Rhodium-catalysed synthesis of fused pyrimidine derivatives employing N-sulfonyl-1,2,3-triazoles as a 1-aza-[4C] synthon

A new synthetic application of N-sulfonyl-1,2,3-triazoles acting as a 1-aza-[4C] synthon via the 1,2-shift reaction of an α-imine rhodium carbene was developed for the synthesis of fused pyrimidine derivatives. The high reactivity of the strained three-membered 2H-azirine ring facilitated the unusual cyclization of electron-deficient dienes with electron-deficient dienophiles. The compatibility was good with common functionalities tolerated. Excellent chemoselectivity was observed, and no reactions occurred between the rhodium carbene and 2H-azirine. The products could be converted into seven-membered multi-functionalized 1H-1,4-diazepine derivatives, illustrating the potential application of the protocol in medium-sized N-heterocycle synthesis.     

A new convenient synthesis of phenanthrene alkaloids from 1-arylmethyl-1,2,3,4-tetrahydroisoquinolines

Hofmann degradation of 1-arylmethyl-1,2,3,4-tetrahydro-2,2-dimethylisoquinolinium iodides with methanolic KOH gave stilbene derivatives, for example, (E)-N-2{2-[2-(phenyl)ethenyl]-4,5-dimethoxyphenyl}ethyl-N,N-dimethylamine. Photochemical electrocyclization of these stilbenes afforded the corresponding phenanthrene alkaloids/phenanthrene derivatives.     

Carbon radical addition to N-sulfonylimines mediated by triethylborane or zinc

The utility of N-sulfonylimines as radical acceptors was investigated under the different reaction conditions such as the stannyl radical-mediated addition reaction, the triethylborane-mediated tin-free radical reaction, and the zinc-mediated aqueous-medium radical reaction. The alkyl radical addition reaction of N-sulfonylimines proceeded effectively without the activation by Lewis acid. These reactions were successfully extended to one-pot reactions for preparing a wide range of amine derivatives.     

Synthetic studies on nogalamycin congeners [3]1,2 total syntheses of (+)-nogarene, (+)-7-deoxynogarol,and (+)-7-con-o-methylnogarol

According to the retrosynthetic perspective, the title total syntheses were accomplished by employing the regioselective Diels-Alder reactions of the (+)-naphthoquinone (5), the CDEF-ring system of nogalamycin congeners, with various structural types of dienes (8, 16, and 26). The highly functionalized dienes (16 and 26) incorporating all the functionalities present in the A-rings of (+)-7-deoxynogarol (3) and (+)-7-con-O-methylnogarol (2), were prepared efficiently by way of the 1 ,4-cyclohexadiene and 2-cyclohexanone derivatives (6 and 21), respectively. Reaction mechanism of the key Diels-Alder reaction was also discussed in terms of its stereoselectivity.     

Preparation of 1,3-dienyl organotrifluoroborates and their Diels-Alder/cross-coupling reactions

2-BF₃-substituted 1,3-butadienes with potassium and tetrabutyl ammonium counterions have been prepared in gram quantities from chloroprene via a simple synthetic procedure. The potassium salt of this new main group element substituted diene has been characterized by ¹H, ¹³C, ¹¹B, and ¹⁹F NMR and the tetra n-butyl ammonium salt was also characterized by X-ray crystallography. Diels-Alder reactions of these dienes with dienophiles such as ethyl acrylate, methyl vinyl ketone, and N-phenylmaleimide are reported as well as subsequent Pd-catalyzed cross-coupling reactions of those Diels-Alder adducts. 4-Phenyl-2-BF₃-substituted 1,3-diene was prepared by magnesium-halogen exchange from the corresponding 2-bromo and iodo dienes. The 4-phenyl-2-bromo-1,3-butadiene was also characterized by X-ray crystallography. 4-Phenyl-2-BF₃-1,3-butadiene was used in Diels-Alder/cross-coupling reactions and the product of a Diels-Alder reaction with N-phenylmaleimide followed by cross-coupling with 4-bromo-benzonitrile was also characterized by X-ray crystallography.     

The use of two optically active N-sulfinyl α-imino esters in the stereoselective aza-Diels-Alder reaction

Diastereoselective aza-Diels-Alder (aza-DA) reactions of ethyl (S)-N-(tert-butanesulfinyl)iminoacetate (2a) and ethyl (S)-N-(p-toluenesulfinyl)iminoacetate (2b) with different dienes including activated, non-activated, cyclic, and acyclic dienes in the presence of Lewis acids are described. Reactions with 2a were found to be more selective. Reactions of unactivated dienes (acyclic and cyclic) with stoichiometric amounts of TMSOTf as Lewis acid afforded the aza-DA adducts in modest yields and in diastereoselectivities up to 99%. A strong preference for Re-approach was observed for 2a. Cyclic dienes gave the exo adducts as major products. For the aza-DA reaction with activated Danishefsky type dienes poor diastereoselectivities were observed. In these cases, the best results were obtained using stoichiometric amounts of BF₃·Et₂O as Lewis acid (up to 69% de, 76% yield). The absolute configurations of six of the addition products were established by chemical correlation with known compounds. Acidic cleavage of the sulfinyl group occurred without racemization to optically active non-proteinogenic α-amino acid ethyl esters.     

Synthesis of 1-thio-phytosphingolipid analogs by microwave promoted reactions of thiols and aziridine derivatives

A practical and versatile method for the synthesis of 1-thio-phytosphingolipid analogs through regioselective nucleophilic ring-opening reactions of phytosphingosine aziridine derivatives with thiols is described. The reactions were carried out with N-acylaziridines and a variety of thiol compounds. Microwave irradiation highly improved the yield of the ring-opening reaction and the intermediate N-acyl adducts were converted into 1-S-phytosphingolipid analogs, such as phytoceramide and phytosphingosine derivatives.     

Asymmetric aza-Diels-Alder reactions of an N-tert-butanesulfinyl α-imino ester

Diastereoselective aza-Diels-Alder (aza-DA) reactions of an N-tert-butanesulfinyl α-imino ester with different dienes including activated and non-activated dienes in the presence of BF₃·OEt₂ are described. Diastereoselectivities up to 99% were observed for acyclic unactivated dienes. The absolute configurations of two aza-DA products have been solved by X-ray analysis.     

Synthesis of tetrahydrophthalazine and phthalamide (phthalimide) derivatives via palladium-catalysed carbonylation of iodoarenes

1,2,3,4-Tetrahydrophthalazin-1-one and 1,2,3,4-tetrahydrophthalazin-1,4-dione derivatives were synthesised in high (up to 85%) and low yields using 2-iodobenzyl bromide and 1,2-diiodobenzene as bifunctional substrates, respectively. Iodoarenes, carbon monoxide and various hydrazine derivatives as N-nucleophiles were used in a three-component palladium-catalysed cascade hydrazinocarbonylation. A similar palladium-catalysed reaction, the aminocarbonylation of 1,2-diiodobenzene, resulted mainly in the formation of two types of major products depending on the amine N-nucleophiles: the use of primary amines yielded N-substituted phthalimides in double carbonylation, while secondary amines react with one of the iodoarene functionalities affording the corresponding 2-iodobenzamides. Due to double carbon monoxide insertion at one or both iodoarene functionalities, ketocarboxamide-carboxamide or bis-ketocarboxamide derivatives could be isolated by the modification of the reaction conditions. Some mechanistic details of the ring-closure reactions and the conditions leading to side-products are also discussed.     

Reactions of epoxides derived from internal perfluoroolefins with o-phenylenediamine and 2-aminophenol

The reactions of epoxy derivatives of internal perfluoroolefins with o-phenylenediamine and 2-aminophenol in dioxane gave 23–67% of the corresponding 2,3-bis(perfluoroalkyl)quinoxalines and 2,3-bis(perfluoroalkyl)-2H-1,4-benzoxazin-2-ols, respectively. When N,N-dimethylacetamide was used as a solvent, the main reaction pathway was anionic isomerization of epoxides into ketones which were then converted into 2-perfluoroalkylbenzimidazoles (in the reactions with o-phenylenediamine) or 2-hydroxy-N-perfluoroalkanoylanilines (in the reactions with 2-aminophenol). The reaction of 3,4-epoxydodecafluorohexane with 2-aminophenol in N,N-dimethylacetamide was accompanied by unusual cyclization to afford 2-pentafluoropropanoyl-2-pentafluoroethyl-1,3-benzoxazolidine.     

Intermolecular Pauson–Khand reactions of N-substituted maleimides

Co₂(CO)₈-mediated intermolecular Pauson–Khand reactions of N-substituted maleimides with terminal alkynes are described, producing maleimide-fused cyclopentenones. The transformation differs from other intermolecular Pauson–Khand-type reactions of electron-deficient olefins, which react with Co₂(CO)₈ and alkynes to produce conjugated dienes, or generally require terminal, monosubstituted olefins to generate cyclopentenones. The reaction works well for N-benzyl, N-aryl, and N-alkyl substituted maleimides, and tolerates branching at the 3-position of the terminal alkyne. N–H maleimide, N–CO₂Me maleimide, and maleic anhydride do not take part in the transformation.     

Exploring the metal-catalyzed reaction of furans with alkyl α-diazomethanesulfonate and α-diazomethanephosphonate: synthesis of ω-acyl-substituted sulfono- and phosphonobutadienes

The metal-catalyzed reactions of neopentyl α-diazomethanesulfonate (DAMS) and diisopropyl α-diazomethanephosphonate (DIDAMP) with furan, 2-methylfuran and 2-methoxyfuran are reported. The products consist mostly of ω-acyl-substituted sulfono- or phosphonobutadienes and exo-cyclopropane derivatives. Treatment of the multicomponent reaction mixtures with iodine afforded exclusively the corresponding (E,E)-sulfono- and phosphono-ω-acylfunctionalized dienes, thus providing a short and efficient synthetic route to these hitherto unreported classes of compounds.     

[4+1] Cycloaddition of N-acylimine derivatives with isocyanides: efficient synthesis of 5-aminooxazoles and 5-aminothiazoles

[4+1] Cycloaddition reaction between isocyanides and N-acylimine derivatives generated from N-acyl N,O-acetals acting as isocyanophiles has been developed. These reactions proceeded smoothly and cleanly to afford the corresponding 5-aminooxazoles in high yields. This reaction was extended to the syntheses of 5-aminothiazoles by using N-thioacyl N,O-acetals. A wide range of N-acyl N,O-acetals, N-thioacyl N,O-acetals, and isocyanides were found to be applicable to this reaction.     

A highly diastereoselective series of Nicholas cyclisation reactions of N-Boc-protected propargylamines

The reaction of N-Boc-protected propargylamine with salicylaldehyde derivatives and their subsequent Nicholas cyclisation reaction to provide a range of novel benzopyrans is reported. The cyclisation reactions proceeded with excellent levels of diastereoselectivity to afford compounds with cis-relative stereochemistry. As far as we are able to ascertain these are the first reported examples of Nicholas cyclisation reactions of propargyl alcohols that bear a terminal alkynyl N-protected amino motif.     

Study on the synthesis of 6-alkylaminouridines via the nucleophilic aromatic substitution reaction of 6-cyanouridine derivatives

6-Cyanouracil derivatives underwent direct substitution reactions with selective primary amines in the presence of N,N-dimethylaminopyridine as a catalyst to give the corresponding 6-alkylaminouracils. This reaction provides a facile access to versatile 6-alkylaminouridine derivatives.     

Hetero Diels-Alder reaction: a novel strategy to regioselective synthesis of pyrimido[4,5-d]pyrimidine analogues from Biginelli derivative

A number of potent pyrimido[4,5-d]pyrimidine analogues have been efficiently synthesized by hetero Diels-Alder cycloaddition of 6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid methyl ester, a Biginelli compound with N-arylidine-N′-methylformamidines and N-arylidine guanidine in dry toluene. Structures of the newly obtained cycloadducts were established on the basis of elemental and spectral (IR, NMR and Mass) data. The molecular mechanism of the observed cycloaddition reaction has been investigated theoretically by means of PM3 semiempirical method. Transition state structure determinations and activation energy calculations have shown the preference for the endo approach over the exo approach of dienophile towards the diene fragments used, which is consistent with the experimental results. The studied cycloadditions proceed via an asynchronous concerted mechanism. It was demonstrated that FMO theory could reasonably predict the relative reactivities between dienes as well as indicating that these reactions belong to normal Diels-Alder type cycloadditions.     

Acyclic ketene aminal phosphates derived from N,N-diprotected acetamides: stability and cross-couplings

The synthesis of a stable ketene aminal phosphate (α-phosphoryloxy enecarbamate) derived from N,N-diprotected acetamide, bearing two different removable protecting groups, is disclosed. This synthetic intermediate underwent successful palladium-catalyzed cross-coupling reactions to afford functionalized enynes and dienes.     

Diselenide-assisted sulfuration of dienes

Various diselenides assist in the sulfuration of dienes giving cyclic di- and tetrasulfides as main products. The reaction requires a 2-fold excess of diselenides to be efficient. Catalytic amounts of diselenides result in lower yields. This is likely due to secondary reactions (polymerization, aromatization) occurring during extended reaction times under catalytic conditions. It was verified that the sulfur-transferring properties of diselenatetrasulfides are virtually identical to those of diselenides combined with sulfur. Contrary to previous claims, not only the cyclic diselenatetrasulfide but also linear diselenatetrasulfides (RSeS_nSeR) transfer sulfur to dienes. A mechanism is proposed and its implications to the nature of diatomic sulfur are discussed.     

Reactions of acceptor substituted thiophene-1,1-dioxides with cyclopentadiene: control of selectivity by substitution

Diels-Alder reactions of thiophene-1,1-dioxides with strong electron withdrawing groups (EWG) were studied experimentally and theoretically. Thiophene-1,1-dioxides with two strong EWG behave as dienophiles and regio- and stereoselectively react with cyclopentadiene to give [2+4] cycloadducts 2a-c, which are derivatives of benzothiophene. In contrast, thiophene-1,1-dioxides with one EWG behave as dienes in the inverse electron demand Diels-Alder reaction yielding dihydro-1H-indenes derivatives. Cope [3,3]-sigmatropic rearrangement of adducts 2a-c was also demonstrated. MP2 calculations successfully rationalize the contrasting regioselectivities of these cycloaddition reactions.     

First example of Diels-Alder reaction in the 2,3,4,4a-tetrahydroquinoline series. Synthesis of hydrogenated 5,8-ethanoquinolines

Diels-Alder reactions in the 2,3,4,4a-tetrahydroquinolines series were studied for the first time. It was shown that these dienes demonstrate only moderate reactivity. [4+2] Cycloaddition occurs stereo- and regioselectively only for alkenes bearing an electron-withdrawing group (acrylonitrile, maleic anhydride, dimethyl acetylene dicarboxylate, methyl propiolate). In this case, endo-Diels-Alder adducts, spiroannelated 5,8-ethanoquinolines, are formed in a high yield. Cyclopentadiene, being a highly reactive diene component, reacts with 2,3,4,4a-tetrahydroquinolines as the dienophile. Electron-rich unsaturated compounds (N-vinylpyrrolidone, vinylethyl ether, phenylacetylene) are inert to this cycloaddition reaction.