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S. E. Cobb et al. / Tetrahedron Letters 52 (2011) 1605–1607
Table 1
aldehyde is converted in two steps into the oximyl chloride 4. The
key step, first developed by Benn in the 1960s,11 is thought to
involve in situ generation of a nitrile oxide from 4 under basic con-
ditions, which reacts with a 1,3-addition reaction with a protected
Reaction conditions and results for the bleach-mediated b-thiohydroximate synthesis
Entry
Oxime
Yield (%)
OH
N
b-D-thioglucopyranose to give the Z-thiohydroximate 5, stereospe-
cifically. Stereoelectronic effects operating during 1,3-addition of
nucelophiles to nitrile oxides are thought to be the reason for the
stereospecificity.12 The final two steps are then sulfonation of the
N-hydroxy group using pyridineÁSO3 complex and deprotection of
the sugar with potassium in methanol.
Over the years this process has been updated and modified,
mainly in the method by which the nitrile oxide is obtained.10
Herein, we report a novel, simple and high yielding procedure for
this key step in glucosinolate synthesis.
1
76
OH
N
2
3
78
63
OH
N
OH
N
The nitrile oxides required for glucosinolate synthesis are
unstable species that are usually generated via the facile elimina-
tion of HCl from an oximyl chloride under basic conditions. Tradi-
tionally, oximyl chlorides are prepared from oximes by reaction
with chlorine gas or N-chlorosuccinimide (NCS) and then isolated,
but are usually used without purification, for coupling to the thio-
glucose (Scheme 1). These reactions are not usually very high
yielding The use of bleach has been described as a convenient re-
agent for the formation of nitrile oxides,13 but this has not been
exploited in glucosinolate synthesis.
Our group has now developed a simple, novel and convenient
method for the formation of thiohydroximate bonds in glucosino-
lates, which generates the intermediate oximyl chlorides in situ,
using inexpensive, common laboratory bleach and provides higher
yields than previous methods over a range of substrates.
The oximes examined were either commercially available or
prepared using the appropriate aldehyde and hydroxylamine
hydrochloride in good yield. These were then used as a mixture
of E- and Z-isomers without further purification.
4
5
77
92
OH
N
Br
OH
N
6
7
65
83
N
OH
N
OTBS
yields over previous two-step methods. The first entry, which gave
a 76% yield, is the precursor to the glucosinolate, gluconasturtiin,
which had been made before in our laboratory in a lower yield of
61%, over two steps via the standard method involving isolation
of the oximyl chloride.16 It was similarly prepared by Gil and
McLeod in 69% yield.15 The oxime from octanal (entry 2) was
previously employed to make heptyl glucosinolate, the thiohy-
droximate being prepared in 61% yield over two steps,17 which is
considerably lower than the 78% yield obtained herein.
The oximes were dissolved in dichloromethane and held in a sep-
arating funnel before the addition of 3 equiv of common laboratory
bleach.14 The biphasic solution was shaken and a blue colour devel-
oped, which is due to the presence of the C-nitroso intermediate.15
The organic layer was then added dropwise to a stirred solution of
2,3,4,6-tetra-O-acetyl-1-thio-b-
D
-glucopyranose in dichlorometh-
Good yields were also observed with both alkenyl and alkynyl
side chains (entries 3 and 4). In previous syntheses of glucosino-
lates with unsaturated side chains, the oximyl chlorides were pre-
pared via nucleophilic chlorination of an alkenyl nitronate from a
nitroalkane precursor, due to the perception that the presence of
the alkene would prevent efficient aldoxime chlorination.10 How-
ever, it can be seen that by using our newly developed method,
but-4-enyl oxime (entry 3), gives a 63% yield, compared to only
13% from the nitroalkane in two steps.18
Entries 5 and 6 are aromatic oximes which would lead to novel
glucosinolate structures. The final oxime (entry 7) gives a b-thiohy-
droximate with a TBS-protected alcohol in its side chain, which
was found to be stable under the reaction conditions, and coupled
in very good yield.
ane (Scheme 2). Finally, triethylamine was added to promote forma-
tion of the nitrile oxide. The order of addition of base was critical to
the coupling procedure, as it was found that thioglucose readily
dimerises under basic conditions. Further optimisation led to an ex-
cess of the oxime being used to achieve the best yields.
A range of substrates was employed to investigate the scope
and utility of the method. The structures were based on the side
chains found in naturally occurring glucosinolates, plus some extra
substrates with unusual side chain functionality, and the results
are summarised in Table 1.
This new procedure was observed to work simply and effi-
ciently with all the oximes that were studied, giving improved
In summary, we have developed a new coupling method for b-
thiohydroximate bond formation using inexpensive and readily
available bleach as the chlorinating agent. This simplified one-step
procedure is easy to carry out, is quick and gives good to excellent
yields over a range of substrates. The method provides a useful
improvement to the general synthetic route to glucosinolates.
HO
HO
N
N
bleach, CH2Cl2
R
Cl
R
H
4
3
AcO
AcO
Et3N
CH2Cl2
O
SH
Acknowledgements
AcO
AcO
AcO
AcO
OH
N
Iain Smellie is acknowledged for his enthusiasm and interest in
the project and for useful discussions. Tomas Lebl and Melanja
Smith assisted with NMR spectroscopy and Caroline Horsbrough
with mass spectrometry. Financial support from the EPSRC and
BBSRC is gratefully acknowledged.
O
S
AcO
R
N
O
AcO
R
5
Scheme 2. Bleach-mediated thiohydroximate synthesis.
Cobb, Susan E.
