Copper-Catalyzed Selenylation of Imidazo[1,2-a]pyridines with

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Copper-Catalyzed Selenylation of Imidazo[1,2a]pyridines with Selenium Powder via a Radical Pathway Pengfei Sun, Min Jiang, Wei Wei, Yuanyuan Min, Wen Zhang, Wanhui Li, Daoshan Yang, and Hua Wang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02865 • Publication Date (Web): 21 Feb 2017 Downloaded from http://pubs.acs.org on February 22, 2017

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The Journal of Organic Chemistry

Copper-Catalyzed Selenylation of Imidazo[1,2-a]pyridines with Selenium Powder via a Radical Pathway Pengfei Sun,a Min Jiang,b Wei Wei,a Yuanyuan Min,c Wen Zhang,a Wanhui Li,a Daoshan Yang,*a and Hua Wang*a a

Institute of Medicine and Materials Applied Technologies, School of Chemistry and

Chemical Engineering, Qufu Normal University, Qufu 273165, Shandong, P. R. China. b

Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology

(Ministry of Education) Department of Chemistry, Tsinghua University Beijing 100084 (China) c

Laboratory and equipment management department, Qufu Normal University, Qufu

273165, Shandong, P. R. China *E-mail: [email protected]; [email protected]

ABSTRACT: A convenient and efficient approach for the formation of nitrogen heterocycle-fused imidazo[1,2-a]pyridine and benzo[b]selenophenes has been developed through copper-catalyzed

direct

selenylation

of

readily

available

2-(2-bromophenyl)imidazo[1,2-a]pyridines via regioselective cleavage of C(sp2)−Br and

C(sp2)−H

bonds

using

readily

available

selenium

powder

as

the

selenylating reagents under ligand- and base-free conditions in air. Preliminary

ACS Paragon Plus Environment


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mechanistic investigations indicated that radical species were involved in the present transformation.

INTRODUCTION: The organoselenium compounds are becoming increasingly important because of their potential biological and medical properties, for example they have antihypertensive, antiviral, anticancer, antimicrobial, and antimicrobial properties.1 In addition, they are important scaffolds in material chemistry,2 and have also been used as versatile reagents in organic synthesis and catalysis.3 This section has been changed to “Hence, developing efficient and novel methods for C-Se bonds formation has always been a research goal of a chemist. Generally, the cross-coupling of boronic acids/aryl halides with selenium sources under transition-metal-catalyzed conditions have been proven to be efficient approaches for the construction of C–Se bonds.4-7 However, the not easily available precursors and selenylation reagents might hamper their wide applications in the pharmaceutical and material industry. From an atomand step-economy stand-point, C−H bonds activation is a fundamental important process in organic chemistry.8 However, research surveys of this synthetic strategy for the C−Se bond construction is surprisingly scarce when compared to the synthesis of C−X (heteroatom) bonds.9 In these protocols, selenylating reagents mainly focus on diselenides and selenyl chlorides which are usually prepared from arylselenols with unpleasant odors and instability.10 Obviously, directly using selenium powder as selenylating reagents for the reaction is most preferred. Unfortunately, reports on the C-H selenylation through directly using selenium powder under catalytic conditions


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are rather limited.11 The imidazo[1,2-a]pyridine framwork is found in numerousnatural products and biological molecules.12 In addition, they are also found in numerous commercially available drugs, such as alpidem,13 raloxifene,14 minodronic acid,15 and zolimidine.16 Futhermore, imidazo[1,2-a]pyridine and its analogues are widely used in the fields of optoelectronics and material sciences as charge transporters.17 Thus, the development of convenient and novel approaches for imidazo[1,2-a] pyridine synthesis and functionalization has received much attention in organic chemistry.18 On the other hand, benzo[b]selenophenes have also received much more attentions owing to their potential biological activity, optical activity, and synthetic utility.19, consequence,

seeking

for

an

efficient

method

for

the

20

As a

formation

of

benzo[b]selenophene/imidazo[1,2-a]pyridine skeletons might be meaningful in pharmaceutical and material chemistry. Recently, using controllable radical chemistry to construct diverse organic molecules has been of growing interest.21 As a continuation of our research interest in chalcogenide molecules synthesis,22 herein, we report

an

efficient

and

simple

approach

for

construction

of

benzo[b]selenophene/imidazo[1,2-a]pyridine framworks using copper catalysis through C-Br and C-H bond functionalization via a radical pathway (Scheme 1).23 Scheme 1. Different Pathways for the Synthesis of C–Se Bonds



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RESULTS AND DISCUSSION In

order

to

explore

the

optimal

catalysis

conditions,

1a

(2-(2-bromophenyl)imidazo[1,2-a]pyridine) and 2 (elemental selenium) were chosen as the standard substrates to investigate the model coupling reaction. As shown in Table 1, the copper salts (10 mol % amount relative to 1a), CuCl, CuBr, CuI, Cu2O, CuO and CuCl2, were investigated in DMSO using K2CO3 (2 equiv ) as the base and 20 mol % 1,10-phenanthroline as the ligand at 130 oC (entries 1-7), validating that CuI was the most effective catalyst (entry 3). Interestingly, control experiments revealed that the ligand and base were not necessary for this transformation, and a higher yield was obtained in the absence of 1,10-phenanthroline and K2CO3 (entry 8, 9 and 10). Next, we studied the influence of solvents on the reaction, and DMF showed the higher activity (compare entries 10-14). Subsequently, we also investigated the effect of the reaction temperature, indicating 130 oC might be more suitable for this transformation (compare entries 11, 15 and 16).


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Table 1. Screening the Optimal Reaction Conditions.a

Entry

Cat.

Additive

Solvent

Yield [%]b,c

1

CuCl

L/K2CO3

DMSO

52

2

CuBr

L/K2CO3

DMSO

71

3

CuI

L/K2CO3

DMSO

74

4

Cu2O

L/K2CO3

DMSO

30

5

CuO

L/K2CO3

DMSO

42

6

CuCl2

L/K2CO3

DMSO

26

7

CuBr2

L/K2CO3

DMSO

21

8

CuI

L

DMSO

69

9

CuI

K2CO3

DMSO

Trace

10

CuI

None

DMSO

80

11

CuI

None

DMF

85

12

CuI

None

NMP

21

13

CuI

None

toluene

13d

14

CuI

None

1,4-Dioxane

30d

15

CuI

None

DMF

82e

16

CuI

None

DMF

78f

a

Reaction conditions: 1a (0.3 mmol), selenium powder 2 (0.6 mmol), catalyst (0.03 mmol), L = 1,10-phenanthroline (0.06 mmol), and K2CO3 (0.6 mmol) in 2 mL of solvent. b Isolated yield. c Under air atmosphere.d In a sealed Schlenk tube. e at 140 oC. f at 120 oC.



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After obtaining those optimum reaction conditions, we evaluate the generality and the scope of substrates for the copper-catalyzed regioselective selenylation reactions (Table 2). Satisfactorily, most of the investigated substrates gave moderate to good yields. Next, we also investigated the electronic effect of the transformation. To our delight, any aryl ring of imidazopyridines bearing electron-donating and -withdrawing groups could be well tolerated, showing no obvious electronic effect in this transformation. Additionally, the hindrance effect of this reaction was also not obvious, imidazopyridines bearing a methyl group at different positions could efficiently reacted

with

selenium

powder,

giving

the

corresponding

benzo[b]selenophene/imidazo[1,2-a]pyridine products in good yields (3n, 3o, 3p and 3q). Fortunately, 6-(2-bromophenyl)imidazo[2,1-b] benzo[d]thiazole was found to be suitable substrate in this transformation, giving the selenylation product in moderate yield (3u). Various substituted groups were tolerated under the current reaction conditions, including methoxy, methyl, C−Cl bond, and C−Br bond (3b, 3d, 3h, 3i and 3s).


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Table

2.

The

Scope

with

Respect

to

the

2-(2-bromophenyl)imidazo[1,2-a]pyridines a, b,c

Me

N

N

N

N Se 3b (84%)

N Se 3a (85%) N

N Se 3c (82%)

Me

N

N N

Se 3d (80%)

Se 3e (78%)

Cl

N Cl

3g (86%)

Cl

N

Se Br

N N

F 3l (77%)

N F

3m (88%)

Me

F

F Br

N Se 3o (73%) N

N

N N

F Se

Se 3p (82%)

F

N

3r (76%) N

MeO

N

Se 3s (74%)

N Se

Me

S N

OMe

F

N

Se Me

3q (84%)

N

Me

N

N Se 3n (82%)

Cl

N

Se

Se 3k (78%)

N

CF3

3i (75%)

OMe

Cl

N Se

Cl

N

3j (80%)

Me

N

N Se 3h (79%)

Cl

N

Se

Br

Me

N Cl

N Se 3f (79%)

N N

Se

F

Cl

N

N

3t (75%)

a

Se 3u (50%)

Reaction conditions: 1 (0.3 mmol), selenium powder 2 (0.6 mmol), and CuI (0.03 mmol) in 2 mL of DMF. b Isolated yield. c Under air atmosphere.



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In order to illuminate the mechanism of the current transformation, some preliminary experiments were performed (Scheme 2). Treatment of 1a with selenium powder in the presence of two equivalent of 2,2,6,6-tetramethylpiperidinyl-1-oxy (TEMPO). Notably, the formation of the desired product 3a was suppressed (Eq. 1. Scheme 2), implying this chemistry might be a radical pathway. Treatment of 1a and 2 under a nitrogen atmosphere (Eq. 2. Scheme 2), the selenylation product 3a was not observed, which demonstrates that dioxygen is necessary in the present transformation. Additionally, treatment of 1a with 2 in the absence of CuI, and no conversion was observed, indicating that the copper catalysis might be necessary in this reaction (Eq. 3. Scheme 2). Interestingly, the diselenide 5 was obtained in 70% yield, when the reaction of 2-phenylimidazo[1,2-a]pyridine 4 with elemental selenium 2 was performed under optimal reaction conditions (Eq. 4. Scheme 2). In order to trap the radical species, two equivalent of TEMPO was added into the current reaction solution, the formation of trapping product of vinyl radical was detected by GC−MS analysis (Eq. 5. Scheme 2, see Supporting Information for more details). Furthermore, no

desired

product

3a

was

detected

when

using

3-bromo-2-(2-bromophenyl)imidazo[1,2-a]pyridine as the substrate (Eq. 5. Scheme 2). These above preliminary experimental results strongly support that II (see Scheme 3) might be the important radical intermediate in the whole reaction.


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Scheme 2. Control Experiment for Mechanistic Studies.

N N Br

+ Se 2

DMF, 130 oC, air TEMPO

N

DMF, 130 oC, N2

N

without CuI N

+ Se 2

DMF, 130 oC, air

1a

(2)

N

Se 3a trace

1a

N

Br

N

CuI

+ Se 2

(1)

N

Se 3a trace

1a

N

Br

N

CuI

(3)

N

Se 3a Not observed N N

N N H

+ Se 2

DMF, 130 oC, air

(4)

Se Se

CuI N

N

4

5 (70%)

Me

N N N Br

1c

Me CuI + Se o 2 DMF, 130 C, air, 3h TEMPO (2 equiv) Examined by ESI-MS

N (5)

Br O N 6 Detected by ESI-MS

Br

N

N N

+ Se 2

CuI DMF, 130 oC, air

Br 7

Se 3a 0%

N

(7)

To gain more insights into this selenylation process, a series of mechanistic studies by Electron spin resonance (ESR) spectra was performed. Firstly, a mixture of CuI, 1a and selenium powder 2 in DMF was tested at room temperature and 130 °C,



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respectively (Fig. 1a). As a result, an ESR signal (g = 2.001) was detected at 130 °C (Fig. 2a, brownness line). In addition, the same signal was also obtained in the absence of selenium powder 2 at 130 °C (Fig. 1a, light green line). Moreover, when α-phenyl-N-tert-butyl nitrone (PBN), a well known free-radical spin-trapping agent, was added to the solution of CuI and 1a, a signal of the trapping radical was observed (g = 2.004, AN = 1.46 mT, AH = 0.24 mT) under the standard conditions (Fig. 1b, red line); however, no radical signal was detected under a nitrogen atmosphere (Fig. 1b, green line). To our delight, a stronger signal was observed when selenium powder 2 was added to the above solution (Fig. 1b, royalblue line). It should be noted that Cu(II) signal (g//=2.28, g⊥=2.07) was observed under the standard conditions. However, treatment of CuI and air only, no Cu(II) signal was detected (Fig. S3, ESI†). Those data illustrated that a radical specie could be generated in the presence of 1a and CuI under aerobic conditions.


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Figure 1. (a) Electron Spin Resonance (ESR) Spectra of the Different Reaction Conditions. (b) ESR Spectra of PBN-Radical Adduct.

Based on the above preliminary results, a plausible mechanism would be herein presented (Scheme 3). Firstly, the Cu(I) is oxidized to Cu(II) by oxygen in air. The single electron transfer takes place between 1a and Cu(II) that generates radical cation I. The intermediate I loses a proton leading to vinyl radical intermediate II, which reacts with elemental selenium to give a selenium free radical III.

Subsequently, the

radical III undergoes an intramolecular cyclization to generate radical intermediate IV. Finally, Cu(I)-mediated bromine abstraction of radical intermediate IV takes place, releasing the product 3a, Br-, and Cu(II).



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Page 12 of 26

Scheme 3. Plausible Mechanism O2

Cu (II)

N

Cu(I)

N

N Br

N + Br

1a

I

N Se . 3a Br

H+

N N N

Cu (II)

Br

II Se 2

Cu (I) N

N

Br

Se IV

.

N

.

N

Br Se III

We have developed an novel and convenient method for the construction of imidazo[1,2-a]pyridine/benzo[b]selenophene skeletons through a copper-catalyzed direct selenylation of readily available 2-(2-bromophenyl)imidazo[1,2-a]pyridines via regioselective cleavage of C(sp2)−Br and C(sp2)−H bonds. The protocol develops a novel model of C–Se bond formation in organic chemistry. Despite some great advantages, this protocol could encounter certain limitations, including high reaction temperature, long reaction time, and metal salt catalysts. As a consequence, it still has much room for improvement.

EXPERIMENTAL SECTION


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General. All reagents used in the manuscript were purchased from the chemical companies. They are all used directly without purification. Imidazo[1,2-a]pyridines were prepared according to previous literatures.24 200-300 mesh silica gel was used as the stationaly phase in column chromatography. 1H NMR spectra were obtained on a BRUKER 500 spectrometer (500 MHz).

13

C NMR spectra were also obtained on a BRUKER 500

spectrometer (500 MHz). Tetramethylsilane (TMS) was used as the internal standard in CDCl3 or DMSO-d6 . EPR spectra were recorded on a JES FA200 (JEOL Co.) spectrometer. HRMS and Mass analyses were recorded by ESI on a TOF mass spectrometer. General experimental procedures. CuI (0.03 mmol), substituted 2-(2-bromophenyl)imidazo[1,2-a]pyridines (1) (0.3 mmol), Se (0.6 mmol), and DMF (2 mL) were added in an over-dried Schlenk tube (25 mL) in sequence. Then the reaction solution was heated at 130oC for 30 h under an air atmosphere. When the time is up, a small portion of silica gel was added to the resulting solution, and the solvent was evaporated by using a rotary evaporator. Finally, the desired product 3 was obtained through column chromatography operation (petroleum ether/ethyl acetate = 10:1–6:1). Compound 3a: Eluent petroleum ether/ethyl acetate (6:1). Yellow solid, 69 mg, 85% yield, mp 205-206 oC. 1H NMR (CDCl3, 500 MHz, ppm) δ 8.27 (d, 1H, J = 10.0 Hz), 7.98 (d, 1H, J = 5.0 Hz), 7.84 (d, 1H, J = 10.0 Hz), 7.72 (d, 1H, J = 10.0 Hz), 7.48 (t, 1H, J = 10.0 Hz), 7.32 (t, 1H, J = 10.0 Hz), 7.19 (t, 1H, J = 10.0 Hz), 6.81 (t, 1H, J =



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10.0 Hz).

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13

C NMR (CDCl3, 125 MHz, ppm) δ 149.5, 148.0, 140.3, 140.0, 127.0,

125.9, 125.8, 124.6, 124.4, 123.0, 118.4, 118.3, 112.2. HRMS m/z calcd. for C13H8N2NaSe [M+Na]+: 294.9745, found: 294.9750. Compound 3b: Eluent petroleum ether/ethyl acetate (6:1). Yellow solid, 72 mg, 84% yield, mp 210-211 oC. 1H NMR (CDCl3, 500 MHz, ppm) δ 8.27 (d, 1H, J = 10.0 Hz), 7.88-7.84 (m, 2H), 7.66 (d, 1H, J = 10.0 Hz), 7.51 (t, 1H, J = 10.0 Hz), 7.34 (t, 1H, J = 10.0 Hz), 7.10 (d, 1H, J = 10.0 Hz), 2.38 (s, 3H). 13C NMR (CDCl3, 125 MHz, ppm) δ 148.5, 147.8, 140.2, 131.1, 128.9, 127.7, 127.0, 125.9, 125.7, 123.0, 122.4, 122.1, 117.6. HRMS m/z calcd. for C14H10N2NaSe [M+Na]+: 308.9901 , found:308.9895 Compound 3c: Eluent petroleum ether/ethyl acetate (8:1). Yellow solid, 71mg, 82% yield, mp 183-185 oC. 1H NMR (CDCl3, 500 MHz, ppm) δ 8.36 (d, 1H, J = 10.0 Hz), 7.90 (d, 1H, J = 10.0 Hz), 7.87 (d, 1H, J = 5.0 Hz), 7.51 (t, 1H, J = 10.0 Hz), 7.34 (t, 1H, J = 10.0 Hz), 7.01 (d, 1H, J = 5.0 Hz), 6.78 (d, 1H, J = 5.0 Hz), 2.74 (s, 3H). 13C NMR (CDCl3, 125 MHz, ppm) δ 150.0, 147.7, 140.1, 131.2, 128.3, 127.0, 125.7, 125.6, 123.3, 123.2, 122.6, 118.9, 112.2, 17.4. HRMS m/z calcd. for C14H10N2NaSe [M+Na]+: 308.9901, found: 308.9895. Compound 3d: Eluent petroleum ether/ethyl acetate (8:1). Yellow solid, 73 mg, 80% yield, mp 178-180 oC. 1H NMR (CDCl3, 500 MHz, ppm) δ 8.28 (d, 1H, J = 10.0 Hz), 8.15 (s, 1H), 7.88 (d, 1H, J = 10.0 Hz), 7.65 (d, 1H, J = 5.0 Hz), 7.53 (t, 1H, J = 10.0 Hz), 7.38 (t, 1H, J = 10.0 Hz), 7.32 (dd, 1H, J = 10.0 Hz).

13

C NMR (CDCl3, 125

MHz, ppm) δ 148.9, 140.3, 130.9, 130.6, 128.8, 127.0, 126.3, 126.1, 125.8, 123.3, 122.5, 120.5, 118.5. HRMS m/z calcd. for C13H7ClN2NaSe [M+Na]+: 328.9355,


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found: 328.9362. Compound 3e: Eluent petroleum ether/ethyl acetate (8:1). Yellow solid, 82 mg, 78% yield, mp 161-162 oC. 1H NMR (CDCl3, 500 MHz, ppm) δ 8.27 (d, 1H, J = 10.0 Hz), 8.24 (s, 1H), 7.88 (d, 1H, J = 10.0 Hz), 7.72 (d, 1H, J = 10.0 Hz), 7.54 (t, 1H, J = 10.0 Hz), 7.38 (t, 1H, J = 10.0 Hz), 7.23 (dd, 1H, J = 10.0 Hz).

13

C NMR (CDCl3, 125

MHz, ppm) δ 148.8, 147.9, 140.3, 130.6, 127.7, 127.4, 127.0, 126.3, 126.1, 124.6, 123.3, 118.8, 106.8. HRMS m/z calcd. for C13H7BrN2NaSe [M+Na]+: 372.8850, found: 372.8858, 374.8862. Compound 3f: Eluent petroleum ether/ethyl acetate (8:1). Yellow solid, 76 mg, 79% yield, mp 180-182 oC. 1H NMR (CDCl3, 500 MHz, ppm) δ 8.14 (d, 1H, J = 10.0 Hz), 8.83 (s, 1H), 7.64 (d, 1H, J = 10.0 Hz), 7.47 (d, 1H, J = 10.0 Hz), 7.11 (d, 1H, J = 10.0 Hz), 2.38(s, 3H). 13C NMR (CDCl3, 125 MHz, ppm) δ 148.7, 146.8, 140.9, 131.1, 129.6, 128.8, 127.9, 126.6, 126.4, 123.4, 122.3, 122.2, 117.6, 18.2. HRMS m/z calcd. for C14H9ClN2NaSe [M+Na]+: 342.9512, found: 342.9517. Compound 3g: Eluent petroleum ether/ethyl acetate (8:1). Yellow solid, 87 mg, 86% yield, mp 270-271 oC. 1H NMR (DMSO-d6, 500 MHz, ppm) δ 9.33 (s, 1H), 8.36 (s, 1H), 8.06 (d, 1H, J = 10.0 Hz), 7.57 (d, 1H, J = 10.0 Hz), 7.55 (d, 1H, J = 10.0 Hz), 7.40 (d, 1H, J = 10.0 Hz).

13

C NMR (DMSO-d6, 125 MHz, ppm) δ 147.8, 147.9,

142.9, 130.4, 129.6, 127.8, 126.4, 126.3, 125.1, 123.5, 120.8, 119.4, 118.6. HRMS m/z calcd. for C13H6Cl2N2NaSe [M+Na]+: 362.8965, found: 362.8972. Compound 3h: Eluent petroleum ether/ethyl acetate (8:1). White solid, 91 mg, 79% yield, mp 262-263 oC. 1H NMR (CDCl3, 500 MHz, ppm) δ 8.25 (s, 1H), 8.17 (d, 1H, J



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= 10.0 Hz), 8.88 (s, 1H), 7.67 (d, 1H, J = 10.0 Hz), 7.50 (d, 1H, J = 10.0 Hz), 7.33 (d, 1H, J = 10.0 Hz).

13

C NMR (CDCl3, 125 MHz, ppm) δ 148.1, 147.9, 141.0, 131.8,

130.9, 129.1, 128.8, 128.1, 126.7, 126.6, 124.6, 123.7, 118.8, 107.1. HRMS m/z calcd. for C13H6BrClN2NaSe [M+Na]+: 406.8460, found:406.8466,408.8469. Compound 3i: Eluent petroleum ether/ethyl acetate (10:1). White solid, 84 mg, 75% yield, mp 180-182 oC. 1H NMR (DMSO-d6, 500 MHz, ppm) δ 9.75 (s, 1H), 8.37 (s, 1H), 8.08 (d, 1H, J = 10.0 Hz), 7.89 (d, 1H, J = 10.0 Hz), 7.57-7.54 (m, 2H).

13

C

NMR (DMSO-d6, 125 MHz, ppm) δ 149.2, 148.6, 143.3, 130.6, 129.4, 127.8, 127.3 (q, JF-C = 6.3 Hz), 126.3, 125.8 (q, JF-C = 336.3 Hz), 123.7, 120.7, 118.6, 114.9 (q, JF-C = 41.3 Hz). HRMS m/z calcd. for C14H6ClF3N2NaSe [M+Na]+: 396.9229, found: 396.9219. Compound 3j: Eluent petroleum ether/ethyl acetate (10:1). Yellow solid, 76 mg, 80% yield, mp 196-198 oC. 1H NMR (CDCl3, 500 MHz, ppm) δ 8.25 (d, 1H, J = 10.0 Hz), 7.94 (d, 1H, J = 10.0 Hz), 7.86 (s, 1H), 7.49 (d, 1H, J = 10.0 Hz), 7.08 (d, 1H, J = 10.0 Hz), 6.85 (t, 1H, J = 10.0 Hz), 2.73 (s, 1H). 13C NMR (CDCl3, 125 MHz, ppm) δ 150.1, 146.5, 140.9, 131.1, 129.6, 128.4, 126.6, 126.4, 123.7, 123.6, 122.5, 118.7, 112.5, 18.5. HRMS m/z calcd. for C14H9ClN2NaSe [M+Na]+: 342.9512, found: 342.9517. Compound 3k: Eluent petroleum ether/ethyl acetate (10:1). Yellow solid, 78 mg, 78% yield, mp 221-222 oC. 1H NMR (CDCl3, 500 MHz, ppm) δ 8.08 (d, 1H, J = 10.0 Hz), 7.85 (d, 1H, J = 10.0 Hz), 7.82 (s, 1H), 7.46 (d, 1H, J = 10.0 Hz), 7.00 (s, 1H), 6.62 (d, 1H, J = 10.0 Hz), 3.90 (s, 1H).

13

C NMR (CDCl3, 125 MHz, ppm) δ 158.0, 151.2,


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146.8, 140.8, 130.7, 129.7, 126.5, 126.4, 125.0, 123.2, 117.0, 107.7, 95.6, 55.6. HRMS m/z calcd. for C14H9ClN2NaOSe [M+Na]+: 358.9461, found: 358.9468. Compound 3l: Eluent petroleum ether/ethyl acetate (10:1). Yellow solid, 63 mg, 73% yield, mp 189-191 oC. 1H NMR (CDCl3, 500 MHz, ppm) δ 8.22 (dd, 1H, J = 10.0 Hz), 8.07 (d, 1H, J = 10.0 Hz), 7.77 (d, 1H, J = 10.0 Hz), 7.61 (d, 1H, J = 10.0 Hz), 7.29-7.25 (m, 2H), 6.93 (t, 1H, J = 10.0 Hz).

13

C NMR (CDCl3, 125 MHz, ppm) δ

161.8, 159.9, 149.6, 147.2, 140.9 (d, JF-C = 8.8 Hz), 130.9, 127.4, 124.5 (d, JF-C = 7.5 Hz), 123.7(d, JF-C = 8.8 Hz), 118.4, 114.0 (d, JF-C = 25.0 Hz), 113.7 (d, JF-C = 23.7 Hz), 112.4. HRMS m/z calcd. for C13H7FN2NaSe [M+Na]+: 312.9651, found: 312.9648. Compound 3m: Eluent petroleum ether/ethyl acetate (10:1). Yellow solid, 85 mg, 88% yield, mp 167-179 oC. 1H NMR (CDCl3, 500 MHz, ppm) δ 8.29 (dd, 1H, J = 10.0 Hz), 8.12 (s, 1H), 7.69 (d, 1H, J = 10.0 Hz), 7.59 (d, 1H, J = 10.0 Hz), 7.29-7.25 (m, 2H). 13

C NMR (CDCl3, 125 MHz, ppm) δ 162.0, 160.1, 148.1(d, JF-C = 21.3 Hz), 147.9,

141.0 (d, JF-C = 10.0 Hz), 127.0 (d, JF-C = 10.3 Hz), 125.8, 123.8 (d, JF-C = 8.8 Hz), 122.3, 120.6, 118.5, 114.3 (d, JF-C = 22.5 Hz), 113.8 (d, JF-C = 25.0 Hz). HRMS m/z calcd. for C13H6ClFN2NaSe [M+Na]+: 346.9261, found: 346.9263. Compound 3n: Eluent petroleum ether/ethyl acetate (10:1). Yellow solid, 90 mg, 82% yield, mp 225-227 oC. 1H NMR (DMSO-d6, 500 MHz, ppm) δ 9.39 (s, 1H), 8.15-8.07 (m, 2H), 7.71 (d, 1H, J = 10.0 Hz), 7.46 (d, 1H, J = 10.0 Hz), 7.38 (t, 1H, J = 10.0 Hz). 13C NMR (DMSO-d6, 125 MHz, ppm) δ 161.7, 159.4, 148.0, 142.8 (d, JF-C =25.2 Hz), 128.1, 127.5, 127.0, 123.5 (d, JF-C =11.2 Hz), 119.5, 118.8, 114.9 (d, JF-C =31.3



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Hz), 114.1 (d, JF-C =28.8 Hz), 106.2. HRMS m/z calcd. for C13H6BrFN2NaSe [M+Na]+: 390.8756, found: 390.8750, 392.8739. Compound 3o: Eluent petroleum ether/ethyl acetate (10:1). Yellow solid, 66 mg, 73% yield, mp 182-184 oC. 1H NMR (CDCl3, 500 MHz, ppm) δ 8.30 (dd, 1H, J = 10.0 Hz), 7.95 (d, 1H, J = 10.0 Hz), 7.60 (d, 1H, J = 10.0 Hz), 7.26 (t, 1H, J = 10.0 Hz), 7.08 (t, 1H, J = 10.0 Hz), 6.86 (t, 1H, J = 10.0 Hz), 2.74 (s, 3H). 13C NMR (CDCl3, 125 MHz, ppm) δ 161.7, 159.8, 150.0, 146.5, 140.8 (d, JF-C = 8.8 Hz), 128.3, 127.5, 123.8 (d, JF-C = 8.8 Hz), 123.5, 122.5, 113.9 (d, JF-C =22.5 Hz), 113.7 (d, JF-C =25.0 Hz), 112.4, 17.4. HRMS m/z calcd. for C14H9FN2NaSe [M+Na]+: 326.9807, found: 326.9813. Compound 3p: Eluent petroleum ether/ethyl acetate (8:1). Yellow solid, 74 mg, 82% yield, mp 165-166 oC. 1H NMR (CDCl3, 500 MHz, ppm) δ 8.20 (dd, 1H, J = 10.0 Hz), 7.93 (d, 1H, J = 5.0 Hz), 7.58 (d, 1H, J = 10.0 Hz), 7.49 (s, 1H), 7.25 (t, 1H, J = 10.0 Hz), 7.73 (d, 1H, J = 10.0 Hz), 2.47 (s, 3H).

13


161.6, 159.7, 150.1, 146.9, 140.8 (d, JF-C = 8.8 Hz), 135.6, 130.9, 123.7, 123.5(d, JF-C = 8.8 Hz), 116.7, 115.0, 113.9 (d, JF-C = 23.8 Hz), 113.7 (d, JF-C = 23.8 Hz), 21.6. HRMS m/z calcd. for C14H9FN2NaSe [M+Na]+: 326.9807, found: 326.9813. Compound 3q: Eluent petroleum ether/ethyl acetate (10:1). Yellow solid, 76 mg, 84% yield, mp 138-140 oC. 1H NMR (CDCl3, 500 MHz, ppm) δ 8.16 (dd, 1H, J = 10.0 Hz), 7.79 (s, 1H), 7.62 (d, 1H, J = 10.0 Hz), 7.56 (d, 1H, J = 10.0 Hz), 7.23 (t, 1H, J = 10.0 Hz), 7.08 (d, 1H, J = 10.0 Hz), 2.36 (s, 3H).

13


161.7, 159.7, 148.6, 146.9, 140.8 (d, JF-C = 23.8 Hz), 127.7, 127.5 (d, JF-C = 8.8 Hz), 123.5 (d, JF-C = 8.8 Hz), 122.1 (d, JF-C = 10.0 Hz), 117.5, 117.0, 114.0 (d, JF-C = 22.5


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Hz), 113.7 (d, JF-C = 25.0 Hz), 18.2. HRMS m/z calcd. for C14H9FN2NaSe [M+Na]+: 326.9807, found: 326.9813. Compound 3r: Eluent petroleum ether/ethyl acetate (10:1). Yellow solid, 69 mg, 76% yield, mp 221-223 oC. 1H NMR (CDCl3, 500 MHz, ppm) δ 8.16 (dd, 1H, J = 10.0 Hz), 7.79 (s, 1H), 7.62 (d, 1H, J = 10.0 Hz), 7.56 (d, 1H, J = 10.0 Hz), 7.23 (t, 1H, J = 10.0 Hz), 7.08 (d, 1H, J = 10.0 Hz), 2.36 (s, 3H).

13


161.7, 159.7, 148.6, 146.9, 140.8 (d, JF-C = 23.8 Hz), 127.7, 127.5 (d, JF-C = 8.8 Hz), 123.5 (d, JF-C = 8.8 Hz), 122.1 (d, JF-C = 10.0 Hz), 117.5, 117.0, 114.0 (d, JF-C = 22.5 Hz), 113.7 (d, JF-C = 25.0 Hz), 18.2. HRMS m/z calcd. for C14H9FN2NaSe [M+Na]+: 326.9807, found: 326.9813. Compound 3s: Eluent petroleum ether/ethyl acetate (6:1). Yellow solid, 71 mg, 74% yield, mp 189-191oC. 1H NMR (DMSO-d6, 500 MHz, ppm) δ 8.15 (dd, 1H, J = 10.0 Hz), 7.89 (d, 1H, J = 5.0 Hz), 7.59 (d, 1H, J = 10.0 Hz), 7.25 (t, 1H, J = 10.0 Hz), 7.04 (s, 1H), 6.65 (d, 1H, J = 10.0 Hz), 3.92 (s, 3H). 13C NMR (DMSO-d6, 125 MHz, ppm) δ 161.5, 159.5, 151.2, 140.7 (d, JF-C = 8.8 Hz), 130.9, 128.8, 127.6, 124.9, 123.3 (d, JF-C =8.8 Hz), 114.0 (d, JF-C = 23.8 Hz), 113.2 (d, JF-C = 25.0 Hz), 107.6, 95.6, 55.6 HRMS m/z calcd. for C14H9FN2NaOSe [M+Na]+: 342.9756, found: 342.9752. Compound 3t: Eluent petroleum ether/ethyl acetate (6:1). Yellow solid, 68 mg, 75% yield, mp 176-178 oC. 1H NMR (CDCl3, 500 MHz, ppm) δ 8.86 (d, 1H, J = 10.0 Hz), 8.04 (d, 1H, J = 10.0 Hz), 7.71 (d, 1H, J = 10.0 Hz), 7.63 (s, 1H), 7.35 (t, 1H, J = 10.0 Hz), 7.05-7.00 (m, 2H), 3.89 (s, 3H).

13

C NMR (CDCl3, 125 MHz, ppm) δ 158.6,

149.2, 147.8, 132.1, 131.9, 128.9, 127.0, 125.4, 120.1, 117.9, 114.5, 112.5, 106.4,



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55.9. HRMS m/z calcd. for C14H10N2NaOSe [M+Na]+: 324.9851, found:324.9859. Compound 3u: Eluent petroleum ether/ethyl acetate (25:1). Red solid, 49 mg, 50% yield, mp 193-195 oC. 1H NMR (CDCl3, 500 MHz, ppm) δ 8.19 (d, 1H, J =10.0 Hz), 7.90 (d, 1H, J = 5.0 Hz), 7.79 (d, 1H, J = 5.0 Hz), 7.60-7.51 (m, 3H), 7.42 (t, 1H, J = 10.0 Hz), 7.33 (t, 1H, J = 10.0 Hz).

13

C NMR (CDCl3, 125 MHz, ppm) δ 150.87,

149.0, 139.4, 131.4, 130.9, 130.6, 129.6, 126.9, 126.4, 125.9, 124.9, 124.7, 124.4, 122.2, 112.6. HRMS m/z calcd. for C15H8N2NaSSe [M+Na]+: 350.9466, found: 350.9462. Compound 5: Eluent petroleum ether/ethyl acetate (10:1). Yellow solid, 57 mg, 70%. 1

H NMR (CDCl3, 500 MHz, ppm) δ 8.39 (d, 1H, J = 5.0 Hz), 8.22 (d, 2H, J = 10.0

Hz), 7.79 (d, 1H, J = 10.0 Hz), 7.57-7.53 (m, 2H), 7.51-7.47 (m, 2H), 7.13 (t, 1H, J = 5.0 Hz). 13C NMR (CDCl3, 125 MHz, ppm) δ 146.9, 131.2, 130.2, 129.7, 129.0, 128.8, 127.4, 125.6, 118.2, 114.8. HRMS m/z calcd. for C26H19N4Se2 [M+H]+:546.9935, found: 546.9941.

ASSOCIATED CONTENT Supporting Information The Suporting Information is available free of charge on The ACS Publications website at: DOI: Detailed EPR experiments of the reaction system; Copies of 1H and 13C NMR spectra for all compounds.

AUTHOR INFORMATION Corresponding Author


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* E-mail: [email protected] * E-mail: [email protected] Notes The authors declare no competing financial interest. ACKNOWLEGEMENTS This work was supported by the the Taishan Scholar Foundation of Shandong Province, National Natural Science Foundation of China (Nos. 21302110, 21302109 and 21675099), and the Natural Science Foundation of Shandong Province (ZR2016JL012 and ZR2015JL004). We thank Jiehua Ding in our laboratory for reproducing the experimental results of 3a and 3f.

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Copper-Catalyzed Selenylation of Imidazo[1,2-a]pyridines with

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