene)methane 7
Compound 7 was obtained as orange powder. Mp 272 ºC (decomp.) (lit.,17b Mp 236 °C as hydrobromide); yield: (2.4 g, 89 %); IR (KBr) 2768, 1681, 1600, 1577, 1456, 1426, 1382, 1327, 1246, 1201, 1161 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 2.49 (6H, s, 2Me), 6.94 (2H, d, J = 7.5 Hz, ArH), 6.98 (2H, t, J = 7.3 Hz, ArH), 7.15 (2H, t, J = 7.1 Hz, ArH), 7.40 (2H, d, J = 7.8 Hz, ArH), 8.02 (1H, s, =CH-).
Procedure for the reduction of 7; synthesis of bis(2-methylindol-3-yl)methane 8
Reduction of 7 (2.7 g, 10 mmol) as dispersed in MeOH (16 mL), was performed by adding powdered NaBH4 (0.2 g, 6 mmol) portion-wise. Within 30 min the suspension changed to a clear and colorless solution. To neutralize excess NaBH4, a few drop of AcOH were added. H2O (10 mL) was added. The mixture cooled to 15 ºC and the precipitate was filtered, washed with 20 mL MeOH-H2O (5:5) and dried to give 95% yield of a white powder which was identical in all respects with the reported compound.21
Bis(2-methyl-indol-3-yl)methane 8
Compound 8 was obtained as a white powder. Mp 234-236 ºC (lit.,21 Mp 235-238 ºC).
Procedure for the synthesis of 9
In a 50 ml, round bottom flask, compounds 7 (10 mmol, 2.72 g) was dissolved in AcOH (30 mL) and compound 2 (5 mmol) was added. The resulting solution was stirred at room temperature about 1 h. The product 9 precipitated from the reaction mixture, from which it was separated by simple vac. filtrations. The filtrate was a complex mixture and was not pursued further.
Tris(2-methyl-1H-indol-3-yl)methane 9
Compound 9 was obtained as pink powder, Mp 320-323 ºC (lit.,15 Mp 333-335 ºC); yield from 2a (40%), 2b (30%), 2c (28%), 2d (31%), 2e (27%). IR (KBr) 3399, 1458, 1340, 1218, 1009, 747 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 1.90 (9H, s, 3Me), 6.09 (1H, s, CH), 6.60 (3H, t, J = 7.6, ArH), 6.78 (3H, d, J = 7.9, ArH), 6.84 (3H, t, J = 7.6, ArH ), 7.18 (3H, d, J = 8.0, ArH ), 10.60 (3H, s, 3NHindole); 13C NMR (125.7 MHz, DMSO-d6) δ 11,7, 30.5, 110.1, 112.2, 117.8, 118.2, 119.3, 128.8, 131.6, 134.8.
Procedure for DDQ oxidation of compound 3a to produce 10
Compound 3a (5 mmol) was dispersed in MeCN (8 mL). Upon gradual addition of a solution of DDQ (0.7 g, 3 mmol) in MeCN (10 mL) suspended powder started to dissolve. The reaction mixture was stirred for 2 h, when a dark red precipitate formed. The solid was filtered, washed with MeCN and dried to give 10 as a dark red powder.
Ethyl bis(2-methyl-1H-indol-3-yl)methylmalonate 10
Compound 10 was obtained as pale yellow powder, Mp 295-296 ºC; yield (1.9 g, 90%); IR (KBr) 3328, 1686, 1546, 1455, 1242, 1025, 750 cm-1; 1H NMR (500 MHz, DMSO-d6) δ 0.80 (6H, t, J = 7.0 Hz, 2OCH2Me), 2.02 (6H, s, 2Me indoles), 3.85-3.89 (4H, m, 2OCH2Me), 6.82 (2H, t, J = 7.6 Hz, ArH), 6.89 (4 H, m, ArH ), 7.26 (2H, d, J = 7.9 Hz, ArH), 11.32 (2H, s, 2NH); 13C NMR (125.7 MHz, DMSO-d6) δ 13.0, 14.4, 60.7, 111.6, 119.0, 120.2, 121.6, 122.2, 128.4, 136.2, 137.5, 146.1, 167.6; MS m/z 429 (M+-1, 3), 347 (12), 235 (5), 176 (100), 142 (64), 100 (32), 57 (20), 41 (31%); Anal. Calcd for C26H26N2O4: C, 72.54; H, 6.09; N, 6.51%. Found: C, 72.51; H, 6.04; N, 6.50 %.

ACKNOWLEDGEMENTS
We kindly thank Prof. M. M. Heravi for reading the manuscript and his helpful comments. Partial financial support from Alzahra University Research Council is gratefully acknowledged.

References

1. a) A. Kaczor and D. Matosiuk, Curr. Org. Chem., 2005, 9, 1237; CrossRef b) V. D. Dyachenko and R. P. Tkachev, Russ. J. Org. Chem., 2003, 39, 757; CrossRef c) V. D. Dyachenko and R. P. Tkachev, Russ. J. Org. Chem., 2006, 42, 149. CrossRef
2. a) I. Hermecz, M. Kajtdr, K. Simon, T. Breining, P. R. Surján, G. Tóth, and Z. Mészáros, J. Org. Chem., 1985, 50, 2918; CrossRef b) K. Senga, T. Novinson, and H. R. Wilson, J. Med. Chem., 1981, 24, 610; CrossRef c) B. Ritter, N. Yokoyama, and A. D. Neubert, J. Med. Chem., 1982, 25, 337; CrossRef d) N. Cho, M. Harada, T. Imaeda, T. Imada, H. Matsumoto, Y. Hayase, S. Sasaki, S. Furuya, N. Suzuki, S. Okubo, K. Ogi, S. Endo, H. Onda, and M. Fujino, J. Med. Chem., 1998, 41, 4190; CrossRef e) E. Stern, G. G. Muccioli, R. Millet, J. F. Goossens, A. Farce, J. H. Poupaert, D. M. Lambert, P. Depreux, and J. P. Hénichart, J. Med. Chem., 2006, 49, 70. CrossRef
3. a) R. Bell, S. Carmeli, and N. Sar, J. Nat. Prod., 1994, 57, 1587; CrossRef b) E. Fahy, B. C. M. Porn, D. J. Faulkner, and K. Smith, J. Nat. Prod., 1991, 54, 564; CrossRef c) P. M. Fresnada, P. Molina, and M. A. Saez, Synlett, 1999, 10, 1651; CrossRef d) C. Gil and S. Bräse, J. Comb. Chem., 2009, 11, 175. CrossRef
4. G. W. Gribble, Comprehensive Heterocyclic Chemistry, Vol. 2, Pergamon Press, New York, 1996, pp. 211–213.
5. a) S. Sreevalsan, I. Jutooru, G. Chadalapaka, M. Walker, and S. Safe, Int. J. Oncol., 2009, 35, 1191; b) J. Hong, I. Samudio, S. Chintharlapalli, and S. Safe, Mol. Carcinog., 2008, 47, 492; CrossRef c) J. Guo, S. Chintharlapalli, S. O. Lee, S. D. Cho, P. Lei, and S. Safe, Cancer. Chemother. Pharmacol., 2010, 66, 141; CrossRef d) V. Boyarskikh, A. Nyong, and J. D. Rainier, Angew. Chem. Int. Ed., 2008, 47, 5374; CrossRef e) Y. Q. Wang, J. Song, H. M. Hong, M. H. Li, and L. Deng, J. Am. Chem. Soc., 2006, 128, 8156; CrossRef f) R. T. Grabe, M. Kobayashi, N. Shimizu, M. Takesue, M. Ozawa, and H. Yukwa, J. Nat. Prod., 2000, 63, 596. CrossRef
6. a) K. Tabatabaeian, M. Mamaghani, N. Mahmoodi, and A. Khorshidi, Can. J. Chem., 2006, 84, 1541; CrossRef b) M. Shiri, M. A. Zolfigol, H. G. Kruger, and Z. Tanbakouchian, Chem. Rev., 2010, 110, 2250; CrossRef c) M. L. Deb and P. J. Bhuyan, Tetrahedron Lett., 2006, 47, 1441; CrossRef d) X. Mi, S. Luo, J. He, and J. P. Cheng, Tetrahedron Lett., 2004, 45, 4567; CrossRef e) A. Khalafinezhad, A. Parhami, A. R. Zare, A. M. Zare, and F. P. Hasaninejad, Synthesis, 2008, 4, 617; CrossRef f) M. Chakrabarty, N. Ghosh, R. Basak, and Y. Harigaya, Tetrahedron Lett., 2002, 43, 4075; CrossRef g) Z. H. Zhang, L. Yin, and Y. M. Wang, Synthesis, 2005, 12, 1949; CrossRef h) V. D. Patil, G. B. Dere, P. A. Rege, and J. J. Patil, Synth. Commun., 2011, 41, 736; CrossRef i) M. M. Heravi, K. Bakhtiari, A. Fatehi, and F. F. Bamoharram, Catal. Commun., 2008, 9, 289; CrossRef j) M. Chakrabarty, R. Mukherjee, A. Mukherji, S. Arima, and Y. Harigaya, Heterocycles, 2006, 68, 1659. CrossRef
7. a) H. Singh and K. Singh, Tetrahedron, 1988, 44, 5897; CrossRef b) H. Singh, R. Sarin, and K. Singh, Heterocycles, 1986, 24, 3039. CrossRef
8. M. Rueping, B. J. Nachtsheim, S. A. Moreth, and M. Bolte, Angew. Chem. Int. Ed., 2008, 47, 593. CrossRef
9. a) S. Sato and T. Sato, Carbohydr. Res., 2005, 340, 2251; CrossRef b) H.-M. Dong, H.-H. Lu, L.-Q. Lu, C-B. Chen, and W.-J. Xiao, Adv. Synth. Catal., 2007, 349, 1597. CrossRef
10. a) X. Li, J. Y. Wang, W. Yu, and L. M. Wu, Tetrahedron, 2009, 65, 1140; CrossRef b) Z. Li, Z. Shi, and C. He, J. Organomet. Chem., 2005, 690, 5049; CrossRef c) W. Lu, C. Jia, T. Kitamura, and Y. Fujiwara, Org. Lett., 2000, 2, 2927. CrossRef
11. G. Giannini, M. Marzi, M. D. Marzo, G. Battistuzzi, R. Pezzi, T. Brunetti, W. Cabri, L. Vesci, and C. Pisano, Bioorg. Med. Chem. Lett., 2009, 19, 2840. CrossRef
12. H. Yu and Z. Yu, Angew. Chem. Int. Ed., 2009, 48, 2929. CrossRef
13. K. Rad-Moghadam and M. Sharifi-Kiasaraie, Tetrahedron, 2009, 65, 8816. CrossRef
14. H. Shang, F. Y. Hao, L. Pan, H. Chen, and M. S. Cheng, Heterocycles, 2011, 83, 1757. CrossRef
15. a) Z. H. Zhang and J. Lin, Synth. Commun., 2007, 37, 209; CrossRef b) M. Chakrabarty, S. Sarkar, A. Linden, and B. K. Stein, Synth. Commun., 2004, 34, 1801. CrossRef
16. P. Bourgeois, J. Mesdouze, and E. Philogène, J. Heterocycl. Chem., 1983, 20, 1043. CrossRef
17. a) R. W. Pfeiffer, Liebigs Annalen, 1925, 441, 275; b) J. R. Majer, Tetrahedron, 1960, 9, 111; CrossRef c) W. Konig, J. Prakt. Chem., 1911, 84, 194 (Chem. Abstr., 1912, 6, 74).
18. H. Xiaoming, H. Shuzhen, L. Kai, G. Yong, X. Jian, and S. Shijun, Org. Lett., 2006, 333.
19. a) P. Churala, S. Dey, S. K. Mahato, J. Vinayagam, P. K. Pradhan, V. S. Giri, P. Jaisankar, T. Hossain, S. Baruri, D. Ray, and S. M. Biswas, Bioorg. Med. Chem. Lett., 2007, 17, 4924; CrossRef b) P. K. Pradhan, S. Dey, V. S. Giri, and P. Jaisankar, Synthesis, 2005, 11, 1779. CrossRef
20. J. Slätt and J. Bergman, Tetrahedron, 2002, 58, 9187. CrossRef
21. a) W. E. Noland, M. R. Venkiteswaren, and R. A. Lovand, J. Org. Chem., 1961, 26, 4249; CrossRef b) E. Leet, J. Am. Chem. Soc., 1959, 81, 6023. CrossRef