Xi Zhang,Zhang Chen,Dong-Xiao Jiang,Lixian Shen,Jinjin Chen,Yao-Fu Zeng,Zhen Wang
Herein, we describe a photochemical strategy for synthesizing tetrahydropyridoindoles via a cascade decarboxylative cyclization between indolyl NHPI esters and alkenes. This protocol showcased a broad substrate scope, accommodating primary, secondary, and tertiary alkyl radicals generated from decarboxylation of NHPI esters. Diverse functional groups, such as esters, amides, alkenes, cyano, trifluoromethyl, aldehyde, and sulfonyl moieties, were well tolerated. Key to the success was the identification of a tetrameric EDA complex, formed from KI, PPh3, the substrate, and di(pyridin-4-yl)amine.
{"title":"Tetrameric Electron Donor–Acceptor Complex-Mediated Cascade Cyclization for the Synthesis of Tetrahydropyridoindole","authors":"Xi Zhang,Zhang Chen,Dong-Xiao Jiang,Lixian Shen,Jinjin Chen,Yao-Fu Zeng,Zhen Wang","doi":"10.1021/acs.joc.6c00083","DOIUrl":"https://doi.org/10.1021/acs.joc.6c00083","url":null,"abstract":"Herein, we describe a photochemical strategy for synthesizing tetrahydropyridoindoles via a cascade decarboxylative cyclization between indolyl NHPI esters and alkenes. This protocol showcased a broad substrate scope, accommodating primary, secondary, and tertiary alkyl radicals generated from decarboxylation of NHPI esters. Diverse functional groups, such as esters, amides, alkenes, cyano, trifluoromethyl, aldehyde, and sulfonyl moieties, were well tolerated. Key to the success was the identification of a tetrameric EDA complex, formed from KI, PPh3, the substrate, and di(pyridin-4-yl)amine.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"14 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Unnatural α-amino acids with sterically congested centers are valuable in pharmaceuticals and materials science, yet their synthesis mechanism remains unclear. This study uses DFT calculations to clarify the mechanism of Cu-catalyzed C(sp3)-H alkylation of amino acid Schiff bases with tertiary alkyl bromides for constructing such compounds. Key findings include the following: the reaction proceeds via a Cu(II)-Cu(I)-Cu(II) redox cycle without Cu(III) intermediates; Cu(II)-acetate promotes aza-allyl radical (R1·) formation through single-electron transfer (SET); the tertiary alkyl radical (R2·) is generated via halogen-atom transfer (XAT) by the Cu(I)-deprotonated Schiff base complex rather than the previously proposed Cu(I)-acetate complex; and R1· preferentially undergoes heterocoupling with R2· over homocoupling to form the desired product. These findings clarify experimentally ambiguous mechanistic issues, explain why the expected heterocoupled product rather than self-coupled byproducts is obtained, and provide important theoretical insights for developing efficient synthetic methods for unnatural α-amino acids.
{"title":"Mechanistic Study on Copper-Catalyzed C(sp3)-H Alkylation of Amino Acid Schiff Bases for Synthesis of Highly Congested Unnatural α-Amino Acids.","authors":"Jiali Peng,Dongju Zhang","doi":"10.1021/acs.joc.5c02980","DOIUrl":"https://doi.org/10.1021/acs.joc.5c02980","url":null,"abstract":"Unnatural α-amino acids with sterically congested centers are valuable in pharmaceuticals and materials science, yet their synthesis mechanism remains unclear. This study uses DFT calculations to clarify the mechanism of Cu-catalyzed C(sp3)-H alkylation of amino acid Schiff bases with tertiary alkyl bromides for constructing such compounds. Key findings include the following: the reaction proceeds via a Cu(II)-Cu(I)-Cu(II) redox cycle without Cu(III) intermediates; Cu(II)-acetate promotes aza-allyl radical (R1·) formation through single-electron transfer (SET); the tertiary alkyl radical (R2·) is generated via halogen-atom transfer (XAT) by the Cu(I)-deprotonated Schiff base complex rather than the previously proposed Cu(I)-acetate complex; and R1· preferentially undergoes heterocoupling with R2· over homocoupling to form the desired product. These findings clarify experimentally ambiguous mechanistic issues, explain why the expected heterocoupled product rather than self-coupled byproducts is obtained, and provide important theoretical insights for developing efficient synthetic methods for unnatural α-amino acids.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"16 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A one-pot, three-component cyclization of 2-hydroxy p-quinone methides and in situ-formed α-imino ketones is described at room temperature to synthesize N-substituted 3,4-dihydro-2H-1,3-benzoxazine using a Ca(II) catalyst. The reaction involves a cascade etherification followed by an intramolecular 1,6-conjugate aza-addition. The NMR spectroscopy of the products indicates that the products are obtained as rotamers. Simple operation, wide substrate scope, and gram-scale synthesis demonstrate the protocol’s competence.
{"title":"Ambiphilic p-Quinone Methides and α-Imino Ketones: Ca(II)-Catalyzed, One-Pot, Three-Component Synthesis of Benzoxazines","authors":"Srinivasarao Yaragorla,Doma Arun","doi":"10.1021/acs.joc.5c03236","DOIUrl":"https://doi.org/10.1021/acs.joc.5c03236","url":null,"abstract":"A one-pot, three-component cyclization of 2-hydroxy p-quinone methides and in situ-formed α-imino ketones is described at room temperature to synthesize N-substituted 3,4-dihydro-2H-1,3-benzoxazine using a Ca(II) catalyst. The reaction involves a cascade etherification followed by an intramolecular 1,6-conjugate aza-addition. The NMR spectroscopy of the products indicates that the products are obtained as rotamers. Simple operation, wide substrate scope, and gram-scale synthesis demonstrate the protocol’s competence.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"83 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
María Jesús Martín,Rogelio Fernández,Carmen Murcia,Laura Coello,Gloria Crespo,Andrés Francesch,Simon Munt,Carmen Cuevas
We report the discovery, structural elucidation, and first total synthesis of two unprecedented marine oxazole derivatives, PM100618 and PM110049, isolated from the Papua New Guinean sponge Rhabdastrella rowi. Both compounds exhibit potent in vitro cytotoxic activity at nanomolar concentrations. A highly convergent and efficient total synthesis of PM100618 and PM110049 was achieved in 22 and 21 steps, respectively (longest linear sequence: 15 steps) through the coupling of two complex fragments. This synthetic route provides ready access to these scarce natural products, enabling advanced pharmacological evaluation and mechanistic studies of this new class of marine-derived anticancer agents.
{"title":"Isolation and First Total Synthesis of PM100618 and PM110049, Two Structurally Distinct Marine-Derived Anticancer Oxazole Derivatives","authors":"María Jesús Martín,Rogelio Fernández,Carmen Murcia,Laura Coello,Gloria Crespo,Andrés Francesch,Simon Munt,Carmen Cuevas","doi":"10.1021/acs.joc.5c03118","DOIUrl":"https://doi.org/10.1021/acs.joc.5c03118","url":null,"abstract":"We report the discovery, structural elucidation, and first total synthesis of two unprecedented marine oxazole derivatives, PM100618 and PM110049, isolated from the Papua New Guinean sponge Rhabdastrella rowi. Both compounds exhibit potent in vitro cytotoxic activity at nanomolar concentrations. A highly convergent and efficient total synthesis of PM100618 and PM110049 was achieved in 22 and 21 steps, respectively (longest linear sequence: 15 steps) through the coupling of two complex fragments. This synthetic route provides ready access to these scarce natural products, enabling advanced pharmacological evaluation and mechanistic studies of this new class of marine-derived anticancer agents.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"20 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147506229","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aliphatic ketones, esters, and acids are fundamental chemical raw materials in organic synthesis. The direct site-selective functionalization of such chemicals is attractive but challenging. Herein, we report a free-radical-promoted β-C-H dehydrogenative coupling reaction of simple aliphatic ketones, esters, and acids with quinones. This protocol provides a new method for the β-C-H functionalization of simple aliphatic carbonyl compounds without the assistance of exogenous directing groups and transition metals, which is different from those observed in traditional methods. In addition, the reaction realizes the challenging β-C-C bond formation of aliphatic ketones, esters, and acids, offering a promising strategy for selective alkylation of quinones.
{"title":"Free-Radical-Promoted β-C-H Functionalization of Simple Aliphatic Ketones, Esters, and Acids with Quinones.","authors":"Jiaran Cao,Ziyu Wang,Jiawang Li,Chuan Yan,Meng Wang,Wenlong Sun,Lizhi Zhang,Zhengbao Xu","doi":"10.1021/acs.joc.5c03182","DOIUrl":"https://doi.org/10.1021/acs.joc.5c03182","url":null,"abstract":"Aliphatic ketones, esters, and acids are fundamental chemical raw materials in organic synthesis. The direct site-selective functionalization of such chemicals is attractive but challenging. Herein, we report a free-radical-promoted β-C-H dehydrogenative coupling reaction of simple aliphatic ketones, esters, and acids with quinones. This protocol provides a new method for the β-C-H functionalization of simple aliphatic carbonyl compounds without the assistance of exogenous directing groups and transition metals, which is different from those observed in traditional methods. In addition, the reaction realizes the challenging β-C-C bond formation of aliphatic ketones, esters, and acids, offering a promising strategy for selective alkylation of quinones.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"35 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Skyler Oneida, Robert Hubbard, Adrienne Shea, Lydia K. Dresler, Matthew T. Bernards, Kristopher V. Waynant
Zwitterionic cross-linkers, when integrated into polyampholytes, create continuous networks of charge density that enhance nonfouling performance via tightly bound ionic solvation layers─outperforming their uncharged counterparts regarding biocompatibility while retaining tunable physical characteristics. Despite their potential in biomedical and environmental applications, zwitterionic cross-linkers remain underexplored. Given that amino acids exhibit intrinsic zwitterionic behavior at physiological pH, peptide-based cross-linkers present a compelling avenue for innovation. In this work, we report the multigram-scale synthesis of serine–serine dimethacrylate (Ser-Ser), an emerging dipeptide-based zwitterionic cross-linker. Multiple synthetic strategies were evaluated, ultimately converging on a streamlined six-step route requiring only three chromatographic purifications. This scalable and efficient synthesis paves the way for a broader investigation and application of peptide-derived zwitterionic cross-linkers in the design of advanced, biocompatible polymeric materials.
{"title":"Optimization and Scale-up of a Peptide-Based Ser-Ser Dimethacrylate Zwitterionic Cross-Linker for Nonfouling Polyampholytes","authors":"Skyler Oneida, Robert Hubbard, Adrienne Shea, Lydia K. Dresler, Matthew T. Bernards, Kristopher V. Waynant","doi":"10.1021/acs.joc.5c02546","DOIUrl":"https://doi.org/10.1021/acs.joc.5c02546","url":null,"abstract":"Zwitterionic cross-linkers, when integrated into polyampholytes, create continuous networks of charge density that enhance nonfouling performance via tightly bound ionic solvation layers─outperforming their uncharged counterparts regarding biocompatibility while retaining tunable physical characteristics. Despite their potential in biomedical and environmental applications, zwitterionic cross-linkers remain underexplored. Given that amino acids exhibit intrinsic zwitterionic behavior at physiological pH, peptide-based cross-linkers present a compelling avenue for innovation. In this work, we report the multigram-scale synthesis of serine–serine dimethacrylate (Ser-Ser), an emerging dipeptide-based zwitterionic cross-linker. Multiple synthetic strategies were evaluated, ultimately converging on a streamlined six-step route requiring only three chromatographic purifications. This scalable and efficient synthesis paves the way for a broader investigation and application of peptide-derived zwitterionic cross-linkers in the design of advanced, biocompatible polymeric materials.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"1 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147496252","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A calcium-catalyzed approach to accessing α-functionalized amines via deacetylation has been developed. Using Ca(NTf2)2/nBuNPF6 as a mild Lewis acid system, a range of α-acetoxy substrates undergo smooth deacetylation and functionalization. The reaction displays excellent substrate tolerance and accommodates diverse nucleophiles, including sulfur, indole, amide, and cyanide derivatives. Furthermore, telescoped deprotection-reprotection protocols enable facile access to a variety of N-protected amines in high yields, providing a simple and practical route to valuable α-functionalized amine scaffolds.
{"title":"Access to α-Functionalized Amines via Calcium-Catalyzed Deacetylations.","authors":"Michael P Cameron,Mark G McLaughlin","doi":"10.1021/acs.joc.5c03185","DOIUrl":"https://doi.org/10.1021/acs.joc.5c03185","url":null,"abstract":"A calcium-catalyzed approach to accessing α-functionalized amines via deacetylation has been developed. Using Ca(NTf2)2/nBuNPF6 as a mild Lewis acid system, a range of α-acetoxy substrates undergo smooth deacetylation and functionalization. The reaction displays excellent substrate tolerance and accommodates diverse nucleophiles, including sulfur, indole, amide, and cyanide derivatives. Furthermore, telescoped deprotection-reprotection protocols enable facile access to a variety of N-protected amines in high yields, providing a simple and practical route to valuable α-functionalized amine scaffolds.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"270 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Huijin Guo, Ji Wu, Ke Cao, Chunguang Zhu, Quanli Zhang, Qiuxia Peng, Zejun Pu, Jiachun Zhong
The innovation of synthetic strategies for incorporating heterocycles into carborane is a significant objective in the realm of carborane chemistry on account of the fact that heterocyclic skeletons are widespread among natural products as well as bioactive molecules and the versatility applications of carboranes in medicinal chemistry and materials science. This method disclosed a facile and practical protocol for the synthesis of 1-benzothiazolyl-o-carboranes through an iodosobenzene-mediated intramolecular oxidative annulation process of C(1)-N-arylthioaacylamino-o-carborane. A series of 1-benzothiazolyl-o-carboranes have been synthesized in good to excellent yields. This work would be an important reference for the synthesis of aromatic heterocycle-carborane derivatives and promote their applications in designing drug candidates and functional materials.
由于杂环骨架在天然产物和生物活性分子中广泛存在，以及杂环烷在药物化学和材料科学中的广泛应用，杂环烷合成策略的创新是碳硼烷化学领域的一个重要目标。本方法通过碘苯介导的C(1)- n -芳基硫酰基氨基-o-碳硼烷分子内氧化环化反应，公开了一种简便实用的合成1-苯并噻唑基-o-碳硼烷的方案。以优异的收率合成了一系列1-苯并噻唑基-邻碳硼烷。本研究为芳香族杂环碳硼烷衍生物的合成提供了重要参考，并促进其在候选药物和功能材料设计中的应用。
{"title":"Iodosobenzene-Mediated Synthesis of 1-Benzothiazolyl-<i>o</i>-Carboranes.","authors":"Huijin Guo, Ji Wu, Ke Cao, Chunguang Zhu, Quanli Zhang, Qiuxia Peng, Zejun Pu, Jiachun Zhong","doi":"10.1021/acs.joc.5c03227","DOIUrl":"https://doi.org/10.1021/acs.joc.5c03227","url":null,"abstract":"<p><p>The innovation of synthetic strategies for incorporating heterocycles into carborane is a significant objective in the realm of carborane chemistry on account of the fact that heterocyclic skeletons are widespread among natural products as well as bioactive molecules and the versatility applications of carboranes in medicinal chemistry and materials science. This method disclosed a facile and practical protocol for the synthesis of 1-benzothiazolyl-<i>o</i>-carboranes through an iodosobenzene-mediated intramolecular oxidative annulation process of C(1)-<i>N</i>-arylthioaacylamino-<i>o</i>-carborane. A series of 1-benzothiazolyl-<i>o</i>-carboranes have been synthesized in good to excellent yields. This work would be an important reference for the synthesis of aromatic heterocycle-carborane derivatives and promote their applications in designing drug candidates and functional materials.</p>","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
An efficient catalyst- and base-free, three-component tandem annulation has been developed for the synthesis of pyrido[4,3-d]pyrimidine-2,4-diones. This strategy employs readily available 5-carbonyl-6-methyluracils, aldehydes, and ammonium iodide under an oxygen atmosphere, affording the target products in good to excellent yields with broad substrate compatibility. The transformation is proposed to proceed via a condensation/cyclization/oxidative dehydrogenation cascade. This method offers notable advantages, such as operational simplicity and environmental benignity, thereby presenting a practical alternative route for the construction of pyrido[4,3-d]pyrimidine-2,4-diones.
{"title":"Three-Component Tandem Annulation for the Synthesis of Pyrido[4,3-d]pyrimidine-2,4-diones.","authors":"Jinjin Chen,Jiaoling Li,Yiming Lei,Kang Liu,Sichen Xu,Tong Chen,Yao-Fu Zeng,Xue Peng,Xinping Liu,Zhen Wang","doi":"10.1021/acs.joc.5c03158","DOIUrl":"https://doi.org/10.1021/acs.joc.5c03158","url":null,"abstract":"An efficient catalyst- and base-free, three-component tandem annulation has been developed for the synthesis of pyrido[4,3-d]pyrimidine-2,4-diones. This strategy employs readily available 5-carbonyl-6-methyluracils, aldehydes, and ammonium iodide under an oxygen atmosphere, affording the target products in good to excellent yields with broad substrate compatibility. The transformation is proposed to proceed via a condensation/cyclization/oxidative dehydrogenation cascade. This method offers notable advantages, such as operational simplicity and environmental benignity, thereby presenting a practical alternative route for the construction of pyrido[4,3-d]pyrimidine-2,4-diones.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"16 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502437","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The commercially available 3d metal salt chromium(III) chloride (0.4 mol %) has demonstrated significant catalytic activity toward the highly selective α-alkylation of benzyl nitriles with benzyl alcohols in the presence of KOtBu (30 mol %) at 140 °C under conventional (99% yield, 24 h) as well as microwave (93% yield, 2 h) heating conditions. The methodology was well scrutinized for a large variation of substrates, which rendered moderate to good yields (up to 98%) with high selectivity. The experiment with elemental mercury suggests the involvement of molecular catalytic species in the reaction. The reaction exhibits a first-order rate dependence relative to the concentration of CrCl3·6H2O, KOtBu, and benzyl alcohol. However, in the case of benzyl nitrile, a linear dependence of the rate was observed only at low concentrations. This suggests the possibility of β-hydride elimination from Cr-benzyloxide as the rate-determining step of the catalytic cycle, with benzyl nitrile inhibiting the transition state. Not surprisingly, in instances where low α-alkylation activity was observed, the yields could be improved by the sequential addition of small portions of benzyl nitrile. Eyring plot analysis using the Arrhenius equation revealed the reaction to have an overall free energy barrier of about 28.6 kcal/mol.
{"title":"α-Alkylation of Nitriles with Alcohols in Air Catalyzed by Chromium Chloride under Microwave Irradiation and Ligand-Free Conditions.","authors":"Himani Narjinari,Akshai Kumar","doi":"10.1021/acs.joc.5c03097","DOIUrl":"https://doi.org/10.1021/acs.joc.5c03097","url":null,"abstract":"The commercially available 3d metal salt chromium(III) chloride (0.4 mol %) has demonstrated significant catalytic activity toward the highly selective α-alkylation of benzyl nitriles with benzyl alcohols in the presence of KOtBu (30 mol %) at 140 °C under conventional (99% yield, 24 h) as well as microwave (93% yield, 2 h) heating conditions. The methodology was well scrutinized for a large variation of substrates, which rendered moderate to good yields (up to 98%) with high selectivity. The experiment with elemental mercury suggests the involvement of molecular catalytic species in the reaction. The reaction exhibits a first-order rate dependence relative to the concentration of CrCl3·6H2O, KOtBu, and benzyl alcohol. However, in the case of benzyl nitrile, a linear dependence of the rate was observed only at low concentrations. This suggests the possibility of β-hydride elimination from Cr-benzyloxide as the rate-determining step of the catalytic cycle, with benzyl nitrile inhibiting the transition state. Not surprisingly, in instances where low α-alkylation activity was observed, the yields could be improved by the sequential addition of small portions of benzyl nitrile. Eyring plot analysis using the Arrhenius equation revealed the reaction to have an overall free energy barrier of about 28.6 kcal/mol.","PeriodicalId":57,"journal":{"name":"Journal of Organic Chemistry","volume":"9 1","pages":""},"PeriodicalIF":4.354,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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