Synthetic studies on indoles and related compounds. XXXI. Chemical confirmation of the synthetic route for the benz[f]indole skeleton and its application

To confirm the structure of ethyl 9-methoxybenz[f]indole ( 8a ) prepared from ethyl pyrrole-2-carboxylate ( 4 ) via a new synthetic route, the following chemical correlation work was performed. Ethyl 9-methoxybenz[f]in-dole ( 8a ) was converted to 1-benzyl-3-methyl-5,6,7,8-tetrahydrobenz[f]indole ( 25 ), which was alternatively and authentically synthesized from ethyl 3-methylpyrrole-2-carboxylate ( 11 ). On the basis of the established route to the benz[f]indole nucleus, two representative benz[f]indoles, benz[f]indole ( 1 ) and 4,9-dioxobenz[f]indole ( 26 ) were synthesized.     

Synthetic entries to 6-fluoro-7-substituted indole derivatives

Three practical synthetic entries of functionalized 6-fluoro-7-substituted indole derivatives were developed in connection with the preparation of 7-fluoro-8-substituted-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid derivatives 11 . The first route, which permits group modification about position 8 of the pyranoindole skeleton, employs 2-bromo-3-fluoroaniline ( 18 ) as a key intermediate, the preparation of which was achieved by either a novel ortho metalation of 15 or via the intermediacy of 22 . The second route utilizes 32 to append a terminally functionalized three carbon side chain onto the indole template and in addition leads to 43 from 40 . The third route to the 7-fluoro-8-substituted-pyranoindole skeleton complements route two in that the synthetic pathway exploits 32 in a nucleophilic fashion to construct a terminally functionalized two carbon appendage onto the indole nucleus.     

二苯并噻吩和吲哚在NiMoS/γ-Al2O3上加氢脱硫和加氢脱氮反应的相互影响

在固定床高压微反装置上考察了预硫化型NiMoS/γ-Al2O3催化剂上二苯并噻吩（DBT）加氢脱硫（HDS）反应和吲哚加氢脱氮（HDN）反应之间的相互影响。结果表明,吲哚对DBT的加氢脱硫反应具有抑制作用,其中对加氢路径（HYD）比对氢解路径（DDS）的抑制作用强,温度升高后,吲哚的抑制作用减弱。吲哚对DBT加氢脱硫反应的抑制作用源于吲哚及其HDN反应的中间产物在活性位上的竞争吸附。DBT和原位生成的H2S促进了催化剂表面硫阴离子空穴（CUS）向B酸位的转化,从而提高1,2-二氢吲哚（HIN）分子中C(sp3)—N键的断裂能力,使得吲哚的转化率和产物中邻乙基苯胺（OEA）的相对含量增大。HDN活性相的形成虽然需要硫原子的参与,但是活性相的保持并不需要大量的硫原子,较高含量硫化物存在时加氢活性位减少,不利于脱氮反应。     

Synthesis of tricyclic indole-2-carboxylic [correction of caboxylic] acids as potent NMDA-glycine antagonists

The practical synthesis of a series of tricyclic indole-2-carboxylic acids, 7-chloro-3-arylaminocarbonylmethyl-1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylic acids, as a new class of potent NMDA-glycine antagonists is described. The synthetic route to the key intermediate 12a comprises a regioselective iodination of 4-chloro-2-nitrotoluene, modified Reissert indole synthesis, Jeffery's Heck-type reaction with allyl alcohol, Wittig-Horner-Emmons reaction, and iodination at the indole C-3 position. The key step in the route is an intramolecular cyclization of 12a to give the tricyclic indole structure. Two methods of cyclization, (1) an intramolecular radical cyclization of 12a and (2) a sequence of intramolecular Heck reaction of 12a followed by a 1,4-reduction, were performed. The resulting tricyclic indole diester 13a was selectively hydrolyzed to afford the desired tricyclic indole monocarboxylic acid 16 on a multihundred gram scale without any chromatographic purifications. Optical resolution of 16 to (-)-isomer 17 and (+)-isomer 18 was carried out, and the resulting isomers were derivatized, respectively. Evaluation of the optically active derivatives for affinity to the NMDA-glycine binding site using the radio ligand binding assay with [(3)H]-5,7-dichlorokynurenic acid revealed that the derivatives of (-)-isomer 17 were more potent than the others and that especially substituted anilide (-)-isomer 24 (K(i) = 0.8 nM) showed high affinity.     

A diastereoselective total synthesis of trans-trikentrin A: a ring contraction approach

A new route to obtain the polyalkylated indole (+/-)-trans-trikentrin A was developed. The synthesis of this natural alkaloid features a thallium(III)-mediated ring contraction reaction to obtain the trans-1,3-disubstituted five-membered ring in a diastereoselective manner. Thallium(III) is chemoselective in this rearrangement, reacting with the olefin without oxidation of the indole moiety. Other key transformations are the Bartoli's reaction to construct the heterocyclic ring and a Heck coupling to add the carbons atom that will originate the nonaromatic cycle.     

Synthesis of the aziridinomitosene skeleton by intramolecular Michael addition of alpha-lithioaziridines: an aromatic route featuring deuterium as a removable blocking group

A convergent synthetic route to the 1,2-aziridinopyrrolo(1,2-a)indole 34 has been developed. Key features of this route include the deuterium kinetic isotope effect to block undesired indole lithiation during tin-lithium exchange from 27a to 30a, the intramolecular Michael addition to generate the enolate 31a, and conversion into 34 by trapping with phenylselenenyl chloride. Reductive cleavage of the N-trityl group in 34 allows access to tetracyclic aziridinomitosenes containing the aziridine N-H subunit. Reduction of the C(9) ester in 34 with LAH gives the primary alcohol 35 with the correct C(9), C(9a), C(10) oxidation state corresponding to the aziridinomitosenes, and deprotection of 34 affords 37.     

Reactions of Indole and Its Derivatives with Cotarnine. Rearrangement of 5-(1-Indolyl)-4-methoxy-6-methyl- 5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinolines

A synthetic route to compounds of the indolyltetrahydroisoquinoline series was developed on the basis of the reaction of cotarnine with indole derivatives. Aminoalkylation of indole and its derivatives with cotarnine occurs regioselectively at the nitrogen atom of the indole fragment to give the corresponding 5-(1-indolyl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinolines. The products were found to undergo rearrangement into isomeric 5-(3-indolyl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro[1,3]dioxolo[4,5-g]isoquinolines which constitute a new class of indolyltetrahydroisoquinoline systems.     

Pentafluorophenylammonium triflate as an efficient, environmentally friendly and novel organocatalyst for synthesis of bis-indolyl methane derivatives

A simple, inexpensive, environmentally friendly and efficient route for the synthesis of bis-indolyl methane derivatives by the reaction of indole or N-methyl indole with aldehydes using pentafluorophenylammonium triflate (PFPAT) as a catalyst is described. PFPAT organocatalyst is air-stable, cost-effective, easy to handle, and easily removed from the reaction mixtures.     

Simple route to 3-(2-indolyl)-1-propanones via a furan recyclization reaction

A simple route to 1-R-3-(2-indolyl)-1-propanones has been elaborated based on recyclization of 2-(2-aminobenzyl)furan derivatives. Being a modification of the Reissert indole synthesis, our approach employs the furan ring as a source of carbonyl function. This approach is general and allows varying of substituents in aromatic ring as well as in 3-position of indole nucleus.     

Parallel synthesis of indolylquinones and their cell-based insulin mimicry

A synthetic route to bis-indolyldihydroxybenzoquinones was adapted for parallel organic synthesis. The route involves selective conjugate addition of an indole to dichlorobenzoquinone promoted by Br?nsted acid, followed by a Lewis acid-promoted conjugate addition of a second indole and a final hydrolysis. Methods for high-throughput purification of the products of this synthesis were also developed. Using these methods, we prepared a library whose structures are based on asterriquinone natural products, which have a wide range of biological activities. In this report, the activities of the library members in activation of the insulin receptor on mammalian cells were examined. Novel compounds were discovered that fall outside earlier developed structure-activity relationships for insulin mimics, supporting the value of systematic investigation (inspired by Nature) for the discovery of novel biologically active molecules.     

Efficient and versatile synthesis of indoles from enamines and imines by cross-dehydrogenative coupling

Complement for Fischer: An efficient palladium-catalyzed indole synthesis proceeds by the intramolecular cross-dehydrogenative coupling of N-aryl imines under mild conditions using molecular oxygen as the sole oxidant. This practical method relies on anilines and ketones as starting materials (and thus the same retrosynthetic disconnection as the Fischer indole synthesis) and will likely become a popular route.     

Polyvinylpolypyrrolidone-supported triflic acid (PVPP·OTf) as a new,efficient, and recyclable heterogeneous catalyst for the synthesis of bis-indolyl methane derivatives

A simple, inexpensive, environmentally friendly and efficient route for the synthesis of bis-indolyl methane derivatives by the reaction of indole or N-methyl indole with aldehydes using polyvinylpolypyrrolidone-supported triflic acid (PVPP·OTf) as a catalyst is described. PVPP·OTf catalyst is air-stable, heterogeneous, cost-effective, easy to handle, and easily removed from the reaction mixtures.     

N-alkenyl indoles as useful intermediates for alkaloid synthesis

A mild cross-coupling reaction to access several N-alkenyl-substituted indoles has been developed. The coupling procedure involves treating a NH-indole with various alkenyl bromides using a combination of 10 mol % of copper(I) iodide and 20 mol % of ethylenediamine as the catalyst in dioxane at 110 °C in the presence of K(3)PO(4) as the base. When treated with acid, these unique enamines produce a dimeric product derived from a preferred protonation reaction at the enamine π-bond. A cationic cyclization reaction of the readily available 2-(2-(1H-indol-1-yl)allyl)cyclopentanol was utilized to construct tetracyclic indole derivatives with a quaternary stereocenter attached to the C(2)-position of the indole ring. An alternative strategy for selective functionalization at the C(2)-position of a N-alkenyl-substituted indole derivative that was also studied involves a radical cyclization of a xanthate derivative. The work described provides an attractive route to the tetracyclic core of some vinca alkaloids, including the tetrahydroisoquinocarbazole RS-2135.     

Total synthesis of the marine pyrroloiminoquinone alkaloid tsitsikammamine A

A concise route to the marine pyrroloiminoquinone alkaloid tsitsikammamine A and a regioisomer was developed. The synthesis was based on a Michael reaction between the indole dione 6 and 2′-amino-1-(4-methoxyphenyl)ethanol.     

An improved,regioselective synthesis of the radiolabelling precursor for the translocator protein targeting positron emission tomography imaging radiotracer [F]GE-180

[¹⁸F]GE-180 has been demonstrated to be a promising new positron emission tomography radiotracer for targeting translocator protein. PET imaging of TSPO will enable measurement of neuroinflammation and microglia activity in vivo. The synthetic route used in the initial discovery of GE-180, whilst enabling the rapid evaluation of the structure–activity relationships (SAR) in this molecular class, was not high yielding and not suitable for scale-up. Here we present an optimised route towards GE-180 and the radiolabelling precursor of [¹⁸F]GE-180 with significantly improved yields due to a strategy which improves the regioselectivity of the key indole formation step of the synthesis.     

General route to the total synthesis of sempervirine analogues containing modified E rings, potential cytostatics

Sempervirine analogues 13a–c with different E rings have been obtained via inverse electron demand Diels–Alder reactions of 5-acetyl-3-(methylsulfanyl)-1,2,4-triazine with cyclic enamines (formation of D and E rings) followed by Fischer indole synthesis under microwave irradiation on solid support (formation of A and B rings) and subsequent annulation of indole derivatives 10a–c via a directed metallation route (formation of C rings).     

Straightforward protocol for the efficient synthesis of varied N-acylated (aza)indole 2-/3-alkanoic acids and esters: optimization and scale-up

A library of approximately 40 N¹-acylated (aza)indole alkanoic esters and acids was prepared employing a microwave-assisted approach. The optimized synthetic route allows for parallel synthesis, variation of the indole substitution pattern, and high overall yield. Additionally, the procedure has been scaled up to yield multi-gram amounts of preferred indole compounds, e.g.: 2′-des-methyl indomethacin 2. The reported compounds were designed as biomedical tools for primary and secondary in vitro and in vivo studies at relevant molecular targets.     

Synthesis of substituted 4-(1H-indol-6-yl)-1H-indazoles as potential PDK1 inhibitors

The development of a preparative route to a series of novel 4-(1H-indol-6-yl)-1H-indazole compounds as potential PDK1 inhibitors is described. The synthetic strategy centres on the late-stage Suzuki cross-coupling of N-unprotected indazole and indole fragments. The use of a monoligated palladium catalyst system was found to be highly beneficial in the cross-coupling reaction. The indazole and indole fragments were constructed by diazotisation/cyclisation and S_NAr/reductive cyclisation sequences, respectively.     

Stereoselective Synthesis of cis-2 and trans-2-(Indol-3-yl) Cyclopropyl Amines,Carboxylic Acids,and Esters

We report a general route for the synthesis of E and Z isomers of indol-3-yl cyclopropyl amines, carboylic acids, and esters. These cyclopropane containing molecules are of interest as conformationally constrained analogues of tryptamine and indole propionic acid, biologically active indoles. The route involves reaction of vinyl indole with ethyl diazoacetate, chromatographic separation of the E and Z stereoisomers of the resulting cyclopropane esters, hydrolysis to form the E and Z cyclopropane acids, and formation of amines by the Curtius reaction.     

A convenient access to 1,3-disubstituted furo[3,4-b]indoles by acid ion-exchange resin-catalyzed furan formation

Efficient synthesis of furo[3,4-b]indoles starting from the corresponding indole is reported. The first route involves derivatization, protection, and deprotection steps, which stretch the syntheses. The second method provides a shorter and more efficient strategy to accessing the furoindole. The innovation starts with alkylation at C-2 of the indole presenting at the C-3 position a ketone-acetal, followed by the cycloaromatization catalyzed by polymeric ion-exchange resins. The second route represents a significant improvement over other methods previously described.