Background: 

Small cyclic frameworks such as cyclobutane and cyclopentane exhibit excellent performance in biological metabolic processes due to their rigidity, so they are widely used by medicinal chemists in the development of many drug candidates. The synthesis of these small cyclic scaffolds is also a subject of interest to chemists. In 2016 and 2017, Prof. Phil S. Baran’s group at The Scripps Research Institute and chemists at Pfizer reported the reactions of strain-release amination and heteroatoms (N, O, S) functionalization facilitated by an external stoichiometric base or additive.^1,2 In following years, strain-release strategies have been dramatically developed to construct a diverse set of small cyclic frameworks holding potential values in new drug discovery. For instance, a systemic work of Lewis acids or metals catalyzed strain-release reactions has been disclosed by Prof. Jianjun Chen’s group at Hunan University.  In 2025, Dr. Lin Huang’s group at Zhejiang Jiuzhou Pharmacetical Co. Ltd. and prof. Peng Yu’s group at Eastern Institute of Technology reported a general approach for strained ring functionalization, catalyzed by DMAP, for diastereocontrolled synthesis of substituted cyclobutanes and cyclopentanes in Journal of American Chemical Society Au.³ 

Text: 

In 2026, Dr. Lin Huang’s group at Zhejiang Jiuzhou Pharmacetical Co. Ltd. and Prof. Peng Yu’s group at Eastern Institute of Technology published a paper of phosphine-catalyzed strain-release alkynylation of bicyclo [1.1.0] butanes in Advanced Synthesis & Catalysis.

In this report, a nucleophilic phosphine catalyst enables the direct addition of a broad range of terminal alkynes to bicyclo[1.1.0]butanes (BCBs) under mild and solvent-free conditions has been disclosed. This phosphine catalyzed strategy is an analog of DMAP catalysis, but it shows an addition of weak nucleophiles of terminal alkynes toward bicyclo[1.1.0]butanes (BCBs), which showed no reaction in DMAP catalysis. Additionally, this achievement also highlights our design of strain-release reaction by nucleophilic catalyst.  

Inspired by previous research, a novel strain-release reaction has been proposed, enabled by the use of a phosphine catalyst. Optimizations for the model reaction were conducted, including the scouting of phosphine catalysts, solvents, and reaction temperatures. The optimal reaction condition was ascertained to be 10 mol% of P(N-Et₂)₃, at a temperature of 50°C, in a solvent-free state, and with a reaction time of 1 hour. Consequently, the target product was isolated in an 84% yield with a value of 1.5 dr. Despite the high efficiency achieved after careful optimization, the diastereoselectivity remained, unfortunately, unsatisfactory at the current stage. Due to the weak nucleophilicity of terminal alkynes, showing challenges for addition reaction with bicyclo[1.1.0]butanes (BCBs), the result of the model reaction is acceptable in synthetic chemistry. 

Next, the reaction scope for this phosphine-catalyzed alkynylation of BCBs has been investigated. Initially, alkynes were evaluated, and indicated that regardless of their electronic properties or substitution patterns (ortho, meta, or para), including chloro, bromo, iodo, fluoro, and trifluoromethyl groups were well tolerated in the reaction. Then, aryl alkynes bearing multiple substituents, such as 3,5-dimethoxy or -difluoro aryl alkyne, and other aromatic alkynes, such as naphthyl-, thiophenyl-, and ferrocenyl-substituted alkynes, also exhibited high reactivity and afforded the corresponding products in moderate to high yields. Although aliphatic alkynes were also reactive, an elevated temperature was required, and the desired products were obtained in comparatively lower yields, less than 40% yields. Furthermore, the generality of this transformation with respect to the BCB substrate was also evaluated. BCBs bearing various substituents on the phenyl ring of the sulfonyl group, including both electron-donating and electron-withdrawing substituents, underwent alkynylation smoothly under the standard conditions, affording the corresponding products in moderate to high yields. In addition, a tertbutylsulfonyl-substituted BCB also exhibited high reactivity, delivering the desired product in 65% yield (46). Notably, this BCB alkynylation was successfully applied to the late-stage modification of several drug derivatives, including Geraniol (47), L-Menthol (48), L-Perillyl alcohol (49), L-Borneol (50), and (-)-Nopol (51), highlighting its potential utility in medicinal chemistry and further demonstrating the broad applicability of this BCB alkynylation reaction.

To demonstrate the practical utility of the protocol, a gram-scale reaction with model substrates was carried out under standard reaction conditions, furnishing the corresponding product in 72% yield. Furthermore, the cyclobutylated alkyne could be readily derivatized into a range of structurally diverse compounds that are otherwise difficult to access, due to the versatility of both the alkyne and aryl sulfonyl group. For examples, the aryl sulfonyl group could be transformed into hydrogen (52), fluorine (54), or alkene (55) under established conditions. Additionally, simultaneous reduction of both the alkyne and sulfonyl moieties could be achieved in a single operation, delivering the corresponding alkylated butane in good yield (53). Collectively, these transformations underscore the broad downstream derivatization potential of the cyclobutylated alkynes and highlight the synthetic value of this BCB alkynylation reaction.

Mechanistic studies, including deuterium labelling reactions, kinetic experiments, Hammett analysis, and high-resolution mass spectrometry (HRMS) for the key design of a covalent intermediate have been performed in the previous report. Regarding the mechanism of this phosphine-catalyzed BCB alkynylation, it was hypothesized that a covalent intermediate, analogous to the previous report, could be generated by the reaction of the catalyst with the BCB substrate. This intermediate would play an essential role in promoting the reaction. A series of experiments have also been conducted, and these experimental results support the design and show further insights into the mechanism.

In conclusion, a catalytic alkynylation of bicyclo[1.1.0]butanes (BCBs) using a phosphine as the catalyst has been developed, without the need for external stoichiometric bases, and additives, and indicates a broad substrate scope and shows good functional tolerance. Although the facile scalability and derivatization of the corresponding cyclobutylated alkyne product demonstrate the synthetic value and practical utility of this protocol, the comparatively lower yields of products by uses of aliphatic alkynes as substrates have been obtained to show the substrate limit of this methodology. In contrast to aromatic alkyne, aliphatic alkyne generally exhibits a weaker acidity and a reduced affinity for bicyclo[1.1.0]butane (BCB). These properties could be responsible for the lower yields of products.  It should be noted that the P atom of the nucleophilic phosphine catalyst exhibits greater polarizability and displays more "softness" than the N atom of DMAP. This offers a range of opportunities for the modification of nucleophilic phosphine catalysts. For instance, there is the potential for the design of highly efficient phosphine catalysts or the chiral modification of phosphine catalysts to enhance the strain-release reaction activities or achieve the chiral strain-release reactions.

Reference 

1. Stain-Release Amination. Gianatassio, R.; Lopchuk, J. M.; Wang, J.; Pan, C.-M.; Malins, L. R.; Prieto, L.; Brandt, T. A.; Collins, M. R.; Gallego, G. M.; Sach, N. W.; Spangler, J. E.; Zhu, H.; Zhu, J.; and Baran, P. S. Science. 2016, 351, 241−246. 

2.  Strain-Release Heteroatom Functionalization: De-velopment, Scope, and Stereospecificity. Lopchuk, J. M.; Fjelbye, K.; Kawamata, Y.; Malins, L. R.; Pan,C.-M.; Gianatassio, R.; Wang, J.; Prieto, L.; Bradow, J.; Brandt, T. A.; Collins, M. R.; Elleraas, J.; Ewanicki, J.; Farrell, W.; Fadeyi, O. O.;Gallego, G. M.; Mousseau, J. J.; Oliver, R.; Sach, N. W.; Smith, J. K.; Spangler, J. E.; Zhu, H.; Zhu, J.; and Baran, P. S.  J. Am. Chem. Soc. 2017, 139, 3209−3226.

3. A general approach for strained ring functionalization via nucleophilic catalysis. Wang, P.^⊥; Deng, C.^⊥; Luo, Z.; Chen, D.; Li, Alex Y.; Li, Y. *; Huang, L. * and Yu, P. * JACS Au. 2025, 5, 5404-5413.

Background: 

Small cyclic frameworks such as cyclobutane and cyclopentane exhibit excellent performance in biological metabolic processes due to their rigidity, so they are widely used by medicinal chemists in the development of many drug candidates. The synthesis of these small cyclic scaffolds is also a subject of interest to chemists. In 2016 and 2017, Prof. Phil S. Baran’s group at The Scripps Research Institute and chemists at Pfizer reported the reactions of strain-release amination and heteroatoms (N, O, S) functionalization facilitated by an external stoichiometric base or additive.^1,2 In following years, strain-release strategies have been dramatically developed to construct a diverse set of small cyclic frameworks holding potential values in new drug discovery. For instance, a systemic work of Lewis acids or metals catalyzed strain-release reactions has been disclosed by Prof. Jianjun Chen’s group at Hunan University.  In 2025, Dr. Lin Huang’s group at Zhejiang Jiuzhou Pharmacetical Co. Ltd. and prof. Peng Yu’s group at Eastern Institute of Technology reported a general approach for strained ring functionalization, catalyzed by DMAP, for diastereocontrolled synthesis of substituted cyclobutanes and cyclopentanes in Journal of American Chemical Society Au.³ 

Text: 

In 2026, Dr. Lin Huang’s group at Zhejiang Jiuzhou Pharmacetical Co. Ltd. and Prof. Peng Yu’s group at Eastern Institute of Technology published a paper of phosphine-catalyzed strain-release alkynylation of bicyclo [1.1.0] butanes in Advanced Synthesis & Catalysis.

In this report, a nucleophilic phosphine catalyst enables the direct addition of a broad range of terminal alkynes to bicyclo[1.1.0]butanes (BCBs) under mild and solvent-free conditions has been disclosed. This phosphine catalyzed strategy is an analog of DMAP catalysis, but it shows an addition of weak nucleophiles of terminal alkynes toward bicyclo[1.1.0]butanes (BCBs), which showed no reaction in DMAP catalysis. Additionally, this achievement also highlights our design of strain-release reaction by nucleophilic catalyst.  

Inspired by previous research, a novel strain-release reaction has been proposed, enabled by the use of a phosphine catalyst. Optimizations for the model reaction were conducted, including the scouting of phosphine catalysts, solvents, and reaction temperatures. The optimal reaction condition was ascertained to be 10 mol% of P(N-Et₂)₃, at a temperature of 50°C, in a solvent-free state, and with a reaction time of 1 hour. Consequently, the target product was isolated in an 84% yield with a value of 1.5 dr. Despite the high efficiency achieved after careful optimization, the diastereoselectivity remained, unfortunately, unsatisfactory at the current stage. Due to the weak nucleophilicity of terminal alkynes, showing challenges for addition reaction with bicyclo[1.1.0]butanes (BCBs), the result of the model reaction is acceptable in synthetic chemistry. 

Next, the reaction scope for this phosphine-catalyzed alkynylation of BCBs has been investigated. Initially, alkynes were evaluated, and indicated that regardless of their electronic properties or substitution patterns (ortho, meta, or para), including chloro, bromo, iodo, fluoro, and trifluoromethyl groups were well tolerated in the reaction. Then, aryl alkynes bearing multiple substituents, such as 3,5-dimethoxy or -difluoro aryl alkyne, and other aromatic alkynes, such as naphthyl-, thiophenyl-, and ferrocenyl-substituted alkynes, also exhibited high reactivity and afforded the corresponding products in moderate to high yields. Although aliphatic alkynes were also reactive, an elevated temperature was required, and the desired products were obtained in comparatively lower yields, less than 40% yields. Furthermore, the generality of this transformation with respect to the BCB substrate was also evaluated. BCBs bearing various substituents on the phenyl ring of the sulfonyl group, including both electron-donating and electron-withdrawing substituents, underwent alkynylation smoothly under the standard conditions, affording the corresponding products in moderate to high yields. In addition, a tertbutylsulfonyl-substituted BCB also exhibited high reactivity, delivering the desired product in 65% yield (46). Notably, this BCB alkynylation was successfully applied to the late-stage modification of several drug derivatives, including Geraniol (47), L-Menthol (48), L-Perillyl alcohol (49), L-Borneol (50), and (-)-Nopol (51), highlighting its potential utility in medicinal chemistry and further demonstrating the broad applicability of this BCB alkynylation reaction.

To demonstrate the practical utility of the protocol, a gram-scale reaction with model substrates was carried out under standard reaction conditions, furnishing the corresponding product in 72% yield. Furthermore, the cyclobutylated alkyne could be readily derivatized into a range of structurally diverse compounds that are otherwise difficult to access, due to the versatility of both the alkyne and aryl sulfonyl group. For examples, the aryl sulfonyl group could be transformed into hydrogen (52), fluorine (54), or alkene (55) under established conditions. Additionally, simultaneous reduction of both the alkyne and sulfonyl moieties could be achieved in a single operation, delivering the corresponding alkylated butane in good yield (53). Collectively, these transformations underscore the broad downstream derivatization potential of the cyclobutylated alkynes and highlight the synthetic value of this BCB alkynylation reaction.

Mechanistic studies, including deuterium labelling reactions, kinetic experiments, Hammett analysis, and high-resolution mass spectrometry (HRMS) for the key design of a covalent intermediate have been performed in the previous report. Regarding the mechanism of this phosphine-catalyzed BCB alkynylation, it was hypothesized that a covalent intermediate, analogous to the previous report, could be generated by the reaction of the catalyst with the BCB substrate. This intermediate would play an essential role in promoting the reaction. A series of experiments have also been conducted, and these experimental results support the design and show further insights into the mechanism.

In conclusion, a catalytic alkynylation of bicyclo[1.1.0]butanes (BCBs) using a phosphine as the catalyst has been developed, without the need for external stoichiometric bases, and additives, and indicates a broad substrate scope and shows good functional tolerance. Although the facile scalability and derivatization of the corresponding cyclobutylated alkyne product demonstrate the synthetic value and practical utility of this protocol, the comparatively lower yields of products by uses of aliphatic alkynes as substrates have been obtained to show the substrate limit of this methodology. In contrast to aromatic alkyne, aliphatic alkyne generally exhibits a weaker acidity and a reduced affinity for bicyclo[1.1.0]butane (BCB). These properties could be responsible for the lower yields of products.  It should be noted that the P atom of the nucleophilic phosphine catalyst exhibits greater polarizability and displays more "softness" than the N atom of DMAP. This offers a range of opportunities for the modification of nucleophilic phosphine catalysts. For instance, there is the potential for the design of highly efficient phosphine catalysts or the chiral modification of phosphine catalysts to enhance the strain-release reaction activities or achieve the chiral strain-release reactions.

Reference 

1. Stain-Release Amination. Gianatassio, R.; Lopchuk, J. M.; Wang, J.; Pan, C.-M.; Malins, L. R.; Prieto, L.; Brandt, T. A.; Collins, M. R.; Gallego, G. M.; Sach, N. W.; Spangler, J. E.; Zhu, H.; Zhu, J.; and Baran, P. S. Science. 2016, 351, 241−246. 

2.  Strain-Release Heteroatom Functionalization: De-velopment, Scope, and Stereospecificity. Lopchuk, J. M.; Fjelbye, K.; Kawamata, Y.; Malins, L. R.; Pan,C.-M.; Gianatassio, R.; Wang, J.; Prieto, L.; Bradow, J.; Brandt, T. A.; Collins, M. R.; Elleraas, J.; Ewanicki, J.; Farrell, W.; Fadeyi, O. O.;Gallego, G. M.; Mousseau, J. J.; Oliver, R.; Sach, N. W.; Smith, J. K.; Spangler, J. E.; Zhu, H.; Zhu, J.; and Baran, P. S.  J. Am. Chem. Soc. 2017, 139, 3209−3226.

3. A general approach for strained ring functionalization via nucleophilic catalysis. Wang, P.^⊥; Deng, C.^⊥; Luo, Z.; Chen, D.; Li, Alex Y.; Li, Y. *; Huang, L. * and Yu, P. * JACS Au. 2025, 5, 5404-5413.

Background: 

Small cyclic frameworks such as cyclobutane and cyclopentane exhibit excellent performance in biological metabolic processes due to their rigidity, so they are widely used by medicinal chemists in the development of many drug candidates. The synthesis of these small cyclic scaffolds is also a subject of interest to chemists. In 2016 and 2017, Prof. Phil S. Baran’s group at The Scripps Research Institute and chemists at Pfizer reported the reactions of strain-release amination and heteroatoms (N, O, S) functionalization facilitated by an external stoichiometric base or additive.^1,2 In following years, strain-release strategies have been dramatically developed to construct a diverse set of small cyclic frameworks holding potential values in new drug discovery. For instance, a systemic work of Lewis acids or metals catalyzed strain-release reactions has been disclosed by Prof. Jianjun Chen’s group at Hunan University.  In 2025, Dr. Lin Huang’s group at Zhejiang Jiuzhou Pharmacetical Co. Ltd. and prof. Peng Yu’s group at Eastern Institute of Technology reported a general approach for strained ring functionalization, catalyzed by DMAP, for diastereocontrolled synthesis of substituted cyclobutanes and cyclopentanes in Journal of American Chemical Society Au.³ 

Text: 

In 2026, Dr. Lin Huang’s group at Zhejiang Jiuzhou Pharmacetical Co. Ltd. and Prof. Peng Yu’s group at Eastern Institute of Technology published a paper of phosphine-catalyzed strain-release alkynylation of bicyclo [1.1.0] butanes in Advanced Synthesis & Catalysis.

In this report, a nucleophilic phosphine catalyst enables the direct addition of a broad range of terminal alkynes to bicyclo[1.1.0]butanes (BCBs) under mild and solvent-free conditions has been disclosed. This phosphine catalyzed strategy is an analog of DMAP catalysis, but it shows an addition of weak nucleophiles of terminal alkynes toward bicyclo[1.1.0]butanes (BCBs), which showed no reaction in DMAP catalysis. Additionally, this achievement also highlights our design of strain-release reaction by nucleophilic catalyst.  

Inspired by previous research, a novel strain-release reaction has been proposed, enabled by the use of a phosphine catalyst. Optimizations for the model reaction were conducted, including the scouting of phosphine catalysts, solvents, and reaction temperatures. The optimal reaction condition was ascertained to be 10 mol% of P(N-Et₂)₃, at a temperature of 50°C, in a solvent-free state, and with a reaction time of 1 hour. Consequently, the target product was isolated in an 84% yield with a value of 1.5 dr. Despite the high efficiency achieved after careful optimization, the diastereoselectivity remained, unfortunately, unsatisfactory at the current stage. Due to the weak nucleophilicity of terminal alkynes, showing challenges for addition reaction with bicyclo[1.1.0]butanes (BCBs), the result of the model reaction is acceptable in synthetic chemistry. 

Next, the reaction scope for this phosphine-catalyzed alkynylation of BCBs has been investigated. Initially, alkynes were evaluated, and indicated that regardless of their electronic properties or substitution patterns (ortho, meta, or para), including chloro, bromo, iodo, fluoro, and trifluoromethyl groups were well tolerated in the reaction. Then, aryl alkynes bearing multiple substituents, such as 3,5-dimethoxy or -difluoro aryl alkyne, and other aromatic alkynes, such as naphthyl-, thiophenyl-, and ferrocenyl-substituted alkynes, also exhibited high reactivity and afforded the corresponding products in moderate to high yields. Although aliphatic alkynes were also reactive, an elevated temperature was required, and the desired products were obtained in comparatively lower yields, less than 40% yields. Furthermore, the generality of this transformation with respect to the BCB substrate was also evaluated. BCBs bearing various substituents on the phenyl ring of the sulfonyl group, including both electron-donating and electron-withdrawing substituents, underwent alkynylation smoothly under the standard conditions, affording the corresponding products in moderate to high yields. In addition, a tertbutylsulfonyl-substituted BCB also exhibited high reactivity, delivering the desired product in 65% yield (46). Notably, this BCB alkynylation was successfully applied to the late-stage modification of several drug derivatives, including Geraniol (47), L-Menthol (48), L-Perillyl alcohol (49), L-Borneol (50), and (-)-Nopol (51), highlighting its potential utility in medicinal chemistry and further demonstrating the broad applicability of this BCB alkynylation reaction.

To demonstrate the practical utility of the protocol, a gram-scale reaction with model substrates was carried out under standard reaction conditions, furnishing the corresponding product in 72% yield. Furthermore, the cyclobutylated alkyne could be readily derivatized into a range of structurally diverse compounds that are otherwise difficult to access, due to the versatility of both the alkyne and aryl sulfonyl group. For examples, the aryl sulfonyl group could be transformed into hydrogen (52), fluorine (54), or alkene (55) under established conditions. Additionally, simultaneous reduction of both the alkyne and sulfonyl moieties could be achieved in a single operation, delivering the corresponding alkylated butane in good yield (53). Collectively, these transformations underscore the broad downstream derivatization potential of the cyclobutylated alkynes and highlight the synthetic value of this BCB alkynylation reaction.

Mechanistic studies, including deuterium labelling reactions, kinetic experiments, Hammett analysis, and high-resolution mass spectrometry (HRMS) for the key design of a covalent intermediate have been performed in the previous report. Regarding the mechanism of this phosphine-catalyzed BCB alkynylation, it was hypothesized that a covalent intermediate, analogous to the previous report, could be generated by the reaction of the catalyst with the BCB substrate. This intermediate would play an essential role in promoting the reaction. A series of experiments have also been conducted, and these experimental results support the design and show further insights into the mechanism.

In conclusion, a catalytic alkynylation of bicyclo[1.1.0]butanes (BCBs) using a phosphine as the catalyst has been developed, without the need for external stoichiometric bases, and additives, and indicates a broad substrate scope and shows good functional tolerance. Although the facile scalability and derivatization of the corresponding cyclobutylated alkyne product demonstrate the synthetic value and practical utility of this protocol, the comparatively lower yields of products by uses of aliphatic alkynes as substrates have been obtained to show the substrate limit of this methodology. In contrast to aromatic alkyne, aliphatic alkyne generally exhibits a weaker acidity and a reduced affinity for bicyclo[1.1.0]butane (BCB). These properties could be responsible for the lower yields of products.  It should be noted that the P atom of the nucleophilic phosphine catalyst exhibits greater polarizability and displays more "softness" than the N atom of DMAP. This offers a range of opportunities for the modification of nucleophilic phosphine catalysts. For instance, there is the potential for the design of highly efficient phosphine catalysts or the chiral modification of phosphine catalysts to enhance the strain-release reaction activities or achieve the chiral strain-release reactions.

Reference 

1. Stain-Release Amination. Gianatassio, R.; Lopchuk, J. M.; Wang, J.; Pan, C.-M.; Malins, L. R.; Prieto, L.; Brandt, T. A.; Collins, M. R.; Gallego, G. M.; Sach, N. W.; Spangler, J. E.; Zhu, H.; Zhu, J.; and Baran, P. S. Science. 2016, 351, 241−246. 

2.  Strain-Release Heteroatom Functionalization: De-velopment, Scope, and Stereospecificity. Lopchuk, J. M.; Fjelbye, K.; Kawamata, Y.; Malins, L. R.; Pan,C.-M.; Gianatassio, R.; Wang, J.; Prieto, L.; Bradow, J.; Brandt, T. A.; Collins, M. R.; Elleraas, J.; Ewanicki, J.; Farrell, W.; Fadeyi, O. O.;Gallego, G. M.; Mousseau, J. J.; Oliver, R.; Sach, N. W.; Smith, J. K.; Spangler, J. E.; Zhu, H.; Zhu, J.; and Baran, P. S.  J. Am. Chem. Soc. 2017, 139, 3209−3226.

3. A general approach for strained ring functionalization via nucleophilic catalysis. Wang, P.^⊥; Deng, C.^⊥; Luo, Z.; Chen, D.; Li, Alex Y.; Li, Y. *; Huang, L. * and Yu, P. * JACS Au. 2025, 5, 5404-5413.