Synthesis of 3,3-dichloro-2-oxindoles from isatin-3-p-tosylhydrazones and (dichloroiodo)benzene

Article abstract of DOI:10.1016/j.tetlet.2015.06.063

Abstract A series of aryl- and N-substituted isatin derivatives were converted to the corresponding isatin-3-p-tosylhydrazones, and these were subjected to a Lewis base-catalyzed chlorination reaction that employs the hypervalent chlorinating agent PhICl₂. The discovery of p-tosylhydrazones as chlorination precursors has expanded the functional group tolerance of the chlorination reaction to now include carbamates, acetamides, and sulfonates. Additionally, this allowed us to circumvent the use of the diazo group in our chlorination reaction, and offers a new avenue for exploring our two-step deoxygenative dihalogenation reaction. We also disclose the use of PhICl₂ for the oxidative chlorination of sulfinates to the corresponding sulfonyl chlorides.

Full text of DOI:10.1016/j.tetlet.2015.06.063

Accepted Manuscript
Synthesis of 3,3-dichloro-2-oxindoles from isatin-3-p-tosylhydrazones and (di-
chloroiodo)benzene
Charlotte Hepples, Graham K. Murphy
PII:
S0040-4039(15)01082-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.06.063
TETL 46455
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
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11 June 2015
22 June 2015
Please cite this article as: Hepples, C., Murphy, G.K., Synthesis of 3,3-dichloro-2-oxindoles from isatin-3-p-
tosylhydrazones and (dichloroiodo)benzene, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.
2015.06.063
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Synthesis of 3,3-dichloro-2-oxindoles from
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Charlotte Hepples and Graham K. Murphy*

1
Tetrahedron Letters
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Synthesis of 3,3-dichloro-2-oxindoles from isatin-3-p-tosylhydrazones and
(dichloroiodo)benzene
Charlotte Hepples and Graham K. Murphy∗
aC2-367, Department of Chemistry, University of Waterloo. 200 University Ave W., Waterloo, ON, Canada, N2L3G1.
ARTICLE INFO
ABSTRACT
Article history:
Received
A series of aryl- and N-substituted isatin derivatives were converted to the corresponding isatin-
3-p-tosylhydrazones, and these were subjected to a Lewis base-catalyzed chlorination reaction
that employs the hypervalent chlorinating agent PhICl2. The discovery of p-tosylhydrazones as
chlorination precursors has expanded the functional group tolerance of the chlorination reaction
to now include carbamates, acetamides and sulfonates. Additionally, this allowed us to
circumvent the use of the diazo group in our chlorination reaction, and offers a new avenue for
exploring our two-step deoxygenative dihalogenation reaction. We also disclose the use of
PhICl2 for the oxidative chlorination of sulfinates to the corresponding sulfonyl chlorides.
Received in revised form
Accepted
Available online
Keywords:
Hypervalent iodine
Oxindole
2009 Elsevier Ltd. All rights reserved.
Halogenation
p-Tosylhydrazone
Sulfonyl Chloride
Oxindoles represent a biologically important class of privi-
leged molecules whose 3,3-disubstituted structural motif is wide-
ly distributed among natural products, pharmaceuticals and agro-
chemicals.1 The 3,3-dihalo motif is one of many substitution pat-
terns one encounters with the 3,3-disubstituted-2-oxindoles, and
the most common of these are the 3,3-difluoro derivatives, where
the fluorination is used as a bioisostere for hydrogen.2 The less
common 3,3-dichloro-2-oxindoles (Figure 1) have also been in-
vestigated as biological agents such as caspase inhibitors (1),3
anticancer agents (2,3),4,5 therapeutics for diabetes (4,5)6,7 or car-
diovascular disease (5)6 and fungicides (6).8 Given the medicinal
and industrial relevance of this motif, it is important to develop
mild, efficient and highly chemoselective halogenation strategies
for this class of compounds.
One strategy for preparing the 3,3-dichloro motif is to treat
substituted isatins (indole-2,3-dione) with reagents such as
WCl6,9 ClSO3H,3,10 SO2Cl2,11 or PCl5,7,12 though each of these
reagents has drawbacks such as their sensitivity to moisture or
being powerful lachrymators. An alternative to these reagents is
(dichloroiodo)benzene, PhICl2 (7), which has been used as a
chlorinating agent since its discovery in 1886.13 The longevity of
this seemingly exotic hypervalent reagent is due in part to its ease
of preparation,14 its stability and the mild, environmentally be-
nign reaction conditions associated with its use. Its modern re-
surgence as a chlorinating agent stems from the fact that it can be
used as a milder, more chemoselective substitute for elemental
chlorine in the chlorination of alkenes, alkynes and arenes.15 Ad-
ditionally, we have recently reported a Lewis base-catalyzed
chlorination of diazocarbonyl compounds16 derived from
phenylacetate17 (eq 1) and 2-oxindole18 (eq 2) scaffolds that em-
ploys PhICl2. These reactions were rapid, chemoselective and
typically high yielding, and constitute a new development in
hypervalent iodine chemistry, as both ligands from the iodane are
transferred in a geminal, rather than a vicinal fashion. A draw-
back of these reactions is the negative properties often associated
with diazo compounds, i.e. that they are potentially carcinogenic
and explosive,19 which has led us to search for additional func-
tional group precursors that could be employed as diazo surro-
gates, or entirely circumvent their use.20
Figure 1. Biologically active 3,3-dichloro-2-oxindole compounds.
———
∗ Corresponding author. Tel.: +1-519-888-4567; fax: +1-519-746-0435; e-mail: graham.murphy@uwaterloo.ca

2
Tetrahedron
Figure 2. Previously proposed mechanism for chlorination of isatin-3-
hydrazones with PhICl2 and proposed reaction sequence for the current work.
A series of isatin-3-hydrazone derivatives (13-15) was pre-
pared by treating the substituted isatins with the corresponding
hydrazides. The N-Me substrate (13a) was chosen for investiga-
tion of the reaction parameters (Table 1), and was initially treated
with 1.1 eq. of iodane 7 and 5 mol% pyridine in DCE at reflux.
Because hydrazones can be converted to azo species when
treated with hypervalent iodine reagents,21 we devised a one-pot,
oxidative chlorination sequence to circumvent the intermediacy
of a diazo species en route to providing the 3,3-dichloro-2-
oxindoles (eq 3).22 This process gave the dichloride products of
aryl- and N-functionalized substrates in good to excellent yield,
and was compatible with a broad range of different steric and
electronic substituents including halogens, ethers, alkyl, allyl,
propargyl and aryl groups. We were unable to test N-acetyl, -
benzoyl, -sulfonyl and N-carbamate derivatives in the reaction as
these groups were incompatible with the aqueous hydrazine used
for hydrazone formation. This shortcoming was a significant
drawback of the two-step process, given the frequency that such
N-substituents are encountered with oxindoles and other scaf-
folds of biological interest. Thus, searched for additional func-
tional groups that are viable gem-dihalogenation precursors, po-
tentially expanding the scope of our two-step deoxygenative
dichlorination and difluorination reactions. Our efforts towards
using electron-deficient hydrazones in the gem-dichlorination
reaction are presented here.
1
Monitoring the reaction by H NMR showed only 52% conver-
sion after one hour, from which the product was recovered in
40% yield. Concerns over the nucleophilicity of the hydrazone
led us to change the Lewis base catalyst to the more active
DMAP (entry 2) or TBAI (entry 3), but this also resulted in in-
complete conversion, and gave the products in low yield. Chang-
ing the hydrazone substituent (entries 4,5) also failed to give
complete conversions, and gave low product yields. Increasing
the amount of iodane to 1.6 eq. (entry 6) caused an increase in
both conversion (62%) and yield (46%) of product. When 2.1 eq.
of iodane 7 was used, the conversion increased to 90%, and the
product was isolated in 70% yield. A final increase to 2.5 eq. of
iodane gave complete conversion, and the product was isolated in
75 % yield in 5 minutes. Thus, p-tosylhydrazone 13a could be
converted to dichloride 11a under identical reaction conditions,
and in nearly identical rate and yield as the conversion from
unsubstituted hydrazones (eq 3).
Inspiration for a solution to the functional group incompatibil-
ity problem came from analyzing both our22 and Barton’s21a
mechanistic proposals for the oxidation of hydrazones with
iodanes (Figure 2). Reaction of the activated iodane (PhICl2ꢀpy)
with hydrazone 12 would give intermediate A, which, in the
presence of chloride anions, would react to lose iodobenzene and
give azo compound B. Association of B with a second equivalent
of the activated iodane would proceed in a similar fashion to give
product 11 while expelling nitrogen gas. Intermediate A might
be exploited, because the reaction should still be feasible upon
substitution of its exotic (-I(Cl)Ph) leaving group for others such
as p-Ts- (13), p-Ns- (14) or Tf- (15). In these cases, the reaction
would give product 11 via the intermediacy of C, expelling the
corresponding sulfinates as byproducts. This sequence would be
analogous to that proposed for the conversion of intermediate B
to dichloride 11. Formation of the substituted hydrazone precur-
sors (13-15) would be compatible with acyl, carbamoyl and
sulfonyl groups, increasing the functional group compatibility of
our chlorination reaction. Furthermore, an additional improve-
ment might also be realized as our current proposal would only
require one equivalent of iodane 7. One concern is the possibility
of the expelled sulfinate reacting with the iodane 7, though to our
knowledge there is no known precedent for this.23 If its full po-
tential is realized, this new dihalogenation strategy would be a
significant improvement over the use of diazocarbonyls as start-
ing materials, and would offer an attractive alternative to existing
strategies for effecting deoxygenative chlorination and, eventual-
ly, fluorination reactions.
Table 1. Chlorination of hydrazone derivatives. (a) Isolated yield. (b) Incom-
plete conversions were observed by 1H NMR analysis. (c) Due to its volatility,
TfCl could not be recovered from the product mixture.
Contrary to our original hypothesis, we were unable to
achieve greater than 40% yield when using 1.1 eq. of iodane 7
with any of the substituted hydrazone substrates. The reaction
mixtures were analyzed by 1H NMR immediately after removing
them from the heat source, and we consistently observed com-
plete consumption of the iodane, even while significant quantities
of the hydrazone remained. Knowing iodane 7 to be stable when
heated under the reaction conditions, we believed iodane decom-
position to not be a factor. Also, given the rates usually observed
for these chlorination reactions, we were surprised that another

3
species in the reaction mixture was successfully outcompeting
the hydrazone for reaction with the iodane. We elucidated the
fate of the iodane by analyzing the reaction side products, where
sulfonyl chlorides (p-TsCl or p-NsCl) were consistently recov-
ered. It has been explicitly stated that p-TsNa does not react with
the electrophilic iodane PhI(OTFA)2 (BTIB) in DCM,24 so we
were especially surprised to see that the sulfinate byproducts
might react so rapidly with iodane 7. To test this hypothesis, we
subjected p-TsNa to the reaction conditions, and it was rapidly
converted to the sulfonyl chloride in 74% yield (eq 4). Based on
this, we conclude the activated iodane complex PhICl2ꢀpy is suf-
ficiently more electrophilic than BTIB, and can rapidly oxidize
various sulfinates (p-Ts–, p-Ns–, Tf –) to the corresponding
sulfonyl chlorides.
tempted to interpret the rate data, based on the assumption that
the transit from D to either E or F was the rate-determining step.
In such a case, substrates bearing electron withdrawing groups on
nitrogen that are capable delocalizing the lone pair (13l-q) would
be slower to react along Path a (D to E), and would be faster to
react along Path b (D to F), again due to the decreased electron
density at nitrogen. As these substrates were the slowest to react,
we initially inferred that Path a could be operative. To try and
support this hypothesis, we conducted a reaction with an exoge-
nous chloride source to determine whether a rate enhancement
was observable, as would be expected if Path b were operative.
When 13d was chlorinated under the standard reaction conditions
in the presence of 1.1 eq. of TBACl, the rate of the reaction
greatly increased, and gave 11d in 68% yield in three minutes.
Therefore, we are unable to provide further insight into the reac-
tion mechanism, other than to conclude that both electronic ef-
fects, and the concentration of chloride ions, can affect the reac-
tion rates. Until further investigations are complete, the
dichlorination from p-toluenesulfonyl hydrazones will require
two equivalents of PhICl2 to achieve complete conversions and
good product yields.
Various p-tosylhydrazone derivatives were then subjected to
the optimal reaction conditions to demonstrate their suitability in
the chlorination reaction, and to compare this new strategy’s effi-
cacy with that observed for simple hydrazones. The unsubstituted
derivative 13b chlorinated rapidly and in good yield, as did 5-
halo derivatives 13c-e. The electron rich 5-Me substrate (13f)
was prone to over-chlorination at C7 when using 2.5 eq. of the
iodane, but decreasing the loading to 2.1 eq. precluded over-
chlorination, and gave 11f in 65% yield. The problem of over-
chlorination was even more pronounced for the highly electron-
rich 5-OMe substrate 13g, where 30% of 11g was produced
along with 35% of 7-Cl-11g. Reducing the loading of 7 to 2.1eq
failed to eliminate the problem, giving 11g in 38% yield and 7-
Cl-11g in 19%. The nitrogen-substituted derivatives (N-iPr, N-
Bn, N-MOM and N-CH2CO2Et, 13h-k) reacted rapidly and
chemoselectively to give the products in good to excellent yield.
One benefit of this new reaction is our ability to prepare the p-
tosylhydrazones on substrates bearing functional groups that are
incompatible with the use of hydrazine. For each of these sub-
strates (N-CO2Bn, N-Boc, N-Ts, N-Ac N-Bz and N-Bz, 13l-q) the
p-tosylhydrazone was prepared from the corresponding isatin,
and subjected to the chlorination reaction. The reactions typically
occurred with high chemoselectivity to give the various products
in good to excellent yield. The lone exception to this was the de-
rivative 13m, which was successfully chlorinated with concomi-
tant loss of the N-Boc group to give 11b as the product in 80%
yield. While the acyl substrates 13o,p were also chlorinated with
ease, separation of the products from the p-TsCl byproduct was
only achieved by chromatography followed by sublimation, re-
sulting in decreased overall yields.
Table 2. Chlorination of isatin-3-tosylhydrazone derivatives. (a) Isolated yield.
(b) PhICl2 (2.1 eq.) was used. (c) Over chlorination product isolated in 19%
yield. (d) Product isolated by chromatography followed by sublimation.
We envision two possible reaction pathways that are con-
sistent with production of both dichloride 11a and the sulfonyl
chlorides (Figure 3). p-Tosylhydrazone 13a can undergo oxida-
tive chlorination upon exposure to the activated iodane, giving
intermediate D, from which the two reaction pathways diverge.
Were intermediate D to undergo a N-assisted expulsion of N2 and
the sulfinate anion (Path a), the resulting intermediate E would
chlorinate to give 11a, and the sulfinate could react with the
iodane to produce p-TsCl well within the reaction time. Con-
versely, if intermediate D was subject to nucleophilic attack at
the sulfonyl by a chloride anion, fragmentation of the adduct
would produce p-TsCl and N2 gas, as well as intermediate F.
Conversion of enolate F to dichloride 11a would require a second
equivalent of PhICl2, proceeding via conventional α-carbonyl
functionalization pathways.25 Presently we cannot distinguish
between these pathways, as the rate and efficacy of the sulfinate
oxidation (Path a) is consistent with our observations. We at-
Figure 3. Illustration of the reaction mechanism.
In conclusion, we have prepared a series of p-tosylhydrazone
derivatives of various isatins, and shown how these hydrazones
are viable starting materials for undergoing the chlorination reac-
tion that employs the stable, easily prepared iodane PhICl2. The
reactions showed consistently high chemoselectivity and gave the
products in good to excellent yield in only a few minutes. Adven-
titious chlorination of the indole ring was observed for the most

4
Tetrahedron
9. Dolci, S.; Marchetti, F.; Pampaloni, G.; Zacchini, S., Dalton
Transactions 2013, 42, 5635.
electron rich of aromatic systems, suggesting these can compete
with the p-tosylhydrazones in the reaction with an activated
iodane complex. We have also demonstrated for the first time
that sulfinate salts can be oxidatively chlorinated with the acti-
vated iodane complex PhICl2ꢀpy. Most importantly, we have
found an alternative to existing strategies for effecting a two-step
deoxygenative dihalogenation reaction. Through the intermedia-
cy of p-tosylhydrazones, we were able to efficiently convert car-
bonyls into dihalides using hypervalent iodine reagents in an op-
erationally-facile process. We are presently applying this new
methodology to the chlorination and fluorination of various mo-
lecular scaffolds, and the results will be disclosed in due course.
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This work was supported financially by the Natural Sciences
and Engineering Research Council (NSERC) of Canada and the
University of Waterloo. CH would like to thank Chemistry Study
Abroad, Newcastle University, for her international exchange.
We would also like to acknowledge Richard Smith of the Univer-
sity of Waterloo Mass Spec Facility for sample analysis.
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Supplementary Material
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