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nation of sub-stoichiometric iodine source and a stoichiometric
oxidant, suggest the involvement of an iodine-based oxidant
in these processes.[27,35] Using benzophenone hydrazone (1) to
investigate oxidation conditions, we found that the use of
N-iodosuccinimide at À788C, together with one equivalent of
base, led to diphenyldiazomethane (2) in reasonable yield
(Table 1, entries 1 to 3) but accompanied by up to 24% of ben-
temperature (Table 1, entry 4). Diphenyldiazomethane (2) was
obtained in good yield under these conditions using a slight
excess of oxidant, while benzophenone azine 3 was produced
as a side product. The use of a solution of potassium hydrox-
ide (1m) in a mixture with THF (ratio 4:1) led to a comparable
yield but improved the purity of the final product obtained
after a simple work-up (Table 1, entry 5). The reduction of
TsNIK produces potassium iodide, which is in turn susceptible
to oxidation to iodine. In the presence of potassium hydroxide,
iodine gives the unstable hypoiodite KOI, which disproportion-
ates at appreciable rates to give potassium iodide and iodate.
In another experiment, we found that an excess of freshly pre-
pared hypoiodite aqueous solution led to partial oxidation of
a solution of hydrazone 1 in ether (Table 1, entry 6). Unfortu-
nately, the yield was low, likely owing to the rapid decay of po-
tassium hypoiodite and to inefficient mass transfers. In this
regard, the potassium salt TsNIK might act as a stable hypoio-
dite equivalent.
Table 1. Oxidation of benzophenone hydrazone using TsNIK and related
reagents.
Entry Conditions
Yield[%][a]
1
2
3
1
2
3
4
5
6
7
8
NIS (1.0 equiv), TMG (1.0 equiv), THF À788C
nd 71
nd 64
nd 81
11
24
7
NIS (1.0 equiv), DBU (1.0 equiv), THF À788C
NIS (1.0 equiv), NEt3 (1.0 equiv), THF À788C
TsNIK (1.1 equiv), THF/H2O (23:2), rt
TsNIK (1.1 equiv), THF/KOH (4:1), rt
aqueous “KOI” (3 equiv), H2O/Et2O, rt
TsNIK (1.1 equiv), DMF, rt
The reaction can also be successfully carried out in dry dime-
thylformamide, giving 88% conversion of the hydrazone 1 into
diazo compound 2 (Table 1, entry 7). Reaction in dry THF was
possible by addition of 18-crown-6 (0.1 equiv) to increase solu-
bility of TsNIK (Table 1, entry 8). Reactions carried out in metha-
nol/water led to poor conversions (Table 1, entry 9). Using the
THF/KOH (1m) solvent system, the sulfonamide resulting from
the reduction of TsNIK was easily and quantitatively removed
from the reaction media by washing with a solution of potassi-
um hydroxide (1m) and extraction in diethyl ether. Moreover,
the product extracted in the organic phase was found to be of
4
84
3
4
94 <1
79 20
11 88
nd
nd
2
nd
42
4
TsNIK (1.05 equiv), THF, 18-crown-6 (0.1 equiv), rt
TsNIK (1.1 equiv), MeOH/H2O (49:1), rt
TsNClNa (1.1 equiv), THF, 18-crown-6 (0.1 equiv), rt 33 25
TsNClNa (1.1 equiv), DMF, 08C to rt 74 21
6
90
9
10
11
53 27
[a] Yields determined by analysis of the product isolated after an aqueous
work-up. nd: not detected. NIS=N-iodo succinimide, DBU=1,8-
diazabicyclo[5.4.0]undec-7-ene, TMG=1,1,3,3-tetramethylguanidine.
1
satisfactory purity (96% by H NMR analysis), and further purifi-
cation was not carried out. p-Toluenesulfonamide, the precur-
sor to TsNIK, was recovered from the aqueous phase by an
acidification/extraction sequence, and in principle can be recy-
cled by treatment with I2/KI/KOH or KI/bleach. In contrast, the
use of TsNClNa (chloramine-T) for hydrazine oxidation proved
unsatisfactory under similar conditions (Table 1, entries 10 and
11).
zophenone azine 3. Based on these results, we sought alterna-
tive methods involving a mild iodinating species capable of
neutralizing the two proton equivalents generated during the
oxidation of the hydrazone, as the less stabilized diazo com-
pounds readily decompose in the presence of acid. The rarely
investigated N-iodo potassium p-toluene-sulfonamide salt 4
(TsNIK, also known as iodamine-T), potassium salt and iodinat-
ed counterpart of the well-established chloramine-T, was se-
lected on the basis of these criteria. This reagent is convenient-
ly and rapidly prepared from inexpensive p-toluenesulfon-
amide in multi-gram quantity and good yield (74%) by treat-
ment with iodine in a mixture of aqueous KI and KOH, and
simply collected by filtration.[36] Alternatively, because iodine is
considered as an “at risk” element,[37] we developed a second
protocol using KI and bleach solution to generate iodine, a pro-
tocol that gave the reagent in 44% yield (Scheme 1).
Based on these encouraging results and in order to establish
the scope of this oxidation, we set out to prepare a number of
hydrazones from diverse ketone precursors. Various a-ketoest-
er and a-ketoamide hydrazones were obtained by condensa-
tion of either commercially or readily available a-keto-esters or
-amides with hydrazine hydrate in presence of a weak Brønst-
ed acid, as previously reported (Table 2).[38,39] The reaction was
carried out in methanol/water using acetic acid (conditions a,
Table 2) or in THF using benzoic acid (conditions b, Table 2),
and under both sets of conditions, hydrazones were obtained
in high yields as separable (E)- and (Z)-isomers. However the
latter set of conditions (b) offer several advantages allowing
the reaction to take place within a few hours, at room temper-
ature, using only one equivalent of acid and hydrazine hydrate,
whereas the original conditions (a) required acetic acid as a co-
solvent and an excess of hydrazine (2 equiv). Excellent conver-
sions into the corresponding hydrazones were obtained for
a range of a-ketoesters (Table 2, entries 1–10) and a-keto-
amides (Table 2, entries 10, 11 and 16–18). Lower yields were
obtained for hydrazones 6m–o (Table 2, entries 13–15) derived
To solubilize the TsNIK reagent, a mixture of THF and water
(ratio 23:2) was first chosen to carry out this reaction at room
Scheme 1. Preparation of N-iodo p-toluenesulfonamide potassium salt
(TsNIK).
Chem. Eur. J. 2014, 20, 4420 – 4425
4421ꢀ 2014 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim