Polyethylene glycol (PEG) promoted hydrodehalogenation of aryl halides

Accepted Manuscript Polyethylene glycol (PEG) promoted hydrodehalogenation of aryl halides Wei Liu, Fang Wang PII: DOI: Reference:

S0040-4039(17)30302-7 http://dx.doi.org/10.1016/j.tetlet.2017.03.016 TETL 48717

To appear in:

Tetrahedron Letters

Received Date: Revised Date: Accepted Date:

13 January 2017 4 March 2017 7 March 2017

Please cite this article as: Liu, W., Wang, F., Polyethylene glycol (PEG) promoted hydrodehalogenation of aryl halides, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.03.016

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Polyethylene glycol (PEG) promoted hydrodehalogenation of aryl halides Wei Liu* and Fang Wang Lipid Chemistry, College of Food Science and Technology, Henan University of Technology, 100 Lianhua Street, Zhengzhou 450001, P. R. China *Corresponding author. E-mail address: [email protected] (Wei Liu)

ABSTRACT: Transition-metal-free hydrodehalogenation of aryl halides (eg. bromides) can take place efficiently in the presence of green polyethylene glycol (PEG-800) and t-BuOK without adding any extra solvents and additives. A radical mechanism is proposed for this transition-metal-free dehalogenation of aryl halides and the role of polyethylene glycol is both reaction promotor and activated alkyl C-H donor. Keywords: Dehalogenation; aryl halides; transition-metal-free; radical; polyethylene glycol

1. Introduction Cross-coupling reactions catalyzed by noble metal catalysts (eg. Pd, Rh, Ru) or cheap metal catalysts (eg. Ni, Cu, Fe, Co) have become one of the most important topics in organic chemistry during the past decades.1 With the recent development of green and sustainable chemistry, chemists are inspired to develop various transitionmetal-free coupling reaction processes.2 In 2010, several groups independently developed transition-metal-free crosscoupling between unactivated arenes and haloarenes through base-promoted homolytic aromatic substitution.3-5 In these processes, a catalytic amount of diamine

1

ligands (eg. phenanthroline4a,c, DMEDA4b) could efficiently catalyze the crosscoupling of aryl iodides/bromides with unactivated arenes (eg. benzene) in the presence of t-butoxide base (eg. t-BuOK). Since then, much attentions have been focused on developing new catalysts6 toward this novel methodology. Meanwhile, this transition-metal-free strategy has been successfully applied in other type of organic reactions, such as intramolecular arylation7, Heck-type coupling8, carbonylation9 and so on. Recently, great efforts have been devoted to develop new methods achieving the hydrodehalogenation of aromatic halides from the synthetic10 and environmental11 points of view. Although many hydrodehalogenation methods based on transitionmetal-catalysis (eg. Pd 12, Rh13, Ni14 and Fe15) have been successfully developed, examples on transition-metal-free version of hydrodehalogenation of aryl halides is still rare.16 Utilization of polyethylene glycols (PEG) as reaction media has attracted much attentions in chemical and pharmaceutical industries.17 Because PEG are cheap, nontoxic, and their properties can be tuned by changing molecular weight,18 different reactions in PEGs have been studied, such as polymerization19, substitution reaction20, oxidation reactions21, and cross-coupling reactions22, etc. In continuation with our ongoing work on transition-metal free approach in crosscoupling reactions,6g, q we proposed that cheap and green PEG could also role as an efficient promotor for cross-coupling of benzene with aryl halides. Herein, we report our results on polyethylene glycol (PEG-800) promoted transition-metal-free hydrodehalogenation of aryl halides (Scheme 1).

2

Other groups' works

X R

t-BuOOt-Bu/Cs 2 CO 3 2-Propanol

H R

Ref . 16a

X R

NaH/LiI THF Ref . 16b

H R

Thi s work PE G X R

?

H R

The roles of PEG Cat aly st Reducing agent Reacti on medi um

Scheme 1. Transition-metal free hydrodehalogenation of aryl halides.

2. Results and discussion We embarked on our research by testing the feasibility of the cross-coupling between 1-iodo-4-methoxybenzene (1a) and benzene using PEG as promotor (Table 1). In the presence of t-BuOK base, introducing PEG-200 (0.02g) as promotor led to 29% of anisole (2a) as hydrodehalogenation product and 30% of 4-methoxybiphenyl (3a) as aryl-aryl coupling product at 80 oC after 12 h (Table 1, entry 1). And the use of PEG-400 and PEG-800 could also produce 31-37% yields of hydrodehalogenation product (2a) and 32-50% yields of arylation product (3a), respectively (Table 1, entries 2-3). When the amount of PEG-800 were increased from 0.02 g to 0.05g, the yields of hydrodehalogenation product (2a) were increased from 37% to 45%, and the yields of aryl-aryl coupling product (3a) were reduced from 50% to 38% (Table 1, entries 3-4). Continuing increasing the amount of PEG-800 (0.1-0.5g) led to increased yields of hydrodehalogenation product 2a (58-79%) and decreased yields of aryl-aryl coupling product 3a (31-12%) (Table 1, entries 5-7). And the reaction using same amount of PEG-400 or PEG-200 afforded much lower conversions (Table 1, entries 89). Control experiment indicated that hydrodehalogenation could not take place in the absence of PEG (Table 1, entry 10). Based on the these observations, we can conclude 3

that polyethylene glycols (PEG) has the potential to promote the transition-metal-free hydrodehalogenation of aryl halides without the aid of any other reducing agents. Table 1. Cross-coupling between Ar-I and benzene in the presence of PEG.a Ph

I PEG/t -BuOK

+

+

80 oC, 12 h OMe 2a

OMe 1a

a

OMe 3a

Entry

PEG

Yield of 2a (%)

Yield of 3a (%)

1

PEG-200 (0.02g)

29

30

2

PEG-400 (0.02g)

31

32

3

PEG-800 (0.02g)

37

50

4

PEG-800 (0.05g)

45

38

5

PEG-800 (0.10g)

58

31

6

PEG-800 (0.20g)

62

27

7

PEG-800 (0.50g)

79

12

8

PEG-400 (0.50g)

16

6

9

PEG-200 (0.50g)

8

<5

10

none

<5

0

Conditions: Ar-I (0.5 mmol), t-BuOK (2.0 mmol), benzene (4.0 mL), 80 oC, 12h. Yields are

determined by GC. PEG-200, 0.02g, 0.1 mmol; PEG-400, 0.02g, 0.05 mmol; PEG-800, 0.02g, 0.025 mmol; PEG-800, 0.50g, 0.625 mmol; PEG-400, 0.50g, 1.25 mmol; PEG-200, 0.50g, 2.50 mmol.

Encouraged by the above results, we conducted on our research by testing 1-iodo4-methoxybenzene (1a) as a model compound in hydrodehalogenation in PEGs solely (Table 2). Considering the tunable molecular weight of PEGs, a set of PEGs, such as PEG-4000, PEG-2000, PEG-1000, PEG-800, PEG-600, PEG-400 and PEG-200 were examined for this transition-metal-free hydrodehalogenation, and PEG-800 showed better yield of hydrodehalogenation (67%) than other PEGs at 100 oC when the 4

reactions were conducted in 1.0 g of PEGs (Table S1, entries 1-7). Increasing the amount of PEG-800 (2.0-3.0g) led to reduced conversions and yields (Table 2, entries 2-3). And decreasing the amount of PEG-800 (0.75-0.5g) led to increased yields of hydrodehalogenation (81-90%) (Table 2, entries 4-5). Then the amount of t-BuOK was optimized. 3.5 equiv of t-BuOK showed similar results with 4.0 equiv of t-BuOK (90-91% yields of hydrodehalogenation) (Table 2, entries 5-6). Continuing decreasing the amount of t-BuOK from 3.0 equiv to 1.0 equiv led to both reduced conversions and yields sharply (Table 2, entries 7-9). Moreover, the reaction temperature was also inverstigated and the results showed that the hydrodehalogenation could also take place efficiently at 80 oC and afford the desired hydrodehalogenation product 2a in 90% yield (Table 2, entry 10). Much lower temperature (60 oC) showed nearly no effect on the hydrodehalogenation reaction (Table 2, entry 11). It was worth noting that other bases, such as t-BuONa, t-BuOLi and KOH showed nearly no effect on this transition-metal-free hydrodehalogenation reaction (Table 2, entries 12-14). Based on the above results, we can conclude that PEG (PEG-800) can not only role as a suitable reaction medium, but also role as an efficient catalyst and reducing agent for this transition-metal-free hydrodehalogenation. Table 2. Optimization of reaction conditions of hydrodehalogenation.a MeO

I

PEG/t -BuOK T, 12 h, N2

MeO

1a

2a o

b

Yield (%)b

Entry

PEG/Base

T ( C)

Conv. (%)

1

PEG800 (1.0g)/t-BuOK

100

86

67

2

PEG800 (2.0g)/t-BuOK

100

45

29

3

PEG800 (3.0g)/t-BuOK

100

27

12

4

PEG800 (0.75g)/t-BuOK

100

95

81

5

PEG800 (0.5g)/t-BuOK

100

100

90

6

c

100

100

91

d

100

97

83

e

100

82

65

f

100

21

7

c

80

100

90

7

8 9

10

PEG800 (0.5g)/t-BuOK PEG800 (0.5g)/t-BuOK

PEG800 (0.5g)/t-BuOK

PEG800 (0.5g)/t-BuOK

PEG800 (0.5g)/t-BuOK

5

11

60

<5

<5

12

c

PEG800 (0.5g)/t-BuONa

80

12

7

13

c

80

<5

<5

80

<5

<5

14

a

PEG800 (0.5g)/t-BuOKc

PEG800 (0.5g)/t-BuOLi PEG800 (0.5g)/KOH

c

Standard reactions conditions: 1a (0.5 mmol), base (4.0 equiv.), 12 h, N2. PEG-800, 0.50g,

0.625 mmol. b Calibrated GC yields were reported using hexadecane as the internal standard. c 3.5 equiv of base was used. d 3.0 equiv of base was used. e 2.0 equiv of base was used. f 1.0 equiv of base was used.

With the optimal reaction conditions (0.5 g of PEG800, 3.5 equiv of t-BuOK, 80 oC, 12h) in hand, we investigated the hydrodehalogenation reaction of various aryl iodides (Scheme 2). In general, electron-rich aryl iodides (1a-1f) took place hydrodehalogenation

reaction

smoothly

and

afforded

the

corresponding

dehalogenated products in excellent yields (84-90%). Sterically hindered aryl iodides, such as 1-iodo-2,4-dimethoxybenzene (1b), 1-iodo-2-methoxybenzene (1c) and 1iodo-2-methylbenzene (1f) were also suitable under the same reaction conditions and afforded the corresponding dehalogenated products in good yields (84-87%), respectively. And 4-iodobiphenyl (1g) underwent hydrodehalogenation reaction and afforded 91% isolated yield of biphenyl as dehalogenated product. 1-fluoro-4iodobenzene (1h), 3-fluoroiodobenzene (1i), 4-chloroiodobenzene (1j), and 3chloroiodobenzene (1k) could all undergo chemoselective hydrodehalogenation n and produced the mono-dehalogenated products in 88-90% yields, respectively. And ethyl 4-iodobenzoate (1l) could produce the dehalogenated product ethyl benzoate in 78% yield.

6

t-BuOK (3.5 equiv)

I

PEG-800, 80 oC, 12 h

R

H R

1

2

MeO

I

MeO

1a, 90%

I

I

OMe

OMe

1b, 87%* I

Me

1c, 87% I

I

Me

Me

Me 1d, 90%

1e , 91% I

1f , 84% I

F

I F

1g, 91%*

1h, 88% I

Cl

1i, 87% I EtO2C

I

Cl 1k, 88%

1j, 90%

1l, 78%*

Scheme 2. Hydrodehalogenation of aryl iodides. Conditions: Ar-I (0.5 mmol), PEG-800 (0.5g, 0.625 mmol), t-BuOK (1.8 mmol), 80 oC, 12 h, N2. Yields are determined by GC. *The yields reported are for products isolated and purified by flash chromatography. Next, other unactive aryl halides, such as aryl bromides were examined as well. 4bromoanisole (4a) was less reactive at 80 oC. Considering the more unactive aromatic C-Br bond in aromatic compounds, increasing the reaction temperature from 80 oC to 120 oC was conducted to promote the cleavage of aromatic C-Br bond, and good conversion of 4-bromoanisole (4a) was observed (Scheme 3). Encouraged by the above results, various aryl bromides were then examined and the results were listed in Scheme

3.

In

general,

electron-rich

aryl

bromides

(4a-4f)

took

place

hydrodehalogenation smoothly and afforded the corresponding dehalogenated products in 84-87% yields, respectively. Dihalide substrates, such as 1-bromo-4chlorobenzene (4g) and 1-bromo-3-chlorobenzene (4h) could both undergo

7

chemoselective hydrodehalogenation and produced the corresponding cleavage of aromatic C-Br bond products in 83-85% yields, respectively. However, aryl chlorides, such as 4-chloroanisole was unactive at 120 oC under the same conditions. t-BuOK (3.5 equiv)

Br

PEG-800, 120 oC, 24 h

R 4

2 Br

MeO

Br MeO

4a, 86% Me

Br OMe

4b, 84%

4c, 85%

Br

Br

Br Me

Me 4d, 87% Cl

H R

4e, 84% Br

Br

4f, 84% EtO2C

Br

Cl 4g , 83%

4h, 85%

4i , 75%*

Scheme 3. Hydrodehalogenation of aryl bromides. Conditions: Ar-Br (0.5 mmol), PEG-800 (0.5g, 0.625 mmol), t-BuOK (1.8 mmol), 120 oC, 24 h, N2. Yields are determined by GC. *The yields reported are for products isolated and purified by flash chromatography. To gain some preliminary insights into the mechanism of such transition-metal-free hydrodehalogenation of aryl halides, we conducted a set of control experiments (Scheme 4). When the reaction was conducted under air atmosphere, nearly no conversion of 4-bromoanisole (4a) was detected, which suggested that this hydrodehalogenation was oxygen sensitive. Moreover, the hydrodehalogenation reaction was almost shut down when 100 mol% of 2,2,6,6-tetramethyl-1piperidinoxyl (TEMPO) or butylated hydroxytoluene (BHT) was added as radical inhibitors. The above control experiments suggested that this transition-metal-free hydrodehalogenation transformation involved a radical reaction mechanism.5

8

MeO

Br

t-BuOK (3.5 equiv) PEG-800, 120 oC, 24 h

4a

H

MeO 2a

"Condi tions" N2 Air TEMPO (100 mol%) BHT (100 mol%)

86% <5% <5% <5%

Scheme 4. Control experiments for this hydrodehalogenation reaction. On the basis of above results and previous studies on t-BuOK-mediated transitionmetal-free coupling reactions6s,23, a plausible mechanism is proposed as shown in Scheme 5. An aryl halide radical anion (A) is generated from aryl halides (1) by SET process in the presence of PEG-800/t-BuOK and converted to an aryl radical (B) upon elimination of X-. Aryl radical B reacts with PEG to afford dehalogenation product 2 and radical (C). From radical C, two possible pathways (Path A and Path B) are presented in Scheme 5. Path A is a deprotonation of radical C with the assistance of tBuOK, followed by another SET with aryl halides to form aryl halide radical anion (A) and di-dehydrogenated PEG (5).24 Path B is a SET process between radical C and aryl halides (1) to produce cation E, followed by a deprotonation by t-BuOK to give di-dehydrogenated PEG (5). Based on the above proposed mechanism, we can conclude that PEG (PEG-800) can not only role as a suitable reaction medium, but also role as an efficient radical initiator and reducing agent for this transition-metalfree hydrodehalogenation of aryl halides.

9

Initiation Ar-X

PEG/t-BuOK SET

1

Ar-X

Ar -X

A

B

Propagation H O

O

Ar

O

Ar -H +

B

2

O C

Pat h A O

O

t-BuOO

O

PT

Ar-X

O

O

ET

C

D

5

+ Ar-X A

Path B O O

O C

O

Ar-X

t-BuO -

ET

PT O

O

O

O 5

E

Scheme 5. Possible mechanism of this hydrodehalogenation.

Conclusion In conclusion, we have developed a transition-metal-free hydrodehalogenation reaction of aryl halides in the presence of PEG-800 and t-BuOK under mild conditions. PEG (PEG-800) can not only role as a suitable reaction medium, but also role as an efficient radical promotor and reducing agent for this transition-metal-free hydrodehalogenation of aryl halides. Both aryl iodides and bromides can be employed as substrate to afford the hydrodehalogenation products in moderate to excellent yields. Control experiments indicated that radical process occurred during the transition-metal-free hydrodehalogenation reaction. Further studies on the mechanism and the application to other reactions are underway in our laboratory, and will be reported in due course.

10

Acknowledgments This work was supported by the National Natural Science Foundation of China (No. 21102036), the Young-aged Backbone Teacher Funds of Henan Province of China (No. 2014GGJS-058) and Basic Research Funds in Henan Universities of Henan University of Technology (No. 2015RCJH01).

A. Supplementary material Supplementary data associated with this article can be found, in the online version

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14

Graphical abstract

X R X = I, Br

t-BuOK PEG-800, 80-120 oC Radi cal process

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H R 21 examples, 75-91% yields

Highlights 1) Transition-metal-free hydrodehalogenation of aryl halides has been developed. 2) Polyethylene glycol and t-BuOK are used without extra solvents and additives. 3) PEG role as an efficient radical promotor and reducing agent.

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