M. H. S. A. Hamid, J. M. J. Williams / Tetrahedron Letters 48 (2007) 8263–8265
8265
References and notes
2
equiv Me NH.HOAc
2
1
.25 mol% [Ru(p-cymene)Cl2]2
.5 mol% dppf
1
. Salvatore, R. N.; Yoon, C. H.; Jung, K. W. Tetrahedron
2
2
001, 57, 7785.
Ph
OH
OH
Ph
NMe2
2. Grigg, R.; Mitchell, T. R. B.; Sutthivaiyakit, S.; Tongpe-
molecular sieves
toluene, reflux, 24 h
nyai, N. J. Chem. Soc., Chem. Commun. 1981, 611.
8
1%
3
. Watanabe, Y.; Tsuji, Y.; Ige, H.; Ohsugi, Y.; Ohta, T. J.
Org. Chem. 1984, 49, 3359.
4
. Fujita, K.; Li, Z.; Yamaguchi, R. Tetrahedron Lett. 2003,
44, 2687.
H N.HOAc
3
1
.25 mol% [Ru(p-cymene)Cl2]2
5. (a) Cami-Kobeci, G.; Slatford, P. A.; Whittlesey, M. K.;
Williams, J. M. J. Bioorg. Med. Chem. Lett. 2005, 15, 535;
2.5 mol% dppf
(
2
b) Cami-Kobeci, G.; Williams, J. M. J. Chem. Commun.
004, 1072.
Ph
5
(PhCH
) N
2 3
molecular sieves
no solvent, reflux, 24 h
equiv
68%
6
7
8
9
. Del Zotto, A.; Baratta, W.; Sandri, M.; Verardo, G.; Rigo,
P. Eur. J. Inorg. Chem. 2004, 524, and references therein.
. Hollmann, D.; Tillack, A.; Michalik, D.; Jackstell, R.;
Beller, M. Chem. Asian J. 2007, 2, 403.
Scheme 4. Alkylation of ammonium acetates.
. Hamid, M. H. S. A.; Williams, J. M. J. Chem. Commun.
2
007, 725.
. Ruffolo, R. R., Jr.; Bondinell, W.; Hubble, J. P. J. Med.
Chem. 1995, 38, 3681.
Ph
Ph
OH
O
Ph
Ph
NR2
+
10. Jaber, M.; Robinson, S. W.; Missale, C.; Caron, M. G.
[
Ru]
H O
3
Neuropharmacology 1996, 35, 1503.
1
1. Duncton, M. A. J.; Roffey, J. R. A.; Hamlyn, R. J.;
Adams, D. R. Tetrahedron Lett. 2006, 47, 2549.
[
Ru]H2
H O
2
12. Wang, H.-J.; Earley, W. G.; Lewis, R. M.; Srivastava, R.
R.; Zych, A. J.; Jenkins, D. M.; Fairfax, D. J. Tetrahedron
Lett. 2007, 48, 3043.
13. (a) Edwards, M. G.; Jazzar, R. F. R.; Paine, B. M.;
Shermer, D. J.; Whittlesey, M. K.; Williams, J. M. J.;
Edney, D. D. Chem. Commun. 2004, 1072; (b) Black, P. J.;
Cami-Kobeci, G.; Edwards, M. G.; Slatford, P. A.;
Whittlesey, M. K.; Williams, J. M. J. Org. Biomol. Chem.
HNR2
NR
2
+
H+
H O
2
Scheme 5. Presumed mechanism of tertiary amine formation.
2
006, 4, 116; (c) Black, P. J.; Edwards, M. G.; Williams, J.
M. J. Eur. J. Org. Chem. 2006, 4367.
4. Guillena, G.; Ramon, D. J.; Yus, M. . Angew. Chem., Int.
Ed. 2007, 46, 2358.
In summary, we have shown that the combination of
Ru(p-cymene)Cl ] with dppf provides a useful catalyst
for the alkylation of secondary amines with alcohols.
The use of potentially harmful alkyl halides is therefore
avoided, and this chemistry has been applied to the syn-
thesis of Piribedil.
1
[
2
2
1
5
1
5. Typical experimental procedure: [Ru(p-cymene)Cl2]2
(
7.7 mg, 0.0125 mmol), dppf (13.9 mg, 0.025 mmol) and
˚
activated 3 A molecular sieves (0.52 g) were added to a
carousel tube and the mixture was exposed to a nitrogen
atmosphere for 10 min. Morpholine (87 lL, 1 mmol) and
benzyl alcohol (103 lL, 1 mmol) followed by anhydrous
toluene (1 mL) were added dropwise. The reaction mixture
was allowed to stir under a nitrogen atmosphere at room
temperature for 10 min and then heated to reflux for 24 h.
The resulting crude was evaporated in vacuo. Purification
by column chromatography eluting with petroleum ether
(bp 40–60 °C)/ethyl acetate (4:1) gave a colourless liquid
(0.150 g, 84%).
Acknowledgements
We thank His Majesty’s Government of Brunei Dar-
ussalam and Universiti Brunei Darussalam for funding
MHSAH under the in-service and training scheme.