Visible-light-induced photocatalyst-free C-3 functionalization of indoles with diethyl bromomalonate

Article abstract of DOI:10.1039/d0gc00292e

A visible-light induced green and efficient method is developed for the synthesis of α-indolyl diethyl malonates. The reaction proceeds without any photocatalysts or ligands in a green solvent in a short time. Moreover, the reaction mechanism has been clearly studied by control experiments, spectrophotometric studies and density functional theory (DFT) calculations. The results showed that the photocatalyst-free transformation may proceed via an XB-promoted radical process. The EDA complex formation of diethyl bromomalonate with a base is the main reason for the reaction initiation.

Full text of DOI:10.1039/d0gc00292e

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DOI: 10.1039/D0GC00292E
ARTICLE
Visible-Light-Induced Photocatalyst-Free C-3 Functionalization of
Indoles with Diethyl Bromomalonate
Guangmiao Gu,‡ Mengmeng Huang,‡ Jung Keun Kim, Jianye Zhang, Yabo Li* and Yangjie Wu*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A visible-light induced green and efficient method is developed for the synthesis of α-indolyl diethyl malonates. The
reaction proceeds without any photocatalysts or ligands in green solvent in short time. Moreover, the reaction mechanism
has been clearly studied by control experiments, spectrophotometric studies and density functional theory (DFT)
calculations. The results showed that the photocatalyst-free transformation may proceed via an XB-promoted radical
process. The EDA complex formation of diethyl bromomalonate with base is the main reason for the reaction initiation.
processes are realized by the following ways: 1) the
modification of reaction substrates to increase their
absorption in visible-light region;8 2) the photoexcitation of
Introduction
Indoles and their derivatives as one of important building
blocks are widely present in natural products, medical
preparations, bioactive molecules, optically active substances
and useful intermediates for organic synthesis.1 In particular,
α-indolyl diethyl malonates not only possess the excellent
properties of indoles, but also increase the possibility of
modifying substituents due to the presence of the malonates.2
The typical methods for the synthesis of these compounds are:
1) Ni-catalyzed [3+2] annulation of 2-bromocyclopenes with
anilines; 2) transition-metal-catalyzed C2-alkylation of indoles
with diazo compounds (Scheme 1, a and b).3 In order to meet
environmental protection requirements and improve the
problem of heavy metal residues, the application of non-
renewable energy and high-dose transition-metal catalysts still
need to be solved.
Recently, visible light as one of clean energy source has been
used for the production various organic compounds via the
photocatalytic process.4 In most cases, it is necessary to apply
the photosensitizers to initiate the photoreactions because of
the poor visible-light absorption of the reaction substrates.5
With this concept, the photocatalytic approaches have been
also used to achieve α-indolyl diethyl malonates (Scheme 1, c
and d).6 However, the difficulty in the purification of heavy
metal residues still exists in these photocatalytic systems.
Therefore, the development of the visible-light-induced
photocatalyst-free approaches has been considered as one of
the most effective ways.7 Generally, the photocatalyst-free
reaction intermediates;9 3) the addition of other radical
initiators;10 4) the EDA (electron donor-acceptor) complexes
construction between substrates, or between substrate and
additive (such as base or oxidant).11 In the type of EDA
complexes, non-covalent interaction of terminal halogen
atoms (R−X, formation σ-hole) with Lewis bases (LBs) plays an
important role in non-covalent photocatalysis12 due to higher
directionality and larger polarizable interacting atoms of their
halogen bonding (XB).13 The formation of the halogen bonding
complexes not only increases the visible-light absorption of the
substrates, but also reduces the dissociation energy of C-X
bond. It may be the main reason for the initiation of a single-
electron-transfer (SET) transformation under mild reaction
conditions.14 Herein, a green and efficient XB-promoted
photocatalyst-free method is developed to construct C-3
functionalization of indoles.
R3
R4O2C
CO2R4
a)
transition metal
heat
R2
+
N
R1
N2
CO2R4
R3
Ar
Br
NHR1
Ni(ClO4)2 6H2O (20 mol %)
CO2R4
CO2R4
ligand (12 mol %)
CO2R4
R2
b)
c)
+
o
DCE, 80 oC, 4A MS
N
R1
R1 = H, alkyl, Boc, pym
R2, R3 = H, alkyl, ester, aryl
R4 = alkyl
CO2R4
[Au]
CO2R4 heat
hv
CDCl3
CO2R4
CO2R4
N
N
R1
R1
Yield = 5-97%
R3
[Ru] or [Ir] or
organic photocatalysts
R4O2C
CO2R4
R2
+
d)
N
R1
blue LED
Br
Scheme 1. Synthetic methods of α-indolyl diethyl malonates.
College of Chemistry, Henan Key Laboratory of Chemical Biology and Organic
Chemistry, Key Laboratory of Applied Chemistry of Henan Universities, Zhengzhou
University,
Zhengzhou,
450052,
P.R.
China.
E-mail: wyj@zzu.edu.cn, ybli@zzu.edu.cn
Results and discussion
Electronic Supplementary Information (ESI) available: CCDC (CCDC 1923193). For
ESI and crystallographic data in CIF or other electronic form see DOI:
10.1039/x0xx00000x
‡These authors contributed equally to this work.
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Green Chemistry
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ARTICLE
Journal Name
Scheme 2. Substrate scope. Reaction conditions: 1 (0.2 mmol), 2 (3.0 equiv.),
On the basis of our previous work,15 the C-H activation of 1-
methyl-2-phenylindole (1a) with diethyl bromomalonate (2)
was chosen as the model reaction. In the presence of Ir(ppy)3
View Article Online
K2HPO4·3H2O (2.0 equiv.), EtOH (1.5 mL), in a quartz tube under Ar at room
DOI: 10.1039/D0GC00292E
temperature for 1 hour, isolated yield.
or [Ir(ppy)2(bpy)]PF6 as
phenylindole
a
photocatalyst, 1-methyl-2-
(1a) was converted into diethyl 2-(1-methyl-2-phenyl-1H-indol-
3-yl)malonate (3a) and 3-bromo-1-methyl-2-phenyl-1H-indole
(4a) in 2 hours, using K2HPO4 3H2O as base and DMF as solvent
.
Table 1. Optimization of reaction conditionsa,b
(Table 1, entries 1-2). Surprisingly, the model reaction could be
carried out in the absence of any photocatalyst affording
products 3a in 81% and 4a in 16% (entry 3). Other bases or
solvents did not improve this transformation (entries 4-10).
The compound 3a could be selectively afforded when the
transformation was carried out in EtOH (entries 10-11). A
better result was achieved at shorter reaction time (entry 11).
The transformation was not carried out without any base or in
darkness (entries 12-13).
As depicted in Scheme 2, various 2-substitutedindoles were
accommodated to produce compounds 3. Generally, the
reactivity of 2-arylindoles with electron-donating groups at the
C5, C6 and C7 positions were higher than that with electron-
withdrawing groups (3a-h). The same electronic effect was
observed for the 2-arylindoles bearing different substituents
on the 2-aryl ring (3j-r). Although the methyl group at the C4
position might hinder the coupling reaction, the desired
product 3i was isolated in 66% yield. 1-Methyl-2-(o-tolyl)-1H-
indole (1s) has a greater steric hindrance than 1,4-dimethyl-2-
phenyl-1H-indole (1i), the corresponding compound 3s was
only obtained in a moderate yield. In addition, the optimized
conditions were also suitable for N-methylindoles substituted
with naphthalenyl (3t) or methyl (3u) group at C2 position.
O
O
EtO
Br
base (2.0 equiv.)
solvent (1.5 mL)
O
O
OEt
+
+
EtO
OEt
3 W blue LED
Ar, time, rt
N
N
N
Br
1a
2
3a
4a
yieldb (%)
entry
base
conv. (%)
3a
79
77
81
4a
10
15
16
.
1c
2d
3
4
5
6
7
8e
9f
10g
11g,h
12g,h
13i
K2HPO4 3H2O
K2HPO4 3H2O
K2HPO4 3H2O
K3PO4 7H2O
KH2PO4
CsOAc
Et3N
K2HPO4 3H2O
K2HPO4 3H2O
89
92
97
.
.
.
trace
67
90
54
59
48
88
81
90
23
30
23
35
12
6
24
36
13
76
75
87
.
.
.
K2HPO4 3H2O
K2HPO4 3H2O
.
3
-
trace
.
j
K2HPO4 3H2O
NR
aReaction conditions: 1a (0.2 mmol), 2 (3.0 equiv.), base (2.0 equiv.), DMF (1.5 mL), in a
quartz tube under Ar at room temperature for 2 hours. bIsolated yield. Ir(ppy)3 (5 mol
c
%). d[Ir(ppy)2(bpy)]PF6 (5 mol %). eCH3CN (1.5 mL) as solvent. fDMSO (1.5 mL) as solvent.
gEtOH (1.5 mL) as solvent. hFor 1 hour. iIn darkness. jNR = No reaction.
EtOOC
COOEt
O
O
O
O
K2HPO4 3H2O (2.0 equiv.)
EtO
R2
R2
R1
R1
standard conditions
exp 1: TEMPO (6 equiv.)
exp 2: BHT (6 equiv.)
+
EtO
OEt
EtOH (1.5 mL)
3 W blue LED
Ar, 1 h, rt
OEt
N
N
O
O
Br
a)
+
EtO
OEt
1a
exp 3: without , TEMPO (6 equiv.)
1
2
3
N
O
N
1a
exp 4: without , BHT (6 equiv.)
Br
EtOOC
EtOOC
EtOOC
1a
1a
exp 5: without
exp 6: without
and base, TEMPO (6 equiv.)
and base, BHT (6 equiv.)
COOEt
COOEt
COOEt
1a
2
MeO
3a
3a
3a
3a
, 0% (for exp 1)
, trace (for exp 2)
, 0% (for exp 3)
, 0% (for exp 4)
N
N
N
O
O
O
3a
3b
3c
, 87%
, 86%
, 59%
EtOOC
EtO
OEt
EtO
OEt
O
O
O
N
O
EtOOC
EtOOC
EtOOC
COOEt
COOEt
COOEt
COOEt
EtO
OEt
F
NC
III
N
N
N
N
+
+
Cl
I
III
III
[ +H] exp 1 for 316.2120
[
[
+H] exp 3 for 168.0805
exp 4 for 168.0806
I
II
II
[ +H] exp 2 for 379.2481
+
exp 3 for 316.2121
3d
3e
3f
3g
, 73%
, 49%
, 20%
, 85%
exp 5 for 316.2120
+Na]+ exp 5 for 183.0626
O
O
EtOOC
EtOOC
EtOOC
EtOOC
exp 6 for 183.0626
OH
N
COOEt
COOEt
COOEt
COOEt
EtO
EtO
OEt
OEt
+
+H]+ exp 1 for 158.1538
exp 3 for 158.1539
exp 5 for 158.1538
[
+H] exp 4 for 319.1385
IV
V
[
N
N
N
N
O
O
O
O
EtO
IV
V
3h
3i
3j
3k
EtOOC
, 85%
, 66%
, 87%
, 78%
OEt
O
O
standard conditions
OEt
exp 7: 0.5 h
EtOOC
EtOOC
EtOOC
b)
COOEt
COOEt
COOEt
COOEt
+
EtO
N
O
N
Br
exp 8:
3a
(5 mol %), 0.5 h
OMe
Cl
COOMe
1a
3a
2
3a
3a
, 38% (for exp 7)
, 56% (for exp 8)
N
N
N
N
O
EtO
EtO
3l
EtOOC
3m
3n
3o
, 77%
, 66%
, 64%
, 70%
OEt
EtOOC
EtOOC
EtOOC
exp 9: standard conditions
COOEt
COOEt
COOEt
COOEt
c)
d)
N
O
O
N
N
N
N
N
O
O
Cl
NO2
EtO
EtO
3s
O
O
, 40%
3p
3q
3r
, 69%
, trace
, 88%
OEt
OEt
standard conditions
EtO
OEt
+
EtOOC
EtOOC
exp 10: 4 h
exp 11: 6 h
COOEt
COOEt
N
Br
3a
2
5a
5a
, 13% (for exp 7)
, 35% (for exp 8)
N
N
3t
3u
, 35%
, 53%
2 | J. Name., 2012, 00, 1-3
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Green Chemistry
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ARTICLE
Scheme 3. Control experiments.
between compound 2 with base (Et3N). According to the
View Article Online
Gaussian calculation results, it is easy to form a σ-hole on the
DOI: 10.1039/D0GC00292E
To obtain
a
detailed mechanistic insight for this
surface of the bromine atom of diethyl bromomalonate (2, Fig.
2),12d, 17 which has the potential to interact with Lewis bases.
Except that, the maximum absorption could reach the blue
region of the visible range (∼480 nm). Applying Job’s method
transformation, several control experiments were carried out
under optimized reaction conditions (Scheme 3). The coupling
reaction was completely quenched by excess amount of
radical scavenger such as butylated hydroxytoluene (BHT) or
2,2,6,6-tetramethylpiperidine 1-oxide (TEMPO) (Scheme 3, a,
exp 1-2), which indicated that the radical might be involved in
this transformation. Meanwhile, five strong molecular ion
peaks were obtained by ESI-MS and attributed to [I+H]+ (exact
mass: 316.2120), [II+H]+ (exact mass: 379.2481), [III+H]+ (exact
mass: 168.0605), [IV+H]+ (exact mass: 158.1538) and [V+H]+
(exact mass: 319.1385) (see ESI Figure S1-15.). These results
indicated that the C-Br bond cleavage of diethyl
bromomalonate (2) might be via a homolytic process (Scheme
3, a, exp 3-6). It was found that product 3a could serve as an
additional photosensitizer in this coupling reaction (Scheme 3,
b). The photodecomposition of product 3a did not proceed
directly without diethyl bromomalonate (2) (Scheme 3, c).
However, the compound 3a could be transformed into diethyl
2-ethoxy-2-(1-methyl-2-phenyl-1H-indol-3-yl)malonate (5a) in
the presence of diethyl bromomalonate (2) (Scheme 3, d).
of continuous variations (see ESI Figure 22),
a molar
donor/acceptor ratio of 1:1 in solution for the EDA complex
(Fig.1, c) was observed. Concomitantly, an association constant
(KEDA) of 2.4 ± 0.19 M-1 for the complex in DMF was
determined by spectrophotometric analysis using the Benesi-
Hildebrand method (see ESI Figure 23.). It might be a reason
for the occurrence of photocatalytic transformation. Based on
the results of the luminescence quenching experiments (Fig. 1,
e), the energy transfer process might contribute to this
transformation.
 - hole
a)
b)
2.5
2.0
1.5
1.0
0.5
0.0
0.4
0.3
0.2
0.1
0.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
1a
2
1a + 2
2
0.08
0.04
0.00
2 + Et
N
3
360
400
440
480
Wavelength/nm
350
400
450
500
Wavelength/nm
350
400
450
500
550
600
Wavelength/nm
c)
[2] + [Et N] = 0.2 M
3
0.015
0.010
0.005
0.000
250
300
350
400
450
500
550
600
Figure 2. Color-filled map of valence electron density of diethyl bromomalonate (2).18
Wavelength/nm
d)
In order to better understand the detailed mechanism of this
reaction, the free energy barriers in the rate determining
addition step for C-C bond formation and the energy profiles
of the reaction were also investigated using Et3N and K2HPO4
as the bases, respectively (Fig. 3). Due to the high excitation
energy, the compound 1a could not be excited under the blue
LED irradiation (Eex = 3.0645 eV). On the other hand, the active
diethyl malonate radical (B) was generated via two pathways
under the blue LED irradiation (훌 = 450 nm): 1) the homolysis
of C-Br bond of diethyl bromomalonate 2 (EC-Br = 55.32
kcal/mol, Path I, see ESI); 2) the decomposition of complexes A
(Path II, Figure 3). Although the reaction of both processes
0
20
40
60
80
100
160
140
120
100
Molar Fraction of 2 (%)
e)
3a (0.05 mM)
3000
2000
1000
0
3a, 2 (0.05 mM)
3a, 2 (0.10 mM)
3a, 2 (0.15 mM)
3a, 2 (0.20 mM)
3a, 2 (0.25 mM)
3a, 2 (0.30 mM)
y = 71.27006+29.15027*x
2
R
= 0.91583
350
400
450
500
1.0
1.5
2.0
1/Et
2.5
-1)
3.0
3.5
Wavelength/nm
N
(M
3
Figure 1. (a) The UV-Vis absorption spectra of 1a, 2 and mixture of 1a and 2 in
DMF ([1a] = 0.13 M, [2] = 0.4 M); (b) The UV-Vis absorption spectra of 2 and
mixture of 2 and triethylamine in DMF ([2] = 0.4 M, [Et3N] = 0.27 M); (c) Job’s
plot of the EDA complexes for the ratio between 1a and 2 with UV-Vis absorption
spectra in DMF; (d) Benesi-Hildebrand plot for the interaction between 1a and 2
in DMF ([2] = 0.05 M); (e) The luminescence quenching experiments of 3a with 2
in EtOH.
cannot be carried out spontaneously (ΔG
> 0), the
decomposition of complexes A (path II) is more likely to occur
than path I. The energy barriers of the nucleophilic attack by
radical B on β-position of 1-methyl-2-phenylindole (1a) is not
high (3.79 kcal/mol). Thus, the generated energy of blue LED is
enough to promote the transformation. As described in the
literatures, the intermediate D might be obtained via a SET
process from the reaction of radical C with base22or substrate
223. According to the calculated results, we are more inclined
to believe that the applied base is more suitable for the single
electron transfer (SET) process. All the calculated results are
consistent well with the experiments, indicating that our
computations should be reasonable.
Due to the formation of the complex [R-Br…O(H)R] between
diethyl bromomalonate (2) and ethanol,16 the investigation of
spectrum analysis was carried out in DMF to avoid the complex
formation. Although the individual diethyl bromomalonate (2,
368 nm) does not absorb light in the visible region (400-700
nm), a weak absorption of reagent mixture (compounds 1a
with 2) was detected in DMF (Fig. 1, a). To evaluate the
function of base, we investigated the interaction of diethyl
.
bromomalonate (2) with Et3N instead of K2HPO4 3H2O because
of the poor solubility of inorganic salt in EtOH (see ESI Scheme
S1.). Surprisingly, a more pronounced red shift was detected
(Fig. 1, b), which could indicate EDA complex formation
Based on the above results, a possible radical mechanism is
proposed (Scheme 4). The photodecomposition of compound
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Green Chemistry
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ARTICLE
Journal Name
2
(Path I) or complexes
Subsequently, the β-dicarbonyl radical B attacks on C-3 the presence of base, the elimination ofDCO3I:p1r0o.1t0o3n9/oDf0GDCr0e0s2u9l2tEs
position of 2-substitutedindoles to generate the in the formation of product 3.
A (Path II) forms radical B. intermediate C. The cation D is afforded via the SET process. In
View Article Online
1
O
O
O
O
O
EtO
OEt
EtO
+
OEt
65.37
B
B
B
B
+ Br + NEt3
d
O
P
HBr
OH
56.60
45.76
dC-C = 2.01
Å
OEt
Br
OK
N
OK
P
O
O
B
+ Br
1a
O
OK
40.54
TS
35.31
OH
B
dBr-O=P = 2.72
Å
A1
OK
OEt
TS
dC-Br = 1.98
Å
A1
O
P
OK
Br
+
31.52
26.18
OH
27.79
C
B
2
TS
22.39
18.66
OEt
D
B
Br
+
+
O
P
K
O
O
Path I
O
C
B
+ NEt3 + Br
16.08
O
Br
O
OH
EtO
O
OK
OEt
OEt
KBr
A2
O
P
OH
O
dBr-(OK)P = 2.78
Å
A2
+
O
5.80
A3
dC-Br = 1.98
Å
OK
N
O
Et3N
O
P
OH
C
4.80
A2
4.74
O
P
OEt
Br
OK
NEt3
A4
4.27
A1
OEt
OH
O
O
O
O
O
O
H
O
OK
EtO
0.0
Br
OEt
P
OK
OEt
D
O
OK
OEt
2
NEt3
K2HPO4
-9.02
O
P
OH
A3
D
dBr-(OH)P = 3.42
Å
Path II
N
A3
OK
D
dC-Br = 1.96
-15.44
Å
O
N
O
O
EtO
HO
P
OH
OEt
Br NEt3
OEt
OK
NEt3
O
3a
-35.15
3a
O
OEt
A4
Et3N HBr
3a
dBr-N = 2.77
A4 dC-Br = 2.00
Å
Å
-35.37
Photochemical initiation
Chian process
Figure 3. Density functional theory calculations. Computed Gibbs free energy profile for the C-H functionalization of 1a with 2, and spin density of transition states
TS1. Energies are given in kcal/mol. Calculated by Gaussian 16 program using B3LYP-D3BJ/6-311+G(d,p)/EtOH (PCM).19 NonCovalent Interaction (NCI) analysis was
carried out using Multiwfn Version 3.7(dev)17a, 20 and VMD version 1.9.3 programs.21
O
photocatalysts or ligands. The reaction mechanism is
O
O
EtO
systematically verified by experimental and calculational
methods. The results of our investigation indicated that the
photocatalyst-free transformation might proceed via a radical
process. The complex formation of diethyl bromomalonate
with base is the main reason for the reaction initiation. The
reaction mechanism was more deeply analysed and discussed
by theoretical method using the Gaussian calculation. The
advantages of this method meet the requirements of
sustainable and green synthetic chemistry, and it provides a
straight forward way to create valuable α-indolyl diethyl
malonates.
O
P
OH
OEt
R2
O
OK
R1
O
P
OH
N
OK
D
O
O
Path II
O
P
OH
HO
P
OH
O
O
OEt
Br
OEt
OK
OK
OK
OK
O
O
EtO
OEt
O
P
Br
Br
OH
2
A1
O
N
O
O
O
Path I
EtO
EtO
OEt
Br
OEt
OEt
R2
OEt
R2
O
P
K
O
O
O
R1
R1
OH
O
O
OK
N
A2
3
C
EtO
OEt
B
O
O
P
OH + KBr
Conflicts of interest
OK
There are no conflicts to declare.
R1
R2
N
1
Scheme 4. The proposed mechanism.
Acknowledgements
This work was supported by the National Natural Science
Foundation (NSF) of China (21172200 and 21302172).
Conclusions
In summary, we have developed a green and mild XB-
promoted radical reaction of 2-substitutedindoles with diethyl
bromomalonate under blue LED irradiation without any
Notes and references
4 | J. Name., 2012, 00, 1-3
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Green Chemistry
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Green Chemistry
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Green Chemistry
View Article Online
DOI: 10.1039/D0GC00292E
Visible-Light-Induced Photocatalyst-Free C-3 Functionalization of
Indoles with Diethyl Bromomalonate
Guangmiao Gu,‡ Mengmeng Huang,‡ Jung Keun Kim, Jianye Zhang, Yabo Li* and Yangjie Wu*
R2
R1
N
1
O
N
O
O
O
EtO
EtO
OEt
OEt
R2
Br
2
R1
K2HPO4
Photocatalyst Free
Green Solvent
1 h
3
Up to 88 %
Intermediate
A2
A visible-light-induced and XB-promoted green approach to construct α-indolyl diethyl
malonates was developed.