Assessing the Limits of Sustainability for the Delépine Reaction

Abstract

Herein, we report our efforts to improve the sustainability of the Delépine reaction for the formation of primary amines from activated alkyl halides. A number of alternative greener, more sustainable solvents to the traditionally employed chloroform were identified, and the use of dimethyl carbonate (DMC) as a solvent was exemplified in the synthesis of a number of pharmaceutically relevant building blocks including the 40 mmol scale synthesis of N-Boc-3-pyrroline. Green chemistry metrics were calculated to identify areas of the Delépine reaction that could potentially be improved upon. Poor atom economy (A.E.) was identified as a key shortcoming of this methodology, although our efforts to improve A.E. and reduce waste were unfortunately unsuccessful. A preliminary thermal safety evaluation was conducted using differential scanning calorimetry due to stability concerns raised over the nature of the products; none of the products were considered to have shock-sensitive or explosive propagating properties. The limits of potential sustainability improvements that could be achieved are critically discussed including the inherent issues with this methodology such as the release of formaldehyde, generation of carcinogenic bis(chloromethyl)­ether, and poor atom economy.

Chlorinated Solvents: Their Advantages, Disadvantages, and Alternatives in Organic and Medicinal Chemistry

“…Of note was that HMTA did not fully solubilize in any of the replacement solvents, yet the reaction still proceeded effectively as suspensions to give products of excellent yields and purity. The optimized methodology relied on dimethyl carbonate as solvent, and a wide range of HMTA salts were synthesized to emphasize the robustness of the methodology …”

“…The optimized methodology relied on dimethyl carbonate as solvent, and a wide range of HMTA salts were synthesized to emphasize the robustness of the methodology. 225 4.2.7. Reductive Amination.…”

Replacement of Less-Preferred Dipolar Aprotic and Ethereal Solvents in Synthetic Organic Chemistry with More Sustainable Alternatives

“…Propylene carbonate occupies a Hansen solvent space close to acetonitrile, see Table 2 , giving a rough indication of comparable solvating ability. Potential applications for carbonate based solvents include, but are not limited to, metal catalyzed cross-coupling reactions, 107 proline-catalyzed aldol reactions, 131 hydrosilylation, 132 cyanohydrin synthesis, 133 proline-catalyzed hydrazination, 134 amine-electrophile S N 2 chemistry, 135 and the Appel reaction. 136 …”

“…Carbonate-based solvents count dimethyl carbonate (DMC), diethyl carbonate, ethylene carbonate, and propylene carbonate, 106 proline-catalyzed aldol reactions, 130 hydrosilylation, 131 cyanohydrin synthesis, 132 proline-catalyzed hydrazination, 133 amine-electrophile S N 2 chemistry, 134 and the Appel reaction. 135 2.4. γ-Valerolactone (GVL)…”

The green solvent: a critical perspective

“…A wealth of additional studies, too many to survey comprehensively, have focussed more narrowly on the replacement of: (i) a single solvent, such as N -methylpyrrolidone (Sherwood et al 2016 ) or N,N- dimethylformamide (Linke et al 2020 ); (ii) a solvent type, such as dipolar aprotics (Duereh et al 2017 ) or chlorinated organics (Jordan et al 2021 ); (iii) a reaction medium for a particular reaction (Avalos et al 2006 ), such as amide coupling (MacMillan et al 2013 ), aldehyde reductive amination (McGonagle et al 2013 ) or the Delépine reaction (Jordan et al 2020 ); (iv) a solvent in a process (Avalos et al 2006 ; Fadel and Tarabieh 2019 ), such as membrane production (Xie et al 2020 ); (v) one or more solvents in a series of products (Isoni et al 2016 ); (vi) one or more solvents in an application, such as cleaning, (Tickner et al 2021 ), lubrication (Dörr et al 2019 ), chromatography (Taygerly et al 2012 ; MacMillan et al 2012 ), or product recovery (López-Porfiri et al 2020 ); (vii) one or more solvents in a technology, such as carbon capture (Borhani and Wang 2019 ), or water-based metal extraction (Binnemans and Jones 2017 ; Peeters et al 2020 ); or (viii) the optimised selection of solvents and anti-solvents in pharmaceutical recrystallization from a defined set of 68 compounds (Tan et al 2019 ).…”