Photoelectrochemical C?H Alkylation of Heteroarenes with Organotrifluoroborates

Article abstract of DOI:10.1002/anie.201814488

A photoelectrochemical method for the C?H alkylation of heteroarenes with organotrifluoroborates has been developed. The merger of electrocatalysis and photoredox catalysis provides a chemical oxidant-free approach for the generation and functionalization

Full text of DOI:10.1002/anie.201814488

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Accepted Article
Title: Photoelectrochemical C–H Alkylation of Heteroarenes with
Organotrifluoroborates
Authors: Hong Yan, Zhong-Wei Hou, and Hai-Chao Xu
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10.1002/anie.201814488
Angewandte Chemie International Edition
COMMUNICATION
Photoelectrochemical C–H Alkylation of Heteroarenes with
Organotrifluoroborates
Hong Yan, Zhong-Wei Hou and Hai-Chao Xu*
Abstract: A photoelectrochemical method for the C–H alkylation of
heteroarenes with organotrifluoroborates has been developed. The
merger of electrocatalysis and photoredox catalysis provides a
chemical oxidant-free approach for the generation and
functionalization of alkyl radicals from organotrifluoroborates. A
variety of heteroarenes are functionalized using primary, secondary
and tertiary alkyltrifluoroborates with excellent regio- and
chemoselectivity.
(Scheme 1b).[10] The proposed photoelectrochemical method,
which combines the reagent-free feature of electrochemistry and
the versatility of photochemistry in radical formation, can
potentially provide a platform for the development of enabling
and sustainable synthetic methodologies. Herein, we report an
unprecedented photoelectrochemical C–H alkylation reaction of
heteroarenes with organotrifluoroborates (Scheme 1c).[11] These
reactions are compatible with the introduction of pimary,
secondary and tertiary alkyl groups to heteroarenes and proceed
in an oxidizing reagent-free fashion.
Organic electrochemistry, which employs traceless electricity to
promote reactions, is an enabling and green synthetic
technology and have been gaining increasing traction.[1] The
electrochemical generation of alkyl radicals dates back in 1847
when Kolbe reported the decarboxylative dimerization of
carboxylic acids.[2] However, application of alkyl radicals
generated on the electrode surface in intermolecular
functionalization reactions has been hampered by undesirable
pathways of the alkyl radicals such as over-oxidation to
carbocations, radical-radical dimerization (Kolbe reaction), and
reaction with the electrode surface that causes electrode
passivation.[3] The use of a redox catalyst to generate the alkyl
radicals in the bulk solution can overcome some of the above-
mentioned problems (Scheme 1a).[4] However, overoxidation to
carbocations are still difficult to avoid because the commonly
employed radical precursors have higher oxidation potentials
than many alkyl radicals, especially tertiary alkyl radicals and
those with α-stablization groups such as π-systems and
heteroatoms.[3e,5,6]
Scheme 1. Reaction design.
Organotrifluoroborates, which are stable and easily available,
have been demonstrated to be excellent precursors for alkyl
radical species.[8a,12] Particularly, Molander and coworkers have
employed these reagents in photoredox-mediated C–H
alkylation of heteroarenes.[8a] We began our study by optimizing
the photoelectrochemical conditions for the alkylation of lepidine
(1) with potassium isopropyltrifluoroborate 2 (Table 1). The
electrolysis was conducted with a constant current in an
undivided cell equipped with a reticulated vitreous carbon (RVC)
anode and platinum plate cathode. A 20 W blue LED was
employed as the light source. The optimal reaction mixture
Photoredox catalysis has emerged as a versatile technology
for the generation of reactive radical species.[7] Because of the
transient nature of the redox active excited state of the
photocatalyst and the organic radical species, overoxidation of
alkyl radicals usually does not occur under photochemical
conditions. Compared with the extensively investigated redox
neutral transformations, photochemical net oxidation reactions
are less explored and generally rely on the use of stoichiometric
chemical oxidants.[7] In this context, visible light-promoted
Minisci alkylation of heteroarenes using oxidizing reagents such
as peroxydisulfate (S2O82−) salts[8a,b] and hypervalent iodine[8c-e]
have been extensively studied because of the importance of
heteroarenes in chemistry and biology.
−
consisted organic dye [Mes-Acr+]ClO4 (3)[13] as the catalyst (5
mol %) and TFA (1 equiv) as the acid additive, in a mixed
solvent of MeCN/H2O (2:1) at RT. Under these conditions, the
desired C–H alkylation product 4 was isolated in 87% yield
(entry 1). Light (entry 2), electricity (entry 3) and the catalyst
(entry 4) were critical for success and the absence of any of
these elements led to the recovery of most of 1. Other catalysts
such as [Ir(dF(CF3)ppy)2(dtbbpy)](PF6) (entry 5) and 4CzlPN[14]
(entry 6) were less efficient probably because of the lower
reduction potentials of their corresponding excited state
compared to that of 3. Increasing the current from 2 mA to 4 mA
(entry 7) or 6 mA (entry 8) led reduced conversion and current
efficiency suggesting the importance of synchronizing the
electrocatalytic and photocatalytic steps. A good yield of 80%
was still obtained when the supporting electrolyte Et4NBF4 was
omitted (entry 9). Although stringent removal oxygen was not
With our continued interest in organic radical chemistry,[9] we
envision the merger of organic electrochemistry and photoredox
catalysis for the development of oxidative radical reactions
[a]
Dr. H. Yan, Z.-W. Hou, Prof. Dr. H.-C. Xu
State Key Laboratory of Physical Chemistry of Solid Surfaces,
College of Chemistry and Chemical Engineering, Xiamen University
Xiamen 361005 (P. R. China)
E-mail: haichao.xu@xmu.edu.cn
Web: http://chem.xmu.edu.cn/groupweb/hcxu/
H.Y. and Z.-W.H. 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.201814488
Angewandte Chemie International Edition
COMMUNICATION
necessary, the yield of 4 decreased to 63% when the reaction
was conducted under air (entry 10).
Table 1. Optimization of reaction conditions.[a]
Entry
Deviation from standard conditions
Yield [%][b]
[a] Reaction conditions: 1 (0.3 mmol), 2 (0.45 mmol), MeCN (4 mL), H2O (2
mL), Et4NBF4 (0.3 mmol), argon, RVC anode, Pt cathode, 2 mA (janode  0.03
mA cm−2), blue LED (450 nm), 10 h (2.5 F mol−1 based on 1). [b] Yield
determined by 1H-NMR analysis using 1,3,5-trimethoxybenzene as the internal
standard. Unreacted 1 in parenthesis. [c] Isolated yield.
The substrate scope regarding the heteroarenes were next
investigated (Scheme 2). The photoelectrochemical C–H
functionalization reaction tolerated many heteroarenes such as
4- or 2-substituted quinolines (5–9), isoquinoline (10), acridine
(11), phenathridine (12), phthalazine (13), quinazolinone (14),
benzothiazole (15), Imidazo[1,2-b]pyridazine (16), and purine
(17). All the heterocycles underwent monoalkylation with
excellent regioselectivity except for phthalazine that afforded
bisalkylation product.[8] In addition, bioactive compounds such as
voriconazole (18), camptothecin (19), fasudil (20) and quinine
(21) underwent regio- and chemoselective monoalkylation. The
secondary amine moiety embedded in fasudil and the tertiary
amine moiety of quinine, which were sensitive to oxidative
decomposition, remained intact during the photoelectrochemical
C–H alkylation probably because these basic functionalities
were protonated under the acidic reaction conditions.
Scheme 2. Scope of heteroarenes. Reaction conditions: Table 1, entry 1, 10 h
(2.5 F mol−1 based on heteroarene) unless otherwise mentioned. [a] Reaction
with 3 equiv of 2. [b] Reaction with potassium cyclohexyltrifluoroborate. [c]
Reaction with 3 equiv of TFA.
The scope of organotrifluoborate was subsequently explored
using lepidine 2 or 2-phenylquinoline as the coupling partner
(Scheme 3). A variety of acyclic (22) and cyclic (23–29)
secondary
organotrifluoroborates
participated
in
the
photoelectrochemical C–H alkylation reaction including those
bearing a ketone carbonyl (27), a Boc-protected amine (28), or a
cyclic ether (29). α-Alkoxyl and tertiary alkyl radicals are oxidized
at potentials much lower than the organotrifluoborates and thus
are prone to undergo overoxidation to carbocations.[3e,6]
Pleasingly,
α-alkoxyl
(30–33)
and
tertiary
(34–39)
organotrifluoroborates also reacted successfully under modified
conditions using either increased loading of the catalyst 3 or
4CzIPN as the catalyst.
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10.1002/anie.201814488
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COMMUNICATION
also serve as an effective alkylation reagent under the
photoelectrochemical conditions [Eq. (1)]. Moreover, the
photoelectrochemical alkylation reaction was applicable to
promote the oxidative addition-cyclization cascade of acrylamide
41, leading to the formation of oxindole 43 [Eq. (2)]. Together,
these results suggested potentially broad applications of the
photoelectrochemical protocol in promoting oxidative radical
reactions.
Scheme 4. Mechanistic proposal. Potentials (E) vs saturated calomel
electrode (SCE).
A possible mechanism for the electrochemical C–H akylation
reaction has been proposed (Scheme 4). Irradiation of the
organic dye Mes-Acr+ (3) leads to its highly oxidizing excited
state 3* (Ered = 2.06 V vs SCE in MeCN).[13a] Single electron
transfer (SET) between 3* and the organotrifluoroborate results
in the acridinyl radical Mes-Acr• and an alkyl radical.[8a,16] The
stable radical Mes-Acr•[13b,c] is oxidized at the anode surface to
regenerate the ground-state catalyst 3. On the other hand, the
alkyl radical reacts with the protonated heteroarene to give the
radical cation I, which loses a proton to give the C-radical
intermediate II.[17] II needs to lose an electron to afford the final
product. However, this radical is probably not oxidized on the
anode surface because it is not expected to have a lifetime long
enough for it to travel to the electrode.[18] The oxidation potential
of II can be estimated using the reduction potential of protonated
quinoline 4 [Ep/2red = −1.19 V vs SCE in MeCN/H2O (2:1)]. Hence,
it is thermodynamically favorable for II to lose an electron to the
ground-state catalyst 3 (Ep/2red = −0.57 V vs SCE in MeCN)[13b] to
form the final functionalized heteroarene product. At the cathode,
protons are reduced to generate H2, obviating the need for
electron and proton acceptors for the C–H alkylation reaction.
In summary, we have developed a chemical oxidant-free C–
H alkylation reaction of heteroarenes with organotrifluoroborates
by merging photoredox catalysis and electrocatalysis. Under the
photoelectrochemical conditions, alkyl radicals are efficiently
generated and participate readily in intermolecular oxidative
transformations without overoxidation to carbocations.
Application of the photoelectrochemical protocol to promote
other oxidative radical reactions are ongoing in our laboratory.
Scheme 3. Scope of organotrifluoroborate. Reaction conditions: Table 1, entry
1, 2–9 F mol−1 (based on heteroarene). [a] 3 equiv of organotrifluoroborate. [b]
20 mol % of 3. [c] Reaction with 5 mol % 4CzIPN as catalyst in MeCN/H2O
(11:1), 65 °C.
1,4-Dihydropyridines, which are prepared in one step from
aldehydes, have been employed as alkyl radical precursors.[15]
Preliminary results showed that 1,4-dihydropyridine 40 could
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10.1002/anie.201814488
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Acknowledgements
Financial
support
of
this
research
from
MOST
(2016YFA0204100), NSFC (21672178), the Fundamental
Research Funds for the Central Universities, the National
Postdoctoral Program for Innovative Talents (BX201700141),
and China Postdoctoral Science Foundation (2018M630730), is
acknowledged.
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Keywords: electrochemistry • photoelectrochemistry • oxidation
• radical reaction • C–H alkylation
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COMMUNICATION
Hong Yan, Zhong-Wei Hou, Hai-Chao
Xu*
Page No. – Page No.
Photoelectrochemical C–H Alkylation
of Heteroarenes with
Organotrifluoroborates
A photoelectrochemical method has been developed for the C–H alkylation of
heteroarenes with organotrifluoroborates under oxidizing reagent-free conditions. A
variety of heteroarenes are functionalized with 1°, 2° and 3° alkyl groups with
excellent regio- and chemoselectivity.
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