Synthesis and Antiviral Evaluation of TriPPPro‐AbacavirTP,TriPPPro‐CarbovirTP,and Their 1′,2′‐cis‐Disubstituted Analogues

Herein we describe the synthesis of lipophilic triphosphate prodrugs of abacavir, carbovir, and their 1′,2′‐cis‐substituted carbocyclic analogues. The 1′,2′‐cis‐carbocyclic nucleosides were prepared by starting from enantiomerically pure (1R,2S)‐2‐((benzyloxy)methyl)cyclopent‐3‐en‐1‐ol by a microwave‐assisted Mitsunobu‐type reaction with 2‐amino‐6‐chloropurine. All four nucleoside analogues were prepared from their 2‐amino‐6‐chloropurine precursors. The nucleosides were converted into their corresponding nucleoside triphosphate prodrugs (TriPPPro approach) by application of the H‐phosphonate route. The TriPPPro compounds were hydrolyzed in different media, in which the formation of nucleoside triphosphates was proven. While the TriPPPro compounds of abacavir and carbovir showed increased antiviral activity over their parent nucleoside, the TriPPPro compounds of the 1′,2′‐cis‐substituted analogues as well as their parent nucleosides proved to be inactive against HIV.     

Bis(benzoyloxybenzyl)‐DiPPro Nucleoside Diphosphates of Anti‐HIV Active Nucleoside Analogues

Nucleoside analogues are extensively used as antiviral and anticancer agents. Their efficiency is dependent on their metabolism into the ultimately active nucleoside triphosphates. Often one step or even more in the metabolism of the nucleoside to the triphosphate is inefficient. To overcome this hurdle, prodrugs of the nucleotides are needed. Bis(acyloxybenzyl)nucleoside diphosphates have been reported by us as a first example of an efficient nucleoside diphosphate prodrug (DiPPro nucleotides). Here, the synthesis and the properties of bis(benzoyloxybenzyl)nucleoside diphosphates of the nucleoside analogues d4T and AZT are disclosed. The synthesis was achieved by using a phosphoramidite/oxidation route. In chemical hydrolysis studies, most of the compounds formed a nucleoside diphosphate. This was confirmed in CEM cell extracts, although the prodrug stability in extracts was lower than in phosphate buffer. Furthermore, the stability and the amount of nucleoside diphosphate formed were dependent on the substituent in the benzoyl moiety. Some of the compounds were more active against HIV in thymidine kinase‐deficient CEM/TK^? cells than were d4T or AZT.     

Synthesis and spectroelectrochemistry of dithieno(3,2‐b:2′,3′‐d)pyrrole derivatives

New π‐conjugated polymers containing dithieno(3,2‐b:2′,3′‐d)pyrrole (DTP) were successfully synthesized via electropolymerization. The effect of structural differences on the electrochemical and optoelectronic properties of the 4‐[4H‐dithieno(3,2‐b:2′,3′‐d)pyrrol‐4‐yl]aniline (DTP–aryl–NH₂), 10‐[4H‐dithiyeno(3,2‐b:2′,3′‐d)pirol‐4‐il]dekan‐1‐amine (DTP–alkyl–NH₂), and 1,10‐bis[4H‐dithieno(3,2‐b:2′,3′‐d)pyrrol‐4‐yl] decane (DTP–alkyl–DTP) were investigated. The corresponding polymers were characterized by cyclic voltammetry, NMR (¹H‐NMR and ¹³C‐NMR), and ultraviolet–visible spectroscopy. Changes in the electronic nature of the functional groups led to variations in the electrochemical properties of the π‐conjugated systems. The electroactive polymer films revealed redox couples and exhibited electrochromic behavior. The replacement of the DTP–alkyl–DTP unit with DTP–aryl–NH₂ and DTP–alkyl–NH₂ resulted in a lower oxidation potential. Both the poly(10‐(4H‐Dithiyeno[3,2‐b:2′,3′‐d]pirol‐4‐il)dekan‐1‐amin) (poly(DTP–alkyl–NH₂)) and poly(1,10‐bis(4H‐dithieno[3,2‐b:2′,3′‐d]pyrrol‐4‐yl) decane) (poly(DTP–alkyl–DTP)) films showed multicolor electrochromism and also fast switching times (<1 s) in the visible and near infrared regions. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014 , 131, 40701.     

Crystallography and Structure–Property Relationships in 2,2′,2″,2′′′,4,4′,4″,4′′′,6,6′,6″,6′′′‐Dodecanitro‐1,1′ : 3′1″ : 3″,1′′′‐ Quaterphenyl (DODECA)

X‐ray crystallographic study of 2,2′,2″,2′′′,4,4′,4″,4′′′,6,6′,6″,6′′′‐dodecanitro‐1,1′ : 3′1″ : 3″,1′′′‐quaterphenyl (DODECA) has been carried out. Nonbonding interatomic distances of oxygen atoms inside of all the nitro groups are shorter than those corresponding to the intermolecular contact radii for oxygen. By means of the DFT B3LYP/6‐31(d, p) method a difference of 136 kJ mol⁻¹ between the X‐ray and DFT structures of DODECA was found. The bearer of the highest initiation reactivity in its molecule in solid phase should be the nitro group at 4′′′‐position, in contrast to those at 2′‐ or 2″‐positions in its isolated molecule. The most reactive nitro group in the DODECA molecule can be well specified by the relationship between net charges on nitro groups and charges on their nitrogen atoms, both of them for the X‐ray structure. The ¹⁵N chemical shift, corresponding to this nitro group for the initiation by impact and shock, correlates very well with these shifts of the reaction centers of the other six “genuine” polynitro arenes.     

Crystallography and Structure–Property Relationships of 2,2″,4,4′,4″,6,6′,6″‐Octanitro‐1,1′ : 3′,1″‐Terphenyl (ONT)

An X‐ray crystallographic study of 2,2″,4,4′,4″,6,6′,6″‐octanitro‐1,1′ : 3′,1″‐terphenyl (ONT) has been carried out. The dihedral angles between benzene rings vary from 84.9° to 89.4°. Nonbinding interatomic distances of oxygen atoms inside all the nitro groups are shorter than the intermolecular contact radii for oxygen. On the basis of the DFT B3LYP/6‐31(d, p) method it was found that the difference between the X‐ray structure in the solid phase and DFT result for the gas phase is 98 kJ mol⁻¹, and the bearer of the highest initiation reactivity of the ONT molecule in the solid phase should be the nitro group at 4″‐position, in contrast to those at 4′‐ or 6′‐position that play this role in the isolated molecule. It has been stated that the nitro groups at the reaction centers of the ONT molecule are relatively well specified by their ¹⁵N NMR chemical shifts.     

Synthesis and Cytostatic and Antiviral Activities of 2′‐Deoxy‐2′,2′‐difluororibo‐ and 2′‐Deoxy‐2′‐fluororibonucleosides Derived from 7‐(Het)aryl‐7‐deazaadenines

A series of sugar‐modified derivatives of cytostatic 7‐heteroaryl‐7‐deazaadenosines (2′‐deoxy‐2′‐fluororibo‐ and 2′‐deoxy‐2′,2′‐difluororibonucleosides) bearing an aryl or heteroaryl group at position 7 was prepared and screened for biological activity. The difluororibonucleosides were prepared by non‐ stereoselective glycosidation of 6‐chloro‐7‐deazapurine with benzoyl‐protected 2‐deoxy‐2,2‐difluoro‐D ‐erythro‐pentofuranosyl‐1‐mesylate, followed by amination and aqueous Suzuki cross‐couplings with (het)arylboronic acids. The fluororibo derivatives were prepared by aqueous palladium‐catalyzed cross‐coupling reactions of the corresponding 7‐iodo‐7‐deazaadenine 2′‐deoxy‐2′‐fluororibonucleoside 20 with (het)arylboronic acids. The key intermediate 20 was prepared by a six‐step sequence from the corresponding arabinonucleoside by selective protection of 3′‐ and 5′‐hydroxy groups with acid‐labile groups, followed by stereoselective S_N2 fluorination and deprotection. Some of the title nucleosides and 7‐iodo‐7‐deazaadenine intermediates showed micromolar cytostatic or anti‐HCV activity. The most active were 7‐iodo and 7‐ethynyl derivatives. The corresponding 2′‐deoxy‐2′,2′‐difluororibonucleoside 5′‐O‐triphosphates were found to be good substrates for bacterial DNA polymerases, but are inhibitors of human polymerase α.     

The DiPPro Approach: Synthesis,Hydrolysis, and Antiviral Activity of Lipophilic d4T Diphosphate Prodrugs

Bioreversible protection of the β‐phosphate group of nucleoside diphosphates (NDPs) as bis(acyloxybenzyl)phosphate esters is presented. To investigate the structure–activity relationship of these potential NDP prodrugs (DiPPro drugs) a series of DiPPro compounds was synthesized bearing fatty acids of various lengths and d4T as a model nucleoside. For synthesis of the lipophilically modified diphosphate group, preformed phosphoramidites were allowed to react with nucleotides, and the β‐P^III moiety was subsequently oxidized. The chemical and enzymatic stability of these prodrugs was studied in different media such as phosphate buffer (pH 7.3) or CEM cell extracts. In all media, the hydrolysis rate was clearly dependent on the acyl moiety and decreased with increasing alkyl chain length. The compounds showed a markedly lower half‐life in cell extracts than in pH 7.3 phosphate buffer due to the presence of enzyme‐catalyzed cleavage. In all media, the DiPPro compounds released d4T diphosphate (d4TDP) as the main product beside d4TMP. In antiviral assays, the compounds proved to be at least as potent as d4T against HIV‐1 and 2 in wild‐type CEM/0 cells. As a proof of concept, compounds with longer acyl residues showed very good anti‐HIV activities in thymidine‐kinase‐deficient cells (CEM/TK^?), indicating their ability to penetrate cell membranes and the delivery of phosphorylated metabolites.     

Organosoluble polyimides derived from asymmetric 2‐substituted‐and 2,2′,6‐trisubstituted‐4,4′‐oxydianilines

We report a new method for the preparation of asymmetric diamines using 4,4′‐oxydianiline (4,4′‐ODA) as the starting material. By controlling the equivalents of bromination agent, N‐bromosuccinimide, we were able to attach bromide and phenyl substituents at the 2‐ or 2,2′,6‐positions of 4,4′‐ODA. Thus, four new asymmetric aromatic diamines, 2‐bromo‐4,4′‐oxydianiline (6), 2,2′,6‐tribromo‐4,4′‐oxydianiline (7), 2‐phenyl‐4,4′‐oxydianiline (8) and 2,2′,6‐triphenyl‐4,4′‐oxydianiline (9), were synthesized by this method. Their structural asymmetry was confirmed using ¹H NMR spectroscopy. Asymmetric polyimides (PI10–PI13) were prepared from these diamines and three different dianhydrides (pyromellitic dianhydride (PMDA), 3,3′,4,4′‐biphenyltetracarboxylic dianhydride and 2,2‐bis(3,4‐dicarboxyphenyl)hexafluoropropane dianhydride) in refluxing m‐cresol. The formed polyimides, except PI10a derived from 6 and PMDA, were all soluble in m‐cresol without premature precipitation during polymerization. These polyimides with inherent viscosity of 0.41–0.96 dL g^?1, measured at a concentration of 0.5 g dL^?1 in N‐methyl‐2‐pyrrolidone at 30 °C, can form tough and flexible films. Because of the structural asymmetry, they also exhibited enhanced solubility in organic solvents. Especially, polyimides PI11a and PI13a derived from 7 and 9 with rigid PMDA were soluble in various organic solvents at room temperature. The structural asymmetry of the prepared polyimides was also evidenced from ¹H NMR spectroscopy. In the ¹H NMR spectrum of PI11a, the protons of pyromellitic moiety appeared in an area ratio of 1:2:1 at three different chemical shifts, which were assigned to head‐to‐head, head‐to‐tail and tail‐to‐tail configurations, respectively. These polyimides also exhibited good thermal stability. Their glass transition temperatures ranged from 297 to 344 °C measured using thermal mechanical analysis. © 2013 Society of Chemical Industry     

Direct (hetero)arylation polymerization for the synthesis of donor–acceptor conjugated polymers based on N‐benzoyldithieno [3,2‐b:2′,3′‐d]pyrrole and diketopyrrolopyrrole toward organic photovoltaic cell application

In this research, new donor–acceptor (D‐A) photovoltaic polymers were synthesized from dithieno[3,2‐b:2′,3′‐d]pyrrole electron donor derivatives, including N‐benzoyldithieno[3,2‐b:2′,3′‐d]pyrrole and N‐(4‐hexylbenzoyl)dithieno[3,2‐b:2′,3′‐d]pyrrole, in combination with the electron deficient unit 2,5‐bis(2‐ethylhexyl)‐3,6‐di(thiophen‐2‐yl)‐2,5‐dihydropyrrolo[3,4‐c]pyrrole‐1,4‐dione via direct (hetero)arylation polymerization. The D‐A conjugated polymers obtained were characterized via ¹H NMR, gel permeation chromatography, Fourier transform infrared spectroscopy, DSC, XRD, photoluminescence and UV–visible methods. In addition, these D‐A polymers were used as activated layers in bilayer and bulk heterojunction structures for the fabrication of organic photovoltaic cells. © 2019 Society of Chemical Industry     

Synthesis and Biological Evaluation of Purine 2′‐Fluoro‐2′‐deoxyriboside ProTides as Anti‐influenza Virus Agents

2′‐Fluoro‐2′‐deoxyguanosine has been reported to have potent anti‐influenza virus activity in vitro and in vivo. Herein we describe the synthesis and biological evaluation of 6‐modified 2′‐fluoro‐2′‐deoxyguanosine analogues and their corresponding phosphoramidate ProTides as potential anti‐influenza virus agents. Whereas the parent nucleosides were devoid of antiviral activity in two different cellular assays, the 5′‐O‐naphthyl(methoxy‐L ‐alaninyl) ProTide derivatives of 6‐O‐methyl‐2′‐fluoro‐2′‐deoxyguanosine, 6‐O‐ethyl‐2′‐fluoro‐2′‐deoxyguanosine, and 2′‐deoxy‐2′‐fluoro‐6‐chloroguanosine, and the 5′‐O‐naphthyl(ethoxy‐L ‐alaninyl) ProTide of 6‐O‐ethyl‐2′‐fluoro‐2′‐deoxyguanosine displayed antiviral EC₉₉ values of ～12 μM . The antiviral results are supported by metabolism studies. Rapid conversion into the L ‐alaninyl metabolite and then 6‐modified 2′‐fluoro‐2′‐deoxyguanosine 5′‐monophosphate was observed in enzymatic assays with yeast carboxypeptidase Y or crude cell lysate. Evidence for efficient removal of the 6‐substituent on the guanine part was provided by enzymatic studies with adenosine deaminase, and by molecular modeling of the nucleoside 5′‐monophosphates in the catalytic site of a model of ADAL1, thus indicating the utility of the double prodrug concept.     

Photoconductivity of 1,2‐(1′,1′,2′,2′‐tetracyanomethanoxymethano)[60]fullerene‐doped PVK

1,2‐(1′,1′,2′,2′‐Tetracyanomethanoxymethano)[60]fullerene, a derivative of C₆₀, is a better electron acceptor than the parent C₆₀. The film of PVK doped with 1.6 wt % of this derivative was prepared and characterized. The micromorphology of the film was studied by transmission electron microscopy (TEM) and high‐resolution transmission electron microscopy (HRTEM). The photoinduced discharge curves and photoconduction spectra of the films were measured. The results showed that PVK doped with the C₆₀ derivative displayed more photoconductivity than that of PVK doped with pure C₆₀ or a mixture of C₆₀ and C₇₀. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 72: 209–213, 1999     

Structure‐Based Design,Synthesis, and Evaluation of 2′‐(2‐Hydroxyethyl)‐2′‐deoxyadenosine and the 5′‐Diphosphate Derivative as Ribonucleotide Reductase Inhibitors

Analysis of the recently solved X‐ray crystal structures of Saccharomyces cerevisiae ribonucleotide reductase I (ScRnr1) in complex with effectors and substrates led to the discovery of a conserved water molecule located at the active site that interacted with the 2′‐hydroxy group of the nucleoside ribose. In this study 2′‐(2‐hydroxyethyl)‐2′‐deoxyadenosine 1 and the 5′‐diphosphate derivative 2 were designed and synthesized to see if the conserved water molecule could be displaced by a hydroxymethylene group, to generate novel RNR inhibitors as potential antitumor agents. Herein we report the synthesis of analogues 1 and 2 , and the co‐crystal structure of adenosine diphosphate analogue 2 bound to ScRnr1, which shows the conserved water molecule is displaced as hypothesized.     

Bacterial Alarmone,Guanosine 5′‐Diphosphate 3′‐Diphosphate (ppGpp), Predominantly Binds the β′ Subunit of Plastid‐Encoded Plastid RNA Polymerase in Chloroplasts

It's alarming : Bacterial alarmone guanosine 5′‐diphosphate 3′‐diphosphate (ppGpp), which is a key regulatory molecule that controls the stringent response, also exists in chloroplasts of plant cells. Cross‐linking experiments with 6‐thioguanosine 5′‐diphosphate 3′‐diphosphate (6‐thioppGpp) and chloroplast RNA polymerase indicate that ppGpp binds the β′ subunit of plastid‐encoded plastid RNA polymerase that corresponds to the Escherichia coli β′ subunit.

     

Phosphine‐Catalyzed Asymmetric [4+2] Annulation of Vinyl Ketones with Oxindole‐Derived α,β‐Unsaturated Imines: Enantioselective Syntheses of 2′,3′‐Dihydro‐1′H‐spiro[indoline‐3,4′‐pyridin]‐2‐ones

A novel asymmetric [4+2] annulation of vinyl ketones with oxindole‐derived α,β‐unsaturated imines has been developed in the presence of a multifunctional thiourea‐phosphine catalyst derived from a natural amino acid, providing the first phosphine‐catalyzed enantioselective synthesis of 2′,3′‐dihydro‐1′H‐spiro[indoline‐3,4′‐pyridin]‐2‐ones in good yields with excellent stereoselectivities under mild conditions.

     

Synthesis and Biological Evaluation of Pyrrolo[2,1‐f][1,2,4]triazine C‐Nucleosides with a Ribose, 2′‐Deoxyribose,and 2′,3′‐Dideoxyribose Sugar Moiety

The synthesis of hitherto unknown pyrrolo[2,1‐f][1,2,4]triazine C‐nucleosides is described. Structural variations (chlorine, bromine, iodine, and cyano groups) were introduced at position 7 of 4‐aza‐7,9‐dideazaadenine. In addition, pyrrolo[2,1‐f][1,2,4]triazine C‐nucleosides bearing a 2′‐deoxy‐, 2′,3′‐dideoxy‐, and 2′,3′‐dehydrodideoxyribose moiety were also prepared. Among these analogues, the pyrrolo[2,1‐f][1,2,4]triazine C‐ribonucleosides with either a hydrogen atom or cyano group at position 7 of the nucleobase displayed potent cytotoxic activity in a panel of various cancer cell lines.     

Synthesis of 3,3′-Bis(2,2′,4,4′,6,6′-Hexanitortilbene)

This paper describes the synthesis of 3,3′bis(2,2′,4,4′,6,6′-hexanitrostilbene) (5). Based on the Ullmann reaction we prepared the title compound in nitrobenzene by using 3-chloro 2,2′,4,4′,6,6′-hexanitroztilbene (4) as the starting material and copper powder as the catalyst. (4) was reacted with hydrazine, not to yield a desired product, azo-3,3′bist(2,2′,4,4′,6,6′-hexanitrostilbene.) but to form a well-known explosive, 2,2′,4,4′,6,6′-hexanitrostibene (6). Differential scanning calorimetrical analysis has shown that (5) begins to decompose at the temperature of 298°C.     

Dithieno[2,3‐d:2′,3′‐d′]naphtho[2,1‐b:3,4‐b′]dithiophene based medium bandgap conjugated polymers for photovoltaic applications

Three novel medium band gap (MBG) conjugated polymers (CPs) (named as P1, P2, and P3, respectively) were developed by copolymerizing 2,7‐dibromo‐10,11‐di(2‐hexyldecyloxy)dithieno[2,3‐d:2′,3′‐d′]naphtho[2,1‐b:3,4‐b′]dithiophene (NDT‐Br) with three different units: 2,5‐bis(tributylstannyl)thiophene, 2,5‐bis(trimethylstannyl)thieno[3,2‐b]thiophene and trans?1,2‐bis(tributylstannyl)ethene, respectively. The thermal, optical, and electrochemical properties of the polymers were investigated. All of the polymers have good thermal stability and medium band gap (～ 1.9 eV). Prototype bulk heterojunction photovoltaic cells based on the blend P1/P2/P3 and [6, 6] phenyl‐C61 butyric acid methyl ester (PC₆₁BM) were assembled and the photovoltaic properties were assessed. Power conversion efficiencies (PCEs) of 1.61% ～ 2.43% have been obtained under 100 mW cm^?2 illumination (AM1.5). © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016 , 133, 43288.     

Synthesis and properties of organosoluble polyimides derived from 2,2′‐dibromo‐ and 2,2′,6,6′‐tetrabromo‐4,4′‐oxydianilines

Two new aromatic diamines, 2,2′‐dibromo‐4,4′‐oxydianiline (DB‐ODA 4 ) and 2,2′,6,6′‐tetrabromo‐4,4′‐oxydianiline (TB‐ODA 5 ), have been synthesized by oxidation, bromination, and reduction of 4,4′‐oxydianiline (4,4′‐ODA). Novel polyimides 6a–f and 7a–f were prepared by reacting DB‐ODA ( 4 ) and TB‐ODA ( 5 ) with several dianhydrides by one‐step method, respectively. The inherent viscosities of these polyimides ranged from 0.31 to 0.99 dL/g (0.5 g/dL, in NMP at 30°C). These polyimides showed enhanced solubilities compared to those derived from 4,4′‐oxydianiline and corresponding dianhydrides. Especially, polyimides 7a , derived from rigid PMDA and TB‐ODA ( 5 ) can also be soluble in THF, DMF, DMAc, DMSO, and NMP. These polyimides also exhibited good thermal stability. Their glass transition temperatures measured by thermal mechanical analysis (TMA) ranged from 251 to 328°C. When the same dianhydrides were used, polyimides 7 containing four bromide substituents had higher glass transition temperatures than polyimides 6 containing two bromide substituents. The effects of incorporating more polarizable bromides on the refractive indices of polyimides were also investigated. The average refractive indices (n_av) measured at 633 nm were from 1.6088 to 1.7072, and the in‐plane/out‐of‐plane birefringences (Δn) were from 0.0098 to 0.0445. It was found that the refractive indices are slightly higher when polyimides contain more bromides. However, this effect is not very obvious. It might be due to loose chain packing resulted from bromide substituents at the 2,2′ and 2,2′,6,6′ positions of the oxydiphenylene moieties. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010     

Synthesis of 3′,4′‐disubstituted terthiophenes. Characterization and electropolymerization. I. 3′,4′‐dibromo‐2,2′:5′,2″‐terthiophene in photovoltaic display

Recent studies on conducting polymers have demonstrated that polymers of 3‐substituted thiophene produce very stable compounds. Although this kind of substitution improves the regularity, structural defects still exist. To overcome this drawback, the polymerization of 3,4‐disubstituted thiophene is proposed as a convenient way of synthesizing regular, highly conjugated conductive polymers. Our interest is thus focused on the synthesis of tetra‐substituted thiophene derivatives, their polymerization, electrochemical properties, spectral characteristics, oxidizing potential, and the feasibility of photocells development. In this article, we report the synthesis and characterization of 3′,4′‐dibromo‐2,2′:5′,2″‐terthiophene which, as such or modified, may be a good starting product for obtaining new monomers of 3′,4′‐disubstituted terthiophenes, that would allow the effect of the substituents on the properties of the respective polymers to be studied. In addition, the monomer was electropolymerized and the resulting deposit was electrochemically and morphologically characterized. Two conclusions were drawn: first, more uniform and homogeneous layers than those of polythiophene are obtained; second, the thin layers of the polymer, electron acceptors, absorb in the visible. Finally, photocells were assembled to investigate their photovoltaic effect. Although the so prepared solar cells showed some photovoltaic effect, the yield was low.© 2006 Wiley Periodicals, Inc. J Appl Polym Sci 102: 5314–5321, 2006     

Synthesis of Substituted 2,2′‐Bipyridines and 2,2′:6′,2′′‐Terpyridines by Cobalt‐Catalyzed Cycloaddition Reactions of Nitriles and α,ω‐Diynes with Exclusive Regioselectivity

A variety of substituted 2,2′‐bipyridines were synthesized by a 1,2‐bis(diphenylphosphino)ethane (dppe)/cobalt chloride hexahydrate (CoCl₂⋅6 H₂O)/zinc‐catalyzed [2+2+2] cycloaddition reaction of diynes and nitriles, with all reactions exhibiting exclusive regioselectivity. Thus, symmetrical and unsymmetrical 1,6‐diynes and 2‐cyanopyridine reacted in the presence of 5 mol % of dppe, 5 mol % of CoCl₂⋅6 H₂O and 10 mol % of zinc powder to provide the corresponding 2,2′‐bipyridines. Under identical reaction conditions, 1‐(2‐pyridyl)‐1,6‐diynes and nitriles reacted smoothly with exclusive regioselectivity to produce 2,2′‐bipyridines in good yield. 2,2′‐Bipyridines were also obtained by the double [2+2+2] cycloaddition reaction of 1,6,8,13‐tetraynes with nitriles. Similarly, 2,2′:6′,2′′‐terpyridines were synthesized from 1‐(2‐pyridyl)‐1,6‐diyne and 2‐cyanopyridine. The regiochemistry observed can be explained by considering the electronic nature of cobaltacyclopentadiene intermediates and nitriles. A survey of the exclusive regiochemical trend gives reasonable credence to the synthetic potential of the present method.