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 375

O

(1.1 equiv)

R OH

12 further examples
using 'catch and release'
purification using

NEt 3 (2 equiv)
Nuc-H (3 equiv)

120°C, 20 min

NMe 2

SO 3 H O

R

MeCN

H Nuc

O SO 3 H

100 psi bpr

109

P

N 3

PhO

and NH 3 in MeOH

(64-90%)
11 examples

OPh
DPPA

(75-95%)

SCHEME 11.27 Curtius rearrangements using diphenylphosphoryl azide.

Typically, the azide monolith has been used to create between 1 and 10mmol of acyl
azides . It can also be regenerated easily by treatment with an aqueous solution

of sodium azide.
The Curtius rearrangement using DPPA as a source of azide with a variety of
carboxylic acids in flow has also been reported (Scheme 11.27) [38]. Here, a solution
of a carboxylic acid with triethylamine plus a suitable nucleophile was loaded as one
reaction stream, which was then combined with a second stream containing DPPA in
the same solvent. An excess of the carboxylic acid was used to ensure complete
consumption of the DPPA. On mixing of the streams, an acyl azide was generated that
on heating in a coil produced the isocyanate that was quenched immediately with an
in situ nucleophile to give the desired products

106

. A mixed acid/base scavenger
workup was used to remove the base, excess carboxylic acid, and the by-product. For
nitrogen-containing heterocyclic carboxylic acid starting materials, it was found
necessary to use a catch-and-release protocol to afford the purified products.
To produce a Boc-protected 110 or Fmoc-protected amine 111 , heating to
120 C for 2min in a flow microwave was required. For 111 , a more hindered base
(2,6-lutidine) and more hindered basic resin (polymer-immobilized 2,6-di- tert -
butylpyridine) were required to prevent in situ protecting group removal under basic
conditions (Scheme 11.28).
Mixed semicarbazide products

109

, on the other hand, were prepared using a
procedure similar to that described in Scheme 11.26. Here, the isocyanate stream

113

107

was directed into a collecting vial containing a hydrazine derivative . This proved

necessary owing to the low solubility of the resulting semicarbazide products in
acetonitrile. Analytically pure material could then be obtained upon filtration of the
precipitated compound (Scheme 11.29).

112

microwave flow coil
120°C, 2 min

O

NMe 2

O SO 3 H

(1.1 equiv)

MgSO 4

Boc

H OEt

R OH

100 psi bpr

Base (2 equiv)
Nuc-H (3 equiv)

120°C, 20 min

110 (89%)

t -Bu

MeCN

O

N

P

N 3

PhO

SO 3 H

t -Bu

OPh
DPPA

Br

O

MeO H Fmoc

100 psi bpr

111 (87%)

SCHEME 11.28 Production of Boc- or Fmoc-protected amines 110 and 111 .