The N-Cumyl Group for Facile Manipulation of Carboxamides, Sulfonamides and Aryl O-Carbamates
Post-Directed ortho Metalation

Directed metalation groups (DMGs) are sometimes compromised by the inability to convert them to different functionalities under mild conditions in post-directed ortho metalation (DoM) steps. [1] The advent of N-cumyl modified carboxamide, sulfonamide and O-carbamate DMGs, [2] whose primary advantages over analogous N-t-Bu [3] and other N-alkyl systems rest in fast and/or mild hydrolysis post-DoM, has opened new possibilities for the manipulation of substituted aromatics (Scheme 1). Starting materials are easily prepared by treating the appropriate benzoyl or sulfonyl chlorides with cumyl amine [4] for access to benzamides and sulfonamides, respectively, or by treating phenyl chloroformate with a secondary N-alkyl-N-cumyl amine [5] for O-carbamates.

This Spotlight reviews several applications of N-cumyl-substituted functional groups in organic synthesis since the preliminary results of 1999. [2]

Scheme 1

References

• 1a Snieckus V. Chem. Rev.  1990,  90:  879 
• 1b Cuevas J.-C. Patil P. Snieckus V. Tetrahedron Lett.  1989,  30:  5841 
• 2 Metallinos C. Nerdinger S. Snieckus V. Org. Lett.  1999,  1:  1183 
• 3 More forcing conditions are required to dealkylate N-t-Bu benzamides; see: Reitz DB. Massey SM. J. Org. Chem.  1990,  55:  1375 
• 4a Cumyl amine can be prepared from cumyl alcohol by a modification of the procedure of: Balderman D. Kalir A. Synthesis  1978,  24 . The azide is reduced with LiAlH₄ (Et₂O/0 °C → r.t. → reflux) or H₂ (Lindlar’s catalyst/EtOH) instead of Raney nickel
• 4b

  Cumyl amine is also commercially available from TCI America: catalogue no. C1293.

• 5 Melnick M. Reich SH. Lewis KK. Mitchell JLJ. Nguyen D. Trippe AJ. Dawson H. Davies JF. Appelt K. Wu B. Musick L. Gehlhaar DK. Webber S. Shetty B. Kosa M. Kahil D. Andrada D. J. Med. Chem.  1996,  39:  2795 
• 6 Charette AB. Chua P. Synlett  1998,  163 
• 8 Chao W. Weinreb SM. Tetrahedron Lett.  2000,  41:  9199 
• 9 Clayden J. Menet CJ. Mansfield DJ. Org. Lett.  2000,  2:  4229 
• 10 Clayden J. Tchabanenko K. Chem. Commun.  2000,  317 
• 11 Metallinos C. Ph.D. Thesis   Queen’s University; Kingston, Ontario, Canada: 2001. 
• 12 Tsukazaki M. Tinkl M. Roglans A. Chapell BJ. Taylor NJ. Snieckus V. J. Am. Chem. Soc.  1996,  118:  685 
• 13 Laufer RS. Veith U. Taylor NJ. Snieckus V. Org. Lett.  2000,  2:  629 

7

Ang, P. J. A.; Metallinos, C.; Snieckus, V., unpublished results.

14

Metallinos, C.; Szillat, H.; Taylor, N. J.; Snieckus, V., manuscript in preparation.