7th International Electronic Conference on Synthetic Organic Chemistry (ECSOC-7), http://www.mdpi.net/ecsoc-7, 1-30 November 2003


[A019]

 

Formation of Biaryls by Homocoupling of Grignard Reagents

 

C. Behloul, D. Guijarro, and M. Yus*

 

Departamento de Química Orgánica, Universidad de Alicante, E-03080 Alicante, Spain.

Tel. +34-965903548, Fax +34-965903549, E-mail: [email protected], http://www.ua.es/dept.quimorg/

 

With one biographical summary

 


 Abstract: Arylic Grignard reagents lead to the formation of biaryls when they are heated at 40deg.C in THF in the absence of any transition metal. The transformation could be applied to a variety of arylic Grignard reagents, although with a limited success.

 

Keywords: arylic Grignard reagents, homocoupling, biaryl synthesis, symmetrical biaryls.

 


 

Introduction

 

          Typical methods for the preparation of biaryl compounds include the classic Ullmann reaction, the homocoupling of aryl halides, sulfonates, diazonium salts, acyl chlorides and organometallic reagents, as well as the cross-coupling of several arylic organometallic reagents (mainly Grignard, organotin, organoboron and organozinc reagents) with arylic electrophiles (i.e. aryl halides, sulfonates or phosphates) [1]. All these methods require the use of transition metals or their salts as promoters or catalysts for the coupling reactions.

 

          During the course of a project in which we were interested in the coupling reaction between arylic Grignard reagents and alkyl iodides, we found that the major product of some of the reactions were biaryl compounds resulting from the homocoupling of the Grignard reagents. We decided to investigate further this transformation and in this communication we present the results that we have obtained.

 

Results and Discussion

 

            When a THF solution of p-tolylmagnesium bromide 1a and an equimolar amount of 1-iodoheptane under nitrogen was stirred for 48 h at room temperature, only a very small amount (7% by GC) of the expected coupling product, 1-p-tolylheptane, was formed. Instead, the major product of the reaction was 4,4’-dimethylbiphenyl 2a in 53% yield (Table 1, entry 1). This surprising result led us to study in depth this homocoupling reaction of arylic Grignard reagents. We first tried to optimize the reaction conditions by using different alkyl iodides. Methyl, isopropyl and tert-butyl iodides were tested, but yields decreased in comparison with the one obtained with 1-iodoheptane (Table 1, entries 2-4). Lithium, sodium and potassium iodides were also tested as additives for the reaction (Table 1, entries 5-7). In the last case, a catalytic amount of 18-crown-6 was used as a phase transfer agent and this combination improved the yield to 62% (Table 1, entry 7). In order to check if the iodide was playing any role in the coupling process, we stirred the solution of the Grignard reagent in the absence of any additive and, surprisingly, the biaryl product 2a was also obtained, although in only a 37% yield (Table 1, entry 8). Since we assumed that a radical reaction was taking place, we changed the reaction conditions in order to favour the generation of radicals. Irradiation of the solution of reagent 1a with a 250 W lamp gave a 49% yield of biaryl 2a (Table 1, entry 9). The use of AIBN as a radical initiator (Table 1, entry 10) or diethyl ether as solvent instead of THF (Table 1, entry 11) did not improve yields. Irradiation of the reaction in which potassium iodide and 18-crown-6 were used as additives (Table 1, entry 12) resulted in a lower yield than the reaction performed under sunlight (Table 1, entry 7). The best yield (70%) was obtained when the solution of 1a was stirred at 40deg.C in the absence of any additive (Table 1, entry 13). Further rise of the temperature to reflux of THF resulted in a diminished yield (Table 1, entry 14).

 

 

Table 1. Homocoupling of Grignard Reagent 1a under different reaction conditions.

 

 

Entry

Additive

T (deg.C)

Yield (%)a

1

n-C7H15I

25

53

2

MeI

25

39

3

i-PrI

25

37

4

t-BuI

25

34

5

LiI

25

32

6

NaI

25

43

7

KI / 18-crown-6b

25

62

8

---

25

37

9

---c

35-40d

49

10

AIBNc,e

35-40d

46

11

---c,f

35-40d

44

12

KI / 18-crown-6b,c

35-40d

47

13

---

40

70

14

---

70

38

 

a Isolated yield after column chromatography (silica gel, hexane) based on the starting Grignard reagent 1a and calculated for the stoichiometry 2 1a ® 2a. b A 10 mol% of 18-crown-6 was used. c The reaction flask was irradiated with a 250 W lamp. d External temperature reached by the reaction flask. e A 5 mol% of AIBN was used. f The solvent was Et2O instead of THF.

 

 

            Having established the optimum reaction conditions, we tried to extend the homocoupling process to several arylic Grignard reagents 1b-1f (Table 2). First, we studied if the halogen atom in the Grignard reagent had any effect in the process and we found that bromide was the best one of choice (compare entries 2-4 in Table 2). The yield of the biaryl product 2 diminished as the methyl group in the aromatic ring was moved from para- to ortho- positions (Table 2, entries 1, 5 and 6). Unfortunately, when the electronic properties of the aromatic ring were changed yields were very low, regardless of the nature of the substituent (Table 2, entries 7 and 8).

 

            Reagents 1a-1bb were commercially available. The rest of the Grignard reagents 1bc-1f were prepared in the usual way from the corresponding aryl halides and magnesium powder.

 

            Concerning the reaction mechanism, although we have no clear explanation for the pathway of the coupling process, we assume that a slow diffusion of atmospheric air into the reaction flask through the septum could take place and the Grignard reagent could be oxidized by molecular oxygen to the corresponding radical, which then would couple to give the biaryl compounds 2. A result that led us to this assumption was the failure of the reaction when it was performed in a tightly closed pressure tube under argon: no biphenyl was detected when phenyl magnesium bromide was heated at 40deg.C under these conditions.

 

              Table 2. Homocoupling of Grignard Reagents 1. Formation of Biaryls 2.

 

 

 

Grignard Reagent

 

Product

Entry

No.

Ar

X

 

No.

Yield (%)a

1

1a

4-MeC6H4

Br

 

2a

70

2

1ba

Ph

Cl

 

2b

---b

3

1bb

Ph

Br

 

2b

51

4

1bc

Ph

I

 

2b

32

5

1c

2-MeC6H4

Br

 

2c

3

6

1d

3-MeC6H4

Br

 

2d

29

7

1e

4-MeOC6H4

Br

 

2e

10

8

1f

4-CF3C6H4

Br

 

2f

17

 

a Isolated yield after column chromatography (silica gel, hexane) based on the starting Grignard reagent 1 and calculated for the stoichiometry 2 1 ® 2. b The expected product was not detected.

 

Conclusion

 

          We have presented a new procedure for the generation of biaryl compounds by homocoupling of arylic Grignard reagents. Although the scope of the process is quite limited, this transformation represents a very easy way to prepare biaryl compounds without the need of using any transition metal.

Experimental Part

 

          For general information, see reference [2]. Grignard reagents 1a, 1ba and 1bb, as well as all reagents used for the preparation of Grignard reagents 1bc-1f, were commercially available (Acros, Aldrich) and were used without further purification. All Grignard reagent solutions were titrated with a 1M solution of sec-butanol in xylene using 1,10-phenanthroline as indicator [3]. Commercially available anhydrous THF (99.9%, water content £ 0.006%, Acros) was used as solvent in all the reactions.

 

Preparation of Grignard Reagents 1bc-1f. Typical Procedure.

 

          A suspension of magnesium powder (50 mesh, 477 mg, 19.6 mmol) in THF (1.5 ml) under nitrogen was prepared in a two necked round bottom flask fitted with a condenser. 1,2-Dibromoethane (0.10 ml, 1.2 mmol) was added, which caused warming up of the reaction mixture and evolution of ethylene. The corresponding aryl halide (15.0 mmol) was then added at such a rate to maintain a gentle reflux of THF. Small portions of THF were added every now and then in order to control the reflux rate. After the addition of the halide was complete, more THF was added in order to complete a total volume of 25 ml of the solvent and the reaction mixture was refluxed for 1 h. The reaction was cooled to room temperature and the resulting solution of the Grignard reagent was titrated following a literature procedure [3]. In order to check if some biaryl had been formed during the process, 2 ml of the Grignard reagent solution were hydrolyzed with 1M HCl (5 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic phases were washed with saturated NaHCO3 (5 ml), water (5 ml) and brine (5 ml) and were then dried over sodium sulfate. After filtration and evaporation of the solvents, the resulting residue was purified by column chromatography (silica gel, hexane) and <5% of biaryl compounds were obtained. Yields indicated in Tables 1 and 2 are corrected by deducting the amount of biaryl compounds present in the Grignard reagent solutions.

 

Homocoupling reaction of Grignard reagents 1. Preparation of biaryl compounds 2. Typical Procedure.

 

          A solution of the Grignard reagent 1 (2.0 mmol, 2.0 ml of a 1M solution in THF) in THF (5 ml) under nitrogen was stirred at 40deg.C for 48 h. The reaction was hydrolyzed with 1M HCl (5 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic phases were washed with saturated NaHCO3 (5 ml), water (5 ml) and brine (5 ml) and were then dried over sodium sulfate. After filtration and evaporation of the solvents, the resulting residue was purified by column chromatography (silica gel, hexane) affording biaryl compounds 2 in the yields indicated in Table 2. Compounds 2a-2f (commercially available) were characterized by comparison of their physical and spectroscopic data with authentic samples.

 

Acknowledgements

 

          This work was financially supported by the DGES from the Spanish Ministerio de Educación y Cultura (MEC) (project no. BQU2001-0538).

 

References

 

[1]     Larock, R. C. Comprehensive Organic Transformations; Wiley-VCH: New York, 1999; chapter 2.

[2]     Yus, M.; Martínez, P.; Guijarro, D. Tetrahedron 2001, 57, 10119.

 

[3]     Watson, S. C.; Eastham, J. F. J. Organomet. Chem. 1967, 9, 165.

 

 

Miguel Yus was born in Zaragoza (Spain) in 1947, and received his BSc (1969), MSc (1971) and PhD (1973) degrees from the University of Zaragoza. After spending two years as a postdoctoral fellow at the Max Planck Institut für Kohlenforschung in Mülheim a.d. Ruhr he returned to Spain to the University of Oviedo where he became assistant professor in 1977, being promoted to full professor in 1987 at the same university. In 1988 he moved to a chair in Organic Chemistry at the University of Alicante. Professor Yus has been visiting professor at different institutions and universities such as ETH-Zentrum, Oxford, Harvard, Uppsala, Marseille and Tucson. He is a member or fellow of the chemical societies of Argentina, UK, Germany, Japan, Spain, Switzerland and USA. Among other awards, Professor Yus received in 1999 the "JSPS Prize" and the "Prix Franco-Espagnol" from the Japanese and French Chemical Societies, respectively. He is co-author of about 325 papers mainly in the field of development of new methodologies involving organometallic intermediates. His current research interest is focused on the preparation of very reactive functionalized organometallic compounds and their use in synthetic organic chemistry, arene-catalysed activation of different metals and preparation of new metal-based catalysts for homogeneous and hetereogeneous selective reactions.