Copper-Catalyzed Oxidative Fragmentation of Alkynes with NFSI Provides Aryl Ketones

Lin Tang, Fang Yang, Hao Cheng, Chen Tan, Chaochao Jin, Hanfei Chen, Yifan Huang, Shuaifei Zhang,

Letter

Copper-Catalyzed Oxidative Fragmentation of Alkynes with NFSI

Provides Aryl Ketones

Weihan Song, and Jiajing Tan*

Cite This: https://dx.doi.org/10.1021/acs.orglett.0c03201

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sı Supporting Information

ABSTRACT: A copper-catalyzed oxidative cleavage reaction of alkynes using NFSI and TBHP was described. Various terminal and

internal alkyne substrates were employed to render quick access to aryl ketone products in moderate to good yields. NFSI not only

functioned as N-centered radical precursors but also engaged in the aryl group migration. Mechanistic studies also suggested the

important role of water in the title reactions.

he carbon−carbon bond skeleton represents the

Scheme 1. Working Hypothesis

foundation of synthetic organic chemistry. A great deal

of eﬀort has been made to construct such bonds to enable

synthesis of functional materials as well as bioactive molecules.

Nevertheless, the carbon−carbon bond cleavage reactions are

less explored and have recently drawn increasing attention, as

they often oﬀer unique reactivities. In particular, alkynes are

well-recognized as one of the most important synthons used in

organic reactions. Compared to their alkane and alkene

counterparts, the cleavage of alkyne functionality remains to be

an elusive task, which is probably due to the high energy barrel

associated with such functionality.

Traditional strategies toward alkyne bond cleavage often

suﬀered from utilizing stoichiometric amounts of organo-

metallic reagents or strong oxidants (Scheme 1). In addition

to alkyne metathesis, catalytic fragmentation of alkynes has

witnessed a resurgence of interest. Recently, many eﬃcient

synthetic protocols have been demonstrated. For instance,

Jiao, Shi, and co-workers developed a gold-catalyzed

fragmentation reaction of alkynes for the concomitant

synthesis of amino tetrazoles and carbamides. Later, Bi et

al. disclosed a silver-catalyzed terminal alkyne cleavage reaction

to synthesize amidines. Although these methods were useful

to a certain degree, most of them required using precious metal

catalysts including Pd, Au, Ag, Rh, Ru, etc. To the best of our

knowledge, direct transforming alkynes to ketones are also rare

abundant copper catalysts. At the onset of our project, we

noticed in the literature that the combination of copper

catalyst and NFSI (N-ﬂuorobenzenesulfonimide) eﬀectively

in literatures reports, despite the fact that ketones are not only

important synthetic intermediates but also useful motifs widely

present in active pharmaceutical gradients, natural products,

Received: September 24, 2020

and advanced materials.

In view of this above-mentioned synthetic gap and our

interest in radical reactions, we hence decided to focus on the

ketone synthesis from simple alkyne cleavage using earth-

XXXX American Chemical Society

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

enabled the addition of N-radicals to alkynes, and the resulting

activated vinyl radical species upon aryl migration could aﬀord

performed under air or oxygen conditions, no higher yield was

obtained (entries 19 and 20).

Under the optimal reaction conditions, we next surveyed the

scope of terminal alkynes (Scheme 2). In general, both

a variety of multifunctionalized products. Notwithstanding

such progress, we questioned whether incorporating extra

oxidants could facilitate the cleavage of Cu/NFSI-activated

alkyne intermediates to furnish the overall alkyne cleavage

products. From a conceptual standpoint, our “addition

activation” and “oxidative cleavage” strategy ought to be

challenging, as Cu(II)/TBHP were well-known to convert

a,b

Scheme 2. Substrate Scope for Alkylation Reaction

alkynes to multiple type of radical species. Furthermore, the

copper-mediated oxidative homocoupling of alkyne might be

problematic. Nevertheless, we herein report a Cu/TBHP-

mediated alkyne cleavage reaction to synthesize aryl ketones

with NFSI as both the radical and aryl sources. Our protocol

displays great substrate scope and is amenable to both terminal

and internal alkynes. Detailed mechanistic studies and scale-up

experiments were also performed (Table 1).

a b

Table 1. Reaction Condition Optimization

entry

variation from standard conditions

yield (%)

none

CuO as catalyst

CuBr as catalyst

Cu(OAc) H O as catalyst

CuI as catalyst

Cu(NO ) ·3H O

Cu(CF SO )

3 2

FeSO ·7H O as catalyst

AgNO as catalyst

trace

N.D.

H O as oxidant

DTBP as oxidant

DCP as oxidant

DCE as solvent

PhMe as solvent

THF as solvent

DMSO as solvent

DMF as solvent

under air

under O₂

a (0.30 mmol), NFSI (2.0 equiv), catalyst (20 mol %), oxidant (3.0

equiv), solvent (2 mL), 80 °C, 4 h, N atmosphere. Isolated yield.

TBHP = tert-butyl hydroperoxide; DTBP = di-tert-butyl hydro-

1 (0.30 mmol), 2a (2.0 equiv), CuSO (20 mol %), TBHP (3.0

peroxide; DCP = dicumyl peroxide.

equiv), CH CN (2 mL), 80 °C, 4 h, N atmosphere. Isolated yield.

5 °C. NFSI (4.0 equiv) and TBHP (5.0 equiv) used.

Guided by the general design, we commenced our

investigation using readily available ethynylbenzene (1a) and

NFSI (2a) as the model substrates. Extensive optimization

studies eventually led to the bond breakage product 3aa in

good yields. With copper(II) sulfate as the catalyst, TBHP as

the oxidant, NFSI as the arylation reagent in acetonitrile at 80

electron-donating (−Me and −n-C H ) and electron-with-

drawing (−F, −Br, −CF , −CN, −NO , and −Cl) groups at

aryl acetylenes were found to be well-tolerated, giving

corresponding diaryl ketone products in 44%−82% yields

(3ab−3an). The alkyne bearing the naphthyl group was also

amenable, giving 3ao in 38% yield. Heterocyclic motifs such as

thienyl and pyridine rings were also tolerated to aﬀord 3ap and

C, the title transformation provided 3aa in 81% isolated yield

under nitrogen atmosphere. We next screened other metal

catalysts, but all of them failed to oﬀer better results (entries

3aq in 35 and 78% yields, respectively. Notably, the benzylic

functionality was well tolerated, even though it is well-known

to be easily oxidized in the presence of metal catalyst and

−10). Further exploration on other peroxides suggested that

TBHP be the optimal oxidant (entries 11−13). Finally, studies

on screening various solvent failed to improve the isolated

yield (entries 14−18). Additionally, when the reaction was

TBHP.

Terminal alkyl acetylenes that were usually

challenging for classical approaches proceeded smoothly in

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

this case to deliver corresponding alkyl aryl ketones (3at−3ax)

in good eﬃciencies. Furthermore, we examined the bis-alkyne

substrate 1w. Both monoketone (3aw) and double-ketone

Scheme 4. Synthetic Applications

(3aw′) products could be obtained in 43% and 52% yield,

respectively, depending on the amount of TBHP and NFSI

used. Moreover, we found that alkynes bearing ester groups

were capable of aﬀording the desired products 3ax and 3ay.

Once the versatility of terminal alkyne was demonstrated, we

then focused our attention on the more challenging internal

alkyne substrates (Scheme 3). Unsymmetrical internal alkynes

a,b

Scheme 3. Substrate Scope for Acylation Reaction

the presence of 20 mol % of CuSO , aﬀording 3aa and 3bd in

8% and 65% yields, respectively.

To investigate the mechanistic pathway, a series of control

experiments were conducted (Scheme 5). In the absence of

either NFSI or TBHP, no target products were observed,

suggesting both of these reagents were indispensable. Next, the

Scheme 5. Control Experiment and Plausible Mechanism

(0.30 mmol), 2a (2.0 equiv), CuSO (20 mol %), TBHP (3.0

equiv), CH CN (2 mL), 80 °C, 4 h, N atmosphere. Isolated yield.

with both aliphatic and phenyl substitution groups were

applied to this transformation, all of which predominately

rendered the diaryl ketone products (3aa) in good yields (61−

7%), which were probably due to the stabilization of

corresponding intermediates enabled by aromatic rings.

Moreover, symmetric aliphatic internal alkynes 1bd and 1be

were successfully employed to oﬀer the target ketones 3bd and

av in 88 and 85% yields, respectively. When 1,2-

diphenylethyne was used as the substrate, both benzophenone-

3aa) and benzil (3bf) were obtained as a 1:3 mixture.

(

Unfortunately, the reaction of cyclododecyne 1bg with NFSI

could not give the corresponding aryl ketone.

To demonstrate the synthetic value of our approach, we

performed the gram-scale experimentations (Scheme 4). The

fragmentation reaction of 10 mmol 1a or 1bd with excess

amount of NFSI and TBHP proceeded smoothly within 4 h in

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Complete contact information is available at:

Letter

radical-trapping experiment with 2,2,6,6-tetramethyl-1-piper-

idinyloxy (TEMPO) was performed under otherwise identical

conditions. No desired product was obtained, supporting a

radical based reaction pathway. Switching the aqueous solution

of TBHP to corresponding decane solution, 3aa was obtained

Chaochao Jin − Department of Organic Chemistry, College of

Chemistry, Beijing University of Chemical Technology (BUCT),

Beijing 100029, China

Hanfei Chen − College of Chemistry and Chemical Engineering,

Xinyang Normal University, Xinyang 464000, China

Yifan Huang − College of Chemistry and Chemical Engineering,

Xinyang Normal University, Xinyang 464000, China

Shuaifei Zhang − College of Chemistry and Chemical

Engineering, Xinyang Normal University, Xinyang 464000,

China

only with 39% yield. When using H O along with TBHP

decane solution, the O -labeling products were also observed.

These control experiments were consistent with the hypothesis

that water played an important role in the title transformations.

Furthermore, we have carefully checked the reaction proﬁles

and determined that aldehyde 4 was the major byproducts in

certain cases.

Weihan Song − College of Chemistry and Chemical Engineering,

Xinyang Normal University, Xinyang 464000, China

Based on these experimental results and literature

https://pubs.acs.org/10.1021/acs.orglett.0c03201

0,15

precedents,

we propose the following tentative reaction

mechanism. The transformation started with the oxidation of

Cu(II) to Cu(III) complex by NFSI. The resulting nitrogen

radical added to alkyne, which then underwent tandem 1,4-aryl

Notes

The authors declare no competing ﬁnancial interest.

migration, extrusion of SO and isomerization to form the α-

imino carbon radical E. Subsequently, E is converted to the α-

imino alcohol F through the reduction of Cu(III) complex to

Cu(II) in the presence of water. Intermediate F underwent the

hydrolysis, and decarbonylation cascade to generate the ﬁnal

product 3aa. In addition, the radical addition of TBHP to E

could aﬀord the α-imino ether H, which oﬀered the side

product 4aa through hydrolysis.

ACKNOWLEDGMENTS

■

L.T. is grateful for the support of the National Natural Science

Foundation of China (21602190) and the Nanhu Scholars

Program for Young Scholars of XYNU. J.J.T. is grateful for the

support of the National Natural Science Foundation of China

21702013) and the Fundamental Research Funds for the

Central Universities (XK1802-6) at Beijing University of

Chemical Technology.

(

To summarize, we developed a CuSO -catalyzed tandem

radical migration and oxidative cleavage reaction of alkynes

with a unique mechanistic pathway. This protocol employed

earth-abundant cooper salts as catalysts and was amenable to

both internal and terminal alkynes oﬀering an alternative

approach toward aryl ketone synthesis. NFSI served as both an

N-radical precursor and an arylation reagent, while TBHP

facilitated the oxidative cleavage. Further studies on reaction

mechanism are currently underway in our laboratory.

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ASSOCIATED CONTENT

sı Supporting Information

■

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.orglett.0c03201.

Experimental procedure, alkyne synthesis, GC-MS and

HRMS analyses of the reaction mixture involving H O ,

characterization data, and NMR spectra of all products

(PDF )

orcid.org/0000-0003-0477-2481

AUTHOR INFORMATION

Corresponding Author

■

Jiajing Tan − Department of Organic Chemistry, College of

Chemistry, Beijing University of Chemical Technology (BUCT),

Beijing 100029, China; orcid.org/0000-0003-3825-9344;

Email: tanjj@mail.buct.edu.cn

Authors

Lin Tang − College of Chemistry and Chemical Engineering,

Xinyang Normal University, Xinyang 464000, China;

Fang Yang − College of Chemistry and Chemical Engineering,

Xinyang Normal University, Xinyang 464000, China

Hao Cheng − College of Chemistry and Chemical Engineering,

Xinyang Normal University, Xinyang 464000, China

Chen Tan − Department of Organic Chemistry, College of

Chemistry, Beijing University of Chemical Technology (BUCT),

Beijing 100029, China

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