Metal-Free Synthesis of Oxazolidine-2,4-diones and 3,3-Disubstituted Oxindoles via ICl-Induced Cyclization

Article abstract of DOI:10.1002/ejoc.201801250

A metal-free method for the construction of oxazolidine-2,4-diones and oxindoles was discussed. Using iodine monochloride (ICl) as both the reaction promoter and iodide source, the iodolactonization of N-Boc acrylamides proceeded readily and provided the corresponding iodo oxazolidine-2,4-diones and oxazolidin-2-ones in good isolated yields. The obtained oxazolidine-2,4-diones can be used as key intermediates in the synthesis of toloxatone. When N-alkyl-N-arylacrylamide derivatives were subjected to the same reaction, iodocarbocyclization products 3,3-disubstituted oxindoles were obtained. The obtained oxindoles can be used as key intermediates in the synthesis of the alkaloids (±)-esermethole and (±)-physostigmine.

Full text of DOI:10.1002/ejoc.201801250

A Journal of
Accepted Article
Title: Metal-free synthesis of oxazolidine-2,4-diones and 3,3-
disubstituted oxindoles via the ICl‑induced cyclization
Authors: Wei Yi, Xing-Xiao Fang, Qing-Yun Liu, and Gong-Qing Liu
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801250
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10.1002/ejoc.201801250
European Journal of Organic Chemistry
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Metal-free synthesis of oxazolidine-2,4-diones and 3,3-
disubstituted oxindoles via the ICl‑induced cyclization
Wei Yi,[a] Xing-Xiao Fang,[a] Qing-Yun Liu[a] and Gong-Qing Liu[a]*
Dedication ((optional))
Abstract: A metal-free method for the construction of oxazolidine-
2,4-diones and oxindoles was discussed. Using iodine monochloride
(ICl) as both the reaction promoter and iodide source, the
iodolactonization of N-Boc acrylamides proceeded readily and
provided the corresponding iodo oxazolidine-2,4-diones and
oxazolidin-2-ones in good isolated yields. The obtained oxazolidine-
2,4-diones can be used as key intermediates in the synthesis of
toloxatone. When N-alkyl-N-arylacrylamide derivatives were
subjected to the same reaction, iodocarbocyclization products 3,3-
disubstituted oxindoles were obtained. The obtained oxindoles can
be used as key intermediates in the synthesis of the alkaloids (±)-
esermethole and (±)-physostigmine.
rearrangement cascade reaction[13] (Scheme 1c).
Despite these advances, general methods for the preparation of
various oxazolidine-2,4-dione are still limited. Furthermore, a
chromatographic step was often required for the removal of
excess amount of reactants and/or catalysts in most cases.
These drawbacks more or less limited the application of these
methods in the preparation of structurally diverse oxazolidine-
2,4-dione compounds. Given the great importance of
electrophilic cyclization, development of a simple, practical,
scalable electrophilic cyclization for the synthesis of the
oxazolidine-2,4-dione framework as well as the application of
these materials in the synthesis of bioactive compound seemed
is very interesting to us. Herein, we report the ICl-mediated
iodolactonization of unsaturated carbamates to prepare iodo-
substituted oxazolidine-2,4-diones and oxazolidin-2-ones as a
continuation of our investigation of the halocyclization of
unfunctionalized olefins[14] (Scheme 1d).
Introduction
Oxazolidine-2,4-dione moiety is an ubiquitous structural feature
in natural products, and it is listed among the most significant
structural components of synthetic lead compounds that exhibit
various
biological
activities
including
anticonvulsant,[1]
antidiabetic,[2] antitumor,[3] anti-inflammatory activity[4] and
cardiotonic[5] (Figure 1). Moreover, oxazolidine-2,4-dione are
also frequently employed as synthons in organic synthesis since
they can be further manipulated by various reactions such as
hydrolysis to hydroxyamides[6]. Accordingly, over the years, a
substantial amount of effort has been devoted to the
development of novel methods for the synthesis of these
compounds.[7] The most general methods for the preparation of
compounds of this class are the condensation of α-hydroxy
amides with dialkyl carbonates[8] or phosgene[2b, 9] and α-hydroxy
esters with urea[10] or isocyanates[11] (Scheme 1a). However, this
method requires preformed α-hydroxy amides or α-hydroxy
esters as a substrate which are sometimes difficult to make.
Additionally, the cyclizations of acrylic acid or propiolic acid
derivatives with CO2 is also an efficient route for the synthesis of
oxazolidine-2,4-diones[12](Scheme 1b). However, transition-
metal catalysts are often required to facilitate these reactions
due to the thermodynamic and kinetic stability of carbon
dioxide,[12e] which involve some drawbacks including their
associated cost, toxicity as well as the issue of metal impurities.
Finally, Li, Lu and coworkers prepared fluorinated oxazolidine-
2,4-diones via an oxy-palladation and formal Wagner−Meerwein
Figure 1. Examples of bioactive oxazolidine-2,4-dione-containing compounds.
[a]
Ms. W.Yi, Mr. X.-X. Fang, Mr. Q.-Y. Liu, and Prof. Dr. G.-Q. Liu
College of Pharmacy, Nantong University
19 Qixiu Road, Nantong, 226001
People’s Republic of China
E-mail: gqliu@ntu.edu.cn
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
Scheme 1. Synthesis of oxazolidine-2,4-diones.
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10.1002/ejoc.201801250
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Results and Discussion
the yield of the reaction (entry 10). Other bases, such as
sodium carbonate and triethylamine, were much less
effective than sodium bicarbonate (entries 11−12).
The iodocyclization of acrylamides is a direct and efficient
method for accessing oxazolidine-2,4-dione derivatives due
to their low cost and step economy (Scheme 1d). Moreover,
the resulting iodinated products could be easily converted
to many different oxazolidine-2,4-dione derivatives upon
conventional nucleophilic substitution reactions, and this
method thus offer an effective route to a variety of
biologically active structures.
Table 1. Optimization of the conditions for the iodocarbocyclization.[a]
entry
reagent
solvent
time
(h)
yield
[b]
base
(%)
Recently,
we
have
shown
that
intramolecular
1
2
3
4
5
6
7
8
'9
10
11
12
-
-
-
-
-
-
PhI(OAc)2, KI
PhI(OAc)2, TMSI
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
hexane
acetone
benzene
CH3CN
CH3CN
CH3CN
CH3CN
24 h
24 h
24 h
24 h
1 h
1 h
1 h
1 h
1 h
79
80
70
62
84
75
60
86
85
halocyclizations of unfunctionalized olefins could be
realized by using hypervalent iodine[14a, 14b] or Cu(II)[14c, 14d]
as the reaction promoters (Scheme 2). Given the
importance of oxazolidine-2,4-diones, we would like to
adopt the halocyclization of acrylamides to prepare these
compounds as an extension of our ongoing work toward the
cyclization of olefins (Scheme 1d).
I2
NIS
ICl
ICl
ICl
ICl
ICl
ICl
ICl
ICl
1 h
1 h
1 h
NaHCO3
Na2CO3
Et3N
89
83
N.R.
[a] The reaction was carried out with 0.5 mmol of 1a in 20 mL of solvent, [b]
isolated yield.
Scheme 2. Intramolecular halocyclizations.
[a]
Scheme 3. Scope on cyclization of carbamate
With this in mind, we initially tested our previously reported
protocols that could promote the intramolecular
halocyclization
of
olefins.
To
our
delight,
(diacetoxyiodo)benzene in combination with potassium
iodide[14a] or trimethylsilyl iodide[14b] was also effective for
promoting the desired iodolactonization of N-Boc
acrylamide 1a, which normally are ineffective in similar
transformations[15] (Table 1, entries 1−2). The O-cyclization
product 2a arose from nucleophilic attack of the carbamate
carbonyl group on the double bond,[16] and the structure of
this compound was established by two-dimensional (2D)
NMR experiments and HRMS experiments. Molecular
iodine and N-iodosuccinimide (NIS), which are commonly
used in iodocyclization reactions,[17] could also be used for
iodolactonization of 1a, but the yields were generally lower
than PhI(OAc)2-induced reactions (entries 3−4). To our
surprise, the reaction could be completed in 1 hour when
iodine monochloride (ICl) was employed as the reaction
promoter (entry 5). More importantly, we found that the
desired product can also be isolated conveniently by simple
[a] The reaction was carried out with 0.5 mmol of substrate, 0.5 mmol of ICl,
and 0.5 mmol of NaHCO3 in 20 mL of CH3CN. [b] 10 mmol scale
extraction after quenching with
a saturated aqueous
Na2S2O3 solution and chromatographic purification can be
avoided. Encouraged by these preliminary results, reactions
in different solvents were then carried out to find suitable
reaction conditions (entries 6−9). Reactions in benzene or
acetonitrile gave promising results. Acetonitrile was finally
chosen as the reaction medium for further studies due to its
low toxicity. Interestingly, products resulting from the
participation of CH3CN were not observed under the current
conditions.[18] Finally, the investigation of the effect of base
showed that the addition of sodium bicarbonate improved
With the optimized conditions in hand, the substrate scope
was studied, and the results are presented in Scheme 3. As
shown in Scheme 3, good to excellent yields were obtained
from a variety of N-Boc protected acrylamides (2a-2q). The
reaction could also be scaled up to 10 mmol to give 2.76 g
(80%) of product 2b. It is remarkable that no additional
iodination occured at furan moiety in 2m under the current
conditions. α, β-Substituted N-Boc acrylamides were also
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10.1002/ejoc.201801250
European Journal of Organic Chemistry
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subjected to the process affording one single diastereomer
in good yield (2o and 2p). The relative configuration in 2o
and 2p was assigned to trans, as expected for a cyclization
via an intermediate iodonium ion. 1,1-Disubstituted olefin
can also undergo cyclization under identical condition, but
resulted exclusively in the formation of the six-membered
Scheme 5. Cyclization of N-methylacrylamide 5a
ring product 1,3-oxazinane-2,4-dione 2q
.
Moreover,
allyl(phenyl)carbamates could all be cyclized under the
optimal conditions, giving oxazolidinones 2r−2u in
satisfactory isolated yields.
Oxindoles have been identified as having diverse properties
such as antitumor,[22] anti-HIV,[23] antimalarial,[24] anti-
To test the synthetic utility of current reaction, functional
group transformations of obtained products were also
pursued (Scheme 4). For example, the oxazolidinedione
moiety in 2b could be easily hydrolyzed under alkaline
conditions. Simultaneously, iodine atom in 2b was replaced
inflammatory,[25]
antibacterial,[26]
antioxidant,[27]
anti-
Alzheimer's,[28] spermicidal,[29] kinase inhibitory,[30] and analgesic
activity.[31] Moreover, oxindoles are important building blocks for
the construction of other nitrogen-containing ring systems.[32]
Thus, structurally diverse oxindole compounds were prepared
using the developed method, and the results are summarized in
Scheme 6. As shown in Scheme 6, the iodocarbocyclization of
N-arylacrylamides proceeded readily and gave rise to the
corresponding oxindole products in good isolated yields. The
presence of an electron-donating group or a halide at the para-
position of the anilide did not significantly influence the reaction
outcome, and no additional iodination of the aromatic ring was
by hydroxyl group, giving α-hydroxyamide
3 in good yield
(Scheme4, eq. 1). In addition, the developed methodology
was successfully applied to the synthesis of toloxatone
(Humoryl®), an antidepressant medicine.[19] The obtained 2t
was treated with KOAc followed by saponification with
K2CO3 in EtOH, giving toloxatone (4) in 75% overall yield
over two steps (Scheme 4, eq. 2). This synthetic route has
the advantage of being higher yielding compared to that
reported in the literature.[20]
observed in these cases (6a−6h). As expected,
a 3,4-
methylenedioxy-substituted anilide gave mixture of two
a
regioisomers (6i/6i’) in a 1.1:1 ratio. The anilides bearing a
cyano or an acetyl moiety gave significantly lower yields
probably due to the low reactivity of the substrate caused by the
strong electron-withdrawing effects of the substituents (6j and
6k). Naphthalene compounds worked well in the current reaction
system, and the corresponding oxindoles were obtained in good
yields (6l and 6m). Furthermore, different alkyl, phenyl or benzyl
substituents on the nitrogen atom had little impact on the course
of the reaction (6n−6s). It is worth mentioning that the benzyl
residue did not participate in the cyclization as none of the
corresponding 1,2-dihydroisoquinolin-3(4H)-one was observed.
Substrates with different substituents at the α-position of the
Michael-acceptor unit were also investigated. Benzyl and phenyl
groups at the α-position of the acrylamide were well-tolerated
and afforded the corresponding iodo oxindoles in 75% and 79%
yields, respectively (6t and 6u). Again, no iodination of the
electron rich-aromatic rings in 6t and 6u was detected. Whereas
oxindoles with iodo-substitution of the aromatic ring were
obtained in the case of acrylamides lacking a para substituent
on the anilide (6v−6x). This might be attributed to the directing
effect of the amino substituent, which caused the other positions
on the phenyl ring to be less reactive than the C5 position.
Scheme 4. Derivatization of obtained products
To further extend the application scope of ICl-promoted
iodocyclization reactions, we next examined the acrylamide
bearing different groups on the nitrogen atom. N-Acetyl or N-
tosyl protected acrylamide failed to react, probably due to poor
electron density. However, when N-methylacrylamide 5a was
subjected to reaction under the standard conditions, an
iodocarbocyclization product oxindole 6a was obtained as a sole
product, albeit at a lower yield (Scheme 5), which was not
consistent with the observations made by Zhu that the
iodocarbocyclization of methacrylamide did not occur when ICl
was used[21]. This can be attributed to the use of different
solvents. Moreover, additional iodination of the benzene ring,
which was frequently encountered in this process,[15a, 21] was not
observed in the current system. By increasing the amount of ICl
to 2.0 equiv., the isolated yield of 6a increased to 90%.
Compared with above iodolactonization, 2 equiv. ICl and long
reaction times were essential to achieve satisfactory yields for
current cases. This may be attributed to the lower nucleophilic
character of the carbon atom than oxygen atom.
Scheme 6. Scope of the iodocarbocyclization reaction. [a]
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10.1002/ejoc.201801250
European Journal of Organic Chemistry
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reductive cyclization, followed by N-methylation. Finally, using a
slightly modified version of the conditions reported by Zhu,[35]
compound 9 was transformed in two steps to (±)-physostigmine
(10) (70% yield over two steps). Using this short and efficient
route, the syntheses of (±)-esermethole and (±)-physostigmine
were achieved in only three steps and 69% overall yield and five
steps and 48% overall yield, respectively.
Scheme 8. Total synthesis of (±)-physostigmine
Conclusions
[a]
In summary, we have developed a metal-free method for the
preparation of oxazolidine-2,4-diones and oxindole derivatives.
Using iodine monochloride as both the reaction promoter and
The reaction was carried out with 0.5 mmol of substrate, 1.0 mmol of ICl,
and 1.0 mmol of NaHCO3 in 20 mL of CH3CN, 5 h
iodide
source,
oxazolidine-2,4-diones
and
3-
The scalability of the current protocol was demonstrated by the
gram-scale synthesis of oxindole 6a. Iodocarbocyclization of N-
arylacrylamide 5a was carried out on a 10-mmol scale, and
product 6a was obtained in 82% yield after recrystallization
(Scheme 7, eq. 1). Substitution of the exocyclic iodine atom in
6a by sodium azide delivered compound 7 (Scheme 7, eq. 2),
which could be converted to a potential antidepressant agent
after simple derivatization.[33]
iodomethyloxindoles could be obtained in good isolated yields at
ambient temperature without special procedures. The reaction
could be carried out on a gram-scale, and the iodide substituent
could be easily converted to other functional groups via
conventional methods. The obtained products can be used as
key intermediates in syntheses of bioactive compound such as
toloxatone, (±)-esermethole and (±)-physostigmine. The good
isolated yields, mild conditions, and operational simplicity make
the current reaction an attractive method for the syntheses of a
variety of medicinally and agrochemically relevant compounds.
Experimental Section
General Experimental Information. All reactions requiring the
exclusion of air and/or moisture were conducted in flame-dried
glassware under an argon atmosphere. Solvents were dried and
distilled prior to use. Acetonitrile was dried over 3Å molecular
sieves and distilled under an argon atmosphere. Cyclohexane,
ethyl acetate and petroleum ether were purchased in technical
quality and were purified by distillation. All other chemicals were
purchased from commercial suppliers and used without prior
Scheme 7. Gram-scale iodocarbocyclization and derivatization of 5a
To further highlight the utility of the developed methodology, we
completed the total synthesis of the acetylcholinesterase
inhibitor physostigmine, which was isolated from the seeds of
the African Calabar bean Physostigma Venenosum.[34] The
iodine atom in oxindole 5b could be replaced by sodium cyanide,
providing product 8 in 88% yield (Scheme 8). Compound 8 was
converted into the natural product (±)-esermethole (9) by
purification
unless
otherwise
stated.
Flash
column
chromatography was performed on silica of 25−40 μm particle
size. NMR spectra were recorded on 400 MHz spectrometers
using standard pulse sequences. Chemical shifts are expressed
in ppm relative to tetramethylsilane referenced to the residual
1
solvent signals (CDCl3: H, δ = 7.26 ppm; 13C, δ = 77.16 ppm).
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10.1002/ejoc.201801250
European Journal of Organic Chemistry
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HRMS–ESI was performed on a Q-TOF instrument with a dual
= 15/1); mp = 110–112 °C. 1H NMR (400 MHz, CDCl3): δ/ppm=
7.33 (d, J = 9.0 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 4.06 (q, J = 7.0
Hz, 2H), 3.68 (d, J = 11.2 Hz, 1H), 3.52 (d, J = 11.2 Hz, 1H),
1.84 (s, 3H), 1.43 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ/ppm= 172.7, 159.4, 153.1, 127.1, 123.0, 115.2, 83.1,
63.8, 21.8, 14.7, 6.3. IR (KBr): 3053, 3002, 1700, 1666, 1506,
1006, 845, 814, 701 cm-1. ESI-HRMS: calc. for [C13H14INO4+
H]+: m/z = 376.0046, found: 376.0043.
5-(Iodomethyl)-3-(4-iodophenyl)-5-methyloxazolidine-2,4-
dione (2e). Compound 2e was prepared according to the
general procedure and isolated as a brown solid (169 mg, 74%
yield) after flash chromatography (petroleum ether/ethyl acetate
= 12/1); mp = 127–128 °C. 1H NMR (400 MHz, CDCl3): δ/ppm=
7.83 (d, J = 8.6 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 3.67 (d, J =
11.3 Hz, 1H), 3.52 (d, J = 11.3 Hz, 1H), 1.84 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ/ppm= 171.1, 151.2, 137.6, 129.4, 126.2,
93.6, 82.3, 20.7, 5.1. IR (KBr): 3010, 2956, 1705, 1628, 1503,
1056, 827, 679, 521 cm-1. ESI-HRMS: calc. for [C11H9I2NO3+H]+:
m/z = 457.8750, found: 457.8741.
source and
chromatography (TLC) was carried out on 0.25 mm silica gel
plates with fluorescence indicator. Melting points were
measured on an electrothermal apparatus with digital
a
suitable external calibrant. Thin-layer
a
a
thermometer. Substrates 1a-1u and 5a-5x were prepared
according to the literature.[13, 36]
General procedure for the synthesis of oxazolidinediones:
To a solution of N-Boc acrylamide (0.5 mmol, 1.0 equiv.) in
acetonitrile (20 mL) were added ICl (0.5 mmol, 1.0 equiv.) and
NaHCO3 (0.5 mmol, 1.0 equiv.). The reaction mixture was stirred
at room temperature until complete disappearance of the
starting material as shown by TLC (usually 1-2 h). The reaction
was next quenched with a saturated aqueous Na2S2O3 solution
and extracted with CH2Cl2. The combined organic layers were
washed with brine, dried and concentrated to give a crude
residue, which was purified by flash column chromatography.
5-(Iodomethyl)-3-(4-methoxyphenyl)-5-methyloxazolidine-
2,4-dione (2a). Compound 2a was prepared according to the
general procedure and isolated as a white solid (161 mg, 89%
yield) after flash chromatography (petroleum ether/ethyl acetate
4-(5-(Iodomethyl)-5-methyl-2,4-dioxooxazolidin-3-
yl)benzonitrile (2f). Compound 2f was prepared according to
the general procedure and isolated as a yellow solid (116 mg,
65% yield) after flash chromatography (petroleum ether/ethyl
acetate = 12/1); mp = 156–158 °C. 1H NMR (400 MHz, CDCl3):
δ/ppm= 7.81 (d, J = 8.7 Hz, 2H), 7.70 (d, J = 8.7 Hz, 2H), 3.69 (d,
1
= 10/1); mp = 129–131 °C. H NMR, COSY (400 MHz, CDCl3):
δ/ppm =7.37 (d, J = 8.8 Hz, 2H, Ar-H2,6), 7.01(d, J = 8.8 Hz, 2H,
Ar-H3,5), 3.85(s, 3H, -OMe), 3.69(d, J = 11.3 Hz, 1H, -CHaCHbI),
3.54(d, J = 11.3 Hz, 1H, -CHaCHbI), 1.85(s, 3H, -CH3). 13C NMR,
HSQC, HMBC (100 MHz, CDCl3): δ/ppm =172.7(-NCO-), 160.0
(Ar-C4), 153.1(-NCO2-), 127.2(Ar-C2,6), 123.5(Ar-C1), 114.7
(Ar-C3, 5), 83.2(-CO2C-), 55.6(-OCH3), 21.6 (-CH3), 6.4(-CH2I).
IR (KBr): 3050, 2928, 1714, 1620, 1375, 1063, 795, 656, 648
cm-1. ESI-HRMS: calc. for [C12H12INO4+ H]+: m/z = 361.9889,
found: 361.9879.
J = 11.3 Hz, 1H), 3.54 (d, J = 11.3 Hz, 1H), 1.87 (s, 3H). 13
C
NMR (100 MHz, CDCl3): δ/ppm= 170.8, 150.7, 133.6, 132.2,
124.7, 116.7, 111.7, 82.5, 20.7, 4.9. IR (KBr): 3011, 2979, 1703,
1640, 1498, 1037, 820, 710, 547 cm-1. ESI-HRMS: calc. for
[C12H9IN2O3+Na]+: m/z = 378.9556, found: 378.9551.
5-(Iodomethyl)-5-methyl-3-phenyloxazolidine-2,4-dione (2g).
5-(Iodomethyl)-5-methyl-3-(p-tolyl)oxazolidine-2,4-dione (2b). Compound 2g was prepared according to the general procedure
Compound 2b was prepared according to the general procedure
and isolated as a yellow solid (141 mg, 82%) after flash
chromatography (petroleum ether/ethyl acetate = 15/1); mp =
106–108 °C. 1H NMR (400 MHz, CDCl3): δ/ppm=7.32 (d, J = 8.6
Hz, 2H), 7.29 (d, J = 8.6 Hz, 2H), 3.67 (d, J = 11.3 Hz, 1H), 3.51
(d, J = 11.3 Hz, 1H), 2.39 (s, 3H), 1.83 (s, 3H). 13C NMR (100
MHz, CDCl3): δ/ppm= 171.5, 151.9, 138.4, 129.0, 127.0, 124.6,
82.1, 20.7, 20.2, 5.4. IR (KBr): 3021, 2982, 1720, 1649, 1500,
1218, 1021, 875, 737, 653 cm-1. ESI-HRMS: calc. for
[C12H12INO3+H]+: m/z = 345.9940, found: 345.9933.
3-(4-Bromophenyl)-5-(iodomethyl)-5-methyloxazolidine-2,4-
dione (2c). Compound 2c was prepared according to the
general procedure and isolated as a brown solid (146 mg, 71%
yield) after flash chromatography (petroleum ether/ethyl acetate
= 15/1); mp = 135–136 °C. 1H NMR (400 MHz, CDCl3): δ/ppm=
7.63 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 8.7 Hz, 2H), 3.68 (d, J =
11.3 Hz, 1H), 3.52 (d, J = 11.3 Hz, 1H), 1.84 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ/ppm= 172.2, 152.3, 132.6, 129.7, 127.1,
123.1, 83.3, 21.8, 6.1. IR (KBr): 3045, 2010, 1701, 1649, 1502,
1068, 873, 653 cm-1. ESI-HRMS: calc. for [C11H9BrINO3+H]+:
m/z = 409.8889, found: 409.8888.
and isolated as a white solid (142 mg, 86% yield) after flash
chromatography (petroleum ether/ethyl acetate = 15/1); mp =
85–88 °C. 1H NMR (400 MHz, CDCl3): δ/ppm= 7.45 – 7.30 (m,
5H), 3.61 (d, J = 11.3 Hz, 1H), 3.45 (d, J = 11.3 Hz, 1H), 1.76 (s,
3H). 13C NMR (100 MHz, CDCl3): δ/ppm= 172.5, 152.8, 130.7,
129.4, 129.2, 125.7, 83.2, 21.8, 6.3. IR (KBr): 3013, 3000, 2878,
1700, 1604, 1499, 1099, 800, 640 cm-1. ESI-HRMS: calc. for
[C11H10INO3+H]+: m/z = 331.9784, found: 331.9777.
3-(Benzo[d][1,3]dioxol-5-yl)-5-(iodomethyl)-5-
methyloxazolidine-2,4-dione (2h). Compound 2h was
prepared according to the general procedure and isolated as a
yellow solid (165 mg, 88% yield) after flash chromatography
(petroleum ether/ethyl acetate = 8/1); mp = 96–97 °C. 1H NMR
(400 MHz, CDCl3): δ/ppm= 6.89 (s, 3H), 6.02 (s, 2H), 3.67 (d, J
= 11.3 Hz, 1H), 3.51 (d, J = 11.3 Hz, 1H), 1.82 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ/ppm= 172.6, 152.9, 148.3, 148.2, 124.0,
120.0, 108.5, 107.1, 102.1, 83.2, 21.7, 6.4. IR (KBr): 3012, 2947,
2793, 1712, 1620, 1501, 1332, 1037, 817, 610, 573 cm-1. ESI-
HRMS: calc. for [C12H10INO5+H]+: m/z = 375.9684, found:
375.9678.
5-(Iodomethyl)-5-methyl-3-(naphthalen-2-yl)oxazolidine-2,4-
dione (2i). Compound 2i was prepared according to the general
procedure and isolated as a yellow solid (150 mg, 79% yield)
after flash chromatography (petroleum ether/ethyl acetate =
10/1); mp = 135–136 °C. 1H NMR (400 MHz, CDCl3): δ/ppm=
3-(4-Ethoxyphenyl)-5-(iodomethyl)-5-methyloxazolidine-2,4-
dione (2d). Compound 2d was prepared according to the
general procedure and isolated as a light red solid (169 mg, 90%
yield) after flash chromatography (petroleum ether/ethyl acetate
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10.1002/ejoc.201801250
European Journal of Organic Chemistry
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7.88 – 7.83 (m, 2H), 7.78 (dd, J = 5.6, 3.2 Hz, 2H), 7.44 (dt, J =
8.0, 2.1 Hz, 3H), 3.61 (d, J = 11.3 Hz, 1H), 3.44 (d, J = 11.3 Hz,
1H), 1.76 (s, 3H). 13C NMR (100 MHz, CDCl3): δ/ppm= 171.6,
151.8, 132.0, 131.9, 128.4, 127.2, 127.0, 126.8, 126.2, 125.9,
124.0, 121.8, 82.2, 20.7, 5.3. IR (KBr): 3023, 3000, 2901, 1714,
1625, 1504, 1138, 814, 711 cm-1. ESI-HRMS: calc. for
[C15H12INO3+H]+: m/z = 381.9940, found: 381.9932.
5-Benzyl-5-(iodomethyl)-3-(p-tolyl)oxazolidine-2,4-dione (2n).
Compound 2n was prepared according to the general procedure
and isolated as an oil (139 mg, 66% yield) after flash
chromatography (petroleum ether/ethyl acetate = 15/1). 1H NMR
(400 MHz, CDCl3): δ/ppm= 7.27 – 7.21 (m, 3H), 7.17 (dd, J = 6.4,
3.2 Hz, 2H), 7.08 (d, J = 8.3 Hz, 2H), 6.67 (d, J = 8.3 Hz, 2H),
3.70 (d, J = 11.3 Hz, 1H), 3.50 (d, J = 11.3 Hz, 1H), 3.25 (d, J =
13.9 Hz, 1H), 3.19 (d, J = 13.9 Hz, 1H), 2.24 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ/ppm= 170.5, 151.8, 138.4, 131.3, 129.1,
128.9, 127.8, 127.2, 126.5, 124.7, 85.4, 40.4, 20.2, 3.8. IR (KBr):
3011, 3009, 2927, 1701, 1625, 1456, 1329, 1257, 1152, 809,
678, 632, 506 cm-1. ESI-HRMS: calc. for [C18H16INO3+H]+: m/z =
422.0253, found: 422.0250.
6-Iodo-3-(p-tolyl)-1-oxa-3-azaspiro[4.5]decane-2,4-dione (2o).
Compound 2o was prepared according to the general procedure
and isolated as a white solid (137 mg, 71% yield) after flash
chromatography (petroleum ether/ethyl acetate = 50/1); mp =
135–137 °C. 1H NMR (400 MHz, CDCl3): δ/ppm= 7.33 (d, J = 8.4
Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 4.28 (dd, J = 13.0, 4.7 Hz, 1H),
2.71 (dd, J = 13.3, 3.9 Hz, 1H), 2.49 (dd, J = 13.7, 3.4 Hz, 1H),
2.40 (s, 3H), 2.11 (dt, J = 13.2, 3.7 Hz, 1H), 1.99 (dd, J = 13.2,
3.9 Hz, 1H), 1.91 (d, J = 17.3 Hz, 1H), 1.72 (dd, J = 13.6, 2.6 Hz,
1H), 1.42 (dt, J = 13.6, 3.7 Hz, 1H), 1.27 (d, J = 11.2 Hz, 1H).
13C NMR (100 MHz, CDCl3): δ/ppm= 171.9, 153.0, 139.3, 130.0,
128.1, 125.8, 85.1, 35.8, 33.8, 29.9, 27.4, 21.4, 21.2. IR (KBr):
3017, 2976, 1704, 1615, 1447, 1400, 1253, 1009, 827, 736, 623
cm-1. ESI-HRMS: calc. for [C15H16INO3+H]+: m/z = 386.0253,
found: 386.0250.
5-(Iodomethyl)-5-methyl-3-(3,4,5-
trimethoxyphenyl)oxazolidine-2,4-dione (2j). Compound 2j
was prepared according to the general procedure and isolated
as a brown solid (162 mg, 77% yield) after flash chromatography
(petroleum ether/ethyl acetate = 5/1); mp = 93–95 °C. 1H NMR
(400 MHz, CDCl3): δ/ppm= 6.64 (s, 2H), 3.86 (s, 6H), 3.85 (s,
3H), 3.68 (d, J = 11.3 Hz, 1H), 3.52 (d, J = 11.3 Hz, 1H), 1.84 (s,
3H). 13C NMR (100 MHz, CDCl3): δ/ppm= 171.5, 152.6, 151.7,
137.6, 125.1, 102.5, 82.1, 59.9, 55.3, 20.8, 5.4. IR (KBr): 3014,
2886, 1696, 1590, 1484, 1140, 1007, 814, 677, 532 cm-1. ESI-
HRMS: calc. for [C14H16INO6+H]+: m/z = 422.0101, found:
422.0094.
3-Benzyl-5-(iodomethyl)-5-methyloxazolidine-2,4-dione (2k).
Compound 2k was prepared according to the general procedure
and isolated as a white solid (157 mg, 91% yield) after flash
chromatography (petroleum ether/ethyl acetate = 6/1); mp = 85–
87 °C. 1H NMR (400 MHz, CDCl3): δ/ppm= 7.45 – 7.41 (m, 2H),
7.36 – 7.31 (m, 3H), 4.70 (s, 2H), 3.53 (d, J = 11.3 Hz, 1H), 3.41
(d, J = 11.3 Hz, 1H), 1.70 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ/ppm= 173.1, 153.8, 134.4, 129.0, 128.8, 128.5, 83.4, 44.1,
21.9, 5.4. IR (KBr): 3029, 2999, 1700, 1627, 1499, 1402, 1076,
937, 826, 629, 573 cm-1. ESI-HRMS: calc. for [C12H12INO3+H]+:
m/z = 345.9940, found: 345.9938.
5-(Iodo(phenyl)methyl)-5-methyl-3-(p-tolyl)oxazolidine-2,4-
dione (2p). Compound 2p was prepared according to the
general procedure and isolated as an oil (147 mg, 70% yield)
after flash chromatography (petroleum ether/ethyl acetate =
30/1). 1H NMR (400 MHz, CDCl3): δ/ppm= 7.43 (dd, J = 6.6, 2.8
Hz, 2H), 7.23 (dd, J = 4.9, 1.8 Hz, 3H), 7.03 (d, J = 8.1 Hz, 2H),
6.49 (d, J = 8.1 Hz, 2H), 5.26 (s, 1H), 2.22 (s, 3H), 1.82 (s, 3H).
13C NMR (100 MHz, CDCl3): δ/ppm= 168.7, 151.6, 138.3, 136.1,
3-(4-Fluorobenzyl)-5-(iodomethyl)-5-methyloxazolidine-2,4-
dione (2l). Compound 2l was prepared according to the general
procedure and isolated as a white solid (158 mg, 87% yield)
after flash chromatography (petroleum ether/ethyl acetate =
15/1); mp = 81–82 °C. 1H NMR (400 MHz, CDCl3): δ/ppm= 7.41
(dd, J = 8.6, 5.3 Hz, 2H), 7.00 (t, J = 8.7 Hz, 2H), 4.67 (d, J =
14.5 Hz, 1H), 4.62 (d, J = 14.5 Hz, 1H), 3.52 (d, J = 11.3 Hz, 1H), 128.9, 128.4, 128.3, 127.8, 126.5, 124.5, 86.5, 31.6, 24.2, 20.1.
3.40 (d, J = 11.3 Hz, 1H), 1.69 (s, 3H). 19F NMR (376 MHz,
CDCl3) δ/ppm=113.1. 13C NMR (100 MHz, CDCl3): δ/ppm=
172.1, 161.7 (d, JC-F = 247.4 Hz), 152.7, 130.1 (d, JC-F = 8.3 Hz),
129. 2 (d, JC-F = 3.3 Hz), 114.7 (d, JC-F = 21.6 Hz), 82.4, 42.3,
20.8, 4.5. IR (KBr): 3057, 2745, 1701, 1593, 1499, 1400, 1283,
1130, 814, 726 504 cm-1. ESI-HRMS: calc. for
[C12H11FINO3+Na]+: m/z = 385.9665, found: 385.9662.
IR (KBr): 3018, 2993, 1721, 1623, 1487, 1321, 1276, 1101, 973,
873, 757, 637 cm-1. ESI-HRMS: calc. for [C18H16INO3+H]+: m/z =
422.0253, found: 422.0249.
5-Iodo-6,6-dimethyl-3-(p-tolyl)-1,3-oxazinane-2,4-dione (2q).
Compound 2q was prepared according to the general procedure
and isolated as a yellow solid (140 mg, 78% yield) after flash
chromatography (petroleum ether/ethyl acetate = 6/1); mp =
163–164 °C. 1H NMR (400 MHz, CDCl3): δ/ppm= 7.29 (d, J = 8.3
Hz, 2H), 7.08 (d, J = 8.3 Hz, 2H), 4.77 (s, 1H), 2.40 (s, 3H), 1.82
(s, 3H), 1.71 (s, 3H). 13C NMR (100 MHz, CDCl3): δ/ppm= 167.1,
149.6, 139.3, 131.7, 130.2, 127.3, 78.1, 29.7, 28.4, 22.6, 21.3.
IR (KBr): 3060, 3001, 2928, 1729, 1635, 1489, 1341, 1306, 1230,
3-(Furan-2-ylmethyl)-5-(iodomethyl)-5-methyloxazolidine-
2,4-dione (2m). Compound 2m was prepared according to the
general procedure and isolated as an oil (106 mg, 63% yield)
after flash chromatography (petroleum ether/ethyl acetate = 6/1).
1H NMR (400 MHz, CDCl3): δ/ppm= 7.35 (dd, J = 1.8, 0.7 Hz,
1H), 6.42 (dd, J = 3.2, 0.7 Hz, 1H), 6.31 (dd, J = 3.2, 1.8 Hz, 1H), 914, 873, 733 cm-1. ESI-HRMS: calc. for [C13H14INO3+ H]+: m/z =
4.71 (s, 2H), 3.52 (d, J = 11.3 Hz, 1H), 3.41 (d, J = 11.3 Hz, 1H),
1.71 (s, 3H). 13C NMR (100 MHz, CDCl3): δ/ppm= 171.6, 152.3,
146.2, 141.9, 109.6, 109.1, 82.5, 35.6, 20.8, 4.3. IR (KBr): 2998,
2768, 1701, 1614, 1499, 1342, 1283, 1173, 917, 824, 737, 640,
544 cm-1. ESI-HRMS: calc. for [C10H10INO4+H]+: m/z = 335.9733,
found: 335.9728.
360.0097, found: 360.0089.
5-(Iodomethyl)-3-phenyloxazolidin-2-one (2r). Compound 2r
was prepared according to the general procedure and isolated
as a yellow solid (121 mg, 80% yield) after flash chromatography
(petroleum ether/ethyl acetate = 6/1); mp = 92–94 °C. 1H NMR
(400 MHz, CDCl3): δ/ppm= 7.53 – 7.50 (m, 2H), 7.39 – 7.34 (m,
2H), 7.14 (t, J = 7.4 Hz, 1H), 4.72 – 4.63 (m, 1H), 4.14 (t, J = 8.9
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10.1002/ejoc.201801250
European Journal of Organic Chemistry
FULL PAPER
Hz, 1H), 3.76 (dd, J = 9.2, 6.1 Hz, 1H), 3.43 (dd, J = 10.4, 4.1 Hz, ESI-HRMS: calc. for [C11H15INO3+H]+: m/z = 210.1130, found:
1H), 3.34 (dd, J = 10.4, 7.9 Hz, 1H). 13C NMR (100 MHz, CDCl3):
δ/ppm= 153.0, 136.8, 128.1, 123.3, 117.4, 70.2, 49.9, 5.4. The
data are in accordance with the literature.[16c]
210.1127.
Synthesis of toloxatone (4). The oxazolidinone 2t (317 mg, 1
mmol) was dissolved in DMF (10 mL), and KOAc (490 mg, 5
mmol) was added to the solution. After stirring the mixture at
70 °C for 10 h, H2O (20 mL) was added, and then the aqueous
layer was extracted with CH2Cl2 (x 4). The organic layers were
combined, washed with H2O and brine, dried over Na2SO4 and
concentrated. The residue was subsequently dissolved in EtOH
(10 mL), and K2CO3 (690 mg, 5 mmol) was added to the solution
at 0 °C. After stirring the mixture at 0 °C for 3 h, H2O (10 mL)
and CH2Cl2 (10 mL) were added, and then the aqueous layer
was extracted with CH2Cl2 (x 3). The organic layers were
combined, washed with H2O and brine, dried over Na2SO4 and
concentrated. Flash column chromatography (petroleum
ether/ethyl acetate = 2/1) afforded toloxatone (4) as a white solid
5-(Iodomethyl)-3-(p-tolyl)oxazolidin-2-one (2s). Compound 2s
was prepared according to the general procedure and isolated
as a yellow solid (135 mg, 85% yield) after flash chromatography
(petroleum ether/ethyl acetate = 6/1); mp = 101–102 °C. 1H NMR
(400 MHz, CDCl3): δ/ppm= 7.42 (d, J = 8.4 Hz, 2H), 7.19 (d, J =
8.4 Hz, 2H), 4.77 – 4.67 (m, 1H), 4.16 (t, J = 8.9 Hz, 1H), 3.78
(dd, J = 9.2, 6.1 Hz, 1H), 3.48 (dd, J = 10.3, 3.9 Hz, 1H), 3.35
(dd, J = 10.2, 8.6 Hz, 1H), 2.33 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ/ppm= 154.1, 135.3, 134.2, 129.7, 118.6, 71.3, 51.2,
20.8, 6.1. IR (KBr): 3011, 2967, 1695, 1506, 1416, 1305, 1039,
779, 590 cm-1. ESI-HRMS: calc. for [C11H12INO2+H]+: m/z =
317.9991, found: 317.9987.
5-(Iodomethyl)-3-(m-tolyl)oxazolidin-2-one (2t). Compound 2t
was prepared according to the general procedure and isolated
as an oil (146 mg, 92% yield) after flash chromatography
(petroleum ether/ethyl acetate = 6/1). 1H NMR (400 MHz,
CDCl3): δ/ppm= 7.29 (s, 1H), 7.23 (d, J = 8.6 Hz, 1H), 7.17 (t, J
= 7.8 Hz, 1H), 6.89 (d, J = 7.3 Hz, 1H), 4.60 (ddd, J = 14.3, 8.3,
4.0 Hz, 1H), 4.06 (t, J = 8.9 Hz, 1H), 3.68 (dd, J = 9.3, 6.1 Hz,
1H), 3.36 (dd, J = 10.4, 4.0 Hz, 1H), 3.26 (dd, J = 10.4, 8.1 Hz,
1H), 2.29 (s, 3H). 13C NMR (100 MHz, CDCl3): δ/ppm= 153.0,
138.1, 136.7, 127.8, 124.2, 118.1, 114.5, 70.1, 50.0, 20.6, 5.3.
(155 mg, 75%). mp = 77 °C (ref,[20a] mp = 75–76 °C). H NMR
1
(400 MHz, CDCl3): δ/ppm= 7.41 (s, 1H), 7.34 (d, J = 8.3 Hz, 1H),
7.31 – 7.26 (m, 1H), 6.98 (d, J = 7.4 Hz, 1H), 4.75 (ddd, J = 12.2,
7.3, 3.8 Hz, 1H), 4.05 (t, J = 8.8 Hz, 1H), 4.03 – 3.99 (m, 1H),
3.99 – 3.96 (m, 1H), 3.78 (dd, J = 12.5, 4.1 Hz, 1H), 2.39 (s, 3H),
1.72 (brs, 1H). 13C NMR (100 MHz, CDCl3): δ/ppm= 154.8, 139.1,
138.1, 128.9, 125.1, 119.2, 115.5, 72.8, 62.9, 46.5, 21.6. The
data are in accordance with the literature.[20a]
General procedure for the synthesis of iodinated oxindoles:
To a solution of N-arylacrylamide (0.5 mmol, 1.0 equiv.) in
IR (KBr): 3002, 2987, 1749, 1623, 1475, 1463, 1357, 1143, 1003, acetonitrile (20 mL) were added ICl (1.0 mmol, 2.0 equiv.) and
955, 866, 741, 657 cm-1. ESI-HRMS: calc. for [C11H12INO2+H]+:
m/z = 317.9991, found: 317.9986.
NaHCO3 (1.0 mmol, 2.0 equiv.). The reaction mixture was stirred
at room temperature until complete disappearance of the
starting material as shown by TLC (usually 3-5 h). The reaction
was next quenched with a saturated aqueous Na2S2O3 solution
and extracted with CH2Cl2. The combined organic layers were
washed with brine, dried and concentrated to give a crude
residue, which was purified by flash column chromatography. In
most of the reactions, the products obtained were essentially
pure by NMR analysis and further silica gel chromatography was
not necessary.
3-(Iodomethyl)-1,3,5,-trimethylindolin-2-one (6a). Compound
6a was prepared according to the general procedure and
isolated as a light red solid (142 mg, 90% yield) after flash
column chromatography (petroleum ether/ethyl acetate = 8/1);
mp = 68–70 °C. 1H NMR (400 MHz, CDCl3): δ/ppm= 7.05 (d, J =
7.2 Hz, 1H), 7.01 (s, 1H), 6.69 (d, J = 7.9 Hz, 1H), 3.44 (d, J =
9.7 Hz, 1H), 3.33 (d, J = 9.7 Hz, 1H), 3.14 (s, 3H), 2.29 (s, 3H),
1.43 (s, 3H). 13C NMR (100 MHz, CDCl3): δ/ppm= 176.8, 139.7,
131.6, 131.2, 127.8, 122.4, 107.0, 47.6, 25.2, 22.1, 20.2, 10.0.
Spectral data are in agreement with literature values.[21]
3-(4-Bromophenyl)-5-(iodomethyl)oxazolidin-2-one
(2u).
Compound 2u was prepared according to the general procedure
and isolated as a white solid (137 mg, 72% yield) after flash
chromatography (petroleum ether/ethyl acetate = 8/1); mp =
152–154 °C. 1H NMR (400 MHz, DMSO): δ/ppm= 7.59 (d, J =
9.2 Hz, 2H), 7.55 (d, J = 9.2 Hz, 2H), 4.75 (td, J = 10.7, 5.2 Hz,
1H), 4.20 (t, J = 9.1 Hz, 1H), 3.67 (dd, J = 9.3, 6.0 Hz, 1H), 3.62
(t, J = 9.1 Hz, 1H), 3.57 (dd, J = 10.7, 4.8 Hz, 1H). 13C NMR (100
MHz, DMSO): δ/ppm= 154.01, 138.0, 132.2, 120.5, 116.0, 71.5,
50.7, 10.0. IR (KBr): 3026, 3001, 2917, 1759, 1616, 1496, 1406,
1296, 1200, 1002, 931, 827, 713, 659 cm-1. ESI-HRMS: calc. for
[C10H9BrINO2+H]+: m/z = 381.8940, found: 381.8935.
Synthesis of α-hydroxyamide 3. Compound 2b (173 mg, 0.5
mmol) and KOH (56 mg, 1 mmol) were dissolved in a mixture of
H2O and EtOH (10 mL, 20:1). The resulting mixture was stirred
for 3 h. The solvent was evaporated, water (5 mL) was added
and the mixture was extracted thrice with dichloromethane (15
mL). The combined extracts were dried over Na2SO4 and
concentrated to give a crude residue, which was purified by flash
column chromatography to give compound 3 as a white solid (74
3-(Iodomethyl)-5-methoxy-1,3-dimethylindolin-2-one
(6b).
Compound 6b was prepared according to the general procedure
and isolated as a white solid (146 mg, 88% yield) after flash
column chromatography (cyclohexane/ethyl acetate = 3/1); mp =
1
1
mg, 71% yield). mp = 86–88 °C. H NMR (400 MHz, CDCl3): H
NMR (400 MHz, CDCl3): δ/ppm= 8.75 (s, 1H), 7.39 (d, J = 8.4
Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 4.08 (brs, 1H), 4.03 (d, J =
11.2 Hz, 1H), 3.53 (brs, 1H), 3.45 (d, J = 11.2 Hz, 1H), 2.29 (s,
3H), 1.37 (s, 3H). 13C NMR (100 MHz, CDCl3): δ/ppm= 172.5,
1
96–97 °C (ref,[21] mp = 101 °C; ref,[37] mp = 94–95 °C). H NMR
(400 MHz, CDCl3): δ/ppm= 6.91 (d, J = 2.5 Hz, 1H), 6.87 (dd, J
= 8.4, 2.5 Hz, 1H), 6.80 (d, J = 8.4 Hz, 1H), 3.83 (s, 3H), 3.52 (d,
133.5, 133.3, 128.5, 118.9, 75.5, 66.6, 21.6, 19.8. IR (KBr): 3503, J = 9.8 Hz, 1H), 3.42 (d, J = 9.8 Hz, 1H), 3.24 (s, 3H), 1.52 (s,
3149, 2989, 2928, 1704, 1615, 1401, 1239, 1162, 976, 793 cm-1. 3H). 13C NMR (100 MHz, CDCl3): δ/ppm = 177.6, 156.1, 136.7,
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10.1002/ejoc.201801250
European Journal of Organic Chemistry
FULL PAPER
133.9, 112.6, 110.4, 108.6, 55.8, 49.0, 26.4, 23.1, 10.8. Spectral
data are in agreement with literature values.[21]
Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 3.52 – 3.45 (m, 1H), 3.39 –
3.33 (m, 1H), 3.21 (s, 3H), 1.50 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ/ppm= 177.2, 143.0, 137.5, 135.0, 131.5, 110.4, 85.2,
48.7, 26.4, 23.0, 10.0. Spectral data are in agreement with
literature values.[21]
5-Ethoxy-3-(iodomethyl)-1,3-dimethylindolin-2-one
(6c).
Compound 6c was prepared according to the general procedure
and isolated as a colorless oil (155 mg, 90% yield) after flash
column chromatography (cyclohexane/ethyl acetate = 6/1). 1H
NMR (400 MHz, CDCl3): δ/ppm = 6.91 (d, J = 2.4 Hz, 1H), 6.86
(dd, J = 8.4, 2.4 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 4.05 (d, J =
7.0 Hz, 1H), 4.02 (d, J = 7.0 Hz, 1H), 3.52 (d, J = 9.8 Hz, 1H),
3.41 (d, J = 9.8 Hz, 1H), 3.23 (s, 3H), 1.51 (s, 3H), 1.43 (t, J =
7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ/ppm = 177.6, 155.4,
136.6, 133.9, 113.3, 111.0, 108.6, 64.1, 49.0, 26.4, 23.1, 14.9,
10.9. IR (KBr): 2957, 2929, 1702, 1601, 1495, 1352, 1287, 1190,
1036, 838, 805, 736, 629 cm-1. ESI–HRMS: calc. for
[C13H16INO2+Na]+: m/z = 368.0123, found: 368.0114.
3-(Iodomethyl)-1,3-dimethyl-5-(trifluoromethoxy)indolin-2-
one (6h). Compound 6h was prepared according to the general
procedure and isolated as a white solid (133 mg, 69% yield)
after flash column chromatography (petroleum ether/ethyl
acetate = 8/1). mp = 73-75°C. 1H NMR (400 MHz, CDCl3):
δ/ppm = 7.23 (d, J = 8.4 Hz, 1H), 7.19 (s, 1H), 6.88 (d, J = 8.4
Hz, 1H), 3.52 (d, J = 9.9 Hz, 1H), 3.42 (d, J = 9.9 Hz, 1H), 3.27
(s, 3H), 1.55 (s, 3H). 19F NMR (376 MHz, CDCl3) δ/ppm= 58.3.
13C NMR (100 MHz, CDCl3): δ/ppm= 177.6, 144.8 (q, J = 2.0 Hz),
141.9, 134.1, 121.8, 119.3, 116.9, 108.7, 48.9, 26.5, 22.9, 9.8.
IR (KBr): 3050, 2930, 1716, 1619, 1493, 1375, 1269, 1138, 817,
615, 548 cm-1. HRMS–ESI: calc. for [C12H11F3INO2+H]+: m/z =
385.9865, found: 385.9855.
7-(Iodomethyl)-5,7-dimethyl-5H-[1,3]dioxolo[4,5-f]indol-
6(7H)-one, 8-(iodomethyl)-6,8-dimethyl-6H-[1,3]dioxolo[4,5-
e]indol-7(8H)-one (6i+6i'). Compound 6i and 6i' was prepared
according to the general procedure and isolated as a yellow oil
(148 mg, 86% yield) after flash column chromatography
(petroleum ether/ethyl acetate = 6/1). 6i/6i'= 1.1/1. 1H NMR (400
MHz, CDCl3): δ/ppm = 6.77 (s, 1H-maj), 6.72 (s, 1H-min), 6.41 (s,
2H-maj, min), 5.90–5.80 (m, 4H-maj, min), 3.67 (d, J = 10.8 Hz,
1H-maj), 3.62 (d, J = 10.8 Hz, 1H-maj), 3.40 (d, J = 9.8 Hz, 1H-
min), 3.28 (d, J = 9.8 Hz, 1H-min), 3.11 (s, 3H-min), 3.10 (s, 3H-
maj), 1.39 (s, 3H-min), 1.31 (s, 3H-maj). 13C NMR (100 MHz,
CDCl3): δ/ppm= 177.0, 176.8, 146.7, 146.6, 142.3, 136.7, 142.2,
136.5, 123.3, 122.0, 103.8, 103.3, 100.2, 91.2, 48.8, 48.1, 47.8,
25.5, 25.4, 21.9, 20.3, 10.3. IR (KBr): 3010, 2927, 1702, 1622,
1477, 1381, 1226, 1110, 1035, 925, 819, 698, 547 cm-1. HRMS–
ESI: calc. for [C12H12INO3+H]+: m/z = 345.9940, found: 345.9933.
3-(Iodomethyl)-1,3-dimethyl-2-oxoindoline-5-carbonitrile (6j).
Compound 6j was prepared according to the general procedure
and isolated as a yellow solid (68 mg, 42% yield) after flash
column chromatography (petroleum ether/ethyl acetate = 4/1).
mp = 122–125 °C (ref,[21] mp = 138–140 °C). 1H NMR (400 MHz,
CDCl3): δ/ppm = 7.61 (dd, J = 8.1, 1.6 Hz, 1H), 7.46 (d, J = 1.4
Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 3.45 (d, J = 10.0 Hz, 1H), 3.34
(d, J = 10.0 Hz, 1H), 3.21 (s, 3H), 1.48 (s, 3H). 13C NMR (100
MHz, CDCl3): δ/ppm= 176.6, 146.1, 133.0, 132.7, 125.1, 118.0,
107.8, 104.9, 47.6, 25.6, 21.8, 8.1. Spectral data are in
agreement with literature values.[21]
5-Fluoro-3-(iodomethyl)-1,3-dimethylindolin-2-one
(6d).
Compound 6d was prepared according to the general procedure
and isolated as a colorless oil (132 mg, 83% yield) after flash
column chromatography (cyclohexane/ethyl acetate = 3/1). 1H
NMR (400 MHz, CDCl3): δ/ppm = 7.06 – 7.02 (m, 2H), 6.81 (dd,
J = 9.2, 4.1 Hz, 1H), 3.51 (d, J = 9.9 Hz, 1H), 3.40 (d, J = 9.9 Hz,
1H), 3.24 (s, 3H), 1.52 (s, 3H). 19F NMR (376 MHz, CDCl3)
δ/ppm= 120.0. 13C NMR (100 MHz, CDCl3): δ/ppm = 177.6,
159.3 (d, J = 241.2 Hz), 139.1, 134.2, 114.9 (d, J = 24.0 Hz),
111.0 (d, J = 24.9 Hz), 108.8 (d, J = 8.1 Hz), 49.1, 26.5, 23.0,
10.1. IR (KBr): 3061, 2927, 1711, 1610, 1484, 1347, 1245, 1126,
1096, 807, 626, 544 cm-1. HRMS–ESI: calc. for
[C11H11FINO+H]+: m/z = 319.9948, found: 319.9959.
5-Chloro-3-(iodomethyl)-1,3-dimethylindolin-2-one
(6e).
Compound 6e was prepared according to the general procedure
and isolated as a yellow solid (136 mg, 81% yield) after flash
column chromatography (petroleum ether/ethyl acetate = 8/1).
mp = 68–70 °C (ref,[37] mp=79–81°C). 1H NMR (400 MHz,
CDCl3): δ/ppm = 7.24 (dd, J = 8.3, 2.1 Hz, 1H), 7.18 (d, J = 2.0
Hz, 1H), 6.73 (d, J = 8.3 Hz, 1H), 3.44 (d, J = 9.9 Hz, 1H), 3.31
(d, J = 9.9 Hz, 1H), 3.16 (s, 3H), 1.44 (s, 3H). 13C NMR (100
MHz, CDCl3): δ/ppm= 176.4, 140.8, 133.2, 127.6, 127.1, 122.2,
108.2, 47.9, 25.4, 21.9, 8.9. Spectral data are in agreement with
literature values.[37]
5-Bromo-3-(iodomethyl)-1,3-dimethylindolin-2-one
(6f).
Compound 6f was prepared according to the general procedure
and isolated as a colorless oil (151 mg, 80% yield) after flash
column chromatography (cyclohexane/ethyl acetate = 3/1). 1H
NMR (400 MHz, CDCl3): δ/ppm = 7.47 (dd, J = 8.3, 1.9 Hz, 1H),
7.39 (d, J = 1.9 Hz, 1H), 6.77 (d, J = 8.3 Hz, 1H), 3.52 (d, J = 9.9
Hz, 1H), 3.40 (d, J = 9.9 Hz, 1H), 3.24 (s, 3H), 1.53 (s, 3H). 13C
NMR (100 MHz, CDCl3): δ/ppm= 177.3, 142.3, 134.6, 131.5,
126.0, 115.4, 109.8, 48.9, 26.4, 23.0, 9.9. IR (KBr): 3061, 2927,
2854, 1711, 1611, 1484, 1415, 1245, 1096, 1013, 808, 626, 544
cm-1. HRMS–ESI: calc. for [C11H11BrINO+H]+: m/z = 379.9147,
found: 379.9138.
5-Acetyl-3-(iodomethyl)-1,3-dimethylindolin-2-one
(6k).
Compound 6k was prepared according to the general procedure
and isolated as a colorless oil (84 mg, 49% yield) after flash
column chromatography (cyclohexane/ethyl acetate = 1/1). 1H
NMR (400 MHz, CDCl3): δ/ppm = 8.00 (dd, J = 8.2, 1.8 Hz, 1H),
7.90 (d, J = 1.8 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 3.55 (d, J = 9.8
Hz, 1H), 3.44 (d, J = 9.8 Hz, 1H), 3.29 (s, 3H), 2.61 (s, 3H), 1.55
(s, 3H). 13C NMR (100 MHz, CDCl3): δ/ppm= 196.7, 178.3, 147.5,
132.9, 132.3, 130.7, 122.5, 107.7, 48.7, 26.6, 26.5, 22.8, 9.8. IR
(KBr): 2967, 2928, 1714, 1605, 1465, 1436, 1355, 1260, 1170,
1011, 872, 740, 628 cm-1. HRMS–ESI: calc. for
[C13H14INO2+Na]+: m/z = 365.9967, found: 365.9983.
5-Iodo-3-(iodomethyl)-1,3-dimethylindolin-2-one
(6g).
Compound 6g was prepared according to the general procedure
and isolated as a white solid (181 mg, 85% yield) after flash
column chromatography (cyclohexane/ethyl acetate = 4/1). mp =
126–127 °C (ref,[21] mp = 129–130 °C) 1H NMR (400 MHz,
CDCl3): δ/ppm= 7.64 (dd, J = 8.2, 1.6 Hz, 1H), 7.53 (d, J = 1.6
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801250
European Journal of Organic Chemistry
FULL PAPER
5-Bromo-3-(iodomethyl)-1,3-dimethyl-1H-benzo[g]indol-
2(3H)-one (6l). Compound 6l was prepared according to the
general procedure and isolated as a brown solid (166 mg, 77%
yield) after flash column chromatography (petroleum ether/ethyl
2.4 Hz, 1H), 6.85 (dd, J = 8.5, 2.4 Hz, 1H), 6.81 (d, J = 8.5 Hz,
1H), 3.82 (s, 3H), 3.77 (dd, J = 14.2, 7.2 Hz, 1H), 3.64 (dt, J =
14.2, 7.2 Hz, 1H), 3.53 (d, J = 9.8 Hz, 1H), 3.42 (d, J = 9.8 Hz,
1H), 1.73 – 1.63 (m, 2H), 1.51 (s, 3H), 1.46 – 1.41 (m, 2H), 0.96
(t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ/ppm= 177.4,
155.5, 136.1, 134.2, 112.6, 110.4, 108.9, 55.8, 48.8, 40.0, 29.6,
23.3, 20.3, 13.8, 10.7. IR (KBr): 3030, 2957, 2929, 1701, 1600,
1435, 1352, 1287, 1037, 804, 629, 466 cm-1. HRMS–ESI: calc.
for [C15H20INO2+H]+: m/z = 374.0617, found: 374.0616.
1
acetate = 8/1). mp= 140–143 °C. H NMR (400 MHz, CDCl3):
δ/ppm= 8.39 (d, J = 8.2 Hz, 1H), 8.30 – 8.19 (m, 1H), 7.60 (s,
1H), 7.55 – 7.46 (m, 2H), 3.76 (s, 3H), 3.52 (d, J = 9.9 Hz, 1H),
3.36 (d, J = 9.9 Hz, 1H), 1.50 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ/ppm= 178.2, 137.5, 131.5, 127.8, 127.7, 126.2, 125.7,
123.0, 121.4, 121.1, 115.6, 47.7, 30.0, 22.0, 8.6. IR (KBr): 3021,
2967, 2921, 1707, 1620, 1465, 1260, 1053, 800, 757, 688, 612,
516 cm-1. HRMS–ESI: calc. for [C15H13BrINO+H]+: m/z =
429.9303, found: 429.9291.
3-(Iodomethyl)-1-isobutyl-5-methoxy-3-methylindolin-2-one
(6q). Compound 6q was prepared according to the general
procedure and isolated as a colorless oil (158 mg, 85% yield)
after flash column chromatography (petroleum ether/ethyl
1
1-(Iodomethyl)-1,3-dimethyl-1H-benzo[e]indol-2(3H)-one
(6m). Compound 6m was prepared according to the general
procedure and isolated as a yellow solid (118 mg, 67% yield)
after flash column chromatography (petroleum ether/ethyl
acetate = 8/1). H NMR (400 MHz, CDCl3): δ/ppm= 6.92 (d, J =
2.5 Hz, 1H), 6.85 (dd, J = 8.5, 2.5 Hz, 1H), 6.80 (d, J = 8.5 Hz,
1H), 3.84 (s, 3H), 3.60 – 3.55 (m, 1H), 3.54 (d, J = 3.4 Hz, 1H),
3.52 – 3.47 (m, 1H), 3.44 (d, J = 3.4 Hz, 1H), 2.18 (dp, J = 13.8,
6.9 Hz, 1H), 1.52 (s, 3H), 1.02 (d, J = 6.7 Hz, 3H), 0.99 (d, J =
6.7 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ/ppm= 177.7, 155.8,
1
acetate = 8/1). mp= 129–130 °C. H NMR (400 MHz, CDCl3):
δ/ppm= 8.00 – 7.87 (m, 2H), 7.80 (d, J = 8.5 Hz, 1H), 7.56 (t, J =
7.1 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.32 – 7.15 (m, 1H), 3.90 (d, 136.5, 134.1, 112.5, 110.4, 109.2, 55.8, 48.8, 47.8, 27.2, 23.7,
J = 9.8 Hz, 1H), 3.84 (d, J = 9.8 Hz, 1H), 3.39 (s, 3H), 1.81 (s,
3H). 13C NMR (100 MHz, CDCl3): δ/ppm= 179.4, 141.1, 130.6,
130.0, 130.0, 129.3, 127.6, 124.0, 123.7, 120.9, 109.6, 50.8,
26.6, 22.3, 9.5. Spectral data are in agreement with literature
values.[21]
20.5, 20.4, 10.6. IR (KBr): 3044, 2958, 2866, 1701, 1602, 1492,
1303, 1218, 1044, 806, 635, 599 cm-1. HRMS–ESI: calc. for
[C15H20INO2+H]+: m/z = 374.0617, found: 374.0618.
3-(Iodomethyl)-5-methoxy-1-(4-methoxyphenyl)-3-
methylindolin-2-one (6r). Compound 6r was prepared
according to the general procedure and isolated as a white solid
(180 mg, 85% yield) after flash column chromatography
1-Benzyl-3-(iodomethyl)-5-methoxy-3-methylindolin-2-one
(6n). Compound 6n was prepared according to the general
procedure and isolated as a yellow solid (167 mg, 82% yield)
after flash column chromatography (cyclohexane/ethyl acetate =
4/1). mp= 139–142 °C. 1H NMR (400 MHz, CDCl3): δ/ppm= 7.41
– 7.21 (m, 5H), 6.91 (d, J = 2.5 Hz,1H), 6.74 (dd, J = 8.5, 2.5 Hz,
1H), 6.65 (d, J = 8.5 Hz, 1H), 5.01 (d, J = 15.6 Hz, 1H), 4.88 (d,
J = 15.7 Hz, 1H), 3.79 (s, 3H), 3.62 (d, J = 9.8 Hz, 1H), 3.49 (d,
J = 9.8 Hz,1H), 1.59 (s, 3H). 13C NMR (100 MHz, CDCl3): δ/ppm
= 177.7, 156.0, 135.7, 135.6, 134.0, 128.7, 127.6, 127.5, 112.5,
110.4, 109.8, 55.8, 49.1, 44.1, 23.7, 10.4. IR (KBr): 3010, 2927,
2868, 1704, 1600, 1493, 1351, 1288, 1037, 963, 804, 680, 629
cm-1. HRMS–ESI: calc. for [C18H18INO2+Na]+: m/z = 430.0280,
found: 430.0284.
1
(petroleum ether/ethyl acetate = 8/1). mp= 119-122 °C. H NMR
(400 MHz, CDCl3): δ/ppm= 7.37 (d, J = 8.8 Hz, 2H), 7.29 (s, 1H),
7.05 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 2.4 Hz, 1H), 6.80 (dd, J =
8.6, 2.4 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.67 (d, J = 9.7 Hz,
1H), 3.48 (d, J = 9.7 Hz, 1H), 1.65 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ/ppm= 177.4, 159.2, 156.3, 137.3, 133.6, 127.9, 127.3,
114.9, 112.8, 110.1, 109.9, 55.9, 55.6, 49.0, 23.1, 11.2. IR (KBr):
3006, 2963, 2836, 1709, 1602, 1512, 1431, 1297, 1027, 846,
823, 633, 609, 574 cm-1. HRMS–ESI: calc. for [C18H18INO3+H]+:
m/z = 424.0410, found: 424.0406.
Ethyl 2-(3-(iodomethyl)-5-methoxy-3-methyl-2-oxoindolin-1-
yl)acetate (6s). Compound 6s was prepared according to the
general procedure and isolated as a yellow oil (131 mg, 65%
yield) after flash column chromatography (petroleum ether/ethyl
acetate = 6/1). 1H NMR (400 MHz, CDCl3): δ/ppm= 6.86 (d, J =
2.5 Hz, 1H), 6.75 (dd, J = 8.5, 2.5 Hz, 1H), 6.60 (d, J = 8.5 Hz,
1H), 4.46 (d, J = 17.5 Hz, 1H), 4.30 (d, J = 17.5 Hz, 1H), 4.13 (q,
J = 7.1 Hz, 2H), 3.73 (s, 3H), 3.45 (d, J = 9.9 Hz, 1H), 3.37 (d, J
= 9.9 Hz, 1H), 1.47 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ/ppm=176.6, 166.6, 155.2, 134.2, 132.6,
111.7, 109.5, 107.7, 60.7, 54.8, 47.9, 40.5, 22.6, 13.1, 9.2. IR
(KBr): 2967, 2928, 1714, 1630, 1498, 1375, 1298, 1208, 1036,
805, 686, 628 cm-1. HRMS–ESI: calc. for [C15H18INO4+H]+: m/z
=404.0359, found: 404.0359.
1-Ethyl-3-(iodomethyl)-5-methoxy-3-methylindolin-2-one
(6o). Compound 6o was prepared according to the general
procedure and isolated as a colorless oil (136 mg, 79% yield)
after flash column chromatography (cyclohexane/ethyl acetate =
1
3/1). H NMR (400 MHz, CDCl3): δ/ppm = 6.90 (d, J = 2.5, 1H),
6.85 (dd, J = 8.5, 2.5 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 3.87 (dq,
J = 14.3, 7.2 Hz,1H), 3.82 (s, 3H), 3.68 (dq, J = 14.3, 7.2 Hz,
1H), 3.53 (d, J = 9.8 Hz, 1H), 3.40 (d, J = 9.8 Hz, 1H), 1.51 (s,
3H), 1.29 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ/ppm
= 177.1, 155.9, 135.7, 134.2, 112.6, 110.5, 108.7, 55.8, 48.8,
34.9, 23.0, 12.8, 10.8. IR (KBr): 3003, 2928, 2868, 1702, 1600,
1494, 1352, 1183, 1037, 804, 629, 588 cm-1. HRMS–ESI: calc.
for [C13H16INO2+Na]+: m/z =368.0123, found: 368.0128.
3-Benzyl-3-(iodomethyl)-5-methoxy-1-methylindolin-2-one
(6t). Compound 6t was prepared according to the general
procedure and isolated as a colorless solid (153 mg, 75% yield)
after flash column chromatography (petroleum ether/ethyl
1-Butyl-3-(iodomethyl)-5-methoxy-3-methylindolin-2-one
(6p). Compound 6p was prepared according to the general
procedure and isolated as a colorless oil (164 mg, 88% yield)
after flash column chromatography (petroleum ether/ethyl
1
acetate = 8/1). mp= 139–142 °C. H NMR (400 MHz, CDCl3):
1
acetate = 8/1). H NMR (400 MHz, CDCl3): δ/ppm= 6.90 (d, J =
δ/ppm=7.05 – 6.99 (m, 3H), 6.79 (dd, J = 7.2, 2.1 Hz, 2H), 6.71
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10.1002/ejoc.201801250
European Journal of Organic Chemistry
FULL PAPER
(d, J = 2.5 Hz, 1H), 6.69 (s, 1H), 6.47 (d, J = 8.9 Hz, 1H), 3.72 (s, overnight. Then 30 mL of CH2Cl2 was added, and the reaction
3H), 3.60 (d, J = 9.8 Hz, 1H), 3.41 (d, J = 9.8 Hz, 1H), 3.06 (d, J
= 5.5 Hz, 2H), 2.91 (s, 3H). 13C NMR (100 MHz, CDCl3): δ/ppm=
175.3, 154.7, 136.3, 134.1, 130.3, 128.8, 126.7, 125.8, 111.9,
110.1, 107.3, 54.8, 53.9, 42.3, 25.1, 8.1. IR (KBr): 3055, 2920,
2831, 1708, 1632, 1496, 1288, 1076, 869, 804, 701, 531 cm-1.
HRMS–ESI: calc. for [C18H18INO2+H]+: m/z =408.0460, found:
408.0455.
mixture was washed with water, dried over Na2SO4, and
concentrated under reduced pressure. The crude product was
purified by flash column chromatography (petroleum ether/ethyl
1
acetate=12:1) to give 7 as a colorless oil. H NMR (400 MHz,
CDCl3): δ/ppm= 7.05 (s, 1H), 7.03 (d, J = 4.5 Hz, 1H), 6.69 (d, J
= 7.8 Hz, 1H), 3.55 (s, 2H), 3.14 (s, 3H), 2.28 (s, 3H), 1.29 (s,
3H). 13C NMR (100 MHz, CDCl3): δ/ppm= 177.1, 140.1, 131.3,
130.4, 127.9, 122.9, 107.1, 56.2, 47.8, 25.4, 20.1, 19.5. Spectral
data are in agreement with literature values.[38]
3-(Iodomethyl)-1,5-dimethyl-3-phenylindolin-2-one
(6u).
Compound 6u was prepared according to the general procedure
and isolated as a yellow solid (149 mg, 79% yield) after flash
column chromatography (petroleum ether/ethyl acetate = 8/1).
mp= 122–125 °C. 1H NMR (400 MHz, CDCl3): δ/ppm= 7.48 (d, J
= 8.1, 1.7 Hz, 2H), 7.37 – 7.28 (m, 3H), 7.26 – 7.20 (m, 2H),
6.86 (d, J = 7.8 Hz, 1H), 4.06 (d, J = 9.7 Hz, 1H), 3.79 (d, J = 9.7
Hz, 1H), 3.25 (s, 3H), 2.44 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ/ppm= 176.2, 141.7, 137.9, 132.3, 131.0, 129.4, 128.8, 128.0,
127.2, 125.7, 108.4, 56.7, 26.6, 21.4, 10.7. IR (KBr): 3020, 2965,
2935, 1715, 1619, 1498, 1350, 1074, 810, 723, 697, 551, 506
cm-1. HRMS–ESI: calc. for [C17H16INO+H]+: m/z = 378.0355,
found: 378.0349.
2-(5-Methoxy-1,3-dimethyl-2-oxoindolin-3-yl)acetonitrile (8).
A solution of oxindole 5b (331 mg, 1 mmol) and sodium cyanide
(147 mg, 3 mmol) was refluxed in CH3CN (20 mL) for 36 h.
Water (10 mL) was added and the mixture was extracted with
CH2Cl2 (3 x 10 mL). The combined organic layers were dried
(Na2SO4) and concentrated to give a crude residue, which was
purified by flash column chromatography (cyclohexane/ethyl
acetate=2:1) to afford compound 8 (202 mg, 88%) as a colorless
oil. 1H NMR (400 MHz, CDCl3): δ/ppm = 7.09 (d, J = 2.4 Hz, 1H),
6.88 (dd, J = 8.5, 2.5 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 3.82 (s,
3H), 3.22 (s, 3H), 2.86 (dd, J = 16.7 Hz, 1H), 2.56 (dd, J = 16.7,
Hz, 1H), 1.52 (s, 3H).13C NMR (100 MHz, CDCl3): δ/ppm = 177.1,
156.4, 136.0, 132.2, 116.6, 113.5, 110.5, 109.1, 55.9, 45.2, 26.6,
26.3, 22.2. Spectral data are in agreement with literature
values.[35]
5-Iodo-3-(iodomethyl)-1,3,4,6-tetramethylindolin-2-one (6v).
Compound 6v was prepared according to the general procedure
and isolated as a yellow solid (136 mg, 60% yield) after flash
column chromatography (petroleum ether/ethyl acetate = 8/1).
1
mp= 120–123 °C. H NMR (400 MHz, CDCl3): δ/ppm= 6.71 (s,
(±)-Esermethole (9). Compound 8 (184 mg, 0.8 mmol) was
dissolved in THF (20 mL), and LiAlH4 (122 mg, 4 mmol) was
added. The reaction mixture was stirred under an argon
atmosphere for 1 h and then heated to reflux for 1 h and cooled
to 0 ºC afterwards. A solution of NaOH (10% in water) was
added carefully until a white solid precipitates. After filtration
over MgSO4 and evaporation of the solvent, the product was
obtained as yellow oil, which was subsequently dissolved in
MeOH (5 mL). Aqueous solution of HCHO (37 wt%, 4 mmol)
was added at 0 °C under an argon atmosphere, and the mixture
was stirred for 30 min. Then the mixture was cooled to 0 °C
before NaBH4 (62 mg, 1.6 mmol) was added slowly, and the
solution was stirred for 15 h at room temperature. The mixture
was quenched at 0 °C with water and extracted with CH2Cl2. The
organic layers were then combined, washed with brine, dried
(Na2SO4) and concentrated. The residue was purified by using
flash column chromatography (CH2Cl2/MeOH= 10:1) to give 9 as
1H), 3.67 (d, J = 9.9 Hz, 1H), 3.61 (d, J = 9.9 Hz, 1H), 3.24 (s,
3H), 2.56 (s, 3H), 2.48 (s, 3H), 1.60 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ/ppm= 178.0, 143.5, 142.6, 137.6, 127.9, 107.7, 102.1,
50.6, 26.3, 24.8, 21.4, 17.8, 8.5. IR (KBr): 2975, 2918, 1712,
1604, 1451, 1327, 1265, 1052, 959, 848, 808, 709, 604, 520 cm-
1. HRMS–ESI: calc. for [C13H15I2NO+H]+: m/z = 455.9321, found:
455.9309.
5-Iodo-3-(iodomethyl)-1,3-dimethyl-1H-benzo[g]indol-2(3H)-
one (6w). Compound 6w was prepared according to the general
procedure and isolated as a yellow oil (148 mg, 62% yield) after
flash column chromatography (cyclohexane/ethyl acetate = 5/1).
1H NMR (400 MHz, CDCl3): δ/ppm= 8.43 – 8.40 (m, 1H), 8.21 –
8.18 (m, 1H), 7.94 (s, 1H), 7.59 – 7.52 (m, 2H), 3.84 (s, 3H),
3.59 (d, J = 9.9 Hz, 1H), 3.43 (d, J = 9.9 Hz, 1H), 1.57 (s, 3H).
13C NMR (100 MHz, CDCl3): δ/ppm= 179.1, 139.6, 134.7, 133.9,
131.2, 129.6, 127.6, 126.7, 122.3, 122.2, 91.8, 48.5, 31.1, 23.0,
9.7. Spectral data are in agreement with literature values.[21]
1
a yellow oil (145 mg, 78%). H NMR, COSY (400 MHz, CDCl3):
5-Iodo-3-(iodomethyl)-1,3,7-trimethylindolin-2-one
(6x).
δ/ppm = 6.68 (dd, J = 8.3, 2.5 Hz, 1H, Ar-H6), 6.65 (d, J = 2.5
Hz, 1H, Ar-H4), 6.40 (d, J = 8.3 Hz, 1H, Ar-H7), 4.17 (s, 1H,
H8a), 3.76 (s, 3H, C5-OMe), 2.92 (s, 3H, N8-CH3), 2.86 – 2.80 (m,
1H, H2), 2.65 (td, J = 9.1, 6.6 Hz, 1H, H2), 2.57 (s, 3H, N1-CH3),
2.09 – 1.94 (m, 2H, H3), 1.47 (s, 3H, C3a-CH3). 13C NMR, HSQC,
HMBC (100 MHz, CDCl3): δ/ppm = 153.2 (C5), 146.3 (C7a),
137.9 (C3b), 112.4 (C6), 109.7 (C4), 107.7 (C7), 98.0 (C8a),
56.0 (-OMe), 53.1 (C2), 52.9(C3a), 40.5 (C3), 38.1 (N8-CH3),
37.7 (N1-CH3), 27.3 (C3a-CH3). Spectral data are in agreement
with literature values.[35]
Compound 6x was prepared according to the general procedure
and isolated as a yellow solid (141 mg, 64% yield) after flash
column chromatography (cyclohexane/ethyl acetate = 5/1). mp =
155–156 °C (ref,[21] mp = 160 °C; ref,[15a] mp = 159–161 °C) 1H
NMR (400 MHz, CDCl3): δ/ppm= 7.33 (s, 1H), 7.27 (d, J = 1.3
Hz, 1H), 3.42 (d, J = 9.8 Hz, 1H), 3.42 (s, 3H), 3.25 (d, J = 9.8
Hz, 1H), 2.47 (s, 3H), 1.40 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ/ppm= 177.0, 139.9, 139.7, 134.4, 128.2, 121.3, 84.3, 47.0,
28.6, 22.2, 17.7, 9.3. Spectral data are in agreement with
literature values.[21]
(±)-Physostigmine (10). (±)-Esermethole (9) (116 mg, 0.5
mmol) was dissolved in CH2Cl2 (10 ml) and 1 M BBr3 solution in
DCM (1.5 mL, 1.5 mmol) was added dropwise to the above
solution with stirring. The resulting mixture was stirred at room
3-(Azidomethyl)-1,3,5-trimethylindolin-2-one (7). Compound
6a was dissolved in 2 mL of DMF, the sodium azide was added,
and the reaction mixture was stirred at room temperature
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Kostlan, J. C. Sircar, C. D. Wright, D. J. Schrier, R. D. Dyer, J. Med.
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temperature for 5 h. The reaction was then quenched with H2O
(1 mL) at 0 °C. The mixture was diluted with EtOAc (10 mL),
washed with H2O (5 mL). The organic phase was dried with
Na2SO4 and evaporated to dryness. The crude product was
used directly in the next step of the reaction without purification.
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mL) was stirred at 0 °C for 10 min before N-succinimidyl-N-
methylcarbamate (95 mg, 0.55 mol) was added. The resulting
mixture was stirred at Room temperature for 2 h, quenched with
water, and extracted with CH2Cl2. The organic layers were then
combined, washed with brine, dried (Na2SO4), and concentrated.
The residue was purified by using flash column chromatography
(CH2Cl2/MeOH = 15:1) to give 10 as a colorless oil (96 mg, 70%).
1H NMR, COSY (400 MHz, CDCl3): δ/ppm =6.83 (dd, J = 8.4, 2.4
Hz, 1H, Ar-H6), 6.78 (d, J = 2.4 Hz, 1H, Ar-H4), 6.37 (d, J = 8.4
Hz, 1H, Ar-H7), 5.00 (brs, 1H, CH3NH-), 4.22 (s, 1H, H8a), 2.95
(s, 3H, N8-CH3), 2.88 (d, J = 4.9 Hz, 3H, CH3NH-), 2.85 – 2.76
(m, 1H, H2), 2.66 (dt, J = 9.4, 7.8 Hz, 1H, H2), 2.57 (s, 3H, N1-
CH3), 2.06 – 1.97 (m, 2H, H3), 1.45 (s, 3H, C3a-CH3)).13C NMR,
HSQC, HMBC (100 MHz, CDCl3): δ/ppm =156.1 (-NHCO-),
149.3 (C7a), 143.3 (C5), 137.2 (C3b), 120.6 (C4), 116.2 (C4),
106.8 (C7), 97.8 (C8a), 53.1 (C2), 52.7 (C3a), 40.5 (C3), 37.9
(N1-CH3), 37.2 (N8-CH3), 27.7 (CH3NH-), 27.1 (C3a-CH3).
Spectral data are in agreement with literature values.[35]
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Acknowledgements
This study was supported by the Natural Science Foundation of
Jiangsu Province in China (BK20170439), Advanced Research
Foundation for Natural Science of Nantong University (16ZY15),
Start-Up Funding for Research of Nantong University (17R40),
Lager Instruments Open Foundation of Nantong University
(KFJN1853), and Science and Technology Plan Projects of
Nantong (MS12017023-7).
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Keywords: oxazolidine-2,4-dione • oxindole • acrylamide • ICl •
iodocyclization
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Metal-free synthesis of oxazolidine-
2,4-diones and 3,3-disubstituted
oxindoles via the ICl‑induced
cyclization
A metal-free method for the construction of oxazolidine-2,4-diones and oxindoles is
reported herein. The resulting products can be used as key intermediates in
syntheses of bioactive compound such as toloxatone, (±)-esermethole and (±)-
physostigmine.
halocyclization.
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