Scalable Photoelectrochemical Dehydrogenative Cross-Coupling of Heteroarenes with Aliphatic C?H Bonds

Article abstract of DOI:10.1002/anie.202005724

Heteroarenes are structural motifs found in many bioactive compounds and functional materials. Dehydrogenative cross-coupling of heteroarenes with aliphatic C?H bonds provides straightforward access to functionalized heteroarenes from readily available materials. Established methods employ stoichiometric chemical oxidants under conditions of heating or light irradiation. By merging electrochemistry and photochemistry, we have achieved efficient photoelectrochemical dehydrogenative cross-coupling of heteroarenes and C(sp³)?H donors through H₂ evolution, without the addition of metal catalysts or chemical oxidants. Mechanistically, the C(sp³)?H donor is converted to a nucleophilic carbon radical through H-atom transfer with chlorine atom, which is produced by light irradiation of anodically generated Cl₂ from Cl^?. The carbon radical then undergoes radical substitution to the heteroarene to afford alkylated heteroarene products.

Full text of DOI:10.1002/anie.202005724

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Accepted Article
Title: Scalable Photoelectrochemical Dehydrogenative Cross-Coupling
of Heteroarenes with Aliphatic C–H Bonds
Authors: Pin Xu, Peng-Yu Chen, and Hai-Chao Xu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202005724
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Scalable Photoelectrochemical Dehydrogenative Cross-Coupling
of Heteroarenes with Aliphatic C–H Bonds
Pin Xu†, Peng-Yu Chen†, Hai-Chao Xu*
Abstract: Heteroarenes are structural motifs found in many
bioactive compounds and functional materials. Dehydrogenative
cross-coupling of heteroarenes with aliphatic C–H bonds provides
straightforward access to functionalized heteroarenes from readily
available materials. Established methods employ stoichiometric
chemical oxidants under conditions of heating or light irradiation. By
merging electrochemistry and photochemistry, we have achieved
efficient photoelectrochemical dehydrogenative cross-coupling of
heteroarenes and C(sp3)–H donors through H2 evolution, without the
addition of metal catalysts or chemical oxidants. Mechanistically, the
C(sp3)–H donor is converted to a nucleophilic C-radical through H-
atom transfer with chlorine atom, which is produced by light
irradiation of anodically generated Cl2 from Cl−. The C-radical then
undergoes radical substitution to the heteroarene to afford alkylated
heteroarene products.
electrochemically-driven radical C–H fluoroalkylation and
acylation of heteroarenes have been achieved,[10] an efficient
electrochemical coupling of electron-deficient heteroarenes with
various C(sp3)–H donors remains unknown probably because
both coupling partners are rather difficult to oxidize and electron-
rich alkyl radicals are prone to oxidation into carbocations under
typical electrochemical conditions.[11]
Dehydrogenative C–H/C–H cross-coupling is one of the most
powerful methods for forging C–C bonds because of its high
step and atom economy, as well as the easy availability of
starting materials.[1] In this context, there has been significant
interest in the cross-coupling of heteroarenes with aliphatic C–H
donors for the synthesis of functionalized heteroarenes (Scheme
1, top), which are prevalent motifs in pharmaceuticals, natural
products and functional materials.[2] These methods generally
Scheme 1. Dehydrogenative cross-coupling of heteroarenes with aliphatic C–
H bonds.
While photochemical dehydrogenative cross coupling via H2
evolution have been reported, the requisite Co-based catalyst
causes reduction and elimination of alkyl radicals, limiting the
scope of the photochemical methods.[12] The merger of
electrochemistry with photochemistry has the potential to unlock
access to reactivities that are difficult to achieve with
electrochemistry or photochemistry alone.[13] Very recently,
involve
a
Minisci-type mechanism,[3] in which C–C bond
formation is achieved by the addition of a carbon-centered
radical to the heteroarene. The key C-radical intermediate can
be generated from the aliphatic C–H donor through hydrogen
atom transfer (HAT) using oxygen- or nitrogen-centered radicals,
which are in turn produced by heat- or light-induced cleavage of
Lambert
and
coworkers
reported
an
elegant
electrophotocatalytic cross-coupling of heteroarenes with
ethers.[14] We have been interested in chemical-oxidant free
Minisci-type reactions and have reported photoelectrochemical
alkylation of heteroarenes with organotrifluoroborates and
carboxylic acids.[15] The use of various C(sp3)–H donors with
different bond dissociation energies (BDE) as coupling partners
in these reactions require the development of new mechanistic
a
chemically labile oxidant such as peroxide (ROOR'),[4]
persulfate (S2O82−),[5] I(III) reagent,[6] or Selectfluor.[7] However,
the use of these chemical oxidants reduces the atom economy
of the whole process and may cause safety concerns, especially
for large scale production.[8]
Organic
electrochemistry,
which
achieves
redox
transformations with traceless electricity instead of oxidants or
reductants, has gained considerable traction in the past few
years due to its inherent sustainability and tunability.[9] The
simultaneously occurrence of anodic oxidation and cathodic
proton reduction allows the dehydrogenative reactions to
proceed through H2 evolution, obviating the need for
stoichiometric electron or proton acceptors. Although
paradigms.
We
report
herein
an
unprecedented
photoelectrochemical method that achieves dehydrogenative
cross-coupling of a wide variety of heteroarenes with various
activated and unactivated C(sp3)–H donors (Scheme 1, bottom).
The photoelectrochemical method that we employed in the
current study involves the conversion of C(sp3)–H to C-radicals
by chlorine radicals (Cl•). The relatively large BDE of HCl (102
kcal mol−1) ensures that Cl• can react with a wide range of
activated and unactivated aliphatic C–H bonds (Scheme 2a).[16,17]
Specifically, Cl• is first generated by the anodic oxidation of Cl−
and the subsequent light-irradiation promoted homolytic
cleavage of the resultant Cl2 (Scheme 2b). The C-radical
generated through hydrogen atom transfer could then add to a
protonated N-heteroaromatic compound to furnish a radical
cation intermediate, which could then undergo rearomatization
with the assistance of Cl•. The continuous anodic generation of
low concentration of Cl2 avoids the use of hazardous Cl2 gas
and reduces unwanted formation of alkyl chloride through Cl2
[*]
P. Xu, P.-Y. Chen, Prof. Dr. H.-C. Xu
State Key Laboratory of Physical Chemistry of Solid Surfaces, Key
Laboratory of Chemical Biology of Fujian Province, iChEM, and
College of Chemistry and Chemical Engineering, Xiamen University
Xiamen 361005 (P. R. China)
E-mail: haichao.xu@xmu.edu.cn
Web: http://hcxu.xmu.edu.cn
These authors contributed equally to this work.
[†]
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.202005724
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trapping of the alkyl radical.[18] The electrons and protons lost
during the C–C cross-coupling are combined at the cathode to
generate H2.
Entry
Deviation from standard conditions
Yield [%][b]
[a] Reaction conditions: RVC anode, Pt cathode, 1 (0.3 mmol), 2 (1 mL),
MeCN (6 mL), Et4NCl (0.09 mmol), HCl (1.8 mmol), 40 C (internal
temperature), 18 h (4.5 F mol–1). [b] Determined by 1H NMR analysis using
1,3,5-trimethoxybenzene as the internal standard. [c] Isolated yield. [d]
Unreacted 1 in parenthesis. [e] Reaction at 40 C in dark.
Scheme 2. Proposed reaction design.
We first investigated the dehydrogenative cross-coupling of
2-phenylquinoline (1) and cyclohexane (2) as a model reaction
(Table 1). After initial optimization, the desired product 3 was
obtained in 92% yield by conducting the photoelectrochemical
reaction under the irradiation of LEDs (392 nm, 10 W) and in an
undivided cell equipped with a reticulated vitreous carbon (RVC)
anode and a Pt cathode (entry 1). The reaction mixture
consisted of Et4NCl (0.3 equiv) and HCl (6 equiv) as chloride
source and acid, respectively, in MeCN. Performing the reaction
in the absence of light (entry 2), electricity (entry 3) or acid (entry
4) led to the complete abolition of product formation, whereas
eliminating Et4NCl (entry 5) resulted in a moderate drop in the
yield of 3. The match of the rate of the electrochemical process
with the photochemical reaction is essential for optimal results.
Increasing the wavelength and power of the LED light to 398 nm
(20 W) or 450 nm (20 W) or the electric current to 4 or 6 mA
similarly caused varying degrees of yield reduction (entries 6–9).
In addition, lowering the amount of HCl to 2 equiv (entry 10) or
cyclohexane to 5 equiv (entry 12), or replacing HCl with TFA
(entry 11) were also found to be less optimal. Although stringent
removal of oxygen was not necessary, running the reaction
under air resulted in moderate yield reduction to 80% (entry 13).
We next explored the substrate scope of the
photoelectrochemical cross-coupling by first reacting a variety of
C(sp3)–H species with 2-phenylquinoline (Scheme 3). Besides
cyclohexane, other cyclic alkanes, including cyclopentane (4),
cycloheptane (5), cyclooctane (6) and cyclododecane (7), were
also suitable coupling partners. Notably, norbornane (8) and 1,4-
epoxycyclohexane (9) both reacted with 2-phenylquinoline in a
regio- and stereoselective manner. It should be emphasized that
1,2-dichloroethane (DCE) was added as a cosolvent in the
synthesis of 5–8 to facilitate the dissolution of the alkane
substrates. To our gratification, our method was also found to be
broadly compatible with activated C(sp3)–H bonds such as
toluene derivatives (10 and 11), ethers (12–19), primary alcohols
(20–25), amide (28), sulfonamide (29) and phosphoramide (30),
most of which would give rise to radical intermediates that are
prone to oxidation into carbocations. Cleavage of the benzylic
C–O bond was observed for the reactions of tetrahydrofuran
(THF), diether ether and the primary alcohols under the standard
reaction conditions. For example, the photoelectrochemical
reaction of THF afforded alcohol 26 as the final product in 78%
yield. Pleasingly, this type of transformations, which has been
reported under photochemical conditions,[19] was avoided by
reducing the acid concentration (12) or by the addition of a
catalytic amount of CeCl3 (20–25). For the reaction of 1,2-
propanediol, the mono alcohol 27 was obtained as the only
identifiable product with or without CeCl3. The mechanism of the
additive CeCl3 to stop C–O cleavage remains unclear. Finally,
the formyl C(sp2)–H bond in formamide could also be activated,
ultimately resulting in the installation of an aminocarbonyl group
on the heteroarenes (31 and 32).
Table 1. Optimization of reaction conditions.[a]
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Scheme 3. Scope of C(sp3)–H species. Reaction conditions: RVC anode, Pt cathode, 2-phenylquinoline (0.3 mmol), C(sp3)–H species (1 mL for liquid or 20 equiv
for solids), MeCN (6 mL), 33–46 C (internal temperature). [a] MeCN/DCE (6 mL/1mL) as solvent. [b] Irradiated with 398 nm LEDs (20 W). [c] MeCN/DCE (6 mL/4
mL) as solvent. [d] 2 equiv of HCl. [e] Reaction in the presence of 2 mol % of CeCl3.
Reaction compatibility with different heteroarenes was next
explored using cyclohexane (2) as the coupling partner (Scheme
4). Quinolines substituted at 2- or 4-position with OMe (33), Me
(34 and 35), Cl (36 and 37), or Br (38 and 39) were all shown to
be well tolerated. Quinoline substrates carrying an OMe- (40),
Cl- (41), or Br-functionalized (42 and 43) benzo ring also
demonstrated satisfactory reaction efficiency. Note that quinoline
reacted to afford a mixture of C2 (28%) and C4 (29%) alkylation
product along with C2,C4-bisalkylated product (20%). Not
surprisingly, cross-coupling between cyclohexane and other
benzo-fused heteroaromatic scaffolds, including isoquinoline
(44–46), phenanthridine (47), quinazoline (48), quinoxaline (49),
phthalazine (50), benzothiazole (51 and 52), and
benzothiophene (54), also occurred in a regioselective manner
on the heterocyclic ring. Benzoxazole (53) underwent
decomposition and failed to afford any desired product. Purine-
derivatives (55 and 56) and imidazo[1,2,-b]pyridazine (57) were
also alkylated regioselectively. We also succeeded in converting
a variety of monocyclic heteroaromatics, such as pyridazine (58
and 59), pyrimidine (60 and 61), pyrazine (62) and the more
challenging pyridine-based compounds (63–68). In addition, the
photoelectrochemical method was applied to the alkylation of
dihydrocinchonidine (69) and bioactive compounds such as
quinoxyfen (70), roflumilast (71), fasudil (72) and acylated
fasudil (73–75). Note that H2O were added to the reactions of
fasudil and acylated fasudil to increase their solubility in the
reaction mixture.
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Scheme 4. Scope of heteroarenes. Reaction conditions: RVC anode, Pt cathode, heteroarene (0.3 mmol), 2 (1 mL), MeCN (6 mL), 34–42 C (internal
temperature). [a] Irradiated with 398 nm LEDs (20 W). [b] 2 equiv of HCl. [c] An inseparable mixture of mono- and bisalkylated products (67% yield, 1:3 ratio) was
obtained under the standard conditions. [d] H2O (0.5 mL) was added.
Initial mechanistic investigations showed that, under
standard reaction conditions, the anode potential for the cross-
coupling between 1 and 2 gradually increased from 0.92 V to
1.04 V vs. Fc+/Fc (Figure S6a). These potentials are positive
enough to oxidize Cl− to Cl2 [Ep (Et4NCl) = 0.79 V vs Fc+/Fc,
MeCN/H2O = 40:1, Figure S6b]. It has been reported that diene
76 can react with Cl2 to generate tetrachlorinated 77 instead of
the radical cyclization-derived adduct 78 (Scheme 6a, top).[20]
Consistent with this, the electrolysis of a solution of 75, Et4NCl
Scheme 5. Gram scale synthesis of compound 15.
and HCl in MeCN produced 77 in 41% yield without the
detection of 78 (Scheme 6a, bottom). Additionally, the cross-
Reaction scale up for photoelectrochemical reactions is
coupling of 79 with 2 in the presence of Cl2, generated by mixing
hampered by low surface area-to-volume ratio of batch reactors,
NaOCl with HCl, furnished the intended target molecule 34
which severely limits light penetration through the reaction
under LED irradiation, whereas no product formation was
media and thus makes it difficult to kinetically balance the
observed when the reaction mixture was shielded from light
photochemical and electrochemical steps. To our gratification,
(Scheme 6b). Combined, these results indicated that Cl2 was
the synthesis of 15 could be conducted on a gram or even
electrochemically generated and critical for promoting the
decagram scale by employing a flow setup (Scheme 5).
subsequent dehydrogenative alkylation reaction. Meanwhile, the
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Scheme 6. Mechanistic experiments.
In summary, we have achieved efficient dehydrogenative
cross-coupling of heteroarenes with aliphatic C–H bonds by
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Acknowledgements
Financial
support
of
this
research
from
MOST
(2016YFA0204100) NSFC (21672178, 21971213) and the
Fundamental Research Funds for the Central Universities.
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Keywords: electrochemistry • photoelectrochemistry •
heterocycles • C-H functionalization • radical reactions
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Pin Xu, Peng-Yu Chen, Hai-Chao Xu
Page No. – Page No.
Scalable Photoelectrochemical
dehydrogenative cross-coupling of
heteroarenes with aliphatic C–H
bonds
Report herein is an efficient photoelectrochemical dehydrogenative cross-coupling of
heteroarenes with C(sp3)–H species through H2 evolution. Chlorine atoms, which are
produced through light irradiation of anodically generated Cl2 from Cl−, abstract a
hydrogen atom from C(sp3)–H bonds to afford C-radicals. The latter undergo Minisci
alkylation to afford the final functionalized heteroarene products.
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