Dearomatization-Rearomatization Strategy for Reductive Cross-Coupling of Indoles with Ketones in Water

Article abstract of DOI:10.1021/acs.orglett.9b00591

N-Alkylation of indoles is one of the important pathways for the construction of various biologically active indole molecules. Using ketones as N-alkylation reagent for indoles has been a great challenge not only because of the competing alkylation reaction of C-3 position but also because of the poor nucleophilicity of the nitrogen atom of indole, in addition to the steric hindrance and lower electrophilicity of the ketones. A dearomatization-rearomatization strategy has been developed for reductive cross-coupling of indoles with ketones in water. Various functional groups and other heterocyclic compounds are tolerated.

Full text of DOI:10.1021/acs.orglett.9b00591

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Dearomatization−Rearomatization Strategy for Reductive Cross-
Coupling of Indoles with Ketones in Water
Zemin Wang,† Huiying Zeng,*,† and Chao-Jun Li*,‡
†The State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222 Tianshui Road, Lanzhou 730000, People’s
Republic of China
‡Department of Chemistry and FQRNT Centre for Green Chemistry and Catalysis, McGill University, 801 Sherbrooke Street West,
Montreal, Quebec H3A 0B8, Canada
S
* Supporting Information
ABSTRACT: N-Alkylation of indoles is one of the important pathways for the
construction of various biologically active indole molecules. Using ketones as N-
alkylation reagent for indoles has been a great challenge not only because of the
competing alkylation reaction of C-3 position but also because of the poor
nucleophilicity of the nitrogen atom of indole, in addition to the steric hindrance
and lower electrophilicity of the ketones. A dearomatization−rearomatization
strategy has been developed for reductive cross-coupling of indoles with ketones in
water. Various functional groups and other heterocyclic compounds are tolerated.
ndoles constitute important heterocyclic systems in many
Recently, our group has developed a dearomatization−
rearomatization strategy for the cross-coupling of phenols11
or diaryl ethers12 with amines or ammonia (Scheme 1a).
Inspired by those works, we posit that reductive dearomatiza-
tion13 of an indole ring to form indoline can improve the
nucleophilicity of nitrogen as well as avoid the C-3 alkylation
1
Inatural products, pharmaceuticals, dyes, and fine chemicals.
Due to their biological activities, the functionalization of
indoles has attracted significant interest for organic chemists.2
Among the indole derivatives, N-substituted indoles are of
particular importance for the construction of various bio-
logically active molecules.3 As the electron lone pair on the
nitrogen atom has been delocalized to the indole ring, the C-3
position of indole has more nucleophilicity than the N-
position, which renders the N-selective alkylation of indoles
difficult. The classical approach to tackle this problem is via the
utilization of strong base to deprotonate the N−H bond in
order to improve the nucleophilicity of nitrogen atom, which
then reacts with alkyl halides. Besides the classical approach,
new elegant methods for N-alkylation of indoles were
developed recently, such as superbase-catalyzed Michael
reactions with α,β-unsaturated compounds,4 hydroamination
with alkenes,5 N-allylic alkylation with allyl esters,6 transition-
metal-catalyzed cross-coupling with boronic acid7 or bismuth
reagent,8 “borrowing hydrogen” methodology with alcohols,9
and carbene insertion into the N−H bonds with methyl
phenyldiazoacetate.10 The above alkylation reagents are often
expensive or unstable, with the exception of the alcohols.
However, only primary alkylation products are obtained when
using primary alcohols as alkylation reagents, which limits the
application of this method. Ketones are cheap, stable, and
abundant commercial chemicals. If ketones are used as
alkylation reagents of indoles, the secondary N-alkylation
products will be generated to diversify their derivatives.
However, such an approach is highly challenging not only
because of the competing alkylation reaction of the C-3
position but also because of the poor nucleophilicity of the
nitrogen atom of indole as well as the steric hindrance and
lower electrophilicity of ketones, especially in aqueous solvent.
Scheme 1. Dearomatization−Rearomatization Strategies for
Our Works
Received: February 16, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00591
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Letter
side reaction; upon reductive amination of indoline with
ketone followed by oxidative rearomatization,14 N-alkylation
indoles will be formed (Scheme 1b). Herein, we report such a
dearomatization−rearomatization strategy for reductive cross-
coupling of indoles with ketones in water, catalyzed by
palladium.
We commenced our initial investigation by reacting indole
(1a) with cyclopentanone (2a) catalyzed by Pd/C15 (10 wt %,
10 mmol %) in aqueous solvent16 (1.0 mL) at 100 °C under an
argon atmosphere for 24 h using sodium formate as hydride
source. Fortunately, a moderate yield (44%) of N-cyclo-
pentylindole was detected (Table 1, entry 1). Other palladium
(Table 1, entry 10). Different hydride sources were then
examined (Table 1, entries 11−15), and 90% yield of N-
cyclopentylindole was obtained by using potassium formate
(Table 1, entry 15). The amount of cyclopentanone was also
important for the reaction: a lower yield (65%) was achieved
when 2.0 equiv of cyclopentanone was used in this reaction
system (Table 1, entry 16), and further increasing the amount
of cyclopentanone to 3 equiv improved the yield to 94%
(Table 1, entry 17). Decreasing or increasing the reaction
temperature lowered the yields (Table 1, entries 18 and 19).
Adjusting the concentration to 0.1 M led to a lower yield
(Table 1, entry 20). Nearly quantitative yield (99%) was
obtained when the concentration was increased to 0.4 M
(Table 1, entry 21).
a
Table 1. Evaluation of Various Conditions
With the optimal reaction conditions in hand, we next
proceeded to explore substituted indoles 1 to react with 3.0
equiv of cyclopentanone (2a) at 100 °C under argon
atmosphere using 10 mol % of Pd(OH)2/C as the catalyst
and 2.5 equiv of potassium formate in water (0.5 mL) for 24 h.
A methyl substituent at the C-3 position had no effect on this
transformation, and excellent yield was obtained (Scheme 2,
2a
[H]
b
entry
catalyst
Pd/C
Pd(OH)2/C
PdCl2
Pd(OAc)2
Pd(OH)2
(mmol)
[H]
(mmol)
3a (%)
1
2
3
4
5
6
7
8
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.4
0.6
0.6
0.6
0.6
0.6
HCO2Na
HCO2Na
HCO2Na
HCO2Na
HCO2Na
HCO2Na
HCO2Na
HCO2Na
HCO2Na
HCO2Na
HCO2Li·H2O
HCO2Cs
HCO2NH4
HCO2H
HCO2K
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
0.4
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
44
48
9
6
8
c
Scheme 2. N-Alkylation of Different Indoles with
a
Cyclopentanone
Pd(PPh3)4
np
59
84
87
81
68
80
83
71
90
65
94
73
51
92
99 (97)
d
e
e
e
e
e
e
e
e
e
e
e
e
e
e
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
Pd(OH)2/C
9
10
11
12
13
14
15
16
17
HCO2K
HCO2K
HCO2K
HCO2K
HCO2K
HCO2K
f
18
g
19
20
h
i
21
a
General conditions: indole 1a (0.2 mmol), 2a (0.5 mmol), [Pd] (10
mol %), H2O (1.0 mL) under an argon atmosphere at 100 °C for 24
b
h. Yields were determined by 1H NMR with nitromethane as internal
c
standard; isolated yield is given in parentheses. Pd(OH)2/C (20 wt
d
e
f
g
%). Pd(OH)2/C (10 wt %). Pd(OH)2/C (5 wt %). 70 °C. 130
h
i
°C. H2O (2.0 mL). H2O (0.5 mL).
catalysts, such as Pd(OH)2/C (20 wt %), PdCl2, Pd(OAc)2,
Pd(OH)2, and Pd(PPh3)4, gave lower yields (Table 1, entries
2−6). Interestingly, when Pd(OH)2/C was used as catalyst,
48% yield of product was detected (Table 1, entry 2), whereas
only 8% yield of the desired product was formed with
Pd(OH)2 (Table 1, entry 5). This information illustrated the
importance of the active carbon to this transformation.
Lowering the loading of palladium hydroxide on active carbon
(10 wt %) increased the yield of 3a to 59% (Table 1, entry 7).
Further decreasing the loading of palladium hydroxide on
active carbon to 5 wt % gave 84% yield (Table 1, entry 8).
Decreasing the amount of sodium formate to 2.5 equiv
increased the yield to 87% (Table 1, entry 9). Further
decreasing the amount to 2.0 equiv lowered the yield to 81%
a
Reaction conditions: indole 1 (0.2 mmol), ketone 2a (0.6 mmol),
Pd(OH)2/C (5 wt %) (10 mol %), and HCO2K (0.5 mmol) in water
(0.5 mL) under Ar at 100 °C for 24 h; yields of isolated products are
provided. HCO2H (0.4 mmol) instead of HCO2K. HCO2H (0.6
mmol) instead of HCO2K.
b
c
B
DOI: 10.1021/acs.orglett.9b00591
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
3b). The yield was decreased to 53% with a methyl at C-2 due
to the increased steric hindrance of the reactive center
(Scheme 2, 3c). The corresponding products were isolated
in good to excellent yields with a methyl substituted at other
positions of indole (C-4, C-5, and C-6 positions) (Scheme 2,
3d−f). Electron-donating substituents on the indole ring also
had no effect, and high to excellent yields were obtained
(Scheme 2, 3g,h). It is interesting to note that the hydroxyl
group was tolerated in this system, generating the correspond-
ing product in 93% yield (Scheme 2, 3i). Electron-withdrawing
groups were also well tolerated in our system (Scheme 2, 4j).
When 1H-indole-6-carboxylic acid, 1H-indole-5-carboxylic
acid, and 4-(1H-indol-3-yl)butanoic acid were used as
substrates, the corresponding products were formed with
good to high yields without interfering by the free acids
(Scheme 2, 3k−m). 2,3-Disubstituted indole substrate, 2,3,4,9-
tetrahydro-1H-carbazole, was successfully cross-coupled with
cyclopentanone in good yield (Scheme 2, 3n).
Scheme 3. N-Alkylation of Indole with Different Ketones
We subsequently proceeded to investigate the generality of
this system with a wide range of ketones. As shown in Scheme
3, various N-alkylated indoles were obtained with moderate to
excellent yields (Scheme 3, 3o−af). With increasing ring size,
the yields of the corresponding N-alkylation products declined
gradually due to the increased steric hindrance of cycloketones
(Scheme 3, 3o,p). When the C-4 position of cyclohexanone
bears a bulky tert-butyl group, a pair of geometric isomers
(2:1) were obtained with excellent yield (95%) (Scheme 3,
3q). The ketal group was tolerated in this system with 92%
yield (Scheme 3, 3r). Heterocyclic ketones also reacted
smoothly with indole to give the corresponding N-alkylated
indoles with high to excellent yields (Scheme 3, 3s−u). 2-
Indanone and the sterically hindered 2-adamantanone also
reacted smoothly in good yields (Scheme 3, 3v−w). Fluorine-
containing cyclohexanone was also tolerated to generate
product 3x efficiently (Scheme 3, 3x). Linear ketone was
also explored, and the N-alkylation product 3y was generated
in excellent yield (96%) (Scheme 3, 3y). Levulinic acid,
bearing a free acid group at the terminal position, also
successfully reacted with indole (Scheme 3, 3z). Product 3aa
was obtained with moderate yield, tolerating a free hydroxyl
group (Scheme 3, 3aa). Ethyl 5-oxohexanoate and ethyl 3-
oxobutanoate also gave high yields (Scheme 3, 3ab−ac). Good
to high yields were obtained when aryl groups substituted at
the terminal position (Scheme 3, 3ad−ae). 3,4-Hexanedione
was also explored under the standard conditions to generate 4-
(indol-1-yl)hexan-3-one (3af) efficiently (Scheme 3, 3af).
To investigate the reaction mechanism, several control
experiments were carried out. No product was detected when
the reaction was explored in the absence of Pd(OH)2/C or
potassium formate (Scheme 4a). Indole (1a) was investigated
under the standard reaction conditions in absence of
cyclopentanone, and indoline (4) was detected in 30% yield
within 5 min (Scheme 4b). Conversely, a 41% yield of indole
(1a) was obtained when indoline (4) was explored under
standard conditions without cyclopentanone (Scheme 4c).
Those results illustrated that indole and indoline were easily
reduced or oxidized in this system, and indoline might be the
intermediate for this transformation. When indoline (4) and
cyclopentanone (2a) were reacted under standard conditions,
80% yield of 3a was generated (Scheme 4d). No such product
was obtained in the absence of palladium catalyst or both
Pd(OH)2/C and potassium formate. In the absence of HCO2K
alone, the N-alkylation product 3a was also formed in 60%
a
Reaction conditions: indole 1a (0.2 mmol), ketone 2 (0.6 mmol),
Pd(OH)2/C (5 wt %) (10 mol %), and HCO2H (0.4 mmol) in water
(0.5 mL) under Ar at 100 °C for 24 h; yields of isolated products are
provided.
yield (Scheme 4d). It is possible that indoline intermediate
condenses with cyclopentanone to form an iminium
intermediate, which undergoes hydrogen transfer via an
azomethine ylide intermediate17 to form a new iminium on
the pyrrolidine ring and then tautomerizes to form product 3a.
To investigate this possibility, indoline (4) and cyclopentanone
(2a) were explored under various acid conditions (such as 0.5
equiv of AcOH, TFA, benzoic acid, or scandium(III) triflate)
in water at 100 °C for 24 h; however, it proved otherwise
(Scheme 4e). The N-cyclopentylindoline (5) was also explored
under the standard conditions, and a 73% yield of oxidized
product N-cyclopentylindole (3a) was detected, together with
27% of compound 5. In the absence of potassium formate, the
yield of compound 3a reached 92% (Scheme 4f). Competing
experiments showed that, when indole (1a) and methyl 1H-
C
DOI: 10.1021/acs.orglett.9b00591
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Control Experiments
Scheme 5. Tentative Mechanism
of pyrrole ring generates indoline B, which condenses with
cyclopentanone C to form iminium D. Then intermediate D is
further reduced to form N-alkylated indoline E. Indoline E
then oxidatively rearomatizes to form the N-alkylated indole F
as well as regenerates HPdIIH.
In conclusion, we have successfully developed a palladium-
catalyzed synthesis of N-alkylation indole from N−H indoles
and ketones via a novel dearomatization−rearomatization
strategy. This strategy successfully elevated the nitrogen
nucleophilic ability of indole via dearomatization and avoided
a competing alkylation reaction of the C-3 position of indole.
Notably, the reaction system also exhibited high chemo-
selectivity: various functional groups including acids, esters,
alcohols, phenols, ethers, and heterocyclic compounds were
tolerated, thereby providing handles for further product
diversifications, especially for N-secondary alkyl derivatives.
Further application of such a dearomatization−rearomatization
strategy is underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00591.
Experimental procedures, additional experimental data,
and compound characterization data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
indole-5-carboxylate (1j) were reacted with cyclopentanone,
28% of 3a and 13% of 3j were formed, respectively (Scheme
4g). This result illustrated that an electron-withdrawing group
at the C-5 position can reduce the nucleophilicity of nitrogen,
resulting in a lower yield for product 3j.
*E-mail: zenghy@lzu.edu.cn.
*E-mail: cj.li@mcgill.ca.
ORCID
On the basis of these experimental results, a plausible
mechanism was proposed for this N-alkylation reaction
(Scheme 5). The HPdIIH species is formed by reacting
Pd(OH)2/C with potassium formate and water. Then
reduction of the indole A by the HPdIIH via dearomatization
Huiying Zeng: 0000-0002-2535-111X
Chao-Jun Li: 0000-0002-3859-8824
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.9b00591
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Liu, H.; Song, J.; Han, B. Nat. Commun. 2017, 8, 14190.
(i) Dominguez-Huerta, A.; Perepichka, I.; Li, C.-J. Commun Chem
2018, 1, 45. (j) Chen, X.-W.; Zhao, H.; Chen, C.-L.; Jiang, H.-F.;
Zhang, M. Angew. Chem., Int. Ed. 2017, 56, 14232−14236. (k) Xie, F.;
Xie, R.; Zhang, J.-X.; Jiang, H.-F.; Du, L.; Zhang, M. ACS Catal. 2017,
7, 4780−4785. (l) Chen, X.; Zhao, H.; Chen, C.; Jiang, H.; Zhang, M.
Chem. Commun. 2018, 54, 9087−9090.
ACKNOWLEDGMENTS
■
We thank Fundamental Research Funds for the Central
Universities (lzujbky-2018-62), the International Joint Re-
search Centre for Green Catalysis and Synthesis, Gansu
Provincial Sci. & Tech. Department (Nos. 2016B01017,
18JR3RA284, and 18JR4RA003), and Lanzhou University for
support of our research. We also thank the Canada Research
Chair (Tier I) foundation, the E.B. Eddy endowment fund,
CFI, NSERC, and FQRNT (C.-J.L.). We thank Mr. Jianjin Yu
in this group (Lanzhou University) for reproducing com-
pound 3i in Scheme 2 and compounds 3o, 3s, and 3ab in
Scheme 3.
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DOI: 10.1021/acs.orglett.9b00591
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