Efficient Synthesis of Eight‐Membered Nitrogen Heterocycles from O‐Propargylic Oximes by Rhodium‐Catalyzed Cascade Reactions

Azocine derivatives were successfully synthesized from O‐propargylic oximes by means of a Rh‐catalyzed 2,3‐rearrangement/heterocyclization cascade reaction. Moreover, the chirality of the substrate was maintained throughout the cascade process to afford the corresponding optically active azocines.     

Microwave‐Assisted Three‐Component Synthesis of Some Novel 1‐Alkyl‐1H‐indole‐2,3‐dione 3‐(O‐Alkyl­oxime) Derivatives as Potential Chemotherapeutic Agents

A convenient and efficient method for a one‐pot conversion of N‐alkylisatins to N‐alkylisatin O‐alkyloximes 7a – 7n as potential chemotherapeutic agents is described (Scheme) (isatin=1H‐indole‐2,3‐dione). In this method, the microwave‐assisted three‐component reaction of N‐alkylisatins 8 , hydroxylamine hydrochloride, and diverse alkyl halides in the presence of K₂CO₃ and Bu₄NBr furnishes the corresponding N‐alkylisatin O‐alkyloximes under solvent‐free condition in short times (2–10 min) and good to excellent yields (62–83%). The O‐alkylation of in situ generated isatin oximes with alkyl halides was achieved regioselectively, and (Z)‐O‐alkyloximes were produced dominantly. PM3 Semi‐empirical quantum‐mechanic calculations were performed to rationalize the evidences, and the calculations indicated a lower heat of formation for the (Z)‐O‐alkyloximes.     

Polycyclic N‐Heterocyclic Compounds. Part 78: Synthesis of N‐[2‐([1,2,4]Oxadiazol‐5‐yl)cyclohepten‐1‐yl]formamide Oximes and Their Evaluation as Inhibitors of Platelet Aggregation

N‐[2‐([1,2,4]Oxadiazol‐5‐yl)cyclohepten‐1‐yl]formamide oximes were synthesized by fusion of (6,7,8,9‐tetrahydro‐5H‐cyclohepta[1,2‐d]pyrimidin‐4‐yl)amidines with hydroxylamine hydrochloride through a subsequent rearrangement reaction. Effects of the products as well as the structurally related N‐[4‐([1,2,4]oxadiazol‐5‐yl)‐2,3‐dihydro[1]benzoxepin‐5‐yl]formamide oximes and N‐[4‐([1,2,4]oxadiazol‐5‐yl)‐2,3‐dihydro[1]benzothiepin‐5‐yl]formamide oximes on platelet aggregation were evaluated.     

Oxazoles formation during O‐alkylation of isonitroso‐naphthols. X‐ray structure of [1,2]naphthoquinone 1‐[O‐(4‐tert‐butyl‐benzyl)‐oxime] and 2‐(4‐tert‐butyl‐phenyl)napth[1,2‐d]oxazole

1‐Nitroso‐2‐naphthol and 2‐nitroso‐1‐naphthol, both in the isonitroso form, react with benzyl bromides in THF and in the presence of triethylamine affording, in low yields, the corresponding O‐benzyl oximes and 2‐aryl naphthoxazoles in a 1:1 ratio, approximately. The structures of O‐benzyl oximes and naphthoxazoles isolated have been determined by X‐ray analysis.     

‘Click Synthesis’ of Some Novel O‐Substituted Oximes Containing 1,2,3‐Triazole‐1,4‐diyl Residues as New Analogs of β‐Adrenoceptor Antagonists

The ‘click synthesis’ of some novel O‐substituted oximes, 7a – 7t , which contain 1,2,3‐triazolediyl residues, as new analogs of β‐adrenoceptor antagonists is described (Schemes 1–4). The synthesis of these compounds was achieved in four to five steps. The formation of oximes of 9H‐fluoren‐9‐one and benzophenone, i.e., 9a and 9b , respectively, followed by their reaction with propargyl bromide, afforded O‐propargyl oximes 10a and 10b , respectively, which by a subsequent CuI‐catalyzed Huisgen cycloaddition with prepared β‐azido alcohols 11a – 11j (Schemes 2 and 3), led to the target compounds 7a – 7t in good yields.     

Nitrosation of Sugar Oximes: Preparation of 2‐Glycosyl‐1‐hydroxydiazene‐2‐oxides

Oximes of glucose, xylose, lactose, fructose, and mannose have been prepared. Nitrosation of the oximes of glucose, xylose, and lactose with NaNO₂/HCl afforded 2‐(β‐glycopyranosyl)‐1‐hydroxydiazene‐2‐oxides, which were isolated as salts 13 , 22 , and 28 . Nitrosation of fructose oxime 29 furnished fructose, whereas nitrosation of mannose oxime 30 with NaNO₂/HCl afforded the 1‐hydroxy‐2‐(β‐d‐ mannopyranosyl)diazene‐2‐oxide 32 , from which the p‐anisidinium salt 31 and the sodium salt 33 were prepared. However, nitrosation of 30 with isopentyl nitrite in aqueous solutions of CsOH or KOH resulted in the formation of the 2‐(α‐D ‐mannofuranosyl)‐1‐hydroxydiazene‐2‐oxide salts 34 and 35 , respectively. Methylation of the ammonium 2‐(β‐D ‐glucopyranosyl)‐1‐hydroxydiazene‐2‐oxide 13 yielded the 1‐methoxy compound, which was benzoylated to afford the tetra‐O‐benzoate 14 a , the structure of which was confirmed by X‐ray diffraction analysis. From the glucose O‐methyloximes 15 and 16 the N‐methoxy‐N‐nitroso‐2,3,4,6‐tetra‐O‐acetyl‐β‐D ‐glucopyranosylamine 18 was prepared. The structure of this compound was confirmed by X‐ray diffraction analysis. Treatment of acetobromoglucose with cupferron furnished the 1‐(2,3,4,6‐tetra‐O‐acetyl‐β‐D ‐glucopyranosyloxy)‐2‐phenyldiazene‐2‐oxide 20 .     

Synthesis and Fungicidal Activity of (1Z, 3Z)‐4,4‐Dimethyl‐1‐substitutedphenyl‐2‐(1H‐1,2,4‐triazol‐1‐yl)‐pent‐1‐en‐3‐one O‐[2,4‐dimethylthiazole(or 4‐methyl‐1,2,3‐thiadiazole)]‐5‐carbonyl Oximes

A series of novel (Z)‐1‐tert‐butyl (or phenyl)‐2‐(1H‐1,2,4‐triazol‐1‐yl)‐ethanone O‐[2,4‐dimethylthiazole (or 4‐methyl‐1,2,3‐thiadiazole) ?5‐carbonyl] oximes 5a – 5c and (1Z, 3Z)‐4,4‐dimethyl‐1‐substitutedphenyl‐2‐(1H‐1,2,4‐triazol‐1‐yl)‐pent‐1‐en‐3‐one O‐[2,4‐dimethylthiazole (or 4‐methyl‐1,2,3‐thiadiazole)‐5‐carbonyl] oximes 6a – 6e were synthesized by the condensations of (Z)‐1‐tert‐butyl (or phenyl)‐2‐(1H‐1,2,4‐triazol‐1‐yl)‐ethanone oximes 3 or (1Z, 3Z)‐4,4‐dimethyl‐1‐substitutedphenyl‐2‐(1H‐1,2,4‐triazol‐1‐yl)‐pent‐1‐en‐3‐one oximes 4 with 2,4‐dimethylthiazole‐5‐carbonyl chloride or 4‐methyl‐1,2,3‐thiadiazole‐5‐carbonyl chloride in the basic condition. Their structures were confirmed by IR, ¹H NMR, mass spectroscopy, and elemental analyses. The results of preliminary bioassays showed the title compounds 5 and 6 exhibited moderate to good fungicidal activities. For example, compound 6c possessed 86.4% inhibition against Fusarium oxysporum, and compound 6b exhibited 86.4 and 100% inhibition against Fusarium oxysporum and Cercospora arachidicola Hori at the concentration of 50 mg/L, respectively.     

Scalable,Transition‐Metal‐Free Direct Oxime O‐Arylation: Rapid Access to O‐Arylhydroxylamines and Substituted Benzo[b]furans

O‐Aryloximes, generated from readily available and inexpensive oximes through transition‐metal‐free O‐arylation, can either be hydrolyzed to O‐arylhydroxylamines or conveniently converted to structurally diverse benzo[b]furans through an environmentally benign, one‐pot [3,3]‐sigmatropic rearrangement/cyclization sequence.     

Polycyclic N‐heterocyclic compounds,part 67: Reaction of 6,7‐substituted N‐(quinazolin‐4‐yl)amidine derivatives with hydroxylamine hydrochloride: Formation of in vitro inhibitors of pentosidine

Reactions of N‐(quinazolin‐4‐yl)amidines and their amide oximes with hydroxylamine hydrochloride gave cyclization products that were formed by an initial ring cleavage of the pyrimidine component followed by a ring closure formation of 1,2,4‐oxadiazole to give N‐[2‐([1,2,4]oxadiazol‐5‐yl)phenyl]formamide oximes. All isolated products were evaluated for in vitro inhibitory activity on the formation of pentosidine, which is one of representative advanced glycation end products. Some products exhibited significant inhibitory activity against pentosidine formation. J. Heterocyclic Chem., (2011).     

Highly Efficient Conversion of Propargylic Amines and CO2 Catalyzed by Noble‐Metal‐Free [Zn116] Nanocages

The reaction of propargylic amines and CO₂ can provide high‐value‐added chemical products. However, most of catalysts in such reactions employ noble metals to obtain high yield, and it is important to seek eco‐friendly noble‐metal‐free MOFs catalysts. Here, a giant and lantern‐like [Zn₁₁₆] nanocage in zinc‐tetrazole 3D framework [Zn₂₂(Trz)₈(OH)₁₂(H₂O)₉?8 H₂O]_n Trz=(C₄N₁₂O)^4? ( 1 ) was obtained and structurally characterized. It consists of six [Zn₁₄O₂₁] clusters and eight [Zn₄O₄] clusters. To our knowledge, this is the highest‐nuclearity nanocages constructed by Zn‐clusters as building blocks to date. Importantly, catalytic investigations reveal that 1 can efficiently catalyze the cycloaddition of propargylic amines with CO₂, exclusively affording various 2‐oxazolidinones under mild conditions. It is the first eco‐friendly noble‐metal‐free MOFs catalyst for the cyclization of propargylic amines with CO₂. DFT calculations uncover that Zn^II ions can efficiently activate both C≡C bonds of propargylic amines and CO₂ by coordination interaction. NMR and FTIR spectroscopy further prove that Zn‐clusters play an important role in activating C≡C bonds of propargylic amines. Furthermore, the electronic properties of related reactants, intermediates and products can help to understand the basic reaction mechanism and crucial role of catalyst 1 .     

Chemistry of N,N‐Bis(silyloxy)enamines,Part 5

Aliphatic nitro compounds can be considered as good precursors of a wide variety of α‐azolyl‐substituted oximes. The double silylation of convenient aliphatic nitro compounds and the subsequent N,C‐coupling of the resulting N,N‐bis(silyloxy)enamines 3 with N‐silylated azoles 4 lead to the formation of the silylated α‐azolyl‐substituted oximes 6 , which can be smoothly desilylated to give the target α‐azolyl‐substituted oximes 5 . The mechanism of the key step of this process – N,C‐coupling – includes the generation of corresponding conjugated nitrosoalkenes 7 (Schemes 4 and 5). The contribution of the chain mechanism in the overall process is considered as well. The studies of the scope and limitations of this reaction, as well as the optimization of its conditions were accomplished. The configuration of the CN bond in oximes was established by NMR.     

Polycyclic N‐heterocyclic compounds. Part 66: Synthesis of N‐[2‐([1,2,4]oxadiazol‐5‐yl)cyclopenten‐1‐yl]formamide oximes and their evaluation as inhibitors of platelet aggregation

N‐[2‐([1,2,4]Oxadiazol‐5‐yl)cyclopenten‐1‐yl]formamide oximes were synthesized by fusion of (6,7‐dihydro‐5H‐cyclopenta[1,2‐d]pyrimidin‐4‐yl)amidines and/or their amide oximes with hydroxylamine hydrochloride through a subsequent rearrangement reaction. Assay of the products for anti‐platelet aggregation activity revealed that certain of them showed promising inhibitory effect on arachidonic acid‐induced platelet aggregation. J. Heterocyclic Chem., (2011).     

Polycyclic N‐Heterocyclic Compounds,Part 72: Reaction of N‐([1]Benzofuro (or Benzothieno)[3,2‐d]pyrimidin‐4‐yl)formamidine and N‐(Pyrido[2,3‐d]pyrimidin‐4‐yl)formamidine Derivatives with Hydroxylamine Hydrochloride

The reactions of N‐([1]benzofuro[3,2‐d]pyrimidin‐4‐yl)formamidines with hydroxylamine hydrochloride gave rearranged cyclization products via ring cleavage of the pyrimidine component accompanied by a ring closure of the 1,2,4‐oxadiazole to give N‐[2‐([1,2,4]oxadiazol‐5‐yl)[1]benzofuran‐3‐yl)formamide oximes. N‐([1]Benzothieno[3,2‐d]pyrimidin‐4‐yl)formamidines and N‐(pyrido[2,3‐d]pyrimidin‐4‐yl)formamidines with hydroxylamine hydrochloride gave similar results.     

Rh‐Catalyzed Reaction of Propargylic Alcohols with Aryl Boronic Acids–Switch from β‐OH Elimination to Protodemetalation

It is known that Rh‐catalyzed reaction of propargylic alcohols with aryl metallic reagents undergoes S_N2’‐type reaction affording allenes via a sequential arylmetalation and β‐OH elimination process. Here we report a Rh/Ag‐cocatalyzed reaction of propargylic alcohols with organoboronic acids affording stereo‐defined (E)‐3‐arylallylic alcohols via arylmetalation and protodemetalation with a high regio‐ and stereoselectivity under very mild conditions. The reaction exhibits a good substrate scope and the compatibility with synthetically useful functional groups with no racemization for optically active propargylic alcohols. Such a reaction may also be extended to homopropargylic alcohols with a remarkable regioselectivity and exclusive E‐stereoselectivity.     

Solid State Regeneration of Carbonyl Compounds from Oximes and Semicarbazones with Poly [N‐Bromo‐Benzene‐1,3‐Disulfonylamide]

Poly [N‐bromo‐benzene‐1,3‐disulfonylamide] [ PBBS ] is a novel and efficient reagent for the conversion of oximes and semicarbazones under solid state to their corresponding carbonyl compounds in high yields.     

Synthesis of Densely Functionalised 5‐Halogen‐1,3‐oxazin‐2‐ones by Halogen‐Mediated Regioselective Cyclisation of N‐Cbz‐Protected Propargylic Amines: A Combined Experimental and Theoretical Study

A very efficient synthesis of 5‐halogen‐1,3‐oxazin‐2‐ones has been accomplished by the halocyclisation reaction of chiral nonracemic N‐carbobenzyloxy (N‐Cbz)‐protected propargylic amines by using I₂, Br₂ and Cl₂ as electrophile sources. The nature of the halogen influences the reaction time and yield. However, in all cases the reaction is totally regioselective taking place through a 6‐endo‐dig process regardless of the nature of the halogen and of the substituents in the starting material. To rationalise the experimental results, theoretical studies at the B3LYP/6‐311G* level have been performed.     

Visible‐Light‐Mediated Generation of Nitrogen‐Centered Radicals: Metal‐Free Hydroimination and Iminohydroxylation Cyclization Reactions

The formation and use of iminyl radicals in novel and divergent hydroimination and iminohydroxylation cyclization reactions has been accomplished through the design of a new class of reactive O‐aryl oximes. Owing to their low reduction potentials, the inexpensive organic dye eosin Y could be used as the photocatalyst of the organocatalytic hydroimination reaction. Furthermore, reaction conditions for a unique iminohydroxylation were identified; visible‐light‐mediated electron transfer from novel electron donor–acceptor complexes of the oximes and Et₃N was proposed as a key step of this process.     

Synthesis of new 3‐(4‐oxo‐4H‐chromen‐3‐yl)‐3a,6a‐dihydropyrrolo[3,4‐d]isoxazole‐4,6‐dione derivatives by 1,3‐dipolar cycloaddition reaction

A series of new 3‐(4‐oxo‐4H‐chromen‐3‐yl)‐3a,6a‐dihydropyrrolo[3,4‐d]isoxazole‐4,6‐dione have been synthesized by the reaction of N‐arylmaleimides with nitrile oxide, prepared from α‐chloro‐4‐oxo‐4H‐chromen‐carbaldehyde oximes in situ through 1,3‐dipolar cycloaddition reaction. The structures of all new compounds were confirmed by elemental analysis, ir,¹H nmr and mass spectral data.     

Studies on the Chemical Reactivity of 6,8‐dibromo‐7‐hydroxychromone‐3‐carboxaldehyde Towards Some Nitrogen Nucleophilic Reagents

The chemical reactivity of 6,8‐dibromo‐7‐hydroxychromone‐3‐carboxaldehyde ( 1 ) was studied towards some nitrogen nucleophilic reagents such as heterocyclic amines, 1,2‐N,N‐binucleophiles, 1,2‐N,O‐binucleophiles, 1,3‐N,N‐binucleophiles, 1,4‐N,N‐binucleophiles, 1,4‐N,O‐binucleophiles, and 1,4‐N,S‐binucleophiles under different reaction conditions.     

An Improved Synthesis of 2‐Acetamido‐2‐deoxy‐ D‐gluconohydroximolactone (PUGNAc), A Strong Inhibitor of β‐N‐Acetylglucosaminidases

O‐(2‐Acetamido‐3,4,6‐tri‐O‐acetyl‐D ‐glucopyranosylidene)amino N‐phenylcarbamate ( 1 ), an established inhibitor of β‐N‐acetylglucosaminidases, has been prepared by an improved six‐step synthesis from N‐acetyl‐D ‐glucosamine.