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 378

H
N R

HO

70-80°C, 30 min

R' O

CaCO 3 SiO 2

R

N

R'

DCM

O

100 psi bpr

SF 3

119

N

(87-95%)
4 examples

(DAST)

SCHEME 11.35 Synthesis of oxazolines 119 using DAST.

range of functional groups, for example, epoxides, alkenes, acetals, amines, esters,
amides, and various heterocycles.
DAST has also been used in cyclodehydration reactions where starting
b -hydroxy amines were converted to the corresponding oxazolines 119 in excellent

yields compared to previously reported procedures (Scheme 11.35).

11.4.5. Seyferth-Gilbert Homologation Using the Bestmann-
Ohira Reagent for the Formation of Acetylenes and Triazoles
The Seyferth-Gilbert homologation using the Bestmann-Ohira reagent 121 has been
used for the production of acetylenes in a flowmicroreactor (Scheme 11.36) [42]. The
reaction proceeds well but requires extensive purification with immobilized reagent
cartridges owing to the large number and quantities of by-products produced in this
reaction sequence.
The aldehyde component and the Bestmann-Ohira reagent were combined

with a secondary stream of potassium tert -butoxide and introduced to a heating coil at
100 C. The exiting flow stream was first scavenged with immobilized benzylamine
heated to 70 C to remove excess aldehyde, then a sulfonic acid resin to both remove
excess base and protonate any phosphoric residues, and finally a dimethylamine
cartridge to remove any acidic material. The pure acetylic compound

121

could then
be collected in high yield. For nitrogen-containing heterocyclic starting materials, the
sulfonic acid resin cartridge was substituted for an alumina packed tube to avoid partial
capture and hydrolysis of the acetylene to a methyl ketone. The reaction was generally
tolerant of functional groups (e.g., halides, nitro compounds, esters, and cyanides).
The procedure was further extended to prepare triazoles by using azides
following an already established procedure (Scheme 11.37) [43]. The cyclization
was initiated by passage through a copper(I) catalyst supported on a dimethylamine
resin. Copper impurities that potentially leached from the resin were subsequently
scavenged using immobilized thiourea, while the products

120

122 could be isolated in

high yield by crystallization (Scheme 11.37).

O O O

P OMe

alumina
or

R H Me

OMe

100°C, 30 min

(1.3-1.5 equiv) N 2

NH 2

SO 3 H NMe 2

MeOH or
MeOH/MeCN
(1:1)

H

121

R

70°C

100 psi bpr

120

t- BuOK in MeOH
(1.2 equiv)

(64-84%)
11 examples

SCHEME 11.36 Synthesis of acetylenes 120 using the Bestmann-Ohira reagent 121 .