- Experimental and Theoretical Studies on Rhodium-Catalyzed Coupling of Benzamides with 2,2-Difluorovinyl Tosylate: Diverse Synthesis of Fluorinated Heterocycles
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Fluorinated heterocycles play an important role in pharmaceutical and agrochemical industries. Herein, we report on the synthesis of four types of fluorinated heterocycles via rhodium(III)-catalyzed C-H activation of arenes/alkenes and versatile coupling with 2,2-difluorovinyl tosylate. With N-OMe benzamide being a directing group (DG), the reaction delivered a monofluorinated alkene with the retention of the tosylate functionality. Subsequent one-pot acid treatment allowed the efficient synthesis of 4-fluoroisoquinolin-1(2H)-ones and 5-fluoropyridin-2(1H)-ones. When N-OPiv benzamides were used, however, [4 + 2] cyclization occurred to provide gem-difluorinated dihydroisoquinolin-1(2H)-ones. Synthetic applications have been demonstrated and the ready availability of both the arene and the coupling partner highlighted the synthetic potentials of these protocols. Mechanistically, these two processes share a common process involving N-H deprotonation, C-H activation, and olefin insertion to form a 7-membered rhodacycle. Thereafter, different reaction pathways featuring β-F elimination and C-N bond formation are followed on the basis of density functional theory (DFT) studies. These two pathways are DG-dependent and led to the open chain and cyclization products, respectively. The mechanistic rationale was supported by detailed DFT studies. In particular, the origins of the intriguing selectivity in the competing β-F elimination versus C-N bond formation were elucidated. It was found that β-F elimination is a facile event and proceeds via a syn-coplanar transition state with a low energy barrier. The C-N bond formation proceeds via a facile migratory insertion of the Rh-C(alkyl) into the Rh(V) amido species. In both reactions, the migratory insertion of the alkene is turnover-limiting, which stays in good agreement with the experimental studies.
- Wu, Jia-Qiang,Zhang, Shang-Shi,Gao, Hui,Qi, Zisong,Zhou, Chu-Jun,Ji, Wei-Wei,Liu, Yao,Chen, Yunyun,Li, Qingjiang,Li, Xingwei,Wang, Honggen
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Read Online
- Pd-catalyzed gem-difluoroallylation of arylboronic acids with γ,γ-difluoroallylic acetates
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A highly regio- and stereo-selective palladium-catalyzed gem-difluoroallylation of arylboronic acids with γ,γ-difluoroallylic acetates has been described. The method allows the synthesis of a variety of gem-difluoroallylated arenes with a tosyloxy group on the CC double bond, thus providing a good opportunity for down-stream transformations.
- Zhang, Bo,Zhang, Xingang
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Read Online
- 6-HETEROARYLOXY BENZIMIDAZOLES AND AZABENZIMIDAZOLES AS JAK2 INHIBITORS
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The present disclosure provides 6-heteroaryloxy benzimidazole and azabenzimidazole compounds and compositions thereof useful for inhibiting JAK2.
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Paragraph 0922; 0923
(2021/11/13)
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- Palladium-Catalyzed Fluoroarylation of gem-Difluoroenynes to Access Trisubstituted Trifluoromethyl Allenes
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Various new transformations of gem-difluoroalkenes leading to trifluoromethyl substituted compounds have been well established in the past years. However, the development of new transformations of gem-difluoroenynes lags much behind. Herein is reported the fluoroarylation of 1,1-difluoro-1,3-enynes with aryl halides in the presence of silver fluoride affording trisubstituted trifluoromethyl allenes under the catalysis of palladium. The reaction features mild conditions, high functional-group tolerance, and high regioselectivity.
- Qi, Shutao,Gao, Shiquan,Xie, Xiaoxiao,Yang, Junfeng,Zhang, Junliang
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p. 5229 - 5234
(2020/07/15)
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- Rhodium-Catalyzed Defluorinative Vinylation of gem-Difluoroalkenes for the Synthesis of 2-Fluoro-1,3-dienes
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Herein, we present a strategy for the formation of 2-fluoro-1,3-diene derivatives via rhodium-catalyzed direct C(sp2)—C(sp2) cross-coupling of gem-difluoroalkenes and acrylamides. By merging Rh(III)-catalyzed C(sp2)–H bond activation and nucleophilic addition/F-elimination of gem-difluoroalkene, an efficient defluorinative vinylation reaction is uncovered, which leads to the generation of 2-fluoro-1,3-dienes in moderate to good yields with excellent stereoselectivity under mild conditions. Preliminary mechanistic study suggests unique effects of fluorine substituents which allow the reactivity profile not observed with the congeners bearing heavier halides.
- Song, Shengjin,Liu, Huan,Wang, Lu,Zhu, Chuan,Loh, Teck-Peng,Feng, Chao
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p. 1036 - 1040
(2019/09/16)
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- DIHYDROPYRIMIDINE COMPOUND AND PREPARATION METHOD AND USE THEREOF
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The present invention relates to a dihydropyrimidine compound having an antiviral activity, a pharmaceutical composition comprising same, a preparation method therefor and the uses thereof in the prevention or treatment of viral diseases including, but no
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Paragraph 0139; 0140
(2019/07/18)
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- Neighboring phenolic group-activated: Gem -difluoroallylboration of imines for the catalyst-free synthesis of gem -difluorohomoallylamines
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We herein report an unprecedented addition reaction of pinacol gem-difluoroallylborates and imines enabled by a neighboring phenolic group in an N-protecting group under catalyst-free conditions, thus facilitating the construction of a wide range of racemic gem-difluorohomoallylamine derivatives. Based on the control experiments, a plausible transition state via the Zimmerman-Traxler model was proposed to elucidate the significance of the neighboring phenolic group, as well as the γ-selectivity of the boronate reagents.
- Yang, Xing,Zhang, Feng,Zhou, Yang,Huang, Yi-Yong
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p. 3367 - 3371
(2018/05/23)
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- Heteroannulation enabled by a bimetallic Rh(III)/Ag(i) relay catalysis: Application in the total synthesis of aristolactam BII
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A redox-neutral bimetallic Rh(iii)/Ag(i) relay catalysis allowed the efficient construction of 3-alkylidene isoindolinones and 3-alkylidene isobenzofuranones. The Rh(iii) catalyst was responsible for the C-H monofluoroalkenylation reaction, whereas the Ag(i) salt was an activator for the follow-up cyclization. The methodology developed was applied as a key step in the rapid total synthesis of the natural product aristolactam BII.
- Ji, Wei-Wei,Lin,Li, Qingjiang,Wang, Honggen
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p. 5665 - 5668
(2017/07/07)
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- NOVEL COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THE TREATMENT OF INFLAMMATORY DISORDERS
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The present invention discloses compounds according to Formula (I), wherein R1, R3, R4, R5, L1, and Cy are as defined herein. The present invention also provides compounds, methods for the production of said compounds of the invention, pharmaceutical compositions comprising the same and their use in allergic or inflammatory conditions, autoimmune diseases, proliferative diseases, transplantation rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformations, and/or diseases associated with hypersecretion of IL6 and/or interferons. The present invention also methods for the prevention and/or treatment of the aforementioned diseases by administering a compound of the invention.
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Paragraph 0236
(2017/02/09)
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- COMPOUNDS USEFUL AS KINASE INHIBITORS
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This invention relates to novel compounds. The compounds of the invention are tyrosine kinase inhibitors. Specifically, the compounds of the invention are useful as inhibitors of Bruton's tyrosine kinase (BTK).The invention also contemplates the use of the compounds for treating conditions treatable by the inhibition of Bruton's tyrosine kinase, for example cancer, lymphoma, leukemia and immunological diseases.
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Paragraph 00405
(2017/07/14)
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- PURINE DERIVATIVES
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The present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein Q, G, ring A, ring B, R1, R2, R3, R4, R5, R5a, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, and m are defined herein. The novel purine derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. Additional embodiments relate to pharmaceutical compositions containing the compounds and to methods of using the compounds and compositions in the treatment of abnormal cell growth in mammals.
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Paragraph 0730; 0731
(2015/05/26)
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- Synthesis of Small 3-Fluoro- and 3,3-Difluoropyrrolidines Using Azomethine Ylide Chemistry
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Here, we report accessing small 3-fluoropyrrolidines and 3,3-difluoropyrrolidines through a 1,3-dipolar cycloaddition with a simple azomethine ylide and a variety of vinyl fluorides and vinyl difluorides. We demonstrate that vinyl fluorides within α,β-unsaturated, styrenyl and even enol ether systems can participate in the cycloaddition reaction. The vinyl fluorides are relatively easy to synthesize through a variety of methods, making the 3-fluoropyrrolidines very accessible.
- McAlpine, Indrawan,Tran-Dubé, Michelle,Wang, Fen,Scales, Stephanie,Matthews, Jean,Collins, Michael R.,Nair, Sajiv K.,Nguyen, Mary,Bian, Jianwei,Alsina, Luis Martinez,Sun, Jianmin,Zhong, Jiaying,Warmus, Joseph S.,O'Neill, Brian T.
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p. 7266 - 7274
(2015/07/28)
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- Preparation of [3H]fluoroethyl tosylate and its use in the labelling of the dopamine transporter radioligand [3H]FE-PE2I
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[3H]Fluoroethyl tosylate, a novel alkylating tritium labelling agent, was synthesized from tritium gas with high specific activity and with 99% radiochemical purity. [3H]Fluoroethyl tosylate was applied in the tritium labelling of the dopamine transporter radioligand [3H]FE- PE2I. Copyright
- Cochrane, Alison R.,Kerr, William John,Sandell, Johan
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p. 447 - 450
(2014/03/21)
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- Direct, nucleophilic radiosynthesis of [18F]trifluoroalkyl tosylates: Improved labelling procedures
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A rapid and efficient protocol to afford the title compound 2-[ 18F]-fluoro-2,2-difluoroethyl tosylate ([18F]7b) is described. Starting from [18F]fluoride ion, labelling reagent 7b was obtained in good yields and a high specific radioactivity. Compound ([ 18F]7b) was then used to synthesise a prospective radiotracer for PET-imaging in dementia.
- Riss, Patrick J.,Ferrari, Valentina,Brichard, Laurent,Burke, Paul,Smith, Robert,Aigbirhio, Franklin I.
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p. 6980 - 6986,7
(2012/12/12)
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- Monofluorovinyl tosylate: A useful building block for the synthesis of terminal vinyl monofluorides via suzuki-Miyaura coupling
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Monofluorovinyl tosylate was developed as a practical vinyl fluoride building block to couple with a variety of arylboronic acids in the presence of a palladium catalyst. The high stereoselectivity of 2-aryl-1-fluoroethene derivatives was achieved. This a
- Zhang, He,Zhou, Chang-Bing,Chen, Qing-Yun,Xiao, Ji-Chang,Hong, Ran
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supporting information; scheme or table
p. 560 - 563
(2011/04/23)
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- A simple, rapid procedure for nucleophilic radiosynthesis of aliphatic [18F]trifluoromethyl groups
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A procedure for the radiosynthesis of aliphatic [18F] trifluoromethyl groups by reacting 1,1-difluorovinyl precursors with [ 18F]fluoride ions, resulting in the equivalent of direct nucleophilic addition of H[18F]F, has been developed. A variety of 18F-labelled model compounds were then obtained and two potential [18F]radiotracers were synthesised by a two step process starting from 1,1-difluorovin-2-yl 4-toluenesulfonate. The method is widely applicable for the synthesis of novel radiotracers in high radiochemical yields and good specific activity.
- Riss, Patrick J.,Aigbirhio, Franklin I.
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supporting information; experimental part
p. 11873 - 11875
(2011/12/04)
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- Efficient synthesis of 2,2-diaryl-1,1-difluoroethenes via consecutive cross-coupling reactions of 2,2-difluoro-1-tributylstannylethenyl p -toluenesulfonate
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2,2-Difluoro-1-tributylstannylethenyl p-toluenesulfonate (2) was reacted with aryl iodides in the presence of 10 mol % of Pd(PPh3)4 and 10 mol % of CuI in DMF at 80 °C for 10-20 h to give the cross-coupled products 3 in 35-97% yields. Further coupling reaction of 3 with arylstannanes in the presence of 5 mol % of Pd(PPh3)4 and 3 equiv of LiBr in DMF at 100 °C for 2-24 h afforded the desired products 5 in 25-78% yields.
- Han, Seung Yeon,Jeong, In Howa
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supporting information; experimental part
p. 5518 - 5521
(2011/02/26)
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- Direct vinylation and difluorovinylation of arylboronic acids using vinyl- and 2,2-difluorovinyl tosylates via the Suzuki-Miyaura cross coupling
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(Chemical Equation Presented) General reaction conditions were developed for the Pd(0)-catalyzed Suzuki-Miyaura coupling reaction of aryl boronic acids with a simple electrophilic vinylation reagent, vinyl tosylate, providing access to styrene derivatives in good yields. The easily accessible vinyl tosylate represents a stable and less toxic alternative to the vinyl halides and the triflate/nonaflate derivatives. Furthermore, this methodology was expanded to provide a facile and straightforward approach for the introduction of a gem-difluorovinyl substituent onto an aromatic ring using the similar and also readily available 2,2-difluorovinyl tosylate as the electrophilic complement.
- Gogsig, Thomas M.,Sobjerg, Lina S.,Lindhardt, Anders T.,Jensen, Kim L.,Skrydstrup, Troels
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p. 3404 - 3410
(2008/09/21)
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- The nucleophilic 5-endo-trig cyclization of 1,1-difluoro-1-alkenes: Ring-fluorinated hetero- and carbocycle synthesis and remarkable effect of the vinylic fluorines on the disfavored process
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The disfavored 5-endo-trig cyclizations have been accomplished for 1,1-difluoro-1-alkenes with nitrogen, oxygen, sulfur, and carbon nucleophiles by taking advantage of the properties of fluorine. β,β-Difluorostyrenes bearing tosylamido, hydroxy, or methylsulfinyl group at the o-position undergo intramolecular nucleophilic substitution with a loss of the vinylic fluorine, leading to 2-fluorinated indole, benzo[b]furan, and benzo[b]thiophene in high yields, 1,1-Difluoro-1-butenes bearing homoallylic tosylamido, hydroxy, mercapto, or iodomethyl group also successfully cyclize via a 5-endo-trig process with the in situ generated intramolecular nucleophiles to afford 2-fluoro-2-pyrroline, 5-fluoro-2,3-dihydrofuran, 5-fluoro-2,3-dihydrothiophene, and 1-fluorocyclopentene. The two vinylic fluorines proved to be essential and play a critical role in these 'anti-Baldwin' cyclizations.
- Ichikawa, Junji,Wada, Yukinori,Fujiwara, Masaki,Sakoda, Kotaro
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p. 1917 - 1936
(2007/10/03)
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- Novel 2,2-difluorovinylzirconocene: A facile synthesis of monosubstituted gem-difluoroolefins via its cross-coupling reaction
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2,2-Difluorovinyl p-toluenesulfonate, readily obtained from 2,2,2-trifluoroethanol, is treated with zirconocene equivalent 'Cp2Zr' to generate the remarkably thermostable nonsubstituted 2,2-difluorovinylzirconocene, which in turn couples with a
- Ichikawa, Junji,Fujiwara, Masaki,Nawata, Hideyuki,Okauchi, Tatsuo,Minami, Toru
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p. 8799 - 8802
(2007/10/03)
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