The diazo route to diazonamide A. Studies on the indole bis-oxazole fragment

[structure: see text] Various approaches to the indole bis-oxazole fragment of the marine secondary metabolite diazonamide A are described, all of which feature dirhodium(II)-catalyzed reactions of diazocarbonyl compounds in key steps. Thus, 3-bromophenylacetaldehyde is converted into an alpha-diazo-beta-ketoester, dirhodium(II)-catalyzed reaction of which with N-Boc-valinamide resulted in N-H insertion of the intermediate rhodium carbene to give a ketoamide that readily underwent cyclodehydration to give (S)-2-(1-tert-butoxycarbonylamino)-2-methylpropyl]-5-(3-bromobenzyl)oxazole-4-carboxamide, after ammonolysis of the initially formed ester. This aryl bromide was then coupled to a 3-formyl-indole-4-boronate under Pd catalysis to give the expected biaryl. Subsequent conversion of the aldehyde group into a second alpha-diazo-beta-ketoester gave a substrate for an intramolecular carbene N-H insertion, although attempts to effect this cyclization were unsuccessful. A second approach to an indole bis-oxazole involved an intermolecular rhodium carbene N-H insertion, followed by oxazole formation to give (S)-2-[1-tert-(butoxycarbonylamino)-2-methylpropyl]-5-methyloxazole-4-carboxamide. A further N-H insertion of this carboxmide with the rhodium carbene derived from ethyl 2-diazo-3-[1-(2-nitrobenzenesulfonyl)indol-3-yl]-3-oxopropanoate gave a ketoamide, cyclodehydration of which gave the desired indole bis-oxazole. Finally, the boronate formed from 4-bromotryptamine was coupled to another diazocarbonyl-derived oxazole to give the corresponding biaryl, deprotection and cyclization of which produced a macrocyclic indole-oxazole derivative. Subsequent oxidation and cyclodehydration incorporated the second oxazole and gave the macrocyclic indole bis-oxazole.     

Synthesis of new di-(3-indolyl)arenes

1,4-Di-(3-indolyl)benzene 6 and 2,8-di-(3-indolyl)dibenzofuran 12 were synthesized from 1,4-diacetylbenzene and 2,8-diacetyldibenzofuran, respectively, via indole synthetic strategies. Investigation into the acid-catalysed formation of macrocyclic systems from these di-(3-indolyl)arenes led to the development of the 18-membered macrocycle 14 from the diindolylbenzene 6, which was capable of undergoing complexation with nickel(II) ions.     

N-H Insertion reactions of rhodium carbenoids. Part 5: A convenient route to 1,3-azoles

Dirhodium(II) carboxylate catalysed reaction of diazocarbonyl compounds 2 in the presence of primary amides 1 results in the formation of α-acylaminoketones 3 (12 examples) by N-H insertion reaction of the intermediate rhodium carbene. The 1,4-dicarbonyl compounds 3 are readily converted into structurally diverse oxazoles 4 (11 examples) by cyclodehydration, thiazoles 5 (10 examples) by treatment with Lawesson's reagent, or imidazoles 6 (2 examples) by reaction with ammonia or methylamine.     

（R）-螺[4，5]癸-2，7-二酮的合成

从环己烯酮出发，经手性催化的Michael加成反应，Wolff重排反应延长碳链， 再利用重氮化合物的C-H插入反应，以8步反应28．5％的总收率合成了手性β，β '-螺二酮．在合成路线中手性中心的构型保持不变．在最后的检测中未发现另一对 映体，开始产生的手性中心在合成过程没有消旋化。     

Highly diastereoselective addition of the lithium enolate of alpha-diazoacetoacetate to N-sulfinyl imines: enantioselective synthesis of 2-oxo and 3-oxo pyrrolidines

The highly enantioselective synthesis of 2-oxo and 3-oxo pyrrolidines has been achieved by diastereoselective addition of the lithium enolate of alpha-diazoacetoacetate to chiral N-sulfinyl imines, followed by photoinduced Wolff rearrangement or Rh(II)-catalyzed intramolecular N-H insertion.     

A facile synthesis of naturally occurring 5-(3-indolyl)oxazoles

A simple and efficient synthesis of naturally occurring 5-(3-indolyl)oxazoles is described. The key steps of this convergent approach are the formation of a 3-tosyloxyacetyl-1-benzenesulfonylindole, a 3-amino-acetyl-1-benzenesulfonylindole hydrochloride and cyclodehydration of an α-acylaminoketone.     

Anhydro base of 4-(3-indolyl)pyrimidine

The reaction of 4-(3-indolyl)pyrimidine methiodide with alkali gives a stable anhydro base, which reacts under mild conditions with methyl iodide to give 1-methyl-4-(1-methyl-3-indolyl)pyrimidinium iodide. On the basis of the calculated molecular diagrams of both compounds it was concluded that they have high reactivities. The reaction of the anhydro base with an aqueous methanol solution of KOH, concentrated NH₄OH, hydrazine hydrate, and a mixture of malonic acid dinitrile with triethylamine leads to 3-acetylindole, 4-(3-indolyl)pyrimidine, 3(5)-(3-indolyl)pyrazole, and 2-amino-3-cyano-6-(3-indolyl)pyridine, respectively. 1-Methyl-4-(1-methyl-3-indolyl)pyrimidinium iodide under the same conditions gives similar compounds that contain a methyl group attached to the indole nitrogen atom. The structures of the synthesized compounds were confirmed by their IR, UV, PMR, and mass spectra.See [1] for our preliminary communication.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 212–218, February, 1982.     

Synthesis and Cytotoxicity of Derivatives of Di(3-indolyl) Selenide

A method has been developed for the synthesis of di(3-indolyl) selenides. From indole and SeO₂. N-Alkyl derivatives of di(3-indolyl) selenide have been obtained in the two-phase system alkyl halide–solid K₂CO₃ (or KOH)–18-crown-6–toluene. It was discovered that N-unsubstituted di(3-indolyl) selenides possess high cytotoxicity on HT-1080 and MG-22A tumor cell lines.     

Synthesis of 1-(2-ethyl-3-indolyl)-1-(3-pyridyl)ethylene and related ellipticine analogues

Indole, 2-methylindole, and 3-etliylindole have been condensed with acetyl- and propionylpyridine, respectively. When propionylpyridine was used as the reactant, the product always was a 1-(pyridyl)-1-indoly[propylene. Condensation of 2-substituted indoles with 3-acetylpyridine gave similar products, whereas a similar condensation with 4-acetylpyridine gave 1,2-bis(3-indolyl)-1-(4-pyridyl)ethanes (e.g. 7a ). Condensation of unsubstituted indole with 3-or 4-acetylpyridine respectively, gave 1,1-bis(3-indolyl)-1-(pyridyl)ethanes (e.g. 6c ).     

Indole derivatives CXV. Synthesis and some transformations of 5-(3-indolyl)isoxazole-3-carboxylic acid

5-(3-Indolyl)isoxazole-3-carboxylic acid and its amide and hydrazide were obtained from ethyl 5-(3-indolyl)isoxazole-3-carboxylate. When 5-(3-indolyl)isoxazole-3-carboxylate is heated, it undergoes decarboxylation with isomerization to 3-(-cyanoacetyl)indole; when it is heated in alcohol with hydrazine and phenylhydrazine in the presence of copper, it undergoes isomerization to 5-(3-indolyl)pyrazole-3-carboxylic and 1-phenyl-5-(3-indolyl)-pyrazole-3-carboxylic acids. 5-(3-Indolyl)pyrazole-3-carboxylic acid hydrazide is formed when a solution of ethyl 5-(3-indolyl)isoxazole-3-carboxylate is refluxed with hydrazine in 96% alcohol.See [1] for communication CXIV.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 936–938, July, 1978.     

Domino carbocationic rearrangement of aryl-2-(1-N-methyl/benzyl-3-indolyl)cyclopropyl ketones: a serendipitous route to 1H-cyclopenta[c]carbazole framework

Aryl-2-(N-methyl/benzyl-3-indolyl)cyclopropyl ketones 2a-m are shown to undergo a novel unexpected domino carbocationic rearrangement in the presence of SnCl(4)/CH(3)NO(2) yielding 2-aroyl-3-aryl-1H-cyclopenta[c]carbazoles 3a-m in good yields. The possible mechanistic pathway for this interesting transformation involves a series of cascade events, (a) electrophilic ring opening of cyclopropyl ketone, (b) intermolecular enol capture of the resulting zwitterionic intermediate, (c) electrophilic dimerization of indole moieties to give tetrahydrocarbazole intermediate and its subsequent aromatization by elimination of an indole moiety and dehydrogenation, and (d) intramolecular aldol condensation of the side chain to give a cyclopentene ring. The overall transformation involves formation of three carbon-carbon bonds along with a fused benzene and a substituted cyclopentene ring in one-pot operation from simple indole precursors.     

Facile chemoselective rhodium carbenoid N-H insertion reactions: synthesis of 3-arylamino- or 3-heteroarylpiperidin-2-ones

Rhodium(II) acetate catalyzed reactions of various substituted 3-diazopiperidin-2-ones with a range of aromatic amines, indoles, and benzotriazole yield exclusively the corresponding N-H insertion products despite competing C-H or O-H insertions. This strategy provides an example of a facile chemoselective N-H insertion reaction delivering a library of 3-arylamino and 3-heteroarylpiperidin-2-one derivatives in high yields.     

Rhodium carbenoid N-H insertion reactions of primary ureas: solution and solid-phase synthesis of imidazolones

[reaction: see text] The solution and solid-phase synthesis of imidazolones is reported. The key step for the preparation of these compounds is the N-H insertion reaction of primary ureas into highly reactive rhodium carbenoid intermediates. Typically, a soluble or support-bound alpha-diazo-beta-ketoester is treated with a rhodium carboxylate catalyst in the presence of a primary urea to give the corresponding N-H insertion product. Subsequent acid-catalyzed cyclodehydration of these insertion products affords the desired imidazolone products.     

Synthesis of 2,5-bis{(diethyl-3′-indolyl)methyl}furan and its N,N′-dimetallated complexes (lithium, sodium and potassium): X-ray crystal structures of 2,5-bis{(diethyl-3′-indolyl)methyl}furan and the polymeric tetrahydrofuran adduct of the dilithiated complex

The synthesis of 2,5-bis{(diethyl-3′-indolyl)methyl}furan by the acid catalysed condensation of 2,5-bis(diethylhydroxymethyl)furan with indole is presented. Dilithium, disodium and dipotassium derivatives are prepared by the reaction of the bis(indole) with n-BuLi, NaH and K, respectively, in the presence of various Lewis bases. The X-ray structures of 2,5-bis{(diethyl-3′-indolyl)methyl}furan and the dilithiated derivative (as a polymeric tetrahydrofuran adduct) are reported.     

Chemistry of diazocarbonyl compounds: XXV. Comparative photochemistry of diazo compounds and sulfur ylides of the 1,3-dioxane-4,6-dione series

Photochemical decomposition of 2,2-dialkyl-5-diazo-1,3-dioxane-4,6-diones in the presence of pyridine, methanol, or dimethyl sulfide as carbene traps involves mainly the Wolff rearrangement which is likely to follow a concerted pattern, while the yield of the “carbene” products does not exceed 27–28%. No carbene intermediates are formed in the photolysis of the corresponding dioxo sulfonium ylides under analogous conditions, and the main photochemical process is 1,2-methyl shift (Stevens rearrangement), followed by photochemical transformations of the primary products according to the Norrish type II pattern.     

Experimental and theoretical investigation of reversible interconversion, thermal reactions, and wavelength-dependent photochemistry of diazo Meldrum's acid and its diazirine isomer, 6,6-dimethyl-5,7-dioxa-1,2-diaza-spiro[2,5]oct-1-ene-4,8-dione

The photochemical or thermal decomposition of diazo Meldrum's acid (1) in methanolic solutions yields ketoester 3a, the product of the Wolff rearrangement, while products produced from the singlet carbene were not detected. This observation, combined with the analysis of activation parameters for the thermal decomposition of 1, as well as with the results of DFT B3PW91/6-311+G(3df,2p) and MP2/aug-cc-pVTZ//B3PW91/6-311+G(3df,2p) calculations, allows us to conclude that the Wolff rearrangement of 1 is a concerted process. The outcome of the photolysis of diazo Meldrum's acid depends on the wavelength of irradiation. Irradiation with 254 nm light results in an efficient (Phi(254) = 0.34) photo-Wolff reaction, while at 355 nm, the formation of diazirine 2 becomes the predominant process (Phi(350) = 0.024). This unusual wavelength selectivity indicates that Wolff rearrangement and isomerization originate from different electronically excited states of 1. The UV irradiation of diazirine 2 leads to the loss of nitrogen and the Wolff rearrangement, apparently via a carbene intermediate. This process is accompanied by a reverse isomerization to diazo Meldrum's acid. Triplet-sensitized photolysis of both isomers results in the formation of Meldrum's acid, the product of a formal reduction of 1 and 2. Mild heating of diazirine 2 produces quantitative yields of diazo Meldrum's acid. The activation parameters for thermal reactions of diazo 1 and diazirino 2 isomers were determined in aqueous and dioxane solutions.     

New fluorogenic probes for oxygen and carbene transfer: a sensitive assay for single bead-supported catalysts.

A high-throughput screening assay for atom transfer catalysis has been developed. This assay is based on two probes, developed herein, which generate highly fluorescent products upon carbene or oxygen atom transfer. The emission wavelength of probes 1 and 5 shift significantly (up to 90 nm) upon epoxidation, allowing detection of product at 3% conversion. Probe 7 is not fluorescent, while fluorescence emission by carbene insertion/rearrangement product 8 allows detection at less than 1% conversion. Such sensitivity allows for examination of single-bead reactions in a high throughput array format (1536 wells per plate), and provides a broad detection window ranging from single to high turnover numbers. Thousands of metal complexes are evaluated in a single screening experiment. Preliminary screening of a diverse ligand library with probe 7 in the presence of Rh(II) uncovered new catalysts capable of cyclopropanation and C-H insertion.     

Indole derivatives. 120. Synthesis of higher ω-(3-indolyl)alkanoic acids by alkylation of indole lactones

The alkylation of indole with the tridecanolide, pentadecanolide, and oxo lactones of ω-hydroxyethoxyundecanoic and ω-hydroxybutoxyundecanoic acids was investigated. Higher indolylalkanoic acids, viz., ω-(3-indolyl)undecanoic, ω-(3-indolyl)tride-canoic, and ω-(3-indolyl)pentadecanoic acids, were obtained. The scheme of the alkylation of indole with oxo lactones, and the difference in the rates of the reactions of the ester and lactone bonds, were established from the reaction products. See [1] for communication 119. Translated from Khimiya Getetotsiklicheskikh Soedinenii, No. 2, pp. 216–217, February, 1980.     

Convenient preparation of indolyl Malonates via Carbenoid insertion

Indoles, when treated with methyldiazomalonate under catalysis by rhodium(II)acetate, undergo C-H and N-H insertion reactions regioselectively depending on the substitution pattern on the indole moiety. In indoles where the 3-position is unsubstituted, high yields of the C3-H insertion product were observed. In 3-alkylindoles, 2-substitution predominated, while N-methyltetrahydrocarbazole yielded the product resulting from insertion into the C6-H bond. Indoles in which the nitrogen is unprotected yield varying degrees of N-H insertion.     

Synthesis of macrocyclic systems derived from di-(2-indolyl)heteroarenes

A number of new 3,6-di-(2-indolyl)-dibenzofuran and carbazole derivatives have been prepared from dibenzofuran and carbazole linkers via the Fischer indole synthesis. The bis-indoles were successfully formylated at C3 and the resulting dicarbaldehydes were combined with diamines to generate indole based imine macrocyclic systems.