A Cascade Approach for the Synthesis of 5-(Indol-3-yl)hydantoin: An Application to the Total Synthesis of (±)-Oxoaplysinopsin B

Article abstract of DOI:10.1021/acs.joc.0c02435

A cascade approach to the synthesis of 5-(indol-3-yl)hydantoin framework has been developed by the reaction of indole with glyoxylic acid/pyruvic acid under a deep eutectic solution, (+)-tartaric acid-dimethylurea. N,N′-Dimethylurea from a deep eutectic solution functions as a reactant as well as a solvent mixture. Isolation of the intermediate, 5-hydroxyhydantoin, and its reaction with indole provides the mechanistic evidence for this reaction. This method was successfully applied in the first total synthesis of an alkaloid, (±)-oxoaplysinopsin B, with an overall yield of 48%.

Full text of DOI:10.1021/acs.joc.0c02435

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A Cascade Approach for the Synthesis of 5‑(Indol-3-yl)hydantoin: An
Application to the Total Synthesis of ( )-Oxoaplysinopsin B
Ponnusamy Pon Sathieshkumar, Metlapalli Durga Anand Saibabu, and Rajagopal Nagarajan*
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ABSTRACT: A cascade approach to the synthesis of 5-(indol-3-
yl)hydantoin framework has been developed by the reaction of
indole with glyoxylic acid/pyruvic acid under a deep eutectic
solution, (+)-tartaric acid-dimethylurea. N,N′-Dimethylurea from a
deep eutectic solution functions as a reactant as well as a solvent
mixture. Isolation of the intermediate, 5-hydroxyhydantoin, and its
reaction with indole provides the mechanistic evidence for this
reaction. This method was successfully applied in the first total synthesis of an alkaloid, ( )-oxoaplysinopsin B, with an overall yield
of 48%.
one-1,1-dioxide followed by its reduction into an α-indolyl-α-
aryl amino acid derivative. The amino acid derivative was
further treated with phosgene to produce a 5-aryl-5-(indol-3-
yl)hydantoin derivative. These strategies relied on the
conversion of functionalities attached to indoles into the
hydantoin moiety and not direct functionalization of the
indole.
Hence, there is a need to develop a new method to
synthesize hydantoin-substituted indoles from an unfunction-
alized and unprotected indole in a short and cost-effective
synthetic route. In this concern, we report a cascade approach
for the synthesis of 5-(indol-3-yl)-1,3-substituted hydantoins
from indole and glyoxylic acid/pyruvic acid using (+)-tartaric
acid-N,N′-dimethylurea (DMU) as a deep eutectic solution
(DES). DMU is involved in the reaction as a reactant in
addition to function as DES. Immediate access to 5-
hydroxyhydantoin through a quick reaction between DMU
and glyoxylic acid has been uncovered during this study.
Further, we exhibit a utility of the method in the first total
synthesis of ( )-oxoaplysinopsin B with a good overall yield.
INTRODUCTION
■
Indole is a distinctive heterocycle that is widely present in
many biologically potent molecules, pharmaceuticals, alkaloids,
and functional materials.1 Functionalization of the indole core
with different motifs could tune biological functions, medicinal
potency, and material characteristics1 and, hence, attracts
synthetic chemists for devising new methods to install diverse
carbocyclic and heterocyclic frameworks on it. New
approaches for the coupling of indole with novel entities are
always of high value. Great effort has been reported for the
substitution/functionalization of indole, mostly by metal-
mediated transformations.2−5 Nevertheless, an elegant ap-
proach for direct functionalization of indole with a biologically
significant drug scaffold, hydantoin,6,7 is not explored so far.
The synthesis of hydantoin-substituted indole has been
established by conventional methods, which involved the
conversion of functionalities attached on indole into respective
indolyl hydantoins by the Bucherer−Bergs method,8a,b Biltz
method,8c and Read method.8d A few other routes were
reported by Shi,9a Tepe,9c and Nakamura.9e In 2008, the Shi
group described a Cu(I)-catalyzed cascade amination-cycliza-
tion of aryl acetic acid esters to synthesize 5-(hetero)-
arylhydantoin derivatives and a 5-(indol-3-yl)hydantoin
derivative as one of the examples with a modest yield.9a
Gong et al. demonstrated an asymmetric version of Shi’s
method using a Lewis base/copper(I) cooperative catalysis
strategy.9b In 2008, Tepe and co-workers developed a method
to synthesize a 5-(indol-3-yl)hydantoin derivative by oxazole
rearrangement of 2-methylallyl-2-(3-(ethoxycarbonyl)-
thioureido)-2-(1-tosyl-1H-indol-3-yl)acetate and further hy-
drolysis.9c Nakamura et al. demonstrated the synthesis of a
substrate of indolylhydantoin as an application of the aza-
Friedel−Crafts reaction product obtained by their developed
method. This strategy involves initial synthesis of (R)-2-
benzhydryl-4-(1H-indol-3-yl)-4-phenyl-1,2,5-thiadiazolidin-3-
RESULT AND DISCUSSION
■
We found a serendipitous formation of 5-(indol-3-yl)-1,3,5-
trimethylhydantoin when attempted to synthesize 2,2-di(1H-
indol-3-yl)propanoic acid 7 with (+)-tartaric acid-N,N′-
dimethylurea as DES. Deep eutectic solution/melt,10 consist-
ing of components from a sustainable and natural source,
Received: October 14, 2020
Published: February 18, 2021
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nontoxic, and nonvolatile, acts as a green alternative to organic
solvents to carry out organic transformations. In general, the
reaction between aldehyde/ketone and indole in a deep
eutectic solution produces a corresponding bisindole prod-
uct.11 In contrast to the formation of the expected bisindole
product, 2,2-di(1H-indol-3-yl)propanoic acid, 6a was pro-
duced exclusively in a 48% of yield over 8 h (Scheme 1).
formation of 5a and enhanced the yield to 68% in 8 h. While
using 3 and 4 equiv of glyoxylic acid, the yield of 5a was
increased to 68% and 90%, respectively when reaction time
was shortened to 4 h, and the temperature was raised to 110
°C (Figure 1).
With the optimized conditions identified, the scope of this
method was investigated with various substituted indoles. A
little influence of inductive factors of the electron-donating
group on the reaction was observed. Most of the substituted
indoles reacted well with glyoxylic acid and pyruvic acid in
DES to furnish analogues of 5a and 6a, respectively, in 78−
93% yields (Scheme 2). In the case of the indole substituted
with electron-withdrawing functionality (−NO2 and −CN) at
the C-5 position, the corresponding product formation was not
observed and resulted in inseparable mixtures. It is a fact that
the electron-withdrawing substituents decrease the electron
density at the third position of the indole, which renders the
usual reactivity, and the same was observed in our reaction.
Further, the synthesis of 5a using a 50% aqueous solution of
glyoxylic acid (less expensive compared to glyoxylic acid
monohydrate) was demonstrated, which gave a 90% yield. This
approach was amenable in a gram-scale synthesis as well with a
minute change in yield. Compounds 5a and 6a were obtained
in 86% and 88% yields, respectively, in a 10 mmol scale
reaction, which implies the scalability and industrial applic-
ability of this method.
Scheme 1. Previous Reports and Present Approach for the
Synthesis of 5-Indolylhydantoin
To check the reactivity of other substituted ureas other than
dimethyl urea, the reaction was examined with urea,
diphenylurea, dicyclohexylurea, and monomethylurea under
optimized conditions. In the case of diphenylurea/dicyclohex-
ylurea, it did not form deep eutectic solution with (+)-tartaric
acid at any higher temperatures. Further, the pyruvic acid/
glyoxylic acid monohydrate and indole were added to the solid
mixture of diphenylurea/dicyclohexylurea and (+)-tartaric acid
at 110 °C; however, the reaction was not successful and did
not give the desired hydantoin. Then, the reaction between
diphenylurea/dicyclohexylurea, pyruvic acid, and indole was
checked using other solvents, instead of a deep eutectic
mixture, such as water, methanol, acetic acid, water−methanol
mixture, and water−acetic acid mixture. However, these
conditions did not produce the corresponding hydantoin,
whereas urea formed a deep eutectic solution with (+)-tartaric
acid but did not produce the respective hydantoin when
pyruvic acid and indole were added; instead, it produced 2,2-
bis(1-H-indolyl) propanoic acid. Monomethyl urea has formed
a deep eutectic solution with (+)-tartaric acid, and the further
addition of pyruvic acid and indole produced respective
hydantoin (6l). When we replaced the glyoxylic acid
monohydrate with phenylglyoxylic acid/phenylpyruvic acid
under optimized reaction conditions, the reaction proceeded
well with the corresponding hydantoin (6k and 6m) in a good
yield (Scheme 2).
Unexpectedly, DMU participated as a reactant in addition to
function as DES. Further, the accessibility of the reaction was
examined with glyoxylic acid monohydrate instead of pyruvic
acid. Fortunately, it proceeded well and furnished 5-(indol-3-
yl)-1,3-dimethylhydantoin (5a).
To the best of our knowledge, there is no literature report
involving a direct approach for the synthesis of 5a or 6a from
indole, glyoxylic acid/pyruvic acid, and dimethylurea. The
formerly discussed methods by Shi, Tepe and, Nakamura are
the routes reported for the synthesis of the core similar to 5a,
which involved functional group conversions, not direct
functionalization of indole. Hence, we envisioned to develop
a method for the direct functionalization of indoles with
hydantoin and extend its application in the total synthesis of
( )-oxoaplysinopsin B.
Indole and glyoxylic acid monohydrate were used as
substrates to study the optimization reaction to produce 5-
indolylhydantoin 5a. We began initial optimization for the
synthesis of 5a by varying the amounts of equivalents of
glyoxylic acid to improve the yield. While using equimolar
quantities of indole and glyoxylic acid, the yield of 5a was
found to be 53%, and the indole was left unreacted even after
24 h. Excess equivalents of glyoxylic acid (2 equiv) favored the
Next, the possible reaction mechanism was investigated. The
expected intermediate was the 5-hydroxy-1,3-dimethylhydan-
toin 8a, as it was found in the reaction mixture in the absence
of indole under the optimized condition. Initially, the focus
was on the reaction between the glyoxylic acid and
dimethylurea to produce 5-hydroxy-1,3-dimethylhydantoin
and study its reaction with indole using (+)-tartaric acid-
dimethylurea deep eutectic conditions. The reaction was
examined with 10 mol % of an acid catalyst (p-TSA, acetic
acid, trichloro/trifluoroacetic acid) in chloroform as a solvent
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Figure 1. Optimization for the synthesis of 5a.
along with (+)-tartaric acid-dimethylurea deep eutectic
conditions (Figure 2).
intramolecular amidation−cyclization of B leads to 5-
hydroxy-1,3-dimethylhydantoin 8a. Intermediate 8a under
the acidic condition undergoes protonation, dehydration, and
then reacts with indole to produce intermediate D, which,
upon fast aromatization, produces product 5a.
Further, we applied this approach to the first total synthesis
of the natural product ( )-oxoaplysinopsin B. ( )-Oxoaply-
sinopsin B (9) is an indole alkaloid that possesses an intriguing
oxindole−imidazolinone (hydantoin) hybrid skeleton. It was
isolated very recently (2019) as a racemic pair of enantiomers
from Xisha Islands sponge Fascaplysinopsis reticulata along with
oxoaplysinopsin A, oxoaplysinopsins C−G, and other natural
products.12 ( )-Oxoaplysinopsin B (9) showed stronger
activity than the positive controls in tyrosine phosphatase 1B
(PTP1B) inhibition (IC50 = 20.8 μM). There is no literature
report to date on its synthesis.
Our approach is depicted in Figure 3. The 3-hydroxy-
oxindole skeleton of 9 can be derived from 5a by oxidation of
an indole moiety. Compound 5a could be obtained by the
present method developed, directly from glyoxylic acid,
dimethylurea, and indole under (+)-tartaric acid-dimethylurea
deep eutectic conditions.
When compound 5a was ready in hand, we envisioned
oxidation of the C-2 position of indole to carbonyl and
introduction of hydroxyl functionality at the C-3 position to
reach 9. In general, the C-2 and C-3 positions of the indole are
electron-rich and are prone to easy oxidation. The oxidation of
the indole, the ring of 5a, was attempted with different
All conditions furnished the product in good to excellent
yields (85−95%). Further, the same reaction was performed
without using any catalyst in neat conditions and, to our
surprise, resulted in 5-hydroxy-1,3-dimethylhydantoin 8a
quantitatively. A careful observation of the reaction time
revealed a very fast reaction profile between glyoxylic acid and
dimethylurea. It was found that under neat conditions 8a was
efficiently produced within a minute in a quantitative yield. To
the best of our knowledge, there is no report for such a direct
and rapid approach for the synthesis of 5-hydroxy-1,3-
dimethylhydantoin 8a at an ambient temperature. The product
8a was converted to its acyl and benzoyl ester for further
confirmation of its structure. The structure of benzoyl ester 8b
was unambiguously confirmed by SC-XRD analysis (Scheme
4). Pyruvic acid was also reacted with DMU and produced
respective 5-hydroxy-1,3,5-trimethylhydantoin (8d) within 15
min in a 91% yield.
To gain insight into the mechanism, further, we studied the
reaction between the 5-hydroxyhydantoin 8a and indole in the
deep eutectic solution at 110 °C, which produced hydantoin
5a (Scheme 3).
This supports that the reaction proceeds through the
formation of 5-hydroxy-1,3-dimethylhydantoin as a reaction
intermediate. The proposed mechanism (Scheme 4) involves
the initial formation of an oxonium intermediate A, and
nucleophilic attack with dimethylurea produces B. The
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Scheme 2. Synthesis of 5a, 6a, and Their Analogues
conditions such as CeCl3−IBX,13 DMDO,14,15 and PCC16 to
produce 9 directly from 5a. However, these methods failed to
furnish 9 (Scheme 5).
Hence, an alternative approach has been designed (Figure 3
and Scheme 6). The revised strategy involves the conversion of
5a into a 3-halo-oxindole derivative followed by substitution of
halogen with hydroxy to obtain 9.
We investigated the conversion of the indole moiety of 5a
into a 3-halo-oxindole derivative by the initial treatment with
NBS or NCS followed by the hydroxylation reaction under
basic conditions.17 After, indolylhydantoin 5a was entirely
consumed (TLC) on a reaction with NBS or NCS; then, the
crude product was treated with a base (NaHCO3, Na2CO3,
K2CO3, KOH, NaOH, Cs2CO3, and Ag2O) to produce 9. The
combination NCS and Ag2O was only found to produce
( )-oxoaplysinopsin B (8%) and its 5-chloro analogue 10
(30%) through a series of optimization. Next, the dechloro-
hydrogenation of 10 with Pd−C/H218 in methanol furnished 9
quantitatively in 30 min. To increase the overall yield, the yield
of 10 had to be enhanced. Hence, 5a was treated with higher
equivalents of NCS to improve the yield of 10. The
investigation of the reaction revealed that, while using four
equivalents of NCS, 10 was produced in 54% yield over 40
min. Further dechloro-hydrogenation was carried out as earlier
method, which produced the ( )-oxoaplysinopsin B in 48%
overall yield starting from indole. The spectral data of
synthesized ( )-oxoaplysinopsin B (9) matched with that of
the isolated compound. The specific rotation of the
synthesized ( )-oxoaplysinopsin B was determined as zero,
which indicates the presence of a racemic mixture. The
structures of ( )-oxoaplysinopsin B (9)19 and 5-chloro
analogue 10 were unambiguously confirmed by SC-XRD
analysis.
CONCLUSION
■
In summary, we have developed an operationally simple route
to synthesize indole substituted with hydantoin in a high yield
for the first time. The mechanistic investigation showed that 5-
hydroxy-1,3-dimethylhydantoin was identified as a reaction
intermediate. Further, this method was utilized in the first total
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Figure 2. Optimization for the synthesis of 8a.
Scheme 3. Synthesis of 5a from 5-Hydroxyhydantoin and Indole
General Experimental Procedure for the Synthesis of 5a
and 6a. A mixture of (+)-tartaric acid (120 mg) and N,N-
dimethylurea (280 mg) was heated in an RB flask at 110 °C on an
oil bath for 5 min to get a clear eutectic mixture. To this mixture was
added glyoxylic acid monohydrate (92 mg, 1 mmol, 4 equiv), and the
mixture was stirred for two minutes; then indole (29 mg, 0.25 mmol,
1 equiv) was added. After complete consumption of indole, the
reaction mixture was quenched while hot by the slow addition of
water and extracted with ethyl acetate (3 × 20 mL). The combined
organic layer was dried over anhydrous sodium sulfate and evaporated
under reduced pressure to obtain the brown mass. Pure product 5a
was isolated by column chromatography using a 40% ethyl acetate−
hexane mixture in a 90% (55 mg) yield. Using the same procedure
analogues of 5a were synthesized. The same procedure was repeated
with pyruvic acid (88 mg, 1 mmol, 4 equiv) instead of glyoxylic acid
monohydrate to synthesize 6a and its analogues. For the synthesis of
synthesis of ( )-oxoaplysinopsin B with a 48% overall yield
from a commercially available indole.
EXPERIMENTAL SECTION
■
Material and Methods. IR measurements were performed in FT-
IR 500. NMR was recorded on a 500/400 MHz (proton) or 125/100
MHz (carbon) Bruker spectrometer. Chemical shift values are
assigned relative to NMR solvent residual peaks, and the splitting
pattern was presented as s, singlet; br s, broad singlet; d, doublet; t,
triplet; dt, doublet of triplet; td, triplet of doublet; m, multiplet.
HRMS was obtained from TOF and quadrupole mass analyzer types.
The crystal data collection was obtained from D8 Quest or Rigaku.
Melting points were recorded in open tubes and uncorrected.
Purification of all synthesized compounds was carried out in 100−200
mesh silica gel columns. All solvents and chemicals purchased were
used as such unless otherwise mentioned.
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Scheme 4. Proposed Mechanism for the Formation of 5a
86% (2.09 g) yield. In the case of using 50% solution of a glyoxylic
acid aqueous solution, a wide-neck, open-mouth RB flask was utilized,
and 8 mL of 50% solution was added in the place of glyoxylic acid
monohydrate over 10 min. The mixture was stirred for an additional
20 min before the indole was added.
For the gram-scale synthesis of 6a, pyruvic acid (2.8 mL, 40 mmol,
4 equiv) was used instead of glyoxylic acid monohydrate to produce
6a in an 88% (2.27g) yield.
Synthesis of 5a from 8a under a Deep Eutectic Solution. A
mixture of (+)-tartaric acid (90 mg) and N,N-dimethylurea (210 mg)
was heated in an RB flask at 110 °C on an oil bath for 5 min to get a
clear eutectic solution. To this were added 8a (144 mg, 1 mmol) and
indole (29 mg, 0.25 mmol, 1 equiv), and the mixture was stirred for 4
h. After completion of the reaction, the reaction mixture was
quenched while hot by the slow addition of water and extracted with
ethyl acetate (3 × 20 mL). The combined organic layer was dried
over anhydrous sodium sulfate and evaporated under reduced
pressure to obtain the brown mass. The pure product was isolated
by column chromatography using a 40% ethyl acetate/hexane mixture
in a 90% (55 mg) yield.
5-(1H-Indol-3-yl)-1,3-dimethylimidazolidine-2,4-dione (5a): 55
mg; 90% yield; off white solid; mp 172−174 °C; Rf = 0.24 (70%
EtOAc/hexane); IR (neat) vmax (cm−1) 3285, 2974, 1754, 1691, 1454;
1H NMR (400 MHz, DMSO-d6) δ 11.30 (br s, 1H), 7.54 (d, J = 2.5
Figure 3. Retrosynthesis of ( )-oxoaplysinopsin B.
Hz, 1H), 7.42 (d, J = 8.1 Hz, 1H), 7.15−7.10 (m, 1H), 6.99 (t, J = 7.8
Hz, 1H), 5.31 (s, 2H), 2.99 (s, 3H), 2.67 (s, 3H); 13C{1H} NMR
(100 MHz, DMSO-d6) δ 172.6, 156.5, 137.1, 127.4, 125.5, 122.1,
119.9, 118.3, 112.5, 106.6, 59.7, 27.8, 25.1; HRMS (ESI) m/z [M +
Na]+ calcd for C13H13N3O2Na 266.0905, found 266.0907.
Scheme 5. Unsuccessful Attempts for the Synthesis of 9
Directly from 5a
5-(5-Bromo-1H-indol-3-yl)-1,3-dimethylimidazolidine-2,4-dione
(5b): 68 mg; 85% yield; off white solid; mp >200 °C; Rf = 0.27 (70%
EtOAc/hexane); IR (neat) vmax (cm−1) 3360, 3120, 2914, 1752, 1697,
1448, 595; 1H NMR (500 MHz, DMSO-d6) δ 11.52 (br s, 1H), 7.58
(d, J = 2.6 Hz,1H), 7.41 (d, J = 8.7 Hz, 1H), 7.34 (d, J = 1.8 Hz, 1H),
7.25 (dd, J = 8.6 Hz, J = 1.9 Hz, 1H), 5.36 (s, 1H), 2.98 (s, 3H), 2.70
(s, 3H); 13C{1H} NMR (125 MHz, DMSO-d6) δ 177.1, 161.3, 140.6,
133.3, 132.3, 129.5, 125.3, 199.3, 117.2, 111.4, 64.0, 32.7, 29.9;
HRMS (ESI) m/z [M + Na]+ calcd for C13H12BrN3O2Na 344.0011,
found 344.0012.
6k phenylglyoxylic acid (134 mg, 1 mmol, 4 equiv) was used in place
of glyoxylic acid monohydrate under optimized conditions. In the case
of 6l, the monomethylurea (280 mg) was used instead of N,N-
dimethylurea under the optimized conditions. The product 6m was
synthesized using phenylpyruvic acid (136 mg, 1 mmol, 4 equiv) in
the place of glyoxylic acid monohydrate under optimized conditions.
For the gram-scale synthesis of 5a and 6a, a mixture of (+)-tartaric
acid (4.80 g) and N,N-dimethylurea (11.2 g) was heated in an RB
flask at 110 °C on an oil bath for 10 min to get a clear eutectic
mixture. To this mixture was added glyoxylic acid monohydrate (3.68
g, 40 mmol, 4 equiv), and the mixture was stirred for two minutes;
then indole (1.17 g, 10 mmol, 1 equiv) was added. The same workup
procedure as earlier was followed, and the product was isolated in an
5-(6-Bromo-1H-indol-3-yl)-1,3-dimethylimidazolidine-2,4-dione
(5c): 70 mg; 88% yield; off white solid; mp 182−184 °C; Rf = 0.33
(70% EtOAc/hexane); IR (neat) vmax (cm−1) 3278, 3123, 2928, 1750,
1
1689, 1451, 585; H NMR (500 MHz, DMSO-d6) δ 11.43 (s, 1H),
7.62 (d, J = 1.6 Hz, 1H), 7.57 (d, J = 2.6 Hz, 1H), 7.16−7.11 (m,
2H), 5.33 (s, 1H), 2.98 (s, 3H), 2.68 (s, 3H); 13C{1H} NMR (125
MHz, DMSO-d6) δ 172.3, 156.5, 138.0, 128.3, 124.6, 122.9, 120.1,
115.1, 114.9, 107.1, 59.4, 27.9, 25.1; HRMS (ESI) m/z [M + Na]+
calcd for C13H12BrN3O2Na 344.0011, found 344.0014.
5-(5-Methoxy-1H-indol-3-yl)-1,3-dimethylimidazolidine-2,4-
dione (5d): 63 mg; 92% yield; off white solid; mp 192−194 °C; Rf =
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Scheme 6. Alternative Approach to the Total Synthesis of ( )-Oxoaplysinopsin B
0.33 (70% EtOAc/hexane); IR (neat) vmax (cm−1) 3314, 3140, 2932,
1748, 1693, 1439, 1058; 1H NMR (500 MHz, CDCl3) δ 8.90 (s, 1H),
7.58 (d, J = 1.8, 1H), 7.37 (d, J = 2.7 Hz, 1H), 7.21 (dd, J = 8.8 Hz, J
= 2.4 Hz, 1H), 7.05 (d, J = 2.36 Hz, 1H), 5.39 (s, 1H), 4.13 (s, 3H),
3.51 (s, 3H), 3.19 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
172.6, 156.5, 154.6, 131.9, 126.1, 125.4, 112.7, 112.7, 106.0, 100.2,
60.0, 55.8, 27.7, 25.1; HRMS (ESI) m/z [M + H]+ calcd for
C14H15N3O3H 274.1192, found 274.1192.
6H), 7.12−7.01 (m, 3H), 5.22 (s, 1H), 3.10 (s, 3H), 2.66 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 172.8, 156.5, 140.2, 136.2,
131.5, 129.1, 128.8, 128.7, 125.9, 122.6, 120.6, 118.1, 111.8, 102.5,
59.3, 27.6, 25.0; HRMS (ESI) m/z [M + H]+ calcd for C19H17N3O2H
320.1399, found 320.1399.
5-(1H-Indol-3-yl)-1,3,5-trimethylimidazolidine-2,4-dione (6a): 59
mg; 92% yield; off white solid; mp >200 °C; Rf = 0.47 (70% EtOAc/
1
hexane); IR (neat) vmax (cm−1) 3261, 3133, 1760, 1699, 1438; H
1,3-Dimethyl-5-(1-methyl-1H-indol-3-yl)imidazolidine-2,4-dione
(5e): 57 mg; 85% yield; off white solid; mp 172−174 °C; Rf = 0.26
(50% EtOAc/hexane); IR (neat) vmax (cm−1) 3248, 2928, 1758, 1692,
NMR (500 MHz, DMSO-d6) δ 11.34 (s, 1H), 7.56 (d, J = 2.4 Hz,
1H), 7.42 (d, J = 8.2 Hz, 1H), 7.13−7.09 (m, 1H), 7.01−6.96 (m,
2H), 3.01 (s, 3H), 2.60 (s, 3H), 1.78 (s, 3H); 13C{1H} NMR (125
MHz, DMSO-d6) δ 175.5, 155.7, 137.2, 126.6, 124.7, 122.0, 120.1,
118.1, 112.6, 110.8, 63.7, 25.2, 25.1, 20.8; HRMS (ESI) m/z [M +
H]+ calcd for C14H15N3O2H 258.1243, found 258.1242.
1
1459; H NMR (500 MHz, CDCl3) δ 7.34−7.24 (m, 3H), 7.16 (s,
1H), 7.15−7.11 (dd, J = 7.5 Hz, J = 0.5 Hz, 1H), 5.08 (s, 1H), 3.79 (s,
3H), 3.15 (s, 3H), 2.86 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
172.1, 156.6, 137.5, 129.5, 125.6, 122.6, 120.3, 118.6, 109.9, 105.4,
59.9, 33.0, 27.8, 25.1; HRMS (ESI) m/z [M + H]+ calcd for
C14H15N3O2H 258.1243, found 258.1238.
5-(5-Chloro-7,7a-dihydro-1H-indol-3-yl)-1,3,5-trimethylimidazo-
lidine-2,4-dione (6b): 57 mg; 78% yield; off white solid; mp 168−170
°C; Rf = 0.48 (70% EtOAc/hexane); IR (Neat):vmax(cm−1) 3298,
5-(1-Hexyl-1H-indol-3-yl)-1,3-dimethylimidazolidine-2,4-dione
(5f): 74 mg; 90% yield; off white solid; mp 62−64 °C; Rf = 0.60 (50%
EtOAc/hexane); IR (neat) vmax (cm−1) 3276, 2914, 1755, 1692, 1418;
1H NMR (500 MHz, CDCl3) δ 7.35 (d, J = 8.3 Hz, 1H), 7.31 (d, J =
8.0 Hz, 1H), 7.24 (t, J = 8.1 Hz, 1H), 7.18 (s, 1H),7.10 (t, J = 7.9 Hz,
1H), 5.09 (s, 1H), 4.09 (t, J = 7.0 Hz, 2H), 3.15 (s, 3H), 2.86 (s, 3H),
1.87−1.82 (m, 2H), 1.35−1.29 (m, 6H), 0.88 (t, J = 6.9 Hz, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 172.1, 156.5, 136.8, 128.4,
1
2932, 1758, 1691, 1482, 636; H NMR (500 MHz, CDCl3) δ 9.05
(brs, 1H), 7.22 (d, J = 8.6 Hz, 1H), 7.12−7.08 (m, 2H), 6.90 (s, 1H),
3.20 (s, 3H), 2.75 (s, 3H), 1.79 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3) δ 176.0, 155.5, 135.1, 126.3, 126.0, 125.2, 123.0, 117.9, 112.9,
110.7, 63.5, 25.2, 25.1, 21.0; HRMS (ESI) m/z [M + H]+ calcd for
C14H14ClN3O2H 292.0853, found 292.0853.
5-(5-Bromo-1H-indol-3-yl)-1,3,5-trimethylimidazolidine-2,4-
dione (6c): 75 mg; 89% yield; off white solid; mp 158−160 °C; Rf =
0.38 (70% EtOAc/hexane); IR (neat) vmax (cm−1) 3308, 2978, 1761,
125.7, 122.3, 120.2, 118.6, 110.0, 105.2, 59.9, 46.6, 31.3, 30.0, 27.7,
26.6, 25.1, 22.5, 13.9; HRMS (ESI) m/z [M + H]+ calcd for
C19H25N3O2H 328.2025, found 328.2027.
1
1701, 1694, 1452, 605; H NMR (500 MHz, CDCl3) δ 9.03 (br s,
1H), 7.25−7.24 (m, 2H), 7.18−7.16 (m, 1H), 6.89 (s,1H), 3.20 (s,
3H), 2.75 (s, 3H), 1.79 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
175.9, 155.5, 135.4, 125.9, 125.8, 125.7, 121.0, 113.9, 113.3, 110.8,
63.5, 25.2, 25.2, 21.0; HRMS (ESI) m/z [M + H]+ calcd for
C14H14BrN3O2H 336.0348, found 336.0348.
5-(6-Bromo-1H-indol-3-yl)-1,3,5-trimethylimidazolidine-2,4-
dione (6d): 75 mg; 89% yield; off white solid; mp 152−154 °C; Rf =
0.47 (70% EtOAc/hexane); IR (neat) vmax (cm−1) 3310, 2937, 1763,
1691, 1450, 552; 1H NMR (500 MHz CDCl3) δ 8.57 (br s, 1H), 7.50
(s, 1H), 7.19 (dd, J = 8.6 Hz, J = 0.9 Hz, 1H), 7.07−7.02 (m, 2H),
3.16 (s, 3H), 2.78 (s, 3H), 1.83 (s, 3H); 13C{1H} NMR (125 MHz,
CDCl3) δ 175.7, 155.7, 137.6, 125.1, 124.1, 123.2, 119.7, 116.4, 114.8,
111.8, 63.6, 25.2, 25.15, 20.9; HRMS (ESI) m/z [M + H]+ calcd for
C14H14BrN3O2H 336.0348, found 336.0342.
5-(1-Benzyl-1H-indol-3-yl)-1,3-dimethylimidazolidine-2,4-dione
(5g): 73 mg; 87% yield; off white solid; mp 168−170 °C; Rf = 0.43
(50% EtOAc/hexane); IR (neat) vmax (cm−1) 3251, 2915, 1751, 1985,
1428; 1H NMR (500 MHz, DMSO-d6) δ 7.34−7.30 (m, 5H), 7.23−
7.21 (m, 2H), 7.15−7.11 (m, 3H), 5.31 (s, 2H), 5.09 (s, 1H), 3.16 (s,
3H), 2.87 (s, 3H); 13C{1H} NMR (125 MHz, DMSO-d6) δ 171.9,
156.5, 137.1, 136.6, 128.9, 128.8, 127.9, 126.9, 125.8, 122.7, 120.5,
118.7, 110.3, 106.1, 59.8, 50.2, 27.7, 25.1; HRMS (ESI) m/z [M +
H]+ calcd for C20H19N3O2H 334.1556, found 334.1557.
1,3-Dimethyl-5-(2-methyl-1H-indol-3-yl)imidazolidine-2,4-dione
(5h): 55 mg; 85% yield; colorless solid; mp 158−160 °C; Rf = 0.46
(70% EtOAc/hexane); IR (neat) vmax (cm−1) 3312, 2911, 1752, 1688,
1438; 1H NMR (500 MHz, CDCl3) δ 8.66 (br s, 1H), 7.23 (d, J = 8.1
Hz, 1H), 7.13−7.03 (m, 3H), 5.05 (s, 1H), 3.21 (s, 3H), 2.76 (s, 3H),
2.01 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 172.8, 156.4,
135.4, 121.8, 121.8, 120.3, 120.3, 117.2, 110.9, 101.7, 58.9, 27.5, 25.1,
11.0; HRMS (ESI) m/z [M + H]+ calcd for C14H15N3O2H 258.1243,
found 258.1243.
5-(5-Methoxy-1H-indol-3-yl)-1,3,5-trimethylimidazolidine-2,4-
dione (6e): 67 mg; 93% yield; off white solid; mp 168−170 °C; Rf =
0.44 (70% EtOAc/hexane); IR (neat) vmax (cm−1) 3320, 2928, 1759,
1
1695, 1451, 1031; H NMR (500 MHz, CDCl3) δ 8.76 (br s, 1H),
7.22 (d, J = 8.8 Hz, 1H), 6.90 (d, J = 2.6 Hz, 1H), 6.84 (dd, J = 8.8
Hz, J = 2.2 Hz, 1H), 6.56 (d, J = 2.0 Hz, 1H), 3.77 (s, 3H), 3.18 (s,
3H), 2.75 (s, 3H), 1.79 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
175.9, 155.8, 154.6, 131.8, 125.2, 124.8, 112.7, 112.5, 110.9, 100.3,
1,3-Dimethyl-5-(2-phenyl-1H-indol-3-yl)imidazolidine-2,4-dione
(5i): 70 mg; 87% yield; colorless solid; mp 186−188 °C; Rf = 0.64
(50% EtOAc/hexane); IR (neat) vmax (cm−1) 3245, 2923, 1766, 1691,
1
1459; H NMR (500 MHz, CDCl3) δ 10.10 (s, 1H), 7.68−7.32 (m,
3736
https://dx.doi.org/10.1021/acs.joc.0c02435
J. Org. Chem. 2021, 86, 3730−3740

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
63.8, 55.7, 25.1, 25.0, 20.7; HRMS(ESI): [M + H]+ calcd for
C15H17N3O3H 288.1348, found 288.1350.
5-Benzyl-5-(1H-indol-3-yl)-1,3-dimethylimidazolidine-2,4-dione
(6m): 73 mg; 87% yield; colorless solid; mp 162−164 °C; Rf = 0.48
(50% EtOAc/hexane); IR (neat) vmax (cm−1) 3302, 2922, 1762, 1694,
1,3,5-Trimethyl-5-(1-methyl-1H-indol-3-yl)imidazolidine-2,4-
dione (6f): 60 mg; 88% yield; off white solid; mp 176−178 °C; Rf =
0.34 (50% EtOAc/hexane); IR (neat) vmax (cm−1) 3278, 2925, 1754,
1689, 1442; 1H NMR (500 MHz, CDCl3) δ 7.31 (d, J = 8.3 Hz, 1H),
7.23 (dt, J = 7.0 Hz, J = 1.0 Hz, 1H), 7.16 (d, J = 8.1 Hz, 1H), 7.13 (s,
1H), 7.09 (dt, J = 7.0 Hz, J = 0.9 Hz, 1H), 3.78 (s, 3H), 3.15 (s, 3H),
2.78 (s, 3H), 1.84 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
175.4, 155.9, 137.5, 128.8, 124.9, 122.3, 120.4, 118.8, 110.0, 109.7,
63.7, 33.0, 25.1, 25.0, 20.9; HRMS (ESI) m/z [M + Na]+ calcd for
C15H17N3O2Na 294.1218, found 294.1219.
1
1455. H NMR (500 MHz, CDCl3); δ 8.54 (s, 1H), 7.43 (d, J = 8.2
Hz, 1H), 7.36−7.37 (d, J = 2.7 Hz, 1H), 7.30−7.34 (m, 3H), 7.22−
7.26 (m, 1H), 7.18−7.20 (m, 2H), 7.14−7.16 (d, J = 7.7 Hz, 1H),
7.11 (m 1H), 3.81−3.40 (m, 2H), 2.87 (s, 3H), 2.81 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3): 174.1, 156.2, 136.6, 133.4, 129.7,
128.5, 127.7, 124.6, 124.2, 123.0, 121.0, 118.7, 111.7, 111.4, 68.4,
38.9, 26.0, 24.6; HRMS (ESI) m/z [M + Na]+ calcd for
C20H19N3O2Na 356.1375 Found 356.1372.
Synthesis of 2,2-Bis(1H-indol-3-yl)propanoic Acid. The
procedure similar to the synthesis of 5a was followed with urea
(280 mg) instead of N,N-Dimethylurea. Once the DES formed by
(+)-tartaric acid (120 mg) and urea (280 mg) at 110 °C, the pyruvic
acid (88 mg 1 mmol, 4 equiv) and indole (29 mg, 0.25 mmol, 1
equiv) were added in a 15 min interval. After complete consumption
of indole, the reaction mixture was quenched while in hot by the slow
addition of water and extracted with ethyl acetate (3 × 20 mL). The
combined organic layer was dried over anhydrous sodium sulfate and
evaporated under reduced pressure to obtain the brown mass. Pure
product 7 was isolated by column chromatography using an 80% ethyl
acetate−hexane mixture in 82% (31 mg) yield.
5-(1-Hexyl-1H-indol-3-yl)-1,3,5-trimethylimidazolidine-2,4-dione
(6g): 76 mg; 89% yield; off white solid; mp 182−184 °C; Rf = 0.70
(50% EtOAc/hexane); IR (neat) vmax (cm−1) 3281, 2947, 1755, 1678,
1439; 1H NMR (500 MHz, CDCl3) δ 7.33 (d, J = 8.4 Hz, 1H), 7.22−
7.15 (m, 3H), 7.07 (t, J = 7.6 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 3.16
(s, 3H), 2.77 (s, 3H), 1.86−1.82 (m, 5H), 1.35−1.30 (m, 6H), 0.88
(t, J = 6.8 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 175.4,
155.9, 136.8, 127.7, 125.0, 122.1, 120.2, 118.9, 110.0, 109.9, 63.7,
46.7, 31.3, 30.0, 26.6, 25.1, 25.0, 22.5, 21.0, 13.9; HRMS (ESI) m/z
[M + H]+ calcd for C20H27N3O2H 342.2182, found 342.2184.
5-(1-Benzyl-1H-indol-3-yl)-1,3,5-trimethylimidazolidine-2,4-
dione (6h): 76 mg; 87% yield; off white solid; mp 188−190 °C; Rf =
0.53 (50% EtOAc/hexane); IR (neat) vmax (cm−1) 3269, 2917, 1759,
2,2-Bis(1H-indol-3-yl)propanoic Acid (7): 31 mg; 82% yield; pink
solid; mp 90−92 °C (reported mp = 90 °C);20 Rf = 0.37 (only
1
EtOAc); IR (neat) vmax (cm−1) 3224, 2939, 2826, 1711; H NMR
1
1694, 1461; H NMR (500 MHz, CDCl3) δ 7.34−7.28 (m, 4H),
(500 MHz, DMSO-d6) δ 12.29 (s, 1H), 10.89 (s, 2H), 7.34−7.32 (m,
4H), 7.05−7.00 (m, 4H), 6.83 (t, J = 7 Hz, 2H), 1.99 (s, 3H);
13C{1H} NMR (125 MHz, DMSO-d6) δ 176.7, 137.2, 126.4, 123.6,
121.2, 121.0, 118.6, 118.4, 111.9, 46.0, 26.5; HRMS (ESI) m/z [M +
Na]+ calcd for C18H14N2O2Na 313.0953, found 313.0939.
Synthesis of Intermediate 8a. N,N-Dimethylurea (88 mg, 1
mmol, 1 equiv) and glyoxylic acid monohydrate (92 mg, 1 mmol, 1
equiv) were stirred in an RB flask for a minute. Then the reaction
mixture was diluted with ethyl acetate (15 mL) and dried over
anhydrous sodium sulfate. The solvent was evaporated under reduced
pressure to obtain 8a in a quantitative yield (143 mg): colorless
liquid; Rf = 0.31 (70% EtOAc/hexane); IR (neat) vmax (cm−1) 3391,
2945, 1774, 1695, 1474; 1H NMR (500 MHz, DMSO-d6) δ 6.92 (d, J
= 8.5 Hz, 1H), 5.02 (d, J = 8.5 Hz, 1H), 2.84 (s, 3H), 3.80 (s, 3H);
13C{1H} NMR (125 MHz, DMSO-d6) δ 171.7, 155.8, 79.9, 26.8,
24.6; HRMS (ESI) m/z [M + Na]+ calcd for C5H8N2O3Na 167.0433,
found 167.0433
7.21−7.17 (m, 3H), 7.13−7.08 (m, 3H), 5.30 (s, 2H), 3.16 (s, 3H),
2.79 (s, 3H), 1.84 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ
175.3, 156.0, 237.2, 136.8, 128.9, 128.3, 127.9, 126.8, 125.3, 122.6,
120.7, 119.0, 110.9, 110.3, 63.8, 50.3, 25.2, 25.1, 21.0; HRMS (ESI)
m/z [M + H]+ calcd for C21H21N3O2H 348.1712, found 348.1710.
1,3,5-Trimethyl-5-(2-methyl-1H-indol-3-yl)imidazolidine-2,4-
dione (6i): 58 mg; 86% yield; off white solid; mp 174−176 °C; Rf =
0.61 (70% EtOAc/hexane); IR (neat) vmax (cm−1) 3273, 2919, 1758,
1
1681, 1454; H NMR (500 MHz, CDCl3) δ 8.48 (br s, 1H), 7.25−
7.19 (m, 2H), 7.10 (t, J = 7.4 Hz, 1H), 7.03 (t, J = 7.2 Hz, 1H), 3.17
(s, 3H), 2.76 (s, 3H), 2.19 (s, 3H), 1.95 (s, 3H); 13C{1H} NMR (125
MHz, CDCl3) δ 176.3, 155.5, 134.9, 134.4, 127.0, 121.5, 120.5, 118.4,
110.7, 105.2, 65.2, 25.2, 24.9, 22.8, 14.0; HRMS (ESI) m/z [M +
Na]+ calcd for C15H17N3O2Na 294.1218, found 294.1211.
1,3,5-Trimethyl-5-(2-phenyl-1H-indol-3-yl)imidazolidine-2,4-
dione (6j): 73 mg; 87% yield; colorless solid; mp 186−188 °C; Rf =
0.67 (50% EtOAc/hexane); IR (neat) vmax (cm−1) 3277, 2926, 1755,
1684, 1459; 1H NMR (500 MHz, CDCl3) δ 8.35 (s, 1H), 7.49−7.40
(m, 6H), 7.34 (d, J = 8.1 Hz, 1H), 7.21 (dd, J = 7.1 Hz, J = 0.9 Hz,
1H), 7.14 (t, J = 7.3 Hz, 1H), 2.91 (s, 3H), 2.76 (s, 3H), 1.66 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 175.7, 155.4, 138.4, 135.3,
133.2, 130.2, 129.1, 128.2, 126.7, 122.5, 120.9, 119.6, 111.1, 107.6,
64.9, 25.2, 24.7, 23.0; HRMS (ESI) m/z [M + H]+ calcd for
C20H19N3O2H 334.1556, found 334.1556
Synthesis of Benzoyl Ester 8b and Acyl Ester 8c. To a
solution of 5-hydroxyhydantoin 8a (72 mg, 0.5 mmol, 1 equiv) in
DCM were added benzoyl chloride (70 mg = 58 μL, 0.55 mmol, 1.1
equiv) followed by triethylamine (79 mg = 0.1 mL, 0.75 mmol, 1.5
equiv) at 0 °C, and the mixture was stirred for 15 min. Then the
reaction mixture was quenched with water (15 mL) and extracted
with ethyl acetate (3 × 20 mL). The combined organic layer was
dried over anhydrous sodium sulfate and evaporated under reduced
pressure, and pure product was isolated by column chromatography
using a 35% ethyl acetate−hexane mixture to obtain 8b in 80% yield.
The same reaction procedure was repeated with acetyl chloride
instead of benzoyl chloride to obtain 8c in 97% yield (181 mg).
1,3-Dimethyl-2,5-dioxoimidazolidin-4-yl benzoate (8b): 198 mg,
80% yield; colorless solid; mp 128−130 °C; Rf = 0.64 (30% EtOAc/
hexane); IR (neat) vmax (cm−1) 2944, 2551, 1786, 1712, 1709, 1681,
5-(1H-Indol-3-yl)-1,3-dimethyl-5-phenylimidazolidine-2,4-dione
(6k): 69 mg; 86% yield; colorless solid; mp 196−198 °C; Rf = 0.34
(50% EtOAc/hexane); IR (neat) vmax (cm−1) 3393, 3304, 1761, 1698,
1
1450; H NMR (500 MHz, DMSO-d6) δ 11.43 (s, 1H), 7.46−7.37
(m, 6H), 7.21 (d, J = 2.5 Hz, 1H), 7.11 (t, J = 8.5 Hz, 1H), 6.92 (t, J
= 8.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 3.02 (s, 3H), 2.70 (s, 3H);
13C{1H} NMR (125 MHz, DMSO-d6) δ 173.7, 156.0, 137.2, 136.7,
129.1, 129.0, 127.8, 127.1, 125.5, 122.1, 119.9, 119.7, 112.6, 110.5,
70.6, 27.0, 25.4; HRMS (ESI) m/z [M + H]+ calcd for C19H17N3O2H
320.1399, found 320.1392.
1
1450; H NMR (500 MHz, CDCl3) δ 8.05 (d, J = 8.5 Hz, 2H), 7.61
(t, J = 7.5 Hz, 1H), 7.46 (t, J = 8.0 Hz, 2H), 6.34 (s, 1H), 3.10 (s,
3H), 3.02 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 167.5, 165.5,
156.1, 134.1, 130.2, 128.6, 128.1, 78.5, 27.9, 25.1; HRMS (ESI) m/z
[M + Na]+ calcd for C12H12N2O4Na 271.0695, found 271.0695.
1,3-Dimethyl-2,5-dioxoimidazolidin-4-yl acetate (8c): 181 mg;
97% yield; colorless liquid; Rf = 0.28 (30% EtOAc/hexane); IR (neat)
5-(1H-Indol-3-yl)-1,5-dimethylimidazolidine-2,4-dione (6l): 48
mg; 79% yield; colorless solid; mp 164−166 °C; Rf = 0.29 (50%
EtOAc/hexane); IR (neat) vmax (cm−1) 3272, 2962, 1749, 1696, 1439;
1H NMR (400 MHz, DMSO-d6) δ 11.89 (s, 1H), 8.72 (s, 1H), 7.41−
7.38 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H), 7.10 (t, J = 7.2 Hz, 1H), 6.99
(t, J = 6.8 Hz, 1H), 2.93 (s, 3H), 1.76 (s, 3H); 13C{1H} NMR (100
MHz, DMSO-d6) δ 176.5, 156.4, 137.2, 125.0, 124.3. 121.8, 119.5,
119.4, 114.0, 112.3, 60.5, 24.6, 24.4; HRMS (ESI) m/z [M + H]+
calcd for C13H13N3O2H 244.1086, found 244.1073
1
vmax (cm−1) 2948, 1789, 1756, 1715, 1460; H NMR (500 MHz,
DMSO-d6) δ 6.08 (s, 1H), 2.88 (s, 3H), 2.83 (s, 3H), 2.14 (s, 3H);
13C{1H} NMR (125 MHz, DMSO-d6) δ 170.3, 168.2, 156.4, 79.3,
28.2, 25.0, 20.8; HRMS (ESI) m/z [M + Na]+ calcd for
C7H10N2O4Na 209.0538, found 209.0536.
3737
https://dx.doi.org/10.1021/acs.joc.0c02435
J. Org. Chem. 2021, 86, 3730−3740

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Synthesis of 5-(Indol-3-yl)-1,3,5-trimethylhydantoin (8d).
The procedure for the synthesis of intermediate 8a was followed with
pyruvic acid (134 mg, 1 mmol, 1 equiv) instead of glyoxylic acid
monohydrate. The reaction was completed in 15 min.
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
5-Hydroxy-1,3,5-trimethylhydantoin (8d):21 148 mg; 91% yield;
colorless liquid; Rf = 0.28 (50% EtOAc/hexane); IR (neat) vmax
AUTHOR INFORMATION
Corresponding Author
1
(cm−1) 3343, 2920, 2849, 1771, 1698 H NMR (500 MHz, DMSO-
■
d6) δ 6.61 (s, 1H), 2.87 (s, 3H), 2.77 (s, 3H), 1.39 (s, 3H); 13C{1H}
NMR (125 MHz, DMSO-d6) δ 173.9, 155.1, 84.0, 24.6, 23.8, 21.0.
Synthesis of ( )-(R)-5-((R)-5-Chloro-3-hydroxy-2-oxoindolin-3-
yl)-1,3-dimethylimidazo-lidine-2,4-dione ( )-(10). To a solution of
5a (61 mg, 0.25 mmol, 1 equiv) in a 5 mL mixture of THF/H2O
(9:1) was added NCS (134 mg, 1 mmol, 4 equiv) at 0 °C, and the
reaction temperature was raised to 30 °C and stirred for 40 min. Then
the reaction mixture was quenched by the addition of water (10 mL)
and extracted with ethyl acetate (3 × 15 mL). The combined organic
layer was dried over anhydrous sodium sulfate and evaporated under
reduced pressure to obtain a crude yellow mass. The crude mass
(without further purification) was stirred with Ag2O (29 mg, 0.13
mmol, 0.5 equiv) in water (1 mL); after 2 h, an additional amount of
water (2 mL) was added and extracted with ethyl acetate (3 × 15
mL). The combined organic layer was dried over anhydrous sodium
sulfate and evaporated under reduced pressure to obtain brown mass.
The product was isolated in a 54% (37 mg) yield by column
chromatography using a 50% ethyl acetate−hexane mixture: pale
yellow solid; mp 172−174 °C; Rf = 0.20 (70% EtOAc/hexane); IR
Rajagopal Nagarajan − School of Chemistry, University of
Hyderabad, Hyderabad, Telangana 500046, India;
orcid.org/0000-0002-4471-8933; Email: nagarajan@
uohyd.ac.in
Authors
Ponnusamy Pon Sathieshkumar − School of Chemistry,
University of Hyderabad, Hyderabad, Telangana 500046,
India
Metlapalli Durga Anand Saibabu − School of Chemistry,
University of Hyderabad, Hyderabad, Telangana 500046,
India; orcid.org/0000-0001-8708-4582
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02435
Author Contributions
1
(neat) vmax (cm−1) 3265, 2919, 1771, 1705, 1620, 1446, 672; H
The manuscript was written through the contributions of all
authors. All authors have given approval to the final version of
the manuscript.
NMR (500 MHz, DMSO-d6+CDCl3) δ 10.60 (br s, 1H), 7.31 (dd, J
= 7.3 Hz, J = 1.3 Hz, 1H), 7.05 (d, J = 2.2 Hz, 1H), 6.82−6.80 (m,
2H), 4.41 (s, 1H), 3.13 (s, 3H), 2.55 (s, 3H); 13C{1H} NMR (125
MHz, DMSO-d6+CDCl3) δ 175.5, 169.0, 157.8, 142.0, 130.4, 129.4,
125.8, 124.5, 111.9, 76.8, 66.5, 32.0, 24.8; HRMS (ESI) m/z [M +
Na]+ calcd for C13H12ClN3O4Na 332.0414, found 332.0409; [α]2D5
+0.00 (c 0.5 in methanol).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Synthesis of ( )-(R)-5-((R)-3-Hydroxy-2-oxoindolin-3-yl)-1,3-di-
methylimidazolidine-2,4-dione; ( )-Oxoaplysinopsin B (9). Thirty
mg of 10 was dissolved in 1 mL of methanol. Palladium (10%) on
charcoal (25 mg) was added to it, and the reaction mixture was stirred
for 30 min under a hydrogen atmosphere (balloon). Then, the
reaction mixture was diluted with ethyl acetate (10 mL) and filtered
through a Celite bed, and the Celite bed was washed with ethyl
acetate (10 mL); the combined filtrate (from filtration + from the
Celite bed wash) was evaporated to obtain 9 in a quantitative yield
(26 mg). The product was used for characterization without further
purification: pale yellow solid; mp 182−184 °C; Rf = 0.20 (70%
EtOAc/hexane); IR (neat) vmax (cm−1) 3511, 3475, 3313, 3153, 1759,
1692, 1617, 1468; 1H NMR (500 MHz, DMSO-d6 δ 10.43 (br s, 1H),
7.22 (dt, J = 7.7, J = 1.2 Hz, 1H), 7.08 (d, J = 7.2 Hz, 1H), 6.90 (dd, J
= 7.5 Hz, J = 0.9 Hz, 1H), 6.78 (d, J = 7.8 Hz, 1H), 6.62 (s, 1H), 4.40
(s, 1H), 3.14 (s, 3H), 2.50 (s, 3H); 13C{1H} NMR (125 MHz,
DMSO-d6) δ 175.3, 168.6, 157.1, 142.6, 130.0, 126.9, 124.1, 121.5,
109.9, 76.3, 66.1, 31.3, 24.2; HRMS (ESI) m/z [M + Na]+ calcd for
C13H13N3O4Na 298.0804, found 298.0802; [α]2D5 +0.00 (c 0.5 in
methanol)
The authors greatly acknowledge SERB, India, for financial
support (EEQ/2017/000422). P.P.S.K. thanks CSIR for SRF,
and M.D.A.S. thanks UGC for a fellowship.
REFERENCES
■
(1) (a) Kaushik, N. K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C.
H.; Verma, A. K.; Choi, E. H. Biomedical importance of indoles.
Molecules 2013, 18, 6620−6662. (b) Sundberg, R. J. The Chemistry of
Indoles; Academic Press: New York, 1970. (c) Brown, R. K. Indoles;
Wiley-Interscience: New York, 1972. (d) Netz, N.; Opatz, T. Marine
Indole Alkaloids. Mar. Drugs 2015, 13, 4814−4914. (e) Zhang, M. Z.;
Chen, Q.; Yang, G.-F. A review on recent developments of indole-
containing antiviral agents. Eur. J. Med. Chem. 2015, 89, 421−441.
(f) Kochanowska-Karamyan, A. J.; Hamann, M. T. Marine indole
alkaloids: potential new drug leads for the control of depression and
anxiety. Chem. Rev. 2010, 110, 4489−4497. (g) Kumari, A.; Singh, R.
K. Medicinal chemistry of indole derivatives: current to future
therapeutic prospectives. Bioorg. Chem. 2019, 89, 103021. (h) Butler,
M. S. Natural products to drugs: natural product derived compounds
in clinical trials. Nat. Prod. Rep. 2005, 22, 162−195.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02435.
(2) (a) Cacchi, S.; Fabrizi, G. Synthesis and functionalization of
indoles through palladium-catalyzed reactions. Chem. Rev. 2005, 105,
2873−920. (b) Verma, A. K.; Kesharwani, T.; Singh, J.; Tandon, V.;
Larock, R. C. A Copper-catalyzed tandem synthesis of indolo- and
pyrrolo[2,1-a]isoquinolines. Angew. Chem., Int. Ed. 2009, 48, 1138−
1143. (c) Qi, L. W.; Mao, J. H.; Zhang, J.; Tan, B. Organocatalytic
asymmetric arylation of indoles enabled by azo groups. Nat. Chem.
2018, 10, 58−64. (d) Rossi-Ashton, J. A.; Clarke, A. K.; Donald, J. R.;
Zheng, C.; Taylor, R. J. K.; Unsworth, W. P.; You, S.-L. Iridium-
catalyzed enantioselective intermolecular indole C2-allylation. Angew.
Chem., Int. Ed. 2020, 59, 7598−7604. (e) Iqbal, R. S. A.; Cid, J.;
Procter, R. J.; Uzelac, M.; Yuan, K.; Ingleson, M. J. Acyl directed
ortho-borylation of anilines and C7 borylation of indoles using just
BBr3. Angew. Chem., Int. Ed. 2019, 58, 15381−15385. (f) Xu, J.; Liang,
L.; Zheng, H.; Chi, Y. R.; Tong, R. Green oxidation of indoles using
■
sı
Experimental procedures; spectral data; crystallographic
1
data of 5a, 8b, 9, and 10; H, 13C, and HRMS spectra
(PDF)
FAIR data, including the primary NMR FID files, for
compounds 5a−5i, 6a−6l, 8a−8d, 9, and 10 (ZIP)
Accession Codes
CCDC 1987312−1987313, 2014062, and 2032805 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/
3738
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J. Org. Chem. 2021, 86, 3730−3740

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
halide catalysis. Nat. Commun. 2019, 10, 4754. (g) Ye, Y.; Kim, S. T.;
Jeong, J.; Baik, M. H.; Buchwald, S. L. CuH-catalyzed enantioselective
alkylation of indole derivatives with ligand-controlled regiodivergence.
J. Am. Chem. Soc. 2019, 141, 3901−3909. (h) Zhou, W. J.; Wang, Z.
H.; Liao, L. L.; Jiang, Y. X.; Cao, K. G.; Ju, T.; Li, Y.; Cao, G. M.; Yu,
D. G. Reductive dearomative arylcarboxylation of indoles with CO2
via visible-light photoredox catalysis. Nat. Commun. 2020, 11, 3263.
(i) Humphrey, G. R.; Kuethe, J. T. Practical methodologies for the
synthesis of indoles. Chem. Rev. 2006, 106 (7), 2875−2911.
(3) (a) Bandini, M.; Eichholzer, A. Catalytic functionalization of
indoles in a new dimension. Angew. Chem., Int. Ed. 2009, 48, 9608−
9644. (b) Pirovano, V. Gold-catalyzed functionalization reactions of
indole. Eur. J. Org. Chem. 2018, 2018, 1925−1945. (c) Sandtorv, A.
H. Transition metal-catalyzed C-H activation of indoles. Adv. Synth.
Catal. 2015, 357, 2403−2435. (d) Das, T.; Kayet, A.; Mishra, R.;
Singh, V. K. Highly fluorescent 1,2-dihydropyrimido[1,6-α]indole: an
efficient metal free synthesis and photophysical study. Chem.
Commun. 2016, 52, 11231−11234. (e) Patel, M.; Saunthwal, R. K.;
Verma, A. K. Base-mediated hydroamination of alkynes. Acc. Chem.
Res. 2017, 50, 240−254. (f) Sherikar, M. S.; Devarajappa, R.; Prabhu,
K. R. Weak coordinating carbonyl-directed rhodium (III)-catalyzed
C-H activation at the C4-position of indole with allyl alcohols. J. Org.
Chem. 2020, 85, 5516−5524. (g) Tian, Y. M.; Guo, X. N.; Wu, Z.;
Friedrich, A.; Westcott, S. A.; Braunschweig, H.; Radius, U.; Marder,
T. B. Ni-catalyzed traceless, directed C3-selective C-H borylation of
indoles. J. Am. Chem. Soc. 2020, 142, 13136−13144. (h) Shah, T. A.;
De, P. B.; Pradhan, S.; Punniyamurthy, T. Transition-metal-catalyzed
site-selective C7-functionalization of indoles: advancement and future
prospects. Chem. Commun. 2019, 55, 572−587.
(4) (a) Dalpozzo, R. Strategies for the asymmetric functionalization
of indoles: an update. Chem. Soc. Rev. 2015, 44, 742−778. (b) Mohr,
Y.; Renom-Carrasco, M.; Demarcy, C.; Quadrelli, E. A.; Camp, C.;
Wisser, F. M.; Clot, E.; Thieuleux, C.; Canivet, J. Regiospecificity in
ligand-free Pd-catalyzed C-H arylation of indoles: LiHMDS as base
and transient directing group. ACS Catal. 2020, 10, 2713−2719.
(c) Li, X.; Sun, J. Organocatalytic enantioselective synthesis of chiral
allenes: remote asymmetric 1,8-addition of indole imine methides.
Angew. Chem., Int. Ed. 2020, 59, 17049−17054. (d) Gu, G.; Huang,
M.; Kim, J. K.; Zhang, J.; Li, Y.; Wu, Y. Visible-light-induced
photocatalyst-free C-3 functionalization of indoles with diethyl
bromomalonate. Green Chem. 2020, 22, 2543−2548. (e) Choi, I.;
Messinis, A. M.; Ackermann, L. C7-Indole amidations and
alkenylations by ruthenium(II) catalysis. Angew. Chem., Int. Ed.
2020, 59, 12534−12540.
(6) (a) Durham, T. B.; Klimkowski, V. J.; Rito, C. J.; Marimuthu, J.;
Toth, J. L.; Liu, C.; Durbin, J. D.; Stout, S. L.; Adams, L.; Swearingen,
C.; Lin, C.; Chambers, M. G.; Thirunavukkarasu, K.; Wiley, M. R.
Identification of potent and selective hydantoin inhibitors of
aggrecanase-1 and aggrecanase-2 that are efficacious in both chemical
and surgical models of osteoarthritis. J. Med. Chem. 2014, 57, 10476−
̈
10485. (b) Rogawski, M. A.; Loscher, W. The neurobiology of
antiepileptic drugs. Nat. Rev. Neurosci. 2004, 5, 553−564. (c) Rodgers,
T. R.; LaMontagne, M. P.; Markovac, A.; Ash, A. B. Hydantoins as
antitumor agents. J. Med. Chem. 1977, 20, 591−594. (d) Sarges, R.;
Sehnur, R. Thienohydantoin derivatives. US Patent 4127665.
(e) Stilz, H. U.; Guba, W.; Jablonka, B.; Just, M.; Klingler, O.;
̈
Konig, W.; Wehner, V.; Zoller, G. Discovery of an orally active non-
peptide fibrinogen receptor antagonist based on the hydantoin
scaffold. J. Med. Chem. 2001, 44, 1158−1176. (f) Vazquez, J.; Garcia-
Jareno, A.; Mondragon, L.; Rubio-Martinez, J.; Perez-Paya, E.;
Albericio, F. Conformationally restricted hydantoin-based peptidomi-
metics as inhibitors of caspase-3 with basic groups allowed at the S3
enzyme subsite. ChemMedChem 2008, 3, 979−985. (g) Wang, C.;
Zhao, Q.; Vargas, M.; Jones, J. O.; White, K. L.; Shackleford, D. M.;
Chen, G.; Saunders, J.; Ng, A. C. F.; Chiu, F. C. K.; Dong, Y.;
Charman, S. A.; Keiser, J.; Vennerstrom, J. L. Revisiting the SAR of
the antischistosomal aryl hydantoin (Ro 13−3978). J. Med. Chem.
2016, 59, 10705−10718.
(7) (a) Su, M.; Xia, D.; Teng, P.; Nimmagadda, A.; Zhang, C.;
Odom, T.; Cao, A.; Hu, Y.; Cai, J. Membrane-active hydantoin
derivatives as antibiotic agents. J. Med. Chem. 2017, 60, 8456−8465.
(b) Saunthwal, R. K.; Cornall, M. T.; Abrams, R.; Ward, J. W.;
Clayden, J. Connective synthesis of 5,5-disubstituted hydantoins by
tandem -amination and α-arylation of silyl ketene acetals. Chem. Sci.
2019, 10, 3408−3412. (c) Steinmetzer, T.; Pilgram, O.; Wenzel, B.
M.; Wiedemeyer, S. J. A. Fibrinolysis inhibitors: potential drugs for
the treatment and prevention of bleeding. J. Med. Chem. 2020, 63,
1445−1472. (d) Konnert, L.; Lamaty, F.; Martinez, J.; Colacino, E.
Recent advances in the synthesis of hydantoins: the state of the art of
a valuable scaffold. Chem. Rev. 2017, 117, 13757−13809.
(8) (a) Kesicki, E. A.; Wang, C.; Patane, M. A.; Kluge, A. F.; Drie, J.
J. H. V. HAT Inhibitors and methods for their use. WO201644777,
2016. (b) Khodaee, Z.; Yahyazadeh, A.; Mahmoodi, N. O. One-pot
synthesis and characterization of some new types of 5,5′-disubstituted
bis(imidazolidine-2,4-diones). J. Heterocycl. Chem. 2013, 50, 288−
292. (c) Havera, H. J.; Strycker, W. G. Derivatives of 5-(indol-3-
yl)hydantoin U. S. Patent 4110536 A, 1978. (d) Wang, C.; Zhang, Z.;
Liu, K.; Yan, J.; Zhang, T.; Lu, G.; Meng, Q.; Chi, H.; Duan, C.
Copper-catalyzed synthesis of indolyl diketones: via C-H oxidation/
diacylation of indoles with arylglyoxal hydrates. Org. Biomol. Chem.
2017, 15, 6185−6193.
(5) (a) Festa, A. A.; Voskressensky, L. G.; Eycken, E. V. D. Visible
light-mediated chemistry of indoles and related heterocycles. Chem.
Soc. Rev. 2019, 48, 4401−4423. (b) Qiu, X.; Wang, P.; Wang, D.;
Wang, M.; Yuan, Y.; Shi, Z. PIII-chelation-assisted indole C7-arylation,
olefination, methylation, and acylation with carboxylic acids/
anhydrides by rhodium catalysis. Angew. Chem., Int. Ed. 2019, 58,
1504−1508. (c) Lv, J.; Zhao, B.; Yuan, Y.; Han, Y.; Shi, Z. Boron-
mediated directed aromatic C-H hydroxylation. Nat. Commun. 2020,
11, 1316. (d) Liu, K.; Song, W.; Deng, Y.; Yang, H.; Song, C.;
Abdelilah, T.; Wang, S.; Cong, H.; Tang, S.; Lei, A. Electrooxidation
enables highly regioselective dearomative annulation of indole and
benzofuran derivatives. Nat. Commun. 2020, 11, 3. (e) Bering, L.;
D’Ottavio, L.; Sirvinskaite, G.; Antonchick, A. P. Nitrosonium ion
catalysis: aerobic, metal-free cross-dehydrogenative carbon-hetero-
atomformation. Chem. Commun. 2018, 54, 13022−13025. (f) Agarwal,
(9) (a) Zhao, B.; Du, H.; Shi, Y. A Cu(I)-catalyzed C-H α-amination
of esters: direct synthesis of hydantoins. J. Am. Chem. Soc. 2008, 130,
7220−7221. (b) Song, J.; Zhang, Z.-J.; Chen, S.-S.; Fan, T.; Gong, L.-
Z. Lewis base/Copper cooperatively catalyzed asymmetric α-
amination of esters with diaziridinone. J. Am. Chem. Soc. 2018, 140,
3177−3180. (c) Hupp, C. D.; Tepe, J. J. 1-Ethyl-3-(3-
dimethylaminopropyl)carbodiimide hydrochloride-mediated oxazole
rearrangement: gaining access to a unique marine alkaloid scaffold. J.
Org. Chem. 2009, 74, 3406−3413. (d) Hupp, C. D.; Tepe, J. J. Total
synthesis of a marine alkaloid from the tunicate Dendrodoa grossularia.
Org. Lett. 2008, 10, 3737−3739. (e) Nakamura, S.; Furukawa, T.;
Hatanaka, T.; Funahashi, Y. Enantioselective aza-Friedel-Crafts
reaction of cyclic ketimines with indoles using chiral imidazoline-
phosphoric acid catalysts. Chem. Commun. 2018, 54, 3811−3814.
̈
̈
̈
S.; Cammerer, S.; Filali, S.; Frohner, W.; Knoll, J.; Krahl, M. P.;
̈
Reddy, K. R.; Knolker, H.-J. Novel Routes to Pyrroles, Indoles and
̈
(10) (a) Gore, S.; Baskaran, S.; Konig, B. Fischer indole synthesis in
Carbazoles - Applications in Natural Product Synthesis. Curr. Org.
Chem. 2005, 9, 1601−1614. (g) Inman, M.; Moody, C. J. Indole
synthesis - something old, something new. Chem. Sci. 2013, 4, 29−41.
(h) Gribble, G. W. Novel chemistry of indole in the synthesis of
heterocycles. Pure Appl. Chem. 2003, 75, 1417−1432. (i) Gribble, G.
W. Recent developments in indole ring synthesis-methodology and
applications. J. Chem. Soc., Perkin Trans. 2000, 1, 1045−1075.
low melting mixtures. Org. Lett. 2012, 14, 4568−457. (b) Gore, S.;
̈
Chinthapally, K.; Baskaran, S.; Konig, B. Synthesis of substituted
hydantoins in low melting mixtures. Chem. Commun. 2013, 49, 5052−
̈
5054. (c) Gore, S.; Baskaran, S.; Konig, B. Efficient synthesis of 3,4-
dihydropyrimidin-2-ones in low melting tartaric acid-urea mixtures.
Green Chem. 2011, 13, 1009−1013. (d) Liu, P.; Hao, J.-W.; Mo, L.-P.;
Zhang, Z.-H. Recent advances in the application of deep eutectic
3739
https://dx.doi.org/10.1021/acs.joc.0c02435
J. Org. Chem. 2021, 86, 3730−3740

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
solvents as sustainable media as well as catalysts in organic reactions.
RSC Adv. 2015, 5, 48675−48704.
(11) (a) Jella, R. R.; Nagarajan, R. Synthesis of indole alkaloids
arsindoline A, arsindoline B and their analogues in low melting
mixture. Tetrahedron 2013, 69, 10249−10253. (b) Chandam, D.;
Mulik, A.; Patil, P.; Jagdale, S.; Patil, D.; Sankpal, S.; Deshmukh, M.
Oxalic acid dihydrate: proline (LTTM) as a new generation solvent
for synthesis of 3,3-diaryloxindole and chromone based bis(indolyl)-
alkanes: green, chromatography free protocol. J. Mol. Liq. 2015, 207,
14−20.
(12) Wang, Q.; Tang, X.-L.; Luo, X.-C.; Voog, N. J. D.; Li, P.-L.; Li,
G.-Q. Aplysinopsin-type and bromotyrosine-derived alkaloids from
the south china sea sponge Fascaplysinopsis reticulata. Sci. Rep. 2019,
9, 2248.
(13) Yadav, J. S.; Reddy, B. V. S.; Reddy, C. S.; Krishna, A. D. CeCl3·
7H2O/IBX-promoted oxidation of 3-alkylindoles to 3-hydroxyox-
indoles. Tetrahedron Lett. 2007, 48, 2029−2032.
(14) Castillo, O. R. S.; Zavala, M. S.; Rodríguez, M. M.; Duarte, L.
E.C.; Ríos, M. S. M.; Nathan, P. J. Preparation of 3-hydroxyoxindoles
with dimethyldioxirane and their use for the synthesis of natural
products. Tetrahedron 2006, 62, 3040−3051.
(15) Bhat, V.; Allan, K. M.; Rawal, V. H. Total synthesis of N-
methylwelwitindolinone D isonitrile. J. Am. Chem. Soc. 2011, 133,
5798−5801.
(16) Kumar, C. N. S. S. P.; Devi, C. L.; Rao, V. J.; Palaniappan, S.
Use of pyridinium chlorochromate and reusable polyaniline salt
catalyst combination for the oxidation of indoles. Synlett 2008, 13,
2023−2027.
(17) (a) Breazzano, S. P.; Boger, D. L. Synthesis and stereochemical
determination of Complestatin A and B (Neuroprotectin A and B). J.
Am. Chem. Soc. 2011, 133, 18495−18502. (b) Fuchs, J. R.; Funk, R. L.
Total synthesis of ( )-Perophoramidine. J. Am. Chem. Soc. 2004, 126,
5068−5069.
(18) (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Metal-mediated
reductive hydrodehalogenation of organic halides. Chem. Rev. 2002,
102, 4009−4091. (b) Lerman, L.; Rosin, M. W.; Nudelman, A. An
improved synthesis of hydroxy indoles. Synthesis 2004, 3043−3046.
(c) Ukisu, Y.; Miyadera, T. Catalytic dechlorination of aromatic
chlorides with Pd/C catalyst in alkaline 2-propanol: activity
enhancement by the addition of methanol. React. Kinet. Catal. Lett.
2006, 89, 341−347.
(19) The similar structure of ( )-9 has been deposited by Kulkarni
in the Cambridge Crystallographic Data Centre and published with
CSD Communication in 2020: Kulkarni, A. https://www.ccdc.cam.ac.
uk/Community/csd-communications/
(20) Sathieshkumar, P. P.; Latha, P.; Nagarajan, R. Total synthesis of
Pseudellone C. Eur. J. Org. Chem. 2017, 3161−3164.
(21) Harayama, T.; Kotoji, K.; Yoneda, F.; Taga, T.; Osaki, K.;
Nagamatsu, T. Oxidation of 1, 3-dimethyl derivatives of pyrimidine
bases with m-chloroperbenzoic acid. Chem. Pharm. Bull. 1984, 32,
2056−2058.
3740
https://dx.doi.org/10.1021/acs.joc.0c02435
J. Org. Chem. 2021, 86, 3730−3740