Recent Large-Scale Applications of Transition Metal-Catalyzed Couplings for the Synthesis of Pharmaceuticals - New Trends in Cross-Coupling: Theory and Applications - page 746

pharmaceuticals. However, thanks to great advances in the design of new
catalytic systems through the use of ligands such as aliphatic diamines,
aromatic amines, amino acids, amino alcohols, imines and 1,3-dicarbonyl
compounds, the Ullmann coupling employing substoichiometric amounts
of metal has seen a resurgence in recent years that has greatly expanded the
application of this technology to make C-N bonds. 148 Since CuI and many of
the ligands currently used are inexpensive, this technology has found several
applications in the field of process chemistry. 149
The process group at GlaxoSmithKline described the implementation of a
Cu-catalyzed Ullmann coupling during the synthesis of GSK2137305 (142), a
spirocyclic glycine transporter inhibitor for the treatment of neurological
and neuropsychiatric disorders (Scheme 15.32). 149d The coupling of aryl
bromide 139 and 4-methylimidazole (140) was initially carried out in the
presence of CuI (0.6 equiv.) and L -histidine (1.2 equiv.), but the high ligand
loading gave rise to substantial by-product formation that complicated the
isolation of 141. In addition, a 4:1 regioisomeric mixture of N-1 and N-3
coupling products was obtained and the undesired regioisomer carried
through subsequent chemistry to generate the corresponding regioisomer of
API 142. With the goal of minimizing the catalyst loading and improving the
regioselectivity of the reaction, screening studies were carried out with a
number of commercially available ligands [ L -proline, ethylene glycol, 1,10-
phenanthroline, ninhydrin, ( )-trans-1,2-diaminocyclohexane, 2-dimethyl-
aminoethanol, N,N 0 -dimethylethylenediamine, trans-N,N 0 -dimethylcyclo-
hexane-1,2-diamine and 8-hydroxyquinoline] in several solvents (DMSO,
o-xylene, toluene, 1,4-dioxane, propionitrile, NMP, n-butyl acetate, DMPU,
1-butanol, 1-pentanol). Alcohols in combination with amines were the most
promising hits, but the isolation of 141 still proved dicult, especially with
low Cu levels (target o 100 ppm). The best results were obtained when the
reaction was carried out in the absence of ligand, since it is known that
heterocycles can perform this role in this type of coupling. In the plant, a
mixture of 139, 140, CuI (15 mol%) and K 2 CO 3 in DMSO (a preferred solvent
on scale) was heated at 130 1C for 36 h. Upon completion of reaction, the
mixture was cooled to 60-70 1C, diluted with i-PrOAc and treated with 3 wt%
aqueous L -cysteine (metal chelator). Following an aqueous work-up and

N

Br N

N

i. CuI (15 mol %)
K 2 CO 3 ,DMSO,130ºC,36h

N

N

O

+

O

H

ii. aqueous workup
( L -cysteine wash)
iii. crystallization from i -PrOAc
54%

O

HN N

O

HN N

NN

F 3 C N

H

141
(5.65 kg,
5% N-3 regioisomer)
<100 ppm Cu

139 140

(3.6 equiv)

142
(GSK2137305)
<10 ppm Cu

Scheme 15.32 Ullmann coupling of aryl bromide 139 and imidazole 140 en route to
GSK2137305.