Anodically Triggered Aldehyde Cation Autocatalysis for Alkylation of Heteroarenes

Article abstract of DOI:10.1002/cssc.201903397

Alkylation of heteroarenes by using aldehydes is a direct approach to increase molecular complexity, which however often involves the use of stochiometric oxidant, strong acid, and high temperature. This study concerns an energy-efficient electrochemical alkylation of heteroarenes by using aldehydes under mild conditions without mediators. Interestingly, the graphite anode can trigger aldehyde cationic species, which act as the effective autocatalysts to react with a range of heteroarenes to produce the corresponding products with excellent regioselectivity and in high yields. Compared to the traditional electro-synthesis approaches, this electro-triggered reaction provides an electricity-saving and eco-friendly route to high-value chemicals.

Full text of DOI:10.1002/cssc.201903397

Accepted Article
Title: Anodically Triggered Aldehyde Cation Auto-Catalysis for
Alkylation of Heteroarenes
Authors: Kedong Yuan, Caiyan Liu, Zihui Xiao, Shuhua Wu, Yongli
Shen, and Yi Ding
This manuscript has been accepted after peer review and appears as an
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To be cited as: ChemSusChem 10.1002/cssc.201903397
Link to VoR: http://dx.doi.org/10.1002/cssc.201903397
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10.1002/cssc.201903397
ChemSusChem
COMMUNICATION
Anodically Triggered Aldehyde Cation Auto-Catalysis for
Alkylation of Heteroarenes
Caiyan Liu,† Zihui Xiao,† Shuhua Wu, Yongli Shen, Kedong Yuan,* and Yi Ding
Abstract: Alkylation of heteroarenes using aldehydes is a direct
approach to increase molecular complexity, which however often
involves the usage of stochiometric oxidant, strong acid and high
temperature. Herein, we report an energy-efficient electrochemical
alkylation of heteroarenes using aldehydes under mild conditions
without mediators. Interestingly, the graphite anode can trigger
aldehyde cationic species, which act as the effective auto-catalysts to
react with a range of heteroarene to produce the corresponding
products with excellent regioselectivity and in high yields. Compared
to the traditional electro-synthesis approaches, this electro-triggered
reaction provides an electricity-saving and eco-friendly route to high
value chemicals.
(N-Heterocyclic carbene, NH4I) would lead to the formation of
esters, thioester and nitrile products.[8]
Alkyl-functionalized heteroarenes have gained increasing
attentions in many applications.[1] For instance, bis/tris heteroaryl
alkane derivatives have been extensively studied in drug,
agrochemical discovery and functional materials.[2] Many alkyl
precursors, including alkyl (pseudo)halides, aldehydes, alcohols
and ethers were used as electrophiles to couple with
heteroarenes by means of either transition metal catalysed
reactions[3] or Lewis Acid/Bronsted acid promoted reactions,[4]
while the use of expensive catalysts, stoichiometric oxidant,
strong acid, high temperature conditions inevitably hampers their
applications. It is thus desirable to develop an economically
attractive and environmentally friendly alternative to existing
approaches.
Direct electrochemical organic syntheses can utilize electrons
as catalysts to activate substrates and achieve expected
transformations without mediator under mild conditions, which
avoid the consumption of catalysts with complicated
procedures.[5] Generally, the interaction between the alkyl
precursors and electrode surface would lead to the formation of
alkyl radicals, wherein the control of reaction selectivity in the
absence of mediators is a challenge[6] due to many alternative
pathways such as radical-radical dimerization or radical over-
oxidation to carbocation.[7] On the other hand, aldehydes are
abundant and readily available reactants, which can be used for
Scheme 1. Nucleophilic substitution of carbonyl compounds.
In our research, we have been seeking efficient
electrochemical approaches that the substrate and electrode
could interact directly to generate reactive species, which could
be tamed by suitable coupling partners without extra mediators or
hash conditions.[9] Interestingly, we observed the electrochemical
acetalization of aldehydes and alcohols would continue even after
a short period electrolysis time, indicating some active species
were playing a catalytic role during the reaction. It was thus
hypothesized to exist an electrochemically triggered catalytic
cycle that could drive the reaction toward complete conversion.
The proposed catalytic cycle depends on the anodically triggered
cationic aldehyde species,[10] which make the reaction as an auto-
catalysis process (Scheme 1b). Although an auto-catalysis
reaction is commonly seen in the polymerization process after
generation of the active species (e.g. cation, anion, radical),[11] it
is scarcely reported in the fine chemical synthesis, possibly due
to inhibition effect during the self-replicating active species in the
reaction cycle.[12] Such an electrochemically triggered
autocatalytic process would avoid the usage of expensive
catalysts and simultaneously decrease energy consumption even
without mediators.
electrophilic alkylation reactions after the enhanced C=O
4e-f]
polarization by Lewis acid (Scheme 1a).[4c,
Notably, the
electrochemical transformation of aldehydes through mediators
Ms.C. Liu, Dr. Z. Xiao, Dr. Y. Shen, Dr. K. Yuan, Prof. Dr. Y. Ding
Tianjin Key Laboratory of Advanced Functional Porous Materials,
Institute for New Energy Materials & Low-Carbon Technologies,
School of Materials Science and Engineering, Tianjin University of
Technology.
Herein, we report an electrochemically triggered aldehyde
cation auto-catalysis reaction, which offers a straight forward
access to bis/tri(heteroaryl) substituted alkane derivatives from
aldehydes and heteroarenes under mild conditions without
mediators (Scheme 1c).
No. 391 Bin Shui Xi Dao Road, Xiqing District, Tianjin 300384,
China
Initially, the electrochemical reaction of benzaldehyde 2a with
2-methylfuran 1a was optimized by screening different electrodes,
supporting electrolytes, and the current intensity conditions (see
Table S1 for more information). Interestingly, the electrochemical
reaction performed in a beaker clearly demonstrated that
E-mail: kedong.yuan@tjut.edu.cn
† The first two authors contributed equally.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/cssc.201903397
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electricity could promote the reaction without extra mediators
(Table 1, entries 1-2). When C(+)//C(-) were used as electrodes,
the reaction carried out in 0.06 M Bu4NClO4/CH3CN electrolyte
under 2 mA constant current in an divided cell gave complete
conversion of 2a, producing the complete C2 alkylation product
3a in 93% isolated yield (entry 3). Surprisingly, we found that
continuous electricity supply was not essential to drive the
reaction, indicating the anode triggered some active species with
sufficient lifetime that played the catalytic role in the subsequent
reaction cycle. Thus, the relationship between electrolysis time
and the conversion of benzaldehyde 2a was investigated in detail.
Organic solvents also affect the efficiency of auto-catalysis
(entries 9, 11-14), and CH3CN was proved to be the best solvent.
(b)
(a)
100
80
100
80
60
40
20
0
3-phenylpropanal
+ 2-methylfuran
4-(trifluoromethyl)benzaldehyde
+ 2-methylfuran
benzaldehyde
+ 2,3-dimethylfuran
60
5 min
10 min
20 min
30 min
40
20
0
2
4
6
8
10 12 14
0
2
4
6
8
10 12 14
Reaction time (h)
Reaction time (h)
Figure 1. Influence of electrolysis time on reactivity for alkylation of 1a with 2a
(a), profiles of reaction performance for various substrates after electrolysis of
5 min (b).
Table 1. Optimization for diheteroarylation of benzaldehyde[a]
.
The influence of electrolysis time on reactivity for alkylation of
1a with 2a was further depicted in Fig. 1a, which clearly illustrated
that the longer electro-excitation time was necessary to drive the
complete conversion of 2a. The same phenomenon was also
observed from other aldehydes, as show in Fig. 2b. 3-
phenylpropanal and 4-(trifluoromethyl)benzaldehyde were almost
completely converted with 1a after an electro-excitation of 5 min,
leading to the formation of C2-alkylated furan products in high
yields (>90%). The reaction between 2,3-dimethyl furan and 2a
was less reactive, while the trend toward product formation over
time was not changed. These experimental results clearly
demonstrated that the electrochemical reaction from aldehyde
and heteroarenes was an auto-catalysis process, which was
triggered by the anode and greatly reduced the electricity
consumption.
Electro-excitation
time/Reaction time
Current
(mA)
Conversion[b]
(%)
Entry
Solvent
1[c]
2 [c]
3
0 min/3 h
3 h/3 h
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
DMF
0
2
2
0
2
2
2
2
2
1
2
2
2
2
0
23
3 h/3 h
100(93)
0
4
0 min/13 h
5 min/13 h
10 min/13 h
20 min/13 h
30 min/13 h
5 min/2 h
5 min/2 h
5 min/2 h
5 min/2 h
5 min/2 h
5 min/2 h
5
74
Table 2. Electrochemical benzylation of 2-methylfuran from aldehydes.[a]
6
74
7
90
8
100
44
9
10
11
12
13
14
40
36
11
DMSO
DCE
15
28
[a] Reaction conditions: 1a (2.5 mmol), 2a (1.0 mmol), Bu4NClO4 (0.06
mmol), CH3CN (10 mL), graphite plates (1.0 cm2) as anode and cathode,
divided cell, electro-excitation current 2 mA, rt. under air. [b] Conversion
were determined by GC using cyclohexylbenzene as the internal standard,
isolated yield was given in parenthesis. [c] Reactions were performed in a
beaker.
Noteworthily, no reactivity was observed without electricity
passed in a divided cell (entry 4), while this reaction could be
motivated by a short electrical pulse of 5 min, giving the
tri(hetero)aryl methane product 3a with complete C2 selectivity
(entry 5). The reactivity was increased significantly with extending
electro-excitation time (entries 5-8), which indicated that a vital
intermediate was formed in the presence of current, which can
autocatalyze the reaction from 1a and 2a. This intermediate was
consumed gradually and finally depleted as current was cut off,
resulting in uncompleted conversion. Control experiment showed
that the constant current was not the key factors for the reaction,
and no obvious reactivity difference was identified (entries 9-10).
[a] Reaction conditions: 1a (2.5 mmol), aldehyde (1.0 mmol), Bu4NClO4 (0.06
mmol), CH3CN (10 mL), graphite plates (1.0 cm2) as anode and cathode, divided
cell, electro-excitation current 2 mA, rt, 3 h, isolated yields.
To simplify the reaction scope study, we performed the
electrochemical alkylation reaction of heteroarenes with
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10.1002/cssc.201903397
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aldehydes using continuous electrolysis time. Therefore, the
electrochemical alkylation of 1a from a variety of aldehydes (2b-
m) were evaluated, as shown in Table 2. Both electron-rich and
electron-deficient para/ortho-substituted benzaldehydes were
accessed, while the electron withdrawing group substituted
aldehydes exhibited higher reactivity than the electron rich ones.
compared to the N-,O-containing heteroarenes.[13] In addition, the
S-containing heteroarenes are easier to be oxidized on the
surface of anode than the other N-, O-containing heteroarenes,
making them less reactive under electrochemical conditions. Both
C2 and C3 alkylation products were observed when the reaction
was performed from 2-bromobenzaldehydes and pyrrole
derivatives, and the C2 alkylation compounds 4c-e were obtained
as the major products with high regioselectivity. C3 alkylation of
indoles were achieved with complete regioselectivity (4f-i), and
For
example,
the
electrochemical
reaction
of
4-
methoxybenzaldehyde (2b) with 1a gave the corresponding
product 3b in 50% isolated yield, while trifluoromethyl or iodine
substituted benzaldehyde underwent C2 selective alkylation of 1a, even N-H free indole, allyl functional group on aldehyde were
giving 3c and 3d in high isolated yields of 98% and 97%,
respectively. Ortho- and meta-substituted aldehydes were well
tolerated to prepare 3e-g in high efficiency. Sensitive but
compatible with the electrochemical procedures, forming the
corresponding products in 83%(4f), 80%(4i) isolated yields,
respectively. Moreover, no obvious steric hindrance effect was
convertible functional groups, such as carbon-carbon triple bonds, observed when ortho-substituted benzaldehyde and indole were
-OH were also investigated, producing 3h-i in acceptable yields
with one step. A trifurylmethane (3j) was obtained from the
reaction of 2-furylaldehyde and 1a in moderate yield. In addition,
aliphatic aldehydes were also efficiently converted under
electrolysis conditions, generating 1,1-bis(heteroaryl) alkanes 3k-
m with moderate to good isolated yields.
used as reactants, which would also be of help to obtain the pure
isolated products compared to simple benzaldehyde 2a.
To further investigate the practicality of the electrochemical
reaction, two representative reactions were carried out on 5 gram-
scale (from 2e, 2f) using a larger H-cell without redundant
optimizations. As shown in Scheme 2, 3e and 3f were obtained in
83%, 67% isolated yield, respectively.
Table 3. Electrochemical alkylation of heteroarenes from aldehydes.[a]
Scheme 2. Gram-scale electrochemical synthesis of 3e and 3f.
Though the exact mechanism for the electrochemical
alkylation of heteroarenes is not clear, the anodic trigger cationic
species clearly play a key role in the catalytic cycle, which is also
verified by our previous DFT study of the interaction between
aldehydes and anode.[9] Additionally, controlled linear sweep
voltammetry (LSV) study of the reaction showed that the
aldehydes were oxidized prior to heteroarenes, which enhanced
its reactivity toward nucleophilic heteroarenes. Notably, the
significant inhibition effects from radical scavengers (TEMPO,
BHT, Scheme S1) for the formation of 3a indicated that the
electrochemical reaction possibly proceeded through a single
electron transfer (SET) mechanism. Based on these results, an
anodically triggered auto-catalysis cycle[14] was proposed to
understand the bis/tri heteroaryl alkanes formation. Initially, the
interaction between aldehydes and anode would lead to the
formation of the aldehyde cation specie A, which is highly reactive
towards nucleophiles due to the enhanced C=O polarization. A
would readily reacts with heteroarenes to generate a positively
charged alcohol intermediate B under the given conditions. The
cationic alcohol intermediate will go through a dehydration
process and react with another heteroarene to give a cationic
tri(heteroaryl) alkane C,[15] accompanied by a dehydration
process. The charge exchange between aldehydes and C leads
to the formation of tri(heteroaryl) alkane product and the self-
replication of A. Thus, the reaction would be an anodically
triggered auto-catalysis process rather than a conventional
electrochemical synthesis. The continuous electrical pulse would
be useful to release the reactive cation species into the reaction
solution, and drive the reaction toward complete conversion.
[a] Reaction conditions: heteroarene (2.5 mmol), aldehyde (1.0 mmol),
Bu4NClO4 (0.06 mmol), CH3CN (10 mL), graphite plates (1 cm2) as anode and
cathode, divided cell, electro-excitation current 2 mA, rt, 3 h, isolated yields. [b]
Yield of mixture of regioisomers, 4e was isolated as a pure product.
Subsequently, the reactivities between different heteroarenes
and aldehydes under electrochemical conditions were
investigated. As shown in Table 3, N-, O-, S-containing
heteroarenes could be transformed into the corresponding
alkylation products with high regioselectivity in moderate to high
yields (4a-i) under simple electrolysis conditions. Notably,
compared with N, O-containing heteroarenes, thiophene was less
reactive, affording the product 4b in moderate isolated yield,
possibly due to the lower nucleophilicity of thiophene derivatives
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[4]
[5]
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were tolerated in this method, generating the complexed bis/tri
heteroaryl alkane derivatives in good yields and regioselectivity.
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Experimental Section
Representative procedure (Table 1, entry 3): A Nafion®117
membrane separated H-type electrolysis cell (15 mL) was
equipped with a pair of graphite electrodes (1.0 cm2), which were
connected to an electrochemical workstation regulated power
supply. CH3CN (10 mL) and BuN4ClO4 (0.06 mmol) were added
to each chamber. To the anodic chamber, 2-methyl furan 1a (2.5
mmol, 205.1 mg) and benzaldehyde 2a (1.0 mmol, 106.1 mg)
were added. The mixture was electrolyzed under constant current
(2 mA) at room temperature with magnetic stirring for 3 hours
under air. After the reaction completion, cyclohexylbenzene (30
μL) was added to the reaction solution as internal standard and a
partial solution was filtered through a short silica gel column for
GC and GC-MS analysis. The combined solution was
concentrated under reduced pressure and purified by column
chromatography on silica gel (petroleum ether/ethyl acetate) to
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1
afford 3a as a pale yellow oil. 3a: H NMR (400 MHz, CDCl3) δ
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The authors thank the National Natural Science Foundation of
China (21702145), the National Science Fund for Distinguished
Young Scholars (51825102) and Natural Science Foundation of
Tianjin City (19JCYBJC17700,18JCYBJC89500) to sponsor our
research.
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Keywords: Electrochemical • Cation species • Auto-catalysis •
12826.
Aldehydes • Heteroarenes
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Entry for the Table of Contents
A pulse of electrical current on anode triggered aldehyde cation species can auto-catalyze the alkylation of heteroarenes to produce
bis/tris heteroaryl alkane derivatives. Aromatic, aliphatic aldehydes are well compatible with the auto-catalysis process, and react with
N, O, S-containing heteroarenes to form valuable products with excellent regioselectivity in high yields. The simple but efficient
electrochemical reaction exhibits excellent functional-group tolerance (alkene, alkyne, -OH, -I) under the neutral and mild reaction
conditions, providing a practical synthetic alternative to existing approaches.
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