Y. Cao et al.
and the spectra obtained were compared with the standard spectra. The
conversion and product selectivity were determined by GC-17A gas chro-
matograph equipped with a HP-FFAP column (30 m ꢁ 0.25 mm) and a
flame ionization detector (FID). For isolation, the combined organic
layer was dried over anhydrous Na2SO4, concentrated, and purified by
silica gel column chromatography.
uct generation; ii) the treatment of N-benzylideneaniline
with benzyl alcohol under identical reaction condition re-
sulted in the formation of only a trace amount of N-phenyl-
benzylamine, and iii) during aniline alkylation with benzyl
alcohol, a small portion of imine (<7.5%) released from
the catalyst, which became the main byproduct and can not
be converted into the desired product by extending the reac-
tion time (see Figure S3). Thus, being different from previ-
Direct N-alkylation of pyrrolidine with benzyl alcohol by using Au/TiO2-
VS: A mixture of pyrrolidine (1.5 mmol), benzyl alcohol (1.5 mmol), Au/
TiO2-VS (1 mol% Au), toluene (1 mL) and n-dodecane (10 mL) as inter-
nal standard were placed into a Teflon-lined autoclave (4 mL capacity).
The resulting mixture was vigorously stirred at 1408C under N2 atmos-
phere (5 atm) for given reaction time. The product was identified by GC-
MS.
ously reported systems (for example, [RuACTHNUTRGNEUNG
(p-cymene)Cl2]2,[5i]
Ru(OH)x/Al2O3,[7a] Pd/MgO[7c]), the results described in the
present work show clearly a unique character of the TiO2
supported Au for N-alkylation of amine with alcohols. Most
importantly, it turns out that the present gold-catalyzed
amine alkylation with alcohol does not involve the free
imine/aldehyde species.
100mmol scale N-alkylation of aniline with benzyl alcohol under solvent-
free conditions: A mixture of aniline (100 mmol, 9.3 g), benzyl alcohol
(100 mmol, 10.8 g), and Au/TiO2-VS (0.0083 mol% Au) were placed into
an autoclave (50 mL capacity). The resulting mixture was vigorously
stirred at 1808C under N2 atmosphere (5 atm) for given reaction time.
For isolation, the combined organic layer was dried over anhydrous
Na2SO4, concentrated, and purified by silica gel column chromatography
to yield the corresponding benzylphenylamine (17.6 g, isolated yield ca.
96%).
Although detailed mechanistic studies remain to be car-
ried out, an initial b-hydride elimination of the alcohol may
be involved in the rate-determining step based on the nega-
tive Hammett 1 value as found for the competitive N-alkyla-
tion of aniline with various substituted benzyl alcohols (1=
À1.32, r2 =0.99, see Figure S4). Taking into account the su-
perior hydrogen transfer activity previously established for
the titania supported Au system,[9] this may well explain the
enhanced N-alkylation activity as observed for Au/TiO2-VS
(see Table 1). In this context, one may assume that the reac-
tion could be further facilitated by the addition of a weak
base, which can promote the initial alcohol dehydrogenation
step.[9] Nevertheless, a significantly retarded formation of
the desired secondary amine has been identified when the
reaction was conducted with Au/TiO2-VS in the presence of
Cs2CO3.[15] Note that this result agrees very well with the
work of Ishida et al.,[16] who found that gold supported on
TiO2 gave similar selectivity (approx. 30%) for the forma-
tion of N-phenylbenzylamine under identical basic condi-
tions. Therefore, it seems that other factors such as the deli-
cate interaction of the Au/TiO2-VS with the involved sub-
strates or intermediates might also be a prerequisite for the
desired reaction pathway. Indeed, we have observed that the
presence of higher concentration of benzaldehyde would
strongly inhibit the final formation of desired N-phenylben-
zylamine with the present gold-catalyzed system.[17]
Acknowledgements
This work was support by the National Natural Science Foundation of
China (20633030, 20721063, and 20873026), New Century Excellent Tal-
ents in the University of China (NCET-09-0305), the National Basic Re-
search Program of China (2003CB615807), and Science & Technology
Commission of Shanghai Municipality (08DZ2270500).
Keywords: alcohols · alkylation · gold · nanoparticles ·
N-alkylation
[1] a) K. P. C. Vollhardt, N. E. Schore, Organic Chemistry: Structure and
Function, 3rd ed., W. H. Freeman, New York, 1999, p. 936, and ref-
erences therein; b) A. A. NuÇez Magro, G. R. Eastham, D. J. Cole-
Hamilton, Chem. Commun. 2007, 3154; c) S. A. Lawrence, Amines:
Synthesis Properties and Applications, Cambridge University, Cam-
bridge, 2004.
[2] a) M. B. Smith, J. March, Advanced Organic Chemistry, 5th ed.,
Wiley, New York, 2001, p. 499; b) R. N. Salvatore, C. H. Yoon, K. W.
d) S. L. Buchwald, C. Mauger, G. Mignani, U. Scholz, Adv. Synth.
[4] a) M. H. S. A. Hamid, P. A. Slatford, J. M. J. Williams, Adv. Synth.
In summary, very small gold nanoparticles supported on
titania acts as an efficient heterogeneous catalyst for the
clean and atom-efficient N-alkylation of amines with alco-
hols in excellent yields under mild and base-free conditions.
This new catalytic system can provide a versatile and envi-
ronmentally benign protocol for the economic synthesis of
amines.
[5] a) S. Bꢃhn, S. Imm, K. Mevius, L. Neubert, A. Tillack, J. M. J. Wil-
61, 4214; f) A. Del Zotto, W. Baratta, M. Sandri, G. Verardo, P.
Rigo, Eur. J. Inorg. Chem. 2004, 524; g) C. T. Eary, D. Clausen, Tet-
rahedron Lett. 2006, 47, 6899; h) C. Gunanathan, D. Milstein,
Experimental Section
General procedure for the direct N-alkylation of alcohols and amines: A
mixture of amine (1.5 mmol), alcohol (1.5 mmol), metal catalysts (0.5
mol% metal), toluene (1 mL), and n-dodecane (10 mL) as internal stan-
dard were placed into a Teflon-lined autoclave (4 mL capacity). The re-
sulting mixture was vigorously stirred at 1208C under N2 atmosphere
(5 atm) for given reaction time. The product was identified by GC-MS
13968
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 13965 – 13969