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

Abstract

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

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

References and Notes

1

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

2 Cross-coupling reactions of 1,4-dibromobenzene derivatives: Dirk SM. Proce DW. Chanteau S. Kosynki DV. Tour JM. Tetrahedron  2001,  57:  5109 

3 Cross-coupling reactions of 1,3-dibromobenzene derivatives: Allen DW. Nowell IW. March LA. Taylor BF. J. Chem. Soc., Perkin Trans. 1  1984,  2523 

Cross-coupling reactions of 1,2-dibromobenzene derivatives:

4a Singh R. Just G. J. Org. Chem.  1989,  54:  4453 

4b Staab HA. Hone M. Krieger C. Tetrahedron Lett.  1988,  29:  1905 

4c Cheng X. Hou G.-H. Xie J.-H. Zhou Q.-L. Org. Lett.  2004,  6:  2381 

4d 1,2-Dibromofuran derivative: Stock C. Hofer F. Bach T. Synlett  2005,  511 

5 For a general review on site selective transition-metal-catalyzed reactions of polyhalogenated heteroaromatic ring systems, see: Schröter S. Stock C. Bach T. Tetrahedron  2005,  61:  2245 

Halogen-metal exchange of 1,4-dibromobenzene derivatives using alkyllithium:

6a Dabrowski M. Kubicka J. Lulinski S. Serwatowski J. Tetrahedron  2005,  61:  6590 

6b Parham WE. Piccirilli RM. J. Org. Chem.  1977,  42:  257 

6c Voss G. Gerlach H. Chem. Ber.  1989,  122:  1199 

6d Gilman H. Langham W. Moore FW. J. Am. Chem. Soc.  1940,  49:  2327 

Halogen-metal exchange of 1,3-dibromobenzene derivatives using alkyllithium:

7a Sunthankar SV. Gilman H. J. Org. Chem.  1951,  16:  8 

7b Barluenga J. Montserrat JM. Florez J. J. Org. Chem.  1993,  58:  5976 

7c Han Y. Walker SD. Young RN. Tetrahedron Lett.  1996,  37:  2703 

7d Hoye TR. Mi L. Tetrahedron Lett.  1996,  37:  3097 

Halogen-metal exchange of 1,2-dibromobenzene derivatives using alkyllithium:

8a Piette JL. Renson L. Bull. Soc. Chim. Belg.  1970,  79:  353 

8b Hardcastle IR. Hunter RF. Quayle P. Tetrahedron Lett.  1994,  35:  3805 

8c Schlosser M. Heiss C. Eur. J. Org. Chem.  2003,  447 

8d Halogen-metal exchange of 1,2,3-trichlorobenzene using alkyllithium: Haiduc I. Gilman H. J. Organomet. Chem.  1968,  13:  P4 

Halogen-metal exchange of 1,2-dibromo-benzene derivatives using isopropylmagnesium chloride:

9a Krasovskiy A. Knochel P. Angew. Chem. Int. Ed.  2004,  43:  3333 

9b Cottet F. Castagnetti E. Schlosser M. Synthesis  2005,  798 

9c Van der Winkel Y. Akkerman OS. Bickelhaupt F. Main Group Met. Chem.  1988,  11:  91 

10 For the preparation of 3-substituted 1,2-dibromo arene derivatives, see: Menzel K. Fisher EL. DiMichele L. Frantz DE. Nelson TD. Kress MH. J. Org. Chem.  2006,  71:  2188 

11a Dabrowski M. Kubicka J. Lulinski S. Serwatowski J. Tetrahedron  2005,  61:  4175 

11b Hoffmann RW. Dehydrobenzene and Cycloalkynes   Academic Press; New York: 1967. 

11c Wickham PP. Hazen KH. Guo H. Jones G. Reuter KH. Scott WJ. J. Org. Chem.  1991,  56:  2045 

11d Wenwei L. Sapountzis I. Knochel P. Angew. Chem. Int. Ed.  2005,  44:  4258 

12 Boudier A. Bromm LO. Lotz M. Knochel P. Angew. Chem. Int. Ed.  2000,  39:  4414 

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.

17 Reetz MT. Harmat N. Mahrwald R. Angew. Chem., Int. Ed. Engl.  1992,  31:  342 

18 It is well known that in THF the Grignard reagents tend to form solvent-separated aggregates. In less-coordinating solvents, like methyl-tert-butyl ether or toluene, the Grignard reagents favor the formation of halogen-bridged dimers. For reference, see: Parris GE. Ashby EC. J. Am. Chem. Soc.  1971,  93:  106 

19 Van der Waals radius: fluoride (135 pm), chloride (175 pm), bromide (185 pm): Iikubo T. Itoh T. Hirai K. Takahashi Y. Kawano M. Ohashi Y. Tomioka H. Eur. J. Org. Chem.  2004,  3004 

Similar conclusions were drawn for the regioselective deprotonation reaction of haloarenes using LDA or LiTMP:

20a Gorecka J. Heiss C. Scopelliti R. Schlosser M. Org. Lett.  2004,  6:  4591 

20b Pozharskii AF. Ryabtsova OV. Ozeryanskii VA. Degtyarev AV. Kazheva ON. Alexandrov GG. Dyachenko OA. J. Org. Chem.  2003,  68:  10109 

20c Marull M. Schlosser M. Eur. J. Org. Chem.  2003,  1576 

20d Mongin F. Marzi E. Schlosser M. Eur. J. Org. Chem.  2001,  2771 

21 An acceleration of exchange reaction using excess of Grignard reagents: Hoffmann RW. Holzer B. Knopff O. Harms K. Angew. Chem. Int. Ed.  2000,  39:  3072 

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.

23 Chou T. Chen S. Chen Y. Tetrahedron  2003,  59:  9939 

24a 1,2-dibromo-3-methoxybenzene (1g) was prepared following a modified procedure of: Shnur RC. Morvilee M. J. Med. Chem.  1986,  29:  770 

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.

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.