Synthesis of novel 3‐ and 5‐substituted indole‐2‐carboxamides

The preparation of several novel 3,5‐substituted‐indole‐2‐carboxamides is described. A 5‐nitro‐indole‐2‐carboxylate was elaborated to the 3‐benzhydryl ester, N‐substituted ester, and carboxylic acid intermedi ates, followed by conversion to the amide and then reduction of the 5‐nitro group to the amine. Indole‐2‐carboxamides with 3‐benzyl and 3‐phenyl substituents were prepared in four steps from either a 3‐bromo indole ester using the Suzuki reaction or from a 3‐keto substituted indole ester. N‐Alkylation of ethyl indole‐2‐carboxylate, followed by amidation and catalytic addition of 9‐hydroxyxanthene gave a 3‐xanthyl‐indole‐2‐carboxamide analog and a spiropyrrolo indole as a side product.     

N‐Methyl‐N‐(1‐phenyl­sulfonyl­indol‐2‐ylmethyl)­aniline

In the title compound, 2‐[(methylphenylamino)methyl]‐1‐(phenylsulfonyl)indole, C₂₂H₂₀N₂O₂S, the indole system is not strictly planar and the dihedral angle between the fused rings is 2.7 (1)°. The angles around the S atom of the sulfonyl substituent deviate significantly from the ideal value for tetrahedral geometry. The pyramidalization at the indole N atom is very small. Of the two C—H?O interactions, one influences the orientation of indole with respect to the sulfonyl group and the other determines the orientation of the phenyl bound to sulfonyl. The phenyl ring of the sulfonyl substituent makes a dihedral angle of 89.6 (1)° with the best plane of the indole. The molecular packing is stabilized by C—H?π and C—H?O hydrogen bonds.     

Transformations of Methyl 2‐[(E)‐2‐(Dimethylamino)‐1‐(methoxycarbonyl)ethenyl]‐1‐methyl‐1H‐indole‐3‐carboxylate

A simple and efficient synthesis of novel 2‐heteroaryl‐substituted 1H‐indole‐2‐carboxylates and γ‐carbolines, compounds 1 – 3 , from methyl 2‐(2‐methoxy‐2‐oxoethyl)‐1‐methyl‐1H‐indole‐3‐carboxylate ( 4 ) by the enaminone methodology is presented.     

An Efficient Ugi‐Azide Four‐Component Approach for the Preparation of Novel 1‐(1H‐tetrazol‐5‐yl)‐10‐chloro‐1,2,3,4‐tetrahydropyrazino[1,2‐a] Indoles

The synthesis of novel 1‐(1H‐tetrazol‐5‐yl)‐10‐chloro‐1,2,3,4‐tetrahydropyrazino[1,2‐a] indole derivatives starting from the initially prepared 1‐(2‐bromoethyl)‐3‐chloro‐1H‐indole‐2‐carbaldehyde is described. A variety of likely biologically relevant pyrazino[1,2‐a] indole‐based 1,5‐disubstituted tetrazoles was obtained in moderate to high yields via an Ugi‐azide reaction. These reactions presumably proceed by the imine formation, intramolecular cyclization to iminium ion, and nucleophilic addition tandem reactions, respectively.     

A facile synthesis of 7‐chloromethyl‐1H‐indole‐2‐carboxylates: Replacement of a sulfonic acid functionality by chlorine

Valuable new synthetic intermediates, 7‐chloromethyl‐1H‐indole‐2‐carboxylates ( 3a‐d ), were prepared by the facile elimination of sulfur dioxide under the influence of thionyl chloride from 2‐ethoxycarbonyl‐1H‐indole‐7‐methanesulfonic acids ( 1a‐d ), easily accessible by Fischer‐type indolisation. The 7‐chloromethylindoles easily underwent methanolysis and aminolysis.     

A scalable Nenitzescu synthesis of 2‐methyl‐4‐(trifluoromethyl)‐1H‐indole‐5‐carbonitrile

2‐Methyl‐4‐(trifluoromethyl)‐1H‐indole‐5‐carbonitrile is a key intermediate in the synthesis of selective androgen receptor modulators discovered in these laboratories. A practical and convergent synthesis of the title compound starting from 4‐nitro‐3‐(trifluoromethyl)phenol and tert‐butyl acetoacetate was developed, including a telescoped procedure for synthesis (without isolation) and Nenitzescu reaction of 2‐trifluoromethyl‐1,4‐benzoquinone. Conversion of the known Nenitzescu indole product to a novel triflate intermediate followed by palladium‐catalyzed cyanation afforded a penultimate carbonitrile. Removal of the C‐3 tert‐butyl ester group on the indole through a decarboxylative pathway completed the synthesis of the title compound in six steps (27% overall yield) from 4‐nitro‐3‐(trifluoromethyl)phenol (five steps, 37% overall yield from tert‐butyl acetoacetate). J. Heterocyclic Chem., (2011).     

Synthesis of 2‐(3‐indolyl)‐1,4‐naphthoquinones using 3‐iodoindoles

The usefulness of 3‐iodoindoles available for introduction of an indole unit is presented. The reaction of various halo‐3‐iodoindoles with 1,4‐naphthoquinone gave the corresponding 2‐(3‐indolyl)‐1‐4,naphthoquinones in moderate yields. The 3‐iodoindole was used for synthesis of a compound containing both naph‐thazarin and indole skeletons.     

A facile synthesis of 4‐, 6‐ and 7‐formyl‐1H‐indole‐2‐carboxylates: The CH2SO3H functionality as a masked formyl group

The valuable new synthetic intermediates, ethyl 4‐, 6‐ and 7‐formyl‐1H‐indole‐2‐carboxylates ( 10, 11, 12 ) were prepared from 2‐ethoxycarbonyl‐1H‐indole‐4‐, 6‐ and 7‐methanesulfonic acids ( 1, 2, 3 ), respectively. The transformation of sulfomethyl group to formyl function was accomplished through elimination of SO₂ to yield ethyl 4‐, 6‐ and 7‐chloromethyl‐1H‐indole‐2‐carboxylates ( 4, 5, 6 ), hydrolysed to ethyl 4‐, 6‐ and 7‐hydroxymethyl‐1H‐indole‐2‐carboxylates ( 7, 8, 9 ), then oxidized to aldehydes ( 10, 11, 12 ). Protection at N1 of indole was not necessary. A marked increase in the rate of hydrolysis of 7‐chloromethyl‐indoles compared to that of 4‐ and 6‐(chloromethyl)indoles was observed.     

Palladium‐catalyzed regioselective C2‐arylation of 5‐aminoindole

Pd(II)‐catalyzed C‐H arylations of 5‐aminoindole using iodobenzenes as aryl source was studied. Despite pivalamide directing group at 5‐position of the indole, the direct C2‐arylation of the indole observed in high yields and with high regioselectivity.     

Nickel‐catalyzed Buchwald–Hartwig amination of pyrimidin‐2‐yl tosylates with indole,benzimidazole and 1,2,4‐triazole

Nickel‐catalyzed Buchwald–Hartwig amination of pyrimidin‐2‐yl tosylates with indole and benzimidazole was achieved using Ni(dppp)Cl₂ as catalyst, yielding a variety of novel C2‐substituted pyrimidine derivatives in good yields. This reaction proved to be tolerant of various pyrimidin‐2‐yl tosylates bearing either electron‐donating or electron‐withdrawing groups as well as nucleophiles including indole, benzimidazole and 1,2,4‐triazole. Copyright © 2016 John Wiley & Sons, Ltd.     

N‐{4‐Bromo‐2‐[(3‐bromo‐1‐phenylsulfonyl‐1H‐indol‐2‐yl)methyl]‐5‐methoxyphenyl}acetamide

In the title compound, C₂₄H₂₀Br₂N₂O₄S, the indole ring system is planar and the S atom has a distorted tetrahedral configuration. The sulfonyl‐bound phenyl ring is orthogonal to the indole ring system and the conformation of the phenyl­sulfonyl substituent with respect to the indole moiety is influenced by intramolecular C—H⃛O hydrogen bonds involving the two sulfonyl O atoms. The mean plane through the acetyl­amido group makes a dihedral angle of 57.0 (1)° with the phenyl ring of the benzyl moiety. In the crystal, glide‐related mol­ecules are linked together by N—H⃛O hydrogen bonds and C—H⃛π interactions to form molecular chains, which extend through the crystal. Inversion‐related chains are interlinked by C—H⃛π interactions to form molecular layers parallel to the bc plane. These layers are interconnected through π–π interactions involving the five‐ and six‐membered rings of the indole moiety.     

Pictet‐spengler synthesis of pyrazole‐fused β‐carbolines

The synthesis of new pyrazolo[4,3‐c]β‐carbolines ( 8a,b ) is achieved by condensation of the appropriate aldehyde with 3‐(4‐amino‐1,3‐dimethylpyrazol‐5‐yl)indole ( 4 ) under Pictet‐Spengler reaction conditions. Regioselective cyclization occurred at the usual indole C‐2 position as evidenced from the ¹H‐and ¹³C nmr spectra of 8a,b which lack the pyrrolic H‐2 signal, present in 4 (δ 7.26, 1H, d, J_ch‐NH = 2‐5 Hz).     

Copper‐catalyzed Synthesis of N‐alkylated 2‐(4‐substituted‐1H‐1,2,3‐triazol‐1‐yl)‐1H‐indole‐3‐carbaldehyde by Step‐wise and One‐pot Three‐component Huisgen's 1,3‐dipolar Cycloaddition Reaction

An efficient method for the synthesis of N‐alkylated 2‐(4‐substituted‐1H‐1,2,3‐triazol‐1‐yl)‐1H‐indole‐3‐carbaldehyde has been developed starting from oxindole and indole using Huisgen's 1,3‐dipolar cycloaddition reaction of organic azides to alkynes. The effect of catalysts and solvent on these reactions has been investigated. Among all these conditions, while using CuSO₄·5H₂O, DMF was found to be the best system for this reaction. It could also be prepared in a one‐pot three‐component manner by treating equimolar quantities of halides, azides, and alkynes. The Huisgen's 1,3‐dipolar cycloaddition reaction was performed using CuSO₄·5H₂O in DMF with easy work‐up procedure.     

Synthesis of Some New Spiro,Isolated and Fused Heterocycles Based on 1H‐indole‐2‐One

The reaction of 3‐benzoylcyanomethylidine‐1(H)‐indole‐2‐one ( 1 ) with a variety of active methylene compounds, thioglycolic acid, glycine, hydrazine hydrate and phenyl hydrazine led to the formation of compounds 4a‐d‐10 . 3‐Thiosemicarbazide‐1(H)‐indole‐2‐one 2 on reaction with α‐halocarbonyl compounds gave compounds 11a‐c, 12a‐c . The latter compounds on heating with phosphoryl chloride, cyclization takes place via losing water to give the angular tetracyclic compounds 13a,b and 14a‐c . Cyanoacetic hydrazone derivative 3 readily cyclized upon heating in triethyl orthoformate to give the tricyclic system, oxopyridazino indole 15 . On the other hand, the reaction of 3 with benzylidine malononitrile and benzylidene ethylcyanoactate gave the pyranyl hydrazone derivatives 16a,b .     

Synthesis,characterization and spectral studies of various newer 4‐benzyloxy‐1H‐indole‐2‐carboxylic acid (arylidene)‐hydrazides

4‐Benzyloxyindole‐2‐carboxylic acid hydrazide reacts with aromatic and heterocyclic aldehydes in alcoholic medium in refluxing conditions to give 4‐benzyloxy‐1H‐indole‐2‐carboxylic acid (arylidene)‐hydrazides, important synthetic intermediates for the synthesis of a newer class of pharmacologically active compounds. We describe here the synthesis of various 4‐benzyloxy‐1H‐indole‐2‐carboxylic acid (arylidene)‐hydrazides by conventional as well as microwave irradiation techniques. The structures of these compounds have been confirmed by spectroscopic techniques (FTIR, NMR and MS). Some of the interesting features of the electron impact mass spectral fragmentation pattern of these compounds are also discussed.     

Facile synthesis of 6‐aryl‐5H‐8‐oxa‐4b, 7‐diaza‐benzo[a]azulen‐9‐one derivatives,new tricyclic heterocycles

8‐Oxa‐4b,7‐diaza‐benzo[a]azulene‐9‐one system, a new tricyclic heterocyclic framework is designed through a simple and convenient synthetic sequence. Its 6‐aryl derivatives are synthesized starting from ethyl indole‐2‐carboxylate. Reaction of differently substituted phenacyl bromides with ethyl indole‐2‐carboxylate, treatment of the resultant N‐substituted indole‐2‐carboxylates with hydroxylamine hydrochloride to provide corresponding oximes, subsequent ester hydrolysis followed by dehydrative cyclisation furnished the desired compounds 5 a‐g .     

A Convenient Synthetic Route to Spiro[indole‐3,4′‐piperidin]‐2‐ones

Starting from 1‐[(tert‐butoxy)carbonyl]piperidine‐4‐carboxylic acid and 2‐bromoaniline, the spiro[indole‐3,4′‐piperidin]‐2‐one system was obtained in three high‐yielding steps: anilide formation, N(1)‐protection, and intramolecular cyclization under Pd catalysis as the key reaction. The preparation of the corresponding 2‐bromoanilide was studied. In extension, the same sequence was developed with 4‐methyl‐ and 4‐nitro‐2‐bromoaniline. In the key step, the NO₂ group led to a rather diminished yield. The transformation of the protected spiro[indole‐3,4′‐piperidin]‐2‐one to the corresponding unprotected dihydroindoles is discussed.     

Indole‐N‐Carboxylic Acids and Indole‐N‐Carboxamides in Organic Synthesis

Indoles are ubiquitous structures that are found in natural products and biologically active molecules. The synthesis of indoles and indole‐involved synthetic methodologies in organic chemistry have been receiving considerable attention. Indole‐N‐carboxylic acids and derived indole‐N‐carboxamides are intriguing compounds, which have been widely used in organic synthesis, especially in multicomponent reactions and C?H functionalization of indoles. This Minireview summarizes the advances of reactions involving indole‐N‐carboxylic acids and indole‐N‐carboxamides in organic chemistry, and discusses the synthetic potential and perspective of this field.     

2‐Diazo‐2H‐indoles

2‐Diazo‐2H‐indoles were prepared by diazotization of the corresponding 1H‐indol‐2‐amines and subsequent neutralization. On the basis of NMR data and ab initio and semiempirical calculations, we suggest that the zwitterionic form A is the most representative structure for 2‐diazo‐2H‐indoles. In fact, spectral data are compatible with a 1H‐indole structure, and the fully optimized molecules gave distances in agreement with those reported for the anion obtained from 1H‐indole. The calculated charges are compatible with a zwitterionic structure in which the negative charge is mainly located at the ring N‐atom at variance with the case of diazopyrroles and 3‐diazo‐3H‐indoles where the negative charge is essentially located on the ipso C‐atom.     

Regio‐ and Chemoselective N‐1 Acylation of Indoles: Pd‐Catalyzed Domino Cyclization to Afford 1,2‐Fused Tricyclic Indole Scaffolds

A concise method for the synthesis of 1,2‐fused tricyclic indole scaffolds by domino cyclization involving a Pd‐catalyzed Sonogashira coupling, indole cyclization, regio‐ and chemoselective N‐1 acylation, and 1,4‐Michael addition is reported. This method provides straightforward access to tetrahydro[1,4]diazepino[1,2‐a]indole and hexahydro[1,5]diazocino[1,2‐a]indole scaffolds.