Review article Egypt. J. Chem. Vol. 60, No.5, pp. 723 - 751 (2017) 51 1H-Indole-3-carboxaldehyde: Synthesis and Reactions Eslam R. El-Sawy*, Heba M. Abo-Salem and Adel H. Mandour Chemistry of Natural Compounds Department, National Research Centre, P.O. Box 12622 Dokki, Giza, Egypt . 1H-Indole-3-carboxaldehyde and its derivatives have represented the key intermediates for the preparation of biologically active compounds as well indole alkaloids. Also, they are important precursors for the synthesis of divers heterocyclic derivatives because their carbonyl groups facilely undergo C–C and C–N coupling reactions and reductions. This review highlights the recent advances in 1H-indole-3-carboxaldhyde chemistry via discussing different synthetic procedures developed for the preparation of its derivatives, as well sheds the light on the most common reactions of 1H-indole-3-carboxaldhyde derivatives and exploitation of these derivatives as the blocks of many biologically active compounds. Keywords: 1H-Indole-3-carboxaldehyde, Synthesis, Reactions, Heterocycles. Introduction depressant (α-methyl-tryptamine)[4], antimicrobial (phytoalexins brassinin and cyclobrassinin) 1H-Indole-3-carboxaldhyde (I3C, 1) is a [5,6], antiviral (chondramide A) [7], anthelmintic natural compound found in tomato seedling, pea (chondriamide C) [8], monoamine oxidase inhibitor seedling, barley, lupine, cabbage and cotton [1]. (aplysinopin) [9], anti-plasmodial (isocryptolepine) 1H-Indole-3-carboxaldehyde (1) represents an [10], antifungal (phytoalexine caulilexins A-C) important starting and intermediate compound [11], inhibit DNA replication and transcription for building many various synthetic and natural (cryptosanginolentine 1) [12] and muscle relaxant biologically active compounds especially with (α,β-cyclopiazonic acid)[13] activities (Fig. 1). antitumor (camalexin [2] coscinamide) [3], anti- H N D 2 D O S NH N CH3 O NH NH N O N H HN N H chondramide A H alph-methyltryptamine camalexin R N AMT H O O coscinamide A, R=Br S N HN N NH N coscinamide B, R=H H SCH3 SCH N NH 3 chondramide C S O N N H H cyclobrassinin Aplysinopin N NH H brassinin CO2Et N N O SCH3 S N N N N H CH3 CH3 H isocryptolepine Cryptosanguinolentine α -Cyclopiazonic acid caulilexin A Figure 1. Bioactive natural compounds from 1H-indole-3-carboxaldhyde *Corresponding author e-mail: [email protected] DOI : 10.21608/EJCHEM.2017.1097.1053 ©2017 National Information and Documentation Center (NIDOC) 724 ESLAM R. EL-SAWY et al. Biosynthesis of natural 1H-indole-3- other hand, brassinin oxidase (BOLm; a fungal carboxaldehyde (1) was first suggested by Tang detoxifying enzyme) mediates the conversion and Bonner who reported that, aldehyde (1) was of the phytoalexin brassinin into 1H-indole- produced via biotransformation of indole-3- 3-carboxaldehyde with equivalent ratio [15] acetic acid (IAA) using crude enzyme which is (Scheme 1). prepared from etiolated pea seedlings [14]. On the CH CH3 S 3 S S PMS S H S PMS H2O H O N H NH NH H CH H2O 2 N S 3 PMSH BOLm O2 HO H C S S O N CH N N O 3 N C H BOLm H H H 1 O phytoalexin brassinin BOLm-1 BOLm-1-ox Scheme 1 Also, bacteria play an important role in [19] or formylation of the potassium salt of indole the biosynthesis of 1 via biotransformation of using carbon monoxide under robust conditions L-tryptophan using Escherichia coli [16]. of heat and pressure [20]. Sommelet reaction on gramine and on indole itself [21] oxidation of 1H-Indole-3-carboxaldhyde and its derivatives N-skatyl-N-phenyl-hydroxylamine [22] and/or are not only the key intermediates for the by hydrolysis of 3-(1,3-dithiolan-2-yl)indole with preparation of biologically active molecules as boron trifluoride diethyl etherate BF3.O(C2H5)2 well indole alkaloids, but also they are important and mercury (II) oxide HgO [23]. precursors for the synthesis of diverse heterocyclic derivatives. In this respect, this review point up Recently, the researchers developed the chemistry and the most common reactions of general and simple approaches by the use of 1H-indole-3-carboxaldhyde and its derivatives. environmentally benign reagents in order to obtain 1H-indole-3-carboxaldyhde (1), for an example: Synthetic methods of the preparation of 1H-Indole- 3-carboxaldhyde Oxidation of gramine methiodides Previously, 1H-indole-3-carboxaldehyde (1) Unusual oxidation of graminemethiodide has been prepared synthetically either via direct [1-(1H-indol-3-yl)-N,N,N-trimethylmethanaminium formylation of indole using e.g., Reimer-Tiemann iodide] (2) using sodium nitrite in N,N- reaction (aq. KOH/CHCl3)[17], Grignard reaction dimethylformamide (DMF) produces 1 in 68% [18], Vilsmeier Haack reaction (POCl3/DMF) yield [24] (Scheme 2). O N NaNO2 DMF N N H H I 1 2 Scheme 2 Alkaline degradation of ascorbigen acetic anhydride in pyridine in the presence of Alkaline degradation of ascorbigen 3 leads 4-dimethylaminopyridine (DMAP) leads to a to a mixture of L-sorbose (4) and L-tagatose mixture of 6 and 7, which are separated by column (5) derivatives. The later ketoses underwent chromatography. Deacetylations of compounds 6 acetylation and open ring of pyranose using and 7 have been accompanied by the formation of 1 with yield (3%) [25] (Scheme 3). Egypt.J.Chem. 60, No.5 (2017) 1H-INDOLE-3-CARBOXALDEHYDE, SYNTHESIS AND REACTIONS 725 H N H OH N OAc OAc O OH HO H H 4 AcO H HO H H OH OH H OAc O Na CO H OH O 2 3 AcO H MeOH N HO H OH H O CH2OAc O CH2OH OH CHO 4 6 Ac2O/pyridine HO DMAP/12h + + OH N H H N H N N H O OH OAc OAc 1 3 HO O 3% OH H H H OAc H OH Na2CO3 H OAc MeOH H OH N H AcO H HO H 5 CH OAc CH OH 5 2 2 7 Scheme 3 Oxidative decarboxylatoin of indole-3-acetic (III) chloride support on functionalized multi- acid wall carbon nano-tubes or with manganese (III) Oxidative decarboxylatoin of indole-3- tetra (4-pyridyl)porphyrin support on cross-linked acetic acid (8) using sodium periodate catalyzed chloromethylated polystyrene, produces 1 in 78% either with manganese(III)-salophen complex, yield [26] (Scheme 4). tetrakis(4-aminophenyl) porphyrinato manganese O O OH NaIO4 Mn (III)-salophen or [Mn(TNH2PP)Cl@MWCNT] N or N H H 8 [Mn(T4PyP)-CMP] 1 Scheme 4 From oximes chloride dihydrate under reflux in acetonitrile and Treatment of (E)-1H-indole-3-carbaldehyde water (4:1) leads to the formation of 1 in 88 % oxime (9) with 2 molar equivalents of cupric yield [27] (Scheme 5). OH N O CuCl2.2H2O CH3CN/H2O o N N 75 C H 9 H 1 Scheme 5 From gramine supported ceric ammonium nitrate (CAN–SiO2) The reaction of gramine (10) with yields 1 in 81% [28] (Scheme 6). formulating species has been generated from hexamethylenetetramine (HMTA) and silica- Egypt.J.Chem. 60, No.5 (2017) 726 ESLAM R. EL-SAWY et al. N O N HMTA, solvent + N CAN-SiO2 N N N N H H 10 Scheme 6 1 Oxidation of skatole (DDQ) in a mixture of tetrahydrofuran and water Oxidation of skatole (3-methylindole) (11) (9:l) at room temperature affords 1 in 30% yield with 2,3-dichloro-5,6-dicyano-p-benzoquinone [29] (Scheme 7). O DDQ THF/H2O (9:1) K2CO3 N N H 11 1 H Scheme 7 Formylation of indole [31] or ; c) using tetramethylethylene-diamine C3-selective formylation of indole (12) has (TMEDA) (13) as a carbon source catalyzed either been achieved either by the use of, a) N-methyl by CuCl2 in acetonitrile with atmospheric oxygen aniline in the presence of ruthenium (III) chloride as oxidant, [32] or catalyzed by Rose Bengal in the as oxidative catalyst [30]; b) ammonium acetate in presence of an aerobic visible-light and oxygen to dimethylsulfoxide as a source of carbon with water afford 1 [33] (Scheme 8) . N O N N 13 H CuCl2/CH3CN, O2 1 Rose Bengal/aerobic N RuCl3/BuNI N H H visible-light 1 12 DMS/H2O NH4OAc (4 equiv) 150 °C 1 Scheme 8 In spite of the development in the methods for for the preparation of 1 due to it is considerably the preparation of 1H-indole-3-carboxaldehyde simple, the yield is almost quantitative, and the (1), it remains to be seen Vilsmeier Haack aldehyde product is obtained in a state of high formylation reaction is the convenient method purity [19] (Scheme 9). H C Cl Cl H N O Cl O N CH O P O N CH O P O NC P Cl Cl Cl Cl Cl Cl pinkish color Cl Vilsmeier haack reagent CH NMe2 H CHNMe2 CH NMe2 aq NaOH NC Ice crushed - H Cl N N H N N H 12 O aq NaOH Scheme 9. Reaction mechanism of Vilsmeier Haack formylation 1, 98% heat of indole (12) to afford 1H-indole-3-carboxaldehyde (1) N H Egypt.J.Chem. 60, No.5 (2017) 1H-INDOLE-3-CARBOXALDEHYDE, SYNTHESIS AND REACTIONS 727 Reactions of 1H-Indole-3-carboxaldehyde catalyst. The reaction occurs through quinazolinone Deformylation intermediate, which is exposed to acid catalyzed Deformylation of 1H-indole-3-carboxaldehyde cleavage and forms deformylated product, indole (1) has been achieved by the use of anthranilamide (12) [34]. (Scheme 10). (14) in the presence of solid acid heterogeneous O O HN O O NH HN NH protonation H NH2 of indolic C3 -H H + + O O S N NH N N O H 2 H H N 1 14 12,25% 50% amperlyst-15 O amperlyst-15 O NH2 + HN N NH2 N H 14 12,90% Scheme 10 N-Alkylation, N-acylation and N-sulfonation The importance and the necessity of protecting such as NaH in order to generate the indole anion, nitrogen of indole-3-carboxaldehyde (1) are well which reacts as a nucleophile with alkyl, acyl established [35].