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 373

O

S

R 2

+

R 1 Cl 100°C, 30 min

H NH 2

O

Polyol SO 3 H

CaCO 3

(1.2 equiv)

DCM

R 1

R 2

100 psi bpr

101
(41-95%)
17 examples

Pd(OAc) 2 (1 mol%)

(i- Pr) 2 NEt (1.2 equiv)

SCHEME 11.23

Synthesis of yne-ones 101 .

H
N

O H 2 N R 3

R 1 Cl

S

rt-100°C
20-30 min

(1 .2 e quiv)

100°C, 30 min

R 3

NH 2

N
H

R 2

Polyol CaCO 3 SO 3 H

N N

DCM R 2

100 psi bpr R 1

102
(53-86%)
9 examples

Pd(OAc) 2 (1 mol%)

(i- Pr) 2 NEt (1.2 equiv)

SCHEME 11.24 Synthesis of pyrazoles 102 .

Here, the desired acyl chloride and acetylene in one reagent stream were combined
with a second stream containing a catalytic amount of Pd(OAc) 2 and base. The
combined reagent streamwas heated at 100 C for 30min and the reactor output was
then purified by passage through a series of four solid reagents and scavengers. First,
a polyol resin was used to remove excess acyl chloride followed by a column of
CaCO 3 to trap the HCl formed during the reaction and to deprotonate any
ammonium salts. The resultant tertiary amine by-product was then trapped on the
sulfonic acid resin before a column of immobilized thiourea finally removed
residual palladium contamination. The yne-one products were obtained in

moderate to high yield (41-95%) and purity following removal of the solvent
(Scheme 11.23).
The yne-one can then be combined with an additional input stream containing,
for example, a hydrazine (or guanidine) derivative. The mixed stream is heated
before passage through a column of calcium carbonate, resulting eventually in the
formation of simple pyrazoles (

101

) or aminopyrimidines (from guanidine) as final
products or as starting materials for other medicinal chemistry programmes
(Scheme 11.24). Excess hydrazine or guanidine can be removed by acidic resins,
thereby preventing the larger dispersion curve normally observed at the end of
multiple column sequences. In this way, a collection of pyrimidines, pyrazoles,
oximes, guanidines, and flavones was obtained, all in high yield and purity.

102

11.4.3. Curtius Rearrangement
The Curtius rearrangement transforms carboxylic acids or acid chlorides to the
corresponding isocyanate functionality. The reaction proceeds via an intermediate
acyl azide that undergoes rearrangement to give a reactive isocyanate that can
be attacked by a nucleophile to give functionalized product. The continuous
production and immediate quenching of the isocyanate also exemplifies another
advantage of flow chemistry, namely, the preparation and immediate consumption