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Synlett 2006(12): 1948-1952  
DOI: 10.1055/s-2006-947362
LETTER
© Georg Thieme Verlag Stuttgart · New York

Regioselective Halogen-Metal Exchange Reaction of 3-Substituted 1,2-Dibromo Arenes: The Synthesis of 2-Substituted 5-Bromobenzoic Acids

Karsten Menzel*a, Lisa Dimicheleb, Paul Millsa, Doug E. Frantza,, Todd D. Nelsona, Michael H. Kressa
a Merck Research Laboratories, Department of Process Research, 466 Devon Park Drive, Wayne, Pennsylvania 19087, USA
b Merck Research Laboratories, Department of Process Research, 126 Lincoln Avenue, Rahway, New Jersey 07065, USA
Fax: +1(215)9932100; e-Mail: karsten_menzel@merck.com;
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Publication History

Received 23 March 2006
Publication Date:
24 July 2006 (online)

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Abstract

Regioselective halogen-metal exchange reactions using isopropylmagnesium chloride were carried out on 3-substituted 1,2-dibromo arenes. Eleven examples are given.

Key words

1,2-dibromobenzene - Grignard reactions - substitutent effect - regioselectivity - carboxylic acids

    References and Notes

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  • 24b

    Preparation of 1,2-Dibromo-3-methoxybenzene ( 1g).
    In a round-bottom flask, 1.12 mL (4.09 mmol) of a 25% w/w solution of MeONa in MeOH was added to a solution of 2,3-dibromo-1-fluorobenzene (500 mg, 1.97 mmol) in MeOH (6 mL) and DMSO (10.5 mL) under nitrogen. The solution was heated to reflux for 2 h and then allowed to cool to 25 °C before being transferred into H2O (20 mL). The stream was extracted three times with a total volume of 60 mL tert-butyl methyl ether. The combined organic layers were washed with H2O (2 × 15 mL), dried over Na2SO4, filtered and concentrated in vacuum. The remaining residue was purified by flash column chromatography (3% EtOAc in hexane) affording 430 mg (60%) of a colorless liquid. 1H NMR (300 MHz, CDCl3): δ = 7.25 (dd, J = 8.1, 1.4 Hz, 1 H), 7.14 (t, J = 8.1 Hz, 1 H), 6.83 (dd, J = 8.2, 1.3 Hz, 1 H), 3.90 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 157.5, 128.8, 126.3, 125.6, 114.9, 110.3, 56.6.
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1

New address: Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9038, USA.

13

Authentic samples of 3-bromo-1-chlorobenzene (2a) and 2-bromo-1-chlorobenzene (3a) are commercially available from Aldrich. Both 2a and 3a can be followed by HPLC and are baseline-separated signals with different retention times. Therefore the regioisomeric distribution of 2a and 3a could be analyzed by integration of the corresponding signal areas.

14

Major by-products of the halogen-metal exchange reaction were debrominated chlorobenzene derivatives and polyhalogenated biphenyls. The debrominated chloro arene may be indicative of a benzyne side reaction.

15

The decomposition was accompanied by copious amounts of chlorobenzene and biphenyl derivatives, which can be generated by a dehydrobenzene pathway.

16

Significant amounts of debrominated arenes and biphenyl derivatives had been identified by GC-MS. The impurity profiles of theses reaction conditions and using n-BuLi were similar.

22

The ratio of 94:6 corresponds to the protonated products of A and B. The regioselectivity was confirmed by commercially available samples of 2- and 3-bromo-benzonitrile.

25

Preparation of 1,2-Dibromo-3-methylbenzene ( 1h).
In a Schlenk flask, a BuLi solution in hexane (1.44 M, 14.7 mL, 21.2 mmol) was diluted with THF (22 mL) under nitrogen. The solution was cooled to -50 °C before 2,2,6,6-tetramethylpiperidine (3.0 g, 21.2 mmol) of was added dropwise. After 15 min the reaction mixture was cooled to -100 °C and then charged with 1,2-dibromobenzene (2.5 g, 10.6 mmol). The reaction mixture was aged for 2 h at -100 °C before 2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxa-borolane (4.90 g, 26.3 mmol) was added. After 30 min at -100 °C the reaction mixture was allowed to warm to 15 °C before brine (20 mL) was added to the reaction mixture. The organic layer was separated and the aqueous phase was extracted two times with a total amount of 20 mL of tert-butyl methyl ether. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum. The remaining solid (3.0 g) was diluted in 5% tert-butyl methyl ether in hexane and purified by flash column chromatog-raphy affording 1.3 g (34%) of a white solid. 1H NMR (300 MHz, CDCl3): δ = 1.42 (s, 12 H), 7.14 (t, J = 7.62 Hz, 1 H), 7.48 (dd, J = 7. 30, 1.52 Hz, 1 H), 7.66 (dd, J = 7.97, 1.60 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ = 24.8, 84.6, 126.0, 127.8, 129.3, 134.4, 135.5 (C-B not seen).
In a Schlenk flask, 2-(2,3-dibromophenyl)-4,4,5,5-tetra-methyl[1,3,2]dioxaborolane (3.0 g, 8.3 mmol) was dissolved in toluene (80 mL), EtOH (8 mL) and 2 M aq K2CO3 solution (8 mL) under nitrogen. The biphasic reaction mixture was charged with MeI (1.42 g, 10.0 mmol) followed by tetrakis (triphenylphosphine)palladium (350 mg, 0.30 mmol). The reaction mixture was heated to 80 °C for 18 h and then cooled down to 0 °C in an ice bath The reaction mixture was charged carefully with a 1 M aq HCl solution (20 mL). The organic layer was separated and the aqueous phase was extracted two times with a total amount of 30 mL of tert-butyl methyl ether. The organic phase was dried over MgSO4, filtered and concentrated in vacuum. The liquid residue was purified by flash column chromatography (1% tert-butyl methyl ether in hexane) affording 1.7 g (82%) of a colorless liquid. 1H NMR (300 MHz, CDCl3): δ = 2.47 (s, 3 H), 7.06-7.11 (m, 1 H), 7.18-7.20 (m, 1 H), 7.45-7.48 (m, 1 H). 13C NMR (75 MHz, CDCl3): δ = 25.0, 125.6, 127.1, 128.0, 129.3, 131.2, 140.8.

26

1,2-Dibromo-3-methylbenzene underwent the halogen-metal exchange with complete consumption in the presence of 7 equiv of isopropylmagnesium chloride. If 1.1 equiv are used, only a 50% conversion is observed at -25 °C after 24 h.

27

The ratio between benzoic acid 4 and 5 in general was determined by a combination of LC-MS and 1H NMR.

28

The regioselective assignments were done by proton-carbon coupling constants along the aromatic ring structure which are different for the regioisomeric structure of 4 and 5, see: Dimichele, L.; Menzel, K.; Mills, P.; Frantz, D. E.; Nelson, T. D. Magn. Reson. Chem. 2006, 44, submitted.

29

Biphenyl 6i was prepared following the experimental procedure described in ref. 25 by using iodobenzene in the cross coupling reaction: 1H NMR (300 MHz, CDCl3): δ = 7.23-7.25 (m, 2 H), 7.34-7.37 (m, 2 H), 7.39-7.44 (m, 3 H), 7.65 (dd, J = 6.29, 3.29 Hz, 1 H). 13C NMR (75 MHz, CDCl3): δ = 125.4, 126.3, 128.0, 128.1 (2 C), 128.2, 129.2 (2 C), 129.8, 132.8, 141.8, 145.5.

30

Biphenyl 6k was prepared following the experimental procedure described in ref. 25 by using 2-iodoanisole in the cross coupling reaction: 1H NMR (300 MHz, CDCl3): δ = 7.60-7.64 (m, 1 H), 7.40 (ddd, J = 8.00, 6.39, 5.11 Hz, 1 H), 7.18-7.23 (m, 2 H), 7.14 (dd, J = 7.42, 1.78 Hz, 1 H), 7.03 (td, J = 7.40, 1.04 Hz, 1 H), 6.99 (d, J = 10.11 Hz, 1 H), 3.79 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 156.3, 142.5, 132.5, 130.8, 130.4, 130.0, 129.6, 127.9, 126.7, 125.6, 120.3, 110.9, 55.5. GC-MS: m/z = 342, 261, 246, 182, 152, 139.

31

Biphenyl 6l was prepared following the experimental procedure described in ref. 25 by using 2-iodo-1-cyano-benzene in the cross coupling reaction: 1H NMR (300 MHz, CD2Cl2): δ = 7.27-7.35 (m, 2 H), 7.40 (dd, J = 7.73, 0.80 Hz, 1 H), 7.53 (dt, J = 1,20, 7.63 Hz, 1 H), 7.68 (dt, J = 1.28, 7.67 Hz, 1 H), 7.74-7.79 (m, 2 H). 13C NMR (75 MHz, CD2Cl2): δ = 125.4, 126.3, 128.0, 128.1 (2 C), 128.2, 129.2 (2 C), 129.8, 132.8, 141.8, 145.5.