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A telescoped, selective, mono N-methylation of Boc-DAB-OH via reductive amination using picoline-borane ; (S)-2-((tert-butoxycarbonyl)amino)-4-(methylamino)butanoic acid

SyntheticPage 947
Submitted Feb 10, 2021, published Feb 23, 2021
Andrew Jordan (, Helen F. Sneddon (

			Reaction Scheme: A telescoped, selective, mono <em>N</em>-methylation of Boc-DAB-OH via reductive amination using picoline-borane&nbsp;

Chemicals Used

Boc-DAB-OH i.e. (S)-4-Amino-2-(tert-butoxycarbonylamino)butanoic acid - Sigma Aldrich 97%
Benzaldehyde - Across 98%
Formaldehyde solution 37% aqueous with 10-15% methanol stabiliser - Alfa Aesar
Pic-BH3 Complex i.e. borane-2-methylpyridine complex - Alfa Aesar 95%
10% Pd/C - Sigma Aldrich
NaOH - VWR 98.5%


To a stirred solution of Boc-DAB-OH (436 mg, 2.0 mmol) in 15 mL of methanol/H2O mixture (5:2) was added benzaldehyde (204 µL, 2.0 mmol) and Pic-BH3 (214 mg, 2.00 mmol). The solution was stirred at room temperature for four hours. After four hours the reaction was cooled to 0 °C and excess aqueous formaldehyde solution (37%) was added (1.6 mL). Caution: an exothermic reaction accompanied by gas evolution occurs on formaldehyde addition. The reaction was stirred for one hour and allowed to warm to room temperature. Volatiles were removed in vacuo and the crude residue was purified by silica gel chromatography (0-10% MeOH:DCM gradient, product Rf 0.45) to give the N-benzyl--methylated intermediate as an off white solid (72% Yield, 460 mg, 1.43 mmol). The intermediate was dissolved in 25 mL of an isopropyl alcohol/H2O mixture (1:5) and 43 mg of 10% Pd/C was added. The reaction mixture was stirred vigorously under a H2 atmosphere for 12 hours. After 12 hours, total debenzylation was confirmed by LCMS. H2 was purged from the reaction mixture with N2 and the catalyst was removed by filtration through a plug of celite. The celite pad was washed with isopropyl alcohol (2 x 10 mL) and added to the filtrate. Volatiles were removed from the combined filtrates in vacuo to give quantitative isolation of the target mono -methylated product (Yield >95%, 332 mg, 1.43 mmol).

Author's Comments

The sequence first involves the mono N-benzylation of the amino acid via reductive amination. The benzyl group acts as a convenient steric block thus preventing bis alkylation. Mono N-methylation is then conveniently achieved in the second step. Debenzylation via hydrogenolysis conveniently furnishes the mono N-methylated amino acid with no dimethylated product present. The methodology combines a Leuckart reduction with the use of Pic-BH3 ; a safer and more sustainable reagent for  conducting reductive amination.

Chromatography free synthesis of N-methyl-N-benzyl-L-Phenylalanine, L-Valine and L-Leucine have been also achieved on a 5 mmol scale by this same sequence. The starting reaction mixtures were dissolved in just methanol with no water, followed by 1 equivalent of powdered NaOH.  The  reductive amination sequence was carried out as above. Note: the L-Phe reaction required the addition of a few drops of conc. HCl to catalyse the reduction. Product isolation was achieved by allowing the reaction mixtures to crystallise at -5°C for 12 hours from methanol treated to pH 8-9 with powdered NaOH.
Isolated yields of N-methyl-N-benzyl- amino acids:
L-Phe: 79%, L-Val: 97%, L-Leu: 83%


N-methyl-Boc-DAB-OH: Off-white solid. 

δ H (400 MHz, Deuterium Oxide) 5.07 – 4.55 (1 H, m), 3.98 (1 H, s), 3.25 – 3.02 (2 H, m), 2.73 (3 H, s), 2.16 (1 H, s), 2.07 – 1.83 (1 H, m), 1.45 (9 H, s).

δ C (101 MHz, Deuterium Oxide) 177.8, 157.5, 79.1, 53.5, 46.3, 32.7, 29.8, 27.6.

Lead Reference

S. Sato, T. Sakamoto, E. Miyazawa and Y. Kikugawa, Tetrahedron, 2004, 60, 7899-7906.

Other References

F. I. McGonagle, D. S. MacMillan, J. Murray, H. F. Sneddon, C. Jamieson and A. J. B. Watson, Green Chemistry, 2013, 15, 1159-1165.
G. Verardo, P. Geatti, E. Pol and A. G. Giumanini, Canadian Journal of Chemistry, 2002, 80, 779-788.
L. Aurelio, R. T. C. Brownlee and A. B. Hughes, Chemical Reviews, 2004, 104, 5823-5846.

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Keywords: amination, amines, amino acids, green, methylation, mono, protecting group, reduction, selective, sustainable

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