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DOI: 10.1055/a-2603-8442
Photocatalytic Hydroalkylation of Trifluoromethyl Alkenes with Gaseous Alkanes in Flow
Financial support from the European Research Council (ERC-CoG 863914-BECAME), the Agencia Estatal de Investigación (PID2023-151875NB-I00), the Xunta de Galicia (ED431C 2022/27; Centro de investigación do Sistema Universitario de Galicia accreditation 2023-2027, ED431G 2023/03) and the European Regional Development Fund (ERDF) is gratefully acknowledged.
Abstract
The conversion of light alkanes into value-added products is becoming a field of high interest within the scientific community, as it avoids the use of prefunctionalized alkylating agents. However, the gaseous nature of these reagents, along with their intrinsic inertness due to their high bond-dissociation energies (99–105 kcal·mol–1), have rendered traditional strategies ineffective or lacking in selectivity. The use of flow-chemistry technology has made a tremendous impact in this field, improving the efficiency of multiphasic processes through improved mass transfer and larger interfacial areas. In this work, we report a new flow-chemistry platform for the photocatalytic hydroalkylation of trifluoromethyl alkenes with both isobutane and n-butane. The methodology provides an efficient alternative for the rapid construction of trifluoromethyl alkanes, which are well-known and important bioisosteres of several functional groups.
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Key words
photocatalysis - flow chemistry - HAT photocatalysis - gaseous alkanes - trifluoromethyl alkanesGaseous alkanes, which are among the most abundant carbon-based chemical feedstocks, have been traditionally used for heating and energy production.[1] However, in the past decades, there has been increasing interest in the scientific community for their use in different organic transformations as sustainable and atom-efficient alkylating reagents.[2] Although the direct use of alkanes helps to avoid traditional prefunctionalization steps (e.g., halogenation or the use of organometallic reagents),[3] several issues must be taken into consideration when these gaseous compounds come into play. The intrinsic inertness of the alkane C–H bond (high bond-dissociation energies, BDE = 99–105 kcal·mol–1) and their low solubility in most organic solvents complicate their use in organic transformations (Scheme [1a], left). In addition, C–H bonds present in the reaction products or even in different common organic solvents are often more reactive, potentially leading to over-reaction problems and competing solvent activation.[2b] [4] In this context, photoinduced hydrogen atom transfer (HAT) catalysis has emerged as a valuable and efficient option for the activation of saturated alkanes under mild conditions (Scheme [1a], right).[2b,5] This strategy has been successfully employed in the C–H functionalization of gaseous alkanes,[6] finding application in the development of various organic transformations, including Giese-type additions to activated alkenes,[7] sulfinylation reactions,[8] and (hetero)arylation under dual metal/photoredox catalysis.[9]
We have recently reported a catalytic methodology for the hydroalkylation of various α-trifluoromethyl alkenes with light alkanes under batch conditions (Scheme [1b]).[10] The protocol relies on the use of saturated alkanes as non-prefunctionalized alkylating agents, which are effectively activated by HAT photocatalysis. Under these conditions, a plethora of trifluoromethyl alkanes were readily obtained in good yields, resulting in a novel strategy for the mild synthesis of these relevant fluorinated scaffolds, which are important bioisosteres of several functional groups.[11] In addition, gaseous alkanes such as methane, ethane, or propane could be effectively used as coupling partners, giving rise to the corresponding alkylated products in good yields. In these reactions, control over the pressure proved to be a key parameter to render the reaction efficient. Indeed, poor results were obtained when isobutane was used, likely due to the limitation imposed by the pressure of the corresponding gas cylinder.
Flow chemistry has emerged in the last few years as a plausible alternative for handling these gaseous reagents.[12] This is mainly due to its intrinsically better mass- and heat-transfer, fast mixing, and larger interfacial areas, which have made flow chemistry the perfect option for the development and enhancement of multiphasic reactions.[13] Furthermore, the ease of pressurization by using commercially available back-pressure regulators allows to outpace gas solubility issues, forcing light alkanes into the liquid phase and thus improving mass transfer. In this sense, the use of gaseous hydrocarbons as direct radical precursors under flow conditions has been successfully exploited over the last few years in different organic transformations.[7b] [8] [9a]
At this point and considering the low pressure at which some gases are commercialized (1.5 bar for isobutane and 1 bar for n-butane), we envisioned the use of a flow-chemistry system to enhance the hydroalkylation of trifluoromethyl alkenes with these gaseous alkanes (Scheme [1c]). In this sense, the employment of back-pressure regulators would afford more precise control over the pressure of the system and thus better control over its efficiency. Notably, this new protocol would provide a straightforward tool for the introduction of tert- and sec-butyl groups, relevant alkyl groups in medicinal chemistry,[14] in important fluorinated motifs.
With that in mind, we started our investigation by reacting trifluoromethyl alkene 1 with isobutane in the presence of a well-established HAT photocatalyst, tetrabutylammonium decatungstate (TBADT) (Table [1], see the Supporting Information for the complete optimization).[15] CD3CN was initially chosen as solvent as a way to avoid the propensity of TBADT to abstract hydrogen atoms from CH3CN.[7b] Initial experiments were performed with a gas-to-liquid ratio of 10:1 (4.3 equiv of isobutane). The reaction mixture was irradiated at 365 nm (high-powered LEDs) using a Vapourtec UV-150 photoreactor (ID = 1.00 mm, V R = 10 mL, see the Supporting Information for further details) with a residence time of 30 minutes. A back-pressure regulator was used to maintain a constant pressure of 4.5 bar in the flow system, forcing isobutane into the liquid phase and thus improving mass transfer. Under these conditions, compound 2 was obtained in 33% yield as a 15:1 mixture of branched/linear regioisomers (2a/2b), together with a trace amount of the solvent activation product (SA) (entry 1). As envisioned, pressure represented a crucial parameter in the transformation, and the use of a lower pressure (1.5 bar) was detrimental to the reaction (entry 2). However, the use of higher pressures (8 bar) did not provide a better yield either (entry 3). We then moved to evaluate the gas-to-liquid ratio using a system pressure of 4.5 bar. Increasing this parameter up to 30:1 (13 equiv of isobutane) resulted in an improved 51% yield (entry 5). However, higher isobutane excesses did not lead to any further increase in yield (see the Supporting Information). At this point, we decided to evaluate sodium decatungstate (NaDT) as HAT photocatalyst, since it has been described that the nature of the polyoxometalate counterion can have a direct impact on the outcome of HAT photocatalysis under flow conditions.[8] [16] Gratifyingly, this change in the photocatalyst cation was found to be beneficial for the reaction, allowing 2a to be obtained as a single regioisomer in 57% yield (entry 6). Although initially less soluble, the use of this catalyst provided a more homogeneous medium compared to TBADT. We believe that this improvement in solubility could be a plausible explanation for the slightly superior reaction outcome.
a Reactions run on a 0.1 mmol scale, with 365 nm high-powered LEDs (61 W output power). SA stands for solvent activation product, detected in less than 5% 19F NMR yield in all cases. See Supporting Information for the complete optimization data.
b Yield and regioisomeric ratios were determined by 19F NMR analysis using α,α,α-trifluorotoluene as internal standard.
c Reactions run on a 0.2 mmol scale.
d Yield of isolated product is shown in parentheses. Regioisomeric ratio was measured by GC-MS analysis.
Finally, we assessed the appropriate residence time for the transformation. Remarkably, residence time could be reduced to only 5 minutes with no decrease in yield, simultaneously improving the overall throughput and the production of the process (Table [1], entries 7–9). Importantly, the reaction could be carried out on a higher scale and using CH3CN as solvent without any erosion in the reaction efficiency (entries 10 and 11), eventually furnishing the desired product 2a in 60% yield with excellent regioselectivity.
Having established optimized conditions, we set out to evaluate the reaction with different trifluoromethyl alkenes (Scheme [2]). Isobutane could be effectively coupled with various heteroaromatic trifluoromethyl alkenes with excellent selectivity. Thus, 3-substituted pyridines gave rise exclusively to products 2 and 3 in 60% and 62% yield, respectively, with outstanding regioselectivity. Different aryl rings were also compatible with this transformation. In these cases, the addition of 1 equiv of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) was necessary to avoid competing β-fluoride elimination that leads to the corresponding gem-difluoroalkene.[10] Under these adjusted conditions, products with aryl rings bearing functional groups such as an ester (4), nitrile (5), or sulfone (6) were obtained in good yields with good to excellent regioselectivity (from 12:1 to ˃20:1). Product 7, which bears an N,N-dimethylsulfonamide group at the aryl moiety, was also obtained with exceptional regioselectivity, albeit in moderate yield (25%, 34% based on recovered starting material). Attempts to improve this result by changing residence time, pressure, or gas-to-liquid ratio were not successful, resulting in only degradation of the starting material under prolonged irradiation conditions. Importantly, the protocol could also be applied to other types of N-heterocycle-containing scaffolds, as demonstrated by the synthesis of pyrimidine derivative 8.
n-Butane, commercialized at a maximum pressure of 1 bar, was next evaluated as a feasible coupling partner for this photocatalytic hydroalkylation reaction in flow with a BPR-controlled pressure of 4.5 bar. For this gaseous alkane, an increase in gas-to-liquid ratio (50:1) was found to be necessary to achieve high levels of conversion. With this new set of conditions in hand, pyridine derivatives 9 and 10 were obtained in good yields with remarkable regioselectivity towards the functionalization of the secondary position of n-butane (rr = 11:1 and 7:1, respectively). As observed for isobutane, the use of substrates bearing aryl rings or a pyrimidine core required the use of HFIP as an additive to selectively afford the corresponding trifluoromethyl alkanes 11–15 in moderate to good yields, again with good levels of regioselectivity (rr = 8:1 to 11:1).
As shown above, electron-deficient (hetero)aromatic trifluoromethyl alkenes proved to be efficient substrates for the photocatalytic hydroalkylation reaction with gaseous alkanes in flow. In contrast, the reaction did not work for trifluoromethyl alkenes bearing electron-rich substituents.[17] This is in accordance with the mechanistic proposal for this transformation (Scheme [3]), where radical intermediate I is formed after the addition of the alkyl radical over the starting trifluoromethyl alkene. This radical species can then be further reduced by the catalyst through a single-electron transfer (SET) event, generating a stabilized carbanion intermediate that can be finally protonated furnishing the desired trifluoromethyl alkane.
Scaling photochemical transformations has always faced several difficulties, mainly associated with the attenuation of light through the reaction pathway as dictated by the Bouguer–Lambert–Beer law, preventing these reactions from being used industrially. In this field, flow chemistry has gained huge attention over the past years, as it has allowed these issues associated with batch photochemistry to be overcome.[12b] [18] Taking this into account, the synthesis of trifluoromethyl alkane 2 could be efficiently scaled up to 1 mmol, furnishing the product in 73% yield with no loss in selectivity (Scheme [4], see the Supporting Information for experimental details). This can be translated into a 931.7 mg·h–1 (3.5 mmol·h–1) production of 2, showing perfect scalability of the described protocol.
In summary, we have developed an efficient protocol for the hydroalkylation of electron-deficient trifluoromethyl alkenes with gaseous alkanes based on HAT photocatalysis in flow.[19] The use of flow-chemistry conditions, which facilitates an increase in pressure using operationally simple back-pressure regulators, allows isobutane and n-butane to be efficiently employed in this transformation, overcoming limitations previously observed when batch chemistry was used. The reaction features excellent atom economy and provides trifluoromethyl alkanes in good yields with high levels of chemo- and regioselectivity, setting the stage for a new and scalable platform for the synthesis of these important fluorinated compounds from readily available chemical feedstocks.
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Conflict of Interest
The authors declare no conflict of interest.
Acknowledgment
We thank RIAIDT-USC for the use of analytical facilities.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2603-8442.
- Supporting Information
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References and Notes
- 1a Kerr RA. Science 2010; 328: 1624
- 1b Cooper J, Stamford L, Azapagic A. Energy Technol. 2016; 4: 772
- 2a Caballero A, Pérez PJ. Chem. Soc. Rev. 2013; 42: 8809
- 2b Pulcinella A, Mazzarella D, Noël T. Chem. Commun. 2021; 57: 9956
- 3a Chu JC. K, Rovis T. Angew. Chem. Int. Ed. 2018; 57: 62
- 3b Das J, Guin S, Maiti D. Chem. Sci. 2020; 11: 10887
- 3c Ali W, Prakash G, Maiti D. Chem. Sci. 2021; 12: 2735
- 3d Sinha SK, Guin S, Maiti S, Biswas JP, Porey S, Maiti D. Chem. Rev. 2022; 122: 5682
- 5a Capaldo L, Ravelli D, Fagnoni M. Chem. Rev. 2022; 122: 1875
- 5b Chang L, Wang S, An Q, Liu L, Wang H, Li Y, Feng K, Zuo Z. Chem. Sci. 2023; 14: 6841
- 5c Velasco-Rubio Á, Martínez-Balart P, Álvarez-Constantino AM, Fañanás-Mastral M. Chem. Commun. 2023; 59: 9424
- 6 For a review, see: Cai B, Cheo HW, Liu T, Wu J. Angew. Chem. Int. Ed. 2021; 60: 18950
- 7a Hu A, Guo J.-J, Pan H, Zuo Z. Science 2018; 361: 668
- 7b Laudadio G, Deng Y, van der Wal K, Ravelli D, Nuño M, Fagnoni M, Guthrie D, Sun Y, Noël T. Science 2020; 369: 92
- 7c Jin Y, Zhang Q, Wang L, Wang X, Meng C, Duan C. Green Chem. 2021; 23: 6984
- 7d Yang Q, Wang Y.-H, Qiao Y, Gau M, Carroll PJ, Walsh PJ, Schelter EJ. Science 2021; 372: 847
- 7e Zhang Q, Liu S, Lei J, Zhang Y, Meng C, Duan C, Jin Y. Org. Lett. 2022; 24: 1901
- 7f Panetti GB, Yang Q, Gau MR, Carroll PJ, Walsh PJ, Schelter EJ. Chem Catal. 2022; 2: 853
- 7g Dai Z.-Y, Zhang S.-Q, Hong X, Wang P.-S, Gong L.-Z. Chem Catal. 2022; 2: 1211
- 7h Raymenants F, Masson TM, Sanjosé-Orduna J, Noël T. Angew. Chem. Int. Ed. 2023; 62: e202308563
- 8 Nagornîi D, Raymenants F, Kaplaneris N, Noël T. Nat. Commun. 2024; 15: 5246
- 9a Pulcinella A, Tiwari PC, Luridiana A, Yamazaki K, Mazzarella D, Sadhoe AK, Alfano AI, Tiekink EH, Hamlin TA, Noël T. Angew. Chem. Int. Ed. 2025; 64: e202413846
- 9b Nair AM, Martínez-Balart P, Barbeira-Arán S, Fañanás-Mastral M. Angew. Chem. Int. Ed. 2025; 64: e202416957
- 10 Martínez-Balart P, Velasco-Rubio Á, Barbeira-Arán S, Jiménez-Cristóbal H, Fañanás-Mastral M. Green Chem. 2024; 26: 11196
- 11a Meanwell NA. J. Med. Chem. 2011; 54: 2529
- 11b Tseng C.-C, Baillie G, Donvito G, Mustafa MA, Juola SE, Zanato C, Massarenti C, Dall’Angelo S, Harrison WT. A, Lichtman AH, Ross RA, Zanda M, Greig IR. J. Med. Chem. 2019; 62: 5049
- 12a Santoro S, Ferlin F, Ackermann L, Vaccaro L. Chem. Soc. Rev. 2019; 48: 2767
- 12b Sambiagio C, Noël T. Trends Chem. 2020; 2: 92
- 12c Govaerts S, Nyuchev A, Noël T. J. Flow Chem. 2020; 10: 13
- 13a Noël T, Hessel V. ChemSusChem 2013; 6: 405
- 13b Plutschack MB, Pieber B, Gilmore K, Seeberger PH. Chem. Rev. 2017; 117: 11796
- 14a Lehman-McKeeman LD, Caudill D, Rodríguez PA, Eddy C. Toxicol. Appl. Pharmacol. 1998; 149: 32
- 14b Bisel P, Al-Momani L, Müller M. Org. Biomol. Chem. 2008; 6: 2655
- 14c Noro JC, Kalaitzis JA, Neilan BA. Chem. Biodivers. 2012; 9: 2077
- 14d Skiba MA, Sikkema AP, Moss NA, Lowell AN, Su M, Sturgis RM, Gerwick L, Gerwick WH, Sherman DH, Smith JL. ACS Chem. Biol. 2018; 13: 1640
- 15a De Waele V, Poizat O, Fagnoni M, Bagno A, Ravelli D. ACS Catal. 2016; 10: 7174
- 15b Ravelli D, Fagnoni M, Fukuyama T, Nishikawa T, Ryu I. ACS Catal. 2018; 8: 701
- 15c Hong B.-C, Indurmuddam RR. Org. Biomol. Chem. 2024; 22: 3799
- 16 Schultz DM, Lévesque F, DiRocco DA, Reibarkh M, Ji Y, Joyce LA, Dropinski JF, Sheng H, Sherry BD, Davies IW. Angew. Chem. Int. Ed. 2017; 56: 15274
- 17 In our previous work (see ref. 10), the hydroalkylation of trifluoromethyl alkenes bearing electron-rich substituents was possible by using a thiol HAT co-catalyst. Unfortunately, this dual catalysis approach proved not to be efficient under flow-chemistry conditions.
- 18a Cambié D, Bottecchia C, Straathof NJ. W, Hessel V, Noël T. Chem. Rev. 2016; 116: 10276
- 18b Rehm TH. Chem. Eur. J. 2020; 26: 16952
- 18c Buglioni L, Raymenants F, Slattery A, Zondag SD. A, Noël T. Chem. Rev. 2022; 122: 2752
- 19 Photocatalytic Hydroalkylation of Electron-Deficient Alkenes; General Procedure: The corresponding trifluoromethyl alkene (0.2 mmol) and NaDT (24.4 mg, 0.01 mmol, 5 mol%) were added to an oven-dried vial equipped with a septum. Anhydrous MeCN (2 mL, 0.1 M) was added, and the solution was finally homogenized by sonication in an ultrasound bath. Anhydrous MeCN was pumped through using both pumps at 0.5 mL·min–1 in order to purge the whole flow system (approximately 10 minutes). After that, the photoreactor was switched on along with the cooled gas generator, equilibrating the temperature of the system at 20–25 °C. The liquid phase was then combined with the gas stream through a T-mixer, with a liquid flow rate of 0.5 mL·min–1 and a gas flow rate of 15 mL·min–1 (30:1 gas-to-liquid ratio) for isobutane or 25 mL·min–1 (50:1 gas-to-liquid ratio) for n-butane. No back pressure regulator was used for this step. After that, the whole reaction mixture was pressurized at 4.5 bar (gauge pressure). Finally, the reaction mixture was pumped over the UV-150 photoreactor (365 nm high-powered LEDs, 61 W output power, 10 mL, fluoropolymer capillary tube, 1/16′′ OD, 1.0 mm ID) at the corresponding flow rate. The obtained crude material was collected into a vial. The solution was filtered through a silica plug and the residue was washed with Et2O (20 mL). Solvent was removed under reduced pressure, and the residue was finally purified by flash column chromatography, furnishing compounds 2–15.
For selected reviews on C(sp3)–H functionalization of alkanes, see:
For reviews on TBADT and HAT catalysis, see:
Corresponding Author
Publication History
Received: 28 March 2025
Accepted after revision: 08 May 2025
Accepted Manuscript online:
08 May 2025
Article published online:
30 June 2025
© 2025. Thieme. All rights reserved
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References and Notes
- 1a Kerr RA. Science 2010; 328: 1624
- 1b Cooper J, Stamford L, Azapagic A. Energy Technol. 2016; 4: 772
- 2a Caballero A, Pérez PJ. Chem. Soc. Rev. 2013; 42: 8809
- 2b Pulcinella A, Mazzarella D, Noël T. Chem. Commun. 2021; 57: 9956
- 3a Chu JC. K, Rovis T. Angew. Chem. Int. Ed. 2018; 57: 62
- 3b Das J, Guin S, Maiti D. Chem. Sci. 2020; 11: 10887
- 3c Ali W, Prakash G, Maiti D. Chem. Sci. 2021; 12: 2735
- 3d Sinha SK, Guin S, Maiti S, Biswas JP, Porey S, Maiti D. Chem. Rev. 2022; 122: 5682
- 5a Capaldo L, Ravelli D, Fagnoni M. Chem. Rev. 2022; 122: 1875
- 5b Chang L, Wang S, An Q, Liu L, Wang H, Li Y, Feng K, Zuo Z. Chem. Sci. 2023; 14: 6841
- 5c Velasco-Rubio Á, Martínez-Balart P, Álvarez-Constantino AM, Fañanás-Mastral M. Chem. Commun. 2023; 59: 9424
- 6 For a review, see: Cai B, Cheo HW, Liu T, Wu J. Angew. Chem. Int. Ed. 2021; 60: 18950
- 7a Hu A, Guo J.-J, Pan H, Zuo Z. Science 2018; 361: 668
- 7b Laudadio G, Deng Y, van der Wal K, Ravelli D, Nuño M, Fagnoni M, Guthrie D, Sun Y, Noël T. Science 2020; 369: 92
- 7c Jin Y, Zhang Q, Wang L, Wang X, Meng C, Duan C. Green Chem. 2021; 23: 6984
- 7d Yang Q, Wang Y.-H, Qiao Y, Gau M, Carroll PJ, Walsh PJ, Schelter EJ. Science 2021; 372: 847
- 7e Zhang Q, Liu S, Lei J, Zhang Y, Meng C, Duan C, Jin Y. Org. Lett. 2022; 24: 1901
- 7f Panetti GB, Yang Q, Gau MR, Carroll PJ, Walsh PJ, Schelter EJ. Chem Catal. 2022; 2: 853
- 7g Dai Z.-Y, Zhang S.-Q, Hong X, Wang P.-S, Gong L.-Z. Chem Catal. 2022; 2: 1211
- 7h Raymenants F, Masson TM, Sanjosé-Orduna J, Noël T. Angew. Chem. Int. Ed. 2023; 62: e202308563
- 8 Nagornîi D, Raymenants F, Kaplaneris N, Noël T. Nat. Commun. 2024; 15: 5246
- 9a Pulcinella A, Tiwari PC, Luridiana A, Yamazaki K, Mazzarella D, Sadhoe AK, Alfano AI, Tiekink EH, Hamlin TA, Noël T. Angew. Chem. Int. Ed. 2025; 64: e202413846
- 9b Nair AM, Martínez-Balart P, Barbeira-Arán S, Fañanás-Mastral M. Angew. Chem. Int. Ed. 2025; 64: e202416957
- 10 Martínez-Balart P, Velasco-Rubio Á, Barbeira-Arán S, Jiménez-Cristóbal H, Fañanás-Mastral M. Green Chem. 2024; 26: 11196
- 11a Meanwell NA. J. Med. Chem. 2011; 54: 2529
- 11b Tseng C.-C, Baillie G, Donvito G, Mustafa MA, Juola SE, Zanato C, Massarenti C, Dall’Angelo S, Harrison WT. A, Lichtman AH, Ross RA, Zanda M, Greig IR. J. Med. Chem. 2019; 62: 5049
- 12a Santoro S, Ferlin F, Ackermann L, Vaccaro L. Chem. Soc. Rev. 2019; 48: 2767
- 12b Sambiagio C, Noël T. Trends Chem. 2020; 2: 92
- 12c Govaerts S, Nyuchev A, Noël T. J. Flow Chem. 2020; 10: 13
- 13a Noël T, Hessel V. ChemSusChem 2013; 6: 405
- 13b Plutschack MB, Pieber B, Gilmore K, Seeberger PH. Chem. Rev. 2017; 117: 11796
- 14a Lehman-McKeeman LD, Caudill D, Rodríguez PA, Eddy C. Toxicol. Appl. Pharmacol. 1998; 149: 32
- 14b Bisel P, Al-Momani L, Müller M. Org. Biomol. Chem. 2008; 6: 2655
- 14c Noro JC, Kalaitzis JA, Neilan BA. Chem. Biodivers. 2012; 9: 2077
- 14d Skiba MA, Sikkema AP, Moss NA, Lowell AN, Su M, Sturgis RM, Gerwick L, Gerwick WH, Sherman DH, Smith JL. ACS Chem. Biol. 2018; 13: 1640
- 15a De Waele V, Poizat O, Fagnoni M, Bagno A, Ravelli D. ACS Catal. 2016; 10: 7174
- 15b Ravelli D, Fagnoni M, Fukuyama T, Nishikawa T, Ryu I. ACS Catal. 2018; 8: 701
- 15c Hong B.-C, Indurmuddam RR. Org. Biomol. Chem. 2024; 22: 3799
- 16 Schultz DM, Lévesque F, DiRocco DA, Reibarkh M, Ji Y, Joyce LA, Dropinski JF, Sheng H, Sherry BD, Davies IW. Angew. Chem. Int. Ed. 2017; 56: 15274
- 17 In our previous work (see ref. 10), the hydroalkylation of trifluoromethyl alkenes bearing electron-rich substituents was possible by using a thiol HAT co-catalyst. Unfortunately, this dual catalysis approach proved not to be efficient under flow-chemistry conditions.
- 18a Cambié D, Bottecchia C, Straathof NJ. W, Hessel V, Noël T. Chem. Rev. 2016; 116: 10276
- 18b Rehm TH. Chem. Eur. J. 2020; 26: 16952
- 18c Buglioni L, Raymenants F, Slattery A, Zondag SD. A, Noël T. Chem. Rev. 2022; 122: 2752
- 19 Photocatalytic Hydroalkylation of Electron-Deficient Alkenes; General Procedure: The corresponding trifluoromethyl alkene (0.2 mmol) and NaDT (24.4 mg, 0.01 mmol, 5 mol%) were added to an oven-dried vial equipped with a septum. Anhydrous MeCN (2 mL, 0.1 M) was added, and the solution was finally homogenized by sonication in an ultrasound bath. Anhydrous MeCN was pumped through using both pumps at 0.5 mL·min–1 in order to purge the whole flow system (approximately 10 minutes). After that, the photoreactor was switched on along with the cooled gas generator, equilibrating the temperature of the system at 20–25 °C. The liquid phase was then combined with the gas stream through a T-mixer, with a liquid flow rate of 0.5 mL·min–1 and a gas flow rate of 15 mL·min–1 (30:1 gas-to-liquid ratio) for isobutane or 25 mL·min–1 (50:1 gas-to-liquid ratio) for n-butane. No back pressure regulator was used for this step. After that, the whole reaction mixture was pressurized at 4.5 bar (gauge pressure). Finally, the reaction mixture was pumped over the UV-150 photoreactor (365 nm high-powered LEDs, 61 W output power, 10 mL, fluoropolymer capillary tube, 1/16′′ OD, 1.0 mm ID) at the corresponding flow rate. The obtained crude material was collected into a vial. The solution was filtered through a silica plug and the residue was washed with Et2O (20 mL). Solvent was removed under reduced pressure, and the residue was finally purified by flash column chromatography, furnishing compounds 2–15.
For selected reviews on C(sp3)–H functionalization of alkanes, see:
For reviews on TBADT and HAT catalysis, see:
