THE NEGISHI CROSS-COUPLING IN THE SYNTHESIS OF NATURAL PRODUCTS AND BIOACTIVE MOLECULES - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 70

Cl Cl

2 steps

n -BuLi, ZnBr 2

N N

N

THF, -70°C

34%

Cl

Br Br ZnBr

216 217

N

X

X

H 2 N

rt
52%

220

214 or 215

X = CH, N

N

TfO

HO

Pd(PPh 3 ) 4 (1 mol% )
THF, 0°C

Ln(OTf)Pd

N

N

N

48%

218 219

SCHEME 2.51 Multikilogram preparation of inhibitors of B-Raf kinase.

Optimization of laboratory-scale synthesis allowed the multikilogram prepa-
ration of the two main building blocks 4-bromo-1-chloroisoquinoline ( 216 ) (2.85 kg)

and trifluoromethanesulfonic acid isoquinolin-7-yl-ester ( 218 ) (10.8 kg) to be used in

the Negishi cross-coupling toward the key intermediate (Scheme 2.51).

The Negishi coupling was straightforward and rapid. No traces of by-products
coming from an hypothetical zincated intermediate formed on the C1 position of
isoquinoline

220

216 were detected, and the arylzinc reagent 217 was stable over 3 h at

50 C. However, the cross-coupling ratewas
strictly dependent on the quality and the amount of palladium catalyst used. The crude
product (79%) was contaminated with 4500 ppm of Zn and 200 ppm of palladium and
was soluble only in DMF, DMA, or pyridine, owing to the presence of an important
amount of complex-bound Zn (7-14 wt%Zn), which also hampered the final coupling
under Buchwald amination conditions. The complex-bound Zn was removed after
treatment of the crude with a solution of ethylenediamine in a 4:1 mixture of water
and THF at 40 C. Interestingly, the Zn-ethylenediamine complex was soluble in
water, while the cross-coupled product

75 C and started to decompose above

was only moderately soluble in THF.
After a crystallization in THF, the Zn level was less than 0.05%. After the last step
involving the Buchwald amination, the final compounds

220

contained
only traces of zinc (less than 10 ppm) and palladium (10-30 ppm), which could be
removed after recrystallization from a mixture of water/ethanol in the presence of
N -ethylenediaminetetraacetic acid disodium salt or acetylcysteine [104], thus lowering
zinc and palladium content below 1 ppm.

214 and 215

2.3.5. mGluR1 Antagonist
Investigation toward the search for novel targets to treat schizophrenia indicated
that 1,4-diaryl-5-methyl-1,2,3-triazole

was a potent and selective mGluR1
antagonist [105], constituted by an aryl-aryl bond built up via a one-pot Negishi
reaction between a bromophthalimidine and a substituted 4-metallatriazole [105],
obtained from an organic azide (Figure 2.20).

221