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 377

O

EWG

O

R

100-120°C, 30 min

EWG

SO 3 H NMe 2

R

MeCN F

116

100 psi bpr

Cl

N

(82-93%)
6 examples

N

F 2BF 4

Selectfluor ®

Electrophilic fluorine reactions with Selectfluor . SCHEME 11.32

the fluoro-Ritter reaction with olefinic substrates can be realized in the same reactor
setup. In the first reaction, a stream of the activated carbonyl was combined with a
stream of Selectfluor and heated between 100 and 120 C (Scheme 11.32). Then the
product stream was purified using immobilized sulfonic acid and dimethylamine
resins to scavenge excess reagents and by-products. This process afforded the desired
products

116

in high yield and excellent purity (Scheme 11.32).
An identical reactor arrangement was then used for the Ritter reaction, whereby
an alkene starting material in the presence of wet acetic acid (

5mol%water) reacts
with acetonitrile. This mixture was heated to 120 C to furnish the desired mono-
fluorinated products 117 (Scheme 11.33).
The reagent DAST is a useful source of fluorine for the transformation of an
alcohol or a carbonyl functionality (aldehyde or activated ketone) to the correspond-
ing mono- or difluorinated products [41]. For example, an alcohol or carbonyl input
stream was combined with DAST in DCM and heated between 70 and 90 C
(Scheme 11.34). Excess DAST along with any residual HF was scavenged using a
calcium carbonate quench, immediately followed by a silica gel plug to trap inorganic
salts. Although this scavenging procedure produces carbon dioxide, this is managed
easily using the continuous flow environment as the generated gas is progressed
through the reactor, avoiding a buildup of pressure. While yields were affected by
the electronics of the carbonyl moiety, the reaction was found to be tolerant of a wide

G

R'

R

AcOH
(<5% H 2 O)

120°C, 30 min

SO 3 H NMe 2

NHAc

R'

MeCN

R

100 psi bpr

F

Cl

N

N

117
5 examples
(83-97%)

F 2BF 4

Ritter reactions with Selectfluor . SCHEME 11.33

O OH

or

R R' R R'

70-90°C, 30 min

CaCO 3 SiO 2

F X

DCM

R R'

100 psi bpr

SF 3

N

118

(X = F or H)
23 examples
alcohols (65-97%)
aldehydes/ketones (50-96%)

(DAST)

SCHEME 11.34 Synthesis of mono- or difluorinated products 118 using DAST.