Efficient and clean gold-catalyzed one-pot selective n-alkylation of amines with alcohols

Article abstract of DOI:10.1002/chem.201001848

Atom-efficient direct N-alkylation: An environmentally clean one-pot selective N-alkylation of amines with an equimolar amount of alcohols via a hydrogen autotransfer pathway was achieved over a titania-supported gold catalyst system in good to excellent yields without additive (see scheme).

Full text of DOI:10.1002/chem.201001848

COMMUNICATION
DOI: 10.1002/chem.201001848
Efficient and Clean Gold-Catalyzed One-Pot Selective N-Alkylation of
Amines with Alcohols
Lin He, Xia-Bing Lou, Ji Ni, Yong-Mei Liu, Yong Cao,* He-Yong He, and
Kang-Nian Fan[a]
The N-alkylation of primary amines to secondary amines
is of fundamental importance in organic synthesis, granting
access to valuable N-alkylamines that are widely used as
pharmacophores in numerous biologically active com-
pounds, dyes, agrochemicals and functionalized materials.[1]
The most commonly used method for N-alkylation is the
coupling of amines with alkyl halides[2] in the presence of
stoichiometric amounts of bases. This procedure, however,
can be problematic due to overalkylation, the toxic nature
of many alkyl halides, as well as the concomitant formation
of large quantities of undesired waste. An alternative envi-
ronmentally-benign approach is the N-alkylation of amines
with readily available alcohols via hydrogen autotransfer,[3]
also known as hydrogen-borrowing process.[4] The applica-
tion of alcohols as alkylating agents has the benefit of high
atom efficiency and the formation of water as the only side
product. Until now, reports are largely focused on Ru-[5] or
Ir-[6] based homogeneous systems, which are not practically
useful because of the problem of reusability and/or the in-
dispensable use of large amounts of additives or co-catalysts.
Although there are several reports on the cross-coupling of
amines and alcohols using heterogeneous catalysts,[7] most of
them suffer from harsh reaction conditions, low turnover
numbers (TONs) and frequencies (TOFs), limited substrate
scope, and/or the use of excess alcohols/amines to achieve
high yields.
nation (TH) of carbonyl compounds with 2-propanol[9] and
oxidant-free dehydrogenation of alcohols under mild condi-
tions.[10] The excellent performance of gold catalysts for hy-
dride transfer has led us to investigate the possibilities of-
fered by Au catalysts for one-pot N-alkylation of amines
using alcohols as alkylating agents. Herein, we present a
simple and versatile gold-catalyzed system for highly selec-
tive N-alkylation of amines under mild conditions. The cata-
lytic system described here is one promising candidate for
the direct coupling of amines and alcohols because of the
following advantages: i) extremely high atom-economical
system achieved by the employment of equimolar amounts
of starting materials with water as the sole by-product;
ii) high catalytic activity and selectivity; iii) without any ad-
ditives and/or cocatalysts, and iv) the reaction can proceed
smoothly under a 100 mmol scale solvent-free conditions. To
the best of our knowledge, this new heterogeneous Au-
mediated catalysis is greener than any of the known alterna-
tives and involves an easy work up.
Initially, the catalytic activity and selectivity for the addi-
tive-free reaction of equimolar amounts of aniline (1a) and
benzyl alcohol (2a) to give N-phenylbenzylamine (3a) were
compared by using various catalysts (Table 1). The titania
supported gold catalysts such as Au/TiO2-WGC (provided
by the World Gold Council) and Au/TiO2-VS (very small
Au NPs ca. 1.8 nm, see Supporting Information) showed
high activities for the transformation (entries 1–3); in partic-
ular, the reaction with Au/TiO2-VS gave 3a in 92% yield
with high selectivity (entry 1). In this case, the average TOF
and the TON reached up to 13.1 hÀ1 and 184, respectively.
There are very few catalysts that are effective under such
benign conditions, the most prominent of which is a homo-
geneous [Cp*IrCl2]2 complex in the presence of a large
excess of NaHCO3 (TOF: 5.5 hÀ1, TON: 94).[6b] In the ab-
sence of the catalyst, the desired secondary amine 3a was
not produced. No formation of 3a was observed in the pres-
ence of just TiO2 (entry 12). Under the conditions described
in Table 1, Au deposited on other supports as well as Pd, Ru
catalysts supported on TiO2 were not effective (entries 4–
Catalysts based on supported gold nanoparticles (NPs)
have shown their efficiency in a broad range of transforma-
tions.[8] We and others have recently reported that supported
gold NPs acted as robust catalysts for the transfer hydroge-
[a] L. He, X.-B. Lou, J. Ni, Dr. Y.-M. Liu, Prof. Dr. Y. Cao,
Prof. Dr. H.-Y. He, Prof. K.-N. Fan
Shanghai Key Laboratory of Molecular Catalysis
and Innovative Materials, Department of Chemistry
Fudan University, Shanghai 200433 (P. R. China)
Fax : (+86)-2165643774
E-mail: yongcao@fudan.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001848.
Chem. Eur. J. 2010, 16, 13965 – 13969
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
13965

Table 1. Direct N-alkylation of aniline with benzyl alcohol (1:1 molar ratio) by various catalysts.[a]
give the desired products in ex-
cellent yields (Table 2, en-
tries 1–11). Benzyl alcohols
with electron-donating groups
react smoothly (entries 2–4),
while substitution of electron-
withdrawing group on the ben-
zene ring decreases the reactivi-
ty (entry 5). The notoriously
difficult secondary alcohols (en-
tries 6, 8 and 9) were successful-
ly converted without any addi-
tives, which has no precedent in
the literature. Moreover, trans-
formation of other nonactivated
aliphatic alcohols proceeded
smoothly to produce the corre-
sponding secondary amines in
high yields (entries 10, 11). The
most noteworthy example is the
reaction of phenethyl alcohol
with aniline to give a 2-phenyl-
ethanamine derivative (entry 7),
Entry
Catalyst
t [h]
Conv.
Yield [%][d]
3a’
[%][c,d]
3a
Others
1
Au/TiO2-VS
Au/TiO2-VS
Au/TiO2-WGC
Au/Al2O3
Au/MgO
Au/ZnO
Au/HAP
Au/CeO2
Au/SiO2
Pd/TiO2
14
19
14
14
14
14
14
14
14
14
14
14
>99
>99
71
49
36
38
29
24
19
92
91
64
36
16
22
21
15
6
7.5
8
6
11
16
13
6
<0.5
<1
1
2
4
3
2
1
1
2[b]
3
4
5
6
7
8
9
10
11
12
8
12
17
5
41
22
n.r.
22
16
–
2
1
–
Ru/TiO2
TiO2 (P25)
–
[a] Reaction conditions: aniline (1.5 mmol), benzyl alcohol (1.5 mmol), toluene (1 mL), catalyst (metal:
0.5 mol%), 1208C, 5 atm N2. n.r.=no reaction. [b] Third run. [c] Conversions based on benzyl alcohol con-
sumption. [d] Determined by GC using n-dodecane as the internal standard.
11), although Au/Al2O3 gave
moderate yield of 3a, the unde-
sirable 3a’ was also produced as
Table 2. Au/TiO2-VS-catalyzed amine alkylation with alcohols.[a]
a by-product (entry 4).
The reaction was completely
Entry
1
Amine
Alcohol
t [h]
Conv. [%][e]
Yield [%][f]
92 (90)
terminated by the removal of
Au/TiO2-VS from the reaction
mixture after 40% conversion
of 1a at 1208C. Further treat-
ment of the filtrate under the
same reaction conditions did
not give any products. More-
over, ICP analysis of the filtrate
confirmed that the Au content
was below the detection limit
(<0.10 ppm). Additionally, the
recovered Au/TiO2-VS could be
reused at least three runs with-
out appreciable loss of the orig-
inal catalytic activity (Table 1,
entry 2). These results indicate
that the observed catalysis is
truly heterogeneous.
14
>99
2
12
5
>99
>99
>99
97
92
3
98 (95)
95
4
13.5
42
36
19
40
43
48
45
5[b]
6[b]
7[b]
8[b]
9[b]
10[b]
11[b]
87
98
93 (90)
96
>99
97
Next, the scope of the pres-
ent
Au/TiO2-VS
catalyzed
94
system with regard to various
combinations of amines and al-
cohols (1:1 molar ratio for all
98
92
examples)
was
examined.
Table 2 showed that the catalyst
system was surprisingly versa-
tile. Structurally diverse alco-
hols, including aromatic, ali-
phatic ones react with aniline to
98
96 (92)
93
96
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Chem. Eur. J. 2010, 16, 13965 – 13969

Gold-Catalyzed One-Pot Selective N-Alkylation of Amines
Table 2. (Continued)
COMMUNICATION
ural products, for example, pro-
line, as well as pharmaceuticals
such as retronecine and opiod
receptor agonists (CJ-15161).
The reaction of this cyclic
amine with benzyl alcohol gave
the desired tertiary amine in ex-
cellent yield after 50 h at 1408C
(see Scheme 1).
Entry
Amine
Alcohol
t [h]
Conv. [%][e]
Yield [%][f]
93
12
24
>99
13
14
28
20
>99
>99
96
96
A heterogeneous direct N-al-
kylation without solvents would
be more desirable for practical
applications. Notably, the Au/
TiO2-VS catalyst system can fa-
cilitate the 100 mmol-scale se-
lective N-alkylation of aniline
with benzyl alcohol under neat
conditions at 1808C (see
Scheme 2). After completion of
the reaction, an impressive se-
lectivity (98%) was achieved
and 17.6 g of the corresponding
15
16
36
20
98
95
>99
90 (87)
17[c]
18[c]
19[d]
31
26
49
>99
>99
71
85
86
51[h]
benzylphenylamine
(isolated
yield ca. 96%) could be isolat-
ed in high purity via a simple
work up.[14]
20[d]
21[d]
55
63
74
69
53[h]
50[h]
In analogy to previously re-
ported homogeneous system-
s,[3a,5,7] the present Au-catalyzed
[a] Reaction conditions: amine (1.5 mmol), alcohol (1.5 mmol), toluene (1 mL), 0.5 mol% Au, 1208C, 5 atm
N2. [b] Amine (1.5 mmol), alcohol (1.5 mmol), toluene (1 mL), 1 mol% Au, 1408C, 5 atm N2. [c] Amine
(0.5 mmol), alcohol (0.5 mmol), toluene (1 mL), 2 mol% Au, 1408C, 5 atm N2. [d] Amine (0.15 mmol), alcohol
(0.15 mmol), toluene (1 mL), 5 mol% Au, 1408C, 5 atm N2. [e] Conversions based on alcohols consumption.
Determined by GC using n-dodecane as the internal standard. [f] Numbers in parenthesis refer to yields of iso-
lated products. [h] In these cases, not only alcohols sever as alkylating agents, but also amines themselves can
act as alkylating agents, leading to undesired formation of appreciable amount of self -coupling products.
N-alkylation
may
proceed
through a sequential reaction
pathway in which three elemen-
a common structural feature found in many medicinal drugs
such as Piriton[11] and Tripelennamine.[12]
Furthermore, the reaction also proceeds successfully with
a number of other primary amines. The transformation of
substituted anilines with benzyl alcohol afforded the corre-
sponding secondary amines in high yields (entries 12–16).
Aliphatic amines, which are difficult to react, could also pro-
ceed smoothly to generate the
Scheme 1. Au/TiO2-VS-catalyzed N-alkylation of pyrrolidine with benzyl
alcohol.
corresponding amines (en-
tries 17, 18). In the more chal-
lenging reactions employing ali-
phatic amines and aliphatic al-
cohols as the reactants, rela-
tively larger amounts of the Au
catalyst were required to
obtain moderate yields (en-
Scheme 2. 100 mmol scale N-alkylation of aniline with benzyl alcohol under solvent-free conditions.
tries 19–21). Nevertheless, the performance was still encour-
aging since these transformations by using heterogeneous
catalysts were scarcely described in the literature. Inspired
by these results we became interested in the synthesis of ter-
tiary amine by N-alkylation of secondary amines with alco-
hols. Pyrrolidine is chosen as the starting amine as it is one
of the simplest alkaloid structures[13] in many important nat-
tary steps (alcohol dehydrogenation, imine formation and
hydrogenation) are involved. Nevertheless, several unusual
phenomena have been observed for the present heterogene-
ous Au-mediated system: i) The reaction between aniline
and benzaldehyde in the presence of a hydrogen donor (2-
propanol) under the same conditions led to exclusive forma-
tion of the corresponding imine with no desired amine prod-
Chem. Eur. J. 2010, 16, 13965 – 13969
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13967

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
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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
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Chem. Eur. J. 2010, 16, 13965 – 13969

Gold-Catalyzed One-Pot Selective N-Alkylation of Amines
COMMUNICATION
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[15] Reaction conditions: aniline (1.5 mmol), benzyl alcohol (1.5 mmol),
Cs2CO3 (1.5 mmol), toluene (1 mL), Au/TiO2-VS (Au: 0.5 mol%),
1208C, 5 atm N2. Under identical conditions, conversion based on
benzyl alcohol is ꢀ20% after 14 h with 30% selectivity for N-phe-
nylbenzylamine. The undesirable imine (N-benzylideneaniline) was
produced as a main by-product in high selectivity (ꢀ50%).
[16] Very recently, N-alkylation of primary amine with alcohol to afford
secondary amines by Au/Al-MIL53 ([Al(OH)ACTHNUTRGNEUNG(bdc)], bdc=benzene-
1,4-dicarboxylate) and Au/TiO2 systems (in presence of basic
CsCO3) was demonstrated by Ishida et al. (see ref. [7d]), but the
yield of N-phenylbenzylamine never exceeded 50%. In addition, the
recycled reuse of the Au/Al-MIL53 was difficult, due to the severe
aggregation of Au clusters to form larger NPs (>10 nm) after the re-
action.
[17] A crossover experiment was carried out with benzyl alcohol
(0.75 mmol) and benzaldehyde (0.75 mmol), which were reacted
with aniline (1.5 mmol) in the presence of Au/TiO2-VS (0.5 mol%
Au). Under these conditions, the aldehyde was immediately convert-
ed into the imine, while the alcohol reacted slowly to form the cor-
responding amine with about only 5% yield after 14 h.
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Published online: November 19, 2010
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
13969