Lithiation of Aryl Bromides Possessing α-Proton of Carbonyl Groups

Abstract

A new methodology for metalation of aryl bromide possessing an active methylene adjacent to carbonyl groups is described. In order to avoid self-quenching, selective deprotonation was necessary prior to halogen-metal exchange reaction. For this purpose, mesityllithium was found to be the best choice. Subsequent treatment with n-BuLi resulted in the lithium-bromine exchange to generate the dianion, which was successfully trapped with some electrophiles in good yield. This method was applied to the efficient synthesis of a novel carbapenem.

Key words

aryllithium - active methylene - lithium-bromine exchange reaction - intramolecular protonation - enolate - mesityllithium

References

• 1a Boudier A. Bromm OD. Lotz M. Knochel P. Angew. Chem. Int. Ed.  2000,  39:  4414 
• 1b Inoue A. Kitagawa K. Shinokubo H. Oshima K. J. Org. Chem.  2001,  66:  4333 
• 1c Kitagawa K. Inoue A. Shinokubo H. Oshima K. Angew. Chem. Int. Ed.  2000,  39:  2481 
• 1d Uchiyama M. Kameda M. Mishima O. Yokoyama N. Koike M. Kondo Y. Sakamoto T. J. Am. Chem. Soc.  1998,  120:  4934 
• Lithium-halogen exchange reaction of aryl halides bearing more acidic functionalities has been reported:
• 2a Beak P. Musick TJ. Liu C. Cooper T. Gallaher DJ. J. Org. Chem.  1993,  58:  7330 
• 2b Narasimhan NS. Sunder N. Liu C. Ammanamanchi R. Bonde BD. J. Am. Chem. Soc.  1990,  112:  4431 
• 2c Beak P. Musick TJ. Chen C.-W. J. Am. Chem. Soc.  1988,  110:  3538 
• 3a Imamura H. Ohtake N. Shimizu A. Sato H. Sugimoto Y. Sakuraba S. Kiyonaga H. Suzuki-Sato C. Nakano M. Nagano R. Yamada K. Hashizume T. Morishima H. Bioorg. Med. Chem. Lett.  2000,  10:  115 
• 3b Nagano R. Shibata K. Adachi Y. Imamura H. Hashizume T. Morishima H. Antimicrob. Agents Chemother.  2000,  44:  489 
• 3c Hashizume T. Morishima H. Drugs of the Future  2001,  25:  833 
• 4a Maeda K. Yamamoto Y. Tomimoto K. Mase T. Synlett  2001,  1808 
• 4b Sugimoto Y. Imamura H. Sako H. Yamada K. Morishima H. Synlett  2001,  1747 
• 4c Imamura H. Shimizu A. Sato H. Sugimoto Y. Sakuraba S. Nakajima S. Abe S. Miura K. Nishimura I. Yamada K. Morishima H. Tetrahedron  2000,  56:  7705 
• 4d Sugimoto Y. Imamura H. Shimizu A. Nakano M. Nakajima S. Abe S. Yamada K. Morishima H. Tetrahedron: Asymmetry  2000,  11:  3609 
• 8a Beck KA. Hoekstra MS. Seeback D. Tetrahedron Lett.  1977,  1187 
• 8b Vedejs E. Lee N. J. Am. Chem. Soc.  1995,  117:  891 
• 10 Kondo Y. Asai M. Miura T. Uchiyama M. Sakamoto T. Org. Lett.  2001,  3:  13 
• 11 Davies GS. Ichihara O. Tetrahedron: Asymmetry  1991,  2:  183 

5

The reaction with n-BuLi resulted in attack on the ester.

6

Magnesium- or zinc-based approaches were all unsuccessful: i-PrMgCl, (i-Pr)₂Mg, Bu₃MgLi, Me₄ZnLi₂ and Rieke Mg-Zn left the substrate unreacted.

7

n-BuLi should be used because thus any nucleophiles would not attack the enolate thus formed.

9

Typical experimental procedure: To a solution of mesityl bromide (876 mg, 4.4 mmol) in THF (15 mL) at -78 °C was added dropwise n-BuLi (2.9 mL of 1.5 M solution in heptane, 4.40 mmol) to form white suspension. The mixture was stirred for 30 min at the same temperature. Arylbromide 5a (1.14 g, 4.40 mmol, dissolved in 7.8 mL of THF) was added to the mixture at -78 °C to form yellow solution which indicated enolate was formed, and stirred for 30 min at the same temperature. n-BuLi (2.7 mL of 1.5 M solution in heptane, 4.0 mmol) was added dropwise at -78 °C and stirred for additional 30 min at the same temperature to complete the reaction. DMF (0.37 mL, 4.8 mmol) was added dropwise to the solution and was stirred for 30 min at the same temperature. Aq NH₄Cl was added to the solution and the product was extracted with EtOAc. The organic layer was washed with water, dried over anhyd Na₂SO₄ and was concentrated in vacuo to yield crude product which was purified by column chromatography using silica to afford 6a (690 mg, 2.95 mmol) in 74% yield.

12

The diastereoselectivity was determined after conversion of 11 to amine 15 (Figure [6] ) by hydrogenation using Pd/C. Enantiomeric purity was determined by HPLC with comparison of a standard sample 17, which was prepared from conjugated ester 9.

Figure 6