Pyrimidyl Group Research Articles

Rhodium-catalyzed site-selective cross-couplings of indoles and pyridotriazoles through carbene insertion

The switchable cross-coupling of indoles and pyridotriazoles through carbene insertion at C2- or C3-positon has been developed in this paper. This highly site-selective C−H carbenoid functionalization is determined by both the Rh-catalyst species and auxiliary groups. [Cp*RhCl2]2 and coordinating pyrimidyl group direct the C−H carbenoid functionalization to occur at the C2-position, while Rh2OAc4 and non-coordinating benzyl group lead the reaction to occur at the C3-position of the indoles. This regioselective C−H functionalization strategy is of significant importance for the discovery of indole drugs.

Long‐Life, High‐Rate Rechargeable Lithium Batteries Based on Soluble Bis(2‐pyrimidyl) Disulfide Cathode

AbstractOrganosulfides are promising candidates as cathode materials for the development of electric vehicles and energy storage systems due to their low‐cost and high capacity properties. However, they generally suffer from slow kinetics because of the large rearrangement of S−S bonds and structural degradation upon cycling in batteries. In this paper, we reveal that soluble bis(2‐pyrimidyl) disulfide (Pym2S2) can be a high‐rate cathode material for rechargeable lithium batteries. Benefiting from the superdelocalization of pyrimidyl group, the extra electrons prefer to be localized on the π* (pyrimidyl group) than σ* (S−S bond) molecular orbitals initially, generating the anion‐like intermedia of [Pym2S2]2− and thus decreasing the dissociation energy of the S−S bond. It makes the intrinsic energy barrier of dissociative electron transfer depleted, therefore the lithium half cell exhibits 2000 cycles at 5 C. This study provides a distinct pathway for the design of high‐rate, long‐cycle‐life organic cathode materials.

Long-Life, High-Rate Rechargeable Lithium Batteries Based on Soluble Bis(2-pyrimidyl) Disulfide Cathode.

Organosulfides are promising candidates as cathode materials for the development of electric vehicles and energy storage systems due to their low-cost and high capacity properties. However, they generally suffer from slow kinetics because of the large rearrangement of S-S bonds and structural degradation upon cycling in batteries. In this paper, we reveal that soluble bis(2-pyrimidyl) disulfide (Pym2 S2 ) can be a high-rate cathode material for rechargeable lithium batteries. Benefiting from the superdelocalization of pyrimidyl group, the extra electrons prefer to be localized on the π* (pyrimidyl group) than σ* (S-S bond) molecular orbitals initially, generating the anion-like intermedia of [Pym2 S2 ]2- and thus decreasing the dissociation energy of the S-S bond. It makes the intrinsic energy barrier of dissociative electron transfer depleted, therefore the lithium half cell exhibits 2000 cycles at 5 C. This study provides a distinct pathway for the design of high-rate, long-cycle-life organic cathode materials.

AIE active quinazoline based probes for selective detection of Fe3+ and acidochromism

Synthesis and thorough characterizations of two A-D-π-A’ type asymmetric donor–acceptor constructs 6-(4-(4-(pyridin-2-yl)piperazin-1-yl)-phenyl)-5,6-dihydrobenzo-[4,5]-imidazo[1,2–c]-quinazoline (P1) and 6-(4-(4-(pyrimidin-2-yl)-piperazin-1-yl)phenyl)-5,6-dihydro-benzo[4,5]-imidazo[1,2–c] quinazoline (P2) have been described. The formation and composition of these compounds have been ascertained by spectroscopic studies (IR, 1H, 13C, ESI–MS, UV/Vis and fluorescence). Quinazoline unit in P1 and P2 acts as acceptor whereas piperazine as donor moiety and their properties has further been tuned by incorporating pyridyl and pyrimidyl group. AIE behaviour of P1 and P2 have been studied in THF/water by absorption and emission spectroscopy by varrying water fraction. Prominent role of the restriction of intra-molecular rotation on (RIR) in AIE for these compounds has been supported by viscosity measurements. Photophysical behaviour and morphology of the aggregates have been investigated by UV/Vis, fluorescence, and scanning electron microscopy (SEM). Owing to asymmetric donor–acceptor (A-D- π -A’) nature these display (twisted intramolecular charge transfer) TICT via D-A unit. In addition, P1 and P2 serve as highly selective and sensitive fluorescence sensor for Fe3+ and Job’s plot analysis suggested 2:1 binding stoichiometry between the metal centre Fe3+ and probes. As well, P1 and P2 display promising reversible acidochromism.

Constructing Cationic Metal-Organic Framework Materials Based on Pyrimidyl as a Functional Group for Perrhenate/Pertechnetate Sorption.

Cationic metal-organic framework (MOF) materials are widely used in the anion separation field, but there are few reports of pyrimidyl ligands as building units. In this work, three new cationic MOFs based on pyrimidyl as functional group ligands were synthesized for the removal of radioactive pertechnetate from aqueous solution. The pyrimidyl ligands were designed by incorporating pyrimidyl units into the skeletons of benzene, triphenylamine, and tetraphenylethylene, respectively. Taking advantage of multiple coordination sites of pyrimidyl groups, three cationic MOFs (ZJU-X11, ZJU-X12, and ZJU-X13) with diverse structures were solvothermally synthesized using silver ion as the metal node. Scanning electron microscopy-energy-dispersive spectroscopy mapping demonstrated that these three cationic MOFs could capture ReO4- via anion exchange, but the sorption capabilities were distinctly different. With 95% removal toward ReO4-, ZJU-X11 showed the strongest anion-exchange competence among the three MOFs. According to the results of batch experiments, ZJU-X11 could achieve sorption equilibrium within 10 min, remove 518 mg of ReO4- per 1 g of ZJU-X11, remove most of ReO4- after four recycles, and maintain satisfactory selectivity in the presence of excess competing anions, which is one of the best MOF materials for removing ReO4-/TcO4- among the three cationic MOFs. This work indicates that the pyrimidyl group is a promising multiple site to build versatile cationic MOFs.

Predictable site-selective functionalization: Promoter group assisted para-halogenation of N-substituted (hetero)aromatics under metal-free condition.

Herein, regioselective para-C-H halogenation of N-pyrimidyl (hetero)aromatics through SEAr (electrophilic aromatic substitution) type reaction is disclosed. SEAr type reaction has been utilized for the C5-bromination of indolines (para-selective) with N-bromosuccinimide under metal and additive-free conditions in good to excellent yields. The developed methodology is also applicable for iodination and challenging chlorination. The pyrimidyl group is identified as a reactivity tuner that also controls the regioselectivity. The present method is also applicable for selective halogenation of aniline, pyridine, indole, oxindole, pyrazole, tetrahydroquinoline, isoquinoline, and carbazole. DFT studies such as Fukui nucleophilicity and natural charge maps also support the observed p-selectivity. Post-functionalization of the title compound into the corresponding arylated, olefinated, and dihalogenated products is achieved in a one-pot, two-step fashion. Late-stage C-H bromination was also executed on drug/natural molecules (harmine, etoricoxib, clonidine, and chlorzoxazone) to demonstrate the applicability of the developed protocol.

Synthesis and Versatile Utilization of 2‐Pyridyl and Pyrimidyl‐Related Reagents

Active (thio)esters and amides were prepared from carboxylic acids and several reagents containing 2‐pyridyl or pyrimidyl moiety. Active (thio)carbonates, thionocarbonate, and thiourea were prepared from (thio)phosgene and 2‐hydroxypyridine or 2‐mercaptopyridine. The acylation of active (thio)esters and amides containing 2‐pyridyl or pyrimidyl groups with various organometallics afforded ketones, aldehydes, esters, amides, and β‐keto esters. The alkoxycarbonylation of active (thio)carbonates with Grignard reagents and amines afforded esters and carbamates, respectively. Active di(thiono)carbonates and thiourea containing the 2‐pyridyl or pyrimidyl moiety have been used in the dehydration of carboxylic acids/alcohols or aldoximes, dehydrosulfurization of thioureas, and (thio)carbonyl transfer of diols or amines to produce esters or nitriles, carbodiimides, cyclic carbonates or isothiocyanates, respectively.

Pyrimidyl-substituted anthracene fluorophores: Syntheses, absorption spectra, and photophysical properties

Twelve new polycyclic aromatic chromophores whose structures recall 9,10-substituted anthracene have been prepared and their absorption spectra, and luminescence properties (both in ethanol and dichloromethane solution at room temperature and in MeOH/EtOH (4:1 v/v) rigid matrix at 77 K) have been analyzed as well as pump-probe transient absorption spectroscopy and computational studies have been performed. The compounds have variously decorated pyrimidyl groups as substituents of the anthracene framework. The compounds are conveniently grouped in two series: 1–4 and 11, in which the pyrimidine nitrogen atoms are on the external side with respect to the anthracene framework (Ext-type compounds), and 5–10, where the pyrimidine nitrogen atoms are pointing towards the anthracene platform (Int-type compounds). Compound 12 contains both a pyrimidine substituent with “inner” nitrogen atoms (“Int”) and a pyrimidine with “outer” nitrogen atoms (“Ext”). All the new species are quite efficient luminophores (spectral range of emission maxima: 400–450 nm at 77 K; 415–520 nm at room temperature; emission lifetimes: 0.25–8.7 ns range; emission quantum yields ranging between 0.08 to 0.99, with a single exception), with their photophysical properties depending on the connection scheme of the pyrimidyl groups to the anthryl platform (i.e., Int-type vs Ext-type compounds). Luminescence originating from locally excited π−π* anthracene-based singlet states, delocalized states largely involving the pyrimidyl moieties, and charge transfer states has been identified. For the Int-type series, the initially-prepared excited state can deactivate via interconversion to a saddle-shaped conformation, opening the way to fast nonradiative decays.

ChemInform Abstract: Multiple Roles of the Pyrimidyl Group in the Rhodium‐Catalyzed Regioselective Synthesis and Functionalization of Indole‐3‐carboxylic Acid Esters.

AbstractPyrimidyl as a directing group plays a crucial role in the reaction of anilines and diazo compounds to form indole‐3‐carboxylic acid ester and in the regioselective functionalization of the products at C‐7.

Multiple Roles of the Pyrimidyl Group in the Rhodium‐Catalyzed Regioselective Synthesis and Functionalization of Indole‐3‐carboxylic Acid Esters

AbstractA regioselective synthesis of indole‐3‐carboxylic acid esters from anilines and diazo compounds has been realized by making use of the pyrimidyl group‐assisted rhodium‐catalyzed CH activation and CN bond formation. The reaction proceeds under mild conditions, exhibits good functional group tolerance and scalability. Reutilization of the pyrimidyl directing group in the resulting products provided an efficient strategy for further C‐7 functionalization of indoles. Moreover, the pyrimidyl moiety could be readily removed as a leaving group to offer various free NH indoles.magnified image

ChemInform Abstract: Cationic Rhodium(III)‐Catalyzed Direct C‐2 Carboxamidation of Indoles with Isocyanates via C—H Bond Functionalization.

AbstractA wide range of indole‐2‐carboxamides is obtained under relatively mild reaction conditions and with broad functional group tolerance using the pyrimidyl group in the substrates as easily installable and removable directing group.

Next Generation XPO1 Inhibitor Shows Improved Efficacy and In Vivo Tolerability in Hematologic Malignancies

▪Restoring nuclear localization of tumor suppressors by blocking exportin 1 (XPO1) holds promise as a new therapeutic paradigm in many cancers, including chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). Oral selective inhibitor of nuclear export (SINE) compounds that covalently modify XPO1 were recently discovered and are exciting new compounds to implement this strategy. Selinexor, the clinical lead SINE, has made progress in Phase I/II clinical trials and is generally well tolerated, but limited to twice weekly dosing, with supportive care. The discovery of novel SINE compounds with improved tolerability is therefore of considerable clinical interest and represents a significant contribution beyond the targeted therapies currently available for hematologic malignancies and a variety of other cancers where upregulation of XPO1 is observed. Presented herein is the discovery of KPT-8602, the next generation SINE compound that shows lower brain penetration, improved tolerability allowing continuous dosing, and improved efficacy beyond any current XPO1 inhibitor. Results: Our crystallography data revealed that KPT-8602 binds covalently to XPO1 through a Michael acceptor that is activated by an electron withdrawing pyrimidyl moiety, allowing a 2-fold increased reversible interaction with XPO1 compared to earlier SINE compounds. The crystal structure of the KPT-8602-XPO1 complex showed interactions between XPO1 and the activating pyrimidyl group. In vitro pull-downs using immobilized GST-nuclear export sequences and purified recombinant XPO1 demonstrated greater reversible binding of KPT-8602 compared to KPT-330 (selinexor). In vivo toxicology studies demonstrated that KPT-8602 possesses lower brain penetration compared to KPT-330 allowing for continuous dosing and improved tolerability. Our results also showed that KPT-8602 induced a comparable level of cytotoxicity as well as inhibition of cell proliferation compared to KPT-330 in primary CLL tumors and in a representative panel of DLBCL cell lines. Furthermore, KPT-8602 inhibited proliferation and induced apoptosis in AML cell lines and primary AML blasts while inducing nuclear accumulation of p53 and NPM1. We hypothesized that these improved pharmacological parameters would allow daily KPT-8602 to abrogate disease progression in CLL and AML animal models. The Eµ-TCL1-C57BL/6 transplant model of CLL was used to evaluate the therapeutic benefit of continuous dosing of KPT-8602. Eµ-TCL1-engrafted mice were treated with KPT-8602 given daily or 2x/week. The KPT-8602 daily cohort had significantly improved survival with a median overall survival of 70 vs 50 days (vs vehicle 33 days), compared to those treated only 2x/week with KPT-8602 (p=0.001). Mice treated with KPT-330 2x/week showed a similar survival to mice treated with KPT-8602 2x/week. Mice given daily KPT-8602 had significantly smaller spleens and reduced circulating leukemic cells compared to all the other groups (p<0.001 for all comparisons). We recently showed the combination of KPT-330 and ibrutinib (bruton tyrosine kinase inhibitor) increases survival compared to ibrutinib alone in Eµ-TCL1-engrafted mice. We therefore tested the effect of KPT-330+ibrutinib or KPT-8602+ibrutinib in a cohort of Eµ-TCL1-engrafted mice compared to any agent alone. Notably, the combination of KPT-8602 to ibrutinib was able to further improve the survival induced by KPT-330+ibrutinib (p=0.008). We next assessed the activity of KPT-8602 in a human leukemia xenograft model of AML where NOD/SCID γ mice were inoculated with MV4-11 cells obtained from spleens of primary MV4-11 xenografts. Recipient mice given KPT-8602 5x/week showed strikingly better outcomes with a median survival of 58 vs 35 days compared to KPT-8602 2x/week (p<0.0001) and KPT-330 2x/week (p<0.0001). Conclusion: Consistent with the in vitro finding of a two-fold enhanced reversibility of XPO1-KPT-8602 binding and lower brain penetration, our data indicate that KPT-8602 allows a prolonged frequent dosing schedule, which leads to an excellent therapeutic benefit and less toxicity in animal models of CLL and AML. These data suggest that KPT-8602 represents a new treatment paradigm and warrants further evaluation in clinical trials of patients with hematologic malignancies, particularly in combination with ibrutinib or other second generation Btk inhibitors. DisclosuresBaloglu:Karyopharm Therapeutics Inc.: Employment, Equity Ownership. Shacham:Karyopharm: Employment, Equity Ownership. Kauffman:Karyopharm: Employment, Equity Ownership. Byrd:Acerta Pharma BV: Research Funding. Chook:Karyopharm Therapeutics Inc.: Consultancy.

Cationic Rhodium(III)‐Catalyzed Direct C‐2 Carboxamidation of Indoles with Isocyanates via CH Bond Functionalization

AbstractA pentamethylcyclopentadienylrhodium(III)‐catalyzed regioselective synthesis of indole‐2‐carboxamides is described employing N‐pyrimidylindoles and isocyanates as coupling partners via CH functionalization. A wide variety of indole‐2‐carboxamides can be synthesized via this method under relatively mild conditions with broad functional group tolerance. The effect of various directing group on this transformation was also studied, unveiling the pyrimidyl group as an easily installable and removable directing group.magnified image

Manganese catalyzed C-H functionalization of indoles with alkynes to synthesize bis/trisubstituted indolylalkenes and carbazoles: the acid is the key to control selectivity.

The Mn-catalyzed C-H alkenylation reactions of indole with terminal- and internal-alkynes have been developed. In the presence of a catalytic amount of acid, the procedure efficiently affords bis/trisubstituted indolyl-alkenes in a highly regio- and stereo-selective manner. Without the addition of acid, the reaction undergoes a [2+2+2] cyclization process to give carbazoles with release of hydrogen gas. Notably, the directing pyrimidyl group can be readily removed. Experimental studies reveal that the reaction is initiated by a C-H activation step and the acid is the selectivity controller via a hydrogen transfer process.

Modified Phenyl Groups on Pyrazin Groups to Synthesized Cobalt String Complexes

In the literature, ligand such as oligo-α-pyridylamines and oligo-naphthyridylamine are usually used in the linear metal string complex. In addition to all of the above, another series of ligand is synthesized by mixing two types of ligands. In other words, the type of ligand contains pyridyl and naphthyridyl groups. Permuting the possible permutation, we can find that symmetrical and the shortest ligand is 2,7-bis(α-pyridylamino)-1,8-naphthyridine (H2bpyany). Complexes contain bpyany2-, hexa-nickel or hexa-cobalt, axial ligands such as chloride and thiocyanate, and anions such as hexafluorophosphate and tetrafluoroborate were published1, 2. Another similar ligand that H2bpyany replaces pyridyl groups by pyrimidyl group is 2,7-bis(α-pyrimidylamino)-1,8-naphthyridine (H2bpmany). Hexanickel complexes with bpmany2- were also published3. According to the above, if we replace pyridyl group by pyrazin group, properties of complexes such as magnetic property, CV and resistance make a change. 2,7-bis(α-pyrazinamino)-1,8-naphthyridine (H2bpzany) and nickel or cobalt ions were reacted. We can get the signal in MALDI, but we cannot isolate the target. Because of this, we modified phenyl groups on pyrazin groups. By 2,7-bis(5-phenyl)-α-pyrazinamino-1,8-naphthyridine (H2bphpzany), [Co5(bphpzany)4(NCS)2] (1), [Co6(bphpzany)4(NCS)2](PF6)n (n=1 (2), n=2 (3)) have been synthesized and the crystal structures for complex 1–3 have been determined by X-ray crystallography. Three complexes are the similar component of four ligands, five or six cobalt ions, two thiocyanates as axial ligands, and hexafluorophosphate as counterions. The structural characterization is that the cobalt chain is helically wrapped by four bphpzany2–. Complex 1–3 have Co510+, Co612+ configurations, and all are air-stable.

Rhodium(III)‐Catalyzed Regioselective Direct C‐2 Alkenylation of Indoles Assisted by the Removable N‐(2‐Pyrimidyl) Group

AbstractThe C‐2‐alkenylindole unit is a key component of numerous natural products and pharmacophores. However, the intermolecular direct construction of the core structural motif remains challenging in organic synthesis. Here we report a new, efficient, and versatile methodology for the synthesis of C‐2‐alkenylindoles through rhodium(III)‐catalyzed direct CH functionalization of indoles with acrylates under air by employing a metal‐directing group strategy. This strategy gives a rare selectivity for the alkenylation N‐(2‐pyrimidyl)indoles at the C‐2 position and provides the functionalized C‐2‐ alkenylindoles under mild conditions with broad substrate tolerance. An expansion of the methodology has also been demonstrated to, for example, the direct alkenylation of pyrrole and facile deprotection of the pyrimidyl group. All the results suggest that this methodology could be served as a highly attractive alternative for the direct construction of biologically important C‐2‐alkenylindoles.magnified image

Copper-Mediated Direct C2-Cyanation of Indoles Using Acetonitrile as the Cyanide Source

A copper-mediated C2-cyanation of indoles using cheap and commercially available acetonitrile as the "nonmetallic" cyanide source was achieved through sequential C-C and C-H bond cleavages. The installation of a removable pyrimidyl group on the indole nitrogen atom is the key for this C2 selectivity. This approach provides a novel and alternative route leading to indole-2-carbonitrile.

Exploring the role of varied-length spacers in charge transfer: a theoretical investigation on pyrimidine-bridged porphyrin dyes

A series of dyes based on a porphyrin donor and a cyanoacrylic acid anchor/acceptor group for solar cell application are investigated with regards to varied-length π-spacers affecting the photo-to-electric conversion efficiency (PCE). Investigations are firstly performed on three porphyrin sensitizers with 1–3 conjugated phenylethynyl (PE) units, which have experimentally proved that the efficiency of power conversion decreases systematically with increasing spacer length. The distances and amounts of charge transfer after photoexcitation are calculated. In the PE bridged porphyrin dyes, the calculated electron injection driving forces and the regeneration driving forces gradually decrease as the distance of the π-spacer increases. Our theoretical calculations can reproduce well the experimental conclusion, showing that the photo-to-electric efficiency has a strong distance dependence for the electron-rich phenyl spacer. Then we replace the phenyl group with a pyrimidyl (PM) group to uncover how the characteristics of the π-spacer affect the performance of optical absorption, charge separation, and the regeneration process, to further improve the power conversion. We find that the adoption of electron-deficient pyrimidyl can break and even remove the distance dependence of the π-spacer. Some integral factors affecting the dye performance, such as short-circuit photocurrent, open-circuit voltage and charge collection efficiency are analyzed. It would help to interpret what role the electron deficient π-spacers with varied lengths will play and how they are expected to behave in the performance of sensitizers. In this regard, this study presents us with a promising way to design novel functional dyes and to utilize the potential advantages of the lengthy spacer dyes.

Fluxional interconversion of divalent palladium complexes having NSNSN ligands between flexible SNS and rigid NNN-coordinated structures

Mono- and dicationic divalent palladium complexes having 2,6-bis(N-heteroarylsulfanylmethyl)pyridine ligands (NSNSN ligands) were synthesized and characterized. The NSNSN ligands were fixed in a rac-SNS tridentate coordination mode in the solid state, while the equilibria among meso-SNS, rac-SNS, and NNN isomers were observed in solution. The equilibrium between the SNS and NNN isomers could be modulated by temperature, as well as by the steric and electronic factors of the NSNSN and monodentate ligands. Lowering the temperature tended to make NNN isomers more predominant compared with SNS isomers. On the other hand, the steric demand between the ligands in the complexes shifted the equilibrium from NNN to SNS isomers. Introduction of pyridyl groups instead of pyrimidyl groups as N-heteroarenes also shifted the equilibrium to SNS isomers. DFT calculation indicated rapid ring inversion of the metallacycle moieties and relatively slow S-inversion in the SNS isomers, a result that was in good agreement with the experimentally observed dynamic behaviors. Both the experimental and theoretical results revealed that the SNS isomers had flexible structures in solution, whereas the NNN isomers were rigid and less dynamic. The mechanistic pathways for interconversion between SNS and NNN isomers were also calculated. Such calculations indicated that a pathway featuring a relatively unstable, distorted ax-SNN intermediate was plausible. The intermediate had an N-heteroarene on the coordinated sulfur atom at an axial position.

ChemInform Abstract: Heterocyclic Derivatives of Long-Chain Diacetylenic Acids.

Acyl derivatives of 2-aminopyridine, 2-aminopyrimidine, 4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl, and 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl were obtained from long-chain diacetylenic acyl chlorides and the corresponding heterocyclic compounds. Spreading isotherms of monolayers on a water surface show that lengthening of the hydrocarbon chain and replacement of the pyridyl groups in these compounds by the more hydrophilic pyrimidyl groups render the films more condensed. Long-chain acyl derivatives of nitroxyl radicals form monolayers possesing a low collapse pressure. ESR spectra of Langmuir-Blodgett films of these radicals before and after photopolymerization were recorded.