Alkyne Precursors Research Articles

Transition Metal-Free Cascade Cyclization of Epoxy-Ynamides: To Go for 1,3-Oxazines or 1,4-Oxazines?

An approach to both 1,3- and 1,4-oxazines is developed by the cascade cyclization of epoxy ynamides under transition metal-free conditions. Thus, while 1,3-oxazines are obtained in a regio- and stereoselective manner by using base, cyclization of epoxy ynamides with sodium azide as a nucleophile results in 1,4-oxazines. Deuterium-labeling experiment demonstrates the role of water as a proton source in the formation of 1,4-oxazines. Epoxy tethered alkyne precursors provide 1,4-oxazines that undergo click reaction.

ChemInform Abstract: Enantiospecific Alkynylation of Alkylboronic Esters.

AbstractVinyl bromide (II) and carbamate (XIII) are applied as alkyne precursors in the enantioselective transformation of the title compounds to the corresponding terminal as well as internal alkynes.

(18)F]Fluoroethyl Triazole Substituted PSMA Inhibitor Exhibiting Rapid Normal Organ Clearance.

Prostate-specific membrane antigen (PSMA) is overexpressed in the epithelium of prostate cancer and nonprostate solid tumor neovasculature. PSMA is increasingly utilized as a target for cancer imaging and therapy. Here, we report the synthesis and in vivo biodistribution of a low-molecular-weight PSMA-based imaging agent, 2-[3-(1-carboxy-5-{3-[1-(2-[(18)F]fluoroethyl)-1H-1,2,3-triazol-yl]propanamido}pentyl)ureido]pentanedioic acid ([(18)F]YC-88), containing an [(18)F]fluoroethyl triazole moiety. [(18)F]YC-88 was synthesized from 2-[(18)F]fluoroethyl azide and the corresponding alkyne precursor in two steps using either a one- or two-pot procedure. Biodistribution and positron emission tomography (PET) imaging were performed in immunocompromised mice using isogenic PSMA(+) PC3 PIP and PSMA(-) PC3 flu xenografts. YC-88 exhibited high affinity for PSMA as evidenced by a Ki value of 12.9 nM. The non-decay corrected radiochemical yields of [(18)F]YC-88 averaged 14 ± 1% (n = 5). Specific radioactivities ranged from 320 to 2,460 Ci/mmol (12-91 GBq/μmol) with an average of 940 Ci/mmol (35 GBq/μmol, n = 5). In an immunocompromised mouse model, [(18)F]YC-88 clearly delineated PSMA(+) PC3 PIP prostate tumor xenografts on imaging with PET. At 1 h postinjection, 47.58 ± 5.19% injected dose per gram of tissue (% ID/g) was evident within the PSMA(+) PC3 PIP tumor, with a ratio of 170:1 of uptake within PSMA(+) PC3 PIP to PSMA(-) PC3 flu tumor placed in the opposite flank. The tumor-to-kidney ratio at 2 h postinjection was 4:1. At or after 30 min postinjection, minimal nontarget tissue uptake of [(18)F]YC-88 was observed. Compared to [(18)F]DCFPyL, which is currently in clinical trials, the uptake of [(18)F]YC-88 within the kidney, liver, and spleen was significantly lower at all time-points studied. At 30 min and 1 h postinjection, salivary gland uptake of [(18)F]YC-88 was significantly less than that of [(18)F]DCFPyL. [(18)F]YC-88 is a new PSMA-targeted PET agent synthesized utilizing click chemistry that demonstrates high PSMA(+) tumor uptake in a xenograft model. Because of its low uptake in the kidney, rapid clearance from nontarget organs, and relatively simple one-pot, two-step radiosynthesis, [(18)F]YC-88 is a viable new PET radiotracer for imaging PSMA-expressing lesions.

Direct Alkynylation of 3H-Imidazo[4,5-b]pyridines Using gem-Dibromoalkenes as Alkynes Source.

C2 direct alkynylation of 3H-imidazo[4,5-b]pyridine derivatives is explored for the first time. Stable and readily available 1,1-dibromo-1-alkenes, electrophilic alkyne precursors, are used as coupling partners. The simple reaction conditions include an inexpensive copper catalyst (CuBr·SMe2 or Cu(OAc)2), a phosphine ligand (DPEphos) and a base (LiOtBu) in 1,4-dioxane at 120 °C. This C-H alkynylation method revealed to be compatible with a variety of substitutions on both coupling partners: heteroarenes and gem-dibromoalkenes. This protocol allows the straightforward synthesis of various 2-alkynyl-3H-imidazo[4,5-b]pyridines, a valuable scaffold in drug design.

Asymmetric synthesis of chiral β-alkynyl carbonyl and sulfonyl derivatives via sequential palladium and copper catalysis.

We present a full account detailing the development of a sequential catalysis strategy for the synthesis of chiral β-alkynyl carbonyl and sulfonyl derivatives. A palladium-catalyzed cross coupling of terminal alkyne donors with acetylenic ester, ketone, and sulfone acceptors generates stereodefined enynes in high yield. These compounds are engaged in an unprecedented, regio- and enantioselective copper-catalyzed conjugate reduction. The process exhibits a high functional group tolerance, and this enables the synthesis of a broad range of chiral products from simple, readily available alkyne precursors. The utility of the method is demonstrated through the elaboration of the chiral β-alkynyl products into a variety of different molecular scaffolds. Its value in complex molecule synthesis is further validated through a concise, enantioselective synthesis of AMG 837, a potent GPR40 receptor agonist.

Synthesis and Properties of (3‐Phenyl‐1‐azulenyl)tetracyanobetadienes and Tris(aryltetracyanobetadiene)s Connected with 1,3,5‐Tri(1‐azulenyl)benzene Core

AbstractTris[(3‐phenyl‐1‐azulenyl)tetracyanobutadiene]s and tris(aryltetracyanobutadiene)s connected to a 1,3,5‐tri(1‐azulenyl)benzene core (tris‐AzTCBDs) have been prepared by the Pd‐catalyzed alkynylation of tris(3‐iodo‐1‐azulenyl)benzene derivative with the corresponding 1‐ethynylazulene or ethynylbenzene derivatives under Sonogashira–Hagihara cross‐coupling conditions, followed by the reaction with tetracyanoethylene (TCNE) in a formal [2 + 2] cycloaddition‐retroelectrocyclization (CA–RE) reaction. The intramolecular charge‐transfer (ICT) interactions of the new chromophores were investigated by the comparison with those of the model tetracyanobutadiene derivatives with azulene substituents (AzTCBDs), which were prepared by the reaction of the corresponding 1‐ethynylazulene derivative with iodoarenes, followed by the CA–RE reaction with TCNE, utilizing UV/Vis spectroscopy and theoretical calculations. The redox behavior of the alkyne precursors and the tetracyanobutadiene derivatives was examined by cyclic voltammetry (CV) and differential pulse voltammetry (DPV), which revealed their multistep electrochemical reduction properties. Moreover, significant color changes of these compounds were observed by visible spectroscopy under the electrochemical reduction conditions.

Novel fluorine-18 labeled 5-(1-pyrrolidinylsulfonyl)-7-azaisatin derivatives as potential PET tracers for in vivo imaging of activated caspases in apoptosis

The programmed type I cell death, defined as apoptosis, is induced by complex regulated signaling pathways that trigger the intracellular activation of executioner caspases-3, -6 and -7. Once activated, these enzymes initiate cellular death through cleavage of proteins which are responsible for DNA repair, signaling and cell maintenance. Several radiofluorinated inhibitors of caspases-3 and -7, comprising a moderate lipophilic 5-(1-pyrrolidinylsulfonyl)isatin lead structure, are currently being investigated for imaging apoptosis in vivo by us and others. The purpose of this study was to increase the intrinsic hydrophilicity of the aforementioned lead structure to alter the pharmacokinetic behavior of the resulting caspase-3 and -7 targeted radiotracer. Therefore, fluorinated and non-fluorinated derivatives of 5-(1-pyrrolidinylsulfonyl)-7-azaisatin were synthesized and tested for their inhibitory properties against recombinant caspases-3 and -7. Fluorine-18 has been introduced by copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) of an alkyne precursor with 2-[18F]fluoroethylazide. Using dynamic micro-PET biodistribution studies in vivo the kinetic behavior of one promising PET-compatible 5-pyrrolidinylsulfonyl 7-azaisatin derivative has been compared to a previously described isatin based radiotracer.

Star-Shaped Macromolecules with the Core of Hexakis-(fluoren-2-yl)benzene and the Periphery of Pyridine: Synthesis and Application as Solution-Processable Electron-Transport Materials.

Three new star-shaped macromolecules with hexakis(fluoren-2-yl)benzene as the core and pyridine as the periphery (2Py-HFB, 3Py-HFB, and 4Py-HFB) are synthesized and characterized. The synthetic conditions of octacarbonyldicobat-catalyzed cycloaddition reaction for different alkyne precursors are investigated. The coordination interaction between the pyridine ring of alkyne precursor and the cobalt catalyst may result in very low yield of the cyclotrimerization product. However, with the increase of the catalyst loading, the yields of the intermediates of cyclopentadienone are enhanced. Then, the desired cyclotrimerization products can be obtained by the Diels-Alder reactions of cyclopentadienone with acetylene in good yield. These new compounds exhibit good thermal stability and favorable electron affinity. By using the new compounds as electron-transporting materials, all-solution-processed phosphorescent organic light-emitting devices (OLEDs) show good performance with a maximum current efficiency of 5.6 cd A(-1) and maximum external quantum efficiency of 4.68%.

Synthesis of a Cytotoxic Amanitin for Biorthogonal Conjugation.

Alpha-amanitin is an exceedingly toxic, naturally occurring, bicyclic octapeptide that inhibits RNA polymerase and results in cellular and organismal death. Here we report the straightforward synthesis of an amanitin analogue that exhibited near-native toxicity. A pendant alkyne was readily installed to enable copper-catalyzed alkyne-azide cycloaddition (CuAAC) to azido-rhodamine and two azide-bearing versions of the RGD peptide. The fluorescent toxin analogue entered cells and provoked morphological changes consistent with cell death. The latter two conjugates are as toxic as the parent alkyne precursor, which demonstrates that conjugation does not diminish toxicity. In addition, we showed that toxicity depends on a single diastereomer of the unnatural amino acid, dihydroxyisoleucine (DHIle), at position 3. The convenient synthesis of a heptapeptide precursor now provides access to bioactive amanitin analogues that may be readily conjugated to biomolecules of interest.

Decarboxylative Alkynyl Termination of Palladium-Catalyzed Catellani Reaction: A Facile Synthesis of α-Alkynyl Anilines via Ortho C-H Amination and Alkynylation.

A palladium-catalyzed synthesis of α-alkynyl anilines is reported. The reaction proceeds via Catellani ortho C-H amination followed by decarboxylative alkynylative amination. Different terminal alkyne precursors were screened, and it was found that alkynyl carboxylic acids were superior over other alkynes, which led to operationally simple reaction conditions (no gradual addition of alkynes) and broad substrate scope. The reactivity of three different components matched well; as a result, relatively higher reaction temperature could be used, greatly shortening the reaction time to 4 h from the previously reported 144 h.

ChemInform Abstract: Rhodium(II)‐Catalyzed Stereocontrolled Synthesis of 2‐Tetrasubstituted Saturated Heterocycles from 1‐Sulfonyl‐1,2,3‐triazoles.

AbstractRhodium‐catalyzed transformation to tetrahydrofuran or tetrahydrothiophene derivatives proceeds with high to excellent diastereoselectivity and yields in the reactions of alkyl‐substituted alkyne precursors.

Synthesis and evaluation of β-hydroxytriazoles and related compounds as antitubercular agents

A new series of β-hydroxytriazoles were synthesized and evaluated as Mycobacterium tuberculosis inhibitors. Our strategy implied the synthesis of alkyne precursors through a Barbier reaction between benzaldehydes and propargyl bromide followed by click chemistry to afford substituted β-hydroxyl benzyltriazoles. These compounds are also key intermediates either for oxidation reactions leading to α,β-diketotriazoles or for elimination reactions affording styryl triazoles. Evaluation of all new compounds for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv resulted in compounds with MIC up to 7 μM.

Solution-phase parallel synthesis of ruxolitinib-derived Janus kinase inhibitors via copper-catalyzed azide-alkyne cycloaddition.

A solution-phase parallel synthesis of triazole-derived ruxolitinib analogues was developed in the current study. The method employs copper-catalyzed azide-alkyne cycloaddition to build up the central triazole template. Product isolation by precipitation and centrifugation is straightforward and yields high purity compounds suited for biological profiling. A simple protocol for accessing the terminal alkyne precursors in high yields was established and a library of ruxolitinib-like triazoles featuring diverse functional groups was prepared. In addition, a model for the binding mode of ruxolitinib to Janus kinase (JAK) 2 is proposed. In contrast to previous models, the pose explains the compound selectivity for JAK1/JAK2 and is in accordance with published structure-activity data. On this basis, a structure-based design hypothesis for inverting the selectivity profile of ruxolitinib is deduced. Application of this strategy identified a moderately potent JAK3 inhibitor (35 nM) with high selectivity against other JAKs, potentially exploiting a covalent binding mode.

Exploring a 2-naphthoic acid template for the structure-based design of P2Y14 receptor antagonist molecular probes.

The P2Y14 receptor (P2Y14R), one of eight P2Y G protein-coupled receptors (GPCR), is involved in inflammatory, endocrine, and hypoxic processes and is an attractive pharmaceutical target. The goal of this research is to develop high-affinity P2Y14R fluorescent probes based on the potent and highly selective antagonist 4-(4-(piperidin-4-yl)-phenyl)-7-(4-(trifluoromethyl)-phenyl)-2-naphthoic acid (6, PPTN). A model of hP2Y14R based on recent hP2Y12R X-ray structures together with simulated antagonist docking suggested that the piperidine ring is suitable for fluorophore conjugation while preserving affinity. Chain-elongated alkynyl or amino derivatives of 6 for click or amide coupling were synthesized, and their antagonist activities were measured in hP2Y14R-expressing CHO cells. Moreover, a new Alexa Fluor 488 (AF488) containing derivative 30 (MRS4174, Ki = 80 pM) exhibited exceptionally high affinity, as compared to 13 nM for the alkyne precursor 22. A flow cytometry assay employing 30 as a fluorescent probe was used to quantify specific binding to P2Y14R. Known P2Y receptor ligands inhibited binding of 30 with properties consistent with their previously established receptor selectivities and affinities. These results illustrate that potency in this series of 2-naphthoic acid derivatives can be preserved by chain functionalization, leading to highly potent fluorescent molecular probes for P2Y14R. Such conjugates will be useful tools in expanding the SAR of this receptor, which still lacks chemical diversity in its collective ligands. This approach demonstrates the predictive power of GPCR homology modeling and the relevance of newly determined X-ray structures to GPCR medicinal chemistry.

A fast way to fluorescence: a fourfold domino reaction to condensed polycyclic compounds.

A fast and efficient palladium-catalyzed fourfold domino Sonogashira/double-carbopalladation/CH-activation reaction that converts simple aromatic systems into complex polycyclic hydrocarbons has been developed. A number of substituted products has thus been prepared in yields up to 89 %. The structural assignment has been confirmed by using single-crystal X-ray crystallography. The products show intriguing fluorescence activity and thus might serve as chemical sensors or fluorescent imaging dyes.

A mechanistic study on the reaction pathways leading to benzene and naphthalene in cellulose vapor phase cracking

The reaction pathways leading to aromatic hydrocarbons such as benzene and naphthalene in gas-phase reactions of multi-component mixtures derived from cellulose fast pyrolysis were studied both experimentally and numerically. A two-stage tubular reactor was used for evaluating the reaction kinetics of secondary vapor phase cracking of the nascent pyrolysates at temperature ranging from 400 to 900 °C, residence time from 0.2 to 4.3 s, and at 241 kPa. The products of alkyne and diene were identified from the primary pyrolysis of cellulose even at low temperature range 500–600 °C. These products include acetylene, propyne, propadiene, vinylacetylene, and cyclopentadiene. Experiments were also numerically validated by a detailed chemical kinetic model consisting of more than 8000 elementary step-like reactions with over 500 chemical species. Acceptable capabilities of the kinetic model in predicting concentration profiles of the products enabled us to assess reaction pathways leading to benzene and naphthalene via the alkyne and diene from primary pyrolysates of cellulose. C3 alkyne and diene are primary precursors of benzene at 650 °C, while combination of ethylene and vinylacetylene produces benzene dominantly at 850 °C. Cyclopentadiene is a prominent precursor of naphthalene. Combination of acetylene with propyne or allyl radical leads to the formation of cyclopentadiene. Furan and acrolein are likely important alkyne precursors in cellulose pyrolysis at low temperature, whereas dehydrogenations of olefins are major route to alkyne at high temperatures.

E-beam Mediated Ligand Dissociation of Alkyne-Dicobaltcarbonyl Complexes as Potential Photochemical Alkyne Precursor

E-mail: kjhwang@hongik.ac.kr Received November 22, 2012, Accepted December 27, 2012 Key Words : Alkyne, Cobalt-complex, Fragmentation, E-beamArrayed alkyne group on a solid surface have been ofinterest for the attachment of diverse agents useful in electronicdevice coating, fluorescence nanopatterning, and surfacereforming.

Platinum Complexes of Alkynyl-Substituted Dimethyldihydropyrenes

A series of photochromic dimethyldihydropyrenes (DHP) bearing ethyne substituents in the 4-position (RDHP-C≡CH; R = H (4), acetyl (5), benzoyl (6), 1-naphthoyl (7), benzo[e] (8)) were prepared for use as precursors to ethynyl ligands. Dehydrohalogenation of the adduct of these ethynes with various PtCl2(L)2 complexes afforded a series of cis and trans square-planar bis(DHP-ethynyl) platinum complexes, (RDHP-C≡C)2Pt(L)2 (cis, R = H, L2 = PEt3 (9), acetyl, PEt3 (10), benzoyl, PEt3 (11), 1-naphthoyl, PEt3 (12), benzo[e], PEt3 (13), benzoyl, PPh3 (14), benzo[e], PPh3 (15); trans, R = H, L2 = dppe (16), benzo[e], dppe (17), acetyl, bipy (18), 1-naphthoyl, bipy (19), H, phen (20)). The DHP-ethynes bearing acyl and benzo[e] substituents on the DHP (5–8) and their platinum complexes (10–19) are photochromic and undergo ring opening to the related cyclophanediene (CPD) isomer on irradiation with visible light (λ >550 nm). In the case of the benzo[e]DHP 8, adding a 4-ethynyl substituent increases the rate of photo-opening 4-fold; however, in the acylDHP series 5–7, addition of a 4-ethynyl group slows the rate of photo-opening by a factor of about 4. The platinum complexes generally open more slowly than the corresponding alkyne precursors, again by a factor of about 4. The rate of photo-opening does not appear to be affected significantly by the nature of the ancillary ligands or the metal geometry, suggesting that there is poor electronic communication between the platinum center and the DHP π system. The thermal back-reaction from the open CPD to closed DHP form is about 50% faster for the metal complexes than for the DHP-ethyne precursor. The platinum complexes and the DHP-ethynes were characterized by NMR and IR spectroscopy and MS and by X-ray crystallography for metal complexes 10, 11, 14, 15, and 17.

ChemInform Abstract: Copper(II)‐Mediated Oxidative Cyclization of Enamides to Oxazoles.

The copper(II)-mediated oxidative cyclization of enamides to oxazoles is reported. A range of 2,5-disubstituted oxazoles were prepared in moderate to good yields in two steps from simple amide and alkyne precursors.

Modular and Stereoselective Synthesis of Tetrasubstituted Helical Alkenes via a Palladium-Catalyzed Domino Reaction

A highly modular and stereoselective synthesis of tetrasubstituted helical alkenes is accomplished by a Pd-catalyzed norbornene-mediated domino reaction. This protocol features the rapid assembly of four C-C bonds via sequential C-H activations and carbopalladations along with efficient access to enantiopure bromoalkyl aryl alkyne precursors using homologative alkynylation as the key transformation. Three distinct elements of stereoselectivity were observed in the preparation of the chiral helical alkenes: retention of stereochemistry of the substrates, induced helical diastereoselectivity in the alkene formation, and the exclusive exo-facial selectivity of the norbornene incorporation.