2-Naphthylmethyl (NAP) as a Versatile Amino Protecting Group, Chemo­selective Removal under Mild Conditions

Abstract

The use of 2-naphthalenemethyl (NAP) as a versatile amino protecting group is reported. Highly efficient and chemo­selective cleavage of protected tertiary amines using DDQ in CH₂Cl₂-MeOH (4:1) has been observed in the presence of various functionalities such as hydroxyl, acetal, alkene, ester, benzyloxy and N-benzyl groups.

Key words

protecting group - amine - 2-naphthalenemethyl (NAP) group - oxidative cleavage - DDQ

References

• 1 Greene TW. Wuts PGM. In Protective Groups in Organic Synthesis   3rd ed.:  Wiley; New York: 1999. 
• 2a Iminosugars: Recent Insights into their Bioactivity and Potential as Therapeutic Agents In Current Topics in Medicinal Chemistry   Martin OR. Compain P. Bentham; Hilversum Netherlands: 2003.  3. p.issue 5 
• 2b Tezuka K. Compain P. Martin OR. Synlett  2000,  1837 
• 2c Rambaud L. Compain P. Martin OR. Tetrahedron: Asymmetry  2001,  12:  1807 
• 2d Martin OR. Saavedra OM. Xie F. Liu L. Picasso S. Vogel P. Kizu H. Asano N. Bioorg. Med. Chem.  2001,  9:  1269 
• 2e Bordier A. Compain P. Martin OR. Ikeda K. Asano N. Tetrahedron: Asymmetry  2003,  14:  47 
• 3a Godin G. Compain P. Masson G. Martin OR. J. Org. Chem.  2002,  67:  6960 
• 3b Masson G. Compain P. Martin OR. Org. Lett.  2000,  2:  2971 
• 4 Cipolla L. Palma A. La Ferla B. Nicotra F. J. Chem. Soc., Perkin Trans. 1  2002,  2161 
• 6a Gaunt MJ. Yu J. Spencer JB. J. Org. Chem.  1998,  63:  4172 
• 6b Gaunt MJ. Boschetti CE. Yu J. Spencer JB. Tetrahedron Lett.  1999,  40:  1803 
• For selected examples of total synthesis using the O-NAP group see:
• 7a Xia J. Alderfer JL. Piskorz F. Matta KL. Chem.-Eur. J.  2001,  7:  356 
• 7b Inoue M. Uehara H. Maruyama M. Hirama M. Org. Lett.  2002,  4:  4551 
• 7c Csávás M. Borbás A. Szilágyi L. Lipták A. Synlett  2002,  887 
• 7d Yvin J.-C, Jamois F, Ferrières V, and Plusquellec D. inventors; PCT Int. Appl. WO  0157053.  ; Chem. Abstr. 2001, 135, 137673
• 8a Xia J. Abbas SA. Locke RD. Piskorz CF. Alderfer JL. Matta KL. Tetrahedron Lett.  2000,  41:  169 
• 8b Wright JA. Yu J. Spencer JB. Tetrahedron Lett.  2001,  42:  4033 
• 9 Ishihara K. Kuroki Y. Yamamoto H. Synlett  1995,  41 
• 11 Iwamura J. Hirao N. Tetrahedron Lett.  1973,  2447 
• 13 For oxidative mono-debenzylation of tertiary amines incorporating two N-benzyl substituents using DDQ or CAN see: Hungerhoff B. Samanta SS. Roels J. Metz P. Synlett  2000,  77 

5

In our case, N-allyl or N-PMB groups were found to be partially or totally cleaved during the deprotection of the acetal function in aq TFA (Scheme [1] ).

10

Typical experimental procedure: To a solution of 8b (1.7 g, 2.86 mmol) in a 4:1 mixture of CH₂Cl₂-MeOH (220 mL) was added DDQ (1.95 g, 8.59 mmol, 3 equiv) under Ar. The solution was stirred at r.t. for 2 h. The crude mixture was evaporated to dryness and then taken into CH₂Cl₂. The solution was washed with sat. aq NaHCO₃ (5 ×). The organic layer was dried (MgSO₄) and concentrated under reduced pressure. Purification on silica gel (petroleum ether-EtOAc, 3:2) afforded the secondary amine 9 as a colorless oil (1.08 g, 83%).

12

Compounds 11, 13 and 15 were synthesized by alkylation of the corresponding secondary amines with 2-bromo-methylnaphthalene.
Typical experimental procedure: To a solution of N-benzyl piperazine (510 mg, 2.89 mmol) in anhyd THF (30 mL) was added NaH in oil (60%, 140 mg, 3.5 mmol) at 0 °C. After 30 min, commercial 2-bromomethylnaphthalene (660 mg, 3 mmol) was added and the mixture was stirred for 24 h at r.t. The reaction was then quenched with a mixture of MeOH (5 mL) and ice (10 g). The product was extracted with CH₂Cl₂ (50 mL). The organic phase was washed with sat. aq NaHCO₃ (2 × 40 mL), dried (MgSO₄) and concentrated under reduced pressure. Purification on silica gel (petroleum ether-EtOAc, 95:5) afforded the tertiary amine 11 (645 mg, 71%).