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Metal-free Visible-light-induced C-H/C-H Cross Dehydrogenative Coupling (CDC) of Quinoxalin-2(H)-ones with Simple Ethers Wei Wei, Leilei Wang, Hui-Lan Yue, Pengli Bao, Weiwei Liu, Changsong Hu, Daoshan Yang, and Hua Wang ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.8b04652 • Publication Date (Web): 07 Nov 2018 Downloaded from http://pubs.acs.org on November 8, 2018

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ACS Sustainable Chemistry & Engineering

Metal-free Visible-light-induced C−H/C−H Cross Dehydrogenative Coupling (CDC) of Quinoxalin-2(H)-ones with Simple Ethers Wei Wei,*†,‡,§ Leilei Wang,† Huilan Yue,*‡ Pengli Bao,† Weiwei Liu,† Changsong Hu,† Daoshan Yang,†,§ Hua Wang† †

School of Chemistry and Chemical Engineering, Qufu Normal University, Qufu, 57

Jingxuan Road, 273165, Shandong, China ‡

Qinghai Provincial Key Laboratory of Tibetan Medicine Research and Key

Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining, 23 Xinning Road, 810008, Qinghai, China. §

College of Chemistry and Molecular Engineering, Qingdao University of Science

and Technology, Qingdao, 53 Zhengzhou Road, 266042, Shandong, China.

ABSTRACT: A convenient and practical metal-free visible-light-promoted method to synthesize 3-oxyalkylated quinoxalin-2(1H)-ones was developed at room temperature. The present transformation could be accomplished through Rose Bengal-catalyzed C−H/C−H cross-dehydrogenative-coupling (CDC) of quinoxalin-2(H)-ones with simple ethers, providing an efficient and operationally simple method to access various 3-oxyalkylated quinoxalin-2(1H)-ones with moderate to good yields. Keywords: visible-light catalysis, metal-free, cross-dehydrogenative-coupling (CDC), atom-economy, 3-oxyalkylated quinoxalin-2(1H)-ones

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INTRODUCTION Quinoxalin-2(1H)-ones represent a valuable class of structural features that are extensively utilized in synthetic chemistry, materials, and pharmaceuticals.1-3 Especially, C3-substituted quinoxalin-2-ones have drawn increasingly synthetic attention from chemists because the C3-substituted groups play an important role in various significant biological activities.4-6 The installation of functional groups in C3position of quinoxalin-2-ones will offer the chance to extend their applications in pharmaceutical chemistry.1-6 Consequently, much efforts have been made to synthesize C3-substituted quinoxalin-2-ones.7-20 Among them, the functionalization of quinoxalin-2(1H)-ones at C3−H position is regarded as a direct and powerful method to

access

C3-substituted

quinoxalin-2-ones.9-20

Recently,

various

C3−H

functionalization strategies including arylation,9-12 acylation,13,14 phosphonation,15,16 and amination17-19 of quinoxalin-2(1H)-ones have been reported. In 2017, Guo and co-workers also presented an elegant iron-catalyzed C−H cyanoalkylation approach to construct 3-cyanoalkylated quinoxalin-2(1H)-ones from quinoxalin-2(1H)-ones and cyclobutanone oxime esters (Scheme 1(a)).20 Despite the significance of these functionalization reactions, there is still great room to develop new, mild, and convenient approach to synthesize other important C3-substituted products through functionalization of quinoxalin-2(1H)-ones at C3 position. Scheme 1. 3-Alkylation of Quinoxalin-2(H)-ones

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Guo's work: N

N

H

R1

+ N R2

OCOC6H5

O

N

Fe(acac)2 (15 mol %)

H

n

R1

MeCN, 100oC, N2

R3 O

N R2

R3 R4

This work:

n CN

R4

(a)

X N

H

R1

+ N R2

O

X H X= O, S

Rose Bengal (1 mol %) 3 W blue LEDs, rt DABCO (1 equiv) TBHP (1 equiv)

N

(b)

R1 N R2

O

Cyclic ethers as the important structural units are widely found in numerous naturally occurring products and biologically active compounds, which have been demonstrated a wide range of biological and pharmaceutical activities.21-24 Construction of cyclic ether derivatives in complex organic molecules remains a great challenge due to the inertness of simple ethers under many conditions. Since the reported work from Li utilized ethers in cross-dehydrogenative-coupling reactions,2527

the oxidative coupling α-C−H of ethers has became one of the most fascinating

protocols to construct multiple α-substituted ether derivatives because of its atom/step economical and sustainable features.28-33 Although various strategies have been reported for the α-C−H functionalization of ethers, most of these approaches were achieved depending on the use of metal catalysts and high temperature.34-38 The development of a mild and metal-free strategy for cross-dehydrogenative-coupling (CDC) α-C−H bond of simple ethers is still a challenging but highly attractive task. Recently, visible-light catalysis has gained a lot of interest as a very useful protocol for the construction of functionalized organic molecules owing to the advantages of high efficiency, mild conditions, energy-saving, and operation simplicity.38-42 In this context, organic dyes have demonstrated to be promising metalfree photoredox catalysts in various visible-light-promoted organic transformations in term of their cheap and low-toxic features.43-45 With our ongoing studies on

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photoredox catalysis46-49 and green organic synthesis,50-56 we herein describe a simple and convenient visible-light promoted approach to access 3-oxyalkylated quinoxalin2(1H)-ones via Rose Bengal-catalyzed C−H/C−H cross-dehydrogenative-coupling (CDC) of quinoxalin-2(H)-ones with simple ethers under mild conditions (Scheme 1(b)). RESULTS AND DISCUSSION Initially, the reaction of 1-methylquinoxalin-2(1H)-one (1a) with THF (2a, tetrahydrofuran) was carried out to screen the reaction conditions at room temperature under illumination of 3 W blue LED lamps. The product 3a was isolated in 14% yield when the model reaction of 1a and 2a was conducted in the presence of TBHP (70% solution in water, 1 equiv) by using of Na2-Eosin Y as the photocatalyst (Table 1, entry 1). Subsequently, a number of photocatalysts such as Eosin Y, Rhodamine B, Eosin B, Acridine Red, and Rose Bengal were examined. Among them, Rose Bengal was demonstrated to be the best catalytic activity to give 3a in 38% yield (Table 1, entry 6). Further investigation found that the addition of a base has significant affection on reaction efficiency. Pyridine and Na2CO3 resulted in an obvious decrease of the yield of 3a, while Cs2CO3, NaOH, DBU, Et3N and DABCO all promoted the reaction (Table 1, entries 7-13). Among these bases tested, DABCO was the best choice (Table 1, entry 13). Replacing TBHP with other oxidants including H2O2, K2S2O8, TBPB, PhI(OAc)2, and O2 all resulted in lower reaction efficiency (Table 1, entries 14-19). A trace amount of 3a was observed by employing of DTBP as the oxidant (Table 1, entry 20). The product was not detected when reaction was conducted in the absence of oxidant (Table 1, entry 21). To our delight, the highest yield of 3a (90%) was obtained when the amount of Rose Bengal was reduced to 1 mol% (Table 1, entry 22). The increase amount of TBHP did not enhance obviously 4 / 23


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the reaction efficiency (Table 1, entries 23 and 24). Moreover, when the model reaction was carried out under illumination of 3 W green or white LED lamps, the corresponding product 3a was isolated in relatively lower yields (Table 1, entries 25 and 26). In contrast, almost no transformation was observed in the absence of photocatalyst (Table 1, entry 27). It is noteworthy that the reaction did not proceed without light-irradiation (Table 1, entry 28). Table 1. Screening of the Reaction Conditions.a N

H +

N

O

1a

Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

H

O

Rose Bengal (2) Rose Bengal (2) Rose Bengal (2) Rose Bengal (2) Rose Bengal (2) Rose Bengal (2) Rose Bengal (2) Rose Bengal (2) Rose Bengal (2) Rose Bengal (2) Rose Bengal (2) Rose Bengal (2) Rose Bengal (2) Rose Bengal (2) Rose Bengal (2) Rose Bengal (1)

N

Oxidant Base, rt, 24h

N

2a

Photocatalyst (mol %) Na2-Eosin Y (2) Eosin B (2) Rhodamine B (2) Acridine Red (2) Eosin Y (2) Rose Bengal (2)

Photocatalyst 3 W blue LEDs

O O

3a

Oxidant (equiv) TBHP (1) TBHP (1) TBHP (1) TBHP (1) TBHP (1) TBHP (1) TBHP (1) TBHP (1) TBHP (1) TBHP (1) TBHP (1) TBHP (1) TBHP (1) H2O2 (1) K2S2O8 (1) PhI(OAc)2 (1) TBPB (1) O2 (balloon) O2 (1) DTBP (1) -TBHP(1) 5 / 23


Base ----

Yield (%)b 14 16 24

---pyridine Na2CO3 Cs2CO3 NaOH DBU Et3N DABCO DABCO DABCO DABCO DABCO DABCO DABCO DABCO DABCO DABCO

18 33 38 trace 10 78 64 55 63 89 73 71 49 73 63 60 trace 0c 90


23 24 25 26 27 28 a

Rose Bengal (1) Rose Bengal (1) Rose Bengal (1) Rose Bengal (1) -Rose Bengal (1)

TBHP (1.2) TBHP (1.5) TBHP (1) TBHP (1) TBHP (1) TBHP (1)

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DABCO DABCO DABCO DABCO DABCO DABCO

89 90 64d 35e trace 0f

Reaction conditions: 1a (0.2 mmol), 2a (2 mL), Photocatalyst (1-2 mol %), Oxidant ( 0.2 mmol),

Base (0.2 mmol), 3 W blue LEDs, rt, 24 h. b Isolated yields based on 1a. c under N2. d 3 W green LEDs. e 3 W white LEDs. f In the dark.

Under the optimal reaction conditions, the scope of the present transformation was further investigated by employing different quinoxalin-2-one derivatives and simple ethers (Table 2). Generally, various quinoxalin-2(1H)-ones bearing the electron-donating or electron-withdrawing groups react well with THF to provide the corresponding products 3a-3h in moderate to good yields. Substrates including halogen and cyano moieties were all well compatible in the present reaction system, offering a chance for further structural modification. The affection of different Nprotecting groups on this transformation was also examined. To our delight, in addition to N-methyl group, various protecting alkyl groups such as N-butyl, Npropynyl, N-benzyl, N-allylic, N-2-oxo-2-phenylethyl, and N-esteryl groups were also well compatible with the present transformation (3i-3p). In addition, N-aryl groups were also utilized in this reaction to give the corresponding products 3q and 3r in good yields. It should be noted that N-free protected quinoxalin-2(1H)-one derivatives were also suitable substrates to afford the desired products 3s and 3t. Furthermore, the application scope of this protocol was expanded to other cyclic and acyclic ethers. Interestingly,

when

the

α-C−H

mono-substituted

cyclic

ether

(i.g.,

2-

methyltetrahydrofuran) was used as the substrate, the reaction occurred selectively in α-C−H substituted position of ether (3u). It was found that the reactions with 1,3dioxolane and tetrahydrothiophene could proceed smoothly to produce 3-oxyalkylated 6 / 23


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products in 61% and 52% yields (3v and 3w), respectively. Six member cyclic ethers including 1,4-dioxane and tetrahydro-2H-pyran could be employed to generate the desired products, albeit in a relatively lower yields (3x and 3y). Importantly, besides cyclic ethers, chain ethers (i.e., dibenzyl ether and diethyl ether) could also be a suitable substrate, producing the desired products 3z and 3z’ in good yields. Table 2. Visible-light-induced C−H/C−H Cross-Dehydrogenative-Coupling of Quinoxalin-2(H)-ones with Simple Ethers.a,b

N

H

R1

+ N R2 1

O

X H X= O, S

Rose Bengal (1 mol %) 3 W blue LEDs, rt DABCO (1 equiv) TBHP (1 equiv)

2

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X N R1 N R2 3

O


O

O

N O

N O

N c

3a (90%, 86% )

3c (75%) O

N

Cl O

O

N

3d (71%)

N

Cl

N

O

O N

N O

N

O

3f (64%)

O

NC

O

N

O

N

3g (65%)

3h (48%)

3i (85%)

O

O

O

N

N

N O

N

O

N

Cl

3e (72%)

N

Br

O

N

O

N N

F

3b (72%)

O F

O

N

N

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O

N

Ph 3j (83%)

3k (85%) O

O

O

N N

3l (81%) N

N O

O O

N

O

N

Ot Bu 3m (78%)

3n (77%)

3q (82%)

3r (89%)

O

O

3s (42%)

Cl

N

Cl

N H

N

3t (36%) S

O

N

3v (61%)d

3y (37%)d

O

N

O

3x (47%)d

Ph O

O

O N

3w (52%)d

O

N

3u (87%)

N

O

O

N

O

O

N

O

O

N

N

O

N

O

N

O O

Ph 3p (68%)

N

N

N

N

N H

O

O

O

N

3o (82%)

N N

O

Ph

O

3z (72%)d

8 / 23


N N

O O

3z' (88%)d

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a

Reaction conditions: 1 (0.2 mmol), 2 (2 mL), Eosin Y (1 mol %), DABCO (0.2 mmol),

TBHP (70% solution in water, 0.2 mmol), air, rt, 24 h.

b

Isolated yields. c 1a (1 mmol), 54 h.

d

TBHP (0.4 mmol), 36 h.

Several control reactions were carried out to elucidate the possible reaction pathway. Firstly, radical trapping experiment was performed by addition of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) to the model reaction of 1a and 2a, this reaction was completely suppressed and TEMPO-trapped complex (TEMPO-THF) was detected (see Supporting information). The above result suggested that a radical process might exist in this reaction (Scheme 2, (a)). Subsequently, the kinetic isotope effect (kH/kD = 9.0) was obviously observed when an equivalent amount of tetrahydrofuran (2a) and D8-tetrahydrofuran (D8-2a) were employed to react with 1methylquinoxalin-2(1H)-one (1a), which indicated that α-C–H bond cleavage in tetrahydrofuran was the rate determining step in the present reaction (see Supporting information). Moreover, the On/Off light-illumination experiments were also conducted to confirm the affection of visible light exposure, and the result showed that the continuous illumination of light is essential for the present reaction (Figure 1). Scheme 2. Control Reaction Experiments

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N

H

N

H

O

H

H +

N 1a

O 2a

1a

N

O

N

Rose Bengal (1 mol %)

+

DABCO (1 equiv) TBHP (1 equiv) hv, rt, 24h TEMPO

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O +

O

N

O

O

(a)

N

Detected by LC-MS

3a (0%)

D D D

O 2a

Rose Bengal (1 mol %) D

D D D D D D O D D-2a

DABCO (1 equiv) TBHP (1 equiv) hv, rt, 24h k H / k D = 9:1

N N

O

N

D

D O

+

O

3a

N

O

(b)

D D

D-3a 3aa + D-3aa (87%)

Figure 1. Visible light Irradiation on/off Experiments

On the basis of above experimental results and previous related reports,20, 57-68 a possible mechanism for this transformation was presented in Scheme 3. Initially, the excited-state Rose Bengal* was generated by irradiation of blue LEDs. Subsequently, a single electron transfer (SET) between Rose Bengal* and TBHP afforded a hydroxide anion and tert-butyloxy radical. Next, the abstraction of a hydrogen from αC−H of tetrahydrofuran (2a) by tert-butyloxy radical gave an alkoxyalkyl radical intermediate 4a. Then, alkoxyalkyl radical intermediate 4a was added to 1a, thus affording nitrogen radical intermediate 5a. The formed intermediate 5a underwent the 1,2-hydrogen shift to produce carbon radical 5a’, which is oxidized by Rose Bengal•+ to give the carbon cation intermediate 6 through a SET process. Finally, the abstraction of β-H from intermediate 6a by base produced the 3-oxyalkylated product

10 / 23


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3a. Scheme 3. Postulated Reaction Pathway O

H t-BuOOH

2a

OH + t-BuO

O 4a

t-BuOH RB 

RB

H N

hv

N RB

O N

1,2-H Shift

H O

N

O 5a'

5a O

O

H N N

1a

O

N

base -H+

O 6a

N

O

3a

CONCLUSIONS In summary, we have developed a new and environmentally friendly visiblelight-induced strategy for the construction of 3-oxyalkylated quinoxalin-2(1H)-ones via Rose Bengal catalyzed C−H/C−H cross-dehydrogenative-coupling (CDC) of quinoxalin-2(H)-ones with simple ethers at room temperature. The present metal-free method, which employs a cheap and low-toxic catalyst, simple starting materials and mild reaction conditions, offers an atom-economic and environmentally benign route to construct various 3-oxyalkylated quinoxalin-2(1H)-ones with moderate to good yields.

EXPERIMENTAL SECTION General experimental procedures. To a solution of ether 2 (2 mL), Rose Bengal (0.002 mmol, 2 mg, 1 mol %), TBHP (70% solution in water, 0.2 mmol, 28 μl), and DABCO (0.2 mmol, 22.4 mg) was added quinoxalin-2(H)-one 1 (0.2 mmol). The reaction mixture stirred under the irradiation of 3 W blue LEDs at room temperature for 24-36 h. After completion of

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the reaction, the solution was then concentrated in vacuum. The residual mixture was purified through flash column chromatography on a silica gel to afford the 3oxyalkylated quinoxalin-2(1H)-one 3.

ASSOCIATED CONTENT AUTHOR INFORMATION Corresponding Author * E-mail: [email protected] (W. Wei) * E-mail: [email protected] (H. Yue) ORCID Wei Wei: 0000-0002-0015-7636 Daoshan Yang: 0000-0002-3047-5416 Notes The authors declare no competing financial interest.

ACKNOWLEGEMENTS We gratefully acknowledge financial support from the Natural Science Foundation of Shandong Province (ZR2018MB009 and ZR2016JL012), International Cooperation Project of Qinghai Province (2017-HZ-806 and 2018-HZ-806), Qinghai key laboratory of Tibetan medicine research (2017-ZJ-Y11), and National Natural Science Foundation of China (No. 21302110 and 21302109).

Supporting Information Figures giving 1H and

13CNMR

spectra for all compounds are prepared. This

information is available free of charge via the Internet at http://pubs.acs.org/.

REFERENCES 12 / 23


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Table of Contents Graphic A facile and efficient metal-free visible-light-promoted method has been developed for the construction of 3-oxyalkylated quinoxalin-2(1H)-ones via C-H/C-H cross-dehydrogenativecoupling of quinoxalin-2(H)-ones with simple ethers at room temperature. X

Rose Bengal (1 mol %) N

H

R1

+ N R2

O

3 W blue LEDs, rt

X H X= O, S

DABCO (1 equiv) TBHP (1 equiv)

 metal-f ree  room temperature  simple operation  high atom economy  eco-f riendly energy source

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N R1 N R2

O

27 examples up to 90% yield

CâH Cross Dehydrogenative

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