Palladium catalyzed-dehalogenation of aryl chlorides and bromides using phosphite ligands.pdf

Journal of Organometallic Chemistry 694 (2009) 473–477

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Journal of Organometallic Chemistry

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Palladium catalyzed-dehalogenation of aryl chlorides and bromides using

phosphite ligands

Jeongju Moon, Sunwoo Lee *

Department of Chemistry, Chonnam National University, 300 Yongbong-dong, Buk-gu, Gwangju 500-757, Republic of Korea

article info

abstract

Article history:

Received 16 September 2008

Received in revised form 25 October 2008

Accepted 31 October 2008

Available online 6 November 2008

The catalytic system based on Pd–phosphite for the dehalogenation reactions of aryl chlorides and bro-

mides is described. The Pd–phosphite catalyst effectively promoted the dehalogenation of aryl halides to

give dehalogenated products in moderate to excellent yields. The aryl chlorides required strong bases

such as NaO t Bu for this transformation, whereas the aryl bromides were dehalogenated in the presence

of weak bases such as Cs 2 CO 3 . This catalytic system exhibited tolerance to functional groups such as

methoxy, amine, hydroxyl, ether, amide, benzyl and ketone groups. It also demonstrated chemoselectiv-

ity in that bromochlorobenzene was converted only to chlorobenzene.

Keywords:

Palladium

Phosphite

Dehalogenation

Aryl bromides

Aryl chlorides

1. Introduction

dehalogenated compounds. Numerous new dehalogenation meth-

ods using palladium [13–15] , rhodium [16] , iron [17] and nickel

[18,19] catalysts have been reported. Palladium is the most com-

monly used transition metal in this transformation.

Recently, N-heterocyclic carbene ligands have been used for the

dehalogenation of aryl chlorides [20] , while the triphenyl phos-

phine ligand, which was most often used as a ligand in the palla-

dium catalyzed-transformation, has been employed for the

dehalogenation of aryl halides and alpha-haloketones [21] . How-

ever, phosphite compounds have never before been used as ligands

in dehalogenation. Therefore, we decided to optimize the condition

for the dehalogenation of aryl halides using the palladium/phos-

phites catalytic system ( Fig. 1 ).

We employed isopropanol, possessing a beta-hydrogen, as the

hydrogen source in a safer and simpler method than using molec-

ular hydrogen. Reactions of 4-chlorotoluene with palladium in iso-

propanol were initially conducted using various kinds of palladium

source and ligand, including phosphites. Table 1 summarizes our

preliminary results for these dechlorination reactions. As expected,

the ligand-free condition afforded dehalogenated product in low

yield (entry 1) and Pd 2 (dba) 3 was the best palladium source among

the tested palladiums (entries 2–5). The phosphites showed better

reactivities than the phosphines did. Phosphite 1 was the best li-

gand, giving the desired product in almost quantitative yield with-

out byproduct derived from homocoupling reaction (entry 5).

Phosphites 2 and 3 afforded the dehalogenated product in good

yield, but gave a homocoupled compound (entries 6 and 7). How-

ever, P(OPh) 3 showed good reactivity without the formation of

homocoupled product (entry 8). Interestingly, the chelating phos-

Palladium catalyzed-transformation reactions have been widely

used in organic synthesis [1] . Among them, carbon–carbon bond

formation, one of the most powerful transformations, has been

extensively investigated over the past 30 years [2] . Recent develop-

ments in cross-coupling methodology allow aryl halides showing

high catalytic activities to be formed under milder conditions. Most

of them have been affected by the ligands. Generally, electron-rich

and bulky monoalkyl phosphines such as P t Bu 3 [3–5] and biphenyl

alkyl phosphines [6–8] showed high activities as the ligand in the

cross-coupling reaction. Moreover, a number of important devel-

opments with phosphine-free ligands such as N-heterocyclic carb-

enes have been reported [9] . However, they suffer some drawbacks

such as sensitivity to air or moisture in the case of phosphine li-

gands and the requirement for multistep synthesis in the case of

carbene. To address this problem, we employed a phosphite-con-

taining, sterically hindered group as the ligand, because phosphites

are less expensive and more stable to air and moisture than phos-

phines. They show good reactivities in Hiyama coupling reaction

and the homocoupling of aryl halides [10,11] . In the latter case,

we found that the dechlorination product was obtained as a

byproduct when aryl chlorides were used in the homocoupling.

Organohalogens are classiﬁed as pollutants due to their persis-

tent toxic effect [12] . Therefore, it is important to develop efﬁcient

methods that transform them into less harmful chemicals such as

* Corresponding author. Tel.: +82 62 530 3385; fax: +82 62 530 3389.

E-mail address: sunwoo@chonnam.ac.kr (S. Lee).

doi:10.1016/j.jorganchem.2008.10.052

474

J. Moon, S. Lee / Journal of Organometallic Chemistry 694 (2009) 473–477

Next, the above optimum catalytic system was tested on aryl

bromides for debromination. The data are summarized in Table

2 . When 4-bromotoluene was treated with NaO t Bu using Pd 2 (dba) 3

and phosphite 1 as the ligand in i-PrOH, the debrominated product,

toluene, was obtained in 91% yield. However, the homocoupling

byproduct was also obtained in 4% yield (entry 1). To reduce the

amount of byproduct, several kinds of alcohol were screened as

solvents. Cyclohexanol afforded the desired product in high yield

and showed a trace amount of homocoupled product (entry 4).

The method using a strong base rarely addresses functional group

compatibility as well as selectivity. To address these problems, we

attempted to use a weak base rather than a strong base. When

Cs 2 CO 3 was used as a base, the conversion yield was superior to

that of other weak bases such as K 2 CO 3 and Na 2 CO 3 (entries 5–

7). When the reaction temperature was increased in the presence

of Cs 2 CO 3 , the toluene product was obtained in almost quantitative

yield without any byproduct (entry 9). When the amount of cata-

lytic loading was decreased to 0.5 mol%, the product yield was

99% (entry 10), whereas at 0.1 mol% catalytic loading, the yield of

dehalogenated product was 60% (entry 11).

Based on the optimized condition, we investigated the scope of

the dehalogenation using phosphite 1 as the ligand for a series of

aryl chlorides and bromides having different electronic and steric

properties. The results for aryl chlorides are summarized in Table

3 . Chlorobenzene and 4-chlorotoluene were completely converted

to dehalogenated product in high yields (entries 1 and 2). The

ortho-, meta- and para-chloroanisoles all showed high yields that

were independent of the substituent position (entries 3–5). This

reaction method showed the tolerance to functional groups such

as amino and hydroxy groups (entries 6 and 7). 1-Chloronaphtha-

lene was converted to naphthalene in 98% yield (entry 8).

In the case of aryl bromides, the reactions were carried out with

0.5 mol% palladium and 0.5 mol% ligand at 120 C for 10 h. Cyclo-

hexanol and Cs 2 CO 3 were employed as solvent and base, respec-

tively. The reaction is generalized for a variety of substrates, as

shown in Table 4 .

t Bu

Fig. 1. Phosphite ligands.

phine ligand 1,1 0 -bis(diphenylphosphino)ferrocene (dppf) afforded

the dehalogenated product in very low yield (entry 11). Recently,

Muzart and coworkers showed that dppf was a suitable ligand

for dehalogenation using dimethylformamide as the hydride

source. However, in this reaction system, the low reactivity of

the chelating ligand is caused by blocking of the beta hydride elim-

ination step. Sterically demanding monophosphine showed low

activity (entry 12) and IPr HCl, which was reported by Nolan group,

afforded the dehalogenated product in high yield (entry 13). When

the amount of catalyst used was decreased to 1 mol%, the product

yield was very low (entry 15), and a minimum catalytic loading of

2.5 mol% was needed for full conversion (entry 14). The reactivity

of the dechlorination was dependent on the nature of the base.

The most effective base was NaO t Bu, whereas other alkoxide bases

such as KO t Bu, NaOMe and KOMe showed low product yield (en-

tries 16–18). Therefore, the optimized conditions for the dehalo-

genation of aryl chlorides were as follows: 1.25 mol% Pd 2 (dba) 3 ,

2.5 mol% phosphite 1, and 1.2 equiv of NaO t Bu in i-PrOH solvent

at 80 C for 3 h.

Table 1

Optimization of conditions for dehalogenation of 4-chlorotoluene. a

Pd 2 (dba) 3 /Ligand

H 3 C

Base, i-PrOH

80 o C, 3 h

Conv. b (%)

Product b (%)

Homo c (%) b

Entry

Palladium

Ligand

Pd mol% (Pd/L = 1/1)

Base

NaO t Bu

– f

Pd(CH 3 CN) 2 Cl 2

–

NaO t Bu

– f

Pd(CH 3 CN) 2 Cl 2

NaO t Bu

– f

PdCl 2

NaO t Bu

– f

Pd(OAc) 2

NaO t Bu

– f

Pd 2 (dba) 3

100

NaO t Bu

Pd 2 (dba) 3

100

NaO t Bu

Pd 2 (dba) 3

100

Pd 2 (dba) 3

P(OPh) 3

2.5

NaO t Bu

– f

NaO t Bu

– f

Pd 2 (dba) 3

PPh 3

2.5

NaO t Bu

Pd 2 (dba) 3

P(o-tol) 3

2.5

Dppf d

NaO t Bu

– f

Pd 2 (dba) 3

2.5

P t Bu 3

NaO t Bu

– f

Pd 2 (dba) 3

2.5

IPr HCl e

NaO t Bu

– f

Pd 2 (dba) 3

2.5

100

NaO t Bu

– f

Pd 2 (dba) 3

2.5

100

Pd 2 (dba) 3

NaO t Bu

– f

KO t Bu

– f

Pd 2 (dba) 3

2.5

– f

Pd 2 (dba) 3

2.5

NaOMe

– f

Pd 2 (dba) 3

2.5

KOMe

a Reaction conditions: 1.0 mmol CH 3 C 6 H 4 Cl, 3 mmol solvent.

b Yields were determined by gas chromatography (GC) by comparison to an internal standard (naphthalene).

c Homocoupled product is 4,4 0 -dimethylbiphenyl.

d 1,1 0 -Bis(diphenylphosphino)ferrocene.

e 1,3-Bis(2,6-diisopropylphenyl)imidazolium chloride.

f No homocoupled product was found.

J. Moon, S. Lee / Journal of Organometallic Chemistry 694 (2009) 473–477

475

Table 2

Optimization of conditions for dehalogenation of 4-bromotoluene. a

Pd 2 (dba) 3 / 1

H 3 C

Base, Solvent

Temp, 10 h

Product b (%)

Homo c (%)

Entry

Pd (mol%)

Temp (C)

Base

Solvent

Conv. (%)

NaO t Bu

2.5

i-PrOH

100

NaO t Bu

2.5

MeOH

NaO t Bu

2.5

EtOH

NaO t Bu

– d

2.5

Cyclohexanol

100

2.5

Cs 2 CO 3

Cyclohexanol

2.5

K 2 CO 3

Cyclohexanol

– d

2.5

Na 2 CO 3

Cyclohexanol

2.5

100

Cs 2 CO 3

Cyclohexanol

– d

2.5

120

Cs 2 CO 3

Cyclohexanol

100

– d

0.5

120

Cs 2 CO 3

Cyclohexanol

100

– d

0.1

120

Cs 2 CO 3

Cyclohexanol

a Reaction conditions: 1.0 mmol CH 3 C 6 H 4 Br, 3 mmol solvent.

b Yields were determined by gas chromatography (GC) by comparison to an internal standard (naphthalene).

c Homocoupled product is 4,4 0 -dimethylbiphenyl.

d No homocoupled product was found.

Table 3

The dehalogenation of aryl chlorides using palladium/phosphite catalyst.

Pd 2 (dba) 3 (1.25 mol%)

1 (2.5 mol%)

NaO t Bu (1.2 equiv)

i-PrOH, 80 o C, 3 h

Yield a (%)

Entry

Aryl chloride

Conv. (%)

Entry

Aryl chloride

Conv. (%)

>99 b

100

MeO

100

H 2 N

>99 b

100

OMe

>99 b

100

OMe

a All compounds are characterized by comparison of gas chromatography (GC) analysis, 1 H and 13 C NMR spectra with authentic samples or literature data.

b Almost quantitative yield.

Bromobenzene, 4-bromotoluene and 1-bromo-4-tert-butylben-

zene were converted to the corresponding debrominated products

in high yields (entries 1–3, respectively). 3-Bromoanisole showed

moderate yield even though the conversion was high, and the

homocoupled product was not found in gas chromatography (GC)

(entry 4). However, 4-bromoanisole afforded 4,4 0 -dimethoxybi-

phenyl as byproduct in 5% yield (entry 5). Even sterically

demanding substrates were converted to the desired product in

high yields (entries 6 and 7). In a similar method to that of aryl

chloride, this reaction method provided the tolerance to func-

tional group such as amino, nitro, hydroxyl and ether (entries

8–11). 2-Bromo-6-methoxynaphthalene was transformed to 2-

methoxynaphthalene in 95% yield (entry 12). 4-Bromobiphenyl

was converted to the biphenyl in 99% yield (entry 13). 2-Bromo-

biphenyl, which is more sterically hindered, showed low conver-

sion and low yield. Nevertheless, its yield was increased to 99%

when NaO t Bu was used as the base instead of Cs 2 CO 3 (entry

14). In the case of 2-bromothiophene, the yields of conversion

and product were low when Cs 2 CO 3 was used as the base. How-

ever, when NaO t Bu was used as the base, 2-bromothiophene was

completely converted to thiophene in 72% yield and produced

bithiophene as the byproduct in 10% yield (entry 15). The reactiv-

ity of 3-bromopyridine was higher than that of 2-bromopyridine.

2-Bromopyridine and 3-bromopyridine resulted in homocoupled

products as byproduct in 7% and 15% yield, respectively (entries

16 and 17). This reaction condition exhibited chemoselectivity

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J. Moon, S. Lee / Journal of Organometallic Chemistry 694 (2009) 473–477

Table 4

The dehalogenation of aryl bromides using palladium/phosphite catalyst. a

Pd 2 (dba) 3 (0. 25 mol%)

(0.5 mol%)

Cs 2 CO 3 (1.2 equiv)

Cyclohexanol, 120 o C, 10 h

Entry

Aryl bromide

Conv. (%)

Yield (%)

Entry

Aryl bromide

Conv. (%)

Yield (%)

100

MeO

100

50 (100) d

46(99) d

100

t Bu

78 b

40 (100) d

38(72) d , e

OMe

78 c

43 f

MeO

65 g

Me 2 N

100

O 2 N

61 b

100

66 b

100

a All compounds are characterized by comparison of gas chromatography analysis, 1 H and 13 C NMR spectra with authentic samples or literature data.

b No homocoupled product was found in gas chromatography (GC).

c 5% Homocoupled byproduct.

d NaO t Bu was used as base instead of Cs 2 CO 3 .

e 10% Homocoupled byproduct.

f 7% Homocoupled product.

g 15% Homocoupled product.

to aryl bromide. 3- and 4-Chlorobromobenzenes were converted

to chlorobenzene. Bromotoluene and benzene were not found in

the reaction mixture, conﬁrming that only debromination oc-

curred (entries 18 and 19). Yus’ group did not achieve the halogen

chemoselectivity using copper catalyst [22] . The substrates hav-

ing amide and ketone groups also afforded the corresponding

debrominated products in moderate to excellent yields without

reducing the carbonyl group (entries 20–22).

As shown in Scheme 1, when the dehalogenation of ﬂuoroben-

zene was carried out under reaction condition that was used for

J. Moon, S. Lee / Journal of Organometallic Chemistry 694 (2009) 473–477

477

Pd 2 (dba) 3 (1.25 mol%)

1 (2.5 mol%)

NaO t Bu (1.2 equiv)

i-PrOH, 80 o C

Pd(0)

20% yield

Pd(II)

Scheme 1. Palladium-catalyzed deﬂuorination.

Pd 2 (dba) 3 (0. 25 mol%)

Ligand (0.5 mol%) or no Ligand

Pd(II)

t Bu

Cs 2 CO 3 (1.2 equiv)

Cyclohexanol, 120 o C

t Bu

Fig. 3. General mechanism of Pd-catalyzed dehalogenation.

100

phites accelerated the reductive elimination steps. Further

mechanistic studies of the reactivity of phosphite ligand are in

progress in our laboratory.

In conclusion, we demonstrated that the sterically hindered

phosphites exhibited good reactivities as ligands in the dehalogen-

ation of aryl bromides and chlorides. To the best of our knowledge,

this is the ﬁrst report of the use of phosphite as a ligand in dehalo-

genation reactions. Aryl chloride required 2.5 mol% catalyst and a

strong base, while 0.5 mol% catalytic loading was sufﬁcient for

the debromination of aryl bromide in the presence of a weak base.

Aryl bromides bearing functional groups such as alkyl, alkoxy, hy-

droxyl, ether, chloro, phenyl, amide, benzyl and ketone can be

transformed to the corresponding debrominated products in high

yields.

Phosphite 1

PPh 3

no ligand

Reaction Time (h)

Fig. 2. Reaction rate of debromination with phosphite 1 and PPh 3 .

Acknowledgment

This work was supported by the Korea Research Foundation

Grant Funded by the Korean Government (MOEHRD, Basic Re-

search Promotion Fund) (KRF-2006-003-C-00178).

dechlorination, the yield of deﬂuorinated product, benzene, was

only 20% as determined by GC. This low yield was attributed to

the strong bond formed between carbon and ﬂuorine atoms.

We compared the reaction rates of the phosphite ligand 1 and

PPh 3 in the debromination of 1-bromo-4-tert-butylbenzene. As

shown in Fig. 2 , phosphite 1 showed better catalytic activity than

PPh 3 . In addition, the debromination without ligand showed very

low reactivity.

The general mechanism of the palladium-catalyzed dehalogen-

ation is described in Fig. 3 [23] . The palladium(0) is the catalyti-

cally active species that generates the oxidative adduct complex.

Metal alkoxide, which is generated from the reaction with alcohol

and base, attacks the palladium and displaces the halogen atom.

The palladium-hydride complex that is produced through the

beta hydride elimination affords a reduced arene product and

regenerates the palladium(0) catalyst. The fact that the cyclohex-

anone was obtained with the same amount of debrominated

products

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in all case of

Table 4 supported the proposed

mechanism.

The phosphorus atom of phosphite 1 is more electron-poor

than that of triphenylphosphine. However, the former had better

reactivity than the latter, as shown in Fig. 2 , which is contrary to

the general belief that electron-rich ligands accelerate the rate of

oxidative addition of aryl halides [24] . It is generally believed that

the rate determining step for dehalogenation is the oxidative

addition of aryl halides. However, in this case, we believe that

the phosphite ligand exerted much greater effect on both the beta

hydride elimination and the reductive elimination steps. The p

acceptor phosphite ligand accelerated the beta hydride elimina-

tion step while the sterically bulky substituted group in phos-

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