Cu-catalyzed cyclization to construct indoles fromN-(ortho-chloromethyl)aryl carbamates and terminal alkynesviaa one-pot reaction

Article abstract of DOI:10.1039/d0nj01981j

In this reaction, a new strategy for the synthesis of indoles fromN-(ortho-chloromethyl)aryl carbamates and terminal alkynesviaCu-catalyzed coupling-cyclization has been developed. The reactions proceeded smoothly under mild conditions with a wide functional group tolerance.

Full text of DOI:10.1039/d0nj01981j

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DOI: 10.1039/D0NJ01981J
Journal Name
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Cu-catalyzed Cyclization to Construct Indoles from N-(ortho-
chloromethyl)aryl Carbamates and Terminal Alkynes in a One-Pot
Reaction
Received 00th January 20xx,
Accepted 00th January 20xx
Yang Shi a,c,†, Gangqiang Wang a,b,†, Hang Wang a,c , Bin Deng a,c, Tao Gao a, Jian Wang a, Haibing
Guo a, Minghu Wu a,* Shaofa Sun a,*
DOI: 10.1039/x0xx00000x
www.rsc.org/
In this reaction, a new strategy for the synthesis of indoles An impressive number of well-established classical methods are
from N-(ortho-chloromethyl)aryl carbamates and terminal now available for the synthesis of indoles since Fischer indole
alkynes via Cu- catalyzed coupling-cyclization has been synthesis.3 Among all the existing synthetic methods for indoles,
developed. The reactions proceeded smoothly under mild those using alkynes as substrates are particularly attractive
conditions with wide functional group tolerance.
because of the wide variability in alkyne reactivity, substituent
tolerance, chemoselectivity, and ability to react with both
Introduction
The indole is one of the most common heterocycles found in nucleophiles and electrophiles. The
excellent reactivity
nature.1 Many indole-containing compounds possess potent between alkynes and nitrogen containing compounds under
biological activity, which has earned this structural core the transition metal-catalyzed cyclization conditions is a useful
description of “privileged” in therapeutic discovery. As alternative to the synthesis of indoles. For example, Larock
important heterocyclic alkaloids, indole and its derivatives have indole synthesis4 is a method for synthesizing indole (Scheme
significant physiological activities. For instance, indole- 1.1) by coupling reaction between o-haloaniline and alkynes
structured drug Pindolol is responsible for the treatment of under Pd catalysis. Inspired by this work, many transition-
arrhythmias, angina pain and hypertension. Indobufen is an metal-catalyzed reactions, including copper, molybdenum,
anticoagulant with significant anticoagulant properties. In iridium, mercury, gold, platinum, and rhodium have been
addition, Indomethacin is a non-steroidal anti-inflammatory explored extensively.5 Because of their economic advantages
drug for rheumatic diseases and multiple arthritis.1c,2 (Figure 1) and potential applications in largescale reactions, copper
As an advantageous structural motif, the excellent performance catalysts have attracted particular attention for this purpose. In
of indole compounds in medicine makes it very meaningful to the past ten years, people have become more and more
explore new synthetic methods.
Figure1: Examples of biologically important molecules containing
enthusiastic about the use of transition metals to catalyse the
synthesis of indole from o-aminophenylacetylene.6 However,
expensive transition metals, ligands and tedious experiments
indole motifs.
were needed. 6l (Scheme 1.2
) In the meanwhile，the using of
the copper-catalyzed domino Sonogashira coupling/cyclization
reaction of N-substituted ortho-haloanilines with terminal
alkynes for the synthesis of indoles became a new strategy.7Our
research group has been interested in the development of novel
reactions for the synthesis of heterocycles.8 Herein, we report a
more convenient synthetic method for the synthesis of 2-
substituted indole.
a.Hubei Key Laboratory of Radiation Chemistry and Functional Materials, Non-power
Nuclear Technology Collaborative Innovation Center, School of Nuclear Technology
and Chemistry & Biology, Hubei University of Science and Technology, Xianning
437100, China
b.School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan
430074, China
c. School of Pharmacy, Hubei University of Science and Technology, Xianning 437100,
China
†These authors contributed equally to this work
d.Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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Scheme 1. Synthesis of indole
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CuI
CH3CN
DMSO
THF
CH3CO2Na
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
50
Vie2w Article 6O0nline
DOI: 10.1039/D0NJ01981J
CuI
CuI
50
50
50
50
50
50
50
50
50
50
50
50
50
50
50
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
trace
53
CuI
CHCl3
Tol.
13
CuI
32
CuI
Dioxane
DMF
34
CuI
60
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CuI
CH2Cl2
EA
49
CuI
56
CuI
CH3OH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
trace
46
Ag2O
Pd(AcO)2
CuCO3
Cu(AcO)2
Cu(CF3SO3)2
Cu2O
trace
51
Results
First, the reaction was investigated using ethyl
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(2(chloromethyl)phenyl)carbamate 1a and ethynylbenzene 2a
.
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Initially, the reaction was carried out at room temperature using
Na2CO3 as the base in acetonitrile (Table 1, entry 1). Gratifyingly,
the desired intramolecular cyclization product was isolated in
46% yield. To our delight, when the reaction temperature
increases, the reaction time is shortened, and the product yield
increased from 46% to 85% (Table 1, entries 1 and 2,
respectively). To further improve the chemical yields, several
bases were screened (Table 1, entries 3–10). However, the With the optimized reaction conditions, substrates scope was
reaction yield has not been significantly improved. Overall, the investigated for this transformation (Scheme 2). Various
use of an organic base is less effective than inorganic base for substituted terminal alkynes with electron-withdrawing and
the reaction. Once an efficient base was identified, the effect of electron-donating groups were compatible under the optimized
the solvent was also investigated. Other commonly used reaction conditions, affording the corresponding products in
solvents such as DMF, CH3CN, CH3OH, 1,4-dioxane, and toluene good yields (80–93%), and the structure of 3b was confirmed
failed to further improve the yield (Table 1, entries 11–19, by X-ray analysis. When terminal alkynes were alkynyl esters,
74
a
Reaction conditions: a mixture of 1a (1.0 mmol), 2a (1.2 mmol), base (1.2
mmol) and Cat. (0.5mmol%) in solvent (2.0 mL) was stirred at 50oC for a
certain period of time.
b Isolated yield.
respectively). Finally, we screened the catalysts such as Ag2O, the reaction yields are higher (3o
, 3p), and the indole product
Pd(AcO)2, CuCO3, Cu(AcO)2, Cu(CF3SO3)2, Cu2O (entries 20–25) can be directly obtained without adding NaOH in the second
and found that the reaction was still optimal under CuI step. When the substrate was a heterocycloalkyne, the yield
conditions. Thus, we established the optimal reaction was also good (3r).
conditions as shown in entry 2a
Table 1. Optimization of reaction conditions
T
Yield
Entrya
Cat.
Solvent
Base
T(h)
(oC)
r.t.
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50
50
50
50
50
50
50
(b/%)
1
2
3
4
5
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8
9
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Na2CO3
Na2CO3
K2CO3
Cs2CO3
NaOH
12
2
46
85
2
35
2
30
2
16
NaHCO3
NEt3
2
84
2
＜10
＜10
＜10
Py.
2
Piperidine
2
2
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Scheme 2. Substrate scope of terminal alkynes.
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The preparative-scale reaction smoothly proceedVeiedw, AartficfloerOdnilninge
the corresponding products in 81% yieldD(O0I.:8190g.10o3f9/3Da0)N.JI0n19t8h1eJ
presence of NaOH, 3a was successfully converted to 5a in 95%
yield (Scheme 4).
Scheme 4. Gram scale experiment and product derivation
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On the basis of the experimental results and literature reports9, a
possible reaction mechanism is depicted in scheme 5. First, the
Sonogashira cross coupling reaction between terminal alkyne
and aminobenzyl chloride under the catalysis of cuprous ion
generates compound
1
2
I
(CCDC: 1995523), then the intramolecular
nucleophilic addition reaction diene intermediate generates
intermediate III under the basic condition, and then
aromatization into compound
3 (CCDC: 1995526).
Scheme 5. Proposed mechanism
Next, various benzyl chlorides
1
underwent cyclization,
4c). Both electron-
affording in 82–93% yields (Scheme 3, 4a
4
-
withdrawing groups and electron-donating groups on
aminobenzyl chloride were tolerated well and reacted smoothly
with ethynylbenzene 2a. Meanwhile, the yield of the reaction is
not affected by using different protecting group as Boc and Cbz
for the amino groups (4d, 4e). In addition, substrates with
substituents at the benzylic position as Me substituent did not
undergo the transformation(4f). Although we had made many
attempts, the addition product was not obtained. We believe it
should be the effect of the chlorine atom which exhibits very
low reactivity compared to other groups such as iodine or
triflate in the Copper-mediated Sonogashira reaction.
Conclusion
Scheme 3. Substrate scope of aminobenzyl chloride
In conclusion, an efficient intramolecular cyclization between N-
(ortho-chloromethyl)aryl carbamates and terminal alkynes to
access indole structures in both good yields and mild conditions
have developed. This new method demonstrates potentials for
the synthesis of indole derivatives containing natural products
and biologically active compounds.
Conflicts of interest
There are no conflicts to declare.
Acknowledgments
This work was supported by the National Research Projects
Cultivation Project (No. 2019-21GP05), and the National Students’
Platform for Innovation and Entrepreneurship Training Program
(201810927008).
To investigate the practical utility of this methodology,
preparation of 3a was carried out on a gram scale reaction (3.9
mmol of 1a and 4.68 mmol of 2a) under the optimized conditions.
Notes and references
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