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).

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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-

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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 NCH 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

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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]. There are two different kinds and sulfonyl halides in DMSO or DMF. In 1998 of protecting groups used on the free N-H of 1; Ottoni et al., [35] have reported new weaker bases a) electron releasing groups (commonly); and b) than the traditional NaH, such as NaOH, KOH and electron withdrawing groups [35]. As a matter NEt3 in ethanol to form N-substituted indole-3- of fact, most of the methods have been used to carboxaldehyds derivatives 15a-u with 80-100% introduce the protect groups require strong bases yields (Scheme 11, Table 1).

O O R-X NaH/DMSO or DMF NaOH or KOH/ EtOH N N H R 1 Scheme 11 15a-u

TABLE 1. N-Substituted-1H-indole-3-carboxaldhydes.

Yield % M.p. [°C]/color ref Compd. R X NaOH KOH NaH

15a CH3 I 64 - - 91-5/ red (p)[36]

15b CH2CH3 I - - 55 84-6/buff (p)[37]

15c CH2Ph Cl - 93 97 102-4/orange (c)[35,38]

15d CH2PhCl(4) Cl - - 89 117-9/brown (p)[39]

15e CH2Ph F(3) Br - 39 - 127-9 [40,41]

15f CH2Ph F(4) Cl - - 76 116-8/brown (p)[39]

15g CH2PhCl2 (2,4) Cl - - 87 121-3/brown (p)[39]

15h CH2Ph F2 (2,4) Cl - - 84 120-2/brown (p)[39] 15i COPh Cl - 84 76 177-9/purple (p)[35,42]

15j COPh-Cl(2) Cl - - 68 162-4/purple (p)[43]

15k COPh-Cl(4) Cl 65 - 73 154-6/purple (p)[42, 44]

15l SO2CH3 Cl - 85 - 127-9/purple (p)[35]

15m SO2Ph Cl 94 95 97 156-8/purple (p)[35,45]

15n SO2Ph Br(4) Cl - 75 - 112-4/purple (p)[43]

15o SO2PhCl(4) Cl - 76 - 113-5/purple (p)[43]

15p COCH3 Br 75 68 - 162-4[35]

15q COOCH2CH3 Br 92 - - 61-3[46]

15r CH2CH2Cl Cl - - 80 188-190[47]

15s CH2(CH2)2N3 Cl - - 53 165-7[47]

15t CH2(CH2)3Br Br - - 62 pale yellow (o)[48]

15u CH2CH=C(CH3)2 Br - - 92 80-2/pale yellow (c)[49] (p): powder; (o): oil; (c): crystals (-): This experiment was not carried out. Egypt.J.Chem. 60, No.5 (2017) 728 ESLAM R. EL-SAWY et al.

Some N-alkylation reactions of aldehyde been first attempted using sodium hydride in 1 have not been completed under the above THF, but the reaction wasn't completed [50,51]. mentioned conditions, so the researchers revealed Grumel et al., [50] and Stevens et al., [51] promising alternative bases and conditions [50,51]. discovered a promising alternative method by For an example, N-alkylation of 1 by benzyl-4-(2- the use of a 3–5M excess of potassium carbonate iodoethyl)-1-piperidine carboxylate, benzyl-4-(2- in acetonitrile and a similar excess of alkenyl iodopropyl)-1-piperidine carboxylate, 4-bromo- bromide under reflux for 24-29hr, to give 16a,b but-1-ene or 5-bromo-2-methyl-pent-2-ene have and 17a,b, respectively (Scheme 12).

O O 5 equiv K2CO3 1.02–3 equiv alkenyl bromide 24–29 h reflux N N H acetonitrile R 1 R R= n R= 1 , n=2, 99% 17a, R =R =H, 91% NCbz 16a 1 2 16b, n=3, 93% R2 17b, R1=R2=CH3, 93% Scheme 12

On the other hand, the desired N-(substituted) phase-transfer catalytic (PTC) conditions utilizing benzylindole-3-carboxaldehydes 18a-e have been triethylbenzyl-ammonium chloride and 50% w/v prepared in 85–90% yield via the reaction of 1 aqueous NaOH solution in dichloromethane [52] with different substituted benzyl halides under (Scheme 13).

O X O R

R N N H - N(CH2CH3)3 Cl 1 50% NaOH aq,DCM, rt R1 18 a-d, R=H; R1=CN, CO2Et, NO2, OCH3 18 e, R=Br, R1=H Scheme 13

Deprotection of nitrogen of 1-H-indole-3- conditions (long time, strongly basic medium) carboxaldehyde [53]. A new mild and neutral deprotection of Sulfonyl groups are often used as protecting N-methylsulfonyl-indole-3-carboxaldehyde (15l) groups for nitrogen of 1 [35,43,45]. Removable using tetrabutylammonium fluoride (TBAF) in of sulfonyl group was achieved via hydrolysis THF has been reported [54] (Scheme 14). of 1 by KOH (or NaOH) in MeOH under harsh

O O

TBAF/THF N N S O H H3C 15l 1 O Scheme 14

Ring opening and subsequent cyclocondensation to give Reaction of electron-rich aminoheterocycles heteroannulated pyridines 20a-c, which can be with N-substituted-1-H-indole-3-carboxaldehydes regarded as purine isosteres [55] (Scheme 15). 1, 15a and 19 resulted in the indole ring opening

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NH2

NC NH2 O H3C N H3C N N NC N NH Ph N 2 NH N N N N Ph DMF/TMSCl AlCl3/MeOH R=H R 19, R=Ph Ph 20a 1, NH 2 20c

NC DMF/TMSCl 15a, R=CH3

NC

NH N N CH3

20b Scheme 15

Chlorosulfonation acid yields 5-chlorosulfonyl-1H-indole-3- Chlorosulfonation of 1 using chlorosulfonic carboxaldehyde (21) [56] (Scheme 16).

O O

o ClO2S ClSO3H, 2h, 70 C N N H H 1 Scheme 16 21

Nitration mentioned reaction conditions give a mixture of Nitration of 1 using a mixture of nitric acid 4-nitro (23a) and 6-nitro-N-methyl-1H-indole-3- (d, 1.37) and acetic acid (1: 80 ml) at 80 ºC for carboxaldehydes (23b) [57]. On the other hand, 1h affords 6-nitro-1H-indole-3-carboxaldehyde nitration of 1 by the use of nitric acid and sulfuric (22) [57]. Whereas, nitration of N-methyl-1H- acid give a mixture of 5-nitro (24) and 6-nitro-1H- indole-3-carboxaldehyde (15a) under the above indole-3-carboxaldehydes (22)[58] (Scheme 17).

O

1 O N N 22 2 H O O O NO2 O O 1 O2N HNO (d, 1.37) HNO (d, 1.37) 15a + 3 3 + conc. H SO AcOH, 80C, 1h N N 2 4 N O N N O2N N 2 H H CH R CH3 3 24 22 1, R=H 23a 23b 15a, R=CH3 Scheme 17

Claisen-Schmidt reaction (α,β-unsaturated unsaturated ketones 25a-p and 26a-p (Scheme ketones) 18), which act as key precursors in the synthesis Reaction of 1 and 15a with various aryl of many biologically important heterocycles methyl ketones in alcohol in the presence of such as pyrimidine, pyridine, benzothiazepine, aqueous alkaline medium and/or piperidine pyrazolines, isoxazole, 1,4-diketones and flavones leads to the formation of the corresponding α,β- [59-66].

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O O

ArCOCH3 Ar 10% alkali or piperidine N EtOH N 1, R=H R 25a-p, R=H 15a, R=CH3 O R 26a-p, R=CH3

Ar= R1 R1= H; 4-Me; 4-OMe; 4-Cl; 4-F; OH; 2-OH; 2-CH2H4N; 2,5-(OMe)2; 3,4-(OMe)2; 4,6-(OMe)2; 3,4,6-(OMe)3 O O H3CO O O H CO OR 3 COCH3 H3CO O OCH3 Scheme 18

Juliae-Kocienski olefination reaction reagent for direct Juliae-Kocienski olefination of 1 2-(Benzo[d]thiazol-2-ylsulfonyl)-1- in the presence of a base to afford α,β-unsaturated phenylethanone (27) has been developed as new ketone 25a [67] (Scheme 19).

O Ph O O O O N O N O O N S Base Ph S O S + Ph S S S O O N H O 27 1 N N H O H Ph O Ph S O O N N O SO2 + + O N S S H N H 25a Scheme 19. Plausible mechanism for Juliae-Kocienski olefination reaction

Knoevenagel reaction formation of the corresponding Knoevenagel Base catalyzed reaction of 1 either with the products 28a-h and 29a-g, respectively [40, 43, active methylene groups of aliphatic or heterocycle 68-81] (Scheme 20). compounds (Knoevenagel reaction) leads to the

R O hethro R hethro H2C CH2(RR)2, base base N N N H H H 28a-h 29a-g H HN N N N CH2(RR)2, a, CH2(CN)2 hethro a, b, O b, CH (COOH) H2C O 2 2 H2N c, NH2CH2COCN H O H d, CH3COCOOH N CH c, N O 3 O d, N e, g, N N O NC S O O H N CH3 N N e, f, g, CH3 S H O N N Cl CN N O CH3 N Ph f, h, Ben O O O Scheme 20

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However, some cases of Knoevenagel 2-thioxo-dihydro-pyrimidine-4,6-dione,82 indan- condensation of 1 have been carried out in the 1,3-dione, 10H-anthracen-9-one [83] and/or presence of acid such as hydrochloric acid and/ 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one [84] or acetic acid, for example, reaction of 1 with yield Knoevenagel products 30a-d. (Scheme 21).

O hethro AcOH or HCl N N H 30a-d 1 O R O O H3C NH hethro= N O O N S N H O Ph Scheme 21

Triphenylphosphine (TPP) has been 3-cyanoacetylindole (31) to give 3-(1-substituted- found to be an efficient catalyst for the 1H-indol-3-yl)-2-(1H-indole-3-carbonyl) acrylo- Knoevenagel condensation of 1, 15a, 15c with nitriles 32a-c [85] (Scheme 22).

H CHO O CN N CN + EtOH, PPh3, rt N HN N O R 1, R=H 31 32a, R=H , R=CH R 15a 3 b,R=CH3 15c, R=CH2Ph c,R=CH Ph Scheme 22 2

Application of microwave assisted the thioxothiazolidin - 4-ones 33 with 1 to afford the Knoevenagel condensation of 3,3'-(1,4- novel bis-(2-thioxo-thiazolidin-4-one) derivatives or 1,3-phenylenebis (methylene)- bis(2- 34 [86] (Scheme 23).

S O S S S MW S N S EtOH (2ml) + N S N S 110°C, 30min HN N N O NH O H O O 34 1 33 Scheme 23

Schiff's bases reaction anisidine, [87] 2-cyanoaniline, [88] 4-amino-5- Condensation of 1H-indole-3-carboxaldhyd pyridin-4-yl-4H-[1,2,4]triazole-3-thiol [89] and with primary amine in the presence of an 3-fluoro-4-morpholin-4-yl-phenylamine [90] electrophilic catalyst leads to the formation of afforded the corresponding aldimines derivatives aldimines =CH=N- (Schiff's bases). For example, 35a-d (Scheme 24). the reaction of 1 with amino compounds, namely

O Ar-NH Ar 2 N alcohol, H N H N 35a-d 1 H N N CN SH OCH N N O 3 N F Scheme 24

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On the other hand, indole Schiff's bases 36 CF3, Cl) at C-3 have been synthesized via acid

bearing a substituent at N-1 (R= H, CH2Ph, COPh) catalyzed reaction of aldehydes 1, 15c, 15i with

in conjunction with CH=N–C6H4X(p) (X= F, Me, primary aromatic amines [91]. (Scheme 25). O

H2N X X

N p-toluenesulfonic acid N EtOH, reflux N 1, R=H R 36 15c, R=Ch Ph R 2 R=H, CH Ph, COPh 15i, R=COPh 2 X=F, CH , CF , Cl Scheme 25 3 3

A host of ammonia derivatives other than Oxime : Oxime 37 has been prepared for the amines also form similar condensation products first time via condensation of 1 with hydroxyl with indole aldehydes. Included in this group are amine hydrochloride in alcohol and in the presence hydroxyl amine, hydrazine, carbohdrazide, acetic of piperidine [92] or sodium hydroxide [93]. acid hydrazide, semicarbazide hydrochloride Whereas, Mahboobi et al., [94] have demonstrated and thiosemicarbazide derivatives. The products an alternative method for the preparation of oxime of these groups are called oxime, hydrazone, 37 via reaction of 1 with ammonium chloride in hydrazide, semicarbazone and thiosemicarbazone the presence of potassium carbonate. On the other derivatives, respectively. hand, Sridhar et al., reported an efficient synthesis of 37 via reaction of 1 with acetohydroxamic acid

using BF3.OEt2 as a catalyst [95] (Scheme 26).

O NH2OH/piperidine or NaOH NOH or NH4Cl/K2CO3 or CH3CONHOH BF .Et O/ MeOH N 3 2 N H reflux, 3.5-8h H 1 37 Scheme 26

Hydrazones (Hydrazine derivatives) : Acid ylmethyl)- hydrazine, [99] (5,6-diphenyl-[1,2,4] catalyzed reaction of 1 with hydrazine hydrate, triazin-3-yl)-hydrazine [100] and ethyl [96,97] and also with some hetero-hydrazine 2-hydrazinyl-5,6-dihydro-5-oxo-4H-1,3,4- derivatives, namely (3-methyl-quinoxalin- thiadiazine-6-carboxylate, [101] yields the 2-yl)-hydrazine, [98] (1H-benzoimidazol-2- corresponding hydrazones 38a-d (Scheme 27).

O H N Het Het-NHNH2 N N alcohol, H H N 38 1 H H N N N N O N N N CH3 N N H S COOEt Scheme 27

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Hydrazide derivatives : The reaction of acetohydrazide, [104](2-phenyl-sulfanylmethyl- aldehydes 1, 15a, 15c, 15i and 58 with benzoimidazol-1-yl)-acetic acid hydrazide carbohdrazide or acetic acid hydrazides derivatives, [105] and (4-phenyl-piperazin-1-yl) acetic acid namely 2-cyanoacetic acide hydrazide, [102] hydrazide [106] has been carried out in alcohol 5-nitro-benzo-[b]thiophene-2-carboxylic acid and in the presence of acid as a catalyst to yield hydrazide, [103] 2-(1,3-dioxoisoindolin-2-yl) the corresponding hydrazide derivatives (39a-e) (Scheme 28). O O NH R N 2 H 1 N R1 H N N alcohol; H O H N H 39a-e 1 O O2N N N N N N S N O Scheme 28

Semicarbazone and thiosemicarbazone of 1 with thiosemicarbazide or different hetero- derivatives : Reaction of 1 with semicarbazide thiosemicarbazide derivatives in methanol in the hydrochloride in the presence of sodium presence of acetic acid 30% afforded thiosemi- acetate yields the corresponding 1H-indole-3- carbazone derivatives 41a-g [109-111] (Scheme 29). semicarbazone (40) [107,108]. Whereas, reaction

S O O NH R NH H 2 NH2 1 2 N R1 H2N N N N H H H N O CH COONa S N 3 N alcohol; H N H H H 41a-g 40 1 NH N R1= NH2, , H3C N H N N N , N Scheme 29

Complex formation been used as ligands to the formation of [Pd(TSC)

Thiosemicarbazones 41, 42a-f obtained via the Cl2] complexes 43a-g [112] (Scheme 30). reaction of 1 with some thiosemicarbazides have

R R S S Cl Pd O HN DMSO HN Cl H N Cl N N NHR Pd H2N Cl DMSO S dry MeOH, reflux N EtOH H N N H H 1 41, R=NH2 43a, R=NH2; b, R=N(CH2)3 42a, R=N(CH2)3; b, R=NHCH2CH3 c, R=NHCH2CH3; d, R=NHCH(CH3)2 c, R=NHCH(CH3)2; d, R=N(CH2CH3)2 e, R=N(CH2CH3)2; f, R=NHC6H4CH3-4 e, R=NHC6H4CH3-4, f, R=NHC6H2F2-2,6 g, R=NHC6H2F2-2,6 Scheme 30

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Some new Cu (II) (46), VO (II) (47), and salts: CuCl2. 2H2O, VOSO4. 2H2O, NiCl2. 6H2O, Ni (II) (48) complexes based on indole-Schiff respectively [113] (Scheme 31). base have been synthesized using the metal

HN HN

CHO H C N O Cl N CH3 H2N CH3 N CH 3 3 Cu + N N N Cl O N CH3 O N CH3 H C N N O N CH3 3 H 1 NH

44 45 complex 46

HN HN

OH2 N CH O N CH H3C N O 3 H3C N O 3 Ni V N N O N CH3 O N CH3 H3C N H3C N OH2 Cl2 OH2 SO4

NH NH

complex 47 complex 48 Scheme 31

Mannish reaction and 2-(3-nitrophenyl)H-imidazo[1,2-a]pyridine Ytterbium triflate [Yb(OTf)3] catalyzes one (49) to give the corresponding Mannish product pot three-components reaction of 1, acetamide 50 [114] (Scheme 32).

NO2

N CHO NO2 O N N H + + Yb(OTf)3, 1,4-dioxane N H N CH CH3 N 2 3 N 120 °C, 12 h H O 1 49 N 50 H Scheme 32

Dyes formation a cationic thermally stable colored open form of a Acid catalized reaction of 1 with 2-methyl- photochromic benzo[1,3]oxazine [115] (Scheme benzo[1,3]oxazine (51) afforded directly 33) polymethine dye 52. This dye has the structure of

O O NH N + TFA N N CF3COO H NO 1 2 51 NO2 HO Scheme 33 52

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Bi and tri-(1H-indole-3-carbaldehyde) indole -3-carbaldehyde (54) on cooling [116] The reaction of 1 with epichlorohydrin in (Scheme 34). DMSO in the presence of NaOH gives bi-1H-

Cl O CHO O O O N N + OH N NaOH, DMSO N H 1 O 53 54 Scheme 34

1H-indole-3-carboxaldehyde (1) on reaction NaOH for 2 days gave bi-indole aldehyde (55) and with xylyl dibromides or 1,3,5-trimethyl-tris- tri-indole aldehyde (56), respectively [117,118]

(bromomethyl)benzene in CH3CN and 25% (Scheme 35).

O Br

O H3C CH3 N R xylyls dibromide N N RBr2 Br CH3 Br H3C CH3

CH3CN N CH3CN,25% NaOH 25% NaOH H 48h 48h 1 O O N CH3 N 55

CH• C• O R O O •HC •HC O 56 Scheme 35

Indolophanes and bisindolostilbenophanes synthesized by intra-, inter- and tandem intra- Divers types of indolophanes (57) and molecular McMurry coupling [117] (Scheme 36). bisindolostilbenophanes (58a,b) have been

Br N O N R Br Br N N N Br Br N (i) CH CN, 25% NaOH, rt, 48 h CH3CN, 3 N (ii) TiCl (30 equiv), Zn (60 equiv), THF, pyridine 25% NaOH, 48 h H 4 N N

57 58 R, •HC Scheme 36

Bis- and triindole derivatives Aldehydes 1, 15c, 15q undergo indium-mediated Bisindolyl alkanes and their derivatives ternary reactions with allyl bromide and indoles constitute an important group of bioactive 12,59 provided symmetrical and unsymmetrical metabolites of terrestrial and marine origin. bisindolyl alkanes 60a-c [119] (Scheme 37).

Egypt.J.Chem. 60, No.5 (2017) 736 ESLAM R. EL-SAWY et al.

O Br + N N indum, THF:H2O (2:1) 30°C, stirr N N R R 1 R R1 1, R=H 60 a, R=R1=H 15c, R=CH Ph 12, R =H 2 1 b, R=CH2Ph; R1=H 15q, R=CH CO Et 59, R =CH 2 2 1 3 c, R=CH2Ph; R1=CH3 Scheme 37

Synthesis of the fused 5H-thiopyrano[2,3- carbaldehyde (61) with indole-2,3-dihydro-2- b:6,5-b'] diindole (63) has been achieved thione (62) in EDDA in acetonitrile in a Q-Tube™ via condensation of 2-(alkylthio)-indole-3- pressure reactor [120] (Scheme 38).

O

SH + S EDDA CH CN, 100°C N N 3 N H H N S H 61 62 63 Scheme 38

Tri(indol-3-yl)methanes 64a and 64b are room temperature [121] or by a mixture of acetic produced in a few minutes via dry reaction of 1 with acid and acetic anhydride [122] (Scheme 39). indole (12) either on Montmorillonite K10 clay at

O HN

M. K10 clay, rt, 5 min + or N N H H CH3CO2H/(CH3CO)2O 1 12 HN N 64a, R=H b, R=COCH3 Scheme 39 R

Cyclic tetraindole (65) has been synthesized Indolenyl sulfonamides via reaction of 1 with sulfamide and platinum Various indolenyl sulfonamides 66a-k, have oxide in catalytic amounts [123] (Scheme 40). been synthesized via condensation of 1 with

HN O H2N NH2 S O O AcOH, PtO2, H2 NH N 60 °C, 4 h H N 1 H NH

Scheme 40 65

Egypt.J.Chem. 60, No.5 (2017) 1H-INDOLE-3-CARBOXALDEHYDE, SYNTHESIS AND REACTIONS 737 different sulfonamides, namely sulfanilamide, sulfamethoxy-pyridazine and sulfacetamide sulfaguanidine, sulfathiazole, sulfamethoxazole, sodium in ethanol (1:1) [124,125] (Scheme 41). sulfaisoxazole, sulfadiazine, sulfamethazine, sulfapyridine, sulfadiazine, sulfamerazine,

O N S R O N 66 H NH N N O O N R= NH2 HN NH N N CH 2 S N CH3 3 H H H CH R 3 O N NN HN R=R1=H HN HN OCH3 N R=R1=CH3 N OCH3 N Na R R=H, R1=CH3

Scheme 41

Kabachnik–Fields reaction (Synthesis of of serine hydrolysis, inhibitors of UDP- α-amino-phosphonate) galactopyranose mutate and anti-tumor agents α-Aminophosphonate, the key substrate [126]. Tillu et al., [126] reported one-pot in the synthesis of α-amino-phosphonic acid, three-component reaction of 1, primary amine shows a number of interesting activities, (p-anizidine) and dibenzyl phosphite using H-beta such as peptidomimetics, enzyme inhibitors, zeolite as a catalyst to afford α-aminophosphonate pharmacogenic agents, herbicides, inhibitors 67 (Scheme 42).

O PhH2CO OCH2Ph MeO NH2 P O NH OCH3 N O PH(OCH2Ph)2 H H-beta zeolite 1 N 67 Scheme 42 H

Synthesis of nitrone derivative oxygen species (ROS) are implicated [127]. For years, the ability of nitrones to act as Samadi et al., reported the preparation of nitrone, a good radical traps has been in the origin of a namely (Z)-α-(1H-3-indolyl) -N-tertbutylnitrone number of basic and clinical studies that aiming (68) via reaction of 1 with N-t-butyl-hydroxyl- at the investigation of their potential therapeutical amine hydrochloride in THF in the presence of applications for the treatment of cerebral ischemia, Na2SO4 and Et3N [127]. (Scheme 43) . or neurodegenerative diseases where reactive

O H R N-t-butylhydroxylamine hydrochloride N N Na2SO4, Et3N, THF, MW O H N 68 1 Scheme 43 H

Reaction with nitromethane (Henary reaction) of a mixture of acetic acid and ammonium acetate Henary reaction involves condensation of to give nitroalkene [128]. McNulty et al., have nitroalkane with aromatic aldehyde in the presence demonstrated the synthesis of 3-(2-nitro-vinyl)-

Egypt.J.Chem. 60, No.5 (2017) 738 ESLAM R. EL-SAWY et al.

1H-indole 69 via reaction of 1 with nitromethan modification by using microwave irradiation or under ultrasound assisted Henery reaction.[128]. ultra sound assisted Henery reaction as the energy Whereas, Rodriguez and Pujol, reported a new source [129] (Scheme 44).

O CH3NO2 NH4OcA/AcOH NO2 ))) CH3NO2 N NH +CH COO- H 4 3 HN 69 1 MW or ))) Scheme 44

Preparation of propargylamines preparation of 3-substituted propargylamine 70 Propargylamines are considered important by three component coupling of 1 with terminal intermediates for the synthesis of many natural alkyne (silyl acetylene), and secondary amine products [130]. Srinivas and Koketsu, have (piperidine) in the presence of AuBr3 as a catalyst reported a simple and efficient route for the [130] (Scheme 45).

O N HN Si Si

N AuBr3 H H2O, 60°C 70 1 N Scheme 45 H Synthesis of heterocycles 15a, 71 and 1,3-cyclic dicarbonyls, namely 4,4- Acridine : A microwave-assisted synthesis has (72a) or 5,5-dimethyl-1,3-cyclo-hexanediones been applied for the synthesis of novel 3,4,6,7-tetr (72b) in the presence of ammonium acetate [131] ahydroacridines73a,b, using substituted aldehydes (Scheme 46).

R1 CH3 O O N

R1 R MW O O + MeOH N R R R O 73a, R=H CH R 3 R b, R=CH3 , R =H N 15a 1 72a, R=H H 71, R1= Br b, R=CH3 Scheme 46

Chromene : Multi-component reaction of 1, catalyst, yielded the 4H-chromene derivative (74) malononitrile and cyclic 1,3-diketones utilizing [132] (Scheme 47). tetrabutyl ammonium fluoride (TBAF) as a

HN O O CN O TBAF 10 mol% + + H2C CN 5 mL H2O N O CN reflux H 1 O NH2 Scheme 47 74

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Cyclohexanone : One-pot reaction of (1 equiv) followed by double aldol condensation afforded of 1 with (3 equiv) of 2-acetylpyridine under cyclohexanone (75) [60]. (Scheme 48) . Claisen-Schmidt condensation, Michael addition,

N O O OH N N COCH3 (3 equiv) OH N NaOH, MeOH, reflux H N 1 N H Scheme 48 75

Diazepine : One pot three component reaction dicarboxylic acid (2,6-PDCA) leads to the of 1, o-phenylenediamine and 3-oxo-butyric formation of 1,5-benzodiazepine derivative 76 acid methyl ester in the presence of 2,6-pyridine [133] (Scheme 49).

O H2N NH2 O NH OCH3

N O O H N H3CO H 1 2,6-PDCA HN 76 Scheme 49

Imidazole : Condensation of 1 with the formation of imidazole derivative 78 [134] phenanthrene-9,10-dione (77) in the presence (Scheme 50). of ammonium acetate and acetic acid leads to

O O O

N + NH4OAc AcOH N N H H 1 77 HN 78 Scheme 50

A cheap and eco-friendly catalyst, namely benzoimidazole 80 via condensation of 1 with p-toluenesulphonic acid on-silica gel, has been used 4-methyl-o-phenelynendiamine in the presence of for a convenient one-pot synthesis of benzimidazole catalytic amount of Cu(II) containing nanosilica 79 from 1 and N-methylbenzene-1,2-diamine 78 triazine dendrimer (Cu(II)-TD@nSiO2) [136] [135]. On the other hand Nasr-Esfahani et al., have (Scheme 51). demonstrated an efficient method for the synthesis

NH2 O HN N CH3 H C NH H3C NH NH2 N 3 2 N HN Cu(II)-TD@nSiO2 N p-toluenesulfonic acid 80 CH3 50°C, air H silica gel, 60 -70°C HN 1 79 Scheme 51 Egypt.J.Chem. 60, No.5 (2017) 740 ESLAM R. EL-SAWY et al.

Isatin acetonitrile at ambient temperature afforded isatin Oxidation of 1 using iodoxy-benzoic acid (81) [137] (Scheme 52).

(IBX) in the presence of CeCl3. 7H2O in aqueous

O O

CeCl .7H O/IBX 3 2 O o N CH3CN/H2O, 80 C N H H 1 Scheme 52 81

Isoxazole induced multi component reaction of 1, ethyl Saikh et al., reported an efficient methodology acetoacetate, hydroxylamine hydrochloride, and for the synthesis of isoxazole (82) via visible light sodium acetate [138] (Scheme 53).

O O O OCH CH + 2 3 + Cl NH OH CH3COONa / aq.C2H5OH O 3 h ν N N H O CH3 N H C 1 H 3 Scheme 53 82

Pyridine ethyl cyanoacetate in n-butanol in the presence of One pot three component reaction of 1, excess ammonium acetate gives the corresponding 2-acetyl-5,6,7,8-tetrahydronaphthalene (83) and cyanopyridone derivative 84 [139] (Scheme 54).

O O O N CH3 + OEt HN N NH4OcA H n-butanol NH 1 83 NC 84 O Scheme 54

ZnCl2-catalyzes one-pot multi-component microwave and conventional methods to yield reaction of 1, malononitrile and thiophenol under thiopyridine derivative (85) [140] (Scheme 55).

O S SH N NC N CH (CN) , 2 equiv H2 N 2 2 H ZnCl2, Ethanol CN 1 reflux or MW 85 N Scheme 55 H

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Cyclocondensation of 1, ethyl acetoacetate and the corresponding 1,4-dihydropyridine (86) [141] ammonium acetate under microwave irradiation (Scheme 56). using La2O3 as a catalyst, leads to the formation of

HN O O

OCH2CH3 + La2O3/solvent free EtOOC COOEt + NH OcA N O CH 4 MW 40-80 s H 3 320 W 1 2 eqiuv H3C N CH3 H Scheme 56 86

Also, cyclocondensation of three-component acid afforded 1,4-dihydropyridine derivative( 87) of 1, ethyl propiolate and 3,4-dimethoxybenzyl [142] (Scheme 57). amine, under heating at 80oC in glacial acetic

NH2 O O EtOOC EtO N N + + O AcOH N OCH 80-100°C H 3 EtO COOEt 1 OCH3 N HN 87 Scheme 57

Purine : One pot reaction of 1 and 5,6-diamino- N-bromosuccinimide (NBS) and azo bis- 1,3-dimethyluracil (88), in acetonitrile isobutyronitrile (AIBN) yields the corresponding and in the presence of catalytic amount of purine derivative (89) [143] (Scheme 58).

O O O NH2 H N NBS/AIBN N + N CH3CN/H2O (9:1) N O N NH2 30C N NH H O N 1 88 Scheme 58 89

Pyrazole : Multi component reaction of under stirring in acetic acid leads to the formation acetylene dicarboxylates, phenylhydrazine and 1 of pyrazolones 90 [144] (Scheme 59).

RO C O NHNH2 2 COR AcOH N + + stirr., rt N N COR 10-18 min H N O Ph 1 H Scheme 59 90 R= Me, Et

Pyrimidine : One-pot three component Fe3O4 particles as a catalyst under solvent-free reaction of 1, malononitrile and benzamidine conditions yields pyrimidine derivative 91 [145]. hydrochloride in the presence of magnetic nano (Scheme 60).

Egypt.J.Chem. 60, No.5 (2017) 742 ESLAM R. EL-SAWY et al.

O

NH2.HCl + CH2(CN)2 + Nano Fe2O4 N 100°C N NH N H 2 HN 1 NC NH2 Scheme 60 91

On the other hand, condensation of 1 with reaction of 1 with ethyl cyanoacetate and urea or urea and ethyl acetoacetate in the presence of thiourea in ethanol in the presence of potassium acid as a catalyst [Biginelli reaction] gives 3,4- carbonate leads to the formation of pyrimidine dihydropyrimidine-2 (1H)-one (92) [146]. Also, derivative 93a,b [68] (Scheme 61).

X O O NHHN HN NH NH2CONH2 CNCH2COOCH2CH3 CH3COCH2COOCH2CH3 O EtOH, acid N NH2C(=X)NH2 H EtOH, K2CO3 HN CN HN CO2Et 1 92 93, X=O Scheme 61 X=S

Quinazoline : Reaction of 1 with anthranilamide leads to the formation of 2,3-dihydroquinazoline in the presence of β-cyclodextrin as a catalyst 94 [147] (Scheme 62).

O O O NH2 NH NH2

N beta-CD/H2O N H 55-60 oC H 1 94 NH Scheme 62

Quinoline : One-pot reaction of 1, fluoride (TBAF) as a catalyst yields the malononitrile and 3,3-dimethyl-5-(phenylamino) corresponding 4H-quinoline derivative 96 [132] cyclohexanone (95) using tetrabutylammonium (Scheme 63).

HN O O O CN CN TBAF 10 mol% + + H2C 5 mL H2O N NH CN reflux H N NH2 1 95 96

Scheme 63

Tetrazole : Multi-component of 1, dipolar cycloaddition afforded (E)-3-(1H-indol- malononitrile and sodium azide in water under 3-yl)-2-(1H-tetrazole-5-yl)acrylonitrile (97) [148] Knoevenagel condensation followed by 1,3 (Scheme 64).

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O CN

CH2(CN)2 N NaN3 N HN N H N N 1 H 97 Scheme 64

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147. Ramesh K., Karnakar K., Satish G., Anil Kumar B. (Received 15/5/2017; S. P. and Nageswar Y. V. D., A concise aqueous accepted 26/7/2017) phase supramolecular synthesis of 2-phenyl-

إندول -3- كاربوكسالدهيد : تخليقه و تفاعالته

إسالم رضا الصاوى ، هبة محمد شحاته أبو سالم وعادل حامد مندور قسم كيمياء المركبات الطبيعية - المركز القومى للبحوث - ص.ب. 12622 دقى - الجيزة - مصر .

االندول-3-كاربوكسالدهيد و مشتقاته يمثلوا الوسيط الرئيسى إلعداد المركبات النشطة بيولوجياً كما انها تمثل الوسيط فى تحضير القلويدات المحتوية على حلقة االندول. أيضا يمثل االندول-3-كاربوكسالدهيد و مشتقاته األساس فى تحضير عديد من مشتقات الحلقات الغير متجانسة و يرجع ذلك إلى مجموعة الكاربونيل و التى تخضع لتفاعالت اإلقتران و اإلختزال.

هذا المرجع يسلط الضوء على التطورات الكيميائية االخيرة و الخاصة باالندول-3-كاربوكسالدهيد من خالل مناقشة الطرق المختلفة و المتطوره لتخليقه و تخليق مشتقاته , كما أنها تسلط الضوء على التفاعالت الهامة و المشهورة الخاصة به و إستخدام هذه المشتقات فى تحضير العديد من المركبات النشطة بيولوجياً.

Egypt.J.Chem. 60, No.5 (2017)