Reinvestigating Raney nickel mediated selective alkylation of amines with alcohols via hydrogen autotransfer methodology

Article abstract of DOI:10.1016/j.apcata.2014.04.009

An efficient, cost-effective use of Raney nickel (R-Ni) a widely used industrial catalyst for N-alkylation using alcohols is highlighted here. The work describes the scope and capability of R-Ni in hydrogen autotransfer reactions enabling its widespread use in the Chemical and Pharmaceutical industry. R-Ni of W4, T4, and W7 grades were prepared and evaluated for alkylation of amines. The best activity and selectivity for mono alkylation of amines were obtained using W4 R-Ni at 1:4 moles of amine to alcohol in xylene at reflux. T4 R-Ni also showed ability to form stable imines. The prepared R-Ni was also recycled and reused for N-alkylation reaction. The optimized methodology was applied for synthesis of Active Pharmaceutical ingredients Piribedil and Mepyramine. The simplicity and wide substrate scope makes this method a preferred Hydrogen Auto-transfer protocol for the alkylation of amines.

Full text of DOI:10.1016/j.apcata.2014.04.009

Applied Catalysis A: General 478 (2014) 241–251
Contents lists available at ScienceDirect
Applied Catalysis A: General
journal homepage: www.elsevier.com/locate/apcata
Reinvestigating Raney nickel mediated selective alkylation of amines
with alcohols via hydrogen autotransfer methodology
Astha Mehtab, A. Thakera, V. Londheb, Santosh R. Nandana,∗
a Ambernath Organics Pvt Ltd, 307/314, Creative Industries Premises, Road No. 2, Sunder Nagar, Kalina, Mumbai 400098, India
b SPP School of Pharmacy & Technology Management, SVKM’s NMIMS, Mumbai 400056, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, cost-effective use of Raney nickel (R-Ni) a widely used industrial catalyst for N-alkylation
using alcohols is highlighted here. The work describes the scope and capability of R-Ni in hydrogen
autotransfer reactions enabling its widespread use in the Chemical and Pharmaceutical industry. R-Ni
of W4, T4, and W7 grades were prepared and evaluated for alkylation of amines. The best activity and
selectivity for mono alkylation of amines were obtained using W4 R-Ni at 1:4 moles of amine to alcohol in
xylene at reflux. T4 R-Ni also showed ability to form stable imines. The prepared R-Ni was also recycled
and reused for N-alkylation reaction. The optimized methodology was applied for synthesis of Active
Pharmaceutical ingredients Piribedil and Mepyramine. The simplicity and wide substrate scope makes
this method a preferred Hydrogen Auto-transfer protocol for the alkylation of amines.
Received 6 November 2013
Received in revised form 31 March 2014
Accepted 5 April 2014
Available online 15 April 2014
Keywords:
Amines
Heterogenous catalyst
Hydrogen autotransfer
N-alkylation
© 2014 Elsevier B.V. All rights reserved.
Raney nickel
1. Introduction
hydrogen. The catalyst in these reactions acts as a hydrogen accep-
tor as well as donor [3].
Synthesis of organic amines forms the crux of industrial organic
chemistry. The C N bond is the most prevalent moiety in inter-
mediates and active pharmaceutical ingredients. The synthesis of
this moiety is extensively achieved by N-alkyl/aryl substitution
reactions. These reactions comprise upto 57% of the total reac-
tions conducted in the R & D process chemistry departments of the
top four drug companies [1]. Conventionally these reactions have
Several catalytic systems have been developed for this reaction,
dominated by the use of expensive homogeneous transition metals.
Amongst them the use of ruthenium [4–6] is prominent followed by
iridium [7–9], palladium [10–12], and platinum [13–15]. In recent
years heterogeneous systems like silicon, alumina, copper and its
derivatives [16] have also been investigated. Raney nickel (R-Ni)
prepared from nickel and aluminum alloy is an effective catalyst for
reductive transformations of organic compounds. This remarkable
hydrogenation ability of R-Ni is well documented, but the dehy-
drogenation capability is less known and under-utilized. The use of
R-Ni as hydrogen autotransfer catalyst was first reported for alkyl-
ation of aliphatic amines with primary alcohols. The reaction was
reported in low boiling alcohol as solvent which resulted in very
low yields [17]. Following this, R-Ni has been reported for alkyl-
ation of aromatic amines where the results indicated that the rate
of reaction was dependent on the concentration of catalyst and also
the formation of aldehyde vapors confirmed that the reaction fol-
lows the hydrogen autotransfer reaction [18,19]. The reports on
alkylation of heterocyclic amines using R-Ni showed low yields of
product [20], whereas reports on the alkylation of sulfonamides in
alcoholic solvents showed a brief study on the reaction kinetics and
on the probable reaction mechanism [21]. Although the literature
does mention experiments and results using R-Ni but little or no
elaboration has been mentioned on the used catalyst, its method
of preparation, its nature, and characteristics. The literature also
2
been executed by SN reaction of amines with alkyl halides or by
reduction of secondary amines [2]. The use of toxic reagents and
complex work-up procedures in these conventional methods leads
to generation of high levels of waste and has other environmental
drawbacks.
Hydrogen autotransfer methodology is a shift toward sustain-
able chemistry along with removal of hazardous practices in amine
synthesis. The reaction allows the use of easily available starting
materials and giving back an ecologically benign byproduct. It is
a type of a domino reaction where catalyst based dehydrogena-
tion occurs, followed by condensation and finally hydrogenation
of the condensed molecule takes place by replacing the removed
∗
Corresponding author. Tel.: +91 9820349596.
E-mail addresses: astha2212@gmail.com (A. Mehta),
santosh.nandan@gmail.com (S.R. Nandan).
http://dx.doi.org/10.1016/j.apcata.2014.04.009
0926-860X/© 2014 Elsevier B.V. All rights reserved.

242
A. Mehta et al. / Applied Catalysis A: General 478 (2014) 241–251
Table 1
Characterization of prepared R-Ni.
Sample
Elemental analysis (%) titration
XRF (%)
Particle size
Ni
Al
Ni
Al
Alloy
T4
W4
W7
49.22
74.58
86.23
78.96
49.54
24.45
13.32
18.28
49.59
73.40
85.44
78.65
49.92
23.98
13.74
20.46
63.79% (152–75 ␮m)
7.66 ␮m
12.18 ␮m
12.45 ␮m
reports limited substrate scope and application of R-Ni as Hydrogen
autotransfer catalyst.
HO
NH2
1
HN
Raney Nickel
In this paper, we would like to fill up the gaps and short falls
of previous literature, along with further scientific addition to R-Ni
mediated alkylation of amines using alcohol. The work sequentially
deals with preparation and characterization of different grades of
R-Ni as agents for hydrogen autotransfer reaction. The prepared
three grades were tested for their activity. The paper further dis-
cusses optimization of reaction conditions for a model reaction.
Additionally the study establishes scope of reaction with differ-
ent amines and alcohols. The major focus of this work includes
selective monoalkylation of amines to prepare secondary amines
with absence of tertiary amine formation. The prepared R-Ni was
recycled and reused for N-alkylation reaction. Finally the condi-
tions have been applied for synthesis of Pharmaceutical Actives like
Piribedil and Mepyramine.
+
3
2
Scheme 1. N-alkylation of aniline using benzyl alcohol.
structures of orthorhombic, hexagonal and face centered cubic,
respectively. On comparing 2ꢀ values obtained from alloy, the pres-
ence of Ni2Al3 can be indicated in prepared R-Ni grades. The spectra
also showed that the other two phases of alloy were leached by
sodium hydroxide to form free Ni and Al(OH)3. The intensity of
Al(OH)3 was seen maximum in T4 grade which also matches ele-
mental analysis and XRF results indicating high Al content. The
content of Al(OH)3 was found to be least in W4.
The images captured by SEM (Fig. 2) shows deformation of the
alloy crystal structure with grayish white deposition of bayerite
on T4 catalyst and slightly amorphous nature of W7. The varia-
tion in the preparation conditions from the same starting material
has resulted in three different grades. The three grades varied
immensely in their morphology as well as in their content espe-
cially Al. These variations may result into an important factor
governing the rate of reaction which was further explored subse-
quently.
2. Results and discussion
2.1. Preparation and characterization of R-Ni
R-Ni [22] of three grades, i.e. T4, W4, and W7 previously reported
in the literature were selected for the study. The grades varied in
the degree of leaching of aluminum from nickel–aluminum (50:50)
alloy (Ni–Al alloy).
2.1.1. Preparation of T4 R-Ni [23]
This grade was prepared by suspending Ni–Al alloy (50:50) in
20% sodium hydroxide solution. The resultant mixture was stirred,
followed by successive addition of 40% sodium hydroxide solution.
The stirring was continued for another 1 h. The resultant suspension
was then centrifuged to obtain R-Ni cake which was washed till pH
10.
2.2. Catalytic testing of prepared R-Ni grades
Alkylation of aniline 1 with benzyl alcohol 2 was chosen as a
model reaction to evaluate the three grades of R-Ni for hydrogen
autotransfer reaction (Scheme 1). The reaction was conducted with
all three grades of prepared R-Ni respectively in xylene at 130 ◦C for
30 h and was monitored by Gas chromatography (GC). The results
are summarized in Table 2.
2.1.2. Preparation of W4 and W7 R-Ni [24,25]
The W4 and W7 grades were prepared by continuous slow addi-
tion of Ni–Al alloy (50:50) to sodium hydroxide solution (26%). The
reaction was further digested by continuous stirring. The resultant
suspension was centrifuged to obtain R-Ni cake, which was washed
till pH 10 for W7 grade and till pH 7 for W4 grade.
The efficient conversion of starting material 1 and 2 to finished
product 3 and intermediate 4 as shown in Table 2 indicated that all
the prepared grades were active for hydrogen autotransfer reaction.
Amongst them W4 R-Ni showed maximum formation of the sec-
ondary amine N-benzyl aniline 3. Whereas the other two grades T4
and W7 showed corresponding benzaldimine 4 as the major prod-
uct. These results highlight that T4 and W7 R-Ni were not efficient
in reducing 4 to 3 to the same extent as W4.
The reaction efficiency can possibly be correlated to a couple of
factors; first assumption could be made to the amount of aluminum
in each of the three grades. The reaction as noticed follows Oppe-
nauer type oxidation mechanism (OPP), as a result the amount of
aluminum may catalyze a hydride shift from alcohol to form car-
bonyl compounds seen in OPP reactions [27]. The other explanation
that can be drawn for decrease in the reducing efficiency of T4 and
W7 can be explained with the aid of prior literature on R-Ni as
reducing agent [28]. This literature states the washing the cata-
lyst and using it in neutral pH condition. Thus possibly the alkaline
nature of T4 and W7 would have affected its reducing capability
in-turn affecting its efficiency as hydrogen autotransfer catalyst.
It is noteworthy that all the three grades of R-Ni did not show
2.1.3. Characterization
The prepared three grades were characterized and compared to
literature report for its nickel (Ni) and aluminum (Al) content, fol-
lowed by X-Ray fluorescence (XRF) and particle size as summarized
in Table 1.
The outcome of elemental analysis conducted by EDTA titration
and the Ni and Al percentage obtained by XRF matched the reported
values [22]. The close similarity of the results indicated that the
alloy was uniformly leached. The continuous stirring and leaching
of Al from alloy has resulted in R-Ni grades of micrometer size.
This porosity obtained by the process also matched the literature
reported values [26].
The XRD results shown in Fig. 1 matched the data reported in
literature [26]. The figure shows three main phases of nickel and
aluminum, i.e. NiAl3, Ni2Al3, and eutectic Al in alloy with lattice

A. Mehta et al. / Applied Catalysis A: General 478 (2014) 241–251
243
Fig. 1. XRD of alloy, T4, W4 and W7.

244
A. Mehta et al. / Applied Catalysis A: General 478 (2014) 241–251
Fig. 2. SEM of alloy, T4, W4 and W7.
Table 2
Catalytic testing of prepared R-Ni.
H
N
N
NH2
N
OH
R-Ni
+
+
+
2
1
3
4
5
Entry
Catalyst
Recovered (%)
Yield (%)
1
2
3
4
1
2
3
W4
T4
W7
–
8
–
12
28
23
62
10
21
26
54
56
Conditions – 1 (30 mmol), 2 (120 mmol), 2 g of R-Ni (16 mmol), xylene, reflux, 30 h.
formation of N,N-dibenzyl amine 5 in-spite of the presence of
excess alcohol.
The time-conversion profile of W4 mediated reaction is shown
in Fig. 3. The plot describes conversion of aniline and benzyl alco-
hol to form benzaldehyde, benzaldimine and N-benzyl aniline. The
formation of benzaldehyde and benzaldimine further confirms that
the reaction follows Oppenauer type oxidation mechanism. At the
end of 25 h, aniline was almost consumed completely. The reaction
was continued till the maximum formation of N-benzyl aniline.
The above reaction was additionally studied to understand the
mechanism and rate-limiting step of the reaction. Literature sur-
vey and preliminary observation of the reaction indicated that the
reaction follows three sequential steps [3]. The reaction begins
with dehydrogenation of benzyl alcohol to benzaldehyde, fol-
lowed by its condensations with aniline to form benzaldimine.
The benzaldimine is then reduced to N-benzyl aniline using the
hydrogen released during dehydrogenation of alcohol. On studying
each reaction independently it was observed that dehydrogena-
tion and hydrogenation reactions are dependent on the presence
Fig. 3. Reaction monitoring.

A. Mehta et al. / Applied Catalysis A: General 478 (2014) 241–251
245
of R-Ni whereas, condensation reaction is independent of R-Ni. The
dehydrogenation of alcohol to aldehyde and reduction of ben-
zaldimine were further studied separately with W4, W7, T4 R-Ni
and without R-Ni. As summarized in Fig. 4 R-Ni is essential for for-
mation of benzaldehyde and N-benzyl aniline. Secondly, the rates of
dehydrogenation of benzyl alcohol and reduction of benzaldimine
were fastest by W4 R-Ni. Interestingly it was also noted that the rate
of reduction is twice the rate of dehydrogenation thus suggesting
that dehydrogenation is the rate-limiting step in this reaction.
observed to be 4 equivalents for every equivalent of amine, Table 2
(entry 1).
The next optimization parameter studied was concentration of
R-Ni in the reaction mixture. The effect was studied over four con-
centration of W4 R-Ni as shown in Table 3, entries 4–7. The results
suggest that the amount of R-Ni used cannot be catalytic; most
probably due to the fact that it needs to adsorb the hydrogen gen-
erated by dehydrogenation of alcohol at 140 ◦C. Since 4 g of catalyst
gave a good yield of 85% of 3, further increasing concentrations of
catalyst were not studied.
In order to understand the role of the solvent in this reaction, the
reaction was carried out in absence of solvent. The reaction mixture
after 24 h showed equal amount of 4 and 3 in the reaction mixture,
Table 3 (entry 8). The reaction using 1,4-dioxane and diglyme as
solvent also showed formation of 3 but the major product obtained
in significant amount was 4, Table 3 (entries 9 and 10). The reaction
with polar aprotic solvents like N-Methyl pyrrolidone (NMP), DMF,
and DMSO deactivate the catalyst for hydrogenation reaction. The
reactions resulted in very low yields of 4 and a major portion of
starting material was recovered unreacted, Table 3 (entries 11–13).
The best yield for 3 with selectivity was obtained using xylene as
solvent, as tested initially, Table 3 (entry 7).
2.3. Optimization of reaction conditions
After selecting W4 as the most favorable form of R-Ni for this
transformation; we turned our attention to optimize reaction con-
ditions. The optimization was done by studying the effect of alcohol
concentration, R-Ni concentration, solvent effect, addition of base
and temperature. The results on varying the above parameters are
summarized in Table 3.
The reduction of benzyl alcohol concentration, i.e. 2 molar
equivalent to aniline led to increase in the formation of 4 sug-
gesting that the hydrogenation step is dependent on the alcohol
concentration. However on increasing the concentration of alcohol
to 8 molar equivalents it lead to the appearance of tertiary amine 5
in the reaction mixture. The increased alcohol concentration results
in decreased selectivity for formation of secondary amines, Table 3
(entries 1–3). The optimum concentration of benzyl alcohol was
In most of the previous reports the effect of base was found to
increase the conversion and dramatically increase the yield [29].
Based on these reports inorganic bases like potassium hydrox-
ide and sodium carbonate were added to the reaction mixture in
Fig. 4. Rate limiting step estimation.

246
A. Mehta et al. / Applied Catalysis A: General 478 (2014) 241–251
Table 3
Reaction optimization.
H
N
N
NH2
N
OH
R-Ni
+
+
+
1
2
3
4
5
Entry
W4 R-Ni
(g)
Molar ratio 1:2
Solvent
Temperature
Additive
Recovered(%)
Yield (%)
3
1 = 30 mmol
1
2
4
5
1
2
3
4
5
6
7
8
9
2
2
2
0.5
1
2
4
4
4
4
4
4
4
4
4
4
4
4
4
4
1:2
1:8
1:16
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:4
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
–
1,4-Dioxane
Diglyme
NMP
DMF
DMSO
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
Xylene
130 ◦
130 ◦
130 ◦
130 ◦
130 ◦
130 ◦
130 ◦
130 ◦
130 ◦
130 ◦
130 ◦
130 ◦
130 ◦
130 ◦
130 ◦
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
4
3
–
–
6
8
22
5
–
12
10
6
18
30
31
36
57
78
85
40
31
35
10
–
–
–
4
78
83
91
90
88
60
52
49
48
30
16
13
42
56
55
32
18
28
12
30
18
15
9
–
13
20
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
2
12
15
8
53
49
51
60
50
4
2
–
–
–
10
11
12
13
14
15
16
17
18-Ia
19-IIa
20-IIIa
2
5
33
21
28
16
–
–
–
–
–
KOH (50 mol%)
Na2CO3 (50 mol%)
100◦C
120◦C
–
–
–
–
–
Reflux (140–160 ◦C)
Reflux
Reflux
10
12
–
–
Reaction time – 30 h.
a
24 h.
50 mol% respectively. The results indicated in Table 3, entries 14
and 15 show that on addition of base, the conversion rate was
drastically affected. Use of a strong base like potassium hydrox-
ide showed that the starting materials were obtained unreacted.
Whereas the presence of a weak base like sodium carbonate
showed selectivity for the formation of 4. This also explains the
earlier observation that W7 and T4 being slightly alkaline in nature
showed more formation of 4 as compared to 3. The presence of
base in the reaction could have led to formation of a partially stable
metal hydride complex and thus affecting the hydrogenation step.
This has resulted in maximizing the yields of the corresponding
imines.
Finally, the effect of varying reaction temperature was stud-
ied by increasing and lowering the reaction temperature, Table 3
(entries 16–18). The results indicated that higher temperature of
reflux conditions increases the yield of 3, maintaining the speci-
ficity for secondary amine formation. It was also noted that at reflux
conditions the reaction rates were also enhanced (24 h v/s 30 h).
Based on results summarized in Table 3, the optimum conditions
for model reaction of aniline and benzyl alcohol were obtained as
follows: Aniline (30 mmol), Benzyl alcohol (120 mmol), W4 R-Ni
(4 g), Xylene, Reflux, and 24 h.
2.5. Scope of the reaction
A series of N-benzyl amines were successfully synthesized
using the above-mentioned conditions. Aromatic, aliphatic, and
heterocyclic amines were successfully alkylated with benzyl alco-
hol. Aniline and substituted anilines like 4-methoxy, 4-fluoro,
3,4-dichloro, 3-chloro, and 2-methyl were successfully alkylated
with benzyl alcohol (16 mmol) and 0.5 g catalyst with isolated
yields ranging from 78.5 to 90.2%, Table 4, entries 1–6. It
was observed that the rate of reaction with electron donating
groups like methyl or methoxy on the ring was faster than the
compounds containing mildly electron withdrawing like the halo-
gens.
Secondary amines like methyl 2-(benzylamino)benzoate, N-
benzylpyridin-2-amine were also synthesized with good yields as
shown in Table 4, entries 7 and 8. A unique feature of this reaction is
the neutral conditions of the reaction at high temperatures which
is evidenced by the stability of methyl esters.
Aliphatic amines like benzyl amine and cyclohexylamine were
found to react extremely fast resulting in high yield of dialkylated
product under the above-mentioned conditions. The reaction was
therefore modified by using 1:1 molar ratios of amine and alcohol.
This lead to monoalkylation with isolated yields in this case that
ranged from 73.8 to 77.7%, Table 4, entries 9 and 10.
Thus the reaction tolerates a wide range of functional groups
like halogens, esters, and ethers. Among the functional groups not
tolerated under the reaction conditions are nitro groups. On using a
nitro group, the starting material was recovered unreacted from the
crude reaction mixture. The reaction was also not successful with
benzamide as it is incapable of forming imines with aldehydes.
The presence of tertiary amines was observed as a byproduct
during N-alkylation of primary aliphatic amines, on excess use
of alcohol. This suggested that the catalyst could be used for the
synthesis of tertiary amines as well. A range of secondary amines
2.4. Reuse of R-Ni
The W4 R-Ni was recovered by filtration of the reaction mixture.
The recovered R-Ni was tested twice for its ability to convert aniline
to N-benzyl aniline. The rate of reaction of the R-Ni was similar
to that of fresh R-Ni. 3 was formed with yields of ≈90% and with
>99% conversion rate. The reaction selectivity was also maintained
throughout all the reactions as shown in Table 3, entries 18–20.
Therefore it is reasonable to assume that the prepared W4 R-Ni can
be reused and no re-activation is required for this reaction.

A. Mehta et al. / Applied Catalysis A: General 478 (2014) 241–251
247
Table 4
N-alkylation of amines using benzyl alcohol.a
Sr. No
1
Amine
Product
Yield (%)c
90.2
NH2
NH
H3CO
F
NH2
2
3
78.5
79.8
H3CO
F
NH
NH2
NH2
NH
Cl
Cl
Cl
Cl
4
5
80.2
79.2
NH
Cl
Cl
NH
NH2
CH3
NH
CH3
NH2
6
7
84.8
80.2
84.2
O
O
O
O
NH2
NH
N
N
8
NH2
NH
N
H
9b
73.8
77.7
NH2
10b
NH2
NH
a
Conditions – amine (4 mmol), benzyl alcohol (16 mmol), W4 R-Ni (0.5 g 4 mmol), xylene, reflux, 24 h.
Conditions – amine (4 mmol), benzyl alcohol (4 mmol), W4 R-Ni (0.5 g 4 mmol), xylene, reflux, 6 h.
Yield – isolated after column chromatography.
b
c
including heterocycles such as benzimidazole, triazole, piperazines,
and tetrahydro isoquinoline were alkylated with alcohols as shown
in Table 5.
gave good isolated yields ranging from 76.3 to 85.5%, Table 6
(entries 1–4).
As seen earlier with aliphatic amines, aliphatic alcohols were
also found to be quite reactive partners under these conditions, thus
1:1 molar ratio of 4-methyl aniline and aliphatic alcohol was taken
to avoid over alkylation. Aliphatic alcohols like 2-ethyl hexanol,
cyclohexyl methanol, and N-heptanol were used as substrates for
the reaction and isolated yields ranged from 67.3 to 77.6%, Table 6
(entries 5–7).
The reactivity of aliphatic alcohols was higher than aromatic
alcohols as the complete conversion of amines was observed within
12 h. The reaction of aliphatic amino alcohols such as dimethy-
lamino ethanol failed giving a series of compound which were
The reactions of N-alkylation of secondary amines using benzyl
alcohol were slower than the reaction with primary amines (32 h).
The problematic substrates in this reaction include imidazole,
pyrazole, and indoles. Imidazole and pyrazole both gave multiple
spots in this reaction methodology thus lacking selectivity.
Subsequently the scope of substrates was studied with differ-
ent primary alcohols and 4-methyl aniline. The catalyst showed
good reactivity with different aromatic and aliphatic alcohols as
shown in Table 6. Aromatic alcohols like benzyl alcohol, 4-chloro
benzyl alcohol, phenyl ethyl alcohol, and(pyridin-2-yl) methanol

248
A. Mehta et al. / Applied Catalysis A: General 478 (2014) 241–251
Table 5
N-alkylation of secondary amines using benzyl alcohol.a
Sr. No
Amine
Product
Yield (%)b
76.4
H3CO
N
1
H3CO
NH
N
H
2
3
75.0
64.9
N
N
NH
Br
H
N
N
N
N
N
Br
4
5
62.7
75.2
N
Br
Br
N
N
NH
N
H
N
6
79.2
N
N
N
a
Conditions – amine (4 mmol), benzyl alcohol (16 mmol), W4 R-Ni (0.5 g, 4 mmol), xylene, reflux, 32 h.
Yield – isolated after column chromatography.
b
difficult to isolate. Similar results were also seen when ruthe-
nium derived catalyst was used for the reaction of dimethylamino
ethanol with 2-amino pyridine [30].
With the ability of W4 R-Ni to alkylate secondary amines
successfully as shown in Table 5, the synthesis of Piribedil an
active pharmaceutical ingredient was carried out. The synthesis of
Piribedil using hydrogen autotransfer has been previously reported
using a ruthenium based catalyst, piperonyl alcohol and 2-(1-
piperazinyl) pyrimidine [9]. This transformation was successfully
carried out with the same efficiency by replacing ruthenium with
R-Ni, a relatively cheaper catalyst (Scheme 2).
It was observed that both aliphatic amines and alcohols exhib-
ited enhanced reactivity under the earlier optimized conditions.
This prompted us to undertake a series of competition experiments
between aliphatic and aromatic amines as shown in Fig. 5.
The competition reactions were conducted between n-Heptanol
7 (4 mmol), 2 (4 mmol) with 4-methyl aniline 6 (1 mmol), or cyclo-
hexylamine 11 (1 mmol). The results indicated that the alkylation
of amines with aliphatic alcohol were the major products i.e. N-
heptyl-4-methylbenzene amine 9 and N-heptyl cyclohexylamine
12. These were formed preferentially in a ratio of 2.3:1 and 3.3:2
respectively. This suggests that reactivity of aliphatic alcohols is
greater than aromatic alcohol.
N
O
OH
+
N
NH
N
O
4mmol
16mmol
In the next experiment 4 mmol of 2 was reacted with the
1 mmol each of 11 and 6. The results showed formation of N-
benzylcyclohexanamine 13 as the major product with yields up
to 65.4% and N-benzyl-4-methylbenzenamine 10 as a by-product.
Similar to the previous experiment 11 and 6 were reacted with
4 equivalents of aliphatic alcohol 7; the results pointed out to
equal yields of 12 and 14 indicating high reactivity of aliphatic
alcohol irrespective of the amine functional group. These exper-
iments suggest that aliphatic amines are more reactive than
aromatic amines but this difference is quite small when com-
pared to the difference in reactivity between aliphatic and aromatic
alcohols.
0.5g
Xylene, Reflux
24hours
Raney Nickel
O
O
N
N
N
N
85%
Scheme 2. Synthesis of piribedil.

A. Mehta et al. / Applied Catalysis A: General 478 (2014) 241–251
249
Fig. 5. Competition reaction.

250
A. Mehta et al. / Applied Catalysis A: General 478 (2014) 241–251
Table 6
N-alkylation of 4-methyl aniline using alcohol.a
Sr. No
1
Alcohol
Product
Yield (%)c
85.5
OH
H3C
H3C
NH
HN
Cl
Cl
2
3
76.3
77.9
HO
HO
H
N
H3C
N
N
4
79.7
H3C
H3C
HN
HN
HO
HO
5b
6b
77.6
68.5
H3C
H3C
HN
HN
HO
HO
7b
67.3
a
Conditions – 4-methyl aniline (4 mmol), alcohol (16 mmol), W4 R-Ni (0.5 g, 4 mmol), xylene, reflux, 24 h.
Conditions – 4-methyl aniline (4 mmol), alcohol (16 mmol), W4 R-Ni (0.5 g 4 mmol), xylene, reflux, 12 h.
Yield – isolated after column chromatography.
b
c
The next API attempted was pyrilamine, an antihistaminic.
3. Conclusion
Pyrilamine was synthesized from N-(2-(dimethylamino)ethyl)
pyridine-2-amine [31] and 4-methoxy benzyl alcohol in an isolated
yield of 82% (Scheme 3).
The current work has demonstrated a new role for R-Ni, an old
widely used reduction catalyst. The identification of W4 as the spe-
cific grade of R-Ni in the same reaction that is capable of both
dehydrogenation and hydrogenation was unexpected. In addition
it also suggests that R-Ni can also be used for selective dehydro-
genation of alcohols to aldehydes. The ability of T4 R-Ni to form
stable imines and lacking the efficiency to undergo hydrogenation
was also an outcome in this work. The neutral conditions, wide
scope of reaction, and the relative reactivities of amines and alco-
hols in this methodology suggest that aliphatic amines and alcohols
are quite active for synthesis of secondary and tertiary amines. This
selectivity can be exploited in synthesis of tertiary amines of indus-
trial and commercial importance. Finally the successful synthesis
of drugs without using harsh alkylating agents such as alkyl and
benzyl chlorides demonstrates the power and simplicity of this
methodology.
+
N
H2N
N
Cl
20mmol
10mmol
200watt,
175°C
Microwave
30min
75%, 4mmol
N
N
N
H
W4 Raney Nickel
OCH3
4. Experimental
HO
Xylene, Reflux
30hours
16mmol
4.1. General methods
All reactions were carried out in oven-dried glassware. TLC with
aluminum foil backed plates coated with 0.2 mm layers of silica
gel 60 F254 (E. Merck, Darmstadt, Germany) were used to moni-
tor reactions where appropriate. Visualization of these plates was
done by a 254 nm UV light and/or KMnO4 or ninhydrin (1%) dip
followed by gentle warming. Organic layers were routinely evap-
orated using Equitron Roteva, 8703.RVR.000 rotary evaporator.
Where necessary, further drying was facilitated by high vacuum.
Column chromatography was carried out using silica gel, 200–400
N
N
N
OCH3
82%
Scheme 3. Synthesis of pyrilamine.

A. Mehta et al. / Applied Catalysis A: General 478 (2014) 241–251
251
mesh of LOBA Chemie. IR spectra were recorded on a Perkin-Elmer
FTIR spectrometer Spectrum RX1, Software Spectrum with only
selected absorbance quoted as ꢁ in cm−1. NMR spectra were run
in DMSO or CDCl3 on Jeol 400-MHz NMR spectrophotometer with
multiple probe facility for 1H, 11B, 13C, 17O, 19F, 31P instrument
model JNM-400 and recorded at the frequency of 1H-400 MHz. The
following abbreviations are used: s – singlet, d – doublet, t – triplet,
app.t – apparent triplet, q – quartet, app.q – apparent quartet, dd –
doublet of doublets, m – multiplet and br – broad. Structural assign-
ments of protons were achieved with comparisons from analogous
literature compounds; references are given in most cases.
melting or boiling point. The analytical data obtained of the known
compounds are in agreement to the reported literature.
Acknowledgments
The authors thank Ambernath Organics Pvt. Ltd. (grant no. 022-
42504000) for sponsoring the project and Monarch catalyst Pvt.
Ltd. for catalyst characterization.
Appendix A. Supplementary data
A microTOF electrospray time-of-flight (ESI-TOF) mass spec-
trometer (Bruker Daltonik GmbH, Bremen, Germany) was used;
this was coupled to an Agilent 1200 LC system (Agilent Tech-
nologies, Waldbronn, Germany). The LC system was used as an
autosampler only. 10 ␮L of sample was injected into a 30:70 flow
of water:acetonitrile at 0.6 mL/min to the mass spectrometer. The
observed mass and isotope pattern perfectly matched the cor-
responding theoretical values as calculated from the expected
elemental formula. Particle size distribution of the alloy was esti-
mated using Sieve analysis conducted on Electromagnetic Sieve
shaker by ElectroPharma, EMS-8 and the particle size of the pre-
pared grades was estimated on Cilas Particle Size analyzer, 990L,
Size expert 9.30. XRF was conducted using Metex, Spectro Xepos
instrument, software X-LabPro. Elemental analysis was performed
using previously reported procedures of EDTA complexometry
titration. SEM analysis was performed using ZEISS Ultra FESEM
instrument equipped with acceleration voltage from 0.1 kV to
30 kV, beam current upto 100 nA and a scintillator detector for
surface structure. Gas chromatographic analysis wherever per-
formed was done on Perkin Elmer Clarus 500, software TCNav.
Unless preparative details are provided, all reagents were com-
mercially available and purchased from Sigma Aldrich, SDFine or
Spectrochem.
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.apcata.
2014.04.009.
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