Use of primary amines for the selective n-alkylation of anilines by a reusable heterogeneous catalyst

Article abstract of DOI:10.1055/s-0033-1339667

Traditionally, anilines can be alkylated with reactive alkyl halides but now more safe reagents such as alcohols or even amines can be used. To overcome the limits of homogeneous catalysis for aniline N-alkylation, we have developed a protocol that employs simple Pd/C as a heterogeneous catalyst under microwave dielectric heating. The process, based on the easy Pd-mediated oxidation of primary amines to imines followed by aniline addition, is characterized by a high atom economy as ammonia is the only other product of the reaction. This kind of aniline alkylation with amines has been carried out both in ionic liquid medium using [bmim]PF₆ or in a more traditional solvent such as THF where the catalyst could be successfully recycled more times. The reusability of the catalyst was further confirmed by using material recycled from the amination in a standard alkene hydrogenation without loss of efficiency. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339667

LETTER
▌2249
lUettsere of Primary Amines for the Selective N-Alkylation of Anilines by a Reusab-
le Heterogeneous Catalyst
Selective N-Alkylation of Anilines by a Reusable Heterogeneous Catalysis
Pasquale Linciano,a Marianna Pizzetti,a Andrea Porcheddu,b Maurizio Taddei*a
a
Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy
Fax +39(057)7234333; E-mail: taddei.m@unisi.it
b
Dipartimento di Chimica e Farmacia, Via Vienna 2, 07100 Sassari, Italy
Received: 26.06.2013; Accepted after revision: 02.08.2013
represents a cheap, widely used and readily available het-
Abstract: Traditionally, anilines can be alkylated with reactive al-
erogeneous catalyst that, compared to the homogeneous
catalysts, reveals many advantages such as easy recovery
and recycling by simple filtration, an extremely low level
kyl halides but now more safe reagents such as alcohols or even
amines can be used. To overcome the limits of homogeneous catal-
ysis for aniline N-alkylation, we have developed a protocol that em-
ploys simple Pd/C as a heterogeneous catalyst under microwave of contamination of the final products, no need for addi-
dielectric heating. The process, based on the easy Pd-mediated oxi-
tional ligands and high stability in acidic or basic media.
dation of primary amines to imines followed by aniline addition, is
Moreover, the coupling of this metal catalyst with MW di-
characterized by a high atom economy as ammonia is the only other
electric heating represents a powerful tool since the high
product of the reaction. This kind of aniline alkylation with amines
MW absorbing ability of the charcoal makes heat conduc-
has been carried out both in ionic liquid medium using [bmim]PF6
tion to the reaction medium more rapid and efficient.8
or in a more traditional solvent such as THF where the catalyst
could be successfully recycled more times. The reusability of the
As alkylation with a tertiary amine is limited by the lower
catalyst was further confirmed by using material recycled from the
availability of the reagents and by the low atom economy
amination in a standard alkene hydrogenation without loss of effi-
(a secondary amine moiety is lost in the process) we de-
ciency.
cided to investigate the possibility of alkylating anilines
Key words: hydrogen transfer, microwave chemistry, oxidation,
under heterogeneous catalysis using primary amines as al-
amination, palladium
kylating agents (Scheme 1).
H
R
N
NH2
+
N
R
N
Aromatic amines are important intermediates and build-
ing blocks in industrial, bioorganic, and preparative or-
ganic chemistry.1 Well-established synthetic methods are
based on N-alkylation of anilines with alkyl halides in the
presence of a base or by reductive amination of carbonyl
compounds. Notwithstanding these protocols, the devel-
opment of new synthetic approaches to amines based on
catalytic methods that allow a reduction of the amount of
by-products, while maintaining high chemoselectivity,
continues to be an intense focus of research. Several meth-
ods to alkylate amines with alcohols have been recently
published.2 Moreover, although the possibility to use
amines as alkylating agents was firstly reported in the
1980’s3 several recent reports describe the alkylation of
anilines with aliphatic amines in the presence of homoge-
neous transition metal catalysts (Rh, Ru, Ir), sometimes
after prolonged heating.4 Most of these methods show
high yield and selectivity in the control of the alkylation,
simply suffering from the standard problems associated
with homogenous ligand based metal catalysis. Some het-
erogeneous catalysts have been recently described for al-
kylation of anilines with alcohols or amines.5 Moreover
benzimidazoles have also been prepared, under heteroge-
neous Pd catalysis, starting from phenylendiamine and
tertiary6 and even primary amines.7 Palladium on charcoal
ref. 5a
R
R
+
H
R
R
R
lost fragment
H
N
NH2
+
H
N
H
this work
N
+
H
R
H
H
lost fragment
Scheme 1 Comparison of aniline alkylation with tertiary vs. primary
amines
The optimized reaction conditions for alkylation with ter-
tiary amines [Pd/C (5 mol%), toluene, MW, 170 °C, 90
min]5a were applied to the reaction of aniline (1) with
N-butyl- (2) and N-cyclohexylamine (3) when the corre-
sponding monoalkylated anilines (4 and 5) were obtained
in 32% and 43% yields, respectively. These preliminary
data demonstrated the feasibility of the transformation
suggesting that Pd/C was able to oxidize N-butylamine to
the corresponding imine and that addition of aniline oc-
curred with ammonia elimination (see Scheme in Table
1). However, conversion was low, as most of the starting
amine remained unreacted. The reaction between aniline
(1) and butylamine (2) was chosen as the model to opti-
mize the conditions (Table 1). As primary amines can poi-
son the active catalyst surface by absorption, the influence
of an acidic additive was evaluated.
SYNLETT 2013, 24, 2249–2254
Advanced online publication: 13.09.2013
Surprisingly, on using a catalytic amount of AcOH (entry
3 in Table 1) or other acids, no conversion was observed
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339667; Art ID: ST-2013-D0587-L
© Georg Thieme Verlag Stuttgart · New York

2250
P. Linciano et al.
LETTER
(data not included in Table 1).9 The influence of the previous results, the amount of the catalyst employed in
amount of primary amine employed with respect to ani- the reaction was increased up to 0.08 mol (calculated on
line was also evaluated with the finding that yields of 4 the limiting amount of amine 2) with the observation that
improved when a aniline/substrate ratio of 2:1 was used an almost quantitative alkylation of aniline occurred in
(entry 4 in Table 1).10 The influence of different solvents [bmim][PF6] giving amine 4 in 97% isolated yield (entry
was also investigated and, amongst those screened, low 11 in Table 1). The increase of the amount of catalyst also
polarity solvents such as toluene or THF gave the better permitted the use of THF (entry 12 in Table 1), whereas
yields, While protic polar solvents lowered the yields, the attempts to shorten reaction time gave unsatisfactory re-
ionic liquid [bmim][PF6] afforded the best results in terms sults (entry 13 in Table 1). Furthermore, the use of differ-
of conversion to the final product giving compound 4 in ent Pd sources was not productive for the reaction yield
60% isolated yield after heating at 170 °C for 90 minutes (entries 14–16 in Table 1). Finally we observed that the
(entry 9 in Table 1). However, attempts to increase the re- use of MW was crucial to obtain the product in short reac-
action temperature or to shorten reaction times by exploit- tion times while, under conventional heating, 24 hours at
ing the properties of the ionic liquid failed. Based on 170 °C were required to obtain compound 4 in good yield
Table 1 Optimization of Reaction Conditionsa
H
NH2
N
H2N
+
2
4
1
cat
cat
cat-H2
N
cat-H2
H2N
1
NH
HN
2a
2c
NH3
2b
Entry
1:2 ratio
Conditions
Yieldb of 4
1
2
1:1.2
1:1.2
1:1.2
2:1
Pd/C (0.04 mol), toluene, 170 °C, MW, 90 min
Pd/C (0.04 mol), toluene, 170 °C, 24 h
32%
35%
32%
48%
–
3
Pd/C (0.04 mol), toluene, 170 °C, MW, 90 min, AcOH (10% mol)
Pd/C (0.04 mol), toluene, 170 °C, MW, 90 min
Pd/C (0.04 mol), EtOH, 170 °C, MW, 90 min
Pd/C(0.04 mol),THF, 170 °C, MW, 90 min
4
5
2:1
6
2:1
37%
5%
7
2:1
Pd/C(0.04 mol), H2O, 170 °C, MW, 90 min
8
2:1
Pd/C(0.04 mol), MeCN, 170 °C, MW, 90 min
Pd/C(0.04 mol), [bmim][PF6], 170 °C, MW, 90 min
Pd/C(0.04 mol), [bmim][PF6], 200 °C, MW, 30 min
Pd/C(0.08 mol), [bmim][PF6], 170 °C, MW, 90 min
Pd/C(0.08 mol), THF, 170 °C, MW, 90 min
16%
60%
39%
97%
99%
63%
12%
32%
–
9
2:1
10
11
12
13
14
15
16
17
2:1
2:1
2:1
2:1
Pd/C (0.08 mol), THF, 170 °C, MW, 60 min
Pd black (0.08 mol), THF, 170 °C, MW, 60 min
Pd on Al2O3 (0.08 mol), THF, 170 °C, MW, 60 min
Pd on BaSO4, (0.08 mol), THF, 170 °C, MW, 60 min
Pd/C (0.08 mol), THF, 170 °C, 24 hc
2:1
2:1
2:1
2:1
95%
a The reaction was performed under N2 in a sealed vial using a CEM Discover microwave synthesizer equipped with an IR temperature sensor
and the maximal internal pressure monitored and maintained under the value of 300 psi.
b Yield of isolated product.
c Reaction was carried out in a sealed vial immersed in preheated oil (170 °C).
Synlett 2013, 24, 2249–2254
© Georg Thieme Verlag Stuttgart · New York

LETTER
Selective N-Alkylation of Anilines by a Reusable Heterogeneous Catalysis
2251
(entry 17 in Table 1). These optimized reaction conditions
(THF, 10% Pd/C, MW, 170 °C, 90 min, 2 equiv of ani-
line)11 were then applied to the synthesis of monoalkylat-
ed anilines in the presence of different aliphatic amines.
The results obtained are summarized in Table 2. The reac-
tion worked well in the presence of linear and branched
amines giving the monoalkylated aniline as the only prod-
uct in satisfactory to very high yields (entries 3, 5 and 6 in
Table 2). With phenethylamine (11), low yields of the cor-
responding alkylated aniline 17 were obtained (entry 7 in
Table 2). On the other hand, when benzylamine (18) was
used, almost complete debenzylation occurred with for-
mation of toluene (21 in Scheme 2) while the use of trypt-
amine (19) led to the formation of 3-ethyl-1H-indole (22)
as the main product.
Table 2 Preparation of N-Alkyl Anilines using Amines
H
THF, 10% Pd/C, MW,
NH2
H
N
N
170 °C, 90 min
R
+
H
R
Amine
Product
Yielda
Entry
1
H
N
H2N
94%
3
5
H
N
H2N
2
3
4
92%
86%
75%
6
12
aniline, Pd/C (10 mol%),
H
N
THF, 170 °C, MW, 90 min
NH2
H2N
7
15
15
21
18
aniline, Pd/C (10 mol%),
THF, 170 °C, MW, 90 min
NH2
13
H
N
H2N
N
H
22
N
H
19
8
aniline, Pd/C (10 mol%),
THF, 170 °C, MW, 90 min
14
NH2
H
N
N
23
20
H2N
5
80%
Scheme 2 Unexpected reactivity of some amines in the presence of
Pd/C
9
15
H
N
H2N
The reaction with allylamine 20 gave quinoline 23 in 65%
yield (Scheme 2), as expected on the basis of an analogous
transformation described to occur on the same substrate
using a homogenous Ru catalyst.12
6
7
72%
36%
10
16
H
N
H2N
Using the same protocol, alkylation also occurred in the
presence of variously substituted anilines (Table 3). As
previously observed, electron-rich substrates led to the
formation of the desired products in good yields, (entries
1–7 in Table 3) while the presence of electron-withdraw-
ing groups on the phenyl ring lowered the conversions due
to the reduced nucleophilicity of the nitrogen (entries 10
and 11 in Table 3). Using p-amino- or o-aminophenol (27,
28), selective alkylation occurred on the nitrogen, provid-
ing a rapid method for the preparation of N-butyl amino-
phenols 39 and 40 without protection on the oxygen
(entries 8 and 9 in Table 3). Surprisingly, very few refer-
ences were found for the preparation of compounds 39
and 40. For example, the synthesis of structurally simple
compound 40 was described to occur via an acid-cata-
lyzed rearrangement of N-alkyl phenoxyureas,13 although,
in principle, a reductive amination of 27 or 28 with the
corresponding carbonyl compounds could be possible.14
Even 2-aminobenzylimidazole (31) was selectively alkyl-
ated at the exocyclic NH2 (entry 12 in Table 3) to give the
corresponding N-butyl derivative 43.15
Ph
Ph
11
17
a Yield of isolated products.
In order to prove the real catalytic nature of the process,
the isolated Pd/C was recycled and its performance eval-
uated in the reaction of 1 within THF or [bmim]PF6 as sol-
vent (Table 4).
After separation of the solution, the catalyst was washed
with THF, H2O and MeOH and dried in an oven at 60 °C.
The use of THF as the solvent, gave a catalyst that re-
tained most of its catalytic activity and efficiency, while
with [bmim]PF6 the activity dropped after three cycles
(Table 4).16 It is worth noting that the Pd/C recovered
from THF could also be successfully employed in hydro-
genation of cyclohexene to cyclohexane (1 atm of H2,
MeOH, 2 h, 95%) whereas, with the material recycled
from the ionic liquid, no alkene hydrogenation occurred
even after 12 hours. We have no explanation for this lack
of activity in the catalyst recycled from ionic liquids.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2249–2254

2252
P. Linciano et al.
LETTER
TEM analysis of the catalyst derived from THF or ionic are almost comparable, in terms of reaction temperature
liquid did not show major differences with respect to the and catalyst loading, to the analogous reactions using al-
original Pd/C.
cohols or amines under homogeneous catalysis.4,5 The ul-
timate goal of the project is to accomplish alkylation
under much lower temperatures and for this reason inves-
tigations with nanostructured Pd are underway in our lab-
oratories.
In conclusion, we have demonstrated that aliphatic prima-
ry amines can be successfully employed for alkylation of
anilines under heterogeneous catalysis. Reaction condi-
tions and catalyst loading, although far from optimization,
Table 3 Alkylation of Different Anilines with Amines
Entry
1
Aniline
Amine
Product
Yielda
88%
H
N
NH2
2
MeO
MeO
24
32
H
N
2
3
4
24
24
24
3
79%
76%
81%
MeO
33
H
N
10
7
MeO
34
H
N
15
MeO
35
H
N
NH2
5
6
7
8
2
2
8
2
79%
94%
86%
73%
OMe
OMe
25
36
37
38
H
N
NH2
26
26
H
N
H
NH2
N
HO
27
28
39
H
N
NH2
9
2
2
67%
36%
OH
OH
40
N
N
H
10
N
NH2
29
41
Synlett 2013, 24, 2249–2254
© Georg Thieme Verlag Stuttgart · New York

LETTER
Selective N-Alkylation of Anilines by a Reusable Heterogeneous Catalysis
2253
Table 3 Alkylation of Different Anilines with Amines (continued)
Entry
11
Aniline
Amine
Product
Yielda
34%
H
NH2
N
2
MeOOC
MeOOC
30
42
N
N
NH2
NH
N
H
12
2
56%
N
H
31
43
a Yield of isolated product.
Table 4 Reuse Test for the Catalysta
Reuse numbera
[bmim]PF6 reaction time
90 min
[bmim]PF6 yield of 4 (%)
THF reaction time
90 min
THF yield of 4 (%)
0
1
2
3
4
95
87
36
97
96
90
91
89b
90 min
90 min
120 min
90 min
90 min
120 min
a Applied to alkylation of 1 with 2.
b After 90 min a conversion of about 75% was determined by GC–MS analysis.
Tillack, A.; Beller, M. Adv. Synth. Catal. 2008, 350, 2099.
(c) Saidi, O.; Blacker, A. J.; Farah, M. M.; Marsden, S. P.;
Williams, J. M. J. Angew. Chem. Int. Ed. 2009, 48, 7375.
(d) Blacker, A. J.; Farah, M. M.; Hall, M. I.; Marsden, S. P.;
Saidi, O.; Williams, J. M. J. Org. Lett. 2009, 11, 2039.
Acknowledgment
The authors thank Sigma-tau Pharmaceuticals Inc. (Pomezia,
Rome, Italy) and MIUR (Rome, PRIN Project No.
2009RMW3Z5_006) for financial support.
(5) (a) Lubinu, M. C.; De Luca, L.; Giacomelli, G.; Porcheddu,
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SuppInigfor
m
o
ti
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(9) This result is in disagreement with the efficient protocol
optimized for the synthesis of benzimidazoles in our
previous work, see ref. 7a.
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(11) General Procedure for the Synthesis of N-Butylaniline
(4) in THF: A 10-mL vial for MW use equipped with a
magnetic stirrer was charged with Pd/C (10% wt, 85 mg,
0.08 mmol) under nitrogen. Anhydrous THF (2 mL), aniline
(1; 186 mg, 2 mmol) and N-butylamine (2; 73 mg, 1 mmol)
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2249–2254

2254
P. Linciano et al.
LETTER
were subsequently added. The mixture was stirred under
MW dielectric heating for 90 min at 170 °C (max internal
pressure 300 psi). After cooling, the crude reaction mixture
was filtered through a pad of Celite® and washed with
MeOH. The collected solvent was dried over anhyd MgSO4,
filtered and removed under vacuum. Purification by flash
chromatography [petroleum ether (40–60)–EtOAc, 9:1]
gave product 4 as a pale yellow oil (149 mg, yield 99%). The
isolated product had the same spectroscopic features as those
compared with reported data17 and was identical to an
authentic sample (GC–MS analysis).
General Procedure for the Synthesis of N-Butylaniline
(4) in [bmim]PF6: A 10-mL vial for MW use equipped with
a magnetic stirrer was charged with [bmim][PF6] (1 g), Pd/C
(10% wt, 85 mg, 0.08 mmol), aniline (1; 186 mg, 2 mmol)
and N-butylamine (2; 73 mg, 1 mmol). The mixture was
stirred under MW dielectric heating for 90 min at 170 °C
(max internal pressure 300 psi). After cooling, the crude
reaction mixture was treated with Et2O (3 × 5 mL), the
ethereal phase was separated, dried over anhydrous MgSO4,
filtered and the solvent was removed under vacuum.
Purification as above gave 4 (141 mg, 97% yield).
(12) Shim, S. C. Synth. Commun. 2001, 31, 3791.
(13) For compound 40 there were only 10 references on
SciFinder by July 2013. See: Endo, Y.; Shudo, S.; Okamoto,
T. Synthesis 1983, 471.
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Lett. 2006, 14, 409. (b) Byun, E.; Hong, B.; De Castro, K.
A.; Lim, M.; Rhee, H. J. Org. Chem. 2007, 72, 9815.
(15) For an analogous alkylation of 31 with 1-butanol under
homogenous Ir catalysis, see: Li, F.; Kang, Q.; Shan, H.;
Chen, L.; Xie, J. Eur. J. Org. Chem. 2012, 5085.
(16) The leaching test was negative. See: Lamblin, M.; Nassar-
Hardy, L.; Hierso, J.-C.; Fouquet, E.; Felpin, F.-X. Adv.
Synth. Catal. 2010, 352, 33; and references cited therein.
(17) Kubo, T.; Katoh, C.; Yamada, K.; Okano, K.; Tokuyama, H.;
Fukuyama, T. Tetrahedron 2008, 64, 11230.
Synlett 2013, 24, 2249–2254
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