Erin T. Pelkey

Synthesis of 2-nitroindoles via the Sundberg indole synthesis

Abstract A three-step sequence has been developed for converting o -nitrobenzaldehydes into 2-nitroindoles. The key step involves the thermolysis of 2-( o -azidophenyl)nitroethylene ( 10 ) in xylenes which gives 2-nitroindole ( 4 ) in 54% yield, akin to the classic Sundberg indole synthesis. This procedure has also been utilized to synthesize 5,6-dimethoxy-2-nitroindole ( 14 ).

Regioselective 1,3-Dipolar Cycloaddition Reactions of Unsymmetrical Münchnones (1,3-Oxazolium-5-olates) with 2- and 3-Nitroindoles. A New Synthesis of Pyrrolo[3,4-b]indoles

Abstract The unsymmetrical mesoionic munchnones 13 (3-benzyl-2-methyl-4-phenyl-1,3-oxazolium-5-olate) and 14 (3-benzyl-4-methyl-2-phenyl-1,3-oxazolium-5-olate) react with the N-protected 2- and 3-nitroindoles 1 (ethyl 2-nitroindole-1-carboxylate), 6 (3-nitro-1-(phenylsulfonyl)indole), and 17 (ethyl 3-nitroindole-1-carboxylate) in refluxing THF to afford in good to excellent yields the pyrrolo[3,4-b]indoles 15 (2-benzyl-1-methyl-3-phenyl-4-carboethoxy-2,4-dihydropyrrolo[3,4-b]indole), 16 (2-benzyl-3-methyl-1-phenyl-4-carboethoxy-2,4-dihydropyrrolo[3,4-b]indole), 18 (2-benzyl-1-methyl-3-phenyl-4-(phenylsulfonyl)-2,4-dihydropyrrolo[3,4-b]indole), and 19 (2-benzyl-3-methyl-1-phenyl-4-(phenylsulfonyl)-2,4-dihydropyrrolo[3,4-b]indole). In several cases the regiochemistry, which is opposite to that predicted by FMO theory, is very high and leads essentially to a single pyrrolo[3,4-b]indole; e.g., 6+13→19 in 74% yield.

Synthesis of unsymmetrical 3,4-diaryl-3-pyrrolin-2-ones utilizing pyrrole Weinreb amides.

A regiocontrolled synthesis of unsymmetrical 3,4-diaryl-3-pyrrolin-2-ones has been achieved in three steps from 1,2-diaryl-1-nitroethenes with pyrrole-2-carboxamides (pyrrole Weinreb amides) serving as the key linchpin intermediates. Two different methods for the preparation of the requisite nitroalkenes were investigated: (1) modified Henry reaction between arylnitromethanes and arylimines; and (2) Suzuki-Miyaura cross-coupling reaction of 2-aryl-1-bromo-1-nitroethenes with arylboronic acids. Some difficulty was encountered in the preparation of arylnitromethanes, thus leading to the exploration of a cross-coupling strategy that proved more useful. A Barton-Zard pyrrole cyclocondensation reaction between 1,2-diaryl-1-nitroethenes and N-methoxy-N-methyl-2-isocyanoacetamide gave the corresponding pyrrole Weinreb amides, which were then converted into the desired 3-pyrrolin-2-ones in two steps. Overall, this method allowed for the construction of 3,4-diaryl-3-pyrrolin-2-ones with complete regiocontrol of the substituents with respect to the lactam carbonyl. The utility of this synthetic methodology was demonstrated by the preparation of eight unsymmetrical and symmetrical 3,4-diaryl-3-pyrrolin-2-ones including the N-H lactam analogue of the selective COX-II inhibitor, rofecoxib.

Nucleophilic addition reactions of 2-nitro-1-(phenylsulfonyl)indole. A new synthesis of 3-substituted-2-nitroindoles

Abstract 2-Nitro-1-(phenylsulfonyl)indole ( 1 ) undergoes nucleophilic addition reactions with the enolates of diethyl malonate and cyclohexanone, lithium dimethylcuprate, and indole anion to afford the corresponding 3-substituted-2-nitroindoles ( 4–6, 8, 9 ) in low to high yields. Reaction of 1-(phenylsulfonyl)-2-(trialkylstannyl)indoles 13 and 14 with tetranitromethane affords the novel isoxazolo[5,4- b ]indole 15 via a 1,3-dipolar cycloaddition reaction with in situ generated nitro formonitrile oxide ( 19 ).

An abnormal Barton–Zard reaction leading to the pyrrolo[2,3-b]indole ring system

The reaction of 3-nitro-N-(phenylsulfonyl)indole 1 with ethyl isocyanoacetate 2 under the Barton–Zard pyrrole synthesis conditions gives ethyl 8-(phenylsulfonyl)-1,8-dihydropyrrolo[2,3-b]indole-2-carboxylate 3 rather than the anticipated ethyl 4-(phenylsulfonyl)-2,4-dihydropyrrolo[3,4-b]indole-3-carboxylate 4.

Preparation of dibenzo[e,g]isoindol-1-ones via Scholl-type oxidative cyclization reactions.

A flexible synthesis of dibenzo[e,g]isoindol-1-ones has been developed. Dibenzo[e,g]isoindol-1-ones represent simplified benzenoid analogues of biological indolo[2,3-a]pyrrolo[3,4-c]carbazol-5-ones (indolocarbazoles), compounds that have demonstrated a wide range of biological activity. The synthesis of the title compounds involved tetramic acid sulfonates. Different aryl groups were introduced at C4 of the heterocyclic ring via Suzuki–Miyaura cross-coupling reactions. Finally, mild Scholl-type oxidative cyclizations mediated by phenyliodine(III) bis(trifluoroacetate) (PIFA) converted some of the latter compounds into the corresponding dibenzo[e,g]isoindol-1-ones. A systematic study of the oxidative cyclization revealed the following reactivity trend: 3,4-dimethoxyphenyl ≫ 3-methoxyphenyl > 3,4,5-trimethoxyphenyl > 4-methoxyphenyl ≈ phenyl. Overall, the oxidative cyclization required at least two methoxy groups distributed in the aromatic rings, at least one of which had to be located para to the site of the cyclization.

Synthesis of Benzo[a]carbazoles and an Indolo[2,3-a]carbazole from 3-Aryltetramic Acids

A simple and flexible approach to 3-pyrrolin-2-one fused carbazoles is disclosed. The key step involves the BF3-mediated electrophilic substitution of indoles with N-alkyl-substituted 3-aryltetramic acids, which provides access to indole-substituted 3-pyrrolin-2-ones. Scholl-type oxidative cyclizations of these materials led to the formation of the corresponding 3-pyrrolin-2-one-fused benzo[a]carbazoles and indolo[2,3-a]carbazoles. This work represents the first synthesis of the benzo[a]pyrrolo[3,4-c]carbazol-3(8H)-one ring system, while the indolo[2,3-a]pyrrolo[3,4-c]carbazol-5-one ring system is found in a number of biologically active compounds including the protein kinase C (PKC) inhibitor, staurosporine.

Metalation of Indole

Metalation reactions involving indoles (and indolines) is reviewed (through 2009). The most common mode of metalation is lithiation. Other metals that have been used, either through direct metalation of indole or through transmetalation, include magnesium, zinc, tin, and boron. This monograph is divided into three sections: metalation directed by a nitrogen functionality, directed ortho metalation by substituents not located at nitrogen, and halogen–metal exchange. All of the sections are organized by the location of the metalation event. The review will have a primary focus on the seminal papers that contributed to the development of metalation reactions and a secondary focus on applications of metalation reactions used in the synthesis of complex indoles including indole natural products.

Chapter 5.2 - Five-membered ring systems: pyrroles and benzo derivatives

This chapter discusses the progress in synthesis and chemistry of pyrroles, indoles, and related fused ring systems. Several specialized reviews on the chemistry of indoles and pyrroles have appear ...

Chapter 5.1 – Five-Membered Ring Systems: Thiophenes & Se, Te Analogs

Publisher Summary Thiophenes continue to play a major role in commercial applications as well as basic research. In addition to its aromatic properties that make it a useful replacement for benzene in small molecule syntheses, thiophene is a key element in superconductors, photochemical switches and polymers. The presence of sulfur-containing components (especially thiophene and benzothiophene) in crude petroleum requires development of new catalysts to promote their removal (hydrodesulfurization, HDS) at refineries. New reports of selenophenes (Se) and tellurophenes (Te) continue to be modest in number. The chapter presents a summary of the electronic properties that leads into reports of electrocyclic chemistry. Recent reports of studies of HDS processes and catalysts are discussed. Thiophene ring substitution reactions, ringforming reactions, the formation of ring-annelated derivatives, and the use of thiophene molecules as intermediates are then presented. Applications of thiophene and its derivatives in polymers and in other small molecules of interest are also presented. Few examples of selenophenes and tellurophenes reported in the past year are presented. The thiophene ring can be elaborated using standard electrophilic, nucleophilic, and organometallic chemistry. The thiophene ring can be synthesized by a variety of methods including sulfur condensations, classical cyclizations, electrocyclizations, and unusual rearrangements. The electron rich nature of the thiophene ring makes it ideal for electrophilic ring annelation reactions especially at the α-positions.