Tube-in-tube reactor synthesis

Synthesis of N-methyl amino acids in a flow tube-in tube reactor with a gas-liquid/liquid-liquid semi-permeable membrane

Liquid-liquid transfer for Teflon® AF 2400 membrane in a tube-in-tube reactor is demonstrated. This concept was proven by application to flow-through synthesis of N-methyl amino acids (3) in two steps via oxazolidinones (2) according to Freidinger et al.1 N-Methyl amino acids are important components in biologically active peptides, e. g. in the immunosuppressant cyclosporine (4).


Scheme 1. N-Methylation of amino acids in two steps.

Both steps for N-methylation of Fmoc amino acids were carried out in a micro-structured tube-in-tube reactor with a semipermeable Teflon® AF 2400 membrane as applied in gas/liquid syntheses by Ley et al.2 In the first step, gaseous formaldehyde passed the inner membrane and provided the acid-catalyzed conversion of Fmoc amino acids to the corresponding oxazolidinones within 1 h at 75 - 80 °C. In the second step, liquid-liquid transfer of trifluoroacetic acid was used for the first time in such a reactor.3


Figure 1. Flow reactors used for the first step (left) and for the second step (right) of N-methyl amino acid synthesis.
Here, the semipermeable membrane selectively mediated permeation of trifluoroacetic acid into solution providing the reductive ring opening of oxazolidinones to give Fmoc N-methyl-amino acids within 1 - 2 h at 75 °C. In this continuous flow process various Fmoc protected α-amino acids could be N-methylated in high yields up to 91 % for the first and 99 % for the second step consistent with literature.1,4 However, flow rates of 3 - 8 mL/h in each step enabled reactions times of only 1 - 3 h in total thus, significantly shorter than performed by traditional methods.


[1] R. M. Freidinger, J. S. Hinkle, D. S. Perlow, B. H. Arison, J. Org. Chem., 48, pp.77-81, 1983..
[2] a) M. O’Brien, I. R. Baxendale, S. V. Ley, Org. Lett., 12, pp. 1596-1598, 2010; b) A. Polyzos, M. O’Brien, T. P. Petersen, I. R. Baxendale, S. V. Ley, Angew. Chem. Int. Ed., 50, pp. 1190-1193, 2011; c) P. Koos, U. Gross, A. Polyzos, M. O’Brien, I. Baxendale, S. V. Ley, Org. Biomol. Chem., 9, pp. 6903-6908, 2011; d) M. O’Brien, N. Taylor, A. Polyzos, I. R. Baxendale, S. V. Ley, Chem. Sci., 2, pp. 1250-1257, 2011; e) S. Newton, S. V. Ley, E. Casas Arcé, D. M. Grainger, Adv. Synth. Catal., 354, pp. 1805-1812, 2012; f) P. B. Cranwell, M. O’Brien, D. L. Browne, P. Koos, A. Polyzos, M. Peῆa-Lopéz, S. V. Ley, Org. Biomol. Chem., 10, pp. 5774-5779, 2012.
[3] A. E. Buba, S. Koch, H. Kunz, H. Löwe, Eur. J. Org. Chem., 21, pp. 4509-4530, 2013.
[4] a) L. Aurelio, J. S. Box, R. T. C. Brownlee, A. B. Hughes, M. M. Sleebs, J. Org. Chem., 68, pp. 2652-2667, 2003; b) B. E. Sleebs, A. B.
Hughes, J. Org. Chem., 72, 3340-3352, 2007; c) S. Zhang, T. Govender, T. Norström, P. I. Arvidsson, J. Org. Chem., 70, pp. 6918-6920, 2005; d) T. Govender, P. I. Arvidsson, Tetrahedron Lett., 47, pp. 1691-1694, 2006