B. T. Gregg et al. / Tetrahedron Letters 50 (2009) 3978–3981
3981
M.; Gregg, B. T. Tetrahedron Lett. 2005, 46, 7553–7557; Wang, H.-J.; Keilman, J.;
Pabba, C.; Chen, Z.-J.; Gregg, B. T. Tetrahedron Lett. 2005, 46, 2631–2634; Sauer,
D. R.; Kalvin, D.; Phelan, K. M. Org. Lett. 2003, 5, 4721–4724; Wang, Y.; Sauer, D.
R. Org. Lett. 2004, 6, 2793–2796; Wang, Y.; Miller, R. L.; Sauer, D. R.; Djuric, S. W.
Org. Lett. 2005, 7, 925–928.
in situ from heteroaromatic halides. A subsequent communication,
which utilizes a similar procedure as described herein, involving
microwave irradiation for the formation of
a,a,a-trisubstituted
amines is in preparation and will be reported on in due course.
7. A representative procedure is as follows: 1-(Naphthalen-2-yl)ethanamine (2):
A 5 mL Biotage microwave process tube with a magnetic stir bar was charged
with 2-naphthonitrile (0.153 g, 1.0 mmol) and THF (3 mL) to which was added
3 M methylmagnesium bromide in diethyl ether (1.17 mL, 3.5 mmol). The
resulting mixture was heated under microwave conditions at 100 °C for 10 min
after which time it was carefully added to a freshly prepared solution of
sodium borohydride (0.076 g, 2.0 mmol) in methanol (5 mL). After stirring for
5 min the reaction mixture was concentrated to dryness under reduced
pressure onto silica gel (3 g). The crude product was purified by flash
chromatography (20 g silica gel, methylene chloride to 80:20 methylene
chloride/methanol) to give the desired product (0.152 g, 89%) as a colorless oil:
1H NMR (300 MHz, CDCl3) d 1.48 (3H, d, J = 6.6 Hz), 4.29 (1H, q, J = 6.6 Hz),
7.41–7.51 (3H, m), 7.79–7.84 (4H, m); ESI MS m/z 172 [M+H]+; HPLC >99%
(AUC).
Acknowledgments
The authors wish to thank Drs. Bruce F. Molino, Douglas Kitch-
en, and Paul Zhichkin for their helpful discussions and suggestions.
References and notes
1. Dominok, G. W.; Oelssner, W. Acta. Biologica et Medica Germanica 1968, 20, 625;
Kukovetz, W. R.; Poech, G.; Holtzman, S.; Paietta, E. Arzneimittel-Forschung
1976, 26, 1321; Kessler, A.; Faure, H.; Petrel, C.; Rognan, D.; Cesario, M.; Ruat,
M.; Dauban, P.; Dod, R. J. Med. Chem. 2006, 49, 5119.
2. Gregg, B. T.; Tymoshenko, D. O.; Razzano, D. A.; Johnson, M. R. J. Comb. Chem.
2007, 9, 507–512; Tymoshenko, D. O.; Gregg, B. T.; Hirsch, M. J.; Butcher, J. L.
Lett. Drug Des. Disc. 2008, 5, 43–47; Gregg, B. T.; Golden, K. C.; Quinn, J. F.;
Tymoshenko, D. O.; Earley, W. G.; Maynard, D. A.; Razzano, D. A.; Rennells, W.
M.; Butcher, J. J. Comb. Chem. 2007, 9, 1036–1040; Yoon, D. S.; Han, Y.; Stark, T.
M.; Haber, J. C.; Gregg, B. T.; Stankovich, S. B. Org. Lett. 2004, 6, 4775–4778.
3. Weiberth, F. J.; Hall, S. S. J. Org. Chem. 1986, 51, 5338–5341.
4. Dejaegher, Y.; Mangelinckx, S.; Kimpe, N. D. Synlett 2002, 0113–0115;
Weiberth, F. J.; Hall, S. S. J. Org. Chem. 1987, 52, 3901–3904; Dollinger,
H.; Mack, J.; Martyres, D.; Jung, B.; Nickolaus, P. US 2006116370, 2006;
Herold, P.; Mah, R.; Tschinke, V.; Stutz, S.; Stojanovic, A.; Marti, C.;
Behnke, D.; Jelakovic, S. WO 2007031558, 2007; Zhao, Z.; O’Brien, J. A.;
Lemaire, W.; Williams, D. L.; Jacobson, M. A.; Sur, C.; Pettibone, D. J.;
Tiller, P. R.; Smith, S.; Hartman, G. D.; Wolkenberg, S. E.; Lindsley, C. W.
Bioorg. Med. Chem. Lett. 2006, 16, 5968–5972; Bender, C. F.;
Widenhoefer, R. A. Org. Lett. 2006, 8, 5303–5305; Vargas-Sanchez, M.;
Couty, F.; Evano, G.; Prim, D.; Marrot, J. Org. Lett. 2005, 7, 5861–5864.
5. Terrasson, V.; Marque, S.; Scarpacci, A.; Prim, D. Synthesis 2006, 1858–1862.
6. Microwave Methods in Organic Synthesis; Larhead, M. O. K., Ed.; Springer: Berlin,
2006; Quinn, J. F.; Razzano, D. A.; Golden, K. C.; Gregg, B. T. Tetrahedron Lett.
2008, 49, 6137–6140; Pabba, C.; Wang, H.-J.; Mulligan, S. R.; Chen, Z.-J.; Stark, T.
8. All compounds were fully characterized by 1H NMR and HPLC/APCI-MS
anaylses and compared to literature results for known compounds.
9. Dollinger, H.; Mack, J.; Martyres, D.; Jung, B.; Nickolaus, P. US 2006116373,
2006.
10.
A
representative
procedure
is
as
follows:
Phenyl(thiophen-2-
yl)methanamine (35):
A
5 mL Biotage microwave process tube with
stir bar was charged with 2-bromothiophene (0.570 g, 3.5 mmol) and
THF (3 mL) to which was added 2 M isopropylmagnesium chloride in
THF (1.75 mL, 3.5 mmol). The resulting mixture was stirred at 0 °C for
30 min after which time benzonitrile (102
resulting mixture was heated under microwave conditions at 100 °C for
5 min after which time it was carefully added to freshly prepared
lL, 1.0 mmol) was added. The
a
solution of sodium borohydride (0.076 g, 2.0 mmol) in methanol (5 mL)
at 0 °C. After stirring for 15 min the reaction mixture was concentrated
to dryness under reduced pressure onto silica gel (3 g). The crude
product was purified by flash chromatography (20 g silica gel, methylene
chloride to 80:20 methylene chloride/methanol) to give the desired
product (0.183 g, 97%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) d
1.93 (2H, s), 5.41 (1H, s), 6.82 (1H, d, J = 3.5 Hz), 6.91 (1H, t, J = 3.5 Hz),
7.20 (1H, d, J = 3.8 Hz), 7.27 (1H, d, J = 7.1 Hz), 7.34 (2H, t, J = 7.0 Hz),
7.41 (2H, d, J = 6.9 Hz); ESI MS m/z 190 [M+H]+; HPLC >99% (AUC).