Cohen reductive lithiation

What is Cohen reductive lithiation?

Cohen and Screttas initially reported this reaction in 1978, but Cohen conducted further investigations. Cohen reductive lithiation involves the reductive lithiation of phenyl thioethers using aromatic radical anions, resulting in the formation of organic lithium compounds that can react with electrophiles to produce a diverse range of molecules.

Cohen reductive lithiation
Cohen reductive lithiation

Additional aromatic radical anions are also used in this reaction, such as:

Cohen reductive lithiation - Aromatic radical anion - lithium 1-(dimethylamino)-2,6-di-tertnaphthalenide LDMAN
Aromatic radical anion: lithium 1-(dimethylamino)-2,6-di-tertnaphthalenide (LDMAN)
Cohen reductive lithiation - aromatic radical anion - lithium p,p-di-tert-butylbiphenylide LDBB
Aromatic radical anion: lithium p,p-di-tert-butylbiphenylide (LDBB)
Cohen reductive lithiation - aromatic radical anion - lithium 2,6-di-tert-butylnaphthalenide LDBN
Aromatic radical anion: lithium 2,6-di-tert-butylnaphthalenide (LDBN)

Currently, the aromatic radical anions employed in this reaction are lithium naphthalenide (LN), lithium 1-(dimethylamino)-naphthalenide (LDMAN), lithium p,p-di-tert-butylbiphenylide (LDBB), and lithium 2,6-di-tert-butylnaphthalenide (LDBN) (see list of acronyms). Apart from phenyl thioethers, this reaction can also reduce acetals, allylic and benzylic ethers, amines, carboxylic acids and esters, epoxides, ketones, nitriles, organic halides, selenides, sulfates, sulfides, sulfones, and tetrahydrofurans. Moreover, this method’s versatility is demonstrated in the preparation of allylsilane, 1,3-diol, highly crowded amines (from α-amino nitriles), butenyl alcohol (via sigmatropic [2,3] rearrangement), and five-membered carbocycles through anionic cyclization with good stereoselectivity.

Unfortunately, aromatic radical anions must be generated in tetrahydrofuran (THF) for this reaction, and no other solvent has successfully produced such anions with lithium counterions, except for dimethyl ether (DME), which works for LDMAN. The reductive lithiation of epoxides and oxetanes involves transferring an electron to an antibonding orbital (LUMO) of the corresponding heterocycle, followed by ring opening to an intermediate containing an oxyanion and a carbon radical.

Two approaches have been devised to stabilize both the LUMO and formed intermediates: employing a Lewis acid (for example, BF3·Et2O) and introducing a vinyl group to the α-position of THF. It was observed that during the reductive lithiation of tetrahydrofurans and tetrahydropyrans, the axial lithio derivative was predominantly obtained from both the axial and equatorial epimers.

References

  • Cohen, T.; Daniewski, W. M. and Weisenfeld, R. B., Tetrahedron Lett., 1978, 4665
  • Screttas, C. G. and Micha-Screttas, M., J. Org. Chem., 1978, 43, 1064
  • Deng, K.; Bensari, A. and Cohen, T., J. Am. Chem. Soc., 2002, 124, 12106
  • Cohen, T.; Kreethadumrongdat, T.; Liu, X. J. and Kulkarni, V., J. Am. Chem. Soc., 2001, 123, 3478
  • Cheng, D.; Zhu, S.; Liu, X.; Norton, S. H. and Cohen, T., J. Am. Chem. Soc., 1999, 121, 10241
  • Chen, F. P.; Mudryk, B. and Cohen, T., Tetrahedron, 1999, 55, 3291
  • Liu, H.; Shook, C. A.; Thiruvazhi, M.; Jamison, J. A. and Cohen, T., J. Am. Chem. Soc., 1998, 120, 605
  • Cohen, T. and Zhu, S., Tetrahedron, 1997, 53, 17607
  • Cohen, T. and Tong, S., Tetrahedron, 1997, 53, 9487
  • Cohen, T.; Zhang, B. and Cherkauskas, J. P., Tetrahedron, 1994, 50, 11569
  • Chen, F.; Mudryk, B. and Cohen, T., Tetrahedron, 1994, 50, 12793
  • Mudryk, B. and Cohen, T., J. Am. Chem. Soc., 1993, 115, 3855
  • Mudryk, B. and Cohen, T., Org. Synth., 1993, 72, 173
  • Cherkauskas, J. P. and Cohen, T., J. Org. Chem., 1992, 57, 6
  • Mudryk, B. and Cohen, T., J. Am. Chem. Soc., 1991, 113, 1866
  • Mudryk, B. and Cohen, T., J. Org. Chem., 1991, 56, 5760
  • Cohen, T. and Doubleday, M. D., J. Org. Chem., 1990, 55, 4784
  • Cohen, T.; Jeong, I.-H.; Mudryk, B.; Bhupathy, M. and Awad, M. M. A., J. Org. Chem., 1990, 55, 1528
  • Mudryk, B. and Cohen, T., J. Org. Chem., 1989, 54, 5657
  • Cohen, T. and Bhupathy, M., Acc. Chem. Res., 1989, 22, 152
  • Cohen, T. and Lin, M.-T., J. Am. Chem. Soc., 1984, 106, 1130
  • Cohen, T. and Matz, J. R., J. Am. Chem. Soc., 1980, 102,6900
  • Cohen, T. and Matz, J. R., Synth. Commun., 1980, 10, 311
  • Cohen, T. andWeisenfeld, R. B., J. Org. Chem., 1979, 44, 3601
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