THE EVOLUTION OF IMMOBILIZED REAGENTS AND THEIR APPLICATION IN FLOW CHEMISTRY FOR THE SYNTHESIS OF NATURAL PRODUCTS AND PHARMACEUTICAL COMPOUNDS - Modern Tools for the Synthesis of Complex Bioactive Molecules - page 383

by flow chemistry
methods involved amide coupling of tyramine 138 and ferulic acid 137 using an
immobilized HOBt cartridge, followed by oxidative dimerization and intramolecular
cyclization (Scheme 11.43) [48]. The reaction progression to

The preparation of the natural product grossamide 140

139 was followed by

inline LC-MS.
For the oxidation step, precursor was diluted (3:1) with a second input

solution containing hydrogen peroxide urea complex and sodium dihydrogen phos-
phate buffer (pH 4.5). The combined flow stream was passed through a prepacked
column with the enzyme horseradish peroxidase (II) supported on silica gel.
Automated LC-MS sampling enabled the reaction progress to be monitored and
provided an opportunity for rapid optimization of flow rates, dilution ratios, and
reagent concentrations.

139

11.5.1. Casein Kinase I Inhibitors
A four-component coupling flow synthesis of a series of casein inhibitors has been
described (Scheme 11.44) [49]. This was achieved by varying substituents at
positions C2, C3, and C6 of the imidazopyridazine core structure

, leading to a
collection of 20 analogues. The first important step necessitated the development
of a continuous flow method to safely scale-up an organometallic reaction at low
temperature. This led to the use of a dual loop system that enabled pumping of the
organometallic species in a continuous fashion. The second step made use of an
immobilized perbromide to ensure monobromination and automated flow device
was equipped with specialized software to effect the third step and optimize the
reaction conditions. Finally, an autosampler was used to perform an automated
S N Ar reaction to give a collection of diversified imidazopyridazine derivatives
145

145

(Scheme 11.44).

_

+

N H Br 3
THF, 30 min
quant.

25°C, 80 min

LiHMDS
Dual loop, 0°C

O N O N.HBr

THF

O

Br

F F

142

141 (92%)

OEt

0°C, 40 min

F

NH 2

DMF

N

Cl N

143

N

Cl

N

N N 177°C, 100 min 120°C, 20 min

N

N N

K 2 CO 3

N N

EtOH

F

F

N

N

N

145 (61%) 144

N

SCHEME 11.44 Flow synthesis of one of a series of casein kinase I inhibitors 145 .