solid-supported reductive amination; solid-supported secondary amine

Daniel Hamza (d.hamza@sussex.ac.uk),
A contribution from the Caddick Group, Sussex

Chemicals Used
4-methylbenzyl amine (any) tetramethylammonium-triacetoxyborohydride acetic acid dichloromethane (distilled from CaH₂) N,N-dimethylformamide

Procedure
Add amine(61.5 mmol, 5 eq, 7.80 mL) to about 20 mL DCM and cool in ice-water bath, add acetic acid (61.5 mmol, 5 eq, 3.52 mL) dropwise to form salt as a slurry. Add slurry to resin (12.7g, 0.967 mmol/g, 12.3 mmol, 1 eq) preswollen in minimum volume DMF. Shake vigorously for about 20 min to form iminium species on solid support. Add Me₄NBH(OAc)₃ slurry in DMF (5 mL) to resin and mix well; shake overnight at room temp. Wash small sample thoroughly with DMF, DCM, Methanol and test for consumption of aldehyde using 2,4-DNP spot test - see separate page. If reaction complete, wash bulk resin sample as described above but if aldehyde still present, add Me₄NBH₂(OAc)₂. Prepare this from Me₄NBH₄ (1 eq) and acetic acid (2 eq) - mix together in DMF until no further evolution of nitrogen gas is observed. Add this to the reductive amination reaction above to drive imine reduction to completion. Yield typically 70-95 % as assessed by FMOC test - see separate synthetic page

Author's Comments
This reaction has typically been performed on scales of 1-10g of resin with yields remaining constant. On solid phase yields do sometimes go down as you scale up the quantities. Repeated around 10 times and routinely used in industry. Be careful not to use too much solvent, concentrations of around 0.5M are good for solid phase reactions to counteract the slower kinetics on resin. This reaction goes well, but sometimes does require a bit of a push to get the imine fully reduced. Sodium cyanoborohydride is a cheap but toxic alternative. The Me₄NBH(OAc)₃ is expensive, but can be made by reacting Me₄NBH₄ with 3 eq of acetic acid. This particular linker is used in the library sythesis of amides.

Data
Assess loading by Fmoc number

Lead Reference
Caddick, S.J.; Wadman, S.N.; Hamza, D. Tetrahedron. Lett. 1999, 40, 7285-7288.

Other References

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