Amino Acids and Peptides in Ball Milling - Ball Milling Towards Green Synthesis: Applications, Projects, Challenges - page 127

stress phenomena (horizontally vibrating or circularly shaking milling) and
quantity of energy delivered to the sample, working at 30 Hz or at 450 rpm
(which corresponded to 7.5 Hz), showing that the two apparatus were not
necessarily interconvertible when performing the same reaction.
The same trend was observed during the solvent-less esterification of the
C-terminal position of amino acids, 35 which is effective in the planetary and
not in the vibrational ball-mill apparatus (Scheme 6.10).
Cycled milling was suitable for the reaction of various dialkyl dicarbonates
such as Boc 2 O, Z 2 O, Moc 2 O [(ROCO) 2 O, with R ¼ O t Bu, Bn, Me, respectively],
carbonates (RO 2 CO, with R ¼ succinimide, Me) or alkyl chloroformates
(ROCOCl, with R ¼ Bn, Me, Et, allyl) with N-protected a-amino acids, in the
presence of DMAP as base. As already illustrated for the N-protection of
amino acids 31 (Scheme 6.8), continuous milling provoked the premature
decomposition of activating agents 37 used in stoichiometric quantity. The
decarboxylative esterification proceeded via formation of a mixed carboxylic-
carbonic anhydride A (Scheme 6.10), which was converted into acylpyr-
idinium derivative B by nucleophilic attack of DMAP. The evolution of
carbon dioxide provided the driving force of the reaction.
Compared to solution synthesis, the preparation of tert-butyl esters from
Boc 2 O presented the advantages of shorter reaction times and reduced
quantity of waste, also avoiding the use of expensive Boc 2 O in excess, Lewis
acids, solvents or t-BuOH to speed up the reaction. Benzyl or methyl ester
derivatives using the highly reactive dicarbonates Z 2 O, Moc 2 O or dimethyl
carbonate were not obtainable under solvent-less mechanochemical acti-
vation because of their fast decomposition. Alternatively, the corresponding
chloroformates reacted straightforwardly, and with the succinimidyl esters
prepared from N,N 0 -disuccinimidyl carbonate (DSC). In all cases, the pure
products were recovered after simple and clean filtration/precipitation work-
up, as already illustrated (Schemes 6.8 and 6.9), with lower environmental
impact compared to solution syntheses.
For the spot-to-spot solvent-free mechanochemical derivatizations of N-or
C-protected amino acids (Schemes 6.9 and 6.10, respectively) the tempera-
ture of the mixtures was 23-25 1C, after vibrational or planetary milling,
ruling out a temperature increase into the milling jar 37 as responsible for the
good yields.
The solvent-free derivatization of the N-orC-terminal position of amino
acids was also reported with N,N 0 -carbonyldiimidazole (CDI) (Scheme 6.11). 38
In a first step, carboxylic acids were eciently transformed into acylimida-
zoles by treatment with CDI as activating agent. Subsequent addition of
amine in a ball-mill reactor furnished, through a highly stereoselective
process, the amino acid derivatives 40 and 41 when using enantiopure
HCl NH 2 -Phe-O t Bu or Boc-NH-Phe-OH, respectively (Scheme 6.11).
Notably, consumption of both the carboxylic acid in the first step and the
acyl-imidazole in the second step were monitored by infrared analyses.
Precipitation of pure final compounds in water, followed by filtration,
afforded the amides 40 and 41 without the need of any organic solvent.