Mesoionic carbene-Breslow intermediates as super electron donors: Application to the metal-free arylacylation of alkenes
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Article
Mesoionic carbene-Breslow intermediates as
super electron donors: Application to the
metal-free arylacylation of alkenes
Wei Liu, Adam Vianna, Zengyu
Zhang, ..., Mohand Melaimi,
Guy Bertrand, Xiaoyu Yan
gbertrand@ucsd.edu (G.B.)
yanxy@ruc.edu.cn (X.Y.)
Highlights
Breslow intermediates derived
from mesoionic carbenes are
super electron donors
A mesoionic-carbene-catalyzed
arylacylation of alkenes is
described
Facile construction of complex
carbonyl compounds from simple
substrates
Breslow intermediates derived from mesoionic carbenes (BIMICs) are highly
reductive species able to reduce iodoarenes under ambient condition. The
reductive power of BIMICs allows for the use of mesoionic carbenes as powerful
catalysts in the inter- and intramolecular arylacylation of alkenes.
Liu et al., Chem Catalysis 1, 1–11
June 17, 2021 ª 2021 Elsevier Inc.
https://doi.org/10.1016/j.checat.2021.03.004
Please cite this article in press as: Liu et al., Mesoionic carbene-Breslow intermediates as super electron donors: Application to the metal-free
arylacylation of alkenes, Chem Catalysis (2021), https://doi.org/10.1016/j.checat.2021.03.004
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Article
Mesoionic carbene-Breslow intermediates
as super electron donors: Application
to the metal-free arylacylation of alkenes
Wei Liu,1 Adam Vianna,2 Zengyu Zhang,1 Shiqing Huang,1 Linwei Huang,1 Mohand Melaimi,2
Guy Bertrand,2,3,* and Xiaoyu Yan1,*
SUMMARY The bigger picture
Classical N-heterocyclic carbenes (NHCs), such as thiazolylidenes, N-Heterocyclic carbenes (NHCs)
1,2,4-triazolylidenes, and imidazol(in)-2-ylidenes, are powerful or- have been demonstrated to be
ganocatalysts for aldehyde transformations through the so-called powerful organocatalysts for
Breslow intermediates (BIs). The reactions usually occur via elec- carbonyl transformations via the
tron-pair-transfer processes. In contrast, the use of BIs in single- so-called Breslow intermediates
electron transfer (SET) pathways is still in its infancy, and the scope (BIs). Recently, NHC-catalyzed
is limited by the moderate reduction potential of BIs derived from reactions via single-electron
classical NHCs (ca. 1.0 V versus standard calomel electrode transfer (SET) pathways have been
[SCE]). Here, we report that BIs from 1,2,3-triazolylidenes, a type developed but still suffer from the
of mesoionic carbene (MIC), have a reduction potential as negative limitation of moderate reduction
as 1.93 V versus SCE and thus are among the most potent organic potential of BIs. In this paper,
reducing agents reported to date. They are reductive enough to taking advantage of highly
undergo SET with iodoarenes, which allows the highly efficient inter- reductive MIC-derived BIs, we
and intramolecular MIC-catalyzed arylacylation of styrenes and describe the three-component
alkenes, respectively. coupling reaction of iodoarenes,
alkenes, and aldehydes catalyzed
INTRODUCTION by mesoionic carbenes (MICs).
This reaction affords various
Over the past decades, N-heterocyclic carbenes (NHCs) have been demonstrated to
substituted ketones and even
be powerful organocatalysts for aldehyde transformations.1–6 The umpolung of al-
polycyclic ketones with readily
dehydes by NHCs7 through the formation of nucleophilic Breslow intermediates
available substrates.
(BIs) was later extended to provide other reactive intermediates, such as acyl azo-
liums, enolates, and homoenolates.8–12 These intermediates react with diverse elec-
trophilic and nucleophilic coupling partners via electron-pair-transfer processes. In
contrast, NHC-catalyzed reactions via single-electron transfer (SET) pathways are
still in their infancy.13–15 In 2008, Studer and co-workers reported the NHC-catalyzed
oxidation of aldehydes by TEMPO via a SET process (Figure 1).16 Other oxidants,
such as nitroarenes, nitroalkenes, CX4, C2Cl6, and sulfonic carbamate, were also em-
ployed to achieve oxidative reactions of aldehydes.17–21 Recently, an important
breakthrough has been reported by Ohmiya, Nagao, and co-workers, who showed
that redox-active esters could be employed as both SET oxidants and alkylating
reagents.22,23 The same group also described a three-component alkylacylation re-
action of alkenes via a radical relay strategy,24 and the Li group achieved the NHC-
catalyzed radical acylfluoroalkylation of olefins with the Togni reagent or polyfluor-
oalkyl halides.25 Ye and co-workers described g- and ε-alkylation with alkyl radicals,
in which an activated alkyl halide was employed as SET oxidant and alkylating re-
agent.26 Hong and co-workers reported the NHC-catalyzed radical coupling of alde-
hydes and Katritzky pyridinium salts.27 However, as a result of the moderate reduc-
tion potential of BIs derived from classical NHCs (ca. 1.0 V versus standard calomel
electrode [SCE]),28–30 these SET catalyzed reactions required a relatively strong
Chem Catalysis 1, 1–11, June 17, 2021 ª 2021 Elsevier Inc. 1
Please cite this article in press as: Liu et al., Mesoionic carbene-Breslow intermediates as super electron donors: Application to the metal-free
arylacylation of alkenes, Chem Catalysis (2021), https://doi.org/10.1016/j.checat.2021.03.004
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Article
Figure 1. BIs for SET reactions
(A) Reduction potential of known BIs and their SET partners.
(B) Breslow intermediates derived from mesoionic carbenes (BIMICs).
(C) Three-component MIC-catalyzed arylacylation of alkenes.
oxidant to ensure the electron-transfer process, which dramatically limits the scope
of the reactions. For much less oxidative substrates, BIs with more negative reduc-
tion potentials are needed. Recently, we reported the formation of BIs derived
from mesoionic carbenes (BIMICs) and their application to the catalytic H/D ex-
change of aldehydes.31 This class of BIs was found to be far more electron rich
than any others previously known and should thus be much more reductive. Herein,
we describe the electrochemistry of BIMICs, which have a reduction potential as
negative as 2.49 V versus Fc/Fc+ (calculated as 1.93 V versus SCE). The oxidation
product, namely the radical form of a deprotonated BIMIC, was unambiguously
characterized by a single-crystal X-ray diffraction study. This type of BI can be clas-
sified as a new organic super electron donor32,33 and is reductive enough to undergo
SET with iodoarenes. This is demonstrated by the highly efficient mesoionic carbene
(MIC)-catalyzed arylacylation of alkenes.
1Department of Chemistry, Renmin University of
China, Beijing 100872, People’s Republic of China
RESULTS AND DISCUSSION 2UCSD-CNRS Joint Research Laboratory (UMI
Initially, we investigated the electrochemistry of BIMIC 3a, which was prepared by 3555), Department of Chemistry and
Biochemistry, University of California, San Diego,
addition of benzaldehyde to MIC 2a,34–37 generated by deprotonation of 1a (Fig- La Jolla, CA 92093-0358, USA
ure 2A). The cyclic voltammogram of 3a shows an irreversible redox process be- 3Lead contact
tween 3a and 4a∙ with an anodic peak potential Epa = 2.49 V and a corresponding *Correspondence: gbertrand@ucsd.edu (G.B.),
cathodic peak potential Epc = 2.59 V (Figure 2F). This is in agreement with an EC yanxy@ruc.edu.cn (X.Y.)
process38 in which the oxidation of 3a is immediately followed by the easy https://doi.org/10.1016/j.checat.2021.03.004
2 Chem Catalysis 1, 1–11, June 17, 2021
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Figure 2. Synthesis and characterization of 3a and 4a∙
(A) Synthesis of 3a.
(B) Synthesis of 4a ∙.
(C) Solid-state structure of 4a ∙ .
(D) EPR of 4a ∙ (top, experimental; bottom, simulated).
(E) Electron spin density of 4a ∙.
(F) Cyclic voltammograms of 3a in tetrahydrofuran (THF) (+(nBu) 4 NPF 6 0.1 mol/L).
(G) Cyclic voltammograms of 4a ∙ in THF (+(nBu) 4 NPF 6 0.1 mol/L).
(H) Cyclic voltammograms of 4a + in THF (+(nBu) 4 NPF 6 0.1 mol/L).
*Refer to the redox of in-situ-generated impurity 1a. (Scan rate: 100 mV/s; E versus Fc/Fc +.)
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Figure 3. Proposed reaction pathway for the MIC-catalyzed arylacylation of alkenes
deprotonation of 3a to generate 4a∙.29 To confirm this redox process, we prepared
the radical form 4a∙ by reducing the deprotonated BIMIC 4a+ with KC8 in tetrahydro-
furan (Figure 2B). The structure of 4a∙ was unambiguously characterized by X-ray
diffraction analysis (Figure 2C) and electron paramagnetic resonance (EPR) (Fig-
ure 2D). Compared with other acyl-carbene radicals derived from NHCs and
CAACs,39–41 the C(carbene)–C(acyl) bond is slightly longer, whereas the dihedral
angle between the carbene ring and the acyl moiety is larger. We performed density
functional theory (DFT) calculations at the B3LYP-D3(BJ)/6-311G** level of theory to
gain more insight into the electronic structure of 4a∙. The SOMO of 4a∙ is mainly
located on the p* orbital of the triazole ring and carbonyl group (see supplemental
information), whereas the spin density is mainly located on N1 and N2 with some
contribution on C2, C40, and O1 (Figure 2E). As expected, EPR spectra of 4a∙ in ben-
zene solution featured a strong signal centered at g = 2.003 with hyperfine coupling
with two nitrogen nuclei (aiso = 6.68 G). In agreement with DFT calculations, the small
hyperfine coupling constants indicate a strong delocalization of the unpaired elec-
tron. The cyclic voltammogram of 4a∙ also shows two irreversible peaks (one oxida-
tion peak at 2.46 V and one reduction peak at 2.63 V), which affords further evi-
dence of the process between 3a and 4a∙ (Figure 2G). In addition, one set of
reversible peaks at E1/2 = 1.53 V was observed, corresponding to the reversible
process 4a∙/4a+. To further confirm our hypothesis, we also carried out a cyclic vol-
tammogram of 4a+, which showed two irreversible peaks and one set of reversible
peaks (Figure 2H). It is noteworthy that the reversible process 4a∙/4a+ was not
observed in Figure 2F, which is due to the instability of 4a+ in the presence of excess
of highly reductive 3a.29
From these results it can be concluded that 3a is the most reductive BI known so far
and is among the most potent organic reducing agents (in the ground state).42 Thus,
we hypothesized that this type of BI derived from MICs should be able to reduce hal-
oarenes under mild conditions. To prove it, we designed a catalytic radical reaction,
namely the three-component arylacylation of alkenes with a MIC as catalyst (Fig-
ure 3). MICs 2, generated in situ by deprotonation of triazoliums 1, should react
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Figure 4. Optimization of the MIC-catalyzed arylacylation
Mes, 2,4,6-trimethylphenyl; Dipp, 2,6-diisopropylphenyl; IMes, 1,3-bis(2,4,6-trimethylphenyl)
imidazolinylidene. Reaction conditions: 7 (0.9 mmol), 8 (0.9 mmol), 9 (0.5 mmol), 1 (0.05 mmol), base
(0.75 mmol), and anhydrous t BuOMe (1.5 mL) for 4 h at 30 C. The reactions were carried out in a
25 mL Schlenk tube.
a
NMR yields (isolated yields are given in parentheses).
b
tBuONa instead of tBuOK.
c
The mixture was stirred at 0 C.
d
The mixture was stirred at 50 C.
with an aldehyde to give the BIMIC 3, which should be deprotonated to its enolate
form and then undergo a SET process with an aryl iodide, giving a persistent radical
4∙ and a transient aryl radical.43 The latter should add to the alkene to yield a very
reactive alkyl radical 5, which could attack 4∙, regenerating the MIC catalyst and af-
fording the arylacylated alkene 6.
To check this hypothesis, we treated a mixture of 4-methoxybenzaldehyde 7a, iodo-
benzene 8a, and styrene 9a in tBuOMe with a catalytic amount of different triazolium
salts (1a-1g) in the presence of tBuOK as a base (Figure 4, entries 1–7). When triazo-
lium salt 1a was used, the arylacylation product 6aaa was formed in 13% yield. 4-Un-
substituted triazolium salts 1b and 1c gave better yields (41% and 51%,
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respectively). Low yields were observed for 4-substituted triazolium 1d and 1e. Sur-
prisingly, 4-ester substituted triazolium with Dipp substituents (1f) gave an 85%
yield, whereas the Mes analog 1g only afforded a rather low yield. Solvent screening
showed tBuOMe to be the best choice (entries 8–11). Using tBuONa instead of
t
BuOK led to much lower yields (entry 12). Temperature variation also lowered the
yields (entries 13 and 14). Importantly, other types of NHC precursors, such as imi-
dazolium 1h, thiazolium 1i, and 1,2,4-triazolium 1j, were ineffective for this reaction
(entries 15–17). The control experiment performed in the presence of tBuOK but in
the absence of the MIC catalyst 1f was also carried out, and no reaction was
observed (entry 18). This result ruled out the hypothesis that tBuOK acted as a cata-
lyst or radical initiator in this reaction.44,45 In addition, the reaction was not influ-
enced by light. Either in the presence of light (day light, blue light, green light) or
in the absence of light, similar yields were obtained.
The scope of the MIC-catalyzed three-component arylacylation reaction was inves-
tigated under the optimized conditions as shown in Figure 5. Aromatic aldehydes
with electron-donating groups afforded the arylacylation products in high yields
(6aaa-6daa), whereas an electron-deficient aromatic aldehyde led to a lower yield
(6eaa). meta- and ortho-Substituted aldehydes afforded the corresponding prod-
ucts in 51% and 42% yield, respectively (6faa and 6gaa), which shows that the ste-
ric hindrance has a significant influence on the reaction. Heterocyclic aryl alde-
hydes gave 6haa–6kaa in 30%–61% yields. A variety of electron-donating and
electron-withdrawing groups were tolerated on aryl iodides (6aba–6aga). 2-Iodo-
naphthalene afforded the desired product in 45% yield (6aha). For heteroaromatic
iodides, such as N-methyl-5-iodoindole, 2-iodopyridine, and 3-iodopyridine, the
MIC-catalyzed reactions were accomplished in 43%–65% isolated yields (6aia–
6aka). Substituted styrenes, such as 4-methoxystyrene, 4-methylstyrene, 3-methyl-
styrene, 4-bromostyrene and 2-vinylnaphthalene, were tolerated under the reac-
tion conditions (6aab–6aaf). When 1-phenyl-1,3-butadiene was used instead of
styrene, both 1,2-addition and 1,4-addition products were formed in a 2:1 ratio.
Interestingly, when 2,3-dimethyl-1,3-butadiene was employed, only the 1,4-addi-
tion product was observed in high yield, whereas some base-induced isomeriza-
tion occurred. In all cases, some amount of diarylethanes, benzyl alcohols, and
esters were formed as side products. The former came from H-abstraction of 5,
whereas the latter resulted from reduction of aldehydes by BIMIC. Consequently,
much lower yields were obtained with bulky substrates and easily reducible sub-
strates; in addition, the process is not efficient with aliphatic aldehydes and
alkenes.
To further extend this reaction, we considered compounds 10 featuring a tethered
aryl iodide and an alkene. In all cases, high yields were observed for the intramo-
lecular arylacylation reaction (Figure 6). 1-Allyloxy-2-iodobenzene 10a reacted
with different aldehydes, affording the corresponding products in 65%–84% iso-
lated yields (11aa–11ca and 11ja). Other substrates with different tether atoms
and substituents were also compatible in the cyclization reaction. 1-(Methylally-
loxy)-2-iodobenzene 10b gave the 11ab in 72% yield. Nitrogen-tethered aryl
iodides and alkene moieties (10c–10e) afforded the products 11ac–11ae in 65%–
76% yields. It is noteworthy that allenes can be employed in this reaction. 2-Iodo-
phenyl allenyl ether gave benzofuran 11af in 78% yield. 2-Iodophenyl homoallyl
ether 10g gave the six-membered chromane derivative 11ag in 79% yield. This re-
action can be further expanded to the construction of polycyclic compounds. The
annulation of 2-iodophenyl-cyclohex-3-enyl ether led to tricyclic ketone 11ah as a
single diastereomer, the structure of which was further confirmed by X-ray
6 Chem Catalysis 1, 1–11, June 17, 2021Please cite this article in press as: Liu et al., Mesoionic carbene-Breslow intermediates as super electron donors: Application to the metal-free
arylacylation of alkenes, Chem Catalysis (2021), https://doi.org/10.1016/j.checat.2021.03.004
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Figure 5. Substrate scope of the MIC-catalyzed arylacylation of alkenes
Reaction conditions: aldehyde 7 (0.9 mmol), aryl iodide 8 (0.9 mmol), alkene 9 (0.5 mmol), 1f
(0.05 mmol), and t BuOK (0.75 mmol) in anhydrous t BuOMe (1.5 mL) at 30 C for 4 h; isolated yields
are based on alkenes.
a
4-Phenyl-1,3-butadiene was employed, and the isomer ratio is given in parentheses.
b
2,3-Dimethyl-1,3-butadiene was employed, and the isomer ratio is given in parentheses.
diffraction analysis. The annulation of 2-iodobenzyl-cyclohex-3-enyl ether 10i gave
11ai in 61% yield as two diastereomers in a 1:1 ratio. Interestingly, the reaction of 2-
iodophenyl-cyclohexen-1-ylmethyl ether 10j gave spirocyclohexane 11aj in 21%
yield as a single diastereomer.
Finally, we performed a radical clock reaction under the standard reaction conditions
by using cyclopropylstyrene as the substrate. The reaction gave the cyclopropyl
ring-opening adduct 12 in 25% yield, which confirmed the radical mechanism of
the MIC-catalyzed arylacylation (Figure 7).
Chem Catalysis 1, 1–11, June 17, 2021 7Please cite this article in press as: Liu et al., Mesoionic carbene-Breslow intermediates as super electron donors: Application to the metal-free
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Figure 6. Substrate scope of the MIC-catalyzed annulation and cascade acylation
Reaction conditions: aldehyde 7 (0.9 mmol), o-iodophenyl alkene 10 (0.5 mmol), 1f (0.05 mmol), and
t
BuOK (0.75 mmol) in anhydrous t BuOMe (1.5 mL) at 30 C for 4 h.
a
Isolated yields are based on alkenes.
b
Single isomer; the stereochemistry was not defined.
Conclusions
It was known that haloarenes could stoichiometrically be activated by super electron
donors, but their functionalization was rarely reported under metal-free condi-
tions.42,46,47 Intramolecular arylacylation reactions have only been achieved with
Pd and Ni catalysts.48–51 In this paper, we have shown that BIMICs are among the
most potent organic reducing agents reported to date in the ground state
Figure 7. Radical clock reaction
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( 2.49 V versus Fc/Fc+). This allows BIMICs to activate iodoarenes under mild con-
ditions and to promote the catalytic inter- and intramolecular arylacylation of al-
kenes, which affords a number of substituted ketones and even polycyclic ketones.
Importantly, triazolium salts of type 1, as well as the ensuing MICs, are readily avail-
able in large quantities with a variety of N- and C-substituents, allowing for a fine-
tuning of their reduction potential and steric environment.34,35 The strong reduction
potential of BIMICs should allow for the activation of more challenging bonds than
classical NHCs, such as thiazolylidenes, 1,2,4-triazolylidene, and imidazol(in)yli-
denes, can do. Other types of MICs are either already known, such as the so-called
abnormal NHCs,52,53 or can certainly be prepared and thus are interesting targets
for SET processes.
EXPERIMENTAL PROCEDURES
Full experimental procedures are provided in the supplemental information.
Resource availability
Lead contact
Further information and requests for resources should be directed to and will be ful-
filled by the lead contact, Guy Bertrand (gbertrand@ucsd.edu).
Materials availability
All other data supporting the findings of this study are available within the article and
the supplemental information or from the lead contact upon reasonable request.
Data and code availability
Data relating to the materials and methods, experimental procedures, DFT calcula-
tions, and NMR spectra are available in the supplemental information. Crystallo-
graphic data of substrates 4a∙ ∙ (CCDC: 2047374) and 11ah (CCDC: 2043281) can
be obtained free of charge from the Cambridge Crystallographic Data Center
(http://www.ccdc.cam.ac.uk/structures/). All other data are available from the au-
thors upon reasonable request.
SUPPLEMENTAL INFORMATION
Supplemental information can be found online at https://doi.org/10.1016/j.checat.
2021.03.004.
ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation of China
(21602249), the Fundamental Research Funds for the Central Universities and the
Research Funds of Renmin University of China (program 20XNLG20), the US Depart-
ment of Energy, Office of Science, Basic Energy Sciences, Catalysis Science Program
under award no. DE-SC0009376, and the American Chemical Society Petroleum
Research Fund (60776-ND1).
AUTHOR CONTRIBUTIONS
W.L., Z.Z., and L.H. conducted the experiments and analyzed the data. S.H. carried
out the computational analyses. A.V. and M.M. synthesized and characterized the
BIMIC radical form. G.B. and X.Y. supervised the project. All authors discussed
the results and wrote the paper.
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DECLARATION OF INTERESTS
The authors declare no competing interests.
Received: January 15, 2021
Revised: March 4, 2021
Accepted: March 12, 2021
Published: April 2, 2021
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