Prof. Dr. Paul Knochel
Academic Research Focus
- Main-group reagents
- Transition element reagents
- Asymmetric Synthesis
- Transition metal catalysis
- Oxidative cross-coupling
- Transition element reagents
- Asymmetric Synthesis
- Transition metal catalysis
- Oxidative cross-coupling
Fields of Application
Publications
8.
B Wei, Y-H Chen, P Knochel
Recent Advances in Halogen–Metal Exchange Reactions Journal Article
In: Accounts of Chemical Research, vol. 57, no. 14, pp. 1951-1963, 2024, ISSN: 0001-4842.
@article{nokey,
title = {Recent Advances in Halogen\textendashMetal Exchange Reactions},
author = {B Wei and Y-H Chen and P Knochel},
url = {https://doi.org/10.1021/acs.accounts.4c00242},
doi = {10.1021/acs.accounts.4c00242},
issn = {0001-4842},
year = {2024},
date = {2024-07-16},
journal = {Accounts of Chemical Research},
volume = {57},
number = {14},
pages = {1951-1963},
abstract = {ConspectusThe halogen\textendashmetal exchange reaction is a very powerful method for preparing functionalized organometallic reagents in the fields of organic and organometallic chemistry. Since its inception, significant interest has been directed toward the on-demand development of new halogen\textendashmetal exchange reactions, primarily through the upgrading of exchange reagents. The enduring quest for optimal reactivity, superior functional group compatibility, and innovative synthetic applications of exchange reagents remains a fundamental objective. In the past several years, the emergence of some significant discoveries in halogen\textendashmetal exchange reactions has proclaimed a renaissance to this field. This Account outlines the latest advances within the domain contributed by the Knochel group, including the main points as follows.The stereoretentive I/Li exchange on stereodefined secondary alkyl iodides was developed for the synthesis of nonstabilized chiral secondary alkyllithium reagents. This provided a straightforward method to access chiral organolithium reagents, which can be trapped by various electrophiles or transmetalated with other metals such as copper, zinc, and magnesium, thus enabling the stereoselective synthesis of a series of functionalized compounds and natural products.Faster halogen\textendashmagnesium and halogen\textendashzinc exchanges in toluene were realized using a novel kind of exchange reagent complexed with lithium alkoxide. These highly efficient exchange reactions are much faster than traditional ones and performed in an industrially friendly solvent. These advantages are of great value in practical synthesis, paving the way for new developments in this evolving area.Halogen\textendashlanthanide exchanges and their novel applications in organic synthesis were established. These new exchanges introduced the lanthanide metals into halogen\textendashmetal exchange reactions for the first time, thereby opening new avenues in synthetic chemistry. Building on these achievements, a comparative analysis of the exchange reaction rates by kinetic study has quantified the relationship between the electronegativity of metals and the rates of halogen\textendashmetal exchanges.Br/Na exchange in continuous flow was achieved using a hexane-soluble exchange reagent, 2-ethylhexylsodium. This approach effectively circumvented the poor solubility of the organosodium reagent, which has proven to be of significant practical value and greatly enhanced the synthetic utility of the organosodium reagent in organic synthesis.These remarkable breakthroughs as mentioned above are fueled mainly by upgrading the exchange reagents, resulting in the development of new halogen\textendashmetal exchange reactions and innovative applications in organic synthesis. Given the importance of halogen\textendashmetal exchanges in synthetic chemistry, the pursuit of other types of exchange reactions, particularly those involving new metals, will be in continuous demand. This Account provides a timely summary of recent progress and will undoubtedly inspire further advances to drive this research field forward.},
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pubstate = {published},
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ConspectusThe halogen–metal exchange reaction is a very powerful method for preparing functionalized organometallic reagents in the fields of organic and organometallic chemistry. Since its inception, significant interest has been directed toward the on-demand development of new halogen–metal exchange reactions, primarily through the upgrading of exchange reagents. The enduring quest for optimal reactivity, superior functional group compatibility, and innovative synthetic applications of exchange reagents remains a fundamental objective. In the past several years, the emergence of some significant discoveries in halogen–metal exchange reactions has proclaimed a renaissance to this field. This Account outlines the latest advances within the domain contributed by the Knochel group, including the main points as follows.The stereoretentive I/Li exchange on stereodefined secondary alkyl iodides was developed for the synthesis of nonstabilized chiral secondary alkyllithium reagents. This provided a straightforward method to access chiral organolithium reagents, which can be trapped by various electrophiles or transmetalated with other metals such as copper, zinc, and magnesium, thus enabling the stereoselective synthesis of a series of functionalized compounds and natural products.Faster halogen–magnesium and halogen–zinc exchanges in toluene were realized using a novel kind of exchange reagent complexed with lithium alkoxide. These highly efficient exchange reactions are much faster than traditional ones and performed in an industrially friendly solvent. These advantages are of great value in practical synthesis, paving the way for new developments in this evolving area.Halogen–lanthanide exchanges and their novel applications in organic synthesis were established. These new exchanges introduced the lanthanide metals into halogen–metal exchange reactions for the first time, thereby opening new avenues in synthetic chemistry. Building on these achievements, a comparative analysis of the exchange reaction rates by kinetic study has quantified the relationship between the electronegativity of metals and the rates of halogen–metal exchanges.Br/Na exchange in continuous flow was achieved using a hexane-soluble exchange reagent, 2-ethylhexylsodium. This approach effectively circumvented the poor solubility of the organosodium reagent, which has proven to be of significant practical value and greatly enhanced the synthetic utility of the organosodium reagent in organic synthesis.These remarkable breakthroughs as mentioned above are fueled mainly by upgrading the exchange reagents, resulting in the development of new halogen–metal exchange reactions and innovative applications in organic synthesis. Given the importance of halogen–metal exchanges in synthetic chemistry, the pursuit of other types of exchange reactions, particularly those involving new metals, will be in continuous demand. This Account provides a timely summary of recent progress and will undoubtedly inspire further advances to drive this research field forward.
7.
K Schwärzer, S K Rout, D Bessinger, F Lima, C E Brocklehurst, K Karaghiosoff, T Bein, P Knochel
In: Chemical Science, vol. 12, no. 39, pp. 12993-13000, 2021, ISSN: 2041-6520.
@article{nokey,
title = {Selective functionalization of the 1H-imidazo[1,2-b]pyrazole scaffold. A new potential non-classical isostere of indole and a precursor of push\textendashpull dyes},
author = {K Schw\"{a}rzer and S K Rout and D Bessinger and F Lima and C E Brocklehurst and K Karaghiosoff and T Bein and P Knochel},
url = {http://dx.doi.org/10.1039/D1SC04155J},
doi = {10.1039/D1SC04155J},
issn = {2041-6520},
year = {2021},
date = {2021-08-30},
urldate = {2021-08-30},
journal = {Chemical Science},
volume = {12},
number = {39},
pages = {12993-13000},
abstract = {We report the selective functionalization of the 1H-imidazo[1,2-b]pyrazole scaffold using a Br/Mg-exchange, as well as regioselective magnesiations and zincations with TMP-bases (TMP = 2,2,6,6-tetramethylpiperidyl), followed by trapping reactions with various electrophiles. In addition, we report a fragmentation of the pyrazole ring, giving access to push\textendashpull dyes with a proaromatic (1,3-dihydro-2H-imidazol-2-ylidene)malononitrile core. These functionalization methods were used in the synthesis of an isostere of the indolyl drug pruvanserin. Comparative assays between the original drug and the isostere showed that a substitution of the indole ring with a 1H-imidazo[1,2-b]pyrazole results in a significantly improved solubility in aqueous media.},
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We report the selective functionalization of the 1H-imidazo[1,2-b]pyrazole scaffold using a Br/Mg-exchange, as well as regioselective magnesiations and zincations with TMP-bases (TMP = 2,2,6,6-tetramethylpiperidyl), followed by trapping reactions with various electrophiles. In addition, we report a fragmentation of the pyrazole ring, giving access to push–pull dyes with a proaromatic (1,3-dihydro-2H-imidazol-2-ylidene)malononitrile core. These functionalization methods were used in the synthesis of an isostere of the indolyl drug pruvanserin. Comparative assays between the original drug and the isostere showed that a substitution of the indole ring with a 1H-imidazo[1,2-b]pyrazole results in a significantly improved solubility in aqueous media.
6.
B Wei, P Knochel
Recent Advances in Cross-Couplings of Functionalized Organozinc Reagents Journal Article
In: Synthesis, vol. 54, no. 02, pp. 246-254, 2021, ISSN: 0039-7881 DOI - 10.1055/a-1589-0150.
@article{nokey,
title = {Recent Advances in Cross-Couplings of Functionalized Organozinc Reagents},
author = {B Wei and P Knochel},
url = {https://www.thieme-connect.com/products/ejournals/abstract/10.1055/a-1589-0150},
doi = {10.1055/a-1589-0150},
issn = {0039-7881 DOI - 10.1055/a-1589-0150},
year = {2021},
date = {2021-08-16},
journal = {Synthesis},
volume = {54},
number = {02},
pages = {246-254},
abstract = {Cross-couplings involving organozinc reagents usually require a Pd-catalyst (Negishi cross-coupling), however, uncatalyzed cross-couplings of zinc organometallics proceed well in the absence of transition-metal catalysts with reactive electrophiles such as benzal 1,1-diacetates, benzhydryl acetates, and iminium trifluoroacetates. Organozinc compounds also undergo C\textendashN bond formation with O-benzoylhydroxylamines or organic azides in the presence of cobalt- or iron-catalysts. Highly diastereoselective and enantioselective cross-couplings can be readily performed with room-temperature configurationally stable alkylzinc species, producing diastereoselectively and enantiomerically enriched products. Finally, highly regioselective magnesiations of functionalized arenes and heteroarenes undergo Negishi (after transmetalation with ZnCl2) or Cu-catalyzed cross-couplings.},
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pubstate = {published},
tppubtype = {article}
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Cross-couplings involving organozinc reagents usually require a Pd-catalyst (Negishi cross-coupling), however, uncatalyzed cross-couplings of zinc organometallics proceed well in the absence of transition-metal catalysts with reactive electrophiles such as benzal 1,1-diacetates, benzhydryl acetates, and iminium trifluoroacetates. Organozinc compounds also undergo C–N bond formation with O-benzoylhydroxylamines or organic azides in the presence of cobalt- or iron-catalysts. Highly diastereoselective and enantioselective cross-couplings can be readily performed with room-temperature configurationally stable alkylzinc species, producing diastereoselectively and enantiomerically enriched products. Finally, highly regioselective magnesiations of functionalized arenes and heteroarenes undergo Negishi (after transmetalation with ZnCl2) or Cu-catalyzed cross-couplings.
5.
B Wei, Q Ren, T Bein, P Knochel
In: Angewandte Chemie International Edition, vol. 60, no. 18, pp. 10409-10414, 2021, ISSN: 1433-7851.
@article{nokey,
title = {Transition-Metal-Free Synthesis of Polyfunctional Triarylmethanes and 1,1-Diarylalkanes by Sequential Cross-Coupling of Benzal Diacetates with Organozinc Reagents},
author = {B Wei and Q Ren and T Bein and P Knochel},
url = {https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.202101682},
doi = {https://doi.org/10.1002/anie.202101682},
issn = {1433-7851},
year = {2021},
date = {2021-02-24},
journal = {Angewandte Chemie International Edition},
volume = {60},
number = {18},
pages = {10409-10414},
abstract = {Abstract A variety of functionalized triarylmethane and 1,1-diarylalkane derivatives were prepared via a transition-metal-free, one-pot and two-step procedure, involving the reaction of various benzal diacetates with organozinc reagents. A sequential cross-coupling is enabled by changing the solvent from THF to toluene, and a two-step SN1-type mechanism was proposed and evidenced by experimental studies. The synthetic utility of the method is further demonstrated by the synthesis of several biologically relevant molecules, such as an anti-tuberculosis agent, an anti-breast cancer agent, a precursor of a sphingosine-1-phosphate (S1P) receptor modulator, and a FLAP inhibitor.},
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Abstract A variety of functionalized triarylmethane and 1,1-diarylalkane derivatives were prepared via a transition-metal-free, one-pot and two-step procedure, involving the reaction of various benzal diacetates with organozinc reagents. A sequential cross-coupling is enabled by changing the solvent from THF to toluene, and a two-step SN1-type mechanism was proposed and evidenced by experimental studies. The synthetic utility of the method is further demonstrated by the synthesis of several biologically relevant molecules, such as an anti-tuberculosis agent, an anti-breast cancer agent, a precursor of a sphingosine-1-phosphate (S1P) receptor modulator, and a FLAP inhibitor.
4.
J Skotnitzki, A Kremsmair, D Keefer, F Schuppel, B L De Bonneville, R De Vivie-Riedle, P Knochel
Regio- and diastereoselective reactions of chiral secondary alkylcopper reagents with propargylic phosphates: preparation of chiral allenes Journal Article
In: Chemical Science, vol. 11, no. 20, pp. 5328-5332, 2020, ISSN: 2041-6520.
@article{,
title = {Regio- and diastereoselective reactions of chiral secondary alkylcopper reagents with propargylic phosphates: preparation of chiral allenes},
author = {J Skotnitzki and A Kremsmair and D Keefer and F Schuppel and B L De Bonneville and R De Vivie-Riedle and P Knochel},
url = {\<Go to ISI\>://WOS:000537133000020},
doi = {10.1039/c9sc05982b},
issn = {2041-6520},
year = {2020},
date = {2020-05-28},
journal = {Chemical Science},
volume = {11},
number = {20},
pages = {5328-5332},
abstract = {The diastereoselective S(N)2 '-substitution of secondary alkylcopper reagents with propargylic phosphates enables the preparation of stereodefined alkylallenes. By using enantiomerically enriched alkylcopper reagents and enantioenriched propargylic phosphates as electrophiles anti-S(N)2 '-substitutions were performend leading to alpha-chiral allenes in good yields with excellent regioselectivity and retention of configuration. DFT-calculations were performed to rationalize the structure of these alkylcopper reagents in various solvents, emphasizing their configurational stability in THF.},
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pubstate = {published},
tppubtype = {article}
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The diastereoselective S(N)2 '-substitution of secondary alkylcopper reagents with propargylic phosphates enables the preparation of stereodefined alkylallenes. By using enantiomerically enriched alkylcopper reagents and enantioenriched propargylic phosphates as electrophiles anti-S(N)2 '-substitutions were performend leading to alpha-chiral allenes in good yields with excellent regioselectivity and retention of configuration. DFT-calculations were performed to rationalize the structure of these alkylcopper reagents in various solvents, emphasizing their configurational stability in THF.
3.
J Skotnitzki, A Kremsmair, B Kicin, R Saeb, V Ruf, P Knochel
In: Synthesis-Stuttgart, vol. 52, no. 6, pp. 873-881, 2020, ISSN: 0039-7881.
@article{,
title = {Stereoselective anti-S(N)2 '-Substitutions of Secondary Alkylcopper-Zinc Reagents with Allylic Epoxides: Total Synthesis of (3S,6R,7S)-Zingiberenol},
author = {J Skotnitzki and A Kremsmair and B Kicin and R Saeb and V Ruf and P Knochel},
url = {\<Go to ISI\>://WOS:000519236300009},
doi = {10.1055/s-0039-1690766},
issn = {0039-7881},
year = {2020},
date = {2020-03-17},
journal = {Synthesis-Stuttgart},
volume = {52},
number = {6},
pages = {873-881},
abstract = {Chiral secondary mixed alkylcopper-zinc reagents were prepared from the corresponding alkyl iodides and reacted with allylic epoxides via an anti -S (N) 2 '-substitution and retention of configuration of the chiral alkylorganometallic, leading to chiral allylic alcohols. This method was used in a total synthesis of the natural product (3 S ,6 R ,7 S )-zingiberenol in 8 steps and 9.7% overall yield [dr (3 S ,6 R ) = 99:1; dr (6 R ,7 S ) = 81:19] starting from commercially available 3-methyl-2-cyclohexenone.},
keywords = {},
pubstate = {published},
tppubtype = {article}
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Chiral secondary mixed alkylcopper-zinc reagents were prepared from the corresponding alkyl iodides and reacted with allylic epoxides via an anti -S (N) 2 '-substitution and retention of configuration of the chiral alkylorganometallic, leading to chiral allylic alcohols. This method was used in a total synthesis of the natural product (3 S ,6 R ,7 S )-zingiberenol in 8 steps and 9.7% overall yield [dr (3 S ,6 R ) = 99:1; dr (6 R ,7 S ) = 81:19] starting from commercially available 3-methyl-2-cyclohexenone.
2.
B S Wei, D C Zhang, Y H Chen, A W Lei, P Knochel
Preparation of Polyfunctional Biaryl Derivatives by Cyclolanthanation of 2-Bromobiaryls and Heterocyclic Analogues Using nBu(2)LaCl.4 LiCl Journal Article
In: Angewandte Chemie-International Edition, vol. 58, no. 44, pp. 15631-15635, 2019, ISSN: 1433-7851.
@article{,
title = {Preparation of Polyfunctional Biaryl Derivatives by Cyclolanthanation of 2-Bromobiaryls and Heterocyclic Analogues Using nBu(2)LaCl.4 LiCl},
author = {B S Wei and D C Zhang and Y H Chen and A W Lei and P Knochel},
url = {\<Go to ISI\>://WOS:000487102700001},
doi = {10.1002/anie.201908046},
issn = {1433-7851},
year = {2019},
date = {2019-08-28},
journal = {Angewandte Chemie-International Edition},
volume = {58},
number = {44},
pages = {15631-15635},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
1.
J Li, E Tan, N Keller, Y-H Chen, P M Zehetmaier, A C Jakowetz, T Bein, P Knochel
Cobalt-Catalyzed Electrophilic Aminations with Anthranils: An Expedient Route to Condensed Quinolines Journal Article
In: Journal of the American Chemical Society, vol. 141, no. 1, pp. 98-103, 2019, ISSN: 0002-7863.
@article{,
title = {Cobalt-Catalyzed Electrophilic Aminations with Anthranils: An Expedient Route to Condensed Quinolines},
author = {J Li and E Tan and N Keller and Y-H Chen and P M Zehetmaier and A C Jakowetz and T Bein and P Knochel},
url = {https://doi.org/10.1021/jacs.8b11466},
doi = {10.1021/jacs.8b11466},
issn = {0002-7863},
year = {2019},
date = {2019-01-09},
journal = {Journal of the American Chemical Society},
volume = {141},
number = {1},
pages = {98-103},
abstract = {The reaction of various organozinc pivalates with anthranils provides anilines derivatives, which cyclize under acidic conditions providing condensed quinolines. Using alkenylzinc pivalates, electron-rich arylzinc pivalates or heterocyclic zinc pivalates produces directly the condensed quinolines of which several structures belong to new heterocyclic scaffolds. These N-heterocycles are of particular interest for organic light emitting diodes with their high photoluminescence quantum yields and long exciton lifetimes as well as for hole-transporting materials in methylammonium lead iodide perovskites solar cells due to an optimal band alignment for holes and a large bandgap.},
keywords = {},
pubstate = {published},
tppubtype = {article}
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The reaction of various organozinc pivalates with anthranils provides anilines derivatives, which cyclize under acidic conditions providing condensed quinolines. Using alkenylzinc pivalates, electron-rich arylzinc pivalates or heterocyclic zinc pivalates produces directly the condensed quinolines of which several structures belong to new heterocyclic scaffolds. These N-heterocycles are of particular interest for organic light emitting diodes with their high photoluminescence quantum yields and long exciton lifetimes as well as for hole-transporting materials in methylammonium lead iodide perovskites solar cells due to an optimal band alignment for holes and a large bandgap.