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.     

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.     

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.     

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.     

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.     

UPLC‐HR‐MS/MS‐based determination study on the metabolism of four synthetic cannabinoids,ADB‐FUBICA,AB‐FUBICA,AB‐BICA and ADB‐BICA,by human liver microsomes

Since 2012, several cannabimimetic indazole and indole derivatives with valine amino acid amide residue have emerged in the illicit drug market, and have gradually replaced the old generations of synthetic cannabinoids (SCs) with naphthyl or adamantine groups. Among them, ADB‐FUBICA [N‐(1‐amino‐3,3‐dimethyl‐1‐oxobutan‐2‐yl)‐1‐(4‐fluorobenzyl)‐1H–indole‐3‐carboxamide], AB‐FUBICA [N‐(1‐amino‐3‐methyl‐1‐oxobutan‐2‐yl)‐1‐(4‐fluorobenzyl)‐1H–indole‐3‐carboxamide], AB‐BICA [N‐(1‐amino‐3‐methyl‐1‐oxobutan‐2‐yl)‐1‐benzyl‐1H‐indole‐3‐carboxamide] and ADB‐BICA [N‐(1‐amino‐3,3‐dimethyl‐1‐oxobutan‐2‐yl)‐1‐benzyl‐1H‐indole‐3‐carboxamide] were detected in China recently, but unfortunately no information about their in vitro human metabolism is available. Therefore, biomonitoring studies to screen their consumption lack any information about the potential biomarkers (e.g. metabolites) to target. To bridge this gap, we investigated their phase I metabolism by incubating with human liver microsomes, and the metabolites were identified by ultra‐performance liquid chromatography–high resolution–tandem mass spectrometry. Metabolites generated by N‐dealkylation and hydroxylation on the 1‐amino‐alkyl moiety were found to be predominant for all these four substances, and others which underwent hydroxylation, amide hydrolysis and dehydrogenation were also observed in our investigation. Based on our research, we recommend that the N‐dealkylation and hydroxylation metabolites are suitable and appropriate analytical markers for monitoring their intake.     

Preparation and reactivity of 5‐substituted azepino[3,4‐b]indoles

Preparation of the 5‐substituted azepino[3,4‐b]indole core structure can be realised through a catalytic Heck reaction. The scope and limitations of this methodology are reported. The reactivity of di‐tert‐butyl 5‐ethoxycarbonylmethylene‐1,3,4,5‐tetrahydro‐1‐oxoazepino[3,4‐b]indole‐2,10‐dicarboxylate (1) was investigated in order to prepare the indole analogue of hymenialdisine and derivatives.     

1H‐Pyrrolo[2,3‐b]pyridine‐3‐acetic acid as a molecular probe for use in auxin physiology

The structural characterization of 1H‐pyrrolo­[2,3‐b]­pyridine‐3‐acetic acid (alternative name: 7‐aza­indole‐3‐acetic acid), C₉H₈N₂O₂, reveals similar molecular geometry, i.e. with the side chain perpendicular to the 7‐aza­indole ring, to that of the natural plant growth hormone indole‐3‐acetic acid (auxin) and its alkyl­ated and halogenated derivatives.     

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).     

Rearrangement of spiro[2H‐1‐benzopyran‐2,2′‐[2H]indoles] to pyrrolo[1,2‐a]indole derivatives

Heating of 1′‐(N‐substituted carbamoyl)methylspiro[2H‐1‐benzopyran‐2,2′‐[2H]indoles] with potassium hydroxide in ethanol yields diastereomeric 5a,13‐methano‐6H‐1,3‐benzoxazepino[3,2‐a]indole‐12‐carbox‐amides. Reduction of the latter with sodium borohydride affords 1,2,3,9a‐tetrahydro‐2‐hydroxyaryl‐9H‐pyrrolo[ 1,2‐a] indole‐3 ‐carboxamides.     

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.     

Indole‐Diterpene Synthetic Studies: Total Synthesis of (−)‐21‐Isopentenylpaxilline

An efficient, stereocontrolled total synthesis of the complex indole‐diterpene alkaloid (?)‐21‐isopentenylpaxilline ( 1 ) has been achieved. Key elements of the synthesis include the stereocontrolled construction of the advanced eastern hemisphere (?)‐ 68 , involving a highly efficient union of the eastern and western fragments (?)‐ 68 and 5 exploiting our 2‐substituted indole synthesis, application of the Negishi π cycloalkylation tactic as a new, potentially general protocol for the construction of ring C, and the fragmentation of a β,γ‐epoxy ketone to introduce the tertiary OH group at C(13) in the indole diterpene skeleton.     

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.     

Synthesis and chemiluminescent activity of 8,9‐dihydrobenzo[g] pyridazino[4,5‐b]indole‐7,10(11H)‐diones

Substituted and unsubstituted naphthylamines were transformed into the corresponding triazole derivatives, which were converted to dimethyl 1H‐benz[g]indole‐2,3‐dicarboxylates by photocyclization. The reaction of the diesters with hydrazine hydrate gave the corresponding 8,9‐dihydrobenzo[g]‐pyridazino[4,5‐b]indole‐7,10(11H)‐diones (5) . One of compounds 5 was found to have chemiluminescent activity similar to luminol.     

One‐Pot,Three‐Component Synthesis of Novel Spiro[3H‐indole‐3,2′‐thiazolidine]‐2,4′(1H)‐diones in an Ionic Liquid as a Reusable Reaction Media

A facile one‐pot, three‐component protocol for the synthesis of novel spiro[3H‐indole‐3,2′‐thiazolidine]‐2,4′(1H)‐diones by condensing 1H‐indole‐2,3‐diones, 4H‐1,2,4‐triazol‐4‐amine and 2‐sulfanylpropanoic acid in [bmim]PF₆ (1‐butyl‐3‐methyl‐1H‐imidazolium hexafluorophosphate) as a recyclable ionic‐liquid solvent gave good to excellent yields in the absence of any catalyst (Scheme 1 and Table 2). The advantages of this protocol over conventional methods are the mild reaction conditions, the high product yields, a shorter reaction time, as well as the eco‐friendly conditions.     

Synthesis and Photochromic Behaviour of Novel 2H‐1‐Benzopyrans (=2H‐Chromenes) Derived from Carbazololes

The synthesis and photochromic properties of new 2,2‐diphenyl‐2H‐1‐benzopyrans, fused to an indole moiety, are described. All compounds exhibit photochromic behaviour in solution at room temperature. The heteroanellation effects are variable and depend on the position and geometry of the fused indole moiety. A general bathochromic shift in the spectra of the open forms is observed. The presence of a N‐methyl group prevents the broadening of the absorption spectra and promotes the instability of some photoinduced forms of compounds with the indole moiety fused at the 5,6 positions of the 2H‐1‐benzopyran skeleton. The enhanced photocolouration efficiency in the near‐UV and the kinetics of thermal bleaching indicate that the novel compounds with an indole moiety fused at the 6,7 positions, particularly those with a linked thiophene moiety, are very interesting molecules for applications in the field of variable optical absorption systems.     

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 .     

Prenylated Indole Alkaloid Derivatives from Marine Sediment‐Derived Fungus Penicillium paneum SD‐44

Three new prenylated indole alkaloids, including two β‐carbolines, penipalines A and B ( 1 and 2 , resp.), and one indole carbaldehyde derivative, penipaline C ( 3 ), as well as two known indole derived analogs, 4 and 5 , were isolated from the deep‐sea‐sediment derived fungus Penicillium paneum SD‐44 cultured in a 500‐l bioreactor. The structures of the new compounds were determined on the basis of 1D‐ and 2D‐NMR spectroscopy, as well as by high‐resolution mass spectrometry. The new compounds 2 and 3 showed potent cytotoxic activities against A‐549 and HCT‐116 cell lines.     

Biology‐Oriented Combined Solid‐ and Solution‐Phase Synthesis of a Macroline‐Like Compound Collection

Macrolines constitute a class of natural products that has more than 100 members and displays diverse biological activities. These compounds feature a cycloocta[b]indole scaffold that represents an interesting target structure for biology‐oriented synthesis (BIOS). We have presented a solid‐phase synthesis of isomerically pure cycloocta[b]indoles by employing the Pictet–Spengler reaction and the Dieckmann cyclization as key steps. The scope of this reaction sequence was investigated in more detail by using various additional diversification procedures, such as Pd‐catalyzed Sonogashira or Suzuki couplings on a solid phase, thus allowing, for example, the generation of 10‐substituted cycloocta[b]indole derivatives. Finally, solution‐phase decoration of the cycloocta[b]indole skeleton by reduction and saponification was evaluated, thereby further extending the scope of the solid‐phase synthesis.     

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.