Pub Date : 2024-10-15DOI: 10.1021/acs.orglett.4c03404
Lili Chen, Gang Liao, Bin Liu
We present the first example of nickel(II)-catalyzed β-C(sp3)–H thiolation of ketones, employing 2-hydrazinopyridine as an efficient directing group. This approach enables the thiolation of a diverse array of ketones at the β-position. The straightforward installation and subsequent removal of the directing group significantly enhance the synthetic versatility and practicality of this transformation.
{"title":"Ligand-Enabled Nickel(II)-Catalyzed β-C(sp3)–H Thiolation of Ketones","authors":"Lili Chen, Gang Liao, Bin Liu","doi":"10.1021/acs.orglett.4c03404","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c03404","url":null,"abstract":"We present the first example of nickel(II)-catalyzed β-C(sp<sup>3</sup>)–H thiolation of ketones, employing 2-hydrazinopyridine as an efficient directing group. This approach enables the thiolation of a diverse array of ketones at the β-position. The straightforward installation and subsequent removal of the directing group significantly enhance the synthetic versatility and practicality of this transformation.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-15DOI: 10.1021/acs.orglett.4c03434
Hengzhao Li, Kemeng Wang, Wangyu Zhao, Xinxin Li, Yijing Fu, Hainam Do, Jie An, Zhaonong Hu
An efficient and chemoselective protocol for the single-electron-transfer (SET) reductive deuteration of thioamides using SmI2 and D2O is reported. This method uniquely produces α,α-dideuterio amines via a thio-ketyl radical intermediate without generating alcohol byproducts, distinguishing it from the SET reduction of amides. The inherent high reactivity of thioamides obviates the need for ligands like Et3N to improve the reducing power of SmI2, thereby enabling milder reaction conditions that are compatible with a broad range of sensitive functional groups. This protocol tolerates both primary and secondary aliphatic and aromatic thioamides, leading to the synthesis of 27 α,α-dideuterio amines and valuable deuterated nitrogen heterocycles with >95% deuterium incorporations.
{"title":"Highly Chemoselective Synthesis of α, α-Dideuterio Amines by the Reductive Deuteration of Thioamides Using Mild SmI2–D2O","authors":"Hengzhao Li, Kemeng Wang, Wangyu Zhao, Xinxin Li, Yijing Fu, Hainam Do, Jie An, Zhaonong Hu","doi":"10.1021/acs.orglett.4c03434","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c03434","url":null,"abstract":"An efficient and chemoselective protocol for the single-electron-transfer (SET) reductive deuteration of thioamides using SmI<sub>2</sub> and D<sub>2</sub>O is reported. This method uniquely produces α,α-dideuterio amines via a thio-ketyl radical intermediate without generating alcohol byproducts, distinguishing it from the SET reduction of amides. The inherent high reactivity of thioamides obviates the need for ligands like Et<sub>3</sub>N to improve the reducing power of SmI<sub>2</sub>, thereby enabling milder reaction conditions that are compatible with a broad range of sensitive functional groups. This protocol tolerates both primary and secondary aliphatic and aromatic thioamides, leading to the synthesis of 27 α,α-dideuterio amines and valuable deuterated nitrogen heterocycles with >95% deuterium incorporations.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-15DOI: 10.1021/acs.orglett.4c03235
Li Sun, Jianwei Liang, Zheng Zhou, Yong Yang
Two aryl substituted phenalenyl derivatives were synthesized, providing an opportunity to study the steric effects on selectivity of phenalenyl dimerization. Owing to σ-dimerization serving as the decisive step in phenalenyl–peropyrene transformation, a chiral peropyrene compound was generated by dimerization of triarylphenalenyl, while tetraarylphenalenyl did not afford any dimerized product. The structure and properties of chiral peropyrene were elaborated. Our study showcases that phenalenyl dimerization could function as a useful tool to synthesize fascinating π-conjugated hydrocarbons.
{"title":"Chiral Peropyrene by Selective Dimerization of Phenalenyl","authors":"Li Sun, Jianwei Liang, Zheng Zhou, Yong Yang","doi":"10.1021/acs.orglett.4c03235","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c03235","url":null,"abstract":"Two aryl substituted phenalenyl derivatives were synthesized, providing an opportunity to study the steric effects on selectivity of phenalenyl dimerization. Owing to σ-dimerization serving as the decisive step in phenalenyl–peropyrene transformation, a chiral peropyrene compound was generated by dimerization of triarylphenalenyl, while tetraarylphenalenyl did not afford any dimerized product. The structure and properties of chiral peropyrene were elaborated. Our study showcases that phenalenyl dimerization could function as a useful tool to synthesize fascinating π-conjugated hydrocarbons.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
We report a visible-light-driven, palladium-catalyzed 1,4-difluoromethylative functionalization of conjugated dienes using chlorodifluoromethane (ClCF2H, Freon-22) as a cost-effective difluoromethyl source. The excited palladium catalyst efficiently reduces the C–Cl bond, which generates a CF2H radical, followed by regioselective SN2’ substitution to afford 1,4-difunctionalized products. This versatile, redox-neutral method accommodates diverse nucleophiles and exhibits broad functional group compatibility, making it suitable for late-stage functionalization in drug discovery and offering a direct route to difluoromethylated molecules.
{"title":"Pd-Catalyzed 1,4-Difluoromethylative Functionalization of 1,3-Dienes Using Freon-22","authors":"Qixin Zhou, Jing Wang, Tiancen Bian, Yan Liang, Weikang Yan, Liejin Zhou, Zuxiao Zhang","doi":"10.1021/acs.orglett.4c03338","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c03338","url":null,"abstract":"We report a visible-light-driven, palladium-catalyzed 1,4-difluoromethylative functionalization of conjugated dienes using chlorodifluoromethane (ClCF<sub>2</sub>H, Freon-22) as a cost-effective difluoromethyl source. The excited palladium catalyst efficiently reduces the C–Cl bond, which generates a CF<sub>2</sub>H radical, followed by regioselective S<sub>N</sub>2’ substitution to afford 1,4-difunctionalized products. This versatile, redox-neutral method accommodates diverse nucleophiles and exhibits broad functional group compatibility, making it suitable for late-stage functionalization in drug discovery and offering a direct route to difluoromethylated molecules.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A photoinduced vitamin-B12-catalyzed meta-C–H bromination/chlorination of phenol derivatives was established using a nitrile directing template and N-bromosuccinimide (NBS)/N-chlorosuccinimide (NCS) as halogenated reagents, and a series of meta-bromination/chlorination products were obtained in yields of 51 to 80%. This strategy overcame the selectivity problem of phenols, which have difficulty obtaining meta-products through conventional electrophilic reactions. Furthermore, natural product resveratrol and an intermediate of the γ-secretase inhibitor were successfully synthesized, which demonstrates the practicability of this method.
{"title":"Photoinduced Vitamin-B12-Catalyzed meta-C–H Bromination/Chlorination of Phenol Derivatives Assisted by a U-Shaped Nitrile Template","authors":"Weiya Zhang, Xianghui Zhu, Huixin Tong, Hongbo Zhao, Yuying Gu, Wenyi Chu","doi":"10.1021/acs.orglett.4c03339","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c03339","url":null,"abstract":"A photoinduced vitamin-B<sub>12</sub>-catalyzed <i>meta</i>-C–H bromination/chlorination of phenol derivatives was established using a nitrile directing template and <i>N</i>-bromosuccinimide (NBS)/<i>N</i>-chlorosuccinimide (NCS) as halogenated reagents, and a series of <i>meta</i>-bromination/chlorination products were obtained in yields of 51 to 80%. This strategy overcame the selectivity problem of phenols, which have difficulty obtaining <i>meta</i>-products through conventional electrophilic reactions. Furthermore, natural product resveratrol and an intermediate of the γ-secretase inhibitor were successfully synthesized, which demonstrates the practicability of this method.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-14DOI: 10.1021/acs.orglett.4c02692
Le-Song Wu, Chen-Yue Wang, Tao Zhou, Bing-Feng Shi
Chiral phosphorus compounds with contiguous P,C-stereogenic centers are widely found in chiral ligands. The synthesis of these skeletons has been scarcely reported. Herein, we developed a Pd(II)-catalyzed chemo-, diastereo-, and enantioselective arylation of diisopropyl phosphinamide enabled by 2-pyridinylisopropyl (PIP) auxiliary and (S)-6,6′-(CN)2-SPINOL. A range of chiral phosphinamides containing contiguous P,C-stereocenters were obtained in good yields (up to 85%) with excellent enantioselectivities (up to >99% ee).
{"title":"Pd(II)-Catalyzed Chemo-, Diastereo-, and Enantioselective C(sp3)–H Arylation to Construct Contiguous Phosphorus and Carbon Stereocenters","authors":"Le-Song Wu, Chen-Yue Wang, Tao Zhou, Bing-Feng Shi","doi":"10.1021/acs.orglett.4c02692","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c02692","url":null,"abstract":"Chiral phosphorus compounds with contiguous <i>P</i>,<i>C</i>-stereogenic centers are widely found in chiral ligands. The synthesis of these skeletons has been scarcely reported. Herein, we developed a Pd(II)-catalyzed chemo-, diastereo-, and enantioselective arylation of diisopropyl phosphinamide enabled by 2-pyridinylisopropyl (PIP) auxiliary and (<i>S</i>)-6,6′-(CN)<sub>2</sub>-SPINOL. A range of chiral phosphinamides containing contiguous <i>P</i>,<i>C</i>-stereocenters were obtained in good yields (up to 85%) with excellent enantioselectivities (up to >99% ee).","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431244","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-14DOI: 10.1021/acs.orglett.4c03184
Kui Zhang, Jie Liu, Yan Li, Yiwei Xu, Lingchao Cai
A straightforward method for the phosphorylation of electron-deficient alkenes and aryl alkynes has been developed, leading to C(sp3)–P and C(sp2)–P bond formation. This process involves the generation of phosphorus radical cation intermediates through the photocatalyzed oxidation of ethyl diarylphosphinites. The coupling with electron-deficient alkenes encompasses a variety of heteroaromatics, including pyridine, (benzo)thiazole, and benzoxazole, as well as α,β-unsaturated esters and amides. Impressively, the coupling of radical cations with aryl alkynes demonstrated remarkable regioselectivity, thereby facilitating the synthesis of rare α-aryl vinyl phosphine oxides.
{"title":"Photocatalytic C(sp3)–P and C(sp2)–P Bond Formation via a Phosphorus Radical Cation","authors":"Kui Zhang, Jie Liu, Yan Li, Yiwei Xu, Lingchao Cai","doi":"10.1021/acs.orglett.4c03184","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c03184","url":null,"abstract":"A straightforward method for the phosphorylation of electron-deficient alkenes and aryl alkynes has been developed, leading to C(sp<sup>3</sup>)–P and C(sp<sup>2</sup>)–P bond formation. This process involves the generation of phosphorus radical cation intermediates through the photocatalyzed oxidation of ethyl diarylphosphinites. The coupling with electron-deficient alkenes encompasses a variety of heteroaromatics, including pyridine, (benzo)thiazole, and benzoxazole, as well as α,β-unsaturated esters and amides. Impressively, the coupling of radical cations with aryl alkynes demonstrated remarkable regioselectivity, thereby facilitating the synthesis of rare α-aryl vinyl phosphine oxides.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Syntheses of guanidino alkaloids (−)-monanchoradin A and (−)-crambescin A2 392 are described. The key feature of the syntheses is the cyclization–carbonylation–cyclization cascade of the optically active propargyl guanidine. The bicyclic guanidino cores bearing an asymmetric center and ester or carboxylic acid functionality were constructed in a single step. The carboxylic acid was then converted to (−)-monanchoradin A and (−)-crambescin A2 392.
介绍了胍类生物碱 (-)-monanchoradin A 和 (-)-crambescin A2 392 的合成。合成的主要特征是光学活性丙炔基胍的环化-羰基化-环化级联反应。带有不对称中心和酯或羧酸官能团的双环胍基核只需一步就能合成。然后将羧酸转化为 (-)-monanchoradin A 和 (-)-crambescin A2 392。
{"title":"Synthesis of (−)-Monanchoradin A and (−)-Crambescin A2 392 Based on a Cyclization–Carbonylation–Cyclization Cascade","authors":"Takuya Tsukamoto, Keisuke Takahashi, Natsuki Murase, Kyoka Someya, Fujino Sakata, Tianci Yue, Taichi Kusakabe, Keisuke Kato","doi":"10.1021/acs.orglett.4c03158","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c03158","url":null,"abstract":"Syntheses of guanidino alkaloids (−)-monanchoradin A and (−)-crambescin A2 392 are described. The key feature of the syntheses is the cyclization–carbonylation–cyclization cascade of the optically active propargyl guanidine. The bicyclic guanidino cores bearing an asymmetric center and ester or carboxylic acid functionality were constructed in a single step. The carboxylic acid was then converted to (−)-monanchoradin A and (−)-crambescin A2 392.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431246","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-14DOI: 10.1021/acs.orglett.4c03469
Mohammad A. Alnajjar, Andreas Hennig
The N-methyl-4-thiophenylpyridinium cation (ThioPy) is a high affinity (Kd ca. 5 nM), fast-exchanging fluorescent probe for cucurbit[7]uril (CB7). The CB7/ThioPy complex shows a unique fluorescence turn-ON response upon displacement by an analyte in sensing application. This enabled the development of a real-time fluorescence assay with the MRFA peptide for the protease thermolysin, which is also suitable for the cancer biomarker cathepsin B. Moreover, liposome encapsulation of CB7/ThioPy in large unilamellar vesicles (LUVs) provided mechanistic insight into intravesicular dye displacement reactions.
{"title":"Fluorescence Turn-ON Displacement Assays with Cucurbit[7]uril–Thiophenylpyridinium Complexes as Host–Dye Reporter Pairs","authors":"Mohammad A. Alnajjar, Andreas Hennig","doi":"10.1021/acs.orglett.4c03469","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c03469","url":null,"abstract":"The <i>N</i>-methyl-4-thiophenylpyridinium cation (ThioPy) is a high affinity (<i>K</i><sub>d</sub> ca. 5 nM), fast-exchanging fluorescent probe for cucurbit[7]uril (CB7). The CB7/ThioPy complex shows a unique fluorescence turn-ON response upon displacement by an analyte in sensing application. This enabled the development of a real-time fluorescence assay with the MRFA peptide for the protease thermolysin, which is also suitable for the cancer biomarker cathepsin B. Moreover, liposome encapsulation of CB7/ThioPy in large unilamellar vesicles (LUVs) provided mechanistic insight into intravesicular dye displacement reactions.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-14DOI: 10.1021/acs.orglett.4c02862
Yi-Miao Wu, Xian-Li Ma, Fang-Yao Li, Chun-Chan Huang, Lei Gao, Ye Zhang, Ying-Ming Pan, Mu-Xue He, Zu-Yu Mo
An electrochemical cyclization/spirocyclization hydroarylation via reductive dearomatization of a series of nonactivated arenes including N-substituted indoles, indole-3-carboxamide derivatives, and iodo-substituted benzamides is described. This protocol boasts high atom efficiency, broad substrate applicability, and excellent selectivity. Utilizing a simple undivided cell, various nonactivated arenes undergo cyclization/spirocyclization through the intramolecular addition of aryl radicals to an aromatic ring, yielding 50 indolines, spirocyclizative hydroarylation products, and phenanthridinones.
{"title":"Dearomative Cyclization/Spirocyclization via Electrochemical Reductive Hydroarylation of Nonactivated Arenes","authors":"Yi-Miao Wu, Xian-Li Ma, Fang-Yao Li, Chun-Chan Huang, Lei Gao, Ye Zhang, Ying-Ming Pan, Mu-Xue He, Zu-Yu Mo","doi":"10.1021/acs.orglett.4c02862","DOIUrl":"https://doi.org/10.1021/acs.orglett.4c02862","url":null,"abstract":"An electrochemical cyclization/spirocyclization hydroarylation via reductive dearomatization of a series of nonactivated arenes including <i>N</i>-substituted indoles, indole-3-carboxamide derivatives, and iodo-substituted benzamides is described. This protocol boasts high atom efficiency, broad substrate applicability, and excellent selectivity. Utilizing a simple undivided cell, various nonactivated arenes undergo cyclization/spirocyclization through the intramolecular addition of aryl radicals to an aromatic ring, yielding 50 indolines, spirocyclizative hydroarylation products, and phenanthridinones.","PeriodicalId":54,"journal":{"name":"Organic Letters","volume":null,"pages":null},"PeriodicalIF":5.2,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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