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 380

R NO 2
(1.5 equiv)

TFA
(1.0 equiv)

60-120°C
30-90 min

NO 2

NH 2

SiO 2

MeCN
or
toluene

R

N

100 psi bpr Bn

TMS N

Bn

OMe

125

(74-93%)
10 examples

124 (1.0 equiv)

SCHEME 11.39 Synthesis of 3-nitropyrrolidines 125 from the nitroalkene.

EWG
(1.5 equiv)

114

R

EWG

NEt 3 F

M

NH 2

R

MeCN

N

Bn

100 psi bpr

126
(83-92%)
8 examples

TMS N

Bn

OMe

124 (1.0 equiv)

SCHEME 11.40 Synthesis of pyrrolidines 126 from the corresponding alkenes.

purified by scavengingwith benzylamine and a plug of silica gel. This also served a dual
purpose of removing unreacted nitroalkene and releasing the product from its initially
formed TFA salt, giving the desired pure nitropyrrolidines

(Scheme 11.39).
Further optimization studies revealed that nitropyrrolidines could be obtained
under milder conditions when a fluoride monolith was used to generate the dipole
component. Here, the starting materials was flown through a fluoride monolith

125

114
that heated the solution to 50-80 C before purifying the exiting stream using
benzylamine resin to afford the pure products in high yields. Furthermore, the new
procedure allowed other electron-withdrawing groups such as esters, sulfonates, and
phosphonates to replace the nitro group on the olefinic coupling partner. By adjusting
the reaction parameters of the flow reactor, evenmore sensitive nitropyrrolidines were
synthesized (Scheme 11.40).
The H-Cube flow hydrogenator was then used to selectively reduce the nitro
group to an amine function, while leaving the benzyl group intact using a Raney nickel
catalyst. Alternatively, by swapping to a Pd/C cartridge, dual reduction of the nitro
group and a debenzylation reaction was facilitated.

11.4.7. 4,5-Disubstituted Oxazoles as Building Blocks
An immobilized strong base in a packed flow tube has been used to transform acid
chlorides and isocyanides to useful 4,5-disubstituted oxazole building blocks for
medicinal or agrochemical programmes (Scheme 11.41) [45]. For example, in order
to prepare the oxazoles 127 , a flow stream containing an acid chloride was mixed with

O

50-100°C

R

O

BEMP NH 2

R Cl

OEt

N

C
N

50°C 200 psi bpr O

reactor chip

127 EtO

25 examples
(83-99%)

O

SCHEME 11.41 Flow synthesis of 4,5-disubstituted oxazoles ( 127 ).