- Ruthenium-Catalyzed Regioselective C(sp2)-H Activation/Annulation of N-(7-Azaindole)amides with 1,3-Diynes Using N-Amino-7-azaindole as the N, N-Bidentate Directing Group
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The ruthenium(II)-catalyzed regioselective annulation of N-(7-azaindole)amides with 1,3-diynes has been demonstrated. Bioactive N-amino-7-azaindole has been used as a new bidentate directing group to furnish an array of 3-alkynylated isoquinolones. Furthermore, the developed protocol works efficiently for both aryl- and heteroaryl-substituted amides producing a range of pharmacologically useful 7-azaindole-based isoquinolones with a wide range of functionality.
- Pati, Bedadyuti Vedvyas,Sagara, Prateep Singh,Ghosh, Asit,Das Adhikari, Gopal Krushna,Ravikumar, Ponneri Chandrababu
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- Excited-state double proton transfer of 7-azaindole dimers in a low-temperature organic glass
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The excited-state double proton transfer of model DNA base pairs, 7-azaindole (7AI) dimers, is explored in a low-temperature organic glass of n-dodecane using picosecond time-resolved fluorescence spectroscopy. Reaction mechanisms are found to depend on the conformations of 7AI dimers at the moment of excitation; whereas planar conformers tautomerize rapidly (10 ps), twisted conformers undergo double proton transfer to form tautomeric dimers on the time scale of 250 ps at 8 K. The proton transfer is found to consist of two orthogonal steps: precursor-configurational optimization and intrinsic proton transfer via tunneling. The rate is almost isotope independent at cryogenic temperatures because configurational optimization is the rate-determining step of the overall proton transfer. This optimization is assisted by lattice vibrations below 150 K or by librational motions above 150 K. The excited-state double proton transfer of model DNA base pairs, 7-azaindole dimers (7AI), is explored in a low-temperature organic glass of n-dodecane using picosecond time-resolved fluorescence spectroscopy. Reaction mechanisms are found to depend on the conformations of 7AI dimers at the moment of excitation; whereas planar conformers tautomerize rapidly, twisted conformers undergo double proton transfer to form tautomeric dimers on the time scale of 250 ps at 8 K. Precursor-configurational optimization is found to determine the overall rate of excited-state double proton transfer at cryogenic temperatures, showing a kinetic isotope effect to be as small as unity.
- Lim, Hyeongtaek,Park, Sun-Young,Jang, Du-Jeon
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- Photochemistry of Transient Tautomer of 7-Azaindole H-Bonded Dimer Studied by Two-Step Laser Excitation Fluorescence Measurements
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Formation of the monomeric tautomer (7H-pyrrolopyridine) in the photodissociation of the transient groun-state dimeric tautomer, generated via excited-state double proton transfer of 7-azaindole H-bonded dimer in 3-methylpentane (MP), was confirmled by transient absorption and two-step laser excitation (TSLE) fluorescence spectroscopies.The intense XeCl laser pulse (308-nm) excitation of the H-bonded dimer in MP at room temperature produced short- (17 μs) and a long-lived (47 μs) transients.The former and latter were ascribed to the dimeric and monomeric tautomers in the ground state, respectively.It is suggested that the second pulse excitation of the short-lived dimeric tautomer induces efficient dissociation to form a monomeric tautomer in the xcited state together with that in the ground state.One-color (308-nm) biphotonic processes within the XeCl laser pulse are therefore responsible for the long-lived monomeric tautomer in the ground state.The decay of the monomeric tautomer in the dark is attributable to the H-transfer reaction to yield 7-azaindole.Significant deuterium isotope effects were found for H-transfer of the monomeric tautomer as well as for photodissociation of the dimeric tautomer.
- Tokumura, Kunihiro,Watanabe, Yukari,Udagawa, Masahiro,Itoh, Michiya
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- Anomalously slow proton transport of a water molecule
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Unusually low proton-transporting ability of a water molecule has been observed in the excited-state proton transfer (ESPT) of a 7-azaindole (7AI) molecule complexed cyclically with a water molecule in diethyl ether and dipropyl ether. In contrast with ultrafast (1 ps) proton diffusion along a systematically structured hydrogen-bond network in an aqueous solution, the proton transport of a water monomer has been observed to be extremely slow (～1 ns) because it is hard for a monomeric water molecule alone to accept or donate a proton. Thus, polar ether molecules surrounding a cyclic hydrogen-bonded 1:1 7AI-water complex (Nc) play a crucial role in the ESPT of Nc. The proton acceptance of a water molecule from the acidic amino group of 7AI via tunneling to form a hydronium ion, which is the rate-determining step, initiates ESPT, and the subsequent rapid proton donation of the hydronium ion to the basic imino group of 7AI takes place barrierlessly to complete ESPT without accumulating any intermediate. Due to the anomalously weak proton-transporting ability of a water monomer, the elaborate reorganization of the hydrogen-bond bridge in Nc to form an optimized precursor configuration is required for proton tunneling.
- Park, Sun-Young,Jeong, Hyeok,Jang, Du-Jeon
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- Solvation of 7-azaindole in alcohols and water: Evidence for concerted, excited-state, double-proton transfer in alcohols
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The proton inventory technique is used for the first time to investigate excited-state proton-transfer processes. The nonradiative pathways of the biological probe, 7-azaindole, in methanol, ethanol, and water are examined. Results in methanol and ethanol demonstrate the involvement of two protons in the transition state for the excited-state double-proton transfer process. These data provide the first experimental evidence suggesting a concerted tautomerization reaction of 7-azaindole in alcohols. The data for 7-azaindole in water are interpreted in terms of a nonradiative pathway that is qualitatively different from that in alcohols. We propose abstraction of the N1 hydrogen by water as a possible nonradiative decay process.
- Chen,Gai,Petrich
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- Sulfoxylate Anion Radical-Induced Aryl Radical Generation and Intramolecular Arylation for the Synthesis of Biarylsultams
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Aryl radical generation from the corresponding aryl halides using an electron donor and subsequent intramolecular cyclization with arenes could be an important advancement in contemporary biaryl synthesis. A green and practically useful synthetic protocol to access diverse six- and seven-membered biarylsultams especially with a free NH group including demonstration of a gram-scale synthesis is reported herein. The sulfoxylate anion radical (SO2-?), generated in situ from the reagents rongalite or sodium dithionite (Na2S2O4), was found to be the key single electron transfer agent forming aryl radicals from aryl halides, which upon intramolecular arylation gives biarylsultams with good to excellent yields. The approach features generation of aryl radicals that remained underexplored, use of a cheap and readily available industrial reagents, and transition metal-free, mild, and green reaction conditions.
- Laha, Joydev K.,Gupta, Pankaj
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supporting information
p. 4204 - 4214
(2022/03/16)
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- Development and Scale-Up of an Improved Manufacturing Route to the ATR Inhibitor Ceralasertib
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Ceralasertib is currently being evaluated in multiple phase I/II clinical trials for the treatment of cancer. Its structure, comprising a pyrimidine core decorated with a chiral morpholine, a cyclopropyl sulfoximine and an azaindole, makes it a challenging molecule to synthesize on a large scale. Several features of the medicinal chemistry and early development route make it unsuitable for the long-term commercial manufacture of the active pharmaceutical ingredient. We describe the investigation and development of a new and improved route which introduces the cyclopropyl moiety in a novel process from methyl 2,4-dibromobutyrate. Following construction of the pyrimidine ring, large-scale chlorination with phosphoryl chloride was performed with a safe and robust work-up. An SNAr reaction required an innovative work-up to remove the unwanted regio-isomer, and then a Baeyer-Villiger monooxygenase enzyme was used to enable asymmetric sulfur oxidation to a sulfoxide. A safe and scalable metal-free sulfoximine formation was developed, and then optimization of a Suzuki reaction enabled the manufacture of high-quality ceralasertib with excellent control of impurities and an overall yield of 16%.
- Graham, Mark A.,Askey, Hannah,Campbell, Andrew D.,Chan, Lai,Cooper, Katie G.,Cui, Zhaoshan,Dalgleish, Andrew,Dave, David,Ensor, Gareth,Galan Espinosa, Maria Rita,Hamilton, Peter,Heffernan, Claire,Jackson, Lucinda V.,Jing, Dajiang,Jones, Martin F.,Liu, Pengpeng,Mulholland, Keith R.,Pervez, Mohammed,Popadynec, Michael,Randles, Emma,Tomasi, Simone,Wang, Shenghua
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- Highly Chemoselective Deoxygenation of N-Heterocyclic N-Oxides Using Hantzsch Esters as Mild Reducing Agents
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Herein, we disclose a highly chemoselective room-temperature deoxygenation method applicable to various functionalized N-heterocyclic N-oxides via visible light-mediated metallaphotoredox catalysis using Hantzsch esters as the sole stoichiometric reductant. Despite the feasibility of catalyst-free conditions, most of these deoxygenations can be completed within a few minutes using only a tiny amount of a catalyst. This technology also allows for multigram-scale reactions even with an extremely low catalyst loading of 0.01 mol %. The scope of this scalable and operationally convenient protocol encompasses a wide range of functional groups, such as amides, carbamates, esters, ketones, nitrile groups, nitro groups, and halogens, which provide access to the corresponding deoxygenated N-heterocycles in good to excellent yields (an average of an 86.8% yield for a total of 45 examples).
- An, Ju Hyeon,Kim, Kyu Dong,Lee, Jun Hee
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supporting information
p. 2876 - 2894
(2021/02/01)
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- Visible-light-mediated organoboron-catalysed metal-free dehydrogenation of N-heterocycles using molecular oxygen
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The surge of photocatalytic transformation not only provides unprecedented synthetic methods, but also triggers the enthusiasm for more sustainable photocatalysts. On the other hand, oxygen is an ideal oxidant in terms of atom economy and environmental friendliness. However, the poor reactivity of oxygen at the ground state makes its utilization challenging. Herein, a visible-light-induced oxidative dehydrogenative process is disclosed, which uses an organoboron compound as the photocatalyst and molecular oxygen as the sole oxidant.Viathis approach, an array of N-heterocycles have been accessed under metal-free mild conditions, in good to excellent yields.
- Wei, Lanfeng,Wei, Yu,Xu, Liang,Zhang, Jinli
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supporting information
p. 4446 - 4450
(2021/06/30)
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- Design and synthesis of novel pyrrolo[2,3-b]pyridine derivatives targeting V600EBRAF
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Several pyrrolo[2,3-b]pyridine-based B-RAF inhibitors are well known and some of them are currently FDA approved as anticancer agents. Based on the structure of these FDA approved V600EB-RAF inhibitors, two series of pyrrolo[2,3-b]pyridine scaffold were designed and synthesized in attempt to develop new potent V600EB-RAF inhibitors. The 38 synthesized compounds were biologically evaluated for their V600EB-RAF inhibitory effect at single dose (10 μM). Compounds with high percent inhibition were tested to determine their IC50 over V600EB-RAF. Compounds 34e and 35 showed the highest inhibitory effect with IC50 values of 0.085 μM and 0.080 μM, respectively. Headed for excessive biological evaluation, the synthesized derivatives were tested over sixty diverse human cancer cell lines. Only compound 35 emerged as a potent cytotoxic agent against different panel of human cancer cell lines.
- Abdel-Maksoud, Mohammed S.,Ali, Eslam M. H.,Ammar, Usama M.,Mersal, Karim I.,Oh, Chang-Hyun,Yoo, Kyung Ho
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- Catalyst-Free N-Deoxygenation by Photoexcitation of Hantzsch Ester
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A mild and operationally simple protocol for the deoxygenation of a variety of heteroaryl N-oxides and nitroarenes has been developed. A mixture of substrate and Hantzsch ester is proposed to result in an electron donor-acceptor complex, which upon blue-light irradiation undergoes photoinduced electron transfer between the two reactants to afford the products. N-oxide deoxygenation is demonstrated with 22 examples of functionally diverse substrates, and the chemoselective reduction of nitroarenes to the corresponding hydroxylamines is also shown.
- Cardinale, Luana,Jacobi Von Wangelin, Axel,Konev, Mikhail O.
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supporting information
(2020/02/15)
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- MnOx/catechol/H2O: A cooperative catalytic system for aerobic oxidative dehydrogenation of N-heterocycles at room temperature
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Amorphous manganese oxide doped by Na+ ion (Na-AMO) was successfully prepared and found to be an efficient heterogeneous catalyst in aerobic oxidative dehydrogenation of N-heterocycles, cooperate with catechol. Na-AMO was fully characterized by XRD, XPS BET H2-TPR, CO2-TPD FT-IR, TEM, SEM and had rich amounts of surface absorbed active oxygen species which are responsible for superior catalytic performance. The synergistic interaction between Na-AMO and catechol makes catalytic system efficient and tolerant, which offers various N-heterocycles in good to excellent yields under mild conditions.
- Tang, Tao,Bi, Xiuru,Meng, Xu,Chen, Gexin,Gou, Mingxia,Liu, Xiang,Zhao, Peiqing
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- DMSO/t-BuONa/O2-Mediated Aerobic Dehydrogenation of Saturated N-Heterocycles
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Aromatic N-heterocycles such as quinolines, isoquinolines, and indolines are synthesized via sodium tert-butoxide-promoted oxidative dehydrogenation of the saturated heterocycles in DMSO solution. This reaction proceeds under mild reaction conditions and has a good functional group tolerance. Mechanistic studies suggest a radical pathway involving hydrogen abstraction of dimsyl radicals from the N-H bond or α-C-H of the substrates and subsequent oxidation of the nitrogen or α-aminoalkyl radicals.
- Cai, Hu,Tan, Wei,Xie, Yongfa,Yang, Ruchun,Yue, Shusheng
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p. 7501 - 7509
(2020/07/07)
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- Reusable, homogeneous water soluble photoredox catalyzed oxidative dehydrogenation of N-heterocycles in a biphasic system: Application to the synthesis of biologically active natural products
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Herein, a simple and efficient method for the oxidative dehydrogenation (ODH) of tetrahydro-β-carbolines, indolines and tetrahydro-(iso)quinolines is described using a reusable, homogeneous cobalt-phthalocyanine photoredox catalyst in a biphasic medium. A biphasic system offers an advantage of easy separation of the product and an efficient reusability of the homogeneous photoredox catalyst. Also, the current system significantly helps to overcome the solubility issue of the substrate and catalyst at room temperature. Its potential applications to organic transformations are demonstrated by the synthesis of various biologically active N-heterocycles such as indoles, (iso)quinolines and β-carbolines and natural products such as eudistomin U, norharmane, and harmane and precursors to perlolyrine and flazin. Without isolation and purification, the catalyst solution can be reused up to 5 times with almost comparable reactivity. Furthermore, the efficiency of the reaction was demonstrated on a gram scale. To the best of our knowledge, this is the first report on ODH reactions using a non noble, reusable and homogeneous cobalt photoredox catalyst under environmentally friendly conditions.
- Abinaya, R.,Baskar, B.,Mariappan, M.,Prasanth, Arun,Sridhar, R.,Srinath, S.
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p. 2575 - 2587
(2020/05/13)
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- Aerobic oxidative dehydrogenation of N-heterocycles over OMS-2-based nanocomposite catalysts: Preparation, characterization and kinetic study
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OMS-2-based nanocomposites doped with tungsten were prepared for the first time and their remarkably enhanced catalytic activity and recyclability in aerobic oxidative dehydrogenation of N-heterocycles were examined in detail. Many tetrahydroquinoline derivatives and a broad range of other N-heterocycles could be tolerated by the catalytic system using a biomass-derived solvent as a reaction medium. Newly generated mixed crystal phases, noticeably enhanced surface areas and labile lattice oxygen of the OMS-2-based nanocomposite catalysts might contribute to their excellent catalytic performance. Moreover, a kinetic study was extensively performed which concluded that the dehydrogenation of 1,2,3,4-tetrahydroquinoline is a first-order reaction, and the apparent activation energy is 29.66 kJ mol-1
- Bi, Xiuru,Tang, Tao,Meng, Xu,Gou, Mingxia,Liu, Xiang,Zhao, Peiqing
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p. 360 - 371
(2020/02/04)
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- Transition-Metal-Free and Visible-Light-Mediated Desulfonylation and Dehalogenation Reactions: Hantzsch Ester Anion as Electron and Hydrogen Atom Donor
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Novel approaches for N- and O-desulfonylation under room temperature (rt) and transition-metal-free conditions have been developed. The first methodology involves the transformation of a variety of N-sulfonyl heterocycles and phenyl benzenesulfonates to the corresponding desulfonylated products in good to excellent yields using only KOtBu in dimethyl sulfoxide (DMSO) at rt. Alternately, a visible light method has been used for deprotection of N-methyl-N-arylsulfonamides with Hantzsch ester (HE) anion serving as the visible-light-absorbing reagent and electron and hydrogen atom donor to promote the desulfonylation reaction. The HE anion can be easily prepared in situ by reaction of the corresponding HE with KOtBu in DMSO at rt. Both protocols were further explored in terms of synthetic scope as well as mechanistic aspects to rationalize key features of desulfonylation processes. Furthermore, the HE anion induces reductive dehalogenation reaction of aryl halides under visible light irradiation.
- Heredia, Micaela D.,Guerra, Walter D.,Barolo, Silvia M.,Fornasier, Santiago J.,Rossi, Roberto A.,Budén, Mariá E.
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supporting information
p. 13481 - 13494
(2020/12/15)
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- Electron Transfer Photoredox Catalysis: Development of a Photoactivated Reductive Desulfonylation of an Aza-Heteroaromatic Ring
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Herein, we report a protocol for desulfonylation of aza-heteroaromatic rings via photoinduced electron transfer and hydrogen atom transfer. This general protocol has a wide substrate range and moderate to good yields. The utility of the method was demonstrated by the chemoselective desulfonylation of a molecule containing both an aliphatic and an aromatic sulfonamide. (Figure presented.).
- Qiang-Liu,Liu, Yu-Xiu,Song, Hong-Jian,Wang, Qing-Min
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supporting information
p. 3110 - 3115
(2020/07/04)
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- Regioselective Functionalization of 7-Azaindole by Controlled Annular Isomerism: The Directed Metalation-Group Dance
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The regioselective functionalization of 7-azaindole by controlled annular isomerism employing a directed metalation-group migration is reported. The N7 carbamoyl azaindoles undergo regioselective metalation and quenching with an electrophile to furnish C6-substituted derivatives which, in the presence of a catalytic amount of ClCONR2 promotes a carbamoyl group shift or dance from N7 to N1. A second directed metalation/electrophile quench sequence leads to 2,6-substituted azaindoles. Optimization of the metalation conditions for C2 and C6, separately and iteratively, is presented. Using the directed metalation group dance strategy, a late-stage deuteration of an antipsychotic drug is described. Overall, the controlled migration of the carbamoyl directing group allows multiple functionalization events of the bioactive azaindole scaffold.
- Dalziel, Michael E.,Patel, Jignesh J.,Kaye, Meagan K.,Cosman, Jennifer L.,Kitching, Matthew O.,Snieckus, Victor
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supporting information
p. 7313 - 7317
(2019/05/10)
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- Palladium catalyzed hydrodefluorination of fluoro-(hetero)arenes
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Palladium catalyzed hydrodefluorination was developed for fine-tuning the properties of fluoro-(hetero)aromatic compounds. The robust reaction can be set up in air, requires only commercially available components, and tolerates a variety of heterocycles and functionalities relevant to drug discovery. Given the prevalence of fluorine incorporation around metabolic hotspots, the corresponding deuterodefluorination reaction may prove useful for converting fluorinated libraries to deuterated analogues to suppress the oxidative metabolism by kinetic isotope effects.
- Gair, Joseph J.,Grey, Ronald L.,Giroux, Simon,Brodney, Michael A.
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supporting information
p. 2482 - 2487
(2019/04/10)
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- Method for synthesizing 7-azaindole which is pharmaceutical intermediate
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The invention discloses a method for synthesizing 7-azaindole which is a pharmaceutical intermediate. The method includes steps of catalyzing 2-amino-3-acetyl-pyridine by catalysts under acidic conditions; carrying out heating by the aid of microwave irradiation to obtain the 7-azaindole by means of preparation. The 2-amino-3-acetyl-pyridine is used as a raw material for the 7-azaindole. The method for synthesizing the 7-azaindole has the advantages that the effective catalysts are utilized, one-pot reaction is carried out, the method is easy to operate and control, few in byproducts and highin product purity and yield, and reaction conditions are mild.
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Paragraph 0019-0054
(2019/03/28)
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- A Reusable Cobalt Catalyst for Reversible Acceptorless Dehydrogenation and Hydrogenation of N-Heterocycles
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The development of robust catalytic systems based on base-metals for reversible acceptorless dehydrogenation (ADH) and hydrogenation of feedstock chemicals is very important in the context of ‘hydrogen storage’. Herein, we report a highly efficient reusable cobalt-based heterogeneous catalyst for reversible dehydrogenation and hydrogenation of N-heterocycles. Both the ADH and the hydrogenation processes operate under mild, benign conditions.
- Jaiswal, Garima,Subaramanian, Murugan,Sahoo, Manoj K.,Balaraman, Ekambaram
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p. 2449 - 2457
(2019/05/10)
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- Preparation method for 7-azaindole
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The invention discloses a preparation method for 7-azaindole, and belongs to technical field of the medicinal chemistry synthesis. The preparation method comprises the following steps: using a compound I, namely 2-amino-3-methylpyridine and N-methylformanilide, to perform an addition elimination reaction under the action of a dehydrating agent, to obtain a compound II; performing intramolecular ring closure on the compound II under the action of strong base, to obtain a target compound III. The preparation method is capable of acquiring the target product through two-step synthesis only. The method is simple in post-treatment, less in side reaction, high in yield, and in comply with requirements of industrial production. (The formula is shown in the description.).
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Paragraph 0031-0039
(2019/01/08)
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- Visible-Light Photocatalyzed Deoxygenation of N-Heterocyclic N-Oxides
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A scalable and operationally simple method is described that allows for the chemoselective deoxygenation of a wide range of N-heterocyclic N-oxides (a total of 36 examples). This visible-light-induced protocol features the use of only commercially available reagents, room-temperature conditions, and unprecedented chemoselective removal of the oxygen atom in a quinoline N-oxide in the presence of a pyridine N-oxide in the same molecule through the judicious selection of a photocatalyst.
- Kim, Kyu Dong,Lee, Jun Hee
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supporting information
p. 7712 - 7716
(2019/01/03)
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- CO2-Catalyzed Efficient Dehydrogenation of Amines with Detailed Mechanistic and Kinetic Studies
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CO2-catalyzed dehydrogenation of amines has been achieved under photocatalytic conditions. With this concept, various amines have been selectively dehydrogenated to the corresponding imines in the presence of different functional groups such as nitrile, nitro, ester, halogen, ether, thioether, and carbonyl or carboxylic acid moieties. At the end, the CO2-catalyzed synthesis of pharmaceutical drugs has been achieved. The CO2 radical has been detected by EPR spectroscopy using DMPO, and the mechanism of this reaction is proposed on the basis of DFT calculations and experimental evidence.
- Riemer, Daniel,Schilling, Waldemar,Goetz, Anne,Zhang, Yu,Gehrke, Sascha,Tkach, Igor,Hollóczki, Oldamur,Das, Shoubhik
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p. 11679 - 11687
(2018/11/23)
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- Ir-Catalyzed Intramolecular Transannulation/C(sp2)-H Amination of 1,2,3,4-Tetrazoles by Electrocyclization
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An efficient strategy for the intramolecular denitrogenative transannulation/C(sp2)-H amination of 1,2,3,4-tetrazoles bearing C8-substituted arenes, heteroarenes, and alkenes is described. The process involves the generation of the metal-nitrene intermediate from tetrazole by the combination of [CpIrCl2]2 and AgSbF6. It has been shown that the reaction proceeds via an unprecedented electrocyclization process. The method has been successfully applied for the synthesis of a diverse array of α-carbolines and 7-azaindoles.
- Das, Sandip Kumar,Roy, Satyajit,Khatua, Hillol,Chattopadhyay, Buddhadeb
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supporting information
p. 8429 - 8433
(2018/07/09)
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- Method for synthesizing intermediate 7-azaindole
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The invention discloses a method for synthesizing an intermediate 7-azaindole. The method comprises the following steps: mixing 2-amino-3-methylpyridine and ethanol, adding a catalyst, heating to 40-60 DEG C, adding oxalate into the mixture, uniformly mixing, carrying out reflux reaction for 1-2 hours, filtering, performing reduced pressure distillation on the filtrate, and recrystallizing to obtain 2-aminopyridine-3-pyruvate; adding the prepared 2-aminopyridine-3-pyruvate into DMF (Dimethyl Formamide), adding acetic acid to be uniformly stirred, adding Ce2O3, heating to 80 DEG C, stirring andcarrying out the reflux reaction for 2-3 hours, filtering, and performing reduced pressure distillation on the filtrate so as to obtain 7-azaindole-2-formic acid; mixing the prepared 7-azaindole-2-formic acid and methylbenzene, heating to 80-90 DEG C, adding ZnO, uniformly mixing, stirring and carrying out the reflux reaction for 2-3 hours, filtering, and performing reduced pressure distillationon the filtrate, thereby obtaining 7-azaindole. The synthetic method disclosed by the invention is simple to operate, mild in conditions, less in by-products, high in product purity and high in product yield.
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Paragraph 0023; 0032; 0037; 0041; 0045; 0050; 0059
(2018/03/24)
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- In-Cell Dual Drug Synthesis by Cancer-Targeting Palladium Catalysts
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Transition metals have been successfully applied to catalyze non-natural chemical transformations within living cells, with the highly efficient labeling of subcellular components and the activation of prodrugs. In vivo applications, however, have been scarce, with a need for the specific cellular targeting of the active transition metals. Here, we show the design and application of cancer-targeting palladium catalysts, with their specific uptake in brain cancer (glioblastoma) cells, while maintaining their catalytic activity. In these cells, for the first time, two different anticancer agents were synthesized simultaneously intracellularly, by two totally different mechanisms (in situ synthesis and decaging), enhancing the therapeutic effect of the drugs. Tumor specificity of the catalysts together with their ability to perform simultaneous multiple bioorthogonal transformations will empower the application of in vivo transition metals for drug activation strategies.
- Clavadetscher, Jessica,Indrigo, Eugenio,Chankeshwara, Sunay V.,Lilienkampf, Annamaria,Bradley, Mark
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supporting information
p. 6864 - 6868
(2017/06/06)
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- Synthesis method of 5-chloro-7-azaindole
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The invention provides a synthesis method of 5-chloro-7-azaindole. The synthesis method comprises the following steps: (1) reacting a dilithium initiator and trimethylbromosilane to prepare silicon-containing organic lithium; (2) reacting 2-amino-3-methylpyridine and di-tert-butyl dicarbonate to prepare 2-N-BOC-amino-3-methylpyridine; (3) performing lithiation on the 2-N-BOC-amino-3-methylpyridine through the silicon-containing organic lithium, and performing delithiation activation, cyclization and dehydration to prepare 7-azaindole; (4) performing hydrogenation reduction reaction on the 7-azaindole to generate 2,3-dihydro-7-azaindole; (5) performing chlorination reaction on the 2,3-dihydro-7-azaindole through liquid chlorine to generate 5-chloro-2,3-dihydro-7-azaindole; and (6) performing dehydrogenation reaction on the 5-chloro-2,3-dihydro-7-azaindole to obtain 5-chloro-7-azaindole. The synthesis method provided by the invention has the advantages of mild conditions and high yield.
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- MAGNETICALLY SEPARABLE IRON-BASED HETEROGENEOUS CATALYSTS FOR DEHYDROGENATION OF ALCOHOLS AND AMINES
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The present invention discloses an iron-based nitrogen doped graphene catalyst, process for preparation thereof and use of said catalyst in oxidant-free catalytic dehydrogenation of alcohols and amines to the corresponding carbonyl compounds, amines and N-heterocylic compounds with extraction of molecular hydrogen as the only by-product.
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Page/Page column 19; 20; 21; 22
(2016/12/22)
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- A 7-aza indole and its preparation method (by machine translation)
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The invention discloses a 7? Aza indole and its preparation method, comprising the following steps: the 2? (Tert-butoxy-carbonyl? Amino)? 3? Methylpyridinio dissolved in ether in water-free, in the ice water bath, drip curafume, control the water bath temperature is 0 °C, sustained reaction 4? 6h, then adding anhydrous DMF, sustained reaction in the ice 30 min; after the reaction is finished adding dilute hydrochloric acid solution, at room temperature, the continued reaction of the ultrasonic separating apparatus in 1.5? 3h, reduced pressure distillation after removing the ether, the pH is adjusted with ammonia water 9? 10, extraction crystallization, to obtain 7? Aza indole of the crude product, recrystallized with ethanol to obtain the target product 7? Aza indole. The method is simple in operation, mild conditions to the environment, improving the production yield and purity of production, is very suitable for large-scale industrial production. (by machine translation)
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Paragraph 0027; 0028; 0029
(2016/12/16)
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- Synthesis of Substituted 4-, 5-, 6-, and 7-Azaindoles from Aminopyridines via a Cascade C-N Cross-Coupling/Heck Reaction
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A practical palladium-catalyzed cascade C-N cross-coupling/Heck reaction of alkenyl bromides with amino-o-bromopyridines is described for a straightforward synthesis of substituted 4-, 5-, 6-, and 7-azaindoles using a Pd2(dba)3/XPhos/t-BuONa system. This procedure consists of the first cascade C-N cross-coupling/Heck approach toward all four azaindole isomers from available aminopyridines. The scope of the reaction was investigated and several alkenyl bromides were used, allowing access to different substituted azaindoles. This protocol was further explored for N-substituted amino-o-bromopyridines.
- Pires, Marina J. D.,Poeira, Diogo L.,Purifica?ao, Sara I.,Marques, M. Manuel B.
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supporting information
p. 3250 - 3253
(2016/07/13)
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- Synthesis of indoles, benzofurans, and related heterocycles via an acetylene-activated SNAr/intramolecular cyclization cascade sequence in water or DMSO
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The synthesis of 2-substituted indoles and benzofurans was achieved by nucleophilic aromatic substitution, followed by subsequent 5-endo-dig cyclization between the nucleophile and an ortho acetylene. The acetylene serves the dual role of the electron withdrawing group to activate the substrate for SNAr, and the C1-C2 carbon scaffold for the newly formed 5-membered heteroaromatic ring. This method allows for the bond forming sequence of Ar-X-N/O-C1 to proceed in a single synthetic step, furnishing indoles and benzofurans in moderate to high yields. Since the method is not transition metal mediated, brominated and chlorinated substrates are tolerated, and benzofuran formation can be conducted using water or water-DMSO mixtures as solvent. This journal is
- Hudson,Bizier,Esdale,Katz
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p. 2273 - 2284
(2015/03/04)
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- A closer look at the bromine-lithium exchange with tert-butyllithium in an aryl sulfonamide synthesis
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A practical protocol for the one-pot synthesis of various aryl sulfonamides, notably of pyridine-core-substituted 7-azaindolyl sulfonamides, is described. A key step is the well-known bromine-lithium exchange reaction of an aryl bromide with tert-butyllithium (t-BuLi). Differing from the common practice to use 2 or more equiv of organolithium, the exact amount of t-BuLi needed for a sufficient exchange reaction is determined for each aryl bromide in a GC-MS-assisted experiment.
- Waldmann, Christopher,Schober, Otmar,Haufe, Guenter,Kopka, Klaus
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supporting information
p. 2954 - 2957
(2013/07/26)
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- PYRIDAZINE AMIDE COMPOUNDS
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The present invention relates to the use of novel triazolopyridine derivatives of formula I: wherein all variable substituents are defined as described herein, which are SYK inhibitors and are useful for the treatment of auto-immune and inflammatory diseases.
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- Deformylation of indole and azaindole-3-carboxaldehydes using anthranilamide and solid acid heterogeneous catalyst via quinazolinone intermediate
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The deformylation of indole and azaindole-3-carboxaldehydes was achieved in the presence of anthranilamide and a solid acid heterogeneous catalyst under reflux conditions in 25-90% yield. The reaction proceeds via quinazolinone intermediate, which undergoes acid catalyzed cleavage to form deformylated product.
- Yadav, Rammohan R.,Battini, Narsaiah,Mudududdla, Ramesh,Bharate, Jaideep B.,Muparappu, Nagaraju,Bharate, Sandip B.,Vishwakarma, Ram A.
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experimental part
p. 2222 - 2225
(2012/05/20)
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- Single bifunctional ruthenium catalyst for one-pot cyclization and hydration giving functionalized indoles and benzofurans
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Chemical equation Presented Bifunctional is more than twice as fun! At low loading, catalyst 1 (see scheme) can form two important heterocycle classes, apparently by attack of XH on a vinylidene intermediate. Aza- and nitroindoles can be formed, and all N-protecting groups tested (alkyl, allyl, sulfonyl) were tolerated. The newly formed ring can be deuterated in one step, and for substrates with two terminal alkynes, cyclization can be followed by hydration, making this catalyst uniquely versatile.
- Nair, Reji N.,Lee, Paul J.,Rheingold, Arnold L.,Grotjahn, Douglas B.
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supporting information; experimental part
p. 7992 - 7995
(2010/09/18)
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- Desulfonylation of indoles and 7-azaindoles using sodium tert-butoxide
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A mild method for the desulfonylation of N-indoles and N-azaindoles is described. Deprotection is carried out under basic conditions, using sodium tert-butoxide in dioxane. Several functionalized indoles and 7-azaindoles were efficiently deprotected by this method, which is mild enough to be used to deprotect compounds including functions that are known to be sensitive to acidic or basic conditions.
- Chaulet, Charlotte,Croix, Cécile,Basset, Joan,Pujol, Maria-Dolores,Viaud-Massuard, Marie-Claude
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experimental part
p. 1481 - 1484
(2010/08/22)
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- Improved synthesis of the selective rho-kinase inhibitor 6-chloro-n4-{3,5-difluoro-4-[(3-methyl-1h-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl} pyrimidin-2,4-diamine
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A highly potent and selective Rho-kinase inhibitor containing a 7-azaindole moiety has been developed at Bayer Schering Pharma. Herein we disclose details of a significantly improved synthesis of the compound in 8.2% overall yield. Key aspects include cost and safety considerations and the uncommon use of a trifluoromethyl group with controllable reactivity as a masked methyl group.
- Schirok, Hartmut,Paulsen, Holger,Kroh, Walter,Chen, Gang,Gao, Ping
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scheme or table
p. 168 - 173
(2010/04/29)
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- Palladium-catalyzed reductive N-heterocyclization of alkenyl-substituted nitroarenes as a viable method for the preparation of bicyclic pyrrolo-fused heteroaromatic compounds
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Palladium-catalyzed, carbon monoxide-mediated reductive N-heterocyclization of nitro-heteroaromatic compounds having an alkene adjacent to the nitro-group affords bicyclic pyrrolo-fused heteroaromatic molecules. This type of reaction was used to prepare the fused bicyclo[3.3.0] ring-system: thieno[3,2-b]pyrrole, thieno[2,3-b]pyrrole, furo[2,3-b]pyrrole, pyrrolo[3,2-d]thiazole, and pyrrolo[2,3-d]imidazole and the bicyclo[4.3.0] ring-systems: pyrrolo[3,2-b]pyridine, pyrrolo[2,3-b]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridazine, and pyrrolo[3,2-d]pyrimidine in 32-94% yield.
- Gorugantula, Sobha P.,Carrero-Martínez, Grissell M.,Dantale, Shubhada W.,S?derberg, Bj?rn C.G.
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experimental part
p. 1800 - 1805
(2010/04/06)
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- Boiling water-catalyzed neutral and selective N-Boc deprotection
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A general protocol for removing Boc groups from various types of nitrogen is reported and a preliminary investigation of the reaction mechanism indicates that water acts as a dual acid/base catalyst at elevated temperature. The Royal Society of Chemistry 2009.
- Wang, Jia,Liang, Yan-Liang,Qu, Jin
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supporting information; experimental part
p. 5144 - 5146
(2009/12/08)
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- Microwave-assisted N-Boc deprotection under mild basic conditions using K3PO4·H2O in MeOH
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A simple and efficient method for the deprotection of secondary Boc-protected amino compounds under mild basic conditions using K3PO4·H2O in MeOH assisted by microwave irradiation has been presented.
- Dandepally, Srinivasa Reddy,Williams, Alfred L.
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scheme or table
p. 1071 - 1074
(2009/05/11)
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- Discovery of [3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl] acetic acids as highly potent and selective inhibitors of aldose reductase for treatment of chronic diabetic complications
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Efforts to identify treatments for chronic diabetic complications have resulted in the discovery of a novel series of highly potent and selective [3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyridin-1-yl] acetic acid aldose reductase inhibitors. The lead candidate, [6-methyl-3-(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-pyrrolo[2,3-b]pyri din-1-yl]acetic acid example 16, inhibits aldose reductase with an IC50 of 8 nM, while being inactive against aldehyde reductase (IC50 > 100 μM), a related enzyme involved in the detoxification of reactive aldehydes.
- Van Zandt, Michael C.,Doan, Brian,Sawicki, Diane R.,Sredy, Janet,Podjarny, Alberto D.
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supporting information; experimental part
p. 2006 - 2008
(2009/11/30)
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- Novel 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines are potent 5-HT6 agonists
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A series of 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 10a-z was prepared as novel 5-HT6 ligands. The best compounds were high affinity, full agonists at 5-HT6 receptors. Several agonists demonstrated good selectivity over other serotonergic and dopaminergic receptors. Acute administration of selective agonist 10e significantly increased extracellular GABA concentrations in rat frontal cortex. This compound also reduced adjunctive drinking behavior in the rat schedule-induced polydipsia assay, possibly predictive of efficacy in obsessive compulsive disorder and other anxiety related disorders.
- Bernotas, Ronald C.,Lenicek, Steven,Antane, Schuyler,Cole, Derek C.,Harrison, Boyd L.,Robichaud, Albert J.,Zhang, Guo Ming,Smith, Deborah,Platt, Brian,Lin, Qian,Li, Ping,Coupet, Joseph,Rosenzweig-Lipson, Sharon,Beyer, Chad E.,Schechter, Lee E.
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experimental part
p. 5153 - 5163
(2009/12/09)
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- Site-selective azaindole arylation at the azine and azole rings via N-oxide activation
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Subjection of N-methyl 6-and 7-azaindole N-oxides to a Pd(OAc) 2/DavePhos catalyst system enables regioselective direct arylation of the azine ring. Following deoxygenation, 7-azaindole substrates undergo an additional regioselective azole direct arylation event in good yield.
- Huestis, Malcolm P.,Fagnou, Keith
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supporting information; scheme or table
p. 1357 - 1360
(2009/09/05)
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- A green N-detosylation of indoles and related heterocycles using phase transfer catalysis
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A practical method for the N-detosylation of indoles and related heterocycles with KOH in THF and water in the presence of a phase transfer catalyst is described. Using a nonalcoholic solvent, this method prevents the formation of toxic alkyl p-toluene-sulfonate and consequently eliminates the formation of even traces of N-alkyl byproduct. This green method is particularly useful for indoles bearing electron-withdrawing groups and for azaindoles.
- Liu, Yugang,Shen, Lichun,Prashad, Mahavir,Tibbatts, Jessica,Repic, Oljan,Blacklock, Thomas J.
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p. 778 - 780
(2013/01/03)
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- A mild and selective method for the N-Boc deprotection by sodium carbonate
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A cleavage of N-tert-butyloxycarbonyl protection by Na2CO3 is reported. The N-free products are obtained in excellent yields. The compatibility of the method with the presence of acidic or basic groups is demonstrated. The reactions were performed on indole, azaindole, indazole, pyrazole, indolinone, quinolinone, and oxazolone.
- El Kazzouli, Sa?d,Koubachi, Jamal,Berteina-Raboin, Sabine,Mouaddib, Abderrahim,Guillaumet, Gérald
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p. 8575 - 8577
(2007/10/03)
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- Pyridine-derived heterocycles as potential photoacylating reagents
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We prepared several pyridine-derived heterocycles and investigated their photoacylating properties. Among representatives of 4 families of compounds (1-acetyl-7-azaindole, 1-acetyl-7-azaindoline, 2-acetamindpyridine and 2-amidopyrimidines), the 2-aminopyrimidine derivatives were the most promising candidates. Photoacylation of dodecylamine yields up to 47% were obtained, upon irradiation with UV light at 254 nm.
- Helgen, Celine,Bochet, Christian G.
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p. 797 - 805
(2007/10/03)
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- Deprotection of N-tosylated indoles and related structures using cesium carbonate
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A very mild, efficient, and convenient method for deprotection of N-tosylated indoles and related structures by cesium carbonate in THF-MeOH is described.
- Bajwa, Joginder S.,Chen, Guang-Pei,Prasad, Kapa,Repi?, Oljan,Blacklock, Thomas J.
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p. 6425 - 6427
(2007/10/03)
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- PROCESS
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The present application provides a process for the production of 7-azaindole systems by reacting a compound of formula I-1 with base
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- A practical synthesis of 7-azaindolylcarboxy-endo-tropanamide (DF 1012)
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An optimised cost-effective synthesis of the new antitussive drug, DF1012, is herewith reported. The new synthetic route to the key intermediate DF1005 is based on the unusual deprotection step of the 1-tert-butyl-3-cyano-7-azaindole intermediate, which can also be regarded as a convenient way for the industrial production of the expensive 7-azaindole 1. The second key intermediate, endo-tropanamine 6, was obtained in high yield by a novel one-pot stereoselective process using a Pd-catalysed reductive amination procedure.
- Allegretti, Marcello,Anacardio, Roberto,Cesta, M. Candida,Curti, Roberto,Mantovanini, Marco,Nano, Giuseppe,Topai, Alessandra,Zampella, Giuseppe
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p. 209 - 213
(2013/09/05)
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- Chemical synthesis of azaindoles
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The present invention relates to a process for the preparation of azaindole derivatives of the formula STR1 wherein Q is hydrogen, C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, hydroxy, aryl or arylC1-4 alkyl; one of X, Y and Z is --N= and the others are --CH=; R1 is hydrogen, C1-6 alkyl, C2-6 alkenyl or C1-6 alkyl substituted by a group selected from aryl or --NR2 R3 where R2 and R3 each independently represent C1-4 alkyl, or R2 and R3, together with the nitrogen atom to which they are attached, form a 4-7 membered saturated heterocyclic ring, optionally containing in the ring an oxygen or sulphur atom or a group NR4 where R4 is C1-4 alkyl, aryl or arylC1-4 alkyl; and R5 is a hydrogen atom or a group selected from C1-6 alkyl or aryl.
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