Recent Large-Scale Applications of Transition Metal-Catalyzed Couplings for the Synthesis of Pharmaceuticals - New Trends in Cross-Coupling: Theory and Applications - page 731

i. NaCN (1.3 equiv), KI (0.2 equiv)
CuI (10 mol%)
MeHN

NH 2

NH 2

NH 2

NHMe (85% wt/wt, 1 equiv)

Et

Et

Br 2 ,CH 2 Cl 2
−

Et

PhMe, 115 ºC, 21 h

ii. CuI (5 mol%)
MeHN NHMe (85% wt/wt, 0.4 equiv)
PhMe, 110 ºC, 18 h
iii. aqueous workup
iv. citric acid wash
v. crystallization from PhMe

10 ºC, 3 h

CN
85
(27.89 kg)

Br

83

84
Telescoped as
PhMe solution

67% (2 steps)

OH

H
N O

Et 2 N OH

O

N
O N

Et

N

86
(ACT-209905)

Scheme 15.18 Cu-catalyzed cyanation for the preparation of intermediate 85.

the oxadiazole moiety on the molecule required the previous installation of a
cyano group. Thus, aniline 83 was first converted to p-bromoaniline 84 with
Br 2 , which was telescoped as a toluene solution. A Cu-catalyzed cyanation
protocol developed by Buchwald 116a was then applied, in which 84 was
treated with stoichiometric NaCN in the presence of catalytic KI and N,N 0 -
dimethylethylenediamine as ligand in toluene at reflux to provide cyanoa-
niline 85. The addition of a second charge of CuI/ligand was required to
push the reaction to completion. Toluene was reported by Buchwald to
perform better than polar, aprotic solvents such as DMF or sulfolane, in
which the reactions tend to stall due to the higher solubility of cyanide. The
role of KI is to generate small amounts of transient aryl iodide, which is then
capable of reacting with NaCN to produce the target aryl cyanide. Upon
completion of reaction, the mixture was subjected to an aqueous work-up
that included a citric acid wash (10% aqueous) to sequester Cu. After con-
centration and cooling, 27.89 kg of cyanide 85 crystallized from toluene in
67% yield over two steps with 99% purity. No information on the residual Cu
level in 85 was provided.

15.2.11 Ring-Closing Metathesis
The adoption of ring-closing metathesis (RCM) 119 by academic and medi-
cinal chemistry groups for the preparation of medium and large rings via
intramolecular olefin coupling has been widespread and a key contributing
factor is that many of the Ru and Mo catalysts display remarkable functional
group tolerance. The Nobel Prize in Chemistry awarded to Yves Chauvin,
Richard Schrock and Robert Grubbs in 2005 120 is a clear testimony to the
importance of this transformation in the chemical armamentarium. How-
ever, large-scale examples of RCM applied to the synthesis of pharma-
ceuticals have been scarce until recently, 121 for two main reasons: (a) the
need for high dilution to minimize intermolecular cross-metathesis as a
competing side reaction, which takes a heavy toll on the throughput of the