An Efficient Approach to Functionalized Indoles from λ3-Iodanes via Acyloxylation and Acyl Transfer

Article abstract of DOI:10.1002/adsc.202000402

Versatile role of λ³-iodanes has been identified between the reaction of hydroquinone and β-enaminones for the synthesis of 5-acyloxy-4-hydroxy indoles. The reaction is proposed to proceed through an intermolecular C?C bond formation, intramole

Full text of DOI:10.1002/adsc.202000402

Title: An Efficient Approach to Functionalized Indoles from λ<sup>3</
sup>-Iodanes via Acyloxylation and Acyl Transfer
Authors: Palaniraja Jeyakannu, Gopal Chandru Senadi, Chun-Hsien
Chiang, Ganesh Kumar Dhandabani, Yu-Ching Chang, and
Jeh-Jeng Wang
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000402
Link to VoR: https://doi.org/10.1002/adsc.202000402

10.1002/adsc.202000402
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
An Efficient Approach to Functionalized Indoles from λ3-
Iodanes via Acyloxylation and Acyl Transfer
Palaniraja Jeyakannu,a,‡ Gopal Chandru Senadi,b,‡ Chun-Hsien Chiang,a Ganesh Kumar
Dhandabani,a Yu-Ching Chang,a Jeh-Jeng Wanga,c*
a Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Road, Sanmin
District, Kaohsiung City, 807 Taiwan, E-mail: jjwang@kmu.edu.tw
b Department of Chemistry, Faculty of Engineering and Technology, SRM Institute of Science and Technology,
Kattankulathur, Chennai - 603203, India
c Department of Medical Research, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Road, Sanmin District,
Kaohsiung City, 807 Taiwan
‡ These two authors contributed equally
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Versatile role of λ3-iodanes has been identified and 1,4-acyl migration. The important features of this work
between the reaction of hydroquinone and -enaminones for include various acyloxylation from λ3-iodanes and broad
the synthesis of 5-acyloxy-4-hydroxy indoles. The reaction is functional group tolerance to deliver 34 examples in
proposed to proceed through an intermolecular C-C bond moderate to good yields.
formation, intramolecular cyclization, acyloxylation
Keywords: Hydroxy indoles; 3-iodane; Nenitzescu;
acyloxylation; 1,4-acyl migration
methodology. Therefore, the development of new
synthetic transformations that allow known structures
to be made more efficiently using reagents that have
Introduction
Indoles are the most abundant class of heterocycles ready accessibility, high reactivity, impressive
found in natural products and pharmaceuticals.[1] In functional group tolerance, reduced toxicity and
particular, 5-hydroxy indoles and its methoxy environmentally benign nature is a significant area of
derivatives are known to exhibit excellent biological research.[7]
acitivties.[2,3] For examples, serotonin is an important
neurotransmitter in the central nervous system,[3a]
roxindole used in the treatment of schizophrenia,[3b]
and arbidol is used as an antiviral drug.[3c] In 1929,
Costin Nenitzescu discovered a reaction between p-
benzoquinone and -enaminoesters to synthesize 5-
hydroxy indoles and named it as Nenitzescu indole
synthesis (Scheme 1a).[4]
Since its discovery, several researchers have made
significant efforts to develop new reaction conditions
for the Nenitzescu synthesis.[5] In this context,
Kuckländer et al reported the reaction of p-
Scheme 1. Previous work on the hydroxy indole synthesis
benzoquinone with -enaminoesters using glacial
acetic to produce 5-acetoxy-4-hydroxy-indole albeit
in low yield.[6a] Subsequent studies revealed that the
Polyvalent iodine chemistry have become a
versatile and highly valuable tool in the organic
synthesis for the construction of a plethora of
bioactive natural products and heterocycles.[8] For
instances, (diacetoxyiodo)benzene (PIDA) or
carbinolamine formed in the Nenitzescu indole
synthesis was the key starting material to afford 5-
acetoxy-4-hydroxy-indoles with the external organic
acids (Scheme 1b).[6] However, the poor substrate
scope of acids and preparation of carbinolamine as a
starting material has limited the scope of this
(bis(trifluoroacetoxy)iodo)benzene
(PIFA)
have
become important reagent for the construction of N-N,
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000402
Advanced Synthesis & Catalysis
Table 1. Optimization Studiesa)
N-S, N-C and C-C bond formations under metal-free
conditions[9,10] On the other hand, several useful
methodologies have been reported for the
acetoxylation of Csp2-H/Csp3-H bonds under
transition-metals and metal-free reaction conditions
using iodobenzene diacetate,[11,12] and other
acetoxylation agents[11g,13] However, to date there is
no report using λ3-iodanes to achieve heterocyclic
ring formation, aromatic Csp2-H bond acyloxylation
and acyl migration in a cascade manner.
yieldb)
entry
solvents
temperature oC
Herein, we report the synthesis of 5-acyloxy-4-
4aa
4aa’
hydroxy-indoles in
a
one-pot fashion from
1
2
3
1,4-dioxane
Trifluorotoluene
THF
rt
rt
rt
rt
rt
25
37
32
42
36
38
-
-
-
-
hydroquinone and -enaminones (Scheme 2) through
a hypervalent iodine mediated C-C bond formation,
intramolecular cyclization, acyloxylation and
aromative 1,4-acyl migration.
4
CH3CN
traces
-
-
5
6
1,2-DCE
DCM
rt
7
DMF
rt
-
8
DMSO
rt
-
-
9
Nitromethane
MeOH
rt
rt
24
24
50
52
51
-
-
10
12
9
10
11
12c)
13d)
14e)
15e)
16e)
17e,f)
18e,g)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
80
80
80
80
60
100
80
80
88 traces
80
75
84
82
traces
traces
traces
traces
Scheme 2. This work on acyloxy-hydroxy indole synthesis
a)
Results and Discussion
All reactions were carried out using 1a (0.25mmol), 2a
(0.5 mmol) and 3a (0.5 mmol) in solvent (0.15 M) for 12 h
under air at indicated temperature unless otherwise noted. b)
The initial studies of this methodology was began
using ethyl-3-phenyl-3-(phenylamino) acrylate 1a,
hydroquinone 2a and iodobenzene diacetate (PIDA)
3a in 1,4 dioxane at room temperature under air for
12 h (Table 1). Interestingly, the 5-acetoxy-4-hydroxy
indole compound 4aa was obtained in 25% yield
(Table 1, entry 1). Changing the solvent from 1,4-
dioxane to other solvents like trifluorotoluene, THF,
CH3CN, 1,2-DCE, DCM, DMF, DMSO, CH3NO2 and
MeOH (Table 1, entries 2-10) disclosed CH3CN as
the choice of solvent by affording compound 4aa in
42% yield along with traces of hydroxy indole 4aa’
(Table 1, entry 3). Increasing the temperature to 80 oC
slightly improved the yield of 4aa and 10% of 4aa’
(Table 1, entry 11). The structure of compound 4aa
and 4aa’ was confirmed by X-ray analysis.[14]
No substantial improvement in the yield under
oxygen and nitrogen atmosphere as compared to open
air (Table 1, entries 12-13). Surprisingly, compound
4aa was produced in 88% yield when the reaction
was performed in a sealed tube with traces of 4aa’
(Table 1, entry 14). The probable reason for the yield
improvement can be attributed to the pressure
developed inside the sealed tube. Either decreasing or
increasing the reaction temperature led to a lower
reaction yield (Table 1, entries 15-16). Replacing,
PIDA with electron donating and electron-
withdrawing 3-iodanes did not improve the yield of
4aa (Table 1, entries 17-18). Thus of the conditions
screened, Table 1, entry 14 is chosen as the optimized
conditions for further studies.
c)
Isolated yield.
Reaction was performed under O2
d)
atmosphere.
Reaction was performed under N2
atmosphere. Reaction was performed in a sealed tube.
1-(diacetoxyiodo)-4-methylbenzene was used instead of
e)
f)
g)
PIDA. 4-(diacetoxyiodo)benzonitrile was used instead of
PIDA. Traces refers to less than 5% of 4aa’
The scope and limitations of this work were tested
by performing the acyloxylation and 1,4-acyl
migration under the optimized conditions with 15
different 3-iodane derivatives (Table 2). A series of
3-iodanes functionalities on R2 group like ethyl- (3b)
tert-butyl-
methylcyclohexyl- (3e) were reacted with ethyl-3-
phenyl-3-(phenylamino) acrylate 1a and
(3c),
cyclohexyl-
(3d),
and
hydroquinone 2a. The desired products 4ab-ae were
obtained smoothly in 65-79% yields. The structure of
compound 4ab was confirmed unambiguously with
the help of single crystal X-ray analysis (Fig.1).[14]
Then, the feasibility of the reaction was examined
with phenyl (3f), 3-MeO-C6H4- (3g), 4-MeO-C6H4-
(3h) and 4-NO2-C6H4- (3i). The reaction worked in all
the cases irrespective or electronic and steric factors
to afford the required products 4af-ai in 60-71%
yields. Of note, the reaction worked well with benzyl
(3j), but-1-enyl- (3k) cinnamyl- (3l) and FMOC-NH-
CH2- (3m) to produce the desired product 4aj-am in
40-81% yields. However, the reaction did not create
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000402
Advanced Synthesis & Catalysis
the acyloxylation products 4an-4ao with trifluoro- methoxy phenyl- (1t) and methyl- (1u). The reaction
(3n), 2-furanyl- (3o) and 2-benzofuranyl- (3p).
proceeded finely to afford the corresponding
compounds 4ta and 4ua in 56-68% yields. By
Table 2. Scope and limitations of -Iodanes for
utilizing
this
strategy,
the
synthesis
of
acyloxylation and 1,4-acyl migrationa,b)
tetrahydrocarbazole framework 4va was successfully
accomplished with 66% yield using cyclic -
enaminones 1v. However, the reaction failed to form
the products 4wa-ya using 2-bromobenzene-1,4-diol
(2b), 1,4-dihydroxynaphthalene (2c) and phenol (2d).
The probable reason could be the rapid decomposition
of the substrates under the standard conditions. In
general, N-alkyl enaminoesters gave better reaction
yields than N-aryl enaminoesters.
Table 3. Scope and limitations of -enaminonesa,b)
a) Reactions was performed in sealed tube. b) Isolated yields.
c) Fluorenylmethyloxycarbonyl (Fmoc)
To illustrate the generality of this methodology, a
series of N-substituted β-enaminones 1b-v were
reacted with hydroquinones 2a-d and PIDA 3a under
the standard reaction conditions (Table 3). An array
of
ethyl
5-acetoxy-4-hydroxy-1H-indole-3-
carboxylate derivatives 4ba-ya was obtained in 51-
81% yields. The reaction proceeded smoothly with R-
functionalities like 2-Et-Ph- (1b), 4-Et-Ph- (1c), 4-
MeO-Ph- (1d), 2,4-di-Me-Ph- (1e), 3,4-di-Me-Ph-
(1f), 3,4-di-MeO-Ph- (1g) to afford product 4ba-ga in
60%-81% yields. When the phenyl group on R-
functionality was attached with halogens like 3-Cl-
(1h), 4-F- (1i), 4-CF3- (1j), and 2,4-di-Cl- (1k) the
yields were slightly suppressed. The reaction
underwent smooth conversion with the R- groups
bearing aliphatic substrates such as n-propyl- (1l), n-
butyl- (1m) and cyclohexyl- (1n) to afford the desired
compounds 4la-na in 74-80% yields. Further
scrutinization of R- groups bearing allyl- (1o), benzyl-
(1p), aryl ethyl- (1q) and 2-(1H-Indol-1-yl) ethyl-
(1r) groups also delivered the expected products in
75-81% yields. Next, the scope of R1- was
investigated by replacing the phenyl group with 4-
a)
Reaction Conditions: Reactions was performed in sealed
tube. b) Isolated yields.
To gain insights into the reaction mechanisms, few
control studies were performed as presented in
Scheme 3. Radical inhibition studies using TEMPO
(2.0 equiv.) and 1, 4-cyclohexadiene (CHD) (2.0
equiv.) under standard conditions gave the desired
compound 4aa in 71% and 67% yields suggesting
that the reaction proceeds via a non-radical pathway
(Scheme 3a). Next, reaction was performed with
benzoquinone 2a’ under the standard reaction
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000402
Advanced Synthesis & Catalysis
iodane gave the intermediate A.[17] Subsequent
reaction of intermediate A with -enaminones 1
resulted in the C-C bond intermediate B.[17]
Intramolecular cyclization of
B
followed by
electrophilic substitution of hydroxy intermediate C
to3-iodane produced the intermediate D.
Elimination of iodobenzene and acid from D afforded
the
carbinolamine
intermediate
7a-hydroxy-
dihyroindole compound E. Acid mediated elimination
of water followed by an in situ aza Michael attack of
carboxylate ion produced the 4-acyloxy product G[6]
through intermediate F. Aromative 1,4-acyl migration
of intermediate G afforded the 5-acyloxy-4-hydroxy
indole derivatives 4. The probable reason for these
migration may be attributed to the formation of stable
hydrogen bonding with the ester group.[6]
Figure 1. X-ray data for compounds 4aa, 4aa’ and 4ab
conditions, considering that hydroquinone can
undergo oxidation to benzoquinone using PIDA.[15]
(Scheme 2b). But the desired product 4aa was not
formed, instead an intramolecular cyclization reaction
of -enaminoester resulted in the formation of
indole.[9f,16] When the reaction was carried out with
hydroxy indole 4aa’ under the standard conditions,
the expected acyloxy-hydroxy-indole 4aa was not
formed (Scheme 2c). This results suggest that the
Nenitzescu product 4aa’ was not the desired
intermediate.
Scheme 4. Plausible Mechanistic Rationale
The synthetic feasibility of the reaction has been
demonstrated on a 2.5 mmol scale for the synthesis of
compound 4aa and 4ga under the standard conditions
as shown in Scheme 5a. The reaction proceeded
smoothly in both the cases with no loss in the product
yields. The synthetic application has been extended to
synthesize bioactive dihydroxy indoles.[18] As a proof
of concept, compound 5ga was prepared under basic
hydrolysis of 4ga (Scheme 5b).
Scheme 3. Control Experiments
A plausible mechanism was proposed in Scheme 4
based on the control experiments. The initial
electrophilic substitution of hydroquinone to-
Scheme 5. Scaleup Feasibility and Hydrolysis Reactions
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000402
Advanced Synthesis & Catalysis
NMR (400 MHz, CDCl3) δ 11.66 (s, 1H), 7.38 – 7.30 (m,
3H), 7.31 – 7.26 (m, 2H), 7.26 – 7.23 (m, 1H), 7.23 – 7.19
(m, 2H), 7.15 (ddd, J = 6.5, 4.6, 2.9 Hz, 2H), 6.93 (d, J =
8.7 Hz, 1H), 6.58 (d, J = 8.7 Hz, 1H), 4.11 (q, J = 7.1 Hz,
Conclusion
We have developed an efficient method for the
synthesis of 5-acyloxy-4-hydroxy indoles from 2H), 2.71 (tt, J = 11.2, 3.6 Hz, 1H), 2.24 – 2.12 (m, 2H),
hydroquinone and -enaminones with 3-iodanes.
1.93 – 1.82 (m, 2H), 1.73 (dd, J = 19.3, 7.6 Hz, 3H), 1.49 –
1.23 (m, 4H), 0.90 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
Control experiment studies were useful in proposing a
CDCl3) δ 174.95, 168.35, 146.45, 142.62, 137.19, 136.46,
new reaction pathway for the first time using 3-
132.66, 131.51, 130.69, 129.15, 128.37, 128.32, 127.32,
119.72, 116.28, 106.21, 101.49, 61.01, 43.12, 29.14, 28.80,
25.83, 25.66, 25.45, 25.31, 13.38; HRMS (ESI): [M+H]+
calcd. for C30H30NO5: 484.2118, found 484.2116.
iodanes. Thirteen acyloxy functional group transfer
followed by acyl migration with different electronic
and steric properties has been accomplished. The
synthetic utility of the product was extended by
preparing 4,5-dihydroxy indole through ester
hydrolysis.
Ethyl 5-(2-cyclohexylacetoxy)-4-hydroxy-1,2-diphenyl-
1H-indole-3-carboxylate (4ae). Following the general
procedure, the title compound was obtain as a brown solid.
o
1
(98 mg, yield = 79 %); Mp. 152-154 C; H NMR (400
MHz, CDCl3) δ 11.99 – 11.22 (s, 1H), 7.43 – 7.10 (m,
10H), 6.96 – 6.89 (m, 1H), 6.58 (d, J = 8.7 Hz, 1H), 4.11 (q,
J = 7.1 Hz, 2H), 2.55 (d, J = 7.0 Hz, 2H), 2.14 – 1.88 (m,
3H), 1.86 – 1.64 (m, 4H), 1.46 – 1.03 (m, 4H), 0.90 (t, J =
7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.95,
168.38, 146.51, 142.67, 137.23, 136.42, 132.56, 131.48,
130.68, 129.17, 128.40, 128.37, 128.35, 127.33, 119.75,
116.27, 106.23, 101.54, 61.04, 42.01, 35.12, 33.04, 26.23,
26.11, 13.38; HRMS (ESI): [M+H]+ calcd. for C31H32NO5:
498.2275, found 498.2274.
Experimental Section
To the stirred solution of 1a-v (0.25 mmol, 1.0 equiv.) and
2a-d (0.5 mmol, 2.0 equiv.) in 0.15 M of acetonitrile was
added 3a-p (0.5 mmol, 2.0 equiv.) at room temperature and
o
the mixture was heated at 80 C in a sealed tube. After
completion by TLC, the reaction mixture was diluted with
water and extracted with ethylacetate. Combined organic
layer was washed with water, brine, dried over sodium
sulfate and evaporated under reduced pressure. The
obtained crude products were purified by column
chromatography using ethyl acetate and hexane as the
eluent to afford the pure compounds 4aa-4ya.
Ethyl
5-(benzoyloxy)-4-hydroxy-1,2-diphenyl-1H-
indole-3-carboxylate (4af). Following the general
procedure, the title compound was obtain as a brown solid.
o
1
(71 mg, yield = 60 %); Mp. 213-215 C; H NMR (400
MHz, CDCl3) δ 11.74 (d, J = 0.4 Hz, 1H), 8.37 – 8.25 (m,
2H), 7.66 – 7.59 (m, 1H), 7.56 – 7.48 (m, 2H), 7.38 – 7.29
(m, 3H), 7.29 – 7.18 (m, 6H), 7.18 – 7.13 (m, 2H), 7.05 (dd,
J = 8.7, 0.4 Hz, 1H), 6.62 (d, J = 8.7 Hz, 1H), 4.08 (q, J =
7.1 Hz, 2H), 0.88 (dd, J = 9.3, 5.0 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 168.33, 165.52, 146.53, 142.83, 137.35,
136.45, 133.20, 132.68, 131.49, 130.70, 130.36, 129.80,
129.19, 128.39, 127.34, 119.74, 116.37, 106.32, 101.67,
61.05, 13.38; HRMS (ESI): [M+H]+ calcd. for C30H24NO5:
478.1649, found 478.1646.
Ethyl 5-acetoxy-4-hydroxy-1,2-diphenyl-1H-indole-3-
carboxylate (4aa). Following the general procedure, the
title compound was obtain as a white solid. (84 mg, yield =
o
1
88 %); Mp. 168-169 C; H NMR (400 MHz, CDCl3) δ
11.75 (s, 1H), 7.38 – 7.29 (m, 3H), 7.30 – 7.17 (m, 6H),
7.17 – 7.10 (m, 2H), 6.95 (d, J = 8.7 Hz, 1H), 6.58 (d, J =
8.7 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 2.40 (s, 3H), 0.89 (t,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.98,
168.37, 146.59, 142.59, 137.28, 136.39, 132.53, 131.44,
130.65, 129.18, 128.42, 128.37, 128.35, 127.34, 119.61,
116.27, 106.26, 101.63, 61.07, 20.79, 13.37; HRMS (EI)
[M]+ calcd. for C25H21NO5: 415.1420, found 415.1425.
Ethyl
4-hydroxy-5-((3-methoxybenzoyl)oxy)-1,2-
diphenyl-1H-indole-3-carboxylate (4ag). Following the
general procedure, the title compound was obtain as a
brown solid. (89 mg, yield = 71 %); Mp. 177-179 oC; H
1
Ethyl
4-hydroxy-1,2-diphenyl-5-(propionyloxy)-1H-
NMR (400 MHz, CDCl3) δ 11.75 (t, J = 1.9 Hz, 1H), 7.99
– 7.88 (m, 1H), 7.83 (dd, J = 2.6, 1.5 Hz, 1H), 7.43 (t, J =
8.0 Hz, 1H), 7.38 – 7.31 (m, 3H), 7.31 – 7.26 (m, 2H), 7.26
– 7.22 (m, 3H), 7.22 – 7.15 (m, 4H), 7.09 – 7.03 (m, 1H),
6.62 (t, J = 9.7 Hz, 1H), 4.10 (dt, J = 10.2, 5.6 Hz, 2H),
3.91 (s, 3H), 0.89 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 168.32, 165.36, 159.56, 146.54, 142.82, 137.36,
136.45, 132.69, 131.48, 131.07, 130.70, 129.41, 129.19,
128.39, 128.37, 127.34, 122.88, 120.12, 119.69, 116.37,
114.37, 106.32, 101.67, 61.05, 55.50, 13.38; HRMS (ESI):
[M+H]+ calcd. for C31H26NO6: 508.1754, found 508.1755.
indole-3-carboxylate (4ab). Following the general
procedure, the title compound was obtain as a brown solid.
o
1
(83 mg, yield = 78 %); Mp. 162-163 C; H NMR (400
MHz, CDCl3) δ 11.69 (s, 1H), 7.36 – 7.28 (m, 3H), 7.28 –
7.16 (m, 5H), 7.15 – 7.11 (m, 2H), 6.93 (dd, J = 8.7, 0.5 Hz,
1H), 6.56 (d, J = 8.7 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 2.76
– 2.62 (m, 2H), 1.32 (t, J = 7.6 Hz, 3H), 0.87 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 173.40, 168.36,
146.52, 142.60, 137.23, 136.42, 132.60, 131.47, 130.67,
129.16, 128.40, 128.36, 127.33, 119.66, 116.28, 106.24,
101.57, 61.04, 27.45, 13.37, 9.29; HRMS (ESI): [M+H]+
calcd. for C26H24NO5: 430.1649, found 430.1651.
Ethyl
4-hydroxy-5-((4-methoxybenzoyl)oxy)-1,2-
diphenyl-1H-indole-3-carboxylate (4ah). Following the
Ethyl
4-hydroxy-1,2-diphenyl-5-(pivaloyloxy)-1H-
general procedure, the title compound was obtain as a
indole-3-carboxylate (4ac). Following the general
brown solid. (78 mg, yield = 62 %); Mp. 178-180 oC; H
1
procedure, the title compound was obtain as an off white
1
NMR (400 MHz, CDCl3) δ 10.10 (s, 1H), 8.06 (m, 1H),
7.91 – 7.78 (m, 2H), 7.42 – 7.30 (m, 2H), 7.25 – 7.19 (m,
3H), 7.07 – 7.01 (m, 2H), 6.88 – 6.82 (m, 2H), 6.66 – 6.60
(m, 2H), 4.27 (m, 2H), 3.83 (s, 3H), 1.24 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 167.70, 166.19,
165.76, 163.46, 150.92, 140.05, 134.14, 132.32, 131.94,
131.74, 129.28, 129.17, 129.12, 128.77, 128.59, 128.19,
122.80, 121.87, 121.77, 115.42, 113.81, 113.49, 74.75,
62.43, 60.40, 55.38, 30.30, 14.30; HRMS (ESI): [M+H]+
calcd. for C31H26NO6: 508.1754, found 508.1754.
solid. (74 mg, yield = 65 %); Mp. 128-130 oC; H NMR
(400 MHz, CDCl3) δ 11.57 (s, 1H), 7.37 – 7.29 (m, 3H),
7.28 – 7.19 (m, 5H), 7.17 – 7.12 (m, 2H), 6.90 (d, J = 8.7,
1H), 6.56 (d, J = 8.7 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 1.45
(s, 9H), 0.89 (t, J = 7.6, 3H); 13C NMR (100 MHz, cdcl3) δ
177.42, 168.34, 146.41, 142.66, 137.19, 136.49, 132.90,
131.53, 130.71, 129.15, 128.39, 128.37, 128.30, 127.31,
119.64, 116.31, 106.20, 101.43, 60.99, 39.09, 27.36, 13.39;
HRMS (ESI): [M+H]+ calcd. for C28H28NO5: 458.1962,
found 458.1961.
Ethyl 4-hydroxy-5-((4-nitrobenzoyl)oxy)-1,2-diphenyl-
1H-indole-3-carboxylate (4ai). Following the general
procedure, the title compound was obtain as a brown solid.
Ethyl
5-((cyclohexanecarbonyl)oxy)-4-hydroxy-1,2-
diphenyl-1H-indole-3-carboxylate (4ad). Following the
general procedure, the title compound was obtain as a
o
1
brown solid. (84 mg, yield = 70 %); Mp. 145-148 oC; H
1
(86 mg, yield = 66 %); Mp. 215-217 C; H NMR (400
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000402
Advanced Synthesis & Catalysis
MHz, CDCl3) δ 12.06 – 11.61 (m, 1H), 8.56 – 8.45 (m, 2H), (ESI): [M+H]+ calcd. for C40H33N2O7: 653.2282, found
8.43 – 8.34 (m, 2H), 7.43 – 7.32 (m, 3H), 7.33 – 7.15 (m, 653.2284.
8H), 7.11 – 7.04 (m, 1H), 6.66 (d, J = 8.7 Hz, 1H), 4.11 (q,
J = 7.1 Hz, 2H), 0.90 (t, J = 7.1 Hz, 3H); 13C NMR (100
Ethyl 5-acetoxy-1-(2-ethylphenyl)-4-hydroxy-2-phenyl-
MHz, CDCl3) δ 168.38, 163.64, 150.68, 146.77, 142.63,
1H-indole-3-carboxylate (4ba). Following the general
137.51, 136.32, 135.31, 132.32, 131.46, 131.31, 130.66,
procedure, the title compound was obtain as a white solid
o
1
129.25, 128.51, 128.48, 128.35, 127.39, 123.56, 119.23,
116.39, 106.34, 101.83, 61.17, 13.37. HRMS (ESI):
[M+H]+ calcd. for C30H23N2O7: 523.1499, found 523.1500.
(66 mg, yield = 60 %); Mp. 180-182 C; H NMR (400
MHz, CDCl3) δ 11.73 (s, 1H), 7.37 – 7.16 (m, 9H), 7.12
(dd, J = 7.8, 1.2 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 6.32 (d,
J = 8.7 Hz, 1H), 4.18 – 4.03 (m, 2H), 2.40 (s, 3H), 2.31 –
Ethyl 4-hydroxy-1,2-diphenyl-5-(2-phenylacetoxy)-1H- 2.12 (m, 2H), 1.02 (t, J = 7.6 Hz, 3H), 0.90 (t, J = 7.1 Hz,
indole-3-carboxylate (4aj). Following the general 3H); 13C NMR (100 MHz, CDCl3) δ 169.91, 168.42, 146.79,
procedure, the title compound was obtain as an off white 142.54, 142.07, 137.40, 134.54, 132.50, 131.27, 130.41,
1
solid. (95 mg, yield = 78 %); Mp. 160-162 oC; H NMR 129.70, 129.39, 128.86, 128.47, 127.20, 126.44, 119.59,
(400 MHz, CDCl3) δ 11.70 (s, 1H), 7.53 – 7.42 (m, 2H), 116.20, 105.99, 101.75, 61.02, 23.23, 20.81, 13.90, 13.39;
7.41 – 7.32 (m, 2H), 7.34 – 7.14 (m, 9H), 7.16 – 7.07 (m, HRMS (EI) [M]+ calcd. for C27H25NO5: 443.1733, found
2H), 6.91 – 6.85 (m, 1H), 6.53 (d, J = 8.7 Hz, 1H), 4.08 (q, 443.1737.
J = 7.1 Hz, 2H), 3.98 (s, 2H), 0.87 (t, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 170.36, 168.36, 146.55, 142.64,
Ethyl 5-acetoxy-1-(4-ethylphenyl)-4-hydroxy-2-phenyl-
1H-indole-3-carboxylate (4ca). Following the general
137.27, 136.38, 133.97, 132.60, 131.43, 130.66, 129.45,
129.16, 128.52, 128.41, 128.34, 127.33, 127.00, 119.53,
procedure, the title compound was obtain as an off white
1
solid (72 mg, yield = 65 %); Mp. 155-157 oC; H NMR
(400 MHz, CDCl3) δ 11.76 (s, 1H), 7.31 – 7.23 (m, 4H),
7.23 – 7.19 (m, 2H), 7.15 (t, J = 5.4 Hz, 2H), 7.07 – 7.02
116.26, 106.24, 101.52, 61.06, 41.01, 13.37. HRMS (ESI):
[M+H]+ calcd. for C31H26NO5: 492.1805, found 492.1805.
Ethyl 4-hydroxy-5-(pent-4-enoyloxy)-1,2-diphenyl-1H- (m, 2H), 6.95 (d, J = 8.7 Hz, 1H), 6.59 (d, J = 8.7 Hz, 1H),
indole-3-carboxylate (4ak). Following the general 4.11 (q, J = 7.1 Hz, 2H), 2.74 – 2.56 (m, 2H), 2.41 (s, 3H),
procedure, the title compound was obtain as an off white 1.23 (t, J = 7.6 Hz, 3H), 0.89 (t, J = 7.1 Hz, 3H); 13C NMR
1
solid. (82 mg, yield = 72 %); Mp. 192-194 oC; H NMR (100 MHz, CDCl3) δ 169.98, 168.40, 146.70, 144.49,
(400 MHz, CDCl3) δ 11.70 (s, 1H), 7.36 – 7.28 (m, 3H), 142.53, 137.42, 133.86, 132.46, 131.56, 130.66, 128.53,
7.28 – 7.16 (m, 5H), 7.15 – 7.10 (m, 2H), 6.92 (d, J = 8.7 128.34, 128.09, 127.30, 119.48, 116.25, 106.08, 101.77,
Hz, 1H), 6.56 (d, J = 8.7 Hz, 1H), 5.97 (ddt, J = 16.8, 10.2, 61.01, 28.36, 20.79, 15.10, 13.37; HRMS (EI) [M]+ calcd.
6.4 Hz, 1H), 5.16 (dq, J = 17.1, 1.6 Hz, 1H), 5.06 (ddd, J = For C27H25NO5: 443.1733, found 443.1736.
10.2, 2.9, 1.3 Hz, 1H), 4.08 (q, J = 7.1 Hz, 2H), 2.76 (dd, J
= 8.2, 6.7 Hz, 2H), 2.58 (dt, J = 8.2, 6.6 Hz, 2H), 0.87 (t, J
Ethyl
5-acetoxy-4-hydroxy-1-(4-methoxyphenyl)-2-
= 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 171.95,
168.35, 146.54, 142.58, 137.23, 136.72, 136.38, 132.50,
131.42, 130.65, 129.16, 128.40, 128.34, 127.32, 119.62,
116.25, 115.55, 101.57, 61.04, 33.39, 29.09, 13.36. HRMS
(ESI): [M+H]+ calcd. for C28H26NO5: 456.1805, found
456.1804.
phenyl-1H-indole-3-carboxylate (4da). Following the
general procedure, the title compound was obtain as an off
o
1
white solid (88 mg, yield = 80 %); Mp. 175-177 C; H
NMR (400 MHz, CDCl3) δ 11.73 (s, 1H), 7.32 – 7.22 (m,
4H), 7.19 (dd, J = 7.9, 1.6 Hz, 2H), 7.08 – 7.01 (m, 2H),
6.94 (d, J = 8.7 Hz, 1H), 6.87 – 6.78 (m, 2H), 6.55 (d, J =
8.7 Hz, 1H), 4.21 – 3.96 (m, 2H), 3.79 (s, 3H), 2.40 (s, 3H),
Ethyl
5-(cinnamoyloxy)-4-hydroxy-1,2-diphenyl-1H- 0.88 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
indole-3-carboxylate (4al). Following the general 170.00, 168.39, 159.19, 142.56, 137.64, 132.48, 131.60,
procedure, the title compound was obtain as an off white 130.64, 129.44, 129.04, 128.36, 127.36, 119.52, 116.18,
solid. (102 mg, yield = 81 %); Mp. 191-192 oC; H NMR 114.33, 114.29, 114.28, 106.02, 101.68, 77.31, 77.00,
1
(400 MHz, CDCl3) δ 11.81 (s, 1H), 7.98 (d, J = 16.0 Hz, 76.68, 61.01, 55.39, 20.79, 13.38; HRMS (ESI): [M+H]+
1H), 7.63 (dt, J = 5.5, 3.6 Hz, 2H), 7.48 – 7.40 (m, 3H), calcd. for C26H24NO6: 446.1598, found 446.1596.
7.39 – 7.31 (m, 3H), 7.31 – 7.20 (m, 5H), 7.20 – 7.14 (m,
2H), 7.07 – 7.02 (m, 1H), 6.80 (d, J = 16.0 Hz, 1H), 6.63 (d,
Ethyl
5-acetoxy-1-(2,4-dimethylphenyl)-4-hydroxy-2-
J = 8.7 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 0.90 (t, J = 7.1
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 168.35, 165.80,
146.54, 146.19, 142.72, 137.30, 136.42, 134.47, 132.48,
131.47, 130.68, 130.37, 129.19, 128.87, 128.41, 128.37,
128.27, 127.34, 119.73, 117.45, 116.32, 106.31, 101.68,
13.37; HRMS (ESI): [M+Na]+ calcd. for C32H25NNaO5:
526.1624, found 526.1625.
phenyl-1H-indole-3-carboxylate (4ea). Following the
general procedure, the title compound was obtain as an off
o
1
white solid (78 mg, yield = 71 %); Mp. 152-154 C; H
NMR (400 MHz, CDCl3) δ 11.72 (s, 1H), 7.36 – 7.17 (m,
6H), 7.03 – 6.86 (m, 4H), 6.31 (d, J = 8.7 Hz, 1H), 4.16 –
4.03 (m, 2H), 2.39 (s, 3H), 2.30 (s, 3H), 1.89 (s, 3H), 0.89
(t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.44,
168.93, 147.29, 143.07, 139.52, 137.50, 136.47, 133.09,
Ethyl 5-(((((9H-fluoren-9-yl)methoxy)carbonyl)glycyl) 132.97, 132.08, 131.95, 130.81, 129.76, 128.94, 127.83,
oxy)-4-hydroxy-1,2-diphenyl-1H-indole-3-carboxylate
127.74, 120.05, 116.76, 106.33, 102.19, 61.49, 21.59,
(4am). Following the general procedure, the title 21.32, 17.97, 13.90; HRMS (EI): [M]+ calcd. for
compound was obtain as a brown solid. (65 mg, yield = C27H25NO5: 443.1733 found 443.1731.
1
40 %); Mp. 182-184 oC; H NMR (400 MHz, CDCl3) δ
11.81 (s, 1H), 11.69 (s, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.61
Ethyl
5-acetoxy-1-(3,4-dimethylphenyl)-4-hydroxy-2-
(t, J = 9.9 Hz, 1H), 7.48 (dd, J = 11.2, 9.8 Hz, 1H), 7.38
(ddd, J = 9.0, 8.4, 6.0 Hz, 2H), 7.36 – 7.26 (m, 5H), 7.28 –
7.19 (m, 4H), 7.21 – 7.14 (m, 2H), 7.16 – 7.07 (m, 2H),
7.03 – 6.84 (m, 1H), 6.55 (dd, J = 17.2, 8.7 Hz, 1H), 5.45
(dd, J = 57.9, 52.7 Hz, 1H), 4.41 (dd, J = 9.3, 6.4 Hz, 2H),
4.25 (dd, J = 20.5, 13.2 Hz, 1H), 4.09 (qd, J = 7.1, 2.8 Hz,
2H), 3.98 (s, 1H), 0.88 (t, J = 7.1Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 170.39, 169.05, 168.38, 168.37, 156.27,
146.73, 146.55, 143.82, 142.63, 142.42, 141.24, 137.42,
137.27, 136.38, 136.29, 133.96, 132.60, 132.12, 131.43,
131.31, 130.66, 130.64, 129.45, 129.22, 129.16, 128.52,
128.48, 128.45, 128.41, 128.34, 128.33, 127.64, 127.37,
127.33, 127.06, 127.00, 125.16, 119.91, 119.53, 119.28,
116.29, 116.26, 116.07, 106.27, 106.24, 101.77, 101.53,
67.25, 61.15, 61.06, 47.09, 42.77, 41.01, 13.37; HRMS
phenyl-1H-indole-3-carboxylate (4fa). Following the
general procedure, the title compound was obtain as an off
o
1
white solid (88 mg, yield = 81 %); Mp. 152-154 C; H
NMR (400 MHz, CDCl3) δ 11.90 (s, 1H), 7.31 – 7.26 (m,
1H), 7.26 – 7.21 (m, 2H), 7.19 (dd, J = 7.9, 1.4 Hz, 2H),
7.04 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 9.0 Hz, 2H), 6.81 (d, J
= 8.0 Hz, 1H), 6.56 (d, J = 8.7 Hz, 1H), 4.08 (q, J = 7.1 Hz,
2H), 2.39 (s, 3H), 2.21 (s, 3H), 2.17 (s, 3H), 0.86 (t, J = 7.1
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 177.42, 168.34,
146.41, 142.66, 137.19, 136.49, 132.90, 131.53, 130.71,
129.15, 128.39, 128.37, 128.30, 127.31, 119.64, 116.31,
106.20, 101.43, 60.99, 39.09, 30.30, 27.36, 27.00, 13.39;
HRMS (ESI): [M+H]+ calcd. for C27H26NO5: 444.1805
found: 444.1804.
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000402
Advanced Synthesis & Catalysis
Ethyl 5-acetoxy-1-(3,4-dimethoxyphenyl)-4-hydroxy-2- 7.33 – 7.27 (m, 2H), 7.01 (d, J = 8.7 Hz, 1H), 6.81 (d, J =
phenyl-1H-indole-3-carboxylate (4ga). Following the 8.7 Hz, 1H), 4.00 (q, J = 7.1 Hz, 2H), 3.86 – 3.71 (m, 2H),
general procedure, the title compound was obtain as a 2.38 (s, 3H), 1.68 (dd, J = 15.2, 7.5 Hz, 3H), 0.78 (t, J =
1
brown solid (71 mg, yield = 60 %); Mp. 144-145 oC; H 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 169.97, 168.19,
NMR (400 MHz, CDCl3) δ 11.76 (s, 1H), 7.36 – 7.24 (m, 146.56, 142.76, 135.43, 132.12, 131.95, 129.92, 128.85,
3H), 7.21 (d, J = 6.8 Hz, 2H), 6.97 (d, J = 8.7 Hz, 1H), 6.84 127.90, 119.13, 116.59, 105.19, 100.73, 60.69, 45.99,
– 6.75 (m, 2H), 6.70 – 6.62 (m, 1H), 6.57 (d, J = 2.1 Hz, 22.88, 20.78, 13.25, 11.23; HRMS (ESI): [M+H]+ calcd.
1H), 4.19 – 4.04 (m, 2H), 3.88 (s, 3H), 3.69 (s, 3H), 2.41 (s, for C22H24NO5: 382.1649, found 382.1651.
3H), 0.89 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 170.07, 168.36, 149.00, 148.69, 146.72, 142.55, 137.40,
Ethyl 5-acetoxy-1-butyl-4-hydroxy-2-phenyl-1H-indole-
132.45, 131.65, 130.53, 129.08, 128.42, 127.38, 120.53,
3-carboxylate (4ma). Following the general procedure, the
119.56, 116.16, 116.03, 111.54, 110.71, 106.00, 101.70,
title compound was obtain as an off white solid. (74mg,
61.05, 55.92, 55.89, 20.77, 13.36; HRMS (EI): [M]+ calcd.
for C27H25NO7: 475.1631, found 475.1625.
o
1
yield = 75 %); Mp. 122-124 C; H NMR (400 MHz,
CDCl3) δ 11.89 (s, 1H), 7.51 – 7.40 (m, 3H), 7.32 – 7.27
(m, 2H), 7.04 – 6.97 (m, 1H), 6.81 (d, J = 8.7 Hz, 1H), 3.99
Ethyl
5-acetoxy-1-(3-chlorophenyl)-4-hydroxy-2- (q, J = 7.1 Hz, 2H), 3.88 – 3.74 (m, 2H), 2.38 (s, 3H), 1.65
phenyl-1H-indole-3-carboxylate (4ha). Following the – 1.59 (m, 2H), 1.17 (m, 2H), 0.78 (m, 6H); 13C NMR
general procedure, the title compound was obtain as a (100 MHz, CDCl3) δ 170.00, 168.20, 146.52, 142.79,
brown solid (68 mg, yield = 61 %); Mp. 153-155 oC; H 135.42, 132.13, 131.96, 129.94, 128.86, 127.91, 119.15,
1
NMR (400 MHz, CDCl3) δ 11.70 (s, 1H), 7.34 – 7.23 (m, 116.62, 105.19, 100.71, 60.70, 44.18, 31.60, 20.80, 19.91,
5H), 7.23 – 7.14 (m, 3H), 7.02 – 6.98 (m, 1H), 6.96 (d, J = 13.46, 13.27; HRMS (ESI): [M+H]+ calcd. for C23H26NO5:
8.7 Hz, 1H), 6.58 (d, J = 8.7 Hz, 1H), 4.15 – 4.03 (m, 2H), 396.1805, found 396.1804.
2.39 (s, 3H), 0.87 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 169.92, 168.22, 146.31, 142.72, 137.55, 137.00,
Ethyl 5-acetoxy-1-cyclohexyl-4-hydroxy-2-phenyl-1H-
134.76, 132.73, 131.06, 130.58, 130.17, 128.72, 128.69,
indole-3-carboxylate (4na). Following the general
128.57, 127.54, 126.66, 119.91, 116.25, 106.77, 101.34,
procedure, the title compound was obtain as an off white
61.20, 20.77, 13.35; HRMS (EI): [M]+ calcd. for
C25H20ClNO5: 449.1030, found 449.1033.
o
1
solid. (78mg, yield = 74 %); Mp. 184-186 C; H NMR
(400 MHz, CDCl3) δ 11.84 (s, 1H), 7.54 – 7.40 (m, 3H),
7.27 – 7.23 (m, 2H), 7.08 (d, J = 8.8 Hz, 1H), 6.96 (d, J =
Ethyl 5-acetoxy-1-(4-fluorophenyl)-4-hydroxy-2-phenyl- 8.8 Hz, 1H), 3.96 (q, J = 7.1 Hz, 2H), 3.84 (s, 1H), 2.39 (s,
1H-indole-3-carboxylate (4ia). Following the general 3H), 1.91 – 1.71 (m, 4H), 1.60 (s, 2H), 1.36 – 0.97 (m, 4H),
procedure, the title compound was obtain as a brown solid. 0.75 (t, J = 7.1 Hz, 3H) ; 13C NMR (100 MHz, CDCl3) δ
o
1
(70 mg, yield = 65 %); Mp. 158-160 C; H NMR (400 170.57, 168.81, 147.31, 143.40, 133.42, 132.32, 130.05,
MHz, CDCl3) δ 11.71 (s, 1H), 7.31 – 7.23 (m, 3H), 7.20 – 129.34, 128.55, 119.06, 110.53, 104.08, 77.86, 77.54,
7.14 (m, 2H), 7.14 – 7.08 (m, 2H), 7.06 – 6.98 (m, 2H), 77.22, 61.20, 57.86, 31.36, 26.45, 25.67, 21.37, 13.76,
6.94 (t, J = 7.2 Hz, 1H), 6.53 (d, J = 8.7 Hz, 1H), 4.09 (q, J 0.53; HRMS (ESI): [M+H]+ calcd. for C25H28NO5:
= 7.1 Hz, 2H), 2.39 (s, 3H), 0.87 (t, J = 7.1 Hz, 3H); 13C 422.1962, found 422.1959.
NMR (100 MHz, CDCl3) δ 169.96, 168.27, 161.98 (d, JC-F
= 247.6 Hz), 146.59, 142.69, 137.34, 132.63, 132.36,
Ethyl 5-acetoxy-1-allyl-4-hydroxy-2-phenyl-1H-indole-
131.28, 130.59, 130.12 (d, JC-F = 8.0 Hz), 128.57, 127.49,
3-carboxylate (4oa). Following the general procedure, the
119.79, 116.26 (d, JC-F = 22.9 Hz), 106.47, 101.37, 61.14,
title compound was obtain as an off white solid. (72mg,
20.78, 13.36; HRMS (EI): [M]+ calcd. for C25H20FNO5:
433.1326, found 433.1318.
o
1
yield = 76 %); Mp. 164-166 C; H NMR (400 MHz,
CDCl3) δ 11.70 (s, 1H), 7.57 – 7.41 (m, 1H), 7.32 (dt, J =
8.1, 2.1 Hz, 1H), 7.01 (d, J = 8.7 Hz, 1H), 6.78 (d, J = 8.7
Ethyl
5-acetoxy-4-hydroxy-2-phenyl-1-(4- Hz, 1H), 5.91 – 5.71 (m, 1H), 5.17 (dd, J = 10.4, 0.8 Hz,
(trifluoromethyl)phenyl)-1H-indole-3-carboxylate (4ja). 1H), 4.92 (dd, J = 17.2, 0.8 Hz, 1H), 4.46 (dt, J = 4.7, 1.7
Following the general procedure, the title compound was Hz, 1H), 4.03 (q, J = 7.1 Hz, 1H), 2.39 (s, 1H), 0.82 (t, J =
obtain as an off white solid. (61 mg, yield = 51 %); Mp. 7.1 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 172.52,
148-150 oC; H NMR (400 MHz, CDCl3) δ 11.71 (s, 1H), 170.73, 149.21, 145.32, 138.17, 134.89, 134.65, 134.15,
1
7.58 (dd, J = 17.2, 7.8 Hz, 2H), 7.36 – 7.22 (m, 5H), 7.17 132.44, 131.63, 130.45, 121.94, 120.07, 119.11, 108.04,
(dd, J = 8.1, 1.4 Hz, 2H), 6.96 (d, J = 8.7 Hz, 1H), 6.57 (d, 103.64, 63.38, 49.32, 23.38, 15.86; HRMS (ESI): [M+H]+
J = 8.7 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 2.39 (s, 3H), 0.88 calcd. for C22H22NO5 : 380.1492, found 380.1494.
(t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.91,
168.17, 146.15, 142.82, 139.65, 136.85, 132.83, 130.95,
Ethyl
5-acetoxy-1-benzyl-4-hydroxy-2-phenyl-1H-
130.60, 128.81, 128.73, 127.63, 126.41 (q, JC-F = 3.6, Hz),
120.04, 116.37, 107.09, 101.19, 77.31, 76.99, 76.67, 61.27,
20.75, 13.34; HRMS (EI): [M]+ calcd. for C26H20F3NO5:
483.1294, found 483.1286.
indole-3-carboxylate (4pa). Following the general
procedure, the title compound was obtain as an off white
o
1
solid. (80mg, yield = 75 %); Mp. 145-147 C; H NMR
(400 MHz, CDCl3) δ 11.72 (s, 1H), 7.53 – 7.32 (m, 3H),
7.31 – 7.11 (m, 5H), 7.05 – 6.85 (m, 3H), 6.66 (d, J = 8.7
Ethyl
5-acetoxy-1-(2,4-dichlorophenyl)-4-hydroxy-2- Hz, 1H), 5.08 (s, 2H), 4.04 (q, J = 7.1 Hz, 2H), 2.38 (s, 3H),
phenyl-1H-indole-3-carboxylate (4ka). Following the 0.82 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
general procedure, the title compound was obtain as a pale 169.88, 168.16, 146.94, 142.74, 136.25, 135.81, 132.38,
yellow solid (74 mg, yield = 62 %); Mp. 123-125 oC; H 131.46, 129.93, 129.02, 128.71, 127.90, 127.55, 126.02,
1
NMR (400 MHz, CDCl3) δ 11.70 (s, 1H), 7.41 (d, J = 8.5 119.49, 116.60, 105.70, 101.31, 80.83, 60.85, 47.94, 20.78,
Hz, 1H), 7.38 – 7.28 (m, 4H), 7.20 (dd, J = 7.9, 1.3 Hz, 2H), 13.28; HRMS (ESI): [M+Na]+ calcd. for C26H23NNaO5:
7.01 – 6.95 (m, 2H), 6.59 (d, J = 8.7 Hz, 1H), 4.11 (q, J = 452.1468, found 452.1469.
7.1 Hz, 2H), 2.41 (s, 3H), 0.89 (t, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 169.90, 168.12, 146.14, 142.82,
Ethyl 5-acetoxy-1-(2,4-dichlorophenethyl)-4-hydroxy-2-
phenyl-1H-indole-3-carboxylate (4qa). Following the
136.86, 135.79, 133.25, 132.86, 130.92, 130.87, 130.53,
130.17, 128.89, 127.72, 127.65, 120.10, 116.25, 107.08,
general procedure, the title compound was obtain as an off
101.12, 61.28, 20.76, 13.33; HRMS (EI): [M]+ calcd. for
C25H19Cl2NO5: 483.0640, found 483.0639.
1
white solid. (102 mg, yield = 80 %); Mp. 145-147 oC; H
NMR (400 MHz, CDCl3) δ 11.72 (s, 1H), 7.51 – 7.44 (m,
1H), 7.40 (dd, J = 11.5, 4.4 Hz, 2H), 7.31 – 7.24 (m, 1H),
Ethyl
5-acetoxy-4-hydroxy-2-phenyl-1-propyl-1H- 7.07 (dd, J = 11.3, 5.2 Hz, 4H), 6.91 (d, J = 8.7 Hz, 1H),
indole-3-carboxylate (4la). Following the general 6.68 (d, J = 8.2 Hz, 1H), 4.11 (t, J = 7.4 Hz, 2H), 4.00 (q, J
procedure, the title compound was obtain as a pale yellow = 7.1 Hz, 2H), 3.02 (t, J = 7.4 Hz, 2H), 2.41 (s, 3H), 0.78 (t,
solid. (76mg, yield = 80 %); Mp. 138-140 C; H NMR J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 170.20,
(400 MHz, CDCl3) δ 11.72 (s, 1H), 7.52 – 7.42 (m, 3H), 168.35, 146.81, 143.24, 135.42, 135.06, 133.88, 133.76,
o
1
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000402
Advanced Synthesis & Catalysis
132.64, 131.94, 131.64, 130.03, 129.68, 129.18, 128.20, 1-(3,4-dimethoxyphenyl)-4,5-dihydroxy-2-phenyl-1H-
127.60, 119.78, 116.88, 105.76, 100.68, 81.10, 61.09, indole-3-carboxylic acid (5ga). A mixture of 4ga (0.1
o
59.06, 43.72, 33.32, 21.06, 13.47; HRMS (ESI): [M+Na]+ mmol) in 2 M NaOH (1.0 mL) was heated at 60 C for 2 h.
o
calcd. for C27H23Cl2NNaO5: 534.0845, found 534.0845.
After completion, the reaction mixture was cooled to 0 C
and made pH to ~ 4 by adding 2N HCl. Then extracted
with EtOAc and washed with water, brine, dried over
sodium sulfate and evaporated under reduced pressure. The
obtained crude products were purified by column
chromatography to afford the pure compound as brown
Ethyl 1-(2-(1H-indol-3-yl)ethyl)-5-acetoxy-4-hydroxy-2-
phenyl-1H-indole-3-carboxylate (4ra). Following the
general procedure, the title compound was obtain as an off
white solid. (97 mg, yield = 81 %); Mp. 162-163 oC; H
1
solid (28 mg, yield = 70 %); Mp. 191-192 oC; H NMR
1
NMR (400 MHz, CDCl3) δ 11.75 (s, 1H), 7.99 (s, 1H), 7.45
(t, J = 7.5 Hz, 1H), 7.39 – 7.29 (m, 3H), 7.15 (t, J = 7.1 Hz,
1H), 7.12 – 7.07 (m, 2H), 7.04 (d, J = 8.7 Hz, 1H), 6.97 (t,
J = 7.1 Hz, 1H), 6.90 (d, J = 8.7 Hz, 2H), 6.73 (d, J = 2.2
Hz, 1H), 4.25 – 4.07 (m, 2H), 3.99 (q, J = 7.1 Hz, 2H), 3.16
– 2.95 (m, 2H), 2.40 (s, 3H), 0.77 (t, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 170.05, 168.22, 146.76, 142.88,
136.11, 135.30, 132.22, 131.73, 129.83, 128.73, 127.89,
126.96, 122.12, 122.07, 119.45, 119.28, 118.15, 116.66,
111.50, 111.15, 105.27, 102.90, 100.71, 77.31, 45.03,
25.53, 20.83, 13.24; HRMS (ESI): [M+Na]+ calcd. for
C29H26N2NaO5: 505.1733, found 505.1735.
(400 MHz, CDCl3) δ 11.30 (s, 1H), 7.37 – 7.27 (m, 5H),
6.95 (d, J = 8.7 Hz, 1H), 6.83 – 6.73 (m, 2H), 6.58 (d, J =
8.7 Hz, 1H), 6.53 (d, J = 2.2 Hz, 1H), 3.87 (d, J = 4.2 Hz,
3H), 3.66 (s, 3H).; 13C NMR (100 MHz, CDCl3) δ 171.19,
149.07, 148.74, 148.03, 139.58, 136.25, 133.99, 130.94,
130.60, 129.05, 128.89, 127.73, 120.45, 115.35, 113.12,
111.47, 110.74, 103.01, 102.13, 55.93. HRMS (EI): [M]+
calcd. for C23H19NO6: 405.1212, found 405.1222.
Acknowledgements
Ethyl
5-acetoxy-4-hydroxy-2-(4-methoxyphenyl)-1-
The authors gratefully acknowledge funding from the Ministry of
Science and Technology (MOST), Taiwan, and the Centre for Re-
search and Development of Kaohsiung Medical University for
400 MHz NMR, LC-MS and GC-MS analyzes.
phenyl-1H-indole-3-carboxylate (4sa). Following the
general procedure, the title compound was obtain as an off
white solid. (75 mg, yield = 68 %); Mp. 178-180 oC; H
1
NMR (400 MHz, CDCl3) δ 11.77 (s, 1H), 7.37 – 7.29 (m,
3H), 7.14 – 7.06 (m, 4H), 6.92 (dd, J = 8.7, 3.5 Hz, 1H),
6.79 – 6.72 (m, 2H), 6.55 (d, J = 8.7 Hz, 1H), 4.12 (q, J =
7.1 Hz, 2H), 3.78 (d, J = 6.1 Hz, 3H), 2.38 (s, 3H), 0.95 (t,
J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.99,
168.47, 159.61, 146.55, 142.54, 137.24, 136.55, 132.51,
132.03, 129.21, 128.38, 128.28, 123.47, 119.44, 116.33,
112.79, 106.12, 101.58, 61.05, 55.17, 20.78, 13.60; HRMS
(EI): [M]+ calcd. for C26H24NO6: 445.1525, found 445.1534.
References
[1] For selected reviews on indole, see: a) J. Bariwal, L. G.
Voskressensky, E. V. V. Eycken, Chem. Soc. Rev. 2018,
47, 3831-3848; b) E. Stempel, T. Gaich, Acc. Chem.
Res. 2016, 49, 2390-2402; c) G. Bartoli, R. Dalpozzo,
M. Nardi, Chem. Soc. Rev. 2014, 43, 4728; d) N. K.
Kaushik, N. Kaushik, P. Attri, N. Kumar, C. H. Kim, A.
K. Verma, E. H. Choi, Molecules, 2013, 18, 6620–6662.
e) Shiri, M. Chem. Rev. 2012, 112, 3508-3549.
Ethyl
5-acetoxy-1-(4-fluorophenyl)-4-hydroxy-2-(4-
methoxyphenyl)-1H-indole-3-carboxylate
(4ta).
Following the general procedure, the title compound was
obtain as an off white solid. (64 mg, yield = 56 %); Mp.
167-169 oC; H NMR (400 MHz, CDCl3) δ 11.75 (s, 1H),
1
7.16 – 6.99 (m, 6H), 6.93 (d, J = 8.7 Hz, 1H), 6.81 – 6.73
(m, 2H), 6.52 (d, J = 8.7 Hz, 1H), 4.12 (q, J = 7.1 Hz, 2H),
3.79 (s, 3H), 2.38 (s, 3H), 0.95 (t, J = 7.1 Hz, 3H); 13C
[2] a) Y. Leblanc, W. C. Black, C.-C. Chan, S. Charleson,
D. Delorme, D. Denis, C. Bayly, J. Y. Gauthier, E. L.
Grimm, R. Gordon, D. Guay, P. Hamel, S. Kargman, C.
K. Lau, J. Mancini, M. Ouellet, D. Percival, P. Roy, K.
Skorey, P. Tagari, P. Vickers, E. Wong, L. Xu, P. Prasit,
Bioorg. Med. Chem. Lett. 1996, 6, 731-736; b) J. M.
Pawlak, V. V. Khau, D. R. Hutchison, M. J. Martinelli,
J. Org. Chem. 1996, 61, 9055-9059.
NMR (100 MHz, CDCl3) δ 169.96, 168.37, 161.8 (d, JC-F
=
247.4 Hz), 159.68, 146.56, 142.60, 137.25, 132.56, 132.53,
132.49, 131.96, 130.11 (d, JC-F = 8.7 Hz), 123.24, 119.60,
116.41, 116.29 (d, JC-F = 22.7 Hz), 106.29, 101.31, 61.11,
55.18, 20.76, 13.58; HRMS (EI): [M]+ calcd. for
C26H22NO6 : 463.1431, found 463.1432.
Ethyl
5-acetoxy-4-hydroxy-2-methyl-1-phenyl-1H-
indole-3-carboxylate (4ua). Following the general
procedure, the title compound was obtain as an off white
[3] a) R. E. Schmitt, M. R. Messick, B. C. Shell, E. K.
Dunbar, H.-F. Fang, K. L. Shelton, B. J. Venton, S. D.
Pletcher, M. Grotewiel, Addict. Biol. 2019; e12779; b)
S. L. Fink, L. Vojtech, J. Wagoner, N. S. J. Slivinski, H.
J. Jackson, R. Wang, S. Khadka, P. Luthra, C. F. Basler,
S. Polyak, J. Sci. Rep. 2018, 8, 8989. c) T. Heinrich, H.
Bo¨ttcher, G. D. Bartoszyk, H. E. Greiner, C. A.
Seyfried, C. V. Amsterdam, J. Med. Chem. 2004, 47,
4677-4683.
solid. (57 mg, yield = 65 %); Mp. 175-176 oC; H NMR
1
(400 MHz, CDCl3) δ 11.71 (s, 1H), 7.66 – 7.45 (m, 3H),
7.37 – 7.18 (m, 2H), 6.84 (d, J = 8.7 Hz, 1H), 6.39 (d, J =
8.7 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 2.47 (s, 3H), 2.36 (s,
3H), 1.42 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 170.00, 168.90, 144.68, 142.15, 137.31, 136.18, 132.46,
129.85, 129.20, 128.26, 118.69, 101.20, 61.40, 20.78,
14.37, 13.84; HRMS (ESI): [M+H]+ calcd. for C20H20NO5:
354.1336, found 354.1336.
5-hydroxy-4-oxo-9-phenyl-2,3,4,9-tetrahydro-1H-
carbazol-6-yl acetate (4va). Following the general
procedure, the title compound was obtain as an off white
[4] C. D. Nenitzescu, Bull. Soc. Chim. Romania. 1929, 11,
37-43.
1
solid. (55 mg, yield = 66 %); Mp. 148-149 oC; H NMR
(400 MHz, CDCl3) δ 11.26 (d, J = 0.5 Hz, 1H), 7.63 – 7.51
(m, 3H), 7.40 – 7.34 (m, 2H), 6.93 – 6.88 (m, 1H), 6.57 (d,
J = 8.6 Hz, 1H), 2.78 (t, J = 6.2 Hz, 2H), 2.66 (dd, J = 7.1,
5.7 Hz, 2H), 2.38 (s, 3H), 2.28 – 2.16 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 196.16, 169.82, 152.57, 142.68,
137.59, 135.64, 132.56, 129.96, 129.17, 127.04, 120.07,
115.21, 114.57, 101.45, 36.37, 23.58, 22.78, 20.77; HRMS
(ESI): [M+Na]+ calcd. for C20H17NNaO4: 358.1049, found
358.1051.
[5] For selected examples for Nenitzescu reaction: a) G. W.
Gribble, Indole Ring Synthesis: From Natural Products
to Drug Discovery, Nenitzescu 5‐Hydroxyindole
Synthesis; John Wiley & Sons Ltd, 2016, pp 188-205
and their references are cited there in; b) V. S.
Velezheva, A. I. Sokolov, A. G. Kornienko, K. A.
Lyssenko, Y. V. Nelyubina, I. A. Godovikov, A. S.
Peregudov, A. F. Mironov, Tetrahedron Lett. 2008, 49,
8
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000402
Advanced Synthesis & Catalysis
7106-7109; c) D. Katkevica, P. Trapencieris, A.
Movassaghi, J. –Q. Yu, J. Am. Chem. Soc. 2014, 136,
10807-10813; i) Q. Li, S.-Y. Zhang, G. He, W. A. Nack,
G. Chen, Adv. Synth. Catal. 2014, 356, 1544-1548; j) P.
Y. Choy, C. P. Lau, F. Y. Kwong, J. Org. Chem. 2011,
76, 80-84.
Boman, I. Kalvins, T. Lundstedt, J. Chemom. 2004, 18,
183-187; d) S. Brase, C. Gil, K. Knepper, Bioorg. Med.
Chem. 2002, 10, 2415-2437; e) D. M. Ketcha, L. J.
Wilson, D. E. Portlock, Tetrahedron. Lett. 2000, 41,
6253-6257.
[12] a) G. Brahmachari, I. Karmakar, Eur. J. Org. Chem.
2019, 2019, 5925-5933; b) N. Thrimurtulu, A. D. K. Pal,
A. Nair, S. Kumar, C. M. R. Volla, Chemistry Select.
2017, 2, 7251-7254; c) C. –Y. Zhao, L. –G. Li, Q. –R.
Liu, C. –X. Pan, G. –F. Su, D. –L. Mo, Org. Biomol.
Chem. 2016, 14, 6795-6803; d) V. Soni, U. N. Patel, B.
Punji, RSC Adv. 2015, 5, 57472-57481.
[6] a) U. Kuckländer, Tedrohedron. 1972, 28, 5251-5259;
b) U. Kuckländer, Tedrohedron. 1973, 29, 921-927; c)
U. Kuckländer, Tedrohedron. 1975, 31, 1631-1639.
[7] a) S.-I. Murahashi, Y. Imada, Chem. Rev. 2019, 119,
4684-4716; b) G. C. Senadi, V. S. Kudale, J.-J. Wang,
Green Chem. 2019, 21, 979-985; c) G. C. Senadi, J.-J.
Wang, Green. Chem. 2018, 20, 3420-3425; d) G. C. [13] a) T. Okada, K. Nobushige, T. Satoh, M. Miura, Org.
Senadi, M. R. Mutra, T. Y. Lu, J.-J. Wang, Green.
Chem. 2017, 19, 4272-4277; e) S. S. K. Boominathan,
J.-J. Wang, Adv. Synth. Catal. 2017, 359, 1844-1848; f)
G. C. Senadi, G. K. Dhandabani, W.-P. Hu, J.-J. Wang,
Green Chem. 2016, 18, 6241-6245; g) A. H. Chughtai,
N. Ahmad, H. A. Younus, A. Laypkov, F. Verpoort,
Chem. Soc. Rev. 2015, 44, 6804-6849.
Lett. 2016, 18, 1150-1153; b) Z. Wang, Y. Kuninobu,
M. Kanai, Org. Lett. 2014, 16, 4790-4793.
[14] CCDC numbers for compounds 4aa, 4aa’ and 4ab are
1935812, 1935813 and 1935814.
[15] A. Pelter, S. Elgendy, Tetrahedron Lett. 1988, 29,
677-680.
[8] Selected examples for polyvalent iodine reactions: a) G.
K. Murphy, L. Racicot, M. S. Carle, Asian J. Org.
Chem. 2018, 7, 837-851; b) Z. Zhao, Y. Luo, S. Liu, L.
Zhang, L. Feng, Y. Wang, Angew. Chem. Int. Ed. 2018,
57, 3792-3796; c) B. Xing, C. Ni, J. Hu, Angew. Chem.
Int. Ed. 2018, 57, 9896-9900; d) A. Yoshimura, V. V.
Zhdankin, Chem. Rev. 2016, 116, 3328-3435; e) M.
Murarka, A. P. Antonchick, Top. Curr. Chem. 2015,
373, 75-104.
[16] Intramolecular cyclization of -enaminoester resulted
in the formation of indole, thereby leaving
benzoquinone unreacted in the reaction (See, ref. 9f).
Whereas, no intramolecular cyclization was observed
with hydroquinone and -enaminoester under the
standard conditions. This results strongly suggest that
benzoquinone was not the intermediate.
[17] a) A. M. Harned, Tetrahedron Lett. 2014, 55, 4681-
4689; b) M. Uyanik, T. Yasui, K. Ishihara, Angew.
Chem. Int. Ed. 2013, 52, 9215-9218.
[9] Selected examples for PIDA and PIFA mediated
reactions: a) Y. Wan, Z. Zhang, N. Ma, J. Bi, G. Zhang,
J. Org. Chem. 2019, 84, 780-791; b) A. Mariappan, K.
Rajaguru, N. M. Chola, S. Muthusubramanian, N.
Bhuvanesh, J. Org. Chem. 2016, 81, 6573-6579; c) S.
Manna, P. O. Serebrennikova, I. A. Utepova, A. P.
Antonchick, O. N. Chupakhin, Org. Lett. 2015, 17,
4588-4591; d) L. Fra, A. Millán, J. A. Souto, K. Muniz,
Angew. Chem. Int. Ed. 2014, 53, 7349-7353; e) R.
Narayan, K. Matcha, A. P. Antonchick, Angew. Chem.
Int. Ed. 2013, 52, 7985-7989; e). A. Correa, I. Tellitu, E.
Domínguez, R. SanMartin, J. Org. Chem. 2006, 71,
3501-3505; f) Y. Du, R. Liu, G. Linn, K. Zhao, Org.
Lett. 2006, 8, 5919-5922.
[18] L. Manzoni, C. Zucal, D. D. Maio, V. G. D’Agostino,
N. Thongon, I. Bonomo, P. Lal, M. Miceli, V. Baj, M.
Brambilla, L. Cerofolini, S. Elezgarai, S. Biasini, C.
Luchinat, E. Novellino, M. Fragai, L. Marinelli, A.
Provenzani, P. Seneci, J. Med. Chem. 2018, 61, 1483-
1498; b) M. C. Pellosi, A. A. Suzukawa, A. C. Scalfo, P.
Di Mascio, C. P. M. Pereira, N. C. de Souza Pinto, D.
de Luna Martins, G. R. Martinez, Arch. Biochem.
Biophys. 2014, 557, 55-64.
[10] a) R. Narayan, K. Matcha, A. P. Antonchick, Chem.
Eur. J. 2015, 21, 14678-14693; b) C.-L. Sun, Z.-J Shi,
Chem. Rev. 2014, 114, 9219-9280.
[11] For recent and selected examples, see: a) A. Shrestha,
M. Lee A. L. Dunn, M. S. Sanford, Org. Lett. 2018, 20,
204-207; b) L. Wang, H. Li, L. Wang, Org. Lett. 2018,
20, 1663-1666; c) A. Mishra, T. K. Vats, M. P. Nair, A.
Das, I. Deb, J. Org. Chem. 2017, 82, 12406-12415; d) F.
C. Sousa e Silva, A. F. Tierno, S. E. Wengryniuk,
Molecules, 2017, 22, 780; e) D. Wang, Z.-W. Li, Z.
Liu, F. Pan, Y.-F. Zhanga, Z.-J. Shi, Org. Chem. Front.
2017, 4, 2097-2101; f) D. Xu, W.-W. Sun, Y. Xie, J.-K.
Liu, B. Liu, Y. Zhou, B. Wu, J. Org. Chem. 2016, 81,
11081-11094; g) K. Chen, b) W.-H. Rao, X.-S. Yin, B.-
F. Shi, Org. Lett. 2015, 17, 3758-3761; h) G. Yang, P.
Lindovska, D. Zhu, J. Kim, P. Wang, R- Y. Tang, M.
9
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000402
Advanced Synthesis & Catalysis
FULL PAPER
An Efficient Approach to Functionalized Indoles
from λ3-Iodanes via Acyloxylation and Acyl
Transfer
Adv. Synth. Catal. Year, Volume, Page – Page
Palaniraja Jeyakannu, Gopal Chandru Senadi,
Chun-Hsien Chiang, Ganesh Kumar Dhandabani
Yu-Ching Chang, Jeh-Jeng Wang*
10
This article is protected by copyright. All rights reserved.