2500
K. J. Butcher, J. Hurst / Tetrahedron Letters 50 (2009) 2497–2500
Representative traditional route
H
N
H
N
O
N
CONH2
CN
a, b
c
N
N
Ph
Ph
Ph
O
H
N
CO2Me
CO2H
N
d, e
f-h
N
N
Ph
Ph
a. Aniline, KCN, AcOH, 2 h b. EtOH recryst. c. cH2SO4 d. KOH, ethylene glycol, 150 °C 4 d e. H2O,
AcOH f. NaH, DMF g. MeI h. Propionic anhydride, reflux, 3 d.
Improved, aniline Bargellini route
O
H
N
O
CO2H
N
CO2Me
a
b, c
N
N
N
Boc
Boc
Boc
a. Aniline, NaOH, CHCl3, THF, 70% b. Propionic anhydride, Et3N, EtOAc, 1h c. MeOH, 2 h, 70% over
2 steps.
Scheme 4.
separated, washed with brine (3 Â 10 ml), dried (Na2SO4), filtered and
concentrated in vacuo to yield 1.47 g (56%) of pale yellow solid. An
Acknowledgments
a
analytical sample was obtained by crystallisation from hexane/ethyl acetate
(4:1) as a colourless solid. TLC heptane + AcOH 5%:ethyl acetate 1:1, Rf 0.5.
MS (ESI): m/z 400 [81Br M-H]+. LC-MS ELSD 100% m/z 400 [81Br M-H]+. 1H
NMR (400 MHz, CDCl3) 7.38 (d, 2H, J = 9 Hz); 6.79 (d, 2H, J = 9 Hz); 3.93–3.80
(m, 2H); 3.19–3.13 (m, 2H); 2.17–2.04 (m, 4H); 1.45 (s, 9H). Microanalysis.
For technical support we thank Stephanie Dupuy, Kerry Para-
dowski, Teresa Parsons and for Letter preparation we thank Dafydd
Owen.
calcd C, 51.01; H, 5.54; N, 3.50%. Found C, 51.06;
H 5.59; N, 3.49%.
4-Bromoaniline (500 mg, 3 mmol) was dissolved in THF (40 ml) and cooled
in an ice bath. NaOH powder (581 mg, 15 mmol) and N-tbutyloxycarbonyl-4-
piperidone (1.79 g, 9 mmol) were added. Chloroform (1.16 ml, 15 mmol) was
added dropwise and the reaction mixture was stirred at 0 °C for 1 h and
then stirred at room temperature for 18 h. The precipitated solid was filtered
off and dissolved in water. The solution was extracted with diethyl ether
(3 Â 20 ml) and the aqueous layer was separated. The aqueous layer was
cooled and acidified with AcOH to pH 3 and extracted with EtOAc (40 ml).
The EtOAc layer was separated, washed with brine (3 Â 10 ml), dried
References and notes
1. Bargellini, G. Gazz. Chim. Ital. 1906, 36, 329.
2. Korger, G. Chem. Ber. 1963, 96, 10.
3. Youseff, A. M.; Safo, M. K.; Danso-Danquah, R.; Joshi, G. S.; Kister, J.; Marden, M.
C.; Abraham, D. J. J. Med. Chem. 2002, 45, 1184.
4. Grella, M. P.; Safo, M. K.; Danso-Danquah, R.; Joshi, G. S.; Kister, J.; Marden, M. C.;
Abraham, D. J. J. Med. Chem. 2000, 43, 4726.
5. Reeve, W. Synthesis 1971, 131.
6. Corey, E. J.; Link, J. O. J. Am. Chem. Soc. 1992, 114, 1906.
(Na2SO4), filtered and concentrated in vacuo to give 651 mg (56%) of
a
yellow foam. TLC heptane + AcOH 5%:ethyl acetate 1:1, Rf 0.5. MS (ESI): m/z
7. Typical procedures: 4-Bromophenol (1.0 g, 6 mmol) was dissolved in THF
(40 ml) and cooled in an ice bath. NaOH powder (1.16 g, 30 mmol) and
N-tbutyloxycarbonyl-4-piperidone (3.58 g, 18 mmol) were added. Chloroform
(2.32 ml, 30 mmol) was added dropwise and the reaction mixture was
stirred at 0 °C for 1 h and then stirred at room temperature for 18 h. The
precipitated solid was filtered off and dissolved in water. The solution was
extracted with diethyl ether (3 Â 20 ml) and the aqueous layer was
separated. The aqueous layer was cooled and acidified with hydrochloric
acid (2 M) to pH 1 and extracted with EtOAc (40 ml). The EtOAc layer was
397 [79Br M-H]+. LC-MS ELSD 100% (ESI) m/z 397 [79Br M-H]+. HRMS (ESI) m/
12
z
399.0913
[
79Br M + H]+ for
C
H24N2O479Br. 1H NMR (400 MHz, CDCl3)
17
7.28 (d, 2H, J = 9 Hz); 6.54 (d, 2H, J = 9 Hz); 3.78–3.71 (m, 2H); 3.29–3.23 (m,
2H); 2.19–2.12 (m, 2H); 1.96–1.90 (m, 2H); 1.45 (s, 9H). Structure was
further confirmed by NMR studies using 13C, gCOSY, HSQC and HMBC.
8. Henriksen, G.; Platzer, S.; Marton, J.; Hauser, A.; Berthele, A.; Schwaiger, M.;
Marinelli, L.; Lavecchia, A.; Novellino, E.; Wester, H.-J. J. Med. Chem. 2005, 48,
7720.