Photocatalytic Hydroalkylation of Trifluoromethyl Alkenes with Gaseous Alkanes in Flow

 

 Buy Article Permissions and Reprints All articles of this category

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.

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

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

• References and Notes

• 1a Kerr RA. Science 2010; 328: 1624
  PubMedSearch in Google Scholar
• 1b Cooper J, Stamford L, Azapagic A. Energy Technol. 2016; 4: 772
  Search in Google Scholar
• 2a Caballero A, Pérez PJ. Chem. Soc. Rev. 2013; 42: 8809
  PubMedSearch in Google Scholar
• 2b Pulcinella A, Mazzarella D, Noël T. Chem. Commun. 2021; 57: 9956
  Search in Google Scholar

For selected reviews on C(sp³)–H functionalization of alkanes, see:
• 3a Chu JC. K, Rovis T. Angew. Chem. Int. Ed. 2018; 57: 62
  CrossrefPubMedSearch in Google Scholar
• 3b Das J, Guin S, Maiti D. Chem. Sci. 2020; 11: 10887
  CrossrefPubMedSearch in Google Scholar
• 3c Ali W, Prakash G, Maiti D. Chem. Sci. 2021; 12: 2735
  PubMedSearch in Google Scholar
• 3d Sinha SK, Guin S, Maiti S, Biswas JP, Porey S, Maiti D. Chem. Rev. 2022; 122: 5682
  CrossrefPubMedSearch in Google Scholar
• 4a Crabtree RH. Chem. Rev. 1995; 95: 987
  CrossrefPubMedSearch in Google Scholar
• 4b Schwarz H. Angew. Chem. Int. Ed. 2011; 50: 10096
  Search in Google Scholar
• 5a Capaldo L, Ravelli D, Fagnoni M. Chem. Rev. 2022; 122: 1875
  CrossrefPubMedSearch in Google Scholar
• 5b Chang L, Wang S, An Q, Liu L, Wang H, Li Y, Feng K, Zuo Z. Chem. Sci. 2023; 14: 6841
  CrossrefPubMedSearch in Google Scholar
• 5c Velasco-Rubio Á, Martínez-Balart P, Álvarez-Constantino AM, Fañanás-Mastral M. Chem. Commun. 2023; 59: 9424
  Search in Google Scholar
• 6 For a review, see: Cai B, Cheo HW, Liu T, Wu J. Angew. Chem. Int. Ed. 2021; 60: 18950
  Search in Google Scholar
• 7a Hu A, Guo J.-J, Pan H, Zuo Z. Science 2018; 361: 668
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 7c Jin Y, Zhang Q, Wang L, Wang X, Meng C, Duan C. Green Chem. 2021; 23: 6984
  CrossrefSearch in Google Scholar
• 7d Yang Q, Wang Y.-H, Qiao Y, Gau M, Carroll PJ, Walsh PJ, Schelter EJ. Science 2021; 372: 847
  CrossrefPubMedSearch in Google Scholar
• 7e Zhang Q, Liu S, Lei J, Zhang Y, Meng C, Duan C, Jin Y. Org. Lett. 2022; 24: 1901
  CrossrefPubMedSearch in Google Scholar
• 7f Panetti GB, Yang Q, Gau MR, Carroll PJ, Walsh PJ, Schelter EJ. Chem Catal. 2022; 2: 853
  Search in Google Scholar
• 7g Dai Z.-Y, Zhang S.-Q, Hong X, Wang P.-S, Gong L.-Z. Chem Catal. 2022; 2: 1211
  Search in Google Scholar
• 7h Raymenants F, Masson TM, Sanjosé-Orduna J, Noël T. Angew. Chem. Int. Ed. 2023; 62: e202308563
  Search in Google Scholar
• 8 Nagornîi D, Raymenants F, Kaplaneris N, Noël T. Nat. Commun. 2024; 15: 5246
  PubMedSearch in Google Scholar
• 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
  Search in Google Scholar
• 9b Nair AM, Martínez-Balart P, Barbeira-Arán S, Fañanás-Mastral M. Angew. Chem. Int. Ed. 2025; 64: e202416957
  Search in Google Scholar
• 10 Martínez-Balart P, Velasco-Rubio Á, Barbeira-Arán S, Jiménez-Cristóbal H, Fañanás-Mastral M. Green Chem. 2024; 26: 11196
  PubMedSearch in Google Scholar
• 11a Meanwell NA. J. Med. Chem. 2011; 54: 2529
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 12a Santoro S, Ferlin F, Ackermann L, Vaccaro L. Chem. Soc. Rev. 2019; 48: 2767
  PubMedSearch in Google Scholar
• 12b Sambiagio C, Noël T. Trends Chem. 2020; 2: 92
  CrossrefSearch in Google Scholar
• 12c Govaerts S, Nyuchev A, Noël T. J. Flow Chem. 2020; 10: 13
  CrossrefSearch in Google Scholar
• 13a Noël T, Hessel V. ChemSusChem 2013; 6: 405
  PubMedSearch in Google Scholar
• 13b Plutschack MB, Pieber B, Gilmore K, Seeberger PH. Chem. Rev. 2017; 117: 11796
  CrossrefPubMedSearch in Google Scholar
• 14a Lehman-McKeeman LD, Caudill D, Rodríguez PA, Eddy C. Toxicol. Appl. Pharmacol. 1998; 149: 32
  PubMedSearch in Google Scholar
• 14b Bisel P, Al-Momani L, Müller M. Org. Biomol. Chem. 2008; 6: 2655
  CrossrefPubMedSearch in Google Scholar
• 14c Noro JC, Kalaitzis JA, Neilan BA. Chem. Biodivers. 2012; 9: 2077
  PubMedSearch in Google Scholar
• 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
  PubMedSearch in Google Scholar

For reviews on TBADT and HAT catalysis, see:
• 15a De Waele V, Poizat O, Fagnoni M, Bagno A, Ravelli D. ACS Catal. 2016; 10: 7174
  Search in Google Scholar
• 15b Ravelli D, Fagnoni M, Fukuyama T, Nishikawa T, Ryu I. ACS Catal. 2018; 8: 701
  CrossrefPubMedSearch in Google Scholar
• 15c Hong B.-C, Indurmuddam RR. Org. Biomol. Chem. 2024; 22: 3799
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 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
  CrossrefPubMedSearch in Google Scholar
• 18b Rehm TH. Chem. Eur. J. 2020; 26: 16952
  CrossrefPubMedSearch in Google Scholar
• 18c Buglioni L, Raymenants F, Slattery A, Zondag SD. A, Noël T. Chem. Rev. 2022; 122: 2752
  CrossrefPubMedSearch in Google Scholar
• 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.

• Supplementary Material