Formation of Oxazoles from Elusive Gold(I) α‐Oxocarbenes: A Mechanistic Study

The gold(I) catalyzed reaction between phenylacetylene, pyridine N‐oxide and acetonitrile leading, via a putative gold‐α‐oxocarbene intermediate, towards an oxazole product has been investigated. A novel mass spectrometric method called “delayed reactant labeling” is used to track consecutive and parallel reactions. It clearly shows that the intramolecular formation of a pyridine adduct of gold‐α‐oxocarbene is in competition with the formation of the oxazole product. The reaction mechanism most probably corresponds to competition between acetonitrile and pyridine in an almost barrierless reaction with putative gold‐α‐oxocarbene within the solvent cage. The detected ionic species have been characterized by helium tagging infrared photodissociation spectroscopy.     

Synthesis of libraries of thiazole, oxazole and imidazole-based cyclic peptides from azole-based amino acids. A new synthetic approach to bistratamides and didmolamides

Treatment of a 1 : 1 mixture of the thiazole-based amino acids 8a and 8b with FDPP-i-Pr(2)NEt in CH(3)CN gave a mixture of the cyclic trimers 14, 15, 16 and 17 and the cyclic tetramers 19 and 23 in the ratio 2 : 7 : 5 : 8 : 1 : 1 and in a combined yield of 70%. Separate coupling reactions between the bisimidazole amino acid 45 and the thiazole/oxazole amino acids 43a and 42a in the presence of FDPP-i-Pr(2)NEt led to the bisimidazole based cyclic trimers 55 and 57 respectively (54-57%) and to the cyclic tetramer 56 (8-11%). Similar coupling reactions involving the bisthiazole and bisoxazole amino acids 49 and 47 with the imidazole/oxazole/thiazole amino acids 41a, 42a and 43a gave rise to the library of oxazole, thiazole and imidazole-based cyclic peptides 58, 59, 60, 61, 62, 63, 64 and 65. A coupling reaction between the bisthiazole amino acid 49 and the oxazole amino acid 73 led to an efficient (36% overall) synthesis of bistratamide H (67) found in the ascidian Lissoclinum bistratum. Coupling reactions involving oxazolines with thiazole amino acids were less successful. Thus, a coupling reaction between the phenylalanine-based oxazoline amino acid 71a and either the thiazole amino acid 8a or the bisthiazole amino acid 74 gave only a 2% yield of the cyclic hexapeptide didmolamide A (4) found in the ascidian Didemnum molle. Didmolamide B (68) was obtained in 9% yield from a coupling reaction between 74 and the phenylalanine threonine amino acid 72, using either FDPP or DPPA.     

Synthesis of antimicrobial agents of tetra-substituted thiophenes from ethyl 5-(2-bromoacetyl)-4-phenyl-2-(phenylamino)thiophene-3-carboxylate

5-(2-Bromoacetyl)-2,3,4-trisubstituted-thiophene was used as a synthetic intermediate to prepare a series of thiophene derivatives and thiophene incorporating oxazole, imidazole, thiazole, pyrrole, and pyridine rings via substitution and cyclo-condensation reactions. The data were extracted from the spectra of the resulting products confirmed their suggested structures. The newly synthesized compounds were screened to evaluate their in vitro antimicrobial activity vs several positive and negative gram bacteria and fungi. The screening data revealed that the thiophene derivative 7a , incorporating a thiazole ring, displayed strong activity against all tested microorganisms when compared with the antibiotics used.     

4-Bromomethyl-2-chlorooxazole--a versatile oxazole cross-coupling unit for the synthesis of 2,4-disubstituted oxazoles

The synthesis of the novel oxazole building block, 4-bromomethyl-2-chlorooxazole, and its palladium-catalysed cross-coupling reactions to make a range of 2,4-disubstituted oxazoles, is described. Selectivity for the 4-bromomethyl position is observed, with Stille coupling effected in good to excellent yields, or Suzuki coupling in moderate yields, to provide a range of 4-substituted-2-chlorooxazoles. Subsequent coupling at the 2-chloro-position can be achieved through either Stille or Suzuki reactions in excellent yields.     

Enantioselective TADMAP-catalyzed carboxyl migration reactions for the synthesis of stereogenic quaternary carbon

The chiral, nucleophilic catalyst TADMAP [1, 3-(2,2,2-triphenyl-1-acetoxyethyl)-4-(dimethylamino)pyridine] has been prepared from 3-lithio-4-(dimethylamino)pyridine (5) and triphenylacetaldehyde (3), followed by acylation and resolution. TADMAP catalyzes the carboxyl migration of oxazolyl, furanyl, and benzofuranyl enol carbonates with good to excellent levels of enantioselection. The oxazole reactions are especially efficient and are used to prepare chiral lactams (23) and lactones (30) containing a quaternary asymmetric carbon. TADMAP-catalyzed carboxyl migrations in the indole series are relatively slow and proceed with inconsistent enantioselectivity. Modeling studies (B3LYP/6-31G*) have been used in qualitative correlations of catalyst conformation, reactivity, and enantioselectivity.     

Aminophenyl-X-azolopyridines as precursors of heterocyclic azo dyes

Aminophenyl-X-azolopyridines (X = O, S, NH) are interesting intermediates for the synthesis of disperse azo dyes and, provided the pyridine nitrogen is quaternized, of their cationic counterparts. A set of novel amines and nitro derivatives is described, and their physical properties and spectral parameters are discussed in comparison with those of analogous compounds. Some dyes in the oxazole series function as probes of the reactivity of the pentatomic ring.     

Progress toward synthesis of diazonamide A. Preparation of a 3-(oxazol-5-yl)-4-trifluoromethyl-sulfonyloxyindole and its use in biaryl coupling reactions

[formula: see text] The synthesis of a 3-oxazol-5-yl-indole-4-triflate is described, featuring a Sch?lkopf reaction to prepare the oxazole. In addition, the participation of this intermediate in biaryl coupling reactions toward the total synthesis of the natural product diazonamide A is presented.     

Computational Study on OH Addition Reactions of Three Sulfonamides in Aqueous Solution

OH addition reactions of cationic,neutral and anionic forms of three sulfonamides(sulfamethoxazole,sulfadiazine and sulfapyridine)in aqueous solution were theoretically studied using density functional theory(DFT)method at the M06-2X/6-311+G(3df,2p)level.Transition state theory was applied to estimate the secondary rate constants for these elementary reactions.The obtained results indicate that OH addition reactions of sulfonamides can take place spontaneously at standard conditions.The anionic form of three sulfonamides has the highest addition activity,while the corresponding cationic form is the most inactive addition reagent.The benzene ring of neutral forms of three sulfonamides is always a more favorable site for OH radical addition than the oxazole,pyrimidine or pyridine ring.C(3)or(and)C(5)atoms of benzene ring are the most favorable positions for OH addition occurring in benzene ring.Although the water solvent has no remarkable effect on OH addition reactions of neutral sulfonamides,it exerts a significant adverse influence on OH addition reactions of ionic sulfonamides.     

Derivatization of a tris-oxazole using Pd-catalyzed coupling reactions of a 5-bromooxazole moiety

Modification at the C5 position of an oxazole ring contained in a 2,4-concatenated tris-oxazole by Pd-catalyzed coupling reactions was performed. Novel Pd-catalyzed amination and alkoxylation of a 5-bromooxazole derivative as well as Suzuki-Miyaura coupling and Migita-Stille coupling have been demonstrated. A wide variety of functional groups, including aryl, heteroaryl, primary and secondary amines, and phenol, were introduced in the 5-bromooxazole moiety in moderate to excellent yields using Pd(OAc)₂/S-PHOS or Pd(OAc)₂/X-PHOS as a catalyst.     

A facile preparation of 4-(1-Acetyl-4(1H)-pyridylidene)-2-oxazohn-5-ones

4-(1-Acetyl-4(1H)-pyridylidene)-2-oxazolin-5-ones were prepared by the reaction of acylglycines with pyridine and acetic anhydride under oxygen. Acidic and alkaline hydrolysis of 2-oxazolin-5-ones provided oxazole derivatives, pyridine derivatives, and carboxylic acids.     

A facile one-pot synthesis of 2-o-cyanoaryl oxazole derivatives mediated by CuCN

A convenient, inexpensive and effective approach to the synthesis of 2-o-cyanoaryl oxazole derivatives has been developed. Generally, the copper-mediated cyclization/coupling reactions afforded corresponding 2-cyanoaryl oxazoles and oxazolines in moderate to excellent yields. The functionalized oxazole derivatives may be useful in biological chemistry and medicinal science. Our investigation indicates that the formation of the oxazole ring might favor the CC bond forming process on the ortho-position of the aryl ring. And CuCN plays dual roles as a Lewis acid catalyst and a C-nucleophile in this transformation.     

Tridentate complexes of 2,6-bis(4-substituted-1,2,3-triazol-1-ylmethyl)pyridine and its organic azide precursors: an application of the copper(II) acetate-accelerated azide-alkyne cycloaddition

Rapid coupling reactions between 2,6-bis(azidomethyl)pyridine and terminal alkynes in the presence of 5 mol% Cu(OAc)(2)·H(2)O without the addition of a reducing agent afford tridentate ligands for first-row transition-metal ions. The chelation between Cu(II) and alkylated nitrogen atoms of the azido groups of 2,6-bis(azidomethyl)pyridine, as observed in the solid state, is credited for the acceleration of the azide-alkyne cycloaddition reactions.     

Novel polyoxazole-based cyclopeptides from Streptomyces sp. Total synthesis of the cyclopeptide YM-216391 and synthetic studies towards telomestatin

A convergent, complementary, synthetic approach to the contiguously linked tris-oxazole units 10, 11 and 12 in telomestatin (1) and YM-216391 (2) is described. The route involves coupling reactions between oxazole 4-carboxylic acids, viz 16a, 16c, 16d and oxazole 2-substituted methylamines, viz 16b, 16e, 17, leading to the amides 18 and 21, followed by cyclodehydrations to the corresponding bis-oxazole oxazolines, e.g. 19, and oxidations of the latter using well-established protocols. The tris-oxazoles 11 and 12 were next converted stepwise into the hexa-oxazole bis-macrolactams 33. Although the bis-macrolactams 33 (cf. 28) could be converted into the corresponding oxazoline-hexa-oxazoles 34 and to the enamides 35, neither of these intermediates could be elaborated to the hepta-oxazole 30en route to telomestatin 1. Likewise, neither the hexa-oxazole 47 or application of an intramolecular Hantzsch oxazole ring-forming reaction from 44b allowed access to the advanced polyoxazole-macrolactam intermediates 48 and 30a, respectively, towards telomestatin. Combination of the tris-oxazole based methylamine 70 with the dipeptide carboxylic acid 71 derived from D-valine and L-isoleucine, leads to the corresponding amide which, in two straightforward steps, is converted into the -amino acid 78. Macrolactamisation of 78, using HATU, next produces the cyclopeptide 79 which is then elaborated to the thiazole and oxazole based cyclopeptide YM-216391 (2). The synthetic cyclopeptide 2 is shown to be the enantiomer of the natural product isolated from Streptomyces nobilis.     

Cobalt‐Catalyzed Cross‐Dehydrogenative C(sp2)−C(sp3) Coupling of Oxazole/Thiazole with Ether or Cycloalkane

Direct C5‐alkylation of oxazole/thiazole with ether or cycloalkane has been achieved through a cobalt‐catalyzed cross‐dehydrogenative coupling (CDC) process in moderate to good yields. This transformation represents the first C(sp²)−C(sp³) cross‐coupling at the C5‐position of the oxazole/thiazole via double C−H bond cleavages. Various functional groups on oxazole/thiazole substrates, as well as water and air, are well‐tolerated with this concise and practical protocol, constituting straightforward access to heterocycles with great medicinal significance. A preliminary mechanism involving a radical process has also been proposed.     

Total Synthesis of the Post‐translationally Modified Polyazole Peptide Antibiotic Goadsporin

The structurally unique polyazole antibiotic goadsporin contains six heteroaromatic oxazole and thiazole rings integrated into a linear array of amino acids that also contains two dehydroalanine residues. An efficient total synthesis of goadsporin is reported in which the key steps are the use of rhodium(II)‐catalyzed reactions of diazocarbonyl compounds to generate the four oxazole rings, which demonstrates the power of rhodium carbene chemistry in organic chemical synthesis.     

Study of the coupling reaction of pyridine in the gas phase

The coupling reaction of pyridine in the gas phase to form bipyridyl and terpyridyl has been studied by electron ionization using an ion trap mass spectrometer. In contrast to the difficulty in carrying out electrophilic substitutions at carbon atoms in the pyridine ring under highly acidic solvent conditions, reactions in the gas phase overcame the conjugate acidification of pyridine in the solvent phase, thus decreasing the hardness of this electrophilic coupling. Through product ion mass spectra of the ion at m/z 157, we have shown that this ion was protonated bipyridyl rather than the ion/molecule adduct. A computational study of the heat of formation surface also supported the formation of polypyridyls through the electrophilic substitution of pyridine. We have confirmed the reaction through a study of pyridine-d(5) coupling in the gas phase.     

Phosphite-oxazole/imidazole ligands in asymmetric intermolecular Heck reaction

We describe the application of a new class of ligands--the phosphite-oxazole/imidazole (L1-L5a-g)--in asymmetric intermolecular Pd-catalyzed Heck reactions under thermal and microwave conditions. These ligands combine the advantages of the oxazole/imidazole moiety with those of the phosphite moiety: they are more stable than their oxazoline counterparts, less sensitive to air and other oxidizing agents than phosphines and phosphinites, and easy to synthesize from readily available alcohols. The results indicate that activities, regio- and enantioselectivities, are highly influenced by the type of nitrogen donor group (oxazole or imidazole), the oxazole and biaryl-phosphite substituents and the axial chirality of the biaryl moiety of the ligand. By carefully selecting the ligand components, we achieved high activities, regio- (up to 99%) and enantioselectivities (up to 99%) using several triflate sources. Under microwave-irradiation conditions, reaction times were considerably shorter (from 24 h to 30 min) and regio- and enantioselectivities were still excellent.     

Heteroaromatic thioamides: Structure and stability of charge transfer complexes with iodine, antithyroid activity

The review generalizes the structural studies on the products of the interaction of antithyroid preparations (heteroaromatic thioamides) with iodine. The n-σ* adducts of imidazol, thiazol, oxazole, pyridine, uracil derivatives with molecular iodine, iodinium salts, and also disulfides formed as a result of thione oxidation in iodine-coordinating solvents are considered. Based on mainly single crystal X-ray diffraction and Raman spectroscopy data, the structural parameters of iodine molecular complexes are shown to be highly sensitive to changes in the type of a heteroatom and substituents in the heteroring. The effect of the structure of heteroaromatic thioamides on their antithyroid activity is analyzed.     

Synthesis of 5-acetyloxazoles and 1,2-diketones from β-alkoxy-β-ketoenamides and their subsequent transformations

Lithiated alkoxyallenes, nitriles, and carboxylic acids have been employed as precursors in a three-component reaction leading to highly substituted β-alkoxy-β-ketoenamides. Upon treatment with trifluoroacetic acid, these enamides could be easily cyclized to 5-acetyloxazole derivatives. The synthesis is very flexible with respect to the substitution pattern at C-2 and C-4 of the oxazole core. A mechanistic suggestion for the oxazole formation is presented on the basis of (18)O-labeled compounds and their mass spectrometric analysis. In several cases, 1,2-diketones are formed as side products or even as major components. The acetyl moiety at C-5 of the oxazole derivatives can efficiently be converted into alkenyl or alkynyl moieties, which allows a multitude of subsequent reactions. Condensation reactions of the acetyl group provided the expected oxime or hydrazone. By applying a Fischer reaction, the phenylhydrazone could be transferred into an indole, which emphasizes the potential of 5-acetyloxazoles for the preparation of highly substituted (poly)heterocyclic systems. The alkynyl group at C-2 is prone to addition reactions, providing an enamine with interesting photophysical properties. Sonogashira couplings were performed with 5-alkynyl-substituted oxazoles, furnishing the expected aryl-substituted products. This alkynyl unit was employed for the preparation of a new, star-shaped trisoxazole derivative. The ability of this multivalent compound to form self-assembled monolayers between the basal plane of highly oriented pyrolytic graphite and 1-phenyloctane was demonstrated by scanning tunneling microscopy (STM). The star-shaped compound seems to prefer the C(3)-symmetric arrangement in this two-dimensional crystal. Two 1,2-diketones were smoothly converted into functionalized quinoxaline derivatives.     

Deprotonative Metalation of Functionalized Aromatics Using Mixed Lithium–Cadmium,Lithium–Indium,and Lithium–Zinc Species

In situ mixtures of CdCl₂?TMEDA (0.5 equiv; TMEDA=N,N,N′,N′‐tetramethylethylenediamine) or InCl₃ (0.33 equiv) with [Li(tmp)] (tmp=2,2,6,6‐tetramethylpiperidino; 1.5 or 1.3 equiv, respectively) were compared with the previously described mixture of ZnCl₂?TMEDA (0.5 equiv) and [Li(tmp)] (1.5 equiv) for their ability to deprotonate anisole, benzothiazole, and pyrimidine. [(tmp)₃CdLi] proved to be the best base when used in tetrahydrofuran at room temperature, as demonstrated by subsequent trapping with iodine. The Cd–Li base then proved suitable for the metalation of a large range of aromatics including benzenes bearing reactive functional groups (CONEt₂, CO₂Me, CN, COPh) or heavy halogens (Br, I), and heterocycles (from the furan, thiophene, pyrrole, oxazole, thiazole, pyridine, and diazine series). Five‐membered heterocycles benefiting from doubly activated positions were similarly dideprotonated at room temperature. The aromatic lithium cadmates thus obtained were involved in palladium‐catalyzed cross‐coupling reactions or simply quenched with acid chlorides.