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 376

O

(1.1 equiv)

R OH

Et 3 N (2 equiv)
Nuc-H (3 equiv)

120°C, 20 min

NMe 2 SO 3 H O

N

H
N R'
112

N

R

MeCN R C +

H H

H 2 N R'

O

O

100 psi bpr

107 113

P

N 3

PhO

Vial containing
nucleophile

(82-93%)
4 examples

OPh
DPPA

SCHEME 11.29

Synthesis of mixed semicarbazide products 113 .

11.4.4. Fluorination Reactions
Fluorine atoms in drug molecules are typically used to improve binding or provide
greater metabolic stability. However, the introduction of fluorine to molecules can
prove difficult due to the hazards associated with the most commonly used fluori-
nating reagents. Using a flow microreactor system with immobilized inline purifi-
cation, many of these hazards are eliminated owing to the contained environment and
the robustness of the reactor tubes [39].
Trifluoromethylation of aldehydes has been demonstrated using TMSCF 3
(Ruppert's reagent) as a source of nucleophilic CF 3 when an immobilized fluoride
was used as the initiating agent [40]. In particular, a fluoride monolith 114 provided a
versatile source of fluoride anions that can be readily prepared using ion exchange
procedures (Scheme 11.30) [37].
The fluoride monolith may then be used to transform aldehydes into

their corresponding trifluoromethylated derivatives (Scheme 11.31). Hence, it was
found that gentle heating of the monolith and the sequential use of heating coils
improved yields in these reactions. The reaction stream was purified using an
immobilized aldehyde to trap any unreacted Ruppert's reagent, while an immobilized
acid deprotects the intermediate silylated product initially formed. Finally, an
immobilized hydrazine then sequesters any unreacted aldehyde. The desired products
115

114

were obtained in high yields after solvent removal (Scheme 11.31).
Alternative flow chemistry methods for the introduction of fluorine involves
the use of other common fluorinating agents such as Selectfluor and diethylamino
sulfurtrifluoride (DAST). The safe workup of these reactions was achieved by the
application of flow synthesis and immobilized reagents. Fluorine atoms may also
be introduced a to an activated ketone using the Selectfluor reagent, while similarly

KF (4 equiv)

NEt 3 Cl

M

M NEt 3 F

104 114

SCHEME 11.30 Synthesis of a fluoride monolith 114 .

O

O O

O

NEt 3 F

R H M

S NH 2

40°C, 100 min

H

114

H SO 3 H OH

THF

R CF 3

40°C, 20 min 100 psi bpr

115
(76-88%)
10 examples

TMS CF 3

Ruppert reagent

SCHEME 11.31 115

Synthesis of trifluoromethylated alcohols using a fluoride

monolith 114 .