Mesoionic carbene-Breslow intermediates as super electron

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Mesoionic carbene-Breslow intermediates assuper electron donors: Application to themetal-free arylacylation of alkenes

Wei Liu, Adam Vianna, Zengyu

Zhang, ..., Mohand Melaimi,

Guy Bertrand, Xiaoyu Yan

[email protected] (G.B.)

[email protected] (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

mailto:[email protected]



Article

Mesoionic carbene-Breslow intermediatesas super electron donors: Applicationto 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

Classical N-heterocyclic carbenes (NHCs), such as thiazolylidenes,1,2,4-triazolylidenes, and imidazol(in)-2-ylidenes, are powerful or-ganocatalysts for aldehyde transformations through the so-calledBreslow intermediates (BIs). The reactions usually occur via elec-tron-pair-transfer processes. In contrast, the use of BIs in single-electron transfer (SET) pathways is still in its infancy, and the scopeis limited by the moderate reduction potential of BIs derived fromclassical NHCs (ca. �1.0 V versus standard calomel electrode[SCE]). Here, we report that BIs from 1,2,3-triazolylidenes, a typeof mesoionic carbene (MIC), have a reduction potential as negativeas �1.93 V versus SCE and thus are among the most potent organicreducing agents reported to date. They are reductive enough toundergo SETwith iodoarenes, which allows the highly efficient inter-and intramolecular MIC-catalyzed arylacylation of styrenes andalkenes, respectively.

INTRODUCTION

Over the past decades, N-heterocyclic carbenes (NHCs) have been demonstrated to

be powerful organocatalysts for aldehyde transformations.1–6 The umpolung of al-

dehydes by NHCs7 through the formation of nucleophilic Breslow intermediates

(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

The bigger picture

N-Heterocyclic carbenes (NHCs)

have been demonstrated to be

powerful organocatalysts for

carbonyl transformations via the

so-called Breslow intermediates

(BIs). Recently, NHC-catalyzed

reactions via single-electron

transfer (SET) pathways have been

developed but still suffer from the

limitation of moderate reduction

potential of BIs. In this paper,

taking advantage of highly

reductive MIC-derived BIs, we

describe the three-component

coupling reaction of iodoarenes,

alkenes, and aldehydes catalyzed

by mesoionic carbenes (MICs).

This reaction affords various

substituted ketones and even

polycyclic ketones with readily

available substrates.

Chem Catalysis 1, 1–11, June 17, 2021 ª 2021 Elsevier Inc. 1

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Please cite this article in press as: Liu et al., Mesoionic carbene-Breslow intermediates as super electron donors: Application to the metal-freearylacylation of alkenes, Chem Catalysis (2021), https://doi.org/10.1016/j.checat.2021.03.004

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.

RESULTS AND DISCUSSION

Initially, we investigated the electrochemistry of BIMIC 3a, which was prepared by

addition of benzaldehyde to MIC 2a,34–37 generated by deprotonation of 1a (Fig-

ure 2A). The cyclic voltammogram of 3a shows an irreversible redox process be-

tween 3a and 4a∙∙ with an anodic peak potential Epa = �2.49 V and a corresponding

cathodic peak potential Epc = �2.59 V (Figure 2F). This is in agreement with an EC

process38 in which the oxidation of 3a is immediately followed by the easy

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.

1Department of Chemistry, Renmin University ofChina, Beijing 100872, People’s Republic of China

2UCSD-CNRS Joint Research Laboratory (UMI3555), Department of Chemistry andBiochemistry, University of California, San Diego,La Jolla, CA 92093-0358, USA

3Lead contact

*Correspondence: [email protected] (G.B.),[email protected] (X.Y.)


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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)4NPF6 0.1 mol/L).

(G) Cyclic voltammograms of 4a∙∙ in THF (+(nBu)4NPF6 0.1 mol/L).

(H) Cyclic voltammograms of 4a+ in THF (+(nBu)4NPF6 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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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 fromMICs 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

Figure 3. Proposed reaction pathway for the MIC-catalyzed arylacylation of alkenes

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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%,

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 tBuOMe (1.5 mL) for 4 h at 30�C. The reactions were carried out in a

25 mL Schlenk tube.aNMR yields (isolated yields are given in parentheses).btBuONa instead of tBuOK.cThe mixture was stirred at 0�C.dThe mixture was stirred at 50�C.

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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 oftBuOK 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

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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).

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 tBuOK (0.75 mmol) in anhydrous tBuOMe (1.5 mL) at 30�C for 4 h; isolated yields

are based on alkenes.a4-Phenyl-1,3-butadiene was employed, and the isomer ratio is given in parentheses.b2,3-Dimethyl-1,3-butadiene was employed, and the isomer ratio is given in parentheses.

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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 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), andtBuOK (0.75 mmol) in anhydrous tBuOMe (1.5 mL) at 30�C for 4 h.aIsolated yields are based on alkenes.bSingle isomer; the stereochemistry was not defined.

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 ([email protected]).

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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http://www.ccdc.cam.ac.uk/structures/



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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