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Journal of the Brazilian Chemical Society

Print version ISSN 0103-5053On-line version ISSN 1678-4790

J. Braz. Chem. Soc. vol.14 no.1 São Paulo Jan./Feb. 2003 



Synthesis of new indolecarboxylic acids related to the plant hormone indoleacetic acid IAA



Flávia A. F. da RosaI, II; Ricardo A. RebeloI; Maria G. NascimentoII

IDepartamento de Química, Universidade Regional de Blumenau, 89010-971, Blumenau, SC, Brazil
Departamento de Química, Universidade Federal de Santa Catarina, 88040-900, Florianópolis, SC, Brazil

Address to correspondence




A síntese dos ácidos 5,6-metilenodioxi-indol-3-il-metanóico 8 e 5,6-metilenodioxi-indol-3-il-acético 13 é descrita. Piperonal foi empregado como material de partida, sendo a construção do heterociclo altamente regioespecífica e está fundamentada na reação de Hemetsberger do correspondente b-azidoestireno. O composto 8 foi obtido como intermediário pivotal na preparação de 13, tendo-se conduzida a reação de Mannich para a introdução da cadeia lateral alquílica. A rota sintética empregada englobou oito etapas e conduziu a formação de 13 com rendimento total de 26%. A formação do heterociclo indólico via ciclização redutiva de o,b-dinitroestireno é também apresentada.


The synthesis of 5,6-methylenedioxy-indol-3-yl-methanoic acid 8 and 5,6-methylenedioxy-indol-3-yl-acetic acid 13 is described. Piperonal was employed as starting material, and the construction of the heterocyclic ring based on the Hemetsberger reaction of the corresponding b-azidostyrene was highly regiospecific. Compound 8 was obtained as a key intermediate towards 13, and a Mannich reaction was used to introduce the required alkyl side chain. The route comprised eight steps giving 13 in 26% overall yield. The formation of the indolic ring via reductive cyclisation of o,b-dinitrostyrene is also presented.

Keywords: indolecarboxylic acids, nitrene insertion, piperonal, plant growth regulator




Plant growth regulators comprise a large number of structurally diverse compounds capable of regulating many biological processes, including cell division, differentiation and enlargement, chloroplast development and senescence. Their wide use in agriculture and plant biotechnology gives them a relevant role in science and technology.1 Distributed in five main classes, the indolic auxines incorporate some of the most important representatives, the endogenous indoleacetic acid-IAA 1, 4-chloro-indoleacetic acid-4-ClIAA 2 and indolebutyric acid-IBA 3.2



In order to access compounds with improved properties in comparison to the endogenous auxines and also to establish their structure-activity relationship, several substituted indolecarboxylic acids have been prepared, including a variety of oxygen benzosubstituted indoles.3-6 However, the methylenedioxy group frequently found in many secondary metabolities has not received much attention. At this point, it is worth mentioning the work of Barreiro et al.7 which focus on the preparation of indolecarboxylic acid analogue to the anti-inflammatory indomethacin from the methylenedioxyarene safrole.

Therefore, in the search for potential plant growth regulators from abundant natural products and their derivatives, presently is described the synthesis of new methylenedioxyindolecarboxylic acids structurally related to IAA.


Results and Discussion

For the synthesis of compounds with the general structure 4, Scheme 1, we considered two complementary main disconnections, D1 and D2, where a vinyl azide and o-b-dinitrostyrene would be the pivotal intermediates in the construction of the heterocyclic ring, respectively. Such compounds can be readily accessed by condensation reactions of the appropriate nucleophile and the commercially available piperonal 5, a derivative of safrole.



For the first synthetic strategy (D1) the Hemetsberger reaction8 was employed (see Scheme 2), and this was initiated with the preparation of the vinyl azide9 6 which, upon heating in refluxing xylene, generated the highly electrophilic singlet nitrene species.10 Thus, the insertion reaction in a less hindered position proceeded at very high yield, giving the desired indole 7 as a single regioisomer (all coupling constants <1Hz).11-13 Hydrolysis of indol 7 under typical reaction conditions provided the new indole 8, which could be regarded as a potential plant growth regulator since such a property has been associated to some aryl homocyclic carboxylic acids.14 For the synthesis of the IAA analogue, the indole unsubstituted heterocyclic ring 9 was required. This was achieved by decarboxylation of indole 8 in solid phase at high temperature, in the presence of barium hydroxide, with the product being obtained as an analytically pure compound, since it was separated from the reaction mixture by sublimation.

Before conducting the reactions for the preparation of the acetic acid derivative, it was decided to investigate the disconnection D2 as a means of accessing 9 without employing precursors substituted at the heterocyclic ring. Therefore, the use of the o,b-dinitrostyrene 11 was examined.15,16 This compound can be readily obtained by the condensation reaction of nitromethane and piperonal to give 10, followed by nitration (Scheme 2). Although 9 had already been prepared by Yang and Chen17 in very high yield (94%), under conditions of catalytic hydrogenation, two other methods were considered. Palladium on carbon with cyclohexene as a source of hydrogen,18 a procedure that had not been previously applied to this system, gave the desired compound in a poor 37% yield. Furthermore, the method has a strong drawback because it requires stoichiometric amount of palladium catalyst. The method of choice, following the literature procedure was the known reductive cyclisation19 of 11 assisted by silicagel in a mixture of 1:3 - benzene:cyclohexane leading to compound 9, as shown in Scheme 2 in 72% yield (single experiment). The compound prepared in this way showed identical (1H and 13C) NMR spectra as, the compound obtained by decarboxylation of 8. Attempts to prepare 9 using toluene instead of the hydrocarbon mixture above afforded the desired product in very poor yield, different to that claimed in the literature.20



For the introduction of the alkyl side chain, 9 was submitted to a Mannich reaction21 to give the expected tertiary amine 12a. In situ quaternization of 12a to provide a better leaving group followed by cyanide nucleophilyc displacement gave 12b (n = 2240 cm-1) in very good yield. Finally, basic hydrolysis of 12b and subsequent acidic workup produced the desired indoleacetic acid 13.22, 23 The total synthesis of the target molecule 13 was accomplished in eight steps via the vinyl azide 6, in a significant overall yield of 26%. On the other hand, the reductive cyclisation of o,b-dinitrostyrene gave 13 in six steps, in an overall yield of 16%.

The plant growth regulatory properties of compounds 7, 8 and 13 are currently under investigation by means of in vitro and in vivo assays. 24,25




Melting points were determined on Kofler melting point apparatus (Microquímica APF-301) and values were uncorrected. IR spectra were recorded with a Perkin-Elmer 781 Spectrophotometer in KBr. 1H and 13C NMR spectra were recorded using Brüker Ac 200 and 300 Spectrometers in solvents as indicated with Me4Si (TMS) as the internal standard. The mass spectra were obtained on a Shimadzu CGMS-QP-2000-A Spectrometer adapted with an EI source. The elemental analyses were obtained on a Carlo Erba-EA 1110 CHNS-O. Column chromatography was performed using silica gel (70-230 mesh), and the reactions were monitored by TLC (the plates were coated with Merck Kiesegel 60GF254 silica gel). The visualization of the compounds on the chromatograph plates was achieved under ultraviolet light and exposure to iodine vapour.

Methyl azidoacetate

A mixture of sodium azide (26 g, 400 mmol) in water (24 mL) was added by stirring to a solution of methyl bromoacetate (50 g, 327 mmol) in methanol (50 mL). The resulting mixture was refluxed for 4 h after which it was cooled to 25 °C and the methanol removed under reduced pressure. The crude product was purified under reduced pressure distillation (bp 72-76 °C, 30 mmHg), to provide the methyl azido acetate as a clear liquid (32.3 g, 99% yield); IR nmax/cm-1 2110 (N3), 1748 (CO) (KBr); 1H NMR (300 MHz, CDCl3) d 3.8 (s, 3H), 3.9 (s, 2H).

Methyl-2-azido(3,4-methylenedioxyphenyl)propenoate (6)

A solution of 3,4-methylenedioxybenzaldehyde (5) (5.0 g, 33 mmol) in methanol (20mL) and methyl azidoacetate (15.3 g, 133 mmol) was added dropwise (1 h) to sodium methoxide solution [prepared from sodium (3.1 g, 135 mmol) in methanol (40 mL)] at –8 °C. The mixture was then stirred for 2 h, maintaining the temperature below 5 °C. The heterogeneous mixture was poured into ice (400 mL) and manually stirred. The yellow suspension was filtered, washed with ice water, and dried in a vacuum oven for 12 h at 70 oC. The yellow solid (7.98 g, 97% yield) was used without further purification in the next step. IR nmax/cm-1 2124 (N3), 1710 (CO), 1256 (COC) (KBr); 1H NMR (300 MHz, CDCl3) d 3.9 (s, 3H), 6.01 (s, 2H), 6.8 (d, 1H, J 8.38 Hz), 6.84 (s,1H), 7.16 (d, 1H, J 8.02 Hz), 7.58 (s, 1H).

Methyl-5,6-methylenedioxyindol-2-yl-carboxylate (7)

A mixture of methyl-2-azido-(3,4-methylenedioxyphenyl)propenoate (6) (2.0 g, 8.1 mmol) and xylene (75 mL) was refluxed for 3 h, when the evolution of N2 had ceased. The xylene was removed under reduced pressure distillation, and the resulting solid was purified by column chromatography, using a mixture of dichloromethane and ethyl acetate (20:5) for elution and providing the pure product (1.6g, 90%); mp 173.2-174.6 °C; IR nmax/cm-1 3324 (NH), 3072 (CH), 1696 (CO), 1248 (COC) (KBr); Elemental analysis: Found: C, 59.98; H, 4.28; N, 6.26. Calc. for C11H9NO4: C, 60.27; H, 4.13; N, 6.39%; 1H NMR (300 MHz, CDCl3) d 3.88 (s, 3H), 5.93 (s, 2H), 6.91 (d, 1H, J 0.36 Hz), 6.94 (d, 1H, J 0.36 Hz), 7.02 (dd, 1H, J 0.9 and 0.84 Hz) 11.03 (s, 1H, NH); 13C NMR (50 MHz, CDCl3) d 51.4, 92.4, 99.2, 100.7, 108.5, 121.2, 125.1, 133.5, 143.8, 147.4, 162.1; MS: m/z 219 (M+, 76%), 187 (100), 159 (67), 133 (25), 101 (34), 93 (22), 75 (25), 50 (27).

5,6-Methylenedioxyindol-2-yl-methanoic acid (8)

A mixture of methyl-5,6-methylenedioxyindol-2-yl-carboxylate (7) (2.3 g, 10 mmol) and sodium hydroxide (2N, 50 mL) was refluxed for 1 h, cooled to 25 °C, and acidified with a solution of HCl (6N, 60 mL). The resulting precipitate was filtered, washed with ice water, and dried in the vacuum oven. The solid was crystallized from methanol giving the pure acid (1.99 g, 92%); mp 250.9 °C with decomposition; IR nmax/cm-1 3344 (NH), 2914 (OH), 1706 (CO), 1288 (COC) (KBr); elemental analysis: Found: C, 58.53; H, 3.42; N, 6.83. Calc. for C10H7NO4: C, 58.54; H, 3.44; N, 6.83%; 1H NMR (300 MHz, DMSO-d6) d 5.93 (s, 2H), 6.91 (s, 1H), 6.94 (s, 1H), 7.02 (dd, 1H, J 0.81 and 0.48 Hz), 11,6 (s, 1H, indole); 13C NMR (50MHz, DMSO-d6) d 92.4, 98.2, 100.8, 108.3, 121.2, 125.0, 133.2, 143.6, 147.2, 163.2; MS: m/z 205 (M+, 80%), 187 (100), 159 (90), 129 (20), 101 (50), 93 (27), 75 (33), 50 (45).

5,6-Methylenedioxyindole (9)

A mixture of 5,6-methylenedioxyindol-2-yl-methanoic acid (8) (0.72 g, 3.5 mmol) and barium hydroxide (0.17 g, 0.55 mmol) was finely ground and heated in "cold trap" using a Bunsen flame under vacuum (20-30 mmHg). The solid was sublimed to provide the pure indole (0.47 g, 84%); mp 109.4-110 °C (Lit.16 108-110 °C); IR nmax/cm-1 3410 (NH), 1206 (COC) (KBr); 1H NMR (200MHz, CDCl3) d 5.92 (s, 2H), 6.42 (s, 1H), 6.84 (s, 1H), 7.00 (s, 1H), 7.06 (s, 1H), 8.02 (s, 1H, indole); 13C (50 MHz, CDCl3) d 91.8, 99.1, 100.5, 102.8, 121.6, 122.7, 130.6, 143, 144.9; MS: m/z 161 (M+, 100%), 103 (38), 76 (33), 50 (23).

5,6-Methylenedioxyindol-3-yl-acetonitrile (12b)

To a mixture of dimethylamine (0.87 g, 19 mmol, 35%) and glacial acetic acid (1.7 g, 28 mmol) at 5 °C, formaldehyde (0.64 g, 21 mmol, 37%) was added. The mixture was stirred and poured into a flask containing 5,6-methylenedioxyindole (9) (1.0 g, 6.2 mmol), allowed to stand for 5 h and was then added slowly to a solution of sodium hydroxide (9 mL, 3.4 mol L-1). The suspension was filtered, washed with ice water, dried in the vacuum oven, provinding the crude 5,6-methylenedioxy-3-(dimethylaminomethyl)-indole (12a).

To a suspension of the crude 12a (0.93 g, 4.3 mmol) and sodium cyanide (0.9 g, 18.4 mmol) in methanol (13 mL) was added dropwise and under stirring dimethyl-formamide (0.6 mL), water (0.6 mL) and methyl iodide (1.4 mL, 22 mmol). The suspension was continuously stirred for an additional 2 h, after which it was poured into cold water. The precipitate was filtered, washed with ice water and dried in the vacuum oven (70 °C). The product 12b was purified by column chromatography using ethyl acetate and dichloromethane (4:1) as eluent (0.63 g, 74%); mp 145.4-146.3 °C; IR nmax/cm-1 3416 (NH), 2240 (CN) (KBr); elemental analysis: Found: C, 65.50; H, 4.11; N, 13.65. Calc for C11H8N2O2 : C, 65.99; H, 4.02; N, 13.99%; 1H NMR (200 MHz, CDCl3) d 3.76 (s, 2H), 5.96 (s, 2H), 6.84 (s, 1H), 6.94 (s, 1H), 7.10 (s, 1H), ~8.02 (s, 1H, indole); 13C NMR (50MHz, CDCl3) d 14.5, 93.5, 97.8, 101.8, 106,0 119.8, 121.4, 123.2, 123.3, 144.2, 146.3; MS: m/z 200 (M+100%), 174 (25).

5,6-Methylenedioxyindol-3-yl-acetic acid (13)

5,6-Methylenedioxyindol-3-yl-acetonitrile (12b) (0.97 g, 4.8 mmol) was added to an aqueous solution of potassium hydroxide (10 mL, 20%). The mixture was heated under reflux for 5 h, cooled to room temperature and acidified with aqueous hydrochloric acid (2 mol L-1). The precipitate formed was filtered, washed with ice water and dried in the vacuum oven to 70 °C. The solid was crystallized from water providing the pure acid (0,77 g, 73%); mp 176-176.6 °C; IR nmax/cm-1 3400 (NH), 2908 (OH), 1698 (CO) (KBr); Found: C, 60.58; H, 4.67; N, 6.36. Calc. for C11H9NO4: C, 60.27; H, 4.13; N, 6.39%; 1H NMR (200 MHz, acetone d6) d 3.66 (s, 2H), 5.89 (s, 2H), 6.86 (s, 1H), 7.01 (s, 1H), 7.12 (s, 1H), 9.92 (s, 1H, indole); 13C NMR (50MHz, Acetone-d6) d 92.8, 98.2, 101.1, 109.2, 122.4, 123, 123.2, 132.3, 143.4, 145.5, 173.3; MS: m/z 219 (M+, 60%), 174 (100).



The synthesis of 2 new indolecarboxylic acids incorporating the methylenedioxy subunit has been successfully achieved from the commercially available piperonal, an important derivative of the natural product safrole. Both nitrene insertion reaction from vinylazide and reductive cyclization from o-b-dinitrostyrene were efficient in the construction of the indole heterocyclic ring. The regulatory properties of compounds 7, 8 and 13 are currently under investigation to establish their potential as plant growth regulators.



The authors are grateful for financial support from CAPES. The facilities provided by UFSC and FURB are also acknowledged. Thanks are also due to Prof. Franco Delle Monache, Universita Cattolica Del Sacro Cuore, Roma, for the 300MHz spectra.



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Address to correspondence
Ricardo A. Rebelo

Received: January 9, 2002
Published on the web: October 18, 2002

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