Lewis Acid Catalyzed Atom-Economic Synthesis of C2-Substituted Indoles from o-Amido Alkynols

Article abstract of DOI:10.1021/acs.orglett.0c00971

Herein we have disclosed a Zn(OTf)₂ catalyzed synthesis of C2-alkyl substituted indole derivatives via unprecedented carbonyl group migration from o-amido alkynols. The key features of this protocol involve N,O-carbonyl group migration, broad s

Full text of DOI:10.1021/acs.orglett.0c00971

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Letter
Lewis Acid Catalyzed Atom-Economic Synthesis of C2-Substituted
Indoles from o‑Amido Alkynols
Amol Milind Garkhedkar, Babasaheb Sopan Gore, Wan-Ping Hu, and Jeh-Jeng Wang*
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ABSTRACT: Herein we have disclosed a Zn(OTf)2 catalyzed synthesis of C2-alkyl substituted indole derivatives via unprecedented
carbonyl group migration from o-amido alkynols. The key features of this protocol involve N,O-carbonyl group migration, broad
substrate scope with varied functionality tolerance, moderate to good yields, and 100% atom economy. The crossover experiments
proved that the migration is happening via an intramolecular pathway.
Scheme 1. Indole Synthesis via Migratory
Cycloisomerization
ndole derivatives, one of the privileged classes of aza-
Iheterocycles, are prevalent in a variety of engrossing
compounds such as natural products, medicinal agents,
alkaloids, and bioactive molecules exhibiting a wide range of
pharmacological activities like anticancer, antiviral, antibacte-
rial, etc.1 Hence a variety of synthetic methodologies have been
developed including some of the classical name reactions such
as Fischer indole synthesis,2 Bischler indole synthesis,3
Sundberg indole synthesis,4 Larock indole synthesis,5 Bartoli
indole synthesis,6 Fukuyama indole synthesis,7 etc. Although
among them, the synthesis of only C2-substituted indoles is
considered as one of the toughest routes yet interesting due to
the poor nucleophilic nature of the C2 position,1b,8 several
groups attempted the classical strategy of 5-endo-dig cyclization
of o-alkynyl aniline/anilide derivatives under transition-metal
(Pd, Rh, Ru, Ag)/Lewis acid catalysis.9 The key steps for this
strategy involves activation of alkyne by π-acidic metal catalysts
followed by protodemetalation of the cyclized intermediate.9f
Furthermore, transition-metal catalyzed migratory cyclo-
isomerization is one of the most powerful and effective
approaches in synthetic chemistry. This approach utilizes the
readily accessible starting materials for the mild and selective
synthesis of densely functionalized heterocyclic scaffolds with
1,n-migration of the functional groups from a heteroatom (N,
O, S) disclosing 100% atom economy.10 These groups include
acyl/formyl,10c,11 sulfonyl,12 allyl,10a,12b,13 propargyl,14 etc.
which have been successfully implemented to synthesize
highly functional indole derivatives via 1,3-migration (Scheme
1a). Recently, Arisawa et al. demonstrated Pd-catalyzed
migratory cycloisomerization of N-allyl-o-allenyl aniline de-
rivatives to give exclusively C2-functional indoles (Scheme
1b).10a However, to the best of our knowledge, there is no any
report on the synthesis of C2-substituted N-unprotected
indoles from o-amido alkynols via N,O-carbonyl group
migration.
On the other hand, alkynols are well-known important
structural precursors for the construction of various hetero-/
carbocycles via endo or exo mode of cycloisomerization with
varied reaction sequences based on the suitable substrates and
reaction conditions.15 Recently our group also contributed in
the synthesis of different O-heterocycles by using o-alkoxy
alkynols as the starting precursor under Lewis/Brønsted acidic
Received: March 16, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00971
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
conditions.16 Hence by considering the importance of
migratory cycloisomerization and our continuous research
interest in Lewis acid mediated reactions,16a,17 we have
represented Lewis acid catalyzed synthesis of C2-alkyl
substituted indoles via unprecedented carbonyl group migra-
tion with an atom economic approach (Scheme 1c).
The preliminary optimization began by using N-(2-(5-
hydroxypent-1-yn-1-yl)phenyl)benzamide (1aa) as a model
substrate with 20 mol % of Zn(OTf)2 and chlorobenzene as
solvent at reflux temperature for 14 h. To our surprise, 3-(1H-
indol-2-yl)propyl benzoate (2aa) was obtained in 74% yield via
intramolecular cyclization and migration (Table 1, entry 1).
temperatures (Table 1, entry 14). However, we did not
observe the desired product. Later, the catalyst loading was
screened (Table 1, entries 15−16) and it was confirmed that
20 mol % of Zn(OTf)2 gave the maximum yield of 2aa (74%).
Finally, the screening of solvents at refluxing temperatures
(Table 1, entries 17−24) revealed that chlorobenzene gave the
maximum yield of 2aa (Table 1, entry 1).
With the optimized conditions in hand, an array of o-amido
pentynols 1 were used for the Lewis acid catalyzed indole
synthesis (Scheme 2). Initially the scope was carried out with
a b
,
Scheme 2. Scope of o-Amido 4-Pentyn-1-ols
a
Table 1. Optimization of Reaction Conditions
Lewis acid
(X mol %)
temp
(°C)
time
(h)
yield
b
entry
solvent
(%)
c
1
2
3
4
5
6
7
8
Zn(OTf)2 (20)
Fe(OTf)2 (20)
Cu(OTf)2 (20)
In(OTf)3 (20)
AgOTf (20)
Cu(OAc)2 (20)
CuBr2 (20)
CuCl2 (20)
CuI2 (20)
InCl3 (20)
FeCl3 (20)
ZnI2 (20)
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
110
130
100
80
14
14
14
14
16
19
14
14
14
14
10
14
14
12
14
14
14
14
14
18
18
15
12
12
74
66
trace
55
48
0
0
trace
∼15
trace
0
62
0
0
63
73
55
58
25
trace
∼18
30
9
10
11
12
13
BF3−Et2O (20)
TfOH (20)
d
14
a
All reactions were carried out using 1 (0.4 mmol) and Zn(OTf)2 (20
mol %) in chlorobenzene (1.5 mL) at 130 °C (oil bath) in the sealed
15
16
17
18
19
20
21
22
23
24
Zn(OTf)2 (10)
Zn(OTf)2 (40)
Zn(OTf)2 (20)
Zn(OTf)2 (20)
Zn(OTf)2 (20)
Zn(OTf)2 (20)
Zn(OTf)2 (20)
Zn(OTf)2 (20)
Zn(OTf)2 (20)
Zn(OTf)2 (20)
b
c
d
tube. Isolated yields. Reaction carried out at 1.0 mmol scale. 30
mol % of Zn(OTf)2 was used.
Toluene
Xylene
Trifluorotoluene
e
electron-donating as well as electron-withdrawing substituents
attached to R like p-Me (1ba), m-Me (1ca), p-Et (1da), 3,4-
diMe (1ea), p-F (1fa), p-Cl (1ga), and p-Br (1ha), to give the
desired compounds 2ba−2ha in 69−77% yields. Next, the
scope of amide derivatives (R1-group) was investigated with
substitutions like p-Me-Ph (1ab), m-OMe-Ph (1ac), p-Cl-Ph
(1ad), and o-Br-Ph (1ae) which afforded the indole derivatives
2ab−2ae in 55−72% yields. Replacing aromatic amides with
heteroaromatic amides (1af−1ag) and cinnamamide (1ah)
also gave the desired products 2af−2ah in 66−71% yields.
Finally the scope was broadened to aliphatic derivatives (1ai−
1ak), and to our delight, the protocol worked smoothly giving
products 2ai−2ak in 65−69% yields.
1,2-DCE
f
THF
70
1,4-dioxane
100
130
130
g
DMF
45
40
h
DMSO
a
All reactions were carried out using 1aa (0.4 mmol) and Lewis acid
(X mol %) in the solvent (1.5 mL) at the indicated time and
temperature (oil bath) in the sealed tube. The entry in bold (entry 1)
highlights the optimized reaction conditions. Isolated yields. PhCl =
chlorobenzene. The reaction was carried out with increasing
temperatures starting from rt to 60 °C to 90 °C to 130 °C. 1,2-
DCE = 1,2-dichloroethane. THF = tetrahydrofuran. DMF = N.N-
dimethylformamide. DMSO = dimethyl sulfoxide.
b
c
d
e
f
g
h
In light of the success with pentynol derivatives, we explored
the scope with different chain lengths of alkynol such as 3-
butyn-1-ol (3) and propargyl alcohol (4) under standard
reaction conditions (Scheme 3). Surprisingly, the reactions
underwent smooth conversion with electron-donating and
-withdrawing groups at either side of the substrates (3aa, 3ba,
3fa, 3ad, 4aa−4ba, 4ab) furnishing the desired products 5ba,
5ad, 6aa−6ba, 6ab in 60−68% yields, except for the
compound 5aa which resulted in inseparable spots observed
The structure of compound 2aa was unambiguously confirmed
by X-ray analysis (CCDC 1986128). Further, we have carried
out the reaction with other metal triflates; however, none of
them improved the yield of 2aa (Table 1, entries 2−5). The
reaction with various copper(II) salts, metal halides, and BF3−
Et2O failed to give the desired compound except for ZnI2
(Table 1, entries 6−13). To confirm the role of Zn(OTf)2, we
carried out the reaction with 20 mol % of TfOH at elevated
B
https://dx.doi.org/10.1021/acs.orglett.0c00971
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
and 1,4-cyclohexadiene gave 2aa in 72%, 74%, and 71% yield,
respectively (Scheme 5, eq 1). This result ruled out the radical
pathway. Further, to understand the pathway of carbonyl
group migration we carried out the reaction of 5-(2-
aminophenyl)pent-4-yn-1-ol (7a) with benzoyl chloride
under standard conditions (Scheme 5, eq 2). However, we
did not observe the desired product 2aa. This experiment
confirms that the carbonyl group is migrating insitu during
indole cyclization. In addition we also executed the crossover
experiment (Scheme 5, eq 3). The equimolar quantities of 1da
and 1ab were reacted under standard conditions and gave the
direct products 2da and 2ab. The cross products 2db and 2aa
Scheme 3. Scope with 3-Butyn-1-ols and Propargyl
Alcohols
a b
,
1
were not detected by H NMR. This experiment proves that
the migration follows an intramolecular pathway.
Based on the control experiments carried out and previous
reports,9,16a a plausible mechanism is outlined in Scheme 6. In
Scheme 6. Plausible Mechanism
a
All reactions were carried out using 3/4 (0.4 mmol) and Zn(OTf)2
(20 mol %) in chlorobenzene (1.5 mL) at 130 °C (oil bath) in the
b
c
d
sealed tube. Isolated yields. 30 mol % of Zn(OTf)2 was used. An
unknown compound was observed along with trace amount of desired
product.
on TLC after reaction. However, compound 5fa was observed
in trace product along with an unknown compound. The
practicality of this protocol was determined by carrying out the
reactions on gram scale for three starting materials with
different benzamide substitutions (Scheme 4).
Scheme 4. Gram Scale Reactions
To understand the mechanism, we carried out a few control
experiments as shown in Scheme 5. Radical inhibition studies
of 1aa under standard reaction conditions with TEMPO, BHT,
the presence of catalytic amounts of Lewis acid, 2-alkynol
benzamide derivatives (1/3/4) will undergo 5-endo-dig
cyclization followed by protolysis to give a C2-substituted
indole intermediate (C) and the Lewis acid will be
regenerated. Later, the Lewis acid will again activate the
amide group of the indole intermediate. This will be the
driving force allowing alcohol to undergo nucleophilic
substitution reaction and subsequent carbonyl migration to
give the desired product (2/5/6).
Scheme 5. Control Experiments
In summary, we have developed a Lewis acid catalyzed
synthesis of C2-alkyl substituted indole derivatives from o-
benzamido alkynols via migratory cycloisomerization. This
protocol attains 100% atom economic efficiency with broad
scope, varied functional group tolerance, and the carbon chain
length of alkynol. Moreover, the crossover experiments also
disclosed that the N,O-carbonyl group migration is happening
via an intramolecular pathway.
ASSOCIATED CONTENT
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General procedures; spectral characterizations; copies of
1H, 13C NMR spectra; HRMS data (PDF)
Accession Codes
CCDC 1986128 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
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Corresponding Author
Jeh-Jeng Wang − Department of Medicinal and Applied
Chemistry, Kaohsiung Medical University, Kaohsiung City 807,
Taiwan; Department of Medical Research, Kaohsiung Medical
University Hospital, Kaohsiung City 807, Taiwan;
orcid.org/0000-0002-3148-1885; Email: jjwang@
kmu.edu.tw
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Authors
Amol Milind Garkhedkar − Department of Medicinal and
Applied Chemistry, Kaohsiung Medical University, Kaohsiung
City 807, Taiwan
Babasaheb Sopan Gore − Department of Medicinal and
Applied Chemistry, Kaohsiung Medical University, Kaohsiung
City 807, Taiwan
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Wan-Ping Hu − Department of Biotechnology, Kaohsiung
Medical University, Kaohsiung City 807, Taiwan
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors acknowledge the funding from Ministry of Science
and Technology (MOST), Taiwan. We also thank the Centre
for Research Resources and Development of Kaohsiung
Medical University for providing 400 MHz NMR support.
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