An efficient palladium-catalyzed N-alkylation of amines using primary and secondary alcohols

Article abstract of DOI:10.1021/cs400799n

PdCl₂ in the presence of dppe or Xantphos(t-Bu) as the ligand is found to be an efficient catalyst for the N-alkylation of various primary and cyclic secondary amines using primary alcohols at 90-130 C under neat conditions. Interestingly, good to excellent yields were achieved when more challenging secondary alcohols were used as alkylating agents at 130-150 C. The reaction could be easily scaled up, as demonstrated for a 10 mmol scale achieving yields up to 90% with a TON of 900.

Full text of DOI:10.1021/cs400799n

Letter
pubs.acs.org/acscatalysis
An Efficient Palladium-Catalyzed N‑Alkylation of Amines Using
Primary and Secondary Alcohols
Tuan Thanh Dang, Balamurugan Ramalingam, Siah Pei Shan, and Abdul Majeed Seayad*
Organic Chemistry, Institute of Chemical and Engineering Sciences, 8 Biomedical Grove, #07-01 Neuros, Singapore 138665.
*
S Supporting Information
ABSTRACT: PdCl in the presence of dppe or Xantphos(t-Bu) as
2
the ligand is found to be an efficient catalyst for the N-alkylation of
various primary and cyclic secondary amines using primary alcohols
at 90−130 °C under neat conditions. Interestingly, good to
excellent yields were achieved when more challenging secondary
alcohols were used as alkylating agents at 130−150 °C. The reaction
could be easily scaled up, as demonstrated for a 10 mmol scale
achieving yields up to 90% with a TON of 900.
KEYWORDS: alkylation, alcohol activation, hydrogen borrowing, palladium catalyst, amine synthesis
INTRODUCTION
inactive alcohols are converted in situ to a more reactive and
■
highly electrophilic carbonyl intermediate by temporary
removal of hydrogen toward nucleophilic addition reactions.
This carbonyl compound undergoes condensation with the
amine to form an imine intermediate, which, upon catalytic
hydrogenation by transferring the borrowed hydrogen, forms
the final alkylated amine. In this overall process, water is
produced as the only byproduct and, hence, offers a sustainable
Amines are important building blocks for the synthesis of
pharmaceuticals, agrochemicals, dyes, and polymers. Several
catalytic methods for the preparation of amines have been
1
,2
reported, such as reductive amination of carbonyl compounds2
or reduction of imines, nitriles and nitro compounds;
3
4
hydroamination; and hydroaminomethylation of unsaturated
5
compounds and metal-catalyzed amination of aryl halides.
Alkylation of amines or ammonia with alkyl halides has been
practiced as the most convenient method for the synthesis of
6
method of using alcohols for N-alkylation reactions.
Most common catalysts used for the alkylation of amines
7
8
2
using alcohols are based on Ru and Ir. Catalysts derived from
alkyl as well as alkyl-aryl amines. This method often produces
9
10
11
12
13
14
other metals, such as Au, Ag, Cu, Fe, Ni, Os, and
overalkylated products, thereby reducing the yield of the
15
2
Rh, have also been explored, and many of them showed very
good activity and selectivity under moderate to higher
temperatures (typically 100−200 °C).
Palladium-based catalysts have generally been employed for
alkylation of amines using allylic alcohols. Recently, a few
desired product. Moreover, the alkyl halides used are often
2
toxic and have mutagenic properties. Hence, developing more
efficient and green alkylation methodologies utilizing non-
hazardous and easily available starting materials would be most
16
2
−9
desirable for future sustainable processes. Recently, less toxic
and more readily available alcohols were used as the alkylating
agents in a greener approach using a catalytic “hydrogen-
1
7−19
palladium-based catalysts, both heterogeneous
and homo-
20
geneous, have been reported using benzylic and aliphatic
primary alcohols as alkylating agents. For example, Corma et al.
reported an efficient bifunctional Pd/MgO solid catalyst for the
N-alkylation of aniline using benzyl alcohol at 180 °C, giving up
6
borrowing” strategy. In this method, as shown in Scheme 1, the
Scheme 1. Hydrogen Borrowing Strategy for the Alkylation
of Amines Using Alcohols
17
to 80% yield of the desired secondary amine product. Shi and
co-workers reported up to 90% yield at 160 °C for 2 h using
1
8
2
.28 wt % Pd/Fe O3 as the catalyst. Reducing the
2
temperature decreased the catalytic activity, and only 65%
yield was reported at 140 °C, even in the presence of 100 mol
%
of base. Aliphatic alcohols gave up to 86% yield at 150 °C
after 24 h. Very recently, Shiraishi et al. reported that up to 98%
yield can be achieved at room temperature using PdNPs on
TiO as the catalyst for the N-alkylation of various anilines
2
Received: September 11, 2013
Revised: October 6, 2013
Published: October 10, 2013
©
2013 American Chemical Society
2536
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ACS Catalysis
Letter
a
Table 1. Optimization of Catalyst and Conditions for N-Alkylation of Aniline Using Benzyl Alcohol
entry
PdX2
ligand
base
temp. (°C)
conversion (%)
product (%)
imine (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
Pd(OAc)2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
Pd(OAc)2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
Xantphos
Xantphos
Xantphos
dppf
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
KOH
130
130
110
110
110
110
110
110
110
110
110
100
100
90
73
100
63
6
26
98
44
n.d.
83
18
43
35
9
44
n.d.
20
5
dppf(t-Bu)
dppf(t-Bu)
dppf(t-Bu)
dppf(t-Bu)
dppf(t-Bu)
dppf(t-Bu)
dppf(t-Bu)
dppf(t-Bu)
dppf(t-Bu)
dppf(t-Bu)
PPh3
100
34
68
52
12
100
94
100
76
91
6
17
16
25
17
2
KOt-Bu
Cs CO3
2
Et N
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
LiOH
99
87
98
35
84
5
n.d.
16
n.d.
41
6
Na CO3
2
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
100
100
100
100
100
100
100
100
100
100
90
2
BINAP
18
12
62
18
13
98
84
98
100
11
8
7
dpePhos
4
cataCXiumA
55
3
7
14
11
2
n.d.
95
82
96
99
dpePhos(Cy)
dppb
2
dppe
2
Xantphos(t-Bu)
dppe
n.d.
b
b
b
96, 58
94, 55
2, 2
b
b
b
Xantphos(t-Bu)
90
97, 76
96, 70
1, 5
a
Aniline (2 mmol), benzyl alcohol (6 mmol), PdX (1 mol %), ligand (1 mol %), base (20 mol %); conversion and yields were determined by GC
2
b
using hexadecane as the internal standard. Reaction was carried out for 15 h.
using both benzyl and aliphatic alcohols under photoirradiation
RESULTS AND DISCUSSION
■
1
9
conditions. A homogeneous catalyst system was reported by
Ramon and co-workers using 1 mol % of Pd(OAc) in the
presence of 100 mol % of CsOH at temperatures of 130−150
C in toluene as the solvent. Up to 99% yield of the alkylated
amines was reported when benzylic alcohols were used as the
Our initial investigations using benzyl alcohol as the alkylating
agent for N-alkylation of aniline showed that homogeneous
palladium catalysts in the presence of a suitable phosphine
ligand and substoichiometric amounts of a base performed
better under solvent-free conditions. Accordingly, Pd(OAc) as
the catalyst in the presence of Xantphos as the ligand and 20
́
2
°
2
2
0
alkylating agents. However, the yield decreased drastically to
6% when aliphatic alcohols such as 1-cyclohexyl carbinol was
2
mol % of NaHCO as the base gave a yield of 26% with 73%
3
used. Challenging secondary alcohols such as 2-octanol were
reported to be inactive under the optimized conditions.
Accordingly, we focused our research on developing simple
catalyst systems that work under relatively mild operating
conditions as well as for challenging substrates. Herein, we
report a homogeneous palladium catalyst system that is active
at temperatures as low as 90 °C for easily oxidizable alcohols as
well as for using aliphatic primary and secondary alcohols as
potential alkylating agents under moderate conditions.
conversion at 130 °C for 24 h, as shown in Table 1 (entry 1).
In this case, ∼44% imine remained unhydrogenated. To our
delight, near quantitative yield was observed when PdCl (entry
2
2
) was used as the catalyst instead of Pd(OAc) under similar
2
conditions. Reducing the temperature to 110 °C decreased
both conversion and yield of the product (entry 3). A quick
screening of different phosphine ligands (Xantphos, dppf,
dppf(t-Bu)) at 110 °C showed that dppf(t-Bu) (entry 5) was
promising and was selected for further evaluation. Screening
2
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ACS Catalysis
Letter
different bases showed that LiOH (entry 10) was one of the
best bases for this reaction, achieving quantitative yield even at
Table 2. Scope of N-Alkylation of Amines Using Primary
Alcohols
1
00 °C (entry 12).
Palladium precursors may have an important role because
Pd(OAc) gave inferior results (entry 13) under the optimized
2
conditions. Further reduction in temperature to 90 °C (entry
14) gave a slightly lower yield and would require a longer
reaction time to achieve quantitative yield.
Under these optimized reaction conditions, some of the
common phosphine ligands, such as PPh , BINAP, dpePhos,
3
etc. (entries 15, 16 and 17) showed very low conversions and
very low yield of the product. No product or a negligible
amount of the product was observed with very low conversions
in the absence of any phosphine ligands (entries 19 and 20).
Ligands such as dpePhos(Cy), dppe, and Xantphos(t-Bu)
(
entries 21, 23 and 24) showed near quantitative conversions
and product yields similar to that of dppf(t-Bu) at 100 °C for
4 h. Decreasing the temperature to 90 °C had only a marginal
change in the yield. Though dppe and Xantphos(t-Bu) (entry
5 and 26) gave similar results after 24 h, a better performance
2
2
with Xantphos(t-Bu) was observed at 90 °C for a lower
reaction time of 15 h. However, we chose dppe for further
investigation and to study substrate scope because dppe is a
relatively inexpensive and readily available ligand in comparison
with Xantphos(t-Bu) and dppf(t-Bu).
Thus, good to excellent yields were achieved for the
alkylation of various primary and cyclic secondary amines
using relatively easily oxidizable benzyl alcohols at 100 °C and
sterically hindered benzylic alcohols as well as aliphatic alcohols
at 130 °C (Table 2). In the case of alkylation of aniline, isolated
yields of 96% and 89% were obtained for the secondary amine
products 1 and 2, by using benzyl alcohol and 4-methyl benzyl
alcohols as the alkylating agents, respectively. ortho-Methoxy-
substituted benzyl alcohol was also active as the alkylating agent
and gave the corresponding secondary amine 3 in 83% yield. p-
Substituted aniline, such as p-benzoyl aniline, gave good yields
of 4 (79%) using benzyl alcohol as the alkylating agent.
Benzylic amines and aliphatic amines underwent alkylation
smoothly with benzyl alcohol to give 5, 6, and 7 in good to
excellent yields. Up to 82% yield was obtained for the
secondary amine 8 when alkylation of cyclohexylamine was
carried out using p-fluorobenzyl alcohol. Aliphatic alcohols as
alkylating agents generally require higher temperatures, and up
to 92% yield of 9 was achieved for the alkylation of aniline with
a,b
1
2
3
R NHR (2 mmol), R OH (6 mmol), PdCl (1 mol %), dppe (1
2
a
mol %), LiOH (20 mol %); yields given are isolated yields. Reaction
carried out at 100 °C. Reaction carried out at 130 °C.
b
to the corresponding ketones as well as the hydrogenation of
the iminium or enamine intermediates.
knowledge, a promising Pd-catalyzed N-alkylation of amines
using secondary alcohols as alkylating agents has not been
reported so far.
6
,22
To the best of our
17−20
To our delight, with the current Pd-
catalyst system, sec-benzylic as well as aliphatic acyclic and
cyclic secondary alcohols gave excellent yields for N-alkylation
of amines under neat conditions (Table 3). Using secondary
benzyl alcohol, alkylation of benzyl amine, hexylamine, and 2-
amino pyridine were achieved in 76% (19), 98% (20), and 70%
(21) yields, respectively at 130 °C. More challenging aliphatic
secondary alcohols required 150 °C for achieving higher yields.
Accordingly, very good yields to the corresponding alkylated
amine products were achieved for alkylation of primary
aliphatic acyclic (22, 72%) and cyclic (23, 95%) amines and
heteroaromatic amine (24, 68%) using 2-octanol as the
alkylating agent. Remarkably, more internal secondary alcohols,
such as 3-octanol and 5-nonanol, also proved to be excellent
alkylating agents, and up to 76% and 62% yields of 25 and 26,
respectively, were obtained for the alkylation of cyclohexyl-
amine. Cyclic secondary amine as substrate also gave promising
yields, and up to 82% and 59% yields of 27 and 28, respectively,
were achieved in the case of piperidine when 2-octanol and 3-
octanol were used as the alkylating agents. Under the present
catalyst system, cyclohexanol can also be used as the alkylating
agent, and up to 87% (29) and 73% (30) yields were achieved
with aniline and piperidine as the substrates.
1
-dodecanol using the present catalyst system at 130 °C.
21
Cyclic secondary amines were also readily alkylated to the
corresponding tertiary amines in excellent yields (Table 2). For
example, tertiary amine 10 was obtained in 94% yield upon
alkylation of piperidine with benzyl alcohol at 100 °C. With
aliphatic alcohols such as homobenzylic alcohol and 1-octanol,
up to 87% and 97% yields of 11 and 12, respectively were
obtained at 130 °C. Seven-membered cyclic secondary amine
was also successfully alkylated using benzyl alcohol and 1-
octanol, achieving 13 and 14 in 74% and 90% yields,
respectively. Heterocyclic tertiary amine 15 was obtained in
84% yield upon alkylation of tetrahydroisoquinoline using
benzyl alcohol. Interestingly, heteroaromatic amines, such as 2-
aminopyridine and tryptamine, were also efficiently alkylated
under these conditions to give the products 16, 17, and 18 in
80%, 94% and 73%, respectively.
Secondary alcohols are challenging alkylating agents
compared with primary alcohols using hydrogen borrowing
strategy because of the difficulty in its in situ dehydrogenation
2
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Letter
Table 3. Scope of N-Alkylation of Amines Using Secondary
Alcohols
Scheme 2. Proposed Catalytic Cycle for the Pd-Catalyzed N-
Alkylation of Amines Using Alcohols
a,b
1
2
3 4
R NHR (2 mmol), R R CHOH (6 mmol), PdCl (2 mol %), dppe
2
reaction. Since this catalyst system offers reactions at fairly mild
conditions, it would be useful for further applications in the
synthesis of complex molecules having various functional
groups and is currently in progress.
(
2 mol %), LiOH (20 mol %); yields given are isolated yields.
Reaction carried out at 130 °C. Reaction carried out at 150 °C.
a
b
Next, we examined the scalability of this palladium catalyzed
methodology. Thus, the standard reaction of N-alkylation of
aniline using benzyl alcohol was scaled up to 10 mmol scale
using 0.1 mol % catalyst at 100 °C for 72 h, achieving up to
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, characterization data of the products,
NMR spectra of products. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
*
S
90% yield and a TON of 900. The yield can be improved upon
further optimization. For example, near quantitative yield was
achieved at 110 °C after 48 h using 0.4 mol % of the catalyst.
A possible catalytic cycle is proposed in Scheme 2 on the
basis of the results obtained and the available literature on
AUTHOR INFORMATION
Corresponding Author
Phone: +65-67998527. Fax: +65- 6464 2102. E-mail: abdul_
seayad@ices.a-star.edu.sg.
■
*
23
similar palladium-catalyzed transformations. Reaction of the
in situ-formed lithium alkoxide with palladium precursor
generates the catalytically active palladium alkoxide species I,
which upon β-hydride elimination generates the palladium
hydride intermediate II and the carbonyl compound. Insertion
of the in situ-generated imine on to Pd−H bond of II generates
the species IV, which upon reaction with alcohol releases the
amine product, thereby regenerating the catalytically active
palladium alkoxide I for further catalysis. The effective
formation of the intermediates III and IV may depend on
the steric and electronic properties of the imine or iminium ion.
Accordingly, alkylation of secondary amine and alkylation using
secondary alcohol would require harsh reaction conditions
compared with that of primary amine and using primary
alcohol.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was funded by “GSK-EDB Singapore Partnership for
Green and Sustainable Manufacturing and the Institute of
Chemical and Engineering Sciences (ICES), Agency for
Science, Technology and Research (A*STAR), Singapore.
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dx.doi.org/10.1021/cs400799n | ACS Catal. 2013, 3, 2536−2540