Amino Acids and Peptides in Ball Milling - Ball Milling Towards Green Synthesis: Applications, Projects, Challenges - page 123

tetrabutylammonium chloride (Scheme 6.7). Various aryl iodo-anilines were
coupled successfully (up to 5 mmol scale with 78% yield), in the presence of
NaCl (5 mg mg 1 aryl halide) as a grinding aid, 29,30 while bromide deriva-
tives failed to give the coupling products. The cross-coupling reaction out-
come was influenced by steric and electronic effects of substituents on the
aromatic ring: electron-withdrawing groups or the proximity of a heteroatom
to the halide led to poor results. The results obtained under ball-milling
conditions were compared to those obtained under usual conditions: (i) on
heating with or without stirring, (ii) under microwave irradiation, (iii) under
high static pressure conditions (200 kg cm 2 ), using an ordinary hydraulic
press for making IR-tablets. The reaction mixture was heated in all cases, at
80 1C, a temperature that matches that generated during milling at full speed
(800 rpm) for 1 h. The yields were always lower compared to ball-mill
experiments (up to 33%), demonstrating that the conditions created during
ball-milling by combination of pressure (rotation of the steel balls), heat,
grinding and stirring were not easy to obtain under usual conditions, af-
firming the power of milling for the positive outcome of the reaction. This
trend was also confirmed for the iodine-promoted intramolecular cyclization
of substituted 2-anilinoenaminones 25 to prepare 2-carbonylated-3-dimethyl-
amino-indoles 26 by solvent-free manual grinding in a mortar (Scheme 6.7). 28
The reactions were generally faster (6-60 min instead of 12 h) and higher
yielding (often quantitative) compared to synthesis in solution using aceto-
nitrile or in the presence of Lewis acids.

6.2.5 Synthesis of Protected Amino Acids
Ball-milling technology was also applied to the solvent-free synthesis of
carbamate N-protected a- and b-amino acids 31

as Boc-, Z-, and Fmoc-

derivatives (Scheme 6.8).
The reactions were performed using two different planetary ball-mill
apparatus and process parameters were also investigated: (i) stainless steel
or tungsten carbide (WC) grinding jar material, (ii) number of grinding
balls, (iii) rotation speed, (iv) mode of operation under cycled or continuous
milling, and (v) grinding additives.
In the one-pot/two-step protocol, the first step relied on the inhibition of
the reactivity of a-orb-carboxylic acid function through the in situ formation
of a transient potassium internal salt, and then stoichiometric amounts of
the suitable protecting group (Boc 2 O, Z-OSu or Fmoc-OSu) were introduced
in the second step (Scheme 6.8). This eco-friendly methodology was general
for all the protecting groups tested in the study, and gave good to excellent
yields of amino acid derivatives without any purification and in a scale from
50 mg up to 1 g of final product. The N-protected amino acid derivatives were
not soluble in water: in the case of N-Fmoc- and N-Z-derivatives, after acid-
ification, the pure product precipitated off the solution and was recovered,
while liquid-liquid extraction was necessary for N-Boc-protected amino
acids. The only by-products were water, CO 2 and t-BuOH (eliminated by