Mechanistic evidence for intermolecular radical carbonyl additions promoted by samarium diiodide

In this work, mechanistic studies were performed to understand the SmI2/H2O-mediated coupling of N-acyl oxazolidinones with acrylates and acrylamides, providing gamma-keto esters and amides, respectively. Our results provide experimental evidence that C-C bond formation via intermolecular radical addition reactions to carbonyl substrates can be promoted by samarium diiodide. Coupling reactions with N-cyclopropylcarbonyl-2-oxazolidinone suggest the alpha,beta-unsaturated esters/amides are reduced by the low-valent lanthanide reagent and not the N-acyl oxazolidinones, as originially proposed (J. Am. Chem. Soc. 2005, 127, 6544). Rate measurements support the preferred reduction of an acrylate or acrylamide by SmI2/H2O in the presence of an N-acyl oxazolidinone. In the absence of the N-acyl oxazolidinone, SmI2/H2O promotes dimerization of the acrylates, whereas the C=C bond of the acrylamides is reduced. In addition, coupling of the Pfp ester of Cbz-protected phenylalanine with an acrylamide leads only to reduction of the acrylamide and recovered ester, whereas the same coupling with the N-acyl oxazolidinone derivative provides the gamma-keto amides. These results imply that a pathway involving nucleophilic acyl substitution cannot take place and that a radical mechanism must be invoked to explain the C-C bond formation. We propose that the acrylate/acrylamide is reduced to a conjugated ketyl radical that adds to the exocyclic carbonyl group of the N-acyl oxazolidinone, activated through bidentate coordination to a lanthanide ion.     

Expanding the scope of the acyl-type radical addition reactions promoted by SmI2

N-acyl oxazolidinones of simple carboxylic acids and amino acids were observed to undergo successful SmI2-promoted couplings with substituted acrylamides and acrylates, affording a variety of functionalized gamma-ketoamides and -esters with yields attaining 85%. As many of these reductive couplings were previously found to be ineffective employing the corresponding 4-pyridylthio esters, the applicability of this methodology has been substantially improved. The methodology has been adapted to prepare structures related to two potent aspartate protease inhibitors, the renin inhibitor aliskiren, and the gamma-secretase inhibitor L-685,458. Finally, a convenient two-step procedure for the preparation of N-acyl oxazolidinones of N-protected amino acids, which provides consistently good yields of the corresponding imide, has been devised.     

The effect of varying substituents on the equilibrium distribution and conformation of macrocyclic steroidal N-acyl hydrazones

The equilibrium distribution of deoxycholate-based macrocyclic N-acyl hydrazones is dependent upon the nature of the substituents at the 3- and 12-position. These substituents can also influence the preferred conformation of the macrocycles. The conversion of pure cyclic dimer and trimer into a mixture of both components, in the presence of trifluoroacetic acid, has been demonstrated and an X-ray crystal structure obtained of a macrocyclic N-acyl hydrazone dimer.     

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.     

Copper-promoted carbon-nitrogen bond formation with 2-iodo-selenophene and amides

We present here carbon-nitrogen bond formation via a coupling reaction of 2-iodo-selenophene catalyzed by Cu(I) in the presence of a base and an inexpensive ligand, and establish the first route to obtaining 2-nitrogen-selenophene derivatives in good yields. We can anticipate that this reaction works well with oxazolidinones, lactams, and aliphatic and aromatic amides, as nitrogen sources, in the absence of any supplementary additives. In addition, the reaction proceeded cleanly under mild reaction conditions and was sensitive to the ratio of amide/2-iodo-selenophene, as well as the nature of the ligand, base, and solvent.     

Theoretical Study of the Dimerization of Chlorophyll (a) and Its Hydrates: Implication for Chlorophyll (a) Aggregation

Dimeric structures chlorophyll (a) (Chla) and their mono‐ and dihydrated have been suggested to play an important role in the mechanism of photoreaction center chlorophyll special pairs PSI and PSII. Despite their functional importance, the molecular basis structures for interacting two Chla molecules and the structural stabilization role of H₂O in the formation of hydrated Chla dimer complexes is poorly understood. In this article, the different coordination modes between two interacting Chla molecules and the configurational (orientation and distance) features between the dimer and bound H₂O molecules are characterized by means of super molecule approach the density functional theory DFT. An estimation of the thermodynamic quantities is made for Chla dimerization and hydration processes. The results indicate that structure including ester linkages via H₂O hydrogen bonding is the most favorable conformation for the dihydrated chlorophyll (a) dimer at B3LYP/6‐31G*‐DCP level of calculation. The dispersion interaction is shown to be of great significance for the Chla dimer stabilization. In aqueous nonpolar solvent, the thermodynamics show that Chla has a slightly stronger driving force for full hydration than for dimerization and that hydration of the dimers is rather weakly exergonic. The tetrahydrated dimers having a similar arrangement to that in crystals of ethyl chlorophyllide (a) dihydrate are found to be more stable than the Chla dihydrated dimer. The data underscore the key role of H‐bonding in the stability of Chla‐H₂O adducts and, in particular, the great importance of the Chla monomeric dihydrated species in the hydration and dimerization of Chla in aqueous media. Clearly, the Chla dihydrates (Chla‐2 H₂O) are found more stable than the monohydrates (Chla‐H₂O) and the Chla dimers (Chla₂), owing to a particular structure in which cooperative interactions occur between the H₂O molecules and Chla. Calculations also indicate that the most thermodynamically preferred pathway for the formation of Chla dimer hydrates can be represented by two steps: the first corresponds to the formation of Chla monomeric dihydrates and the second is the dimerization of the dihydrates on to tetrahydrated Chla dimers. These results allow to obtain a new possible pathway for Chla dimer formation processes and could provide new insights to the aggregation of chlorophyll (a) in solution.     

Synthesis of symmetrical and unsymmetrical diindolylmethanes via acid-catalysed electrophilic substitution reactions

A range of activated indole-2-carboxylate derivatives was prepared via the Hemetsberger indole synthesis. Vilsmeier formylation was explored to establish regioselectivity and to prepare a range of new indole carbaldehydes. The indole aldehydes were reduced to the corresponding hydroxymethylindoles in good yields by the use of sodium borohydride in THF. Symmetrical 4,4′-, 6,6′- and 7,7′-diindolylmethanes were prepared via the acid-catalysed reaction of the corresponding hydroxymethylindoles. Furthermore, the treatment of methyl 4-hydroxymethyl-5,6-dimethoxyindole-2-carboxylate and a range of methyl indole esters with acetic acid led to the formation of unsymmetrical 4,6′- and 4,7′-dindolylmethanes.     

2-phenyl-4-bis(methylthio)methyleneoxazol-5-one: versatile template for diversity oriented synthesis of heterocycles

4-Bis(methylthio)methylene-2-phenyloxazol-5-one (1) has been shown to be a versatile template for the synthesis of novel heterocyclic scaffolds. The key protocol involves nucleophilic ring opening of 1 with various primary aliphatic, aromatic amines and diamines to give open-chain amide adducts which are transformed into 4-bis(methylthio)methylene-2-phenyl-1-alkyl/arylimidazol-5-(4H)-ones (5) in good yields in the presence of anhydrous NaOAc/AcOH. Similarly, the amide adducts 4h-i from 3,4-dimethoxyphenylethylamine and tryptamine undergo interesting rearrangement in the presence of POCl(3) to furnish 1-(2-phenyl-5-methylthio-4-thiazolyl)dihydroisoquinoline and β-carboline derivatives 8-9 in good yields. The amide adduct 14 from o-phenylenediamine on exposure to refluxing acetic acid or in the presence of Ag(2)CO(3) affords substituted 3H-1,5-benzodiazepinone, 2-(5-methylthio-2-phenyl-4-oxazolyl)-1H-benzimidazole and trisubstituted oxazole (15-17), whereas the bis-adduct from ethylenediamine yields ethylene bridge tethered bis-imidazole 23 and bis-oxazole 24 under similar reaction conditions. Probable mechanisms for the formation of various products have been suggested.     

Thermodynamics and kinetics of indole oligomerization: Preliminary results in aqueous sulfuric acid

Reaction rates and equilibrium constants of indole dimerization and trimerization in aqueous sulfuric acid at 298 K are reported. The equilibrium of oligomerization is attained in about 4–5 h, and formation of oligomers with more than three monomeric unit is not observed. The equilibrium of formation of the indole dimer is influenced by the protonation equilibrium of indole, which means the pK_IH values of indole strongly influences equilibria and kinetics of the whole process. In the evaluation of the kinetic constants, the pK_IH values of indole have been taken into account; in this way, the kinetic constant of formation of the dimer (k_D) results almost four order of magnitude larger than that of the trimer (k_T), suggesting a higher electrophilicity of the 3H‐indolium cations with respect to the protonated dimer (which is an aliphatic ammonium salt). Further indole addition to the trimer, which is a protonated 2‐alkyl‐aniline, does not occur, since the anilinium ion is ineffective as an electrophile. © 2008 Wiley Periodicals, Inc. Int J Chem Kinet 41: 107–112, 2009     

Chloromethylaluminum 2 (2-propenyl)anilide - a convenient reagent for the conversion of lactones into protected hydroxy acids

The title reagent reacts with γ and δ lactones to provide hydroxy amides which can be easily converted into protected N-acyl indoles. Mild saponification provides indole and the protected hydroxy acid.     

Asymmetric synthesis of beta2-amino acids: 2-substituted-3-aminopropanoic acids from N-acryloyl SuperQuat derivatives

Conjugate addition of lithium dibenzylamide to (S)-N(3)-acryloyl-4-isopropyl-5,5-dimethyloxazolidin-2-one (derived from l-valine) and alkylation of the resultant lithium beta-amino enolate provides, after deprotection, a range of (S)-2-alkyl-3-aminopropanoic acids in good yield and high ee. Alternatively, via a complementary pathway, conjugate addition of a range of secondary lithium amides to (S)-N(3)-(2'-alkylacryloyl)-4-isopropyl-5,5-dimethyloxazolidin-2-ones, diastereoselective protonation with 2-pyridone, and subsequent deprotection furnishes a range of (R)-2-alkyl- and (R)-2-aryl-3-aminopropanoic acids in good yield and high ee. Additionally, the boron-mediated aldol reaction of beta-amino N-acyl oxazolidinones is a highly diastereoselective method for the synthesis of a range of beta-amino-beta'-hydroxy N-acyl oxazolidinones.     

Tricopper(II) complexes of unsymmetrical macrocycles incorporating phenol and pyridine moieties: the development of two stepwise routes

Two stepwise approaches to preparing large unsymmetrical macrocycles incorporating diethylenetriamine lateral units are described: the first utilises protecting group chemistry, whereas the second exploits irreversible amide bond formation in the presence of an excess of the amine. In the first approach condensation of two equivalents of N-acetyldiethylenetriamine 1 with 2,6-diformyl-4-methylphenol, followed by a sodium borohydride reduction of the newly formed imine bonds and acidic removal of the protecting groups, yields a phenol-containing "two-armed" precursor as an HCl salt 2. Using the second approach the new pyridine-containing "two-armed" precursor , is prepared from 2,6-dimethylpyridinedicarboxylate and an excess of diethylenetriamine. These two "two-armed" di-primary amine precursors, 2 (after reaction with KOH) and 3, can be condensed with the dicarbonyl head units of choice. The lead templated condensation of 2 with 2,6-diacetylpyridine results in the formation of the macrocyclic dilead(II) complex {[Pb(II)(2)(L1)(Cl)](ClO(4))(2)}(infinity) 4. Transmetallation of 4 with three equivalents of copper(II) perchlorate produces Cu(II)(3)(L1)(OH)(ClO(4))(4) 5. Condensation of 3 with 2,6-diacetylpyridine or 2,6-diformylpyridine in the presence of barium(ii) ions results in the macrocyclic complexes [Ba(II)(H(2)L2)](ClO(4))(2) 6 and [Ba(II)(H(2)L3)](ClO(4))(2) 7, respectively. Copper(II) acetate templates the formation of the crystallographically characterised unsymmetrical macrocyclic complex [Cu(II)(3)(L4)(OH)(NCS)(2)].EtOH, 8.EtOH, from 3, 2,6-diformyl-4-methylphenol and NaNCS.     

Direct entry to peptidyl ketones via SmI2-mediated C-C bond formation with readily accessible N-peptidyl oxazolidinones

In this work, a new method for the preparation of peptidyl ketones is presented employing a SmI(2)/H(2)O-mediated coupling of N-peptidyl oxazolidinones with electron-deficient alkenes. The requisite peptide imides were easily prepared by solution-phase peptide synthesis starting from an N-acyl oxazolidinone derivative of an amino acid. Importantly, they could be used directly in the C-C bond-forming step without the need for further functionalization. Coupling of these peptide derivatives with a second peptide possessing an N-terminal acryloyl group leads to ketomethylene isosteres of glycine-containing peptides. This method represents an alternative means for ligating two small peptides through a C-C bond-forming step.     

Can decarbonylation of acyl radicals be overcome in radical addition reactions? En route to a solution employing N-acyl oxazolidinones and SmI2/H2O

The application of acyl radicals in radical addition reactions in the absence of a CO atmosphere is generally limited to aryl or alpha-unsubstituted alkyl acyl radicals due to competing decarbonylations where the rate constant for this degradation process surpasses 104 s-1. In this work, a potential solution to avoid the problem of decarbonylations is presented employing N-acyl oxazolidinones which are reduced to acyl radical equivalents in the presence of samarium diiodide and water. In the company of an acrylamide, acrylate, or acrylonitrile, the product from a formal acyl radical addition is obtained in yields up to 87%. Examples are given where the decarbonylation rate constants even exceed 108 s-1. It is proposed that the reaction proceeds via a ketyl-like intermediate.     

The structure of melanins and melanogenesis—III The structure of sepiomelanin

New degradation products of sepiomelanin have been obtained. Alkali fusion yields, in addition to other compounds, 5,6-dihydroxyindole, 5,6-dihydroxyindole-2-carboxylic acid, 4-methyl-cathechol and a compound, which is probably 5,6-dihydroxyindole-4,7-dicarboxylic acid. These products constitute the first proof of the indole structure of a natural melanin. The carboxyl group of 5,6-dihydroxyindole-2-carboxylic acid is not formed during alkali fusion, but pre-exists in the macromolecule. Cysteic acid, taurine, glycine and aspartic acid were obtained by oxidation of sepiomelanin with hydrogen peroxide in acetic acid. The formation of cysteic acid indicates that sepiomelanin is bound to the protein by means of cysteine. Taurine is clearly an artifact generated by decarboxylation of cysteine. Glycine and aspartic acid probably are derived from the pyrrole moiety of the indole units: they also result from the oxidation of 5,6-dihydroxyindole-2-carboxylic acid.

Oxidation of methylated sepiomelanin yields 3-carbomethoxypyrrole-2,5-dicarboxylic acid and 5-carbomethoxypyrrole-2,3-dicarboxylic acid; isolation of the former further proves the presence of pyrrole units in sepiomelanin, whereas formation of the latter is further evidence that some indole (probably dopachrome) units of the macromolecule have a carboxyl group in position 2.     

Benzene C-H activation by platinum(II) complexes of bis(2-diphenylphosphinophenyl)amide

The amido diphosphine complexes [PNP]PtMe and [PNP]PtOTf, where [PNP]- is bis(2-diphenylphosphinophenyl)amide, effectively activate the benzene C-H bond in the presence of an appropriate Lewis acid or base, leading to the formation of [PNP]PtPh quantitatively.     

Novel method for synthesis of unsymmetrical bis(indolyl)alkanes catalyzed by ceric ammonium nitrate (CAN) under ultrasonic irradiation

The reaction of indole with (1H-indol-3-yl)(alkyl) methanol was catalyzed efficiently by ceric ammonium nitrate under ultrasonic irradiation to afford the unsymmetrical bis(indolyl)alkane in good to excellent yields.     

A new and efficient method for the synthesis of 3-(2-nitrophenyl)pyruvic acid derivatives and indoles based on the Reissert reaction

The formation of 3-(2-nitrophenyl)pyruvic acid and its amide and ester derivatives – key compounds for the Reissert indole synthesis – was achieved under various reaction conditions via the acid catalyzed hydrolysis of 5-(2-nitrobenzyliden)-2,2-dimethyl-1,3-oxazolidin-4-one, which is readily available from 3-(2-nitrophenyl)oxirane-2-carboxamide. A new and highly efficient method for the synthesis of indole-2-carboxylic acid derivatives via the intramolecular reductive cyclization of o-nitrophenylpyruvic acid and its amide and ester derivatives was developed using Na₂S₂O₄ in dioxane/water at reflux.     

Transacylation of alpha-aryl-beta-keto esters

The acyl group of an alpha-aryl-beta-keto ester was readily transferred to N-, O-, and S-nucleophiles. The transacylation from arylated diethyl 3-oxoglutarate to amines led to unsymmetrical malonic acid amide esters in high yields. The present reaction proceeded under mild conditions without formation of detectable byproducts. Only simple experimental manipulations were required. This reaction was also found to be sensitive to steric factors, which enabled the chemoselective monoacylation of diamines and amino alcohols without any modifications such as protection.     

InBr3-promoted divergent approach to polysubstituted indoles and quinolines from 2-ethynylanilines: switch from an intramolecular cyclization to an intermolecular dimerization by a type of terminal substituent group

Use of a 2-ethynylaniline having an alkyl or aryl group on the terminal alkyne selectively produced a variety of polyfunctionalized indole derivatives in moderate to excellent yields via indium-catalyzed intramolecular cyclization of the corresponding alkynylaniline. In contrast, employment of a substrate with a trimethylsilyl group or with no substituent group on the terminal triple bond, exclusively afforded polysubstituted quinoline derivatives in good yields via indium-promoted intermolecular dimerization of the ethynylaniline. This indium catalytic system successfully accommodated the intramolecular cyclization of other arylalkyne skeletons involving a carboxylic acid and an amide group.