1-(2′-Anilinyl)prop-2-yn-1-ol rearrangement for oxindole synthesis

Article abstract of DOI:10.1002/chem.201202606

A synthetic method that relies on NIS (N-iodosuccinimide)-mediated cycloisomerization reactions of 1-(2′-anilinyl)prop-2-yn-1-ols to gem-3-(diiodomethyl)indolin-2-ones and 2-(iodomethylene)indolin-3-ones has been developed. The reactions were shown to be chemoselective, with secondary and tertiary alcoholic substrates exclusively giving the 3- and 2-oxindole products, respectively. In the case of the latter, the transformation features an unprecedented double 1,2-OH and 1,2-alkyl migration relay. Density functional theory (DFT) calculations based on proposed iodoaminocyclization species provide insight into this unique divergence in product selectivity. Copyright

Full text of DOI:10.1002/chem.201202606

DOI: 10.1002/chem.201202606
1-(2’-Anilinyl)prop-2-yn-1-ol Rearrangement for Oxindole Synthesis
Prasath Kothandaraman, Bing Qin Koh, Taweetham Limpanuparb, Hajime Hirao,* and
Philip Wai Hong Chan*[a]
Abstract:
A
synthetic method that
ondary and tertiary alcoholic substrates
exclusively giving the 3- and 2-oxindole
products, respectively. In the case of
the latter, the transformation features
an unprecedented double 1,2-OH and
1,2-alkyl migration relay. Density func-
tional theory (DFT) calculations based
on proposed iodoaminocyclization spe-
cies provide insight into this unique di-
vergence in product selectivity.
relies on NIS (N-iodosuccinimide)-
mediated cycloisomerization reactions
of 1-(2’-anilinyl)prop-2-yn-1-ols to gem-
3-(diiodomethyl)indolin-2-ones and 2-
(iodomethylene)indolin-3-ones
been developed. The reactions were
shown to be chemoselective, with sec-
Keywords: alcohols · cyclization ·
domino reactions · N-iodosuccin-
imide · oxindoles
has
Introduction
Oxindoles are common struc-
tural motifs found in a myriad
of pharmaceutically interesting
compounds and bioactive natu-
ral products (Figure 1).[1–7] The
nitrogen heterocycle is also an
invaluable chemical probe in
biomimetic studies and a ver-
satile building block in organic
synthesis. For this reason, the
Figure 1. Examples of bioactive natural products.
development of methods to
construct this member of the
indole family in an efficient manner with control of product
substitution patterns, from low-cost and readily accessible
substrates, continues to be actively pursued.[1,8]
cohols 1 with molecular iodine (Scheme 1a).[11a,g] In con-
trast, there are no studies that explore the potential iodo-
AHCTUNGTREGaNNNU minocyclization chemistry of this class of compounds that
One approach for nitrogen ring synthesis that has come
under increasing attention over the years is the iodoamino-
cyclization of alkenes, alkynes, and allenes with an amine
nucleophile and iodide source under Lewis or Brønsted acid
or base catalysis.[9–11] This has included a handful of synthetic
strategies to form a variety of N-heterocycles from readily
available unsaturated alcohols.[11,12] A recent notable exam-
ple is the synthesis of 2-acyl-1H-indoles and 3-iodoquino-
lines that relied on the cycloisomerization of propargylic al-
contain a terminal alkyne moiety. This is surprising in view
of recent work by our group that shows gold(I)-catalyzed cy-
[a] Dr. P. Kothandaraman, B. Q. Koh, Dr. T. Limpanuparb,
Prof. Dr. H. Hirao, Prof. Dr. P. W. H. Chan
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
Singapore 637371 (Singapore)
Fax : (+65)6791-1961
E-mail: waihong@ntu.edu.sg
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202606.
Scheme 1. Iodoaminocyclization reactivities of 1-(2’-anilinyl)prop-2-yn-1-
ols 1.
1978
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 1978 – 1985

FULL PAPER
Table 1. Optimization of the reaction conditions.[a]
cloisomerization of such substrates to have the propensity to
undergo 1,3-allylic alcohol isomerization (1,3-AAI) upon ad-
dition of the nitrogen nucleophile to the alkyne moiety.[13d,f]
We therefore anticipated that a new cascade process in
these compounds might ensue if the initial cyclization step,
which involves the addition of the nitrogen nucleophile to
the alkyne moiety, was triggered by an electrophilic iodide
source instead of the metal catalyst. In doing so, and as part
of an ongoing program examining the utility of alcohol pro-
electrophiles in heterocyclic synthesis,[13] we discovered that
when R1 ¼H, the resultant putative iodoaminocyclization
species A generated in situ by NIS was susceptible to a 1,2-
hydroxyl shift (Scheme 1b).[14] This was followed by a 1,2-
alkyl migration and oxidation of the alcohol moiety to give
the gem-3-(diiodomethyl)indolin-2-one ring system. On the
other hand, in substrates where R1 =H, we found that a 1,2-
hydride shift and oxidation of the secondary carbinol carbon
center occurred to give 2-(iodomethylene)indolin-3-one de-
rivatives (Scheme 1c). To our knowledge, the construction
of 2- and 3-oxindoles in this manner by the iodoaminocycli-
zation of a propargylic substrate with NIS is not known.
Moreover, the reaction leading to 2-oxindoles represents an
exceedingly rare example of both a 1,2-OH shift and a
double migration involving two functional groups mediated
by NIS.[14,15] The role of NIS in this context is notable as it
extends the synthetic utility of this reagent beyond that of
cycloiodinations, functional group deprotections/protections,
iodinations, oxidations, and semipinacol rearrangements.
Herein, we disclose the details of this chemistry, which
offers an expedient and chemoselective approach to these
two new and potentially useful classes of oxindole com-
pounds in good to excellent yields. A density functional
theory (DFT) calculation study on the origin of the diver-
gence in product selectivity is also presented.
Entry
NIS [equiv]
Solvent
Time [h]
Yield [%][b]
2a
4a
5a
1[c]
2
2
2
3
3
3
3
3
3
MeNO2
MeNO2
MeNO2
MeNO2
MeCN
18
3
1
24
3
18
18
18
5
17
86
96
22
82
53
47
68
–
–
–
–
–
–
–
–
–
–
–
61
–
–
–
–
–
3
4[d]
5
6
7
8
9
A
1,4-dioxane
DMSO
MeNO2
[e]
–
[f]
[e]
–
–
[a] Unless otherwise stated, all reactions were performed in distilled sol-
vent with 0.06 mmol of 1a and heated at reflux. [b] Yield of isolated
product. [c] Reaction performed at room temperature. [d] Reaction per-
formed with non-distilled MeNO2. [e] Mixture of byproducts obtained
that could not be identified by 1H NMR analysis or mass spectrometry.
[f] Reaction performed with 3 equiv of I2.
Results and Discussion
The 1-(2’-anilinyl)prop-2-yn-1-ols studied in this work were
prepared from the reaction of the corresponding 2-tosylami-
nophenyl ketone with ethynylmagnesium bromide following
literature procedures.[16] By choosing 1a as the model sub-
strate, we began our investigations by examining its transfor-
mations with NIS to establish the optimal reaction condi-
tions (Table 1). This initially revealed that the treatment of
1a with 2 equiv of NIS in MeNO2 at room temperature for
18 h gave 2a and 4a in 17 and 68% yield, respectively
(Table 1, entry 1). The structure of the 2-oxindole was deter-
Figure 2. ORTEP drawing of 2a with thermal ellipsoids at 50% probabil-
ity levels.[17]
yield of 2a (22%), as well as 5a in 61% yield (Table 1,
entry 4).[13d] Likewise, an inspection of entries 5–7 in Table 1
shows that changing the solvent from MeNO2 to MeCN, 1,2-
dichloroethane, or 1,4-dioxane gave lower product yields of
47–82%. Replacing MeNO2 with DMSO as the solvent was
found to lead to a mixture of side products that could not
be identified by 1H NMR analysis of the crude mixture
(Table 1, entry 8). Similarly, the analogous reaction mediat-
ed by molecular iodine, which is shown to promote the in-
tramolecular cyclization of substituted 2-alkynylanilines to
2-acyl-1H-indoles and 3-iodoquinolines, in place of NIS was
found to be ineffective (Table 1, entry 9).[11a,g] On the basis
of the above results, the reaction of 1a with 3 equiv of NIS
1
mined on the basis of H NMR spectroscopic analysis and
X-ray crystallography (Figure 2).[17] By repeating the reac-
tion at reflux for 3 h, the suppression of 4a was found to
give 2a as the sole adduct in 86% yield (Table 1, entry 2). A
further increase of 10% in the product yield and a shorter
reaction time of 1 h for complete substrate consumption was
achieved by increasing the amount of NIS from 2 to 3 equiv
(Table 1, entry 3). In contrast, repeating this reaction in
non-distilled MeNO2 was found to give a markedly lower
Chem. Eur. J. 2013, 19, 1978 – 1985
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1979

H. Hirao, P. W. H. Chan et al.
Table 2. NIS-mediated rearrangement of 1b–p.[a]
in MeNO2 at reflux for 1 h provided the optimum condi-
tions.
To define the scope of the present reaction, we next
turned our attention to the reactions of a series of tertiary
1-(2’-anilinyl)prop-2-yn-1-ols and the results are summarized
in Table 2. These experiments showed that with 3 equiv of
NIS, the conditions were found to be broad and a variety of
gem-3-(diiodomethyl)indolin-2-ones 2 could be furnished in
32–98% yield from the corresponding substrates 1b–p
(Table 2). Tertiary alcohols with a pendant electron-with-
drawing (1b and 1c) or electron-donating (1d) group, or a
benzo-fused ring (1 f) on the aniline ring, were found to be
tolerated under the reaction conditions and provided the
corresponding products 2b–d and 2 f in excellent yields of
up to 98%. Similarly, reactions of substrates containing a
Me, naphthyl, or aryl group with an electron-donating or
electron-withdrawing substituent at the ortho or para posi-
tion on the carbinol carbon center, as in 1g and 1i–n, were
found to proceed well, providing 2g and 2i–n in 67–90%
yield. The presence of an Ac instead of a tosyl (Ts) protect-
ing group on the nitrogen center was found to have no influ-
ence on the course of the reaction, and 2o and 2p were
formed in 81 and 84% yield, respectively. Under the stand-
ard conditions, the reaction of starting alcohols with a pend-
ant p-OMe (1e) or benzo[d]ACTHNUTRGENU[GN 1,3]dioxole (1h) substituent on
the aniline moiety were the only examples found to give the
corresponding products 2e and 2h in lower yields of 45 and
32%, respectively.
With the reaction conditions for forming the 2-oxindole
established, we next investigated the applicability of this
new method for the synthesis of 2-(iodomethylene)indolin-
3-one derivatives. As shown in Scheme 1c, we reasoned that
a change in the mode of reactivity should be accomplished
by switching from a tertiary to a secondary alcohol sub-
strate. With this in mind, we first tested the reaction of 1q
with 3 equiv of NIS in MeNO2 at room temperature for 3 h
(Table 3). This experiment gave 3a in 87% yield and as an
inseparable mixture of E/Z isomers in a ratio of 5:1. The
structure of the 3-oxindole adduct was determined on the
basis of 1H NMR spectroscopic measurements and X-ray
crystallographic analysis (Figure 3).[17] A similar outcome
was observed on applying these conditions to other second-
[a] Unless otherwise stated, all reactions were performed with
1
(68 mmol) and NIS (0.21 mmol) in distilled MeNO2 and heated at reflux
for 1–1.5 h; refer to the Supporting Information for individual reaction
times. [b] Values in parentheses represent yield of isolated product [%].
[c] Reaction performed with 0.272 mmol of NIS. [d] Reaction performed
for 3.5 h. [e] Reaction performed for 18 h.
ACHTUNGTRENNUNGary alcohols 1r–v. In these reactions, the corresponding 2-
(iodomethylene)indolin-3-one products 3b–f were formed in
yields of 66–92% as inseparable mixture of E/Z stereoiso-
ACHTUNGTRENNUNGmers in ratios of up to 4:1. Additionally, no other side prod-
1
ucts were detected based on H NMR analysis of the crude
mixtures.
A plausible mechanism for the present NIS-mediated cy-
cloisomerization reactions is outlined in Scheme 2. This
could involve addition of NIS to the alkyne moiety of 1. As
a result, this triggers nucleophilic attack by the pendant to-
sylamido group in a 5-exo-dig manner to produce the cation-
ic nitrogen ring species A. Deprotonation of this newly
formed adduct would then give the vinyl iodide intermedi-
ate 4, which can react with a further equivalent of NIS to
give the gem-diiodo species B. This is the active species
(when R¼H) that undergoes the double migration process
involving a 1,2-shift of the OH group to the iminium cation
carbon center to give indolin-2-ol adduct C (Scheme 2,
route 1). This is followed by oxidative 1,2-migration of the
CHI2 moiety from the C2 to C3 position in C. Subsequent
deprotonation of the resultant oxonium species D would
then deliver 2. In the case where R=H in the substrate, it is
thought that 1,2-hydride migration from the carbinol to the
iminium carbon center, followed by oxidation of the hydrox-
1980
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Chem. Eur. J. 2013, 19, 1978 – 1985

1-(2’-Anilinyl)prop-2-yn-1-ol Rearrangement for Oxindole Synthesis
Table 3. NIS-mediated rearrangement of 1q–v.[a]
FULL PAPER
Scheme 2. Proposed mechanism for NIS-mediated reactions of 1.
This argument was further supported by the observation
that when a solution of 4a in MeNO2 was subjected to
2 equiv of NIS and heated at reflux for 1 h, the expected 2-
oxindole 2a was obtained as the sole product in 86% yield.
The formation of the aldehyde side product 5a could be due
to competitive nucleophilic substitution of 4 by H2O that is
present in non-distilled MeNO2. Indeed, our findings show-
ing 2a and 5a could be obtained in 17 and 66% yield on
treating 4a with 2 equiv of NIS in non-distilled MeNO2
heated at reflux for 24 h would suggest this to be the case.
Next, to support the mechanistic premise put forward in
Scheme 2 for the divergence in product selectivity, we per-
[a] All reactions were performed with 1 (68 mmol) and NIS (0.21 mmol)
in distilled MeNO2 at room temperature for 3 h. [b] Values in parenthe-
ses represent yield of isolated product [%] and ratio of the E/Z isomers,
respectively. [c] Reaction performed for 6 h.
formed DFT calculations at the B3LYP/
(others)] level, taking into account the solvent effect of
MeNO2 by the integral equation formalism variant of the
polarizable continuum model (IEFPCM) method
ACHTUNGTREN[NGNU SDD(I),6-31G*-
AHCTUNGTRENNUNG
(Figure 4).[18–21] The reported energy values include zero-
point energy corrections as obtained from frequency calcula-
tions at the same level. UCSF Chimera was used for draw-
ing the molecules.[22] We examined routes 1 and 2 shown in
Scheme 2 (from intermediate B) with R being Ph or H.
Route 1 was found to be more favorable than route 2 when
R=Ph (Figure 4a), which is consistent with the proposed
mechanism in Scheme 2. This path begins with 1,2-migration
of the hydroxyl group via an epoxide-like transition state,
and the energy barrier of 19.1 kcalmolꢀ1 for this migration
is readily surpassed. The OH migration is followed by a 1,2-
shift of the CHI2 group, which also has a low energy barrier
(15.9 kcalmolꢀ1), to give intermediate D. These results sug-
gest that the reaction with R=Ph is likely to follow these
two steps and the final product 2 is generated upon deproto-
nation of D. In contrast, when R=H, a 1,2-hydride shift was
found to be more favorable than the 1,2-OH migration in
the initial step (Figure 4b). The energy barrier for the hy-
dride shift was rather low (16.8 kcalmolꢀ1), supporting the
hypothesis that the reaction with R=H follows route 2.
However, a subsequent step involving a 1,2-shift of the CHI2
group, as shown in Scheme 2, route 2, was found to require
an energy barrier of 38.0 kcalmolꢀ1. This unusually high ac-
tivation energy disfavors the mechanism shown in Scheme 2,
Figure 3. ORTEP drawing of 3a with thermal ellipsoids at 50% probabil-
ity levels.[17]
yl moiety in B, occurs preferentially to give the oxonium
species E (Scheme 2, route 2). Deprotonation of this cation-
ic ring adduct would then give the indolin-3-one intermedi-
ate F, which eliminates HI to provide 3. Although fortuitous,
the formation of 4a from the cyclization of 1a at room tem-
perature under the conditions described in Table 1, entry 1
argues in favor of the mechanism proposed in Scheme 2.
Chem. Eur. J. 2013, 19, 1978 – 1985
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1981

H. Hirao, P. W. H. Chan et al.
uct. Therefore, our DFT calcu-
lations suggest that the E2
mechanism operates in the
second half of the reaction
when R=H. When MeNO2 was
used instead of NHS as a base
for the reaction, the relative en-
ergies of TSe2,E and TSe2,Z were
35.3 and 38.5 kcalmolꢀ1, respec-
tively. Thus, it is more likely
that the E2 reaction is triggered
by NHS rather than by MeNO2.
Conclusion
In summary, we have developed
an NIS-mediated strategy for
the construction of highly func-
tionalized 2-(iodomethylene)in-
dolin-3-ones and gem-3-(diiodo-
methyl)indolin-2-ones from sec-
ondary and tertiary 1-(2’-anili-
nyl)prop-2-yn-1-ols, respective-
ly. Our studies suggest that
complete control over product
selectivity is possible by exploit-
ing the differing functional
group migratory aptitude of the
alcohol moiety in these second-
AHCTUNGTERGaNNUN ry and tertiary substrates. In
the case of the tertiary alcohols,
which lead to 2-oxindole prod-
ucts, the nitrogen-ring-forming
process also provided a unique
example of a double migratory
Figure 4. Energy profiles (in kcalmolꢀ1) for the reactions with a) R=Ph and b) R=H (solid and dotted lines
indicate routes 1 and 2, respectively) and bond distances given in ꢂ.
cascade reaction involving
a
1,2-OH migration followed by a
1,2-alkyl shift. Efforts to ex-
plore the scope and synthetic
route 2 in which X is generated after E; indeed, the forma-
tion of a product derived from X was not observed in the
experiment.
applications of the present reactions are currently underway
and will be reported in due course.
In an attempt to find a likely pathway from E toward the
experimentally obtained 3, we examined the possibility of
an E2 reaction, assuming that NHS acts as a base which can
abstract a proton from F (Figure 5). Two distinct conformers
of a complex between F and NHS (F’E and F’Z), which differ
in the conformation of the CHI2 group, led to different
products, 3’E and 3’Z, respectively. These products are similar
to the experimentally obtained 3. As shown in Figure 5, the
energy barrier for the E2 reaction that yields the E product
is 24.9 kcalmolꢀ1, which is much lower than that of the
second step involving 1,2-shift of CHI2 (38.0 kcalmolꢀ1,
Figure 4). Moreover, the calculated preference for formation
of the E product by the E2 mechanism is consistent with the
experimentally observed E/Z ratios of up to 5:1 in the prod-
Experimental Section
General procedure for NIS-mediated reactions of 1a–1p: A solution of 1
(0.07 mmol) in nitromethane (1.5 mL) was added dropwise to a solution
of NIS (45 mg, 0.20 mmol) in nitromethane (1 mL) at room temperature
under a nitrogen atmosphere. The resulting mixture was stirred and
heated at reflux, and monitored for completion by TLC analysis. On
completion of the reaction, the mixture was cooled to room temperature,
quenched with saturated aqueous Na2S2O3·5H2O solution (5 mL), and ex-
tracted with EtOAc (3ꢁ10 mL). The combined organic layers were
washed with brine (20 mL), dried over Na2SO4 and concentrated under
reduced pressure. Purification by flash column chromatography on silica
gel (eluent: n-hexane/EtOAc=19:1) gave the product 2.
General procedure for NIS-mediated reactions of 1q–1v: A solution of 1
(0.07 mmol) in nitromethane (1.5 mL) was added dropwise to a solution
1982
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1-(2’-Anilinyl)prop-2-yn-1-ol Rearrangement for Oxindole Synthesis
FULL PAPER
1448, 1381, 1165, 1089 cmꢀ1; HRMS
(ESI): m/z calcd for C23H20NO3SI2:
643.9253 (M++H); found: 643.9254.
3-(Diiodomethyl)-5-methoxy-3-phenyl-
1-tosylindolin-2-one
(2e):
Yellow
solid; m.p. 188–1908C; 1H NMR
(CDCl3, 300 MHz): d=8.02 (1H, d,
J=9.0 Hz), 7.93 (2H, d, J=8.4 Hz),
7.65 (1H, d, J=2.7 Hz), 7.37–7.23
(7H, m), 7.10 (1H, dd, J=2.7, 9.0 Hz),
5.75 (1H, s), 3.91 (3H, s), 2.36 ppm
(3H, s); 13C NMR (CDCl3, 75 MHz):
d=172.4, 156.7, 145.7, 136.8, 133.1,
129.6, 129.5, 129.0, 128.4, 127.2, 115.2,
114.9,
111.8,
62.3,
55.8,
21.7,
ꢀ22.3 ppm; IR (NaCl, neat): n˜ =2962,
1749, 1681, 1597, 1492, 1373, 1159,
1089 cmꢀ1; HRMS (ESI): m/z calcd for
C23H20NO4SI2: 659.9203 (M++H);
found: 659.9200.
3-(Diiodomethyl)-3-phenyl-1-tosyl-
1H-benzo[f]indol-2
G
(2 f):
White solid; m.p.
217–2198C;
1H NMR (CDCl3, 300 MHz): d=8.56
(1H, s), 8.50 (1H, s), 8.01 (2H, d, J=
8.4 Hz), 7.96 (2H, s) 7.63 (1H, t, J=
6.9), 7.56 (1H, t, J=6.9), 7.38–7.23
Figure 5. Energy profiles (in kcalmolꢀ1) for the E2 mechanism in route 2 with bond distances given in ꢂ.
of NIS (45 mg, 0.20 mmol) in nitromethane (1 mL) at room temperature
under a nitrogen atmosphere. The resulting mixture was stirred at room
temperature and monitored for completion by TLC analysis. On comple-
tion of the reaction, the mixture was quenched with saturated aqueous
Na2S2O3·5H2O solution (5 mL) and extracted with EtOAc (3ꢁ10 mL).
The combined organic layers were washed with brine (20 mL), dried over
Na2SO4, and concentrated under reduced pressure. Purification by flash
column chromatography on silica gel (eluent: n-hexane/EtOAc=19:1)
gave the product 3.
(7H, m), 5.85 (1H, s), 2.36 ppm (3H, s); 13C NMR (CDCl3, 75 MHz): d=
172.2, 146.0, 136.9, 136.8, 134.4, 134.3, 130.3, 129.6, 129.0, 128.7, 128.5,
128.4, 128.1, 127.7, 127.3, 126.0, 125.2, 111.0, 61.8, 21.7, ꢀ21.2 ppm; IR
(NaCl, neat): n˜ =1749, 1635, 1597, 1492, 1448, 1381, 1172, 1089 cmꢀ1
;
HRMS (ESI): m/z calcd for C26H20NO3SI2: 679.9253 (M++H); found:
679.9258.
3-(Diiodomethyl)-3-methyl-1-tosylindolin-2-one (2g): White solid; m.p.
186–1888C; 1H NMR (CDCl3, 300 MHz): d=8.03 (1H, d, J=8.7 Hz),
8.00 (2H, d, J=8.4 Hz), 7.78 (1H, d, J=7.4 Hz), 7.48 (1H, td, J=1.0,
7.1 Hz), 7.29 (2H, d, J=8.4 Hz), 7.25 (1H, d, J=0.9 Hz), 5.24 (1H, s),
2.39 (3H, s), 1.47 ppm (3H, s); 13C NMR (CDCl3, 75 MHz): d=173.3,
145.4, 138.9, 130.2, 130.0, 129.7, 128.5, 124.3, 123.1, 113.8, 53.9, 26.3, 21.7,
ꢀ23.5 ppm; IR (NaCl, neat): n˜ =3444, 1745, 1602, 1462, 1379, 1300, 1176,
1085 cmꢀ1; HRMS (ESI): m/z calcd for C17H16NO3SI2: 567.8940 (M+
+H); found: 567.8941.
3-(Diiodomethyl)-3-phenyl-1-tosylindolin-2-one (2a): White solid; m.p.
1
186–1888C; H NMR (CDCl3, 300 MHz): d=8.07 (2H, t, J=7.9 Hz), 7.96
(2H, d, J=8.4 Hz), 7.58 (1H, td, J=1.2, 8.1 Hz), 7.43 (1H, td, J=0.9,
7.5 Hz), 7.38–7.24 (7H, m), 5.75 (1H, s), 2.37 ppm (3H, s); 13C NMR
(CDCl3, 75 MHz): d=172.4, 145.9, 139.9, 136.8, 134.5, 130.6, 129.6, 129.1,
129.0, 128.4, 128.2, 127.2, 125.4, 124.7, 114.1, 62.1, 21.7, ꢀ21.8 ppm; IR
(NaCl, neat): n˜ =1751, 1597, 1462, 1381, 1176, 1087, 952 cmꢀ1; HRMS
(ESI): m/z calcd for C22H18NO3SI2: 629.9097 (M++H); found: 629.9095.
7-(Diiodomethyl)-7-methyl-5-tosyl-5H-[1,3]dioxoloACTHUNTGRNENUG[4,5-f]indol-6ACHTUNGTRENNUNG(7H)-
one (2h): Colorless gum; 1H NMR (CDCl3, 300 MHz): d=7.97 (2H, d,
J=8.1 Hz), 7.64 (1H, s), 7.29 (2H, d, J=8.4 Hz), 7.26 (1H, s), 6.05 (2H,
s), 5.20 (1H, s), 2.39 (3H, s), 1.42 ppm (3H, s); 13C NMR (CDCl3,
100 MHz): d=172.5, 148.9, 145.9, 144.7, 134.7, 133.0, 129.7, 128.5, 122.5,
103.7, 101.8, 97.2, 54.1, 29.7, 26.2, 21.7, 1.0, 0.0, ꢀ22.4 ppm; IR (NaCl,
neat): n˜ =2962, 1749, 1681, 1492, 1373, 1190, 1176, 1089 cmꢀ1; HRMS
(ESI): m/z calcd for C18H16NO5SI2: 611.8839 (M+ +H); found: 611.8834.
5-Chloro-3-(diiodomethyl)-3-phenyl-1-tosylindolin-2-one (2b): Yellow
solid; m.p. 160–1628C; 1H NMR (CDCl3, 300 MHz): d=8.06 (2H, d, J=
9.3 Hz), 7.93 (2H, d, J=8.4 Hz), 7.56 (1H, dd, J=2.1, 8.7 Hz), 7.37–7.25
(7H, m), 5.70 (1H, s), 2.38 ppm (3H, s); 13C NMR (CDCl3, 75 MHz): d=
172.3, 146.1, 138.4, 136.3, 134.2, 130.7, 130.3, 129.9, 129,7, 129.3, 129.2,
128.4, 127.0, 125.5, 115.3, 62.2, 21.8, 1.0, ꢀ23.3 ppm; IR (NaCl, neat): n˜ =
1751, 1597, 1463, 1382, 1307, 1178, 1089 cmꢀ1; HRMS (ESI): m/z calcd
for C22H17ClNO3SI2: 663.8707 (M++H); found: 663.8716.
3-(Diiodomethyl)-3-(p-tolyl)-1-tosylindolin-2-one (2i): Yellow solid; m.p.
1
195–1978C; H NMR (CDCl3, 300 MHz): d=8.08 (2H, t, J=8.7 Hz), 7.95
(2H, d, J=8.1 Hz), 7.57 (1H, td, J=1.2, 8.0 Hz), 7.39 (1H, td, J=0.7,
7.6 Hz), 7.24 (2H, d, J=6.6 Hz), 7.16 (2H, d, J=8.4 Hz), 7.08 (2H, d, J=
8.1 Hz), 5.73 (1H, s), 2.36 (3H, s), 2.29 ppm (3H, s); 13C NMR (CDCl3,
75 MHz): d=172.5, 145.8, 139.8, 139.2, 134.6, 133.9, 130.5, 129.7, 129.6,
128.4, 127.1, 125.4, 124.6, 114.1, 61.9, 21.7, 21.2, ꢀ21.2 ppm; IR (NaCl,
neat): n˜ =3412, 1751, 1602, 1460, 1381, 1192, 1176, 1087 cmꢀ1; HRMS
(ESI): m/z calcd for C23H20NO3SI2: 643.9253 (M++H); found: 643.9250.
5-Bromo-3-(diiodomethyl)-3-phenyl-1-tosylindolin-2-one (2c): White
solid; m.p. 163–1658C; 1H NMR (CDCl3, 300 MHz): d=8.20 (1H, d, J=
2.1 Hz), 8.00 (1H, d, J=9.0 Hz), 7.93 (2H, d, J=8.4 Hz), 7.71 (1H, dd,
J=2.1, 8.7 Hz), 7.37–7.24 (7H, m), 5.70 (1H, s), 2.38 ppm (3H, s);
13C NMR (CDCl3, 75 MHz): d=171.8, 146.2, 138.9, 136.3, 134.2, 133.6,
130.3, 129.7, 129,3, 129.2, 128.4, 128.3, 127.0, 117.7, 115.6, 62.1, 21.8, 1.0,
ꢀ23.3 ppm; IR (NaCl, neat): n˜ =3439, 1753, 1597, 1492, 1382, 1305, 1176,
1089 cmꢀ1; HRMS (ESI): m/z calcd for C22H17NBrO3SI2: 707.8202 (M+
+H); found: 707.8237.
3-(4-Chlorophenyl)-3-(diiodomethyl)-1-tosylindolin-2-one (2j): White
solid; m.p. 200–2028C; 1H NMR (CDCl3, 300 MHz): d=8.09 (1H, d, J=
7.2 Hz), 8.06 (1H, d, J=7.4), 7.93 (2H, d, J=8.1 Hz), 7.60 (1H, td, J=
1.2, 8.0 Hz), 7.41 (1H, td, J=0.8, 7.5 Hz), 7.28–7.21 (6H, m), 5.69 (1H,
s), 2.38 ppm (3H, s); 13C NMR (CDCl3, 75 MHz): d=172.2, 146.0, 139.9,
135.3, 135.2, 134.4, 130.8, 129.6, 129.2, 128.6, 128.4, 127.9, 125.2, 124.8,
114.3, 61.7, 21.7, ꢀ22.9 ppm; IR (NaCl, neat): n˜ =3433, 1749, 1600, 1490,
1462, 1382, 1176, 1089 cmꢀ1; HRMS (ESI): m/z calcd for C22H17NO3SClI2:
663.8707 (M++H); found: 663.8714.
3-(Diiodomethyl)-5-methyl-3-phenyl-1-tosylindolin-2-one (2d): White
1
solid; m.p. 194–1968C; H NMR (CDCl3, 300 MHz): d=8.03 (1H, s), 7.96
(3H, t, J=4.2 Hz), 7.45–7.20 (8H, m), 5.74 (1H, s), 2.54 (3H, s),
2.37 ppm (3H, s); 13C NMR (CDCl3, 75 MHz): d=172.7, 145.8, 141.1,
136.9, 134.6, 129.6, 129.0, 128.4, 127.2, 125.4, 125.2, 125.1, 114.7, 62.0,
22.3, 21.7, 1.0, ꢀ21.2 ppm; IR (NaCl, neat): n˜ =3417, 1751, 1614, 1597,
Chem. Eur. J. 2013, 19, 1978 – 1985
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1983

H. Hirao, P. W. H. Chan et al.
3-(4-Bromophenyl)-3-(diiodomethyl)-1-tosylindolin-2-one (2k): Yellow
solid; m.p. 180–1828C; 1H NMR (CDCl3, 300 MHz): d=8.11 (1H, d, J=
8.1 Hz), 8.06 (1H, d, J=7.2), 7.93 (2H, d, J=8.4 Hz), 7.60 (1H, td, J=
1.2, 8.0 Hz), 7.36–7.32 (3H, m), 7.25 (2H, d, J=7.8 Hz), 7.16 (2H, d, J=
8.7 Hz), 5.69 (1H, s), 2.38 ppm (3H, s); 13C NMR (CDCl3, 75 MHz): d=
172.4, 146.0, 139.9, 135.8, 134.4, 132.2, 130.8, 129.6, 128.9, 128.4, 127.8,
125.2, 124.8, 123.5, 114.3, 61.8, 21.7, ꢀ23.1 ppm; IR (NaCl, neat): n˜ =
3676, 1751, 1598, 1487, 1460, 1382, 1176, 1087 cmꢀ1; HRMS (ESI): m/z
calcd for C22H17NO3SBrI2: 707.8202 (M++H); found: 707.8200.
100 MHz): d=184.8, 182.7, 149.1, 148.4, 145.5, 145.4, 145.3, 140.5, 140.0,
139.4, 137.9, 137.5, 133.7, 132.7, 130.6, 129.9, 129.8, 129.5, 129.3, 129.2,
128.9, 128.6, 122.3, 122.0, 87.7, 82.0, 21.7, 21.0, 20.9, 19.6, 18.9 ppm; IR
(NaCl, neat): n˜ =1716, 1618, 1587, 1481, 1371, 1170, 1141, 1087 cmꢀ1
;
HRMS (ESI): m/z calcd for C18H17NO3SI: 453.9974 (M++H); found:
453.9976.
2-(Iodomethylene)-7-methoxy-1-tosylindolin-3-one (3c): Yellow gum;
E/Z (1.6:1); 1H NMR (CDCl3, 400 MHz): d=8.02 (1H, s, minor), 7.93
(1H, s, major), 7.57 (2H, d, J=8.2, minor), 7.31–7.14 (11H, m), 3.97
(3H, s, minor), 3.90 (3H, s, major), 2.38 (3H, s, major), 2.36 ppm (3H, s,
minor); 13C NMR (CDCl3, 100 MHz): d=182.4, 152.2, 151.8, 148.0, 145.1,
144.9, 140.4, 138.4, 133.4, 132.4, 130.3, 129.5, 129.2, 128.5, 128.3, 128.2,
128.1, 120.6, 120.1, 116.7, 116.4, 85.9, 81.8, 56.7, 56.4, 21.7 ppm; IR (NaCl,
neat): n˜ =1716, 1620, 1597, 1496, 1438, 1375, 1170, 1087 cmꢀ1; HRMS
(ESI): m/z calcd for C17H15NO4SI: 455.9767 (M++H); found: 455.9771.
3-([1,1’-Biphenyl]-4-yl)-3-(diiodomethyl)-1-tosylindolin-2-one (2l): White
solid; m.p. 184–1868C; 1H NMR (CDCl3, 300 MHz): d=8.13 (2H, d, J=
8.4 Hz), 7.96 (2H, d, J=8.1), 7.63–7.50 (5H, m), 7.43 (3H, t, J=7.4 Hz),
7.35 (3H, d, J=8.4 Hz), 7.25 (2H, d, J=7.8 Hz), 5.79 (1H, s), 2.35 ppm
(3H, s); 13C NMR (CDCl3, 75 MHz): d=172.4, 145.9, 141.4, 140.0, 139.9,
135.7, 134.5, 130.6, 129.6, 128.9, 128.4, 128.3, 127.8, 127.7, 127.6, 127.0,
125.4, 124.7, 114.2, 62.0, 21.7, ꢀ21.9 ppm; IR (NaCl, neat): n˜ =1749, 1600,
1517, 1462, 1382, 1192, 1178, 1089 cmꢀ1; HRMS (ESI): m/z calcd for
C28H22NO3SI2: 705.9410 (M++H); found: 705.9415.
5-Bromo-2-(iodomethylene)-1-tosylindolin-3-one (3d): Yellow gum; E/Z
(2:1); 1H NMR (CDCl3, 400 MHz): d=8.34 (1H, s, minor), 8.13 (1H, s,
major), 8.03 (1H, d, J=8.0 Hz, minor), 7.90 (1H, d, J=8.7 Hz, major),
7.81–7.77 (2H, m), 7.67 (1H, s), 7.48 (2H, d, J=8.3 Hz), 7.29 (2H, d, J=
8.2 Hz), 7.20 (2H, d, J=8.2 Hz), 7.11 (2H, d, J=8.1 Hz), 2.36 (3H, s,
minor), 2.33 ppm (3H, s, major); 13C NMR (CDCl3, 100 MHz): d=180.6,
149.4, 146.2, 146.0, 145.7, 139.5, 139.0, 132.8, 131.3, 130.1, 129.8, 127.8,
127.7, 127.6, 127.5, 127.2, 126.6, 122.6, 120.6, 119.1, 118.7, 87.3, 78.6,
21.7 ppm; IR (NaCl, neat): n˜ =2926, 1716, 1597, 1458, 1355, 1305, 1172,
1089 cmꢀ1; HRMS (ESI): m/z calcd for C16H12NO3SI81Br: 505.8746 (M+
+H); found: 505.8753.
3-(Diiodomethyl)-3-(naphthalen-2-yl)-1-tosylindolin-2-one (2m): Yellow
solid; m.p. 231–2338C; 1H NMR (CDCl3, 300 MHz): d=8.16 (2H, t, J=
7.1 Hz), 7.92 (2H, d, J=8.4), 7.80 (2H, d, J=8.4 Hz), 7.70–7.60 (2H, m),
7.55–7.44 (5H, m), 7.17 (2H, d, J=8.1 Hz), 5.90 (1H, s), 2.28 ppm (3H,
s); 13C NMR (CDCl3, 75 MHz): d=172.4, 145.9, 139.9, 134.4, 134.2, 133.1,
132.9, 130.7, 129.6, 129.1, 128.5, 128.4, 128.3, 127.6, 127.5, 127.1, 126.6,
125.5, 124.8, 123.6, 114.3, 62.4, 21.6, ꢀ22.3 ppm; IR (NaCl, neat): n˜ =
1751, 1600, 1521, 1460, 1382, 1178, 1089 cmꢀ1; HRMS (ESI): m/z calcd
for C26H20NO3SI2: 679.9253 (M++H); found: 679.9259.
2-(Iodomethylene)-1-tosyl-1H-benzo[f]indol-3ACTHNUGRTENUNG(2H)-one (3e): Brown
5-Chloro-3-(diiodomethyl)-3-(2-fluorophenyl)-1-tosylindolin-2-one (2n):
Yellow gum; 1H NMR (CDCl3, 300 MHz): d=8.03 (1H, d, J=9.0 Hz),
8.00 (2H, d, J=8.4), 7.80 (1H, s), 7.51 (1H, dd, J=2.0, 8.9 Hz), 7.40–7.34
(1H, m), 7.31 (2H, d, J=8.4 Hz), 7.13–7.06 (1H, m), 7.01 (1H, t, J=
7.7 Hz), 6.84 (1H, t, J=7.7 Hz), 6.20 (1H, s), 2.40 ppm (3H, s); 13C NMR
(CDCl3, 75 MHz): d=170.7, 146.2, 134.3, 131.3, 131.2, 130.7, 130.4, 129.9,
129.8, 128.6, 124.8, 117.7, 117.4, 115.0, 21.8, 1.0 ppm; IR (NaCl, neat): n˜ =
3676, 1757, 1597, 1463, 1382, 1190, 1178, 1087 cmꢀ1; HRMS (ESI): m/z
calcd for C22H16NO3SClFI2: 681.8613 (M++H); found: 681.8619.
gum; E/Z (4:1); 1H NMR (CDCl3, 400 MHz): d=8.46 (1H, s, major),
8.35 (1H, s, minor), 8.29 (1H, s, major), 8.21 (1H, s, major), 8.12 (1H, s,
minor), 8.08 (1H, s, minor), 7.99–7.88 (3H, m), 7.68–7.64 (1H, m), 7.55–
7.49 (3H, m), 7.28 (1H, d, J=8.3 Hz, minor), 7.13 (2H, d, J=8.2 Hz,
major), 6.98 (2H, d, J=8.2 Hz, minor), 2.31 (3H, s, major), 2.24 ppm
(3H, s, minor); 13C NMR (CDCl3, 100 MHz): d=183.8, 182.3, 147.1,
145.6, 145.2, 143.7, 140.5, 138.1, 137.4, 135.4, 133.3, 132.0, 131.4, 130.6,
130.4, 130.0, 129.9, 129.5, 128.8, 127.8, 127.2, 127.0, 126.9, 126.6, 126.5,
124.4, 124.2, 118.7, 113.9, 85.5, 75.3, 21.6, 21.5 ppm; IR (NaCl, neat): n˜ =
3676, 1716, 1629, 1419, 1373, 1174, 1116, 1018 cmꢀ1; HRMS (ESI): m/z
calcd for C20H15NO3SI: 475.9817 (M++H); found: 475.9814.
1-Acetyl-3-(diiodomethyl)-3-methylindolin-2-one (2o): Yellow solid; m.p.
114–1168C; 1H NMR (CDCl3, 400 MHz): d=8.27 (1H, d, J=8.24 Hz),
7.77 (1H, d, J=7.6 Hz), 7.43 (1H, t, J=8.54 Hz), 7.28 (1H, t, J=7.6 Hz),
5.39 (1H, s), 2.69 (3H, s), 1.55 ppm (3H, s); 13C NMR (CDCl3,
100 MHz): d=176.6, 170.4, 139.6, 130.1, 129.8, 125.2, 122.5, 116.7, 54.2,
26.7, 25.9, ꢀ22.2 ppm; IR (NaCl, neat): n˜ =3076, 1751, 1604, 1477, 1463,
1371, 1168, 1089 cmꢀ1; HRMS (ESI): m/z calcd for C12H12NO2I2: 455.8958
(M++H); found: 455.8966.
4-Chloro-2-(iodomethylene)-1-tosylindolin-3-one (3 f): Yellow gum; E/Z
(4:1); 1H NMR (CDCl3, 400 MHz): d=8.35 (1H, s, minor), 8.09 (1H, s,
major), 7.92 (1H, d, J=8.2 Hz, major), 7.61–7.56 (1H, m), 7.49 (2H, d,
J=8.4 Hz, minor), 7.31 (2H, d, J=8.3 Hz, major), 7.21 (1H, dd, J=4.0,
8.0 Hz, minor), 7.11 (2H, d, J=8.1 Hz, major), 2.37 (3H, s, minor),
2.33 ppm (3H, s, major); 13C NMR (CDCl3, 100 MHz): d=179.4, 151.9,
146.0, 145.8, 136.7, 136.2, 133.1, 131.5, 130.1, 129.7, 128.4, 127.8, 127.2,
127.1, 122.7, 119.3, 115.2, 86.7, 21.6 ppm; IR (NaCl, neat): n˜ =1708, 1598,
1589, 1467, 1429, 1373, 1172, 1087 cmꢀ1; HRMS (ESI): m/z calcd for
C16H12NO3SClI: 459.9271 (M++H); found: 459.9269.
1-Acetyl-3-(diiodomethyl)-3-phenylindolin-2-one (2p): Yellow solid; m.p.
157–1618C; 1H NMR (CDCl3, 400 MHz): d=8.39 (1H, d, J=8.24 Hz),
8.11 (1H, d, J=7.64 Hz), 7.55 (1H, t, J=7.86 Hz), 7.42 (1H, t, J=
7.62 Hz), 7.32–7.38 (5H, m) 5.96 (1H, s), 2.62 ppm (3H, s); 13C NMR
(CDCl3, 100 MHz): d=174.9, 170.4, 140.7, 137.3, 130.3, 129.0, 128.2,
127.3, 125.0, 124.8, 117.0, 62.6, 26.7, ꢀ21.3 ppm; IR (NaCl, neat): n˜ =
1751, 1716, 1604, 1494, 1477, 1371, 1186, 1089 cmꢀ1; HRMS (ESI): m/z
calcd for C17H14NO2I2: 517.9114 (M++H); found: 517.9122.
(E)-2-(Iodomethylene)-3-phenyl-1-tosylindolin-3-ol
(4a):[13d]
Yellow
1
solid; H NMR (CDCl3, 400 MHz): d=7.91 (1H, d, J=8.3 Hz), 7.58 (2H,
d, J=8.2 Hz), 7.31 (2H, d, J=8.2 Hz), 7.24 (2H, d, J=8.1 Hz), 7.12 (3H
m), 7.01 (3H, m), 6.95 (1H, d, J=7.5 Hz), 2.65 (1H, s), 2.41 ppm (3H, s);
13C NMR (CDCl3, 100 MHz): d=148.0, 145.3, 142.3, 139.7, 135.1, 133.6,
130.2, 129.8, 128.2, 127.6, 127.3, 126.0, 125.6, 125.3, 116.6, 82.9, 65.9,
21.7 ppm; MS (ESI): m/z (%): 504 [M+H]+.
2-(Iodomethylene)-1-tosylindolin-3-one (3a): Yellow solid; E/Z (4.6:1);
m.p. 143–1458C; 1H NMR (CDCl3, 300 MHz): d=8.27 (1H, s, major),
8.13 (1H, d, J=9.0 Hz, major), 8.07 (1H, s, minor), 8.00 (1H, d, J=
8.1 Hz, minor), 7.74–7.67 (2H, m), 7.55 (2H, d, J=7.5 Hz, minor), 7.49
(2H, d, J=8.4 Hz), 7.30–7.24 (2H, m), 7.17 (2H, d, J=8.4 Hz, major),
7.06 (2H, d, J=8.1 Hz, minor), 2.34 (3H, s, major), 2.30 ppm (3H, s,
minor); 13C NMR (CDCl3, 75 MHz): d=183.3, 146.8, 145.7, 136.9, 135.1,
133.2, 129.9, 129.5, 127.8, 127.2, 127.0, 125.6, 125.1, 124.9, 117.0,
21.6 ppm; IR (NaCl, neat): n˜ =3446, 1707, 1606, 1458, 1363, 1199, 1174,
1083 cmꢀ1; HRMS (ESI): m/z calcd for C16H13INO3S: 425.9661 (M++H);
found: 425.9668.
3-Phenyl-1-tosyl-1H-indole-2-carbaldehyde (5a):[13d] Yellow solid;
1H NMR (CDCl3, 400 MHz): d=10.22 (1H, s), 8.30 (1H, d, J=8.5 Hz),
7.83 (2H, d, J=8.3 Hz), 7.58–7.52 (2H, m), 7.45 (5H, m), 7.26 (1H, m),
7.24 (2H, d, J=6.5 Hz), 2.36 ppm (3H, s); 13C NMR (CDCl3, 100 MHz):
d=182.4, 145.3, 138.2, 135.8, 135.2, 132.5, 130.5, 130.4, 129.7, 129.3, 129.2,
129.0, 128.4, 127.2, 124.6, 122.6, 115.7, 21.7 ppm; MS (ESI): m/z (%): 376
[M+H]+.
2-(Iodomethylene)-5,7-dimethyl-1-tosylindolin-3-one (3b): Yellow solid;
E/Z (2:1); m.p. 168–1708C; 1H NMR (CDCl3, 400 MHz): d=7.99 (1H, s,
major), 7.88 (1H, s, minor), 7.41 (1H, s, major), 7.39 (1H, s, minor), 7.22
(1H, s, major), 7.14–7.06 (4H, m), 2.68 (3H, s, minor), 2.65 (3H, s,
major), 2.37 (6H, s, minor), 2.34 ppm (6H, s, major); 13C NMR (CDCl3,
1984
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 1978 – 1985

1-(2’-Anilinyl)prop-2-yn-1-ol Rearrangement for Oxindole Synthesis
FULL PAPER
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Acknowledgements
This work is supported by a College of Science Start-Up Grant from Na-
nyang Technological University (NTU) and a Science and Engineering
Research Council Grant (092 101 0053) from A*STAR, Singapore. An
Undergraduate Research Experience on Campus stipend (to B.Q.K.)
from NTU is also acknowledged and we thank Dr. Yongxin Li of this Di-
vision for providing the X-ray crystallographic data reported in this
work, and the High Performance Computing Center at NTU for comput-
er resources.
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Received: July 24, 2012
Revised: October 16, 2012
Published online: November 30, 2012
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