- Hydration of pyridylketenes: Formation of acid enol and dihydropyridine (Eneaminone) transients
-
2-, 3-, and 4-Pyridylketenes 4 formed in water by photochemical Wolff rearrangements using flash photolysis undergo rapid hydration forming transient intermediates observed by UV spectroscopy. 3-Pyridylketene (3-4) formed the acid enol intermediate 3-10 which was converted to the acid 3-11, and phenylketene gave similar behavior. 4-Pyridylketene (4-4) reacted with a similar initial rate constant of 5.0 × 104 s-1 for decay of an absorption at 275 nm, with concomitant formation of a strong absorption at 370 nm with the same rate constant. The intermediate absorbing at 370 nm decayed with a lifetime 2.4 × 103 fold longer than that of the ketene, and is identified as 4-(carboxymethylene)-1,4-dihydropyridine (4-13), resulting from conjugate 1,6-addition of H2O to 4-4. 2-Pyridylketene (2-4) underwent hydration with a similar rate constant of 1.1 × 104 s-1 forming a transient with a UV absorption with maxima at 310 and 380 nm that decayed with biexponetial kinetics, with rate constants slower than the rate of formation by factors of 5.2 and 110, respectively. These results are interpreted as indicating the presence of two species, namely Z- and E-2-(carboxymethylene)-1,2-dihydropyridines (2-13), resulting from conjugate 1,4-addition of H2O to 2-4. The identifications of the 1,2- and 1,4-(carboxymethylene)dihydropyridines 2- and 4-13 were confirmed by comparison of their UV spectra with those of the corresponding N-methyl derivatives. The amination of 2-pyridylketene in CH3CN was reinvestigated, and spectroscopic evidence, computational studies, and preparation of the N-methyl analogue demonstrated formation of the 1,2-dihydropyridine Z-2-8f as the long-lived intermediate.
- Allen, Annette D.,Fedorov, Andrei V.,Tidwell, Thomas T.,Vukovic, Sinisa
-
-
Read Online
- Catalyst-Free Annulation of 2-Pyridylacetates and Ynals with Molecular Oxygen: An Access to 3-Acylated Indolizines
-
A catalyst and additive-free annulation of 2-pyridylacetates and ynals under molecular oxygen was the first developed, affording 3-acylated indolizines in good to excellent yields. Molecular oxygen was used as the source of the carbonyl oxygen atom in indolizines. This approach was compatible with a wide range of functional groups, and especially it has been successfully extended to unsaturated double bonds and triple bonds, which were difficult to prepare by previous methods in a single step.
- Chen, Zhengwang,Liang, Pei,Ma, Xiaoyue,Luo, Haiqing,Xu, Guohai,Liu, Tanggao,Wen, Xiaowei,Zheng, Jing,Ye, Hui
-
supporting information
p. 1630 - 1639
(2019/01/26)
-
- A One-Pot Sonogashira Coupling and Annulation Reaction: An Efficient Route toward 4 H -Quinolizin-4-ones
-
An efficient one-pot Sonogashira coupling and annulation reaction affording 4 H -quinolizin-4-ones in moderate to excellent yields is described. A variety of substituted iodoarenes and 2-alkylazaarenes were well tolerated, and especially the unsaturated double and triple bonds were compatible under the standard conditions.
- Chen, Zhengwang,Liu, Tanggao,Ma, Xiaoyue,Liang, Pei,Long, Lipeng,Ye, Min
-
supporting information
p. 863 - 867
(2019/04/25)
-
- METHODS OF USING SPLICING MODULATORS
-
This disclosure relates to methods for the treatment of neoplastic disorders by administering Compound 1, or a pharmaceutically acceptably salt thereof, on its own and/or as part of a conjugate or composition, and inducing production of at least one neoantigen.
- -
-
Paragraph 182
(2019/12/25)
-
- CERTAIN PLADIENOLIDE COMPOUNDS AND METHODS OF USE
-
The present disclosure provides novel pladienolide compounds, pharmaceutical compositions containing such compounds, and methods for using the compounds as therapeutic agents. These compounds may be useful in the treatment of cancers, particularly cancers in which agents that target the spliceosome and mutations therein are known to be useful. Also provided herein are methods of treating cancers by administering at least one compound disclosed herein and at least one additional therapy.
- -
-
Page/Page column 240
(2019/11/04)
-
- Palladium-Catalyzed Carbonylative Direct Transformation of Benzyl Amines under Additive-Free Conditions
-
In this communication, we developed a new procedure for the direct carbonylative transformation of benzyl amines. Using dimethyl carbonate as the solvent, methyl 2-arylacetates can be produced in good to excellent yields from the corresponding primary, secondary, and tertiary benzyl amines with palladium as the catalyst. Notably, no base or any other additive is required here. In addition, our procedure can also be applied in the preparation of methylphenidate, which is a marketing drug and used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy.
- Li, Yahui,Wang, Zechao,Wu, Xiao-Feng
-
p. 738 - 741
(2018/01/17)
-
- Regioselective Hydrogenolysis of Donor-Acceptor Cyclopropanes with Zn-AcOH Reductive System
-
A convenient low-cost method for regioselective ring-opening of donor-acceptor cyclopropanes with the Zn-AcOH reductive system was developed. The general character of the method was displayed via efficient reduction of a representative series of 2-(het)arylcyclopropane-1,1-diesters as well as donor-acceptor cyclopropanes with other types of electron-withdrawing activating groups. This method opens a rapid access to γ-substituted propyl-1,1-diesters, ketoesters, cyanoesters, cyanoamides, dinitriles, etc., many of which are not readily accessible with alternative methods. The utility of the synthesized compounds was demonstrated by transforming them into valuable acyclic and cyclic compounds (including pharmacologically relevant carbazoles, δ-lactams, and oxindole derivatives).
- Ivanov, Konstantin L.,Villemson, Elena V.,Latyshev, Gennadij V.,Bezzubov, Stanislav I.,Majouga, Alexander G.,Melnikov, Mikhail Ya.,Budynina, Ekaterina M.
-
p. 9537 - 9549
(2017/09/23)
-
- A SOLID STATE FORM OF PLADIENOLIDE PYRIDINE COMPOUNDS AND METHODS OF USE
-
The present disclosure provides a novel solid state form of pladienolide pyridine compounds, compositions comprising at least one such solid state form, and methods of preparation and use and the same. The novel solid state form of pladienolide pyridine compounds may be useful in the treatment of cancer, such as, for example, cancers in which agents that target the spliceosome and mutations therein are known to be useful.
- -
-
Paragraph 0069
(2017/06/12)
-
- METALLO-BETA-LACTAMASE INHIBITORS
-
The present invention relates to compounds of formula (I) that are metallo-β-lactamase inhibitors, the synthesis of such compounds, and the use of such compounds for use with β-lactam antibiotics for overcoming resistance.
- -
-
Paragraph 0363
(2016/12/01)
-
- RhIII-Catalyzed C-H Activation with Pyridotriazoles: Direct Access to Fluorophores for Metal-Ion Detection
-
The first C-H bond activation with pyridotriazoles as coupling partners is presented using a RhIII catalyst. The pyridotriazoles can be used as new carbene precursors in C-H activation for direct access to novel fluorescent scaffolds. These tunable fluorophores can be applied for the detection of metal ions.
- Kim, Ju Hyun,Gensch, Tobias,Zhao, Dongbing,Stegemann, Linda,Strassert, Cristian A.,Glorius, Frank
-
supporting information
p. 10975 - 10979
(2015/09/15)
-
- Pladienolide Pyridine Compounds and Methods of Use
-
The present invention provides novel pladienolide pyridine compounds, pharmaceutical compositions containing such compounds, and methods for using the compounds as therapeutic agents. These compounds may be useful in the treatment of cancer, particularly cancers in which agents that target the spliceosome and mutations therein are known to be useful.
- -
-
Paragraph 0099; 0100
(2015/12/31)
-
- Tetrazolylhydrazides as selective fragment-like inhibitors of the JumonjiC-domain-containing histone demethylase KDM4A
-
The JumonjiC-domain-containing histone demethylase 2A (JMJD2A, KDM4A) is a key player in the epigenetic regulation of gene expression. Previous publications have shown that both elevated and lowered enzyme levels are associated with certain types of cancer, and therefore the definite role of KDM4A in oncogenesis remains elusive. To identify a novel molecular starting point with favorable physicochemical properties for the investigation of the physiological role of KDM4A, we screened a number of molecules bearing an iron-chelating moiety by using two independent assays. In this way, we were able to identify 2-(1H-tetrazol-5-yl)acetohydrazide as a novel fragment-like lead structure with low relative molecular mass (Mr=142 Da), low complexity, and an IC50 value of 46.6 μm in a formaldehyde dehydrogenase (FDH)-coupled assay and 2.4 μm in an antibody-based assay. Despite its small size, relative selectivity against two other demethylases could be demonstrated for this compound. This is the first example of a tetrazole group as a warhead in JMJD demethylases. Anchor fragment: To develop non-promiscuous metalloenzyme inhibitors, a metal-complexing acetohydrazide group was integrated in a tetrazolyl fragment, which can be matured into a scaffold to promote further selectivity at the ligand backbone binding site of these emerging drug targets.
- Rüger, Nicole,Roatsch, Martin,Emmrich, Thomas,Franz, Henriette,Schüle, Roland,Jung, Manfred,Link, Andreas
-
supporting information
p. 1875 - 1883
(2015/11/10)
-
- Synthesis of Quinolines by Visible-Light Induced Radical Reaction of Vinyl Azides and α-Carbonyl Benzyl Bromides
-
A visible-light induced radical reaction of vinyl azides and α-carbonyl benzyl bromides was developed, which provides an efficient route to polysubstituted quinolines via a C-C and C-N bond formation sequence.
- Wang, Qile,Huang, Jun,Zhou, Lei
-
supporting information
p. 2479 - 2484
(2015/08/18)
-
- METALLO-BETA-LACTAMASE INHIBITORS
-
The present invention relates to compounds of formula (I) that are metallo-β-lactamase inhibitors, the synthesis of such compounds, and the use of such compounds for use with β-lactam antibiotics for overcoming resistance.
- -
-
Page/Page column 60
(2015/08/06)
-
- Higher-order cyclopropenimine superbases: Direct neutral br?nsted base catalyzed michael reactions with α-aryl esters
-
The synthesis and characterization of six new classes of higher-order superbases, including five that incorporate cyclopropenimine functionality, has been achieved. We propose a nomenclature that designates these as the CG2, GC2, PC3, PC1, C3, and GP2 classes of superbases. The pKBH+ values were measured to be between 29.0 and 35.6 in acetonitrile. Linear correlations of ten superbase basicities vs that of their substituents demonstrated the insulating effect of the cyclopropenimine core. The molecular structures of several of these materials were obtained by single-crystal X-ray analysis, revealing interesting aspects of conformational bias and noncovalent organization. The types of superbasic cores and substituents were each reliably shown to affect selectivity for deprotonation over alkylation. Higher-order cyclopropenimine and guanidine superbase stability to hydrolysis was found to correlate to basicity. Finally, a GC2 base was found to catalyze conjugate additions of α-aryl ester pronucleophiles, representing the first report of a neutral Br?nsted base to catalyze such reactions.
- Nacsa, Eric D.,Lambert, Tristan H.
-
supporting information
p. 10246 - 10253
(2015/09/01)
-
- Expedient synthesis of α-(2-azaheteroaryl) acetates via the addition of silyl ketene acetals to azine- N -oxides
-
A new and expedient synthesis of α-(2-azaheteroaryl) acetates is presented. The reaction proceeds rapidly under mild conditions via the addition of silyl ketene acetals to azine-N-oxides in the presence of the phosphonium salt PyBroP. This procedure affords diverse α-(2-azaheteroaryl) acetates which are highly desirable components/building blocks in molecules of pharmaceutical interest but are traditionally challenging to synthesize via contemporary methods. The reaction optimization and mechanism as well as a novel electronically enhanced PyBroP derivative are described.
- Londregan, Allyn T.,Burford, Kristen,Conn, Edward L.,Hesp, Kevin D.
-
p. 3336 - 3339
(2014/07/08)
-
- Asymmetric palladium-catalyzed hydroarylation of styrenes and dienes
-
Alkenes are desirable and highly versatile starting materials for organic transformations, and well-known substrates for palladium catalysis. Typically, these reactions result in the formation of a new alkene product via β-hydride elimination. In contrast to this scenario, our laboratory has been involved in the development of alkene hydro- and difunctionalization reactions, where β-hydride elimination can be controlled. We report herein the development of an asymmetric palladium-catalyzed hydroarylation, which yields diarylmethine products in up to 75% ee. Interestingly, a linear free energy relationship is observed between the steric bulk of the ligand within a certain range and the ee of the reaction.
- Podhajsky, Susanne M.,Iwai, Yasumasa,Cook-Sneathen, Amanda,Sigman, Matthew S.
-
supporting information; experimental part
p. 4435 - 4441
(2011/08/06)
-
- Palladium-catalyzed decarboxylative couplings of 2-(2-Azaaryl)acetates with aryl halides and triflates
-
Pd-catalyzed decarboxylative cross-couplings of 2-(2-azaaryl)acetates with aryl halides and triflates have been discovered. This reaction is potentially useful for the synthesis of some functionalized pyridines, quinolines, pyrazines, benzoxazoles, and benzothiazoles. Theoretical analysis shows that the nitrogen atom at the 2-position of the heteroaromatics directly coordinates to Pd(II) in the decarboxylation transition state.
- Shang, Rui,Yang, Zhi-Wei,Wang, Yan,Zhang, Song-Lin,Liu, Lei
-
supporting information; experimental part
p. 14391 - 14393
(2010/12/19)
-
- Catalytic asymmetric cyclopropanation of heteroaryldiazoacetates
-
Rh2(S-DOSP)4-catalyzed decomposition of heteroaryldiazoacetates in the presence of styrene results in highly diastereoselective and enantioselective cyclopropanations. Heteroaryldiazoacetates containing both electron-rich and electron-deficient heterocycles, such as thiophene, furan, pyridine, indole, oxazole, isoxazole, and benzoxazole, are effective in this chemistry. These studies broaden the range of diazo compounds containing both electron-withdrawing and electron-donating groups, which undergo highly diastereoselective cyclopropanations.
- Davies,Townsend
-
p. 6595 - 6603
(2007/10/03)
-