- Direct Synthesis of β-Amino Aldehydes from Linear Allylic Esters Using O2as the Sole Oxidant
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A tandem isomerization-anti-Markovnikov oxidation of linear allylic imidic esters is developed using bis(benzonitrile)palladium chloride as the catalyst and O2 as the sole oxidant, regiospecifically giving β-amino aldehydes as the product. tert-Butyl nitrite works as a simple, and the only, redox cocatalyst. tBuOH proves to be a crucial solvent for achieving excellent yield and specificity toward anti-Markovnikov aldehyde products.
- Lei, Shu-Hui,Zhong, Ya,Cai, Xian-Peng,Huang, Qing,Qu, Jian-Ping,Kang, Yan-Biao
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p. 9273 - 9276
(2021/12/06)
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- ARYL SULFONAMIDES AS SMALL MOLECULE STAT3 INHIBITORS
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The present disclosure provides pharmaceutical compositions comprising aryl sulfonamide Stat3 small molecule inhibitors and certain pharmaceutically acceptable salts thereof, and methods of their use for treating cancer.
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-
Paragraph 00289; 00290
(2021/01/29)
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- Novel hybrid conjugates with dual estrogen receptor α degradation and histone deacetylase inhibitory activities for breast cancer therapy
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Hormone therapy targeting estrogen receptors is widely used clinically for the treatment of breast cancer, such as tamoxifen, but most of them are partial agonists, which can cause serious side effects after long-term use. The use of selective estrogen receptor down-regulators (SERDs) may be an effective alternative to breast cancer therapy by directly degrading ERα protein to shut down ERα signaling. However, the solely clinically used SERD fulvestrant, is low orally bioavailable and requires intravenous injection, which severely limits its clinical application. On the other hand, double- or multi-target conjugates, which are able to synergize antitumor activity by different pathways, thus may enhance therapeutic effect in comparison with single targeted therapy. In this study, we designed and synthesized a series of novel dual-functional conjugates targeting both ERα degradation and histone deacetylase inhibiton by combining a privileged SERD skeleton 7-oxabicyclo[2.2.1]heptane sulfonamide (OBHSA) with a histone deacetylase inhibitor side chain. We found that substituents on both the sulfonamide nitrogen and phenyl group of OBHSA unit had significant effect on biological activities. Among them, conjugate 16i with N-methyl and naphthyl groups exhibited potent antiproliferative activity against MCF-7 cells, and excellent ERα degradation activity and HDACs inhibitory ability. A further molecular docking study indicated the interaction patterns of these conjugates with ERα, which may provide guidance to design novel SERDs or PROTAC-like SERDs for breast cancer therapy.
- Zhao, Chenxi,Tang, Chu,Li, Changhao,Ning, Wentao,Hu, Zhiye,Xin, Lilan,Zhou, Hai-Bing,Huang, Jian
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- Meta Selective C-H Borylation of Sterically Biased and Unbiased Substrates Directed by Electrostatic Interaction
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An electrostatically directed meta borylation of sterically biased and unbiased substrates is described. The borylation follows an electrostatic interaction between the partially positive and negative charges between the ligand and substrate. With this strategy, it has been demonstrated that a wide number of challenging substrates, especially 4-substituted substrates, can selectively be borylated at the meta position. Moreover, unsubstituted substrates also displayed excellent meta selectivity. The reaction employs a bench-stable ligand and proceeds at a milder temperature, precluding the need to synthesize a bulky and sophisticated ligand/template.
- Chaturvedi, Jagriti,Haldar, Chabush,Bisht, Ranjana,Pandey, Gajanan,Chattopadhyay, Buddhadeb
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supporting information
p. 7604 - 7611
(2021/05/26)
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- Electrochemical approach to trifluoroacetamide synthesis from 1,1,1-trichloro-2,2,2-trifluoroethane (CFC-113a) catalyzed by B12complex
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One-pot synthetic approach to produce trifluoroacetamide has been developed using an electrochemical method with the B12 complex as a catalyst under mild conditions, in open air at room temperature. Thirty examples of trifluoroacetamide were synthesized from 1,1,1-trichloro-2,2,2-trifluoroethane (CFC-113a) in moderate to good yields. This user-friendly strategy is compatible with a broad range of trifluoroacetamide syntheses.
- Moniruzzaman, Mohammad,Yano, Yoshio,Ono, Toshikazu,Hisaeda, Yoshio,Shimakoshi, Hisashi
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- Exploring the PROTAC degron candidates: OBHSA with different side chains as novel selective estrogen receptor degraders (SERDs)
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As the mutant estrogen receptor (ER) continues to be characterized, breast cancer is becoming increasingly difficult to cure when treated with hormone therapy. In this regard, a strategy to selectively and effectively degrade the ER might be an effective alternative to endocrine therapy for breast cancer. In a previous study, we identified a novel series of 7-oxabicyclo[2.2.1]heptene sulfonamide (OBHSA) compounds as full ER antagonists while lacking the prototypical ligand side chain that has been widely used to induce antagonism of ERα. Further crystal structure studies and phenotypic assays revealed that these compounds are selective estrogen receptor degraders (SERDs) with a new mechanism of action. However, from a drug discovery point of view, there still is room to improve the potency of these OBHSA compounds. In this study, we have developed new classes of SERDs that contain the OBHSA core structure and different side chains, e.g., basic side chains, long alkyl acid side chains, and glycerol ether side chains, to simply mimic the degrons of proteolysis targeting chimera (PROTAC) and then investigated the structure-activity relationships of these PROTAC-like hybrid compounds. These novel SERDs could effectively inhibit MCF-7 cell proliferation and demonstrated good ERα degradation efficacy. Among the SERDs, compounds 17d, 17e and 17g containing a basic side chain with a N-trifluoroethyl substituent and a para methoxyl group at the phenyl group of the sulfonamide turned out to be the best candidates for ER degraders. A further docking study of these compounds with ERα elucidates their structure-activity relationships, which provides guidance to design new PROTAC degrons targeting ER for breast cancer therapy. Lastly, easy modification of these PROTAC-like SERDs enables further fine-tuning of their pharmacokinetic properties, including oral availability.
- Li, Yuanyuan,Zhang, Silong,Zhang, Jing,Hu, Zhiye,Xiao, Yuan,Huang, Jian,Dong, Chune,Huang, Shengtang,Zhou, Hai-Bing
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-
- Carbon-Carbon Bond Formation of Trifluoroacetyl Amides with Grignard Reagents via C(O)-CF3 Bond Cleavage
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The reaction of trifluoroacetyl amides with Grignard reagent for the substitution of CF3 group with various alkyl or aryl groups is described. A variety of aryl, quinolin-8-yl, and (hetero)alkyl functional groups as well as F, Cl, and Br atoms are well tolerated. These moisture-stable and easily available trifluoroacetyl amides can be conveniently obtained and used as new versatile precursors for isocyanates. The control experiments show that the reaction proceeds via an isocyanate intermediate and/or alkoxide/amide dual anionic intermediate.
- Zhu, Longzhi,Le, Liyuan,Yan, Mingpan,Au, Chak-Tong,Qiu, Renhua,Kambe, Nobuaki
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p. 5635 - 5644
(2019/05/10)
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- KOtBu-Promoted Transition-Metal-Free Transamidation of Primary and Tertiary Amides with Amines
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This work discloses transamidation of primary and tertiary amides with a range of aryl, heteroaryl, and aliphatic amines using potassium tert-butoxide. The reaction proceeds at room temperature under transition-metal-free conditions providing secondary amides in high yields. Moreover, reaction of cyclopropyl amine with tertiary amides proceeds with ring-opening to provide a rapid access to enamides.
- Ghosh, Tridev,Jana, Snehasish,Dash, Jyotirmayee
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supporting information
p. 6690 - 6694
(2019/09/12)
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- Overcoming inaccessibility of fluorinated imines-synthesis of functionalized amines from readily available fluoroacetamides
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Although imines are convenient substrates for the synthesis of functionalized amines, they may be hard to obtain, as in the case of fluorinated imines. To aid in overcoming this issue, we propose a protocol of corresponding amine synthesis from simple fluoroacetic acid-derived amides using Schwartz's reagent.
- Czerwiński, Pawe? J.,Furman, Bart?omiej
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supporting information
p. 9436 - 9439
(2019/08/15)
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- Copper-Catalyzed Coupling Reaction of (Hetero)Aryl Chlorides and Amides
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Cu2O/N,N′-bis(thiophen-2-ylmethyl)oxalamide is established to be an effective catalyst system for Goldberg amidation with inferior reactive (hetero)aryl chlorides, which have not been efficiently documented by Cu-catalysis to date. The reaction is well liberalized toward a variety of functionalized (hetero)aryl chlorides and a wide range of aromatic and aliphatic primary amides in good to excellent yields. Furthermore, the arylation of lactams and oxazolidinones is achieved. The present catalytic system also accomplished an intramolecular cross-coupling product.
- De, Subhadip,Yin, Junli,Ma, Dawei
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supporting information
p. 4864 - 4867
(2017/09/23)
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- Design, Synthesis, and Evaluation of the Highly Selective and Potent G-Protein-Coupled Receptor Kinase 2 (GRK2) Inhibitor for the Potential Treatment of Heart Failure
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A novel class of therapeutic drug candidates for heart failure, highly potent and selective GRK2 inhibitors, exhibit potentiation of β-adrenergic signaling in vitro studies. Hydrazone derivative 5 and 1,2,4-triazole derivative 24a were identified as hit compounds by HTS. New scaffold generation and SAR studies of all parts resulted in a 4-methyl-1,2,4-triazole derivative with an N-benzylcarboxamide moiety with highly potent activity toward GRK2 and selectivity over other kinases. In terms of subtype selectivity, these compounds showed enough selectivity against GRK1, 5, 6, and 7 with almost equipotent inhibition to GRK3. Our medicinal chemistry efforts led to the discovery of 115h (GRK2 IC50 = 18 nM), which was obtained the cocrystal structure with human GRK2 and an inhibitor of GRK2 that potentiates β-adrenergic receptor (βAR)-mediated cAMP accumulation and prevents internalization of βARs in β2AR-expressing HEK293 cells treated with isoproterenol. Therefore, 115h appears to be a novel class of therapeutic for heart failure treatment.
- Okawa, Tomohiro,Aramaki, Yoshio,Yamamoto, Mitsuo,Kobayashi, Toshitake,Fukumoto, Shoji,Toyoda, Yukio,Henta, Tsutomu,Hata, Akito,Ikeda, Shota,Kaneko, Manami,Hoffman, Isaac D.,Sang, Bi-Ching,Zou, Hua,Kawamoto, Tetsuji
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p. 6942 - 6990
(2017/09/07)
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- Lanthanum(III) triflate catalyzed direct amidation of esters
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Lanthanum trifluoromethanesulfonate is an effective single-component catalyst for synthesizing a variety of amides directly from esters and amines under mild conditions. Highly selective amidation of esters and amines, as well as catalyst-controlled amidation of esters, demonstrated the effectiveness of the catalyst system.
- Morimoto, Hiroyuki,Fujiwara, Risa,Shimizu, Yuhei,Morisaki, Kazuhiro,Ohshima, Takashi
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supporting information
p. 2018 - 2021
(2014/05/06)
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- The development of N-aryl trifluoroacetimidate-based benzyl and allyl protecting group reagents
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An exploration of the role of para-substituents on the balance between stability and reactivity of N-phenyl trifluoroacetimidates prompted the discovery of new reagents for the addition of allyl and benzyl protecting groups, namely O-allyl and O-benzyl N-
- Tsabedze, Sinele B.,Kabotso, Daniel E.K.,Pohl, Nicola L.B.
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p. 6983 - 6985
(2013/12/04)
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- Bicyclic core estrogens as full antagonists: Synthesis, biological evaluation and structure-activity relationships of estrogen receptor ligands based on bridged oxabicyclic core arylsulfonamides
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Compounds that block estrogen action through the estrogen receptor (ER) or downregulate ER levels are useful for the treatment of breast cancer and endocrine disorders. In our search for structurally novel estrogens having three-dimensional core scaffolds, we found some compounds with a 7-oxabicyclo[2.2.1]heptene core that bound well to the ERs. The best of these compounds, a phenyl sulfonate ester (termed OBHS for oxabicycloheptene sulfonate), was a partial antagonist on both ERα and ERβ. Although OBHS bears no structural resemblance to other estrogen antagonists, it appears to achieve its partial antagonist character by stabilizing a novel conformation of the ER that involves a significant distortion of helix-11. To enhance the antagonist properties of these oxabicyclo[2.2.1]heptane core ligands, we expanded the functional diversity of OBHS by replacing the sulfonate with secondary or tertiary sulfonamides (-SO2NR-), isoelectronic and potentially isostructural molecular replacements. An array of 16 OBHS sulfonamide analogues were prepared through a Diels-Alder reaction of a 3,4-diarylfuran using various N-aryl vinyl sulfonamide dienophiles. While the more polar secondary sulphonamides were weak ligands, certain of the tertiary sulfonamides had very good ER binding affinity. In HepG2 cell reporter gene assays, the sulphonamides had moderate potency, but they showed lower intrinsic transcriptional activity on ERα than the selective estrogen receptor modulator (SERM) hydroxytamoxifen or OBHS, and they were inverse agonists on ERβ. Thus, the behaviour of these OBH-sulfonamides more closely mirrors the activity of full antagonists like the drug fulvestrant (ICI 182780), and their greater antagonist biocharacter appears to arise from an accentuated distortion of helix-11.
- Zhu, Manghong,Zhang, Chen,Nwachukwu, Jerome C.,Srinivasan, Sathish,Cavett, Valerie,Zheng, Yangfan,Carlson, Kathryn E.,Dong, Chune,Katzenellenbogen, John A.,Nettles, Kendall W.,Zhou, Hai-Bing
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supporting information
p. 8692 - 8700
(2013/01/15)
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- A simple and efficient method for trifluoroacetylation of arylamines using trifluoroacetic acid and triphosgene
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A simple and efficient one-pot procedure for trifluoroacetylation of arylamines using trifluoroacetic acid and triphosgene is reported. A mixed trifluoroacetic anhydride generated in situ reacts with a variety of arylamines to give the corresponding trifluroacetamides in high yields.
- Han, Ki-Jong,Kim, Misoo
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experimental part
p. 559 - 561
(2012/06/04)
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- Trifluoroacetylation of amines with trifluoroacetic acid in the presence of trichloroacetonitrile and triphenylphosphine
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We developed a mild and convenient trifluoroacetylation process for amines using a combination of trichloroacetonitrile and triphenylphosphine. The reaction that we designed is applicable to the trifluoroacetylation of a wide variety of amines, including amines with stereogenic centers, which underwent trifluoroacetylation without racemization.
- Kim, Joong-Gon,Jang, Doo Ok
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scheme or table
p. 683 - 685
(2010/04/02)
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- A one-pot procedure for trifluoroacetylation of arylamines using trifluoroacetic acid as a trifluoroacetylating reagent
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A convenient procedure for the preparation of aryl trifluoroacetamides from aryl amines is described that employs 2-4 M equiv of trifluoroacetic acid in refluxing xylene as a trifluoroacetylating agent. Addition of an amount of pyridine that is equimolar to the amount of trifluoroacetic acid present in the reaction mixture facilitates the trifluoroacetylation of rather basic arylamines.
- Ohtaka, Junpei,Sakamoto, Takeshi,Kikugawa, Yasuo
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experimental part
p. 1681 - 1683
(2009/09/05)
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- One-pot synthesis of highly functionalized stable ketenimines of 2,2,2-trifluoro-N-aryl-acetamides
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Three-component reaction of alkyl isocyanides and dialkyl acetylenedicarboxylates in the presence of 2,2,2-trifluoro-N-aryl-acetamides in dichloromethane at ambient temperature afforded dialkyl 2-(N-(aryl)-2,2,2-trifluoroacetamido)-3-(alkylimino) methylene-succinate derivatives in excellent yields.
- Anary-Abbasinejad, Mohammad,Moslemine, Mohammad H.,Anaraki-Ardakani, Hossein
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experimental part
p. 368 - 371
(2009/12/01)
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- Copper-catalyzed synthesis of primary arylamines from aryl halides and 2,2,2-trifluoroacetamide
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A catalytic method was developed to synthesize primary arylamines from the corresponding aryl bromides and iodides under mild conditions (yields = 80-99%). Crystalline 2,2,2-trifluoroacetamide was used as ammonia surrogate and CuI/N,N′-dimethyl ethylenediamine was used as catalyst to achieve the C-N cross-coupling.
- Tao, Chuan-Zhou,Li, Juan,Fu, Yao,Liu, Lei,Guo, Qing-Xiang
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-
- SULFONAMIDES AS SELECTIVE ESTROGEN RECEPTOR
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Compounds, pharmaceutically acceptable salts, stereoisomers and prodrugs thereof, that are ER ligands and particularly to such compounds that are ER beta-selective and/or ER beta-specific ligands. Compounds herein include certain compounds which are ER be
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Page/Page column 13-14; 24
(2008/06/13)
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- Trifluoroacetylation of arylamines using poly-phosphoric acid trimethylsilylester (PPSE)
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A new, simple and useful procedure is described for the trifluoroacetylation of arylamines using trifluoroacetic acid and poly-phosphoric acid trimethylsilylester (PPSE) as the condensation agent.
- López, Simón E.,Pérez, Yelsi,Restrepo, Jelem,Salazar, José,Charris, Jaime
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p. 566 - 569
(2007/12/27)
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- Unexpected formation of N,N-disubstituted formamidines from aromatic amines, formamides and trifluoroacetic anhydride
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An intriguing selectivity towards the formation of the formamidine was observed upon the reaction of an amine with sodium hydride and trifluoroacetic anhydride in dimethyl formamide. Various aromatic amines were reacted with a series of N,N-disubstituted formamides as a solvent under the influence of trifluoroacetic anhydride to thoroughly probe this behaviour. A trend in selectivity is discussed and a proposed mechanism for the reaction is also presented.
- Mekhalfia, Abdelaziz,Mutter, Roger,Heal, William,Chen, Beining
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p. 5617 - 5625
(2007/10/03)
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- Facile synthesis of α-fluoro substituted amidines from imidoyl chlorides and some of its application
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A series of α-fluoro subustituted amidines were synthesized from corresponding fluorinated imidoyl chlorides in good to excellent yields and some of its applications are outlined in our programs.
- Wu, Yong-Ming,Zhang, Min,Li, Yi-Qun
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p. 1168 - 1174
(2008/03/28)
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- Direct microwave promoted trifluoroacetylation of aromatic amines with trifluoroacetic acid
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A simple microwave-promoted procedure has been developed for the direct preparation of trifluoroacetanilides. An equimolar mixture of substituted anilines and trifluoroacetic acid was microwave irradiated at short reaction times, giving the corresponding anilides in high yields and purity.
- Salazar, José,López, Simón E.,Rebollo, Oscar
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p. 111 - 113
(2007/10/03)
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- Radical-mediated synthesis of trifluoroethyl amines and trifluoromethyl ketones from alkyl iodides
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Radical reaction of alkyl iodides with trifluoromethyl phenylsulfonyl oxime ether 10 and hexamethylditin at 300 nm in benzene afforded the corresponding trifluoromethyl oxime ethers 11 in high yields, which were reduced into the 2,2,2-trifluoroethyl amines with lithium aluminium hydride. The trifluoroethyl amines could be converted into the corresponding trifluoromethyl ketones by treatment with NBS and DBU.
- Kim, Sunggak,Kavali, Rajesh
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p. 7189 - 7191
(2007/10/03)
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- Metal-assisted reactions. Part 29. Structure and hydrogenolysis of C-N bonds in derivatives of aromatic amines. Bond length and electronegativity changes from X-ray crystallographic data
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Pseudosaccharyl and phenyltetrazolyl derivatives 1-6 were prepared with the aim of weakening the originally strong C-N bond in aromatic amines and facilitating its hydrogenolysis. Structural analyses of the amines 1-6 by 1H and 13C NMR spectroscopy and X-ray diffraction methods have revealed major changes in C-N bond lengths on derivatization as a result of changes in conjugation. These changes are discussed in relation to the observed reactivity of compounds 1-6 towards catalytic and non-catalytic C-N bond hydrogenolysis.
- Brigas, Amadeu F.,Clegg, William,Dillon, Christopher J.,Fonseca, Custodia F.C.,Johnstone, Robert A.W.
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p. 1315 - 1324
(2007/10/03)
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- A novel synthesis of isocyanates and ureas via β-elimination of haloform
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A novel synthesis of isocyanates via base-induced β-elimination of haloform from N-monosubstituted trihaloacetamides is described. The rate of reaction exhibits a strong dependence on the nature of the trihalomethyl group. Thus, while the reaction of tribromoacetamides proceeds at room temperature and the reaction of trichloroacetamides requires heating in polar solvents, no reaction could be observed for any of the corresponding trifluoro derivatives. This novel β-elimination of haloform from stable and readily available trihaloacetamides was applied to a 'one-pot' synthesis of ureas which avoids the use of phosgene and isolation of isocyanates.
- Braverman,Cherkinsky,Kedrova,Reiselman
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p. 3235 - 3238
(2007/10/03)
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- A novel one-pot method for reductive conversion of azides to acyl amines with acetic anhydride and trimethyl chlorosilane
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A combination of acetic anhydride and chloro-trimethylsilane has been shown to effect the conversion of a variety of azides to the corresponding acetylated amines in excellent yields without affecting other functional groups such as ether, ester, halide etc.
- Barua, Apurba,Bez, Ghanashyam,Barua, Nabin C.
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p. 553 - 554
(2007/10/03)
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- Design and synthesis of new hypocholesterolemic organosilanes with antioxidant properties
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(Arylamino)methylsilane derivatives 3 have been prepared and identified as potent inhibitors of human LDL oxidation mediated by copper(II). Combination of this property with the structural requirement of squalene epoxidase inhibitors led to the design and synthesis of the (arylamino)methylsilane derivative 4 which was characterised as the first potent, orally active squalene epoxidase inhibitor with antioxidant properties.
- Gotteland,Delhon,Junquero,Oms,Halazy
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p. 533 - 538
(2007/10/03)
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- Synthesis of 1-Trifluoroacetyl-3-dialkylaminomethyl-5-monosubstituted Benzimidazoline-2-thiones using Trifluoroacetic Acid as an Acylating Agent
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1-Trifluoroacetyl-3-dialkylaminomethyl-5-monosubstituted benzimidazoline-2-thiones have been synthesized from p-substituted anilines which were acetylated with trifluoroacetic acid.The trifluoroacetanilides were nitrated, reduced and cyclised with carbon
- Joshi, Krishna C.,Misra, Ram A.,Jain, Renuka,Sharma, Kanti
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p. 409 - 412
(2007/10/02)
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