Biomedical Engineering Reference
In-Depth Information
AIBN
1-dodecanol
Cl
Et
3
N
(at least 2.5 equi
v)
60°C, 48 h
(recycling)
NaN
3
(aq)
(0.1 M, 40 mL)
80°C, 20 h
NEt
3
Cl
NEt
3
N
3
M
Cl
M
M
+
160 mins
103
104
105
(3.5 mmol.g
-1
)
SCHEME 11.25
Synthesis of an azide monolith
105
.
of reactive or, in this case, hazardous intermediates, which in batch mode could be
a serious safety risk.
To solve potential safety problems, an azide monolith has been developed and
used to synthesize acyl azides in flow, which can then undergoCurtius rearrangements
to give a variety of aryl isocyanates [37]. An alternative method has also been used to
produce the acyl azides on a 25 g scale, continuously, from diphenylphosporyl azide
(DPPA) and a carboxylic acid [38]. Performing this reaction continuously on a small
scale or with an immobilized azide source greatly increases the safety during the
generation of these compounds and demonstrates the potential for scaling up these
reactions safely and easily.
Azide monolith
made
by polymerizing vinyl benzyl chloride and divinylbenzene using AIBN, with 1-
dodecanol used as the porogen. Monolith
105
was prepared from a Merrifield-type monolith
103
was then converted to its quaternary
ammonium form using triethylamine, resulting in a chloride counterion to the
monolith
103
. This monolith can subsequently be ion exchanged with an aqueous
solution of sodium azide to give the stable azide monolith
104
105
, which can be safely
stored and handled (Scheme 11.25).
The utility of this monolith was demonstrated when an acid chloride was eluted
through the monolith at ambient temperature, followed by a plug of drying agent to
remove any water released from the monolith to generate the acyl azide
106
, which
can be isolated in high yield and purity (Scheme 11.26).
In order to obtain the Curtius rearrangement products, the acyl azide inter-
mediate continues its passage through a heated coil at 120
C, whereupon rear-
rangement to the corresponding isocyanate
occurs. The output stream was
collected into a microwave vial containing the desired nucleophile and heated to
100
C for 10min. The resulting products
107
108
wereobtainedinhighyieldandpurity.
O
N
3
NEt
3
N
3
M
O
105
Br
MgSO
4
or NaSO
4
106
R
Cl
13 min
MeCN
N
25°C
R
C
O
107
100 psi bpr
120°C, 40 min
O
10 examples
(64-90%, > 95% purity)
Nuc-H
R
N
H
Nuc
108
Microwave vial
100°C, 10 min
SCHEME 11.26
Synthesis of acyl azides
106
and derivatives
108
.
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