Robust and Scalable Reductive Amination Protocol for Electron-Poor Heterocyclic Amines Using Et₃SiH/TFA as Reducing Agent

Abstract

A facile reductive amination procedure for electron-poor heterocyclic amines with aromatic and aliphatic aldehydes has been developed. The key to success was the use of triethylsilane (Et₃SiH) as reducing agent, in combination with trifluoroacetic acid (TFA) in refluxing CH₂Cl₂. The reductive aminations are fast and clean, and allow for the isolation of the alkylated amines in high yields and purity after crystallization or chromatographic purification. The robustness and scalability of the process has been demonstrated for one substrate combination on 750 g scale, leading to the isolation of the corresponding product in 93% yield.

Key words

reductive amination - process chemistry - scale-up - amines - heterocycles - silanes

• References

• 1a Afanasyev OI, Kuchuk K, Usanov DL, Chusov D. Chem. Rev. 2019; 119: 11857
• 1b Roughley SD, Jordan AM. J. Med. Chem. 2011; 54: 3451
• 1c Gusak KN, Ignatovich ZV, Koroleva EV. Russ. Chem. Rev. 2015; 84: 288
• 1d Podyacheva E, Afanasyev OI, Tsygankov AA, Makarova M, Chusov D. Synthesis 2019; 51: 2667
• 1e Tripathi RP, Verma SS, Pandey J, Tiwari V. Curr. Org. Chem. 2008; 12: 1093
• 2a Abdel-Magid AF, Mehrman SJ. Org. Process Res. Dev. 2006; 10: 971
• 2b Abdel-Magid AF, Maryanoff CA, Carson KG. Tetrahedron Lett. 1990; 31: 5595
• 3a Hutchins RO, Natale NR. Org. Prep. Proced. Int. 1979; 11: 201
• 3b Lane CF. Synthesis 1975; 135
• 4a Irrgang T, Kempe R. Chem. Rev. 2020; 120: 9583
• 4b Murugesan K, Senthamarai T, Chandrashekhar VG, Natte K, Kamer PC. J, Beller M, Jagadeesh RV. Chem. Soc. Rev. 2020; 49: 6273

For selected examples of reductive aminations with electron-deficient amines, see:
• 5a Pletz J, Berg B, Breinbauer R. Synthesis 2016; 48: 1301
• 5b Dasa BG, Ghorai P. Chem. Commun. 2012; 48: 8276
• 5c McLaughlin M, Palucki M, Davies IW. Org. Lett. 2006; 8: 3307
• 5d Boros EE, Thompson JB, Katamreddy SR, Carpenter AJ. J. Org. Chem. 2009; 74: 3587
• 6 A Reaxys substructure search yielded a single reductive amination literature report for the corresponding methyl ester of 2a with an isoxazolecarbaldehyde. The reductive amination was performed with NaBH3CN (2.0 eq.) and AcOH (14.0 eq.) in MeOH with molecular sieves at rt. Reported yield: 44%. Jakob-Roetne R, Lucas MC, Thomas A. WO2010127975A1, 2010

The N-acetylation is believed to be the result of nucleophilic attack by the amines on the triacetoxyborohydride and has been described in previous publications:
• 7a Marchini P, Liso G, Reho A, Liberatore F, Moracci FM. J. Org. Chem. 1975; 40: 3453
• 7b Gribble GW, Jasinski JM, Pellicone JT, Panetta JA. Synthesis 1978; 766
• 8a Pesti J, Larson GL. Org. Process Res. Dev. 2016; 20: 1164
• 8b Larson GL, Liberatore RJ. Org. Process Res. Dev. 2021; 25: 1719
• 8c Larson GL, Fry JL. Ionic and Organometallic-Catalyzed Organosilane Reductions . In Organic Reactions, Vol. 71. Denmark SE. Wiley and Sons; Hoboken: 2008
• 8d Larson GL. Silicon-Based Reducing Agents. Silicon Compounds: Silanes & Silicones. Gelest; 2020: 1-24 ; https://technical.gelest.com/wp-content/uploads/2020/10/Silicon-Based_Reducing_Agents.pdf
• 8e Larson GL. Chim. Oggi/Chem. Today 2013; 31: 36
• 9 Our process has been further scaled up at an external CMO with success: on 44.8 kg scale of 2, product 1 was isolated with identical yield and purity as in our kilolab run in a 30 L reactor (93% yield, HPLC: 99.8% a/a).