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DOI: 10.1002/chem.201101992

Dehydrogenative Heck Reaction of Furans and Thiophenes with Styrenesunder Mild Conditions and Influence of the Oxidizing Agent on the Reaction

Rate

Alexandre Vasseur, Jacques Muzart, and Jean Le Bras*[a]

Transition-metal-catalyzed reactions dealing with CH ac-

tivation is a challenging task in organic chemistry.[1] The Pd-

catalyzed couplings of arenes with alkenes through CH ac-

tivation, also called intermolecular dehydrogenative Heck

reactions (DHRs), have gained interest these past years.[2]

Despite noticeable progresses, the substrate scope is often

limited to olefins bearing an electron-withdrawing group as

the coupling partner, which limits the applications of thesereactions. We have recently reported an efficient method for

the coupling of furans with styrenes, which allowed the use

of chlorinated and fluorinated substrates.[3] However, bromi-

nated substrates were reluctant to react. These compounds

would allow the synthesis of valuable products for further

functionalization through other cross-coupling reactions.

Glorius et al. have recently shown that brominated com-

pounds can be formed with no proto-debromination using

Rh catalysts; however few examples have been reported

and the scope of substrates remains to be developed. [4] A

recent example has been reported by Zhang et al. using pal-

ladium catalysts, but the method requires the presence of a

removable pyridylsulfinyl group on the arenes.[5] Among the

arenes used in DHRs, furans and thiophenes have received

little attention. The former are acid sensitive and the latter

require elevated temperatures,[6] due to their higher aromat-

ic resonance energy and stability.[7] We report herein the

DHRs, under mild conditions, of furans and thiophenes with

styrenes, including brominated substrates. The influence and

the role of the oxidizing agent on the activity of the catalyst

are also discussed.

We noticed an induction period during our previous study

that depends on the nature of the furan, the transformation

being faster with electron-rich furans.[3] We also observed

that the solvent can have a decisive influence on the courseof the reaction. Low-coordinating solvents led to Heck-type

products,[3] whereas coordinating solvents gave difurylal-

kanes.[8] We have pursued our investigations on the influ-

ence of the solvent on the DHR of heterocycles with styr-

enes. The coupling of 2-methylfuran (1 a) and 2-methylthio-

phene (1 b) with styrene (2 a) has been studied at room tem-

perature over 4 h, in the presence of Pd (OAc)2 as catalyst,benzoquinone (BQ) as oxidizing agent, AcOH as solvent,

and a series of co-solvents (Table 1). The reaction was gen-

erally ineffective (Table 1, entries 17). Only DMSO strong-

ly improved the efficiency of the reaction leading to 3 aa in64% isolated yield (Table 1, entry 8). This is a surprising

result since DMSO is a coordinating solvent, and we expect-

ed the formation of difurylalkanes under such conditions.[8]

Interestingly, 2-methylthiophene (1 b) could also be coupled

with 2 a in 58% yield at room temperature over 4 h

(Table 1, entry 9). The yield of 3 ba was increased to 67%

when the reaction time was prolonged to 24 h (Table 1,

entry 10). This is an interesting improvement, since reported

methods for the DHR of thiophenes require 60120 8C and

are limited to olefins bearing an electron-withdrawing

group.[6] The use of catalytic amounts of BQ and Cu II in as-

sociation with O2 reduced the yield of 3 ba (Table 1,

entry 11). The scope of the process was then examined

(Table 2). After slight modifications to the original proce-

[a] A. Vasseur, Dr. J. Muzart, Dr. J. Le Bras

Institut de Chimie Molculaire de Reims-UMR 6229

CNRS-Universit de Reims Champagne-Ardenne

UFR des Sciences Exactes et Naturelles

BP 1039, 51687 REIMS Cedex 2 (France)

Fax: (+33)3-26-91-31-66E-mail: [email protected]

Supporting information for this article is available on the WWW

under http://dx.doi.org/10.1002/chem.201101992.

Table 1. Optimization of the coupling of 2-methylfuran (1 a) and 2-meth-

ylthiophene (1 b) with styrene (2 a).[a]

Entry 1 Co-solvent 3

[%][b]

1 1 a Et2O 11

2 1 a CF3CH2OH 83 1 a MeOH 8

4 1 a tBuOH 9

5 1 a CH2Cl2 11

6 1 a DMF 9

7 1 a DMA 8

8 1 a DMSO 67 (64)

9 1 b DMSO 58

10[c] 1 b DMSO (67)

11[d] 1 b DMSO 45

[a] 1 (2.0 mmol), 2 a (1.0 mmol), Pd(OAc)2 (0.05 mmol), BQ (2.0 mmol),AcOH (2 mL), co-solvent (2 mL), RT, 4 h. [b] GC yield, isolated yield in

parenthesis. [c] The reaction was performed over 24 h. [d] BQ

(0.5 equiv), Cu(OAc)2 (0.1 equiv), O2 (gas bag) instead of BQ(2.0 mmol), 24 h.

Chem. Eur. J. 2011, 00, 0 0 2011 Wi ley-VC H Verl ag G mbH & C o. KGaA, Weinheim

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Table 2. Coupling of furans and thiophenes 1 with styrenes 2.[a]

Entry 1 2 Pd

[%]

t

[h]

3 [%][b] Entry 1 2 Pd

[%]

t

[h]

3 [%][b]

1 1 c 2 a 5 24 3 ca 68 14 1 b 2 b 5 24 3 bb 90

2 1 d 2 a 5 24 3 da 79 15 1 b 2 c 5 24 3 bc 56

3[c] 1 e 2 a 5 48 3 ea 40 16 1 h 2 b 10 24 3 hb 56

4 1 f 2 a 5 24 3 fa 78 17 1 h 2 c 5 24 3 hc 68

5 1 a 2 b 5 24 3 ab 73 18 1 i 2 a 5 48 3 ia 72

6 1 d 2 b 5 24 3 db 61 19 1 i 2 d 5 48 3 id 88

7[d] 1 g 2 a 5 24 3 ga 54 20 1 i 2 e 5 48 3 ie 92

8[d] 1 g 2 b 10 48 3 gb 40 21 1 i 2 b 5 48 3 ib 65

9 1 h 2 a 5 24 3 ha 72 22 1 j 2 a 10 48 3 ja 77

10 1 b 2 d 5 24 3 bd 97 23 1 j 2 d 10 48 3 jd 76

11 1 b 2 e 5 24 3 be 59 24 1 j 2 b 10 48 3 jb 56

12 1 h 2 d 5 24 3 hd 70 25 1 j 2 c 10 48 3 jc 57

13 1 h 2 e 5 24 3 he 80

[a] 1 (2 mmol), 2 (1 mmol), BQ (2 mmol), AcOH (2 mL), DMSO (2 mL), RT, conv. 100%, 2448 h. [b] Isolated product yield. [c] Reaction performed at

40 8C. [d] 1 g (5.0 mmol).

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dure, furans and thiophenes were successfully coupled with

styrenes to give Heck-type products in medium to good

yields. Some reactions required 10% catalyst loading to ach-

ieve a total conversion of 2. The reactions were performed

at RT, except in the case of 1 e, and all compounds were ob-

tained as the E isomer. As previously observed,[3] 2-substi-

tuted furans bearing either an electron-donating group(Table 2, entry 1) or an electron-withdrawing group

(entry 3) reacted at the C5 position. Interestingly, furfuryl

alcohol 1 f, was successfully coupled without the need of a

protection of the alcohol function (Table 2, entry 4). It

should be noted that no trace of furfural or furoic acid were

detected by GC, showing that the method is highly selective

towards the CH activation. Furthermore, the method is

compatible with brominated styrenes and furans (Table 2,

entries 5, 6, and 8). 2-Alkylthiophenes were coupled with

various chlorinated and brominated styrenes (Table 2, en-

tries 1017). Interestingly, chlorinated and brominated thio-

phenes also react at room temperature with halogenated

styrenes in fair yields but require a longer reaction time(Table 2, entries 1921 and 2325). The syntheses of 3 jb and

3 jc could be performed in similar yields at 40 8C over 24 h.

Halogenated thiophenes are precursors for the synthesis of

oligothiophene-based materials,[9] therefore the method pro-

vides a new entry for the synthesis of such molecules under

mild conditions. To learn about the CH activation step, we

performed a kinetic study with 1 b and monodeuterated

thiophene d-1 b (Figure 1). A significant isotope effect was

observed (kH/D=4.0), which is consistent with a mechanism

involving a Pd-mediated CH cleavage step rather than a

Lewis acid-mediated FriedelCrafts reaction.[10] The cou-

pling of 1 b with 2 a has shown that the oxidizing agent has

an influence on the yield of the reaction (Table 1, entry 11).

We have therefore performed kinetic experiments to deter-

mine the role of BQ in the mechanism. The kinetic of the

coupling of 1 b with 2 a was monitored by GC using 1.0 and

2.0 equiv of BQ (Figure 2). The initial rate was unchanged,

showing that BQ has no influence on the C

H activation.Working with 1.0 equiv of BQ has however a small effect on

the rate after the initial stage of the reaction. The use of O 2with 0.5 equiv of BQ and 0.1 equiv of Cu (OAc)2 has a stron-ger impact. For the coupling of furan 1 a with 2 a, the use of

1.0 equiv of BQ had a negative impact on the rate of the for-

mation of 3 aa after the initial stage of the reaction

(Figure 3). This effect was however not observed when tert-

butyl acrylate (2 f) was used instead of2 a (Figure 4). The in-

duction period observed in a mixture of Et2O/AcOH as sol-

vent was attributed to the complexation of the catalytic

trimer [Pd(OAc)2]3 by furan leading to the dimeric or mono-meric Pd active species.[3] We did not observe any induction

period using a DMSO/AcOH mixture. Indeed, DMSO can

act as a ligand to give the monomeric palladium complex A

(Scheme 1).[11] Computational studies by Sakaki et al. have

shown that after the CH activation of arenes by Pd(OAc)2,the palladium center in the resulting ArPdOAc is more elec-

Figure 1. Kinetic isotope effect. Conditions: Pd(OAc)2 (0.05 mmol), 1(2.0 mmol), 2 a (1.0 mmol), BQ (2.0 mmol), AcOH (2 mL), DMSO

(2 mL), RT.

Figure 2. Dependence of the yield of 3 ba on [BQ]. Conditions: Pd(OAc)2(0.05 mmol), 1 b (2.0 mmol), 2 a (1.0 mmol), AcOH (2 mL), DMSO

(2 mL), RT. ^=BQ (2 equiv); &=BQ (1 equiv); ~=BQ (0.5 equiv), Cu-(OAc)2 (0.1 equiv), O2 (1 atm).

Figure 3. Dependence of the yield of3 aa on [BQ]. Conditions: Pd(OAc)2(0.05 mmol), 1 a (2.0 mmol), 2 a (1.0 mmol), AcOH (2 mL), DMSO

(2 mL), RT.^=

BQ (2 equiv);&=

BQ (1 equiv).

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tron-rich than in Pd(OAc)2, and can easily coordinateBQ.[12] We propose that CH activation of 1 by A leads to

B, which would interact with BQ. The resulting complex C,

which is less electron-rich than B, interacts with electron-

rich styrenes 2ae leading to D. The differences observed

on the effect of BQ between Figures 2 and 3 are due to the

fact that 1 a is more nucleophilic than 1 b,[13] and probably

leads to an electron-rich B, which requires the presence ofBQ for the coordination of styrenes. Electron-poor alkenes,

such as 2 f, would interact directly with B, and would be less

sensitive to the amount of BQ. From D, insertion of the C=

C bond into the ArPd bond is followed by a b-H elimina-

tion leading to 3 and the reoxidation of palladium. It should

be noted that C or D could lead to the insertion of BQ into

the PdAr bond. We have performed a classical Heck reac-

tion using BQ (1.0 mmol) and 2 a (1.0 mmol) in the presence

of methyl 4-iodobenzoate (1.0 mmol), Pd(OAc)2(0.05 mmol), PPh3 (0.25 mmol) and NEt3 (1.4 mmol) in

THF. Only (E)-methyl 4-styrylbenzoate was observed, show-

ing that 2 a is more prone than BQ to perform an insertion

reaction. Therefore, complex D probably evolves as pro-

posed in Scheme 1. We suspect that the formation of D is

faster than the insertion of BQ into the PdAr bond of C.

Finally, an electron-poor benzoquinone should facilitate the

interaction of C with 2. Indeed, we have observed that the

reaction of 1 a with 2 a is more efficient in the presence of

one equivalent of 2-chlorobenzoquinone than one equiva-lent of BQ (Figure 5).

Conclusion

Furans and thiophenes were coupled with styrenes through

CH activation under mild conditions. The method is com-

patible with halogenated substrates, including brominated

thiophenes and styrenes. Compared with the previously re-

ported RhIII-catalyzed reactions, this method is advanta-

geous with a wider scope of substrates and cost-effective

PdII catalysts. DMSO and benzoquinone have an influence

on the efficiency of the process. It is proposed that DMSO

acts as a ligand, whereas benzoquinone interacts with the

ArPdOAc(DMSO)2 intermediate to give the less electron-rich species ArPdOAc(BQ)(DMSO), which is more suscep-tible to coordinate the electron-rich styrenes than

ArPdOAc(DMSO)2.

Experimental Section

General procedure for the coupling of 1 with 2 : A round bottom flask

was charged with BQ (216.2 mg, 2.0 mmol), Pd(OAc)2 (11.222.4 mg,0.050.1 mmol), AcOH (2.0 mL), DMSO (2.0 mmol), 1 (2.05.0 mmol)

and 2 (1.0 mmol). The mixture was stirred at room temperature for 24

48 h. Et2O (20 mL) was then added. A saturated aqueous solution of

NaHCO3 (20 mL) was then slowly added with rapid stirring. The organic

phase was washed with NaOH (2m, 20 mL) and H2O (20 mL). The com-

bined aqueous phases were extracted with Et 2O (20 mL). The combined

organic phases were dried over MgSO4, and then evaporated to dryness.

Compound 3 was isolated from purification by flash chromatography

(SiO2, petroleum ether 100% or petroleum ether/EtOAc, 98:270:30).

Figure 4. Dependence of the yield of 3 af on [BQ]. Conditions: Pd(OAc)2(0.05 mmol), 1 a (2.0 mmol), 2 f (1.0 mmol), AcOH (2 mL), DMSO

(2 mL), RT. ^=BQ (2 equiv); &=BQ (1 equiv).

Scheme 1. Proposed catalytic cycle.

Figure 5. Dependence of the yield of 3 aa on the nature of the oxidant.

Conditions: Pd(OAc)2 (0.05 mmol), 1 a (2.0 mmol), 2 a (1.0 mmol),AcOH (2 mL), DMSO (2 mL), RT. ^=BQ (1 equiv); &=2Cl-BQ

(1 equiv).



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Acknowledgements

We are indebted to Rgion Champagne-Ardenne and CNRS for a Ph.D.

studentship to A. V. and for financial support.

Keywords: CH activation dehydrogenation furans

Heck reaction palladium thiophenes

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Received: June 28, 2011

Published online:&& &&, 2011

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COMMUNICATIONDehydrogenative Heck Reaction
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Heck Reaction

A. Vasseur, J. Muzart,

J. Le Bras* .................... &&&&&&&&

Dehydrogenative Heck Reaction of

Furans and Thiophenes with Styrenesunder Mild Conditions and Influence

of the Oxidizing Agent on the Reac-

tion Rate

C

H vs. C

Br in Heck: The directdehydrogenative coupling of furans

and thiophenes with styrenes occurs

under mild conditions (see scheme).

This method allows the coupling of

brominated substrates through C

Hbond activation. In addition, DMSO

and benzoquinone had a positive

effect on the reaction rate.



&6&

J. Le Bras et al.

a chemistry european -asap.3

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