Scheme 3 N-alkylation of amine 1 with other alcohols. aConversion was
1
determined by H NMR analysis; other examples are isolated yields.
Scheme 6 Formation of N-phenylpiperidine.
Other amines were also amenable to N-alkylation (Scheme 4).
The racemic amine 8 was converted into product 9 and the use of
enantiomerically pure (S)-8 afforded enantiomerically pure (S)-9
(. 97 ee), as determined from the 1H NMR spectrum in the
presence of (S)-acetylmandelic acid.
Alkylation of aminopyridine 10 was successful, although in this
case, some amide (PhCH2CONHPy) was formed, presumably due
to oxidation of the relatively stable intermediate hemi-aminal.
Nevertheless, the use of anilines in alkylation reactions with
alcohols is usually unsuccessful, and we were pleased to discover
that the [Ru(p-cymene)Cl2]2–dppf combination was successful for
the formation of a range of N-phenylamines 13–18 (Scheme 5).
Cyclisation of diol 19 with aniline afforded N-phenyl heterocycle
20 (Scheme 6). However, a greater catalyst loading was needed to
avoid formation of the lactone and other side products.
In summary, we report a method for the N-alkylation of amines
with alcohols using a commercially available ruthenium catalyst–
ligand combination. The reaction conditions are relatively mild
and are applicable to the alkylation of anilines as well as aliphatic
amines.
Scheme 4 N-alkylation of amines with phenethyl alcohol.
We thank His Majesty’s Government of Brunei Darussalam
and Universiti Brunei Darussalam for funding MHSAH under the
in-service and training scheme.
Notes and references
{ Typical experimental procedure: [Ru(p-cymene)Cl2]2 (15.3 mg,
0.025 mmol), dppf (27.7 mg, 0.05 mmol), K2CO3 (13.8 mg, 0.1 mmol)
˚
and activated molecular sieves (0.52 g, 3 A) were added to a carousel tube
and the mixture was exposed to a nitrogen atmosphere for 10 minutes. tert-
Butylamine (105 mL, 1 mmol), phenethyl alcohol (119 mL, 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 minutes and then heated to reflux for 24 hours. The
reaction mixture was filtered through Celite1 and washed with
dichloromethane. The filtrate was collected and the solvents were
evaporated in vacuo to yield a reddish-brown crude mixture. Purification
by column chromatography on silica gel eluting with diethyl ether gave the
title compound 3 (0.16 g, 88% yield) as a pale yellow liquid. 1H NMR
(300 MHz, CDCl3) d = 1.01 (9H, s), 2.68–2.80 (4H, m), 7.10–7.25 (5H, m).
13C NMR (75.4 MHz, CDCl3) d = 29.4 (CH3), 37.6 (CH2), 44.5 (CH2),
50.7 (C), 126.5 (CH), 128.8 (CH), 129.1 (CH), 140.6 (C). This is consistent
with literature data.11
1 (a) R. N. Salvatore, A. S. Nagle and K. W. Jung, J. Org. Chem., 2002,
67, 674; (b) C. Chiappe and D. Pieraccini, Green Chem., 2003,
5, 193.
2 (a) F. Fache, F. Valot, A. Milenkovic and M. Lemaire, Tetrahedron,
1996, 52, 9777; (b) S. Bhattacharyya, Tetrahedron Lett., 1994, 35, 2401;
(c) A. K. Szardening, T. S. Burkoth, G. C. Look and D. A. Campbell,
J. Org. Chem., 1996, 61, 6720 and references therein.
3 (a) Y. Watanabe, Y. Tsuji, H. Ige, Y. Ohsugi and T. Ohta, J. Org.
Chem., 1984, 49, 3359; (b) R. A. T. M. Abbenhuis, J. Boersma and
G. van Koten, J. Org. Chem., 1998, 63, 4282 and references therein; (c)
Y. Tsuji, K.-T. Huh and Y. Watanabe, Tetrahedron Lett., 1986, 27, 377;
Scheme 5 N-alkylation of aniline with different alcohols. aConversion
was determined by 1H NMR analysis; other examples are isolated yields.
726 | Chem. Commun., 2007, 725–727
This journal is ß The Royal Society of Chemistry 2007
Hamid, Malai Haniti S. A.
