Silica-functionalized CuI: An efficient and selective catalyst for N-benzylation, allylation, and alkylation of primary and secondary amines in water

Article abstract of DOI:10.1080/00397911.2013.828077

Silica-functionalized CuI has been reported as an efficient and selective catalyst for the selective mono-N- and N,N-dibenzylation, allylation, and alkylation of primary amines with benzylic, allylic, and alkyl halides using NaOH as base in aqueous medium. By changing the reaction temperature, mono- or di-benzylation, allylation, or alkylation could be achieved in good yield and selectivity. Secondary amines have also been benzylated, allylated, and alkylated under similar conditions. SiO₂-CuI has been characterized by Fourier transform-infrared, atomic absorption spectrometry, thermalgravimetric analysis, X-ray diffraction, scanning electron microscopy, and transmission electron microscopy, and found to be highly selective and recyclable under the reaction conditions. [Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications for the following free supplemental resource(s): Full experimental and spectral details.] Copyright

Full text of DOI:10.1080/00397911.2013.828077

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Silica-Functionalized CuI: An Efficient
and Selective Catalyst for N-Benzylation,
Allylation, and Alkylation of Primary and
Secondary Amines in Water
Tahira Shamim a , Vineet Kumar a & Satya Paul a
a Department of Chemistry , University of Jammu , Jammu , India
Accepted author version posted online: 28 Oct 2013.Published
online: 27 Dec 2013.
To cite this article: Tahira Shamim , Vineet Kumar & Satya Paul (2014) Silica-Functionalized CuI: An
Efficient and Selective Catalyst for N-Benzylation, Allylation, and Alkylation of Primary and Secondary
Amines in Water, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 44:5, 620-632, DOI: 10.1080/00397911.2013.828077
To link to this article: http://dx.doi.org/10.1080/00397911.2013.828077
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Synthetic Communications1, 44: 620–632, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.828077
SILICA-FUNCTIONALIZED CuI: AN EFFICIENT AND
SELECTIVE CATALYST FOR N-BENZYLATION,
ALLYLATION, AND ALKYLATION OF PRIMARY AND
SECONDARY AMINES IN WATER
Tahira Shamim, Vineet Kumar, and Satya Paul
Department of Chemistry, University of Jammu, Jammu, India
GRAPHICAL ABSTRACT
Abstract Silica-functionalized CuI has been reported as an efficient and selective catalyst
for the selective mono-N- and N,N-dibenzylation, allylation, and alkylation of primary
amines with benzylic, allylic, and alkyl halides using NaOH as base in aqueous medium.
By changing the reaction temperature, mono- or di-benzylation, allylation, or alkylation
could be achieved in good yield and selectivity. Secondary amines have also been benzylated,
allylated, and alkylated under similar conditions. SiO2-CuI has been characterized by
Fourier transform–infrared, atomic absorption spectrometry, thermalgravimetric analysis,
X-ray diffraction, scanning electron microscopy, and transmission electron microscopy,
and found to be highly selective and recyclable under the reaction conditions.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords Aqueous conditions; heterogeneous catalysis; N-alkylations; selectivity;
silica-functionalized CuI
INTRODUCTION
Replacement of homogeneous with heterogeneous catalysis and replacement of
volatile organic solvents by environmentally friendly ones such as water have been key
areas of research in recent years. Among various heterogeneous catalysts developed
over the past decades,[1] silica-supported nanometals have taken the lead because of
their greater activity and selectivity.[2] Recently, use of water has been explored in
heterogenized homogeneous catalysis, because it is non-toxic, non-inflammable,
Received March 20, 2013.
Address correspondence to Satya Paul, Department of Chemistry, University of Jammu, Jammu
180 006, India. E-mail: paul7@rediffmail.com
620

SiO2-CuI-CATALYZED ALKYLATION OF AMINES
621
abundantly available, inexpensive, and cheap. During the past two decades, a large
number of reactions have been performed successfully in aqueous media.[3] It is
generally found that organic compounds have limited solubility in water, and efficient
water-mediated reactions with high selectivities and reactivities are still relatively
limited. Hence, there is a need for close examination of such research areas. Our main
motive for using water as a reaction medium is aimed at reducing the use of organic
solvents and acheiving more selectivity.
Amines and their derivatives are some of the most common structural features
of various naturally occuring biologically active compounds and are widely used as
basic intermediates for the preparation of dyes, solvents, fine chemicals, fluorescence
probes, pharamaceuticals, agrochemicals, and catalysts for polymerization.[4] Owing
to the immense importance of amines and their derivatives, the development of
versatile and efficient methods for their synthesis have become an active area of
research.[5] Traditionally, amines are benzylated, allylated, and alkylated by treat-
ment with suitable halide in the presence of a base[6] such as KOH or t-BuOK,
sodium amide, CsOH, thallium(I)ethoxide, CsF=celite, and Hunig’s base. In some
cases, methanol, dimethyl carbonate, and dimethylsulfate have also been used as
alkylating agents.[7] Various other methods[8] include Mannich-type reaction,
reductive and catalytic amination, metal-initiated amination of alkenes, alkynes,
and aryl halides, deamination of quaternary hydrazinium halides, and reduction
of N-tosylamidines. Although these methods are quite reliable, most of them
(especially those involving direct nucleophilic attack of amines to halides) suffer
from overalkylation, thus leading to a mixture of secondary and tertiary amines
and even quaternary ammonium salts. The prevention of overalkylation becomes
more difficult when highly reactive alkylating agents such as methyl, ethyl, benzyl,
and allyl halides are used as alkylating agents.[9] Recently, various groups have car-
ried out selective N-alkylation of amines with excellent yields. For example, Chiappe
et al.[10] have carried out the selective mono-N-alkylation of anilines in ionic liquids;
Marzaro et al.[11] have reported the selective N-alkylation of amines using alkyl
halides in an aqueous basic (NaOH) medium under microwave irradiation, which
has been found to be quite satisfactory[12] but requires the use of specialized micro-
wave equipment; and Zhao et al.[13] have used iron(III) bromide in combination with
dl-pyroglutamic acid and 1,2,3,4,5-pentamethylcyclopenta-1,3-diene at 160 ꢀC under
an Ar atmosphere for carrying out selective N-alkylation. Though this method
involves the use of quite expensive additives, high selectivity makes this method
quite attractive. Zhang et al.[14] have used iron oxide–immobilized palladium catalyst
for the selective N-alkylation of amines with alcohols under base- and organic
Scheme 1. N- and N,N-Dibenzylation, allylation, and alkylation of primary amines using SiO2-CuI in
water.

622
T. SHAMIM, V. KUMAR, AND S. PAUL
Scheme 2. N-Benzylation, allylation, and alkylation of secondary amines using SiO2-CuI in water.
ligand–free conditions with excellent yields. Again this method requires high tem-
perature and argon atmosphere to obtain good yield and selectivity.
To make this synthesis selective as well as economical, we herein describe the
selective mono-N- and N,N-dibenzylation, allylation, and alkylation of primary
(Scheme 1) and secondary amines (Scheme 2) in an aqueous medium under mild
conditions. Advantages of this protocol include no need for organic solvents, low
reaction temperature, no need for inert atmosphere, good yield of products with
greater selectivity, and both mono-N- and N,N-dialkylation could be achieved by just
changing the reaction temperature.
RESULTS AND DISCUSSION
The silica-functionalized Cu(I) iodide [SiO2-CuI] was prepared according to our
earlier reported work[15] with slight modification (Scheme 3). The SiO2-CuI was char-
acterized in a way similar to that reported earlier.[15] For X-ray diffractometry (S1),
Scheme 3. Preparation of silica-functionalized Cu(I) iodide.

SiO2-CuI-CATALYZED ALKYLATION OF AMINES
623
scanning electron microscopy (SEM) image (S2), and transmission electron
microscopy (TEM) micrograph (S3), see the electronic supporting information.
Catalytic activity of SiO2-CuI was studied for the selective N-benzylation,
allylation, and alkylation of primary amines. Benzyl amine was selected as the test
substrate and benzylation, allylation, and alkylation were carried out with benzyl
chloride, allyl bromide, and n-butyl chloride using NaOH as base in various solvents
such as toluene, acetonitrile, ethanol, and water (Table 1) at different temperatures so
as to achieve maximum selectivity for mono-N-alkylation. The results in Table 1 indi-
cated that water is an excellent reaction medium in terms of selectivity. Further,
addition of phase-transfer catalyst (TBAB) has increased reaction rate by facilitating
the migration of a reactant from one phase into another where reaction occurs. Such
rate enhancements have already been reported elsewhere.[16] The reaction conditions
were screened for various temperatures between 0 and 80 ꢀC, and 15 ꢀC was the opti-
mum reaction temperature for mono-N-alkylation, because at higher temperature,
dialkylation also occurs and hence selectivity for monoalkylation decreases. It
was also found that the reaction remained selective for a certain period of time
(i.e., 4 h) with 80% conversion of benzyl amine to dibenzyl amine. If the reaction
was carried out beyond this time, dialkylation starts and selectivity decreases. So to
keep the reaction selective, we stopped the reaction after this time, and mono-N-alky-
lated product was separated by column chromatography. Thus, the optimum con-
ditions selected are benzyl amine (0.5 mmol), benzyl chloride or allyl bromide or n-
butyl chloride (0.5 mmol), NaOH (2 mmol), TBAB (0.25 mmol), and SiO2-CuI
(0.1 g, 5 mol% Cu), and 15 ꢀC as the reaction temperature using water as the reaction
medium. To demonstrate the generality of the developed protocol, various primary
amines were subjected to N-benzylation, allylation, and alkylation using SiO2-CuI
in water at 15 ꢀC and excellent results were obtained (Table 2).
Once we were able to carry out the N-benzylation, allylation, and alkylation
selectively, then reaction conditions were screened for the selective N,N-dibenzylation,
Table 1. Effect of solvent on SiO2-CuI-catalyzed N-benzylation, allylation, and alkylation of amines at
15 ꢀC in water
N-Benzylation
N-Allylation
N-Alkylation
Entrya
Solventb
Time (h)
Yield (%)
Time (h)
Yield (%)
Time (h)
Yield (%)
1
2
3
4
Toulene
Ethanol
Acetonitrile
Water
4
4
4
4
20
25
40
75
4
4
4
4
15
20
40
75
8
8
8
8
10
10
20
75
aReaction was carried out by stirring a mixture of amine (0.5 mmol), halide (0.5 mmol), NaOH
(2 mmol), TBAB (0.25 mmol), and SiO2-CuI (0.1 g, 5 mol% Cu) at 15 ꢀC in different solvents.
bYield refers to column chromatography yield.

624
T. SHAMIM, V. KUMAR, AND S. PAUL
Table 2. SiO2-CuI-catalyzed N-benzylation, allylation, and alkylation of primary amine with benzyl
chloride, allyl bromide, or n-butyl chloride at 15 ꢀC in water
Entrya
R
R0
Time (h)
Yieldb (%)
Mp or Bp=lit. mp or bp
1
2
C6H5CH2
4-BrC6H4
4-ClC6H4
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
=
CH2 CHCH2
=
CH2 CHCH2
=
CH2 CHCH2
=
CH2 CHCH2
4
4
4
4
4
3
3
3
3
3
8
9
9
9
9
75
74
74
72
74
74
73
73
72
72
74
72
72
71
72
103–104=104[18]
52–53=51–52[19]
46–47=46–47[19]
245–246=244–245[20]
51–52=52–53[19]
liq=bp 115–117[21]
liq=bp 145.5–147[22]
liq=bp 267–270[23]
liq=bp 105–109[24]
liq=bp 126–127[25]
liq=bp 124–126[26]
liq=bp 95–96[27]
liq=bp 89–90[27]
liq=bp 70–71[27]
liq=bp 80–81[27]
3
4
4-CH3C6H4
4-OCH3C6H4
C6H5CH2
5
6
7
4-BrC6H4
4-ClC6H4
8
9
4-CH3C6H4
4-OCH3C6H4
C6H5CH2
=
CH2 CHCH2
10
11
12
13
14
15
n-C4H9
n-C4H9
n-C4H9
n-C4H9
n-C4H9
4-BrC6H4
2-ClC6H4
4-CH3C6H4
4-OCH3C6H4
aReaction was carried out by stirring a mixture of amine (0.5 mmol), halide (0.5 mmol), NaOH
(2 mmol), TBAB (0.25 mmol), and SiO2-CuI (0.1 g, 5 mol% Cu) at 15 ꢀC in water (4 mL).
bYield refers to column chromatography yield.
allylation, and alkylation using SiO2-CuI. Benzyl amine was again selected as the test
substrate and dibenzylation, allylation, and alkylation were carried out with benzyl
chloride, allyl bromide, and n-butyl chloride respectively using NaOH as base under
similar conditions but for extended period of time. It was found that up to 15 h, the
conversion to disubstitution increased but reaction did not go to completion. To drive
the reaction to completion, the reaction temperature was increased up to 100 ꢀC, and
surprisingly the reaction was completed in 2 h. No monosubstituted product was
observed on thin-layer chromatography (TLC). Thus, the optimum conditions for
disubstitution selected are benzyl amine (0.5 mmol), benzyl chloride, allyl bromide
or n-butyl chloride (1 mmol), NaOH (2 mmol), TBAB (0.25 mmol) and SiO2-CuI
(0.1 g, 5 mol% Cu), water (4 mL), and 70–100 ꢀC as the reaction temperature. To
demonstrate the generality of the developed protocol, various primary amines were
subjected to N,N-dibenzylation, allylation, and alkylation using SiO2-CuI in water
at 70–100 ꢀC, and excellent results were obtained (Table 3).
The SiO2-CuI-catalyzed N-benzylation, allylation, and alkylation of secondary
amines has also been attempted. To select the optimum reaction conditions, morph-
oline was selected as the test substrate, and benzylation, allylation, and alkylation was
carried out with benzyl chloride, allyl bromide, and n-butyl chloride respectively
under similar conditions as for N,N-disubstitution. Different solvents have been
screened (Table 1) and again we found that water was the most suitable solvent.
TBAB also increased the reaction rate. The optimum conditions selected are morph-
oline (0.5 mmol), benzyl chloride, allyl bromide, or n-butyl chloride (0.5 mmol),

SiO2-CuI-CATALYZED ALKYLATION OF AMINES
625
Table 3. SiO2-CuI catalyzed N,N-dibenzylation, allylation, and alkylation of primary amine with benzyl
chloride, allyl bromide, or n-butyl chloride at 70–100 ꢀCa in water
Entryb
R
R0
Time (h)
Yieldc (%)
Mp or Bp=lit. mp or bp (ꢀC)
1
2
C6H5CH2
4-BrC6H4
4-ClC6H4
4-CH3C6H4
4-OCH3C6H4
C6H5CH2
4-BrC6H4
4-ClC6H4
C6H5CH2
4-BrC6H4
4-ClC6H4
4-CH3C6H4
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
2
6
94
93
93
92
92
93
93
92
93
90
90
90
90–91=91[28]
125–126=124–126[29]
103–104=104–105[30]
63–64=63–64[31]
85–86=85–87[31]
liq=bp 89[32]
3
6
4
5.5
5.5
9
5
=
CH2 CHCH2
6
7
CH2 CHCH2
=
CH2 CHCH2
10
10
21
22
23
23
liq. (oil)[33]
=
8
liq=bp 95–97[34]
liq=bp 134–136[35]
liq=bp 156–158[36]
liq=bp 107–112[37]
liq=bp > 260[37]
9
n-C4H9
n-C4H9
n-C4H9
n-C4H9
10
11
12
aAllylation was carried out at 70 ꢀC.
bReaction was carried out by stirring a mixture of amine (0.5 mmol), halide (1 mmol), NaOH (2 mmol),
TBAB (0.25 mmol), and SiO2-CuI (0.1 g, 5 mol% Cu) at 70–100 ꢀC in water (4 mL).
cIsolated yield (entries 1–5), column chromatography yield (entries 6–12).
NaOH (2 mmol), TBAB (0.25 mmol), SiO2-CuI (5 mol%, 0.1 g), water (4 mL), and
100 ꢀC as the reaction temperature. To demonstrate the generality of the developed
protocol, various secondary amines were chosen, and excellent results were obtained
(Table 4).
To find out the role of SiO2-CuI for N-benzylation, allylation, and alkylation,
we carried out the reaction in the case of entries 1, 6, 11 (Table 2) with activated
silica, 3-aminopropyl silica (AMPS), ligand-grafted silica (imine), and in the absence
of SiO2-CuI under the similar conditions as applied for SiO2-CuI. The results are
summarized in Table 5. Thus, it was found that SiO2-CuI catalyses the reaction and
the corresponding amine was obtained in good yield and selectivity. It is pertinent to
mention that reaction does take place without any catalyst, but regioselectivity is
poor. The possible explaination for the catalytic activity of SiO2-CuI might be
illustrated on the basis of cyclic mechanism reported earlier.[17] Catalytic oxidative
addition of Cu(I) into the aryl–halogen bond take place to form the copper(III)
intermediate, which undergoes an exchange of the halide with the nucleophile (i.e.,
amine) to form another intermediate, which finally undergo subsequent reductive elim-
ination to form the product, and Cu(I) catalyst is regenerated back. Several literature
reports evoke the involvement of copper(III) intermediate in the Ullmann reaction
mechanism.[17]
In the case of heterogeneous catalysis, deactivation and hence recyclability
are the important issues. To test this, a series of seven consecutive runs for the
N-benzylation of benzyl amine (entry 1, Table 2) and N,N-dibenzylation of benzyl
amine (entry 1, Table 3) were carried out, and the results are represented in Fig. 1,

626
T. SHAMIM, V. KUMAR, AND S. PAUL
Table 4. SiO2-CuI-catalyzed N-benzylation, allylation, and alkylation of secondary amines with benzyl
chloride, allyl bromide, or n-butyl chloride at 100 ꢀC in watera
Entry
Amine
R0
Time (h)
Yieldb (%)
Mp or Bp = lit. mp or bp (ꢀC)
1
2
Morpholine
Imidazole
Piperidine
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
=
CH2 CHCH2
=
CH2 CHCH2
2
4
96
85
97
50
94
94
51
93
78
92
68
194–195=194[38]
72–73=71–72[39]
177–178=178–179[40]
87–88=86–87[41]
liq=bp 156–158[32]
50–51=51–52[42]
liq=bp 185–195[43]
liq=bp 67–68[44]
237–238=238–239[45]
liq=bp 176[46]
3
1
4
Diphenyl amine
Morpholine
Piperidine
5
5
3
6
2
=
CH2 CHCH2
7
Diphenyl amine
Morpholine
Imidazole
5
8
n-C4H9
n-C4H9
n-C4H9
n-C4H9
2
9
15
2
10
11
Piperidine
Diphenyl amine
20
liq=bp 145–147[47]
aReaction was carried out by stirring a mixture of amine (0.5 mmol), halide (0.5 mmol), NaOH
(2 mmol), TBAB (0.25 mmol), and SiO2-CuI (0.1 g, 5 mol% Cu) at 100 ꢀC in water (4 mL).
bIsolated yield (entries 1–4) and column chromatography yield (entries 5–11).
which demonstrated that SiO2-CuI is highly active, selective, stable, and recyclable.
Up to run 5, there was no loss of activity; however, after run 5, there was a signifi-
cant decrease in the activity of the catalyst. This decrease in the activity may be due
to the microscopic changes on the surface of the catalyst. Further, negligible leaching
of Cu was observed by AAS analysis.
Table 5. Effect of catalyst on the N-benzylation, allylation, and alkylation of amines at 15 ꢀC in water
N-Benzylation
N-Allylation
N-Alkylation
Entry
Catalyst
Time (h)
Yield (%)
Time (h)
Yield (%)
Time (h)
Yield (%)
1
2
3
4
5
No catalyst
Silica
AMPS
4
4
4
4
4
30
40
40
45
75
4
4
4
4
4
25
30
30
40
74
8
8
8
8
8
Traces
10
10
Imine
SiO2-CuI
10
74
aReaction was carried out by stirring a mixture of amine (0.5 mmol), halide (0.5 mmol), NaOH
(2 mmol), TBAB (0.25 mmol), and SiO2-CuI (0.1 g, 5 mol% Cu) at 15 ꢀC in water (4 mL).
bYield refers to column chromatography yield.

SiO2-CuI-CATALYZED ALKYLATION OF AMINES
627
Figure 1. Recyclability of SiO2-CuI.
CONCLUSION
In conclusion, we have developed a mild, simple, and cost-effective procedure
for selective N-benzylation, allylation, and alkylation; N,N-dibenzylation, allylation,
and alkylation of primary amines; and N-benzylation, allylation, and alkylation of
secondary amines in the presence of recyclable SiO2-CuI using water as the reaction
medium. Moreover, the mild reaction conditions, high selectivity, good yield of
products, ease of workup, and cost-effective procedure will make the present method
a useful and important addition to the present methodologies for the synthesis of
N-substituted secondary and tertiary amines.
EXPERIMENTAL
All chemicals used were purchased from Aldrich Chemical Company. A Bruker
DPX-200 NMR spectrometer (200 MHz) in CDCl3 using tetramethylsilane as an
1
internal standard was used for recording H NMR spectra; a Perkin-Elmer FTIR
spectrophotometer using KBr disc was used for IR; and mass spectral data were
recorded on an Esquire 3000 (ESI). Thermal analysis was done on a DTG-60
Shimadzu thermal analyzer with heating rate of 10 ꢀC=min, x-ray diffraction patterns
were measured on a Bruker AXSD8 X-ray diffraction spectrometer, SEM was studied
on a Jeol T-300 scanning electron microscope, and transmission electron microscopy
(TEM) was done on a H7500 Hitachi. The amount of copper in SiO2-CuI was deter-
mined on a GBC 932 AB atomic absorption spectrophotometer manufactured in
Australia. The catalyst was stirred in diluted HCl for 5 h and then subjected to
AAS analysis. All yields refer to the isolated or column chromatography yields.
General Procedure for the Selective N-Benzylation, Allylation, and
Alkylation or N,N-Dibenzylation, Allylation, and Alkylation of
Primary and Secondary Amines
SiO2-CuI (0.1 g, 5 mol% Cu) was added to a mixture of amine (0.5 mmol),
benzyl chloride, allyl bromide, or n-butyl chloride (0.5 mmol for N-substitution

628
T. SHAMIM, V. KUMAR, AND S. PAUL
and 1 mmol for N,N-disubstitution), NaOH (2 mmol), and TBAB (0.25 mmol) in a
round-bottom flask (25 mL) in water (4 mL). The reaction mixture was stirred at
15 ꢀC (in the case of N-benzylation, allylation, or alkylation of primary amines,
Table 2) or 70–100 ꢀC (in the case of N,N-dibenzylation, allylation, or alkylation
of primary amines, Table 3), and 100 ꢀC (N-benzylation, allylation, and alkylation
of secondary amines, Table 4) for an appropriate time. After completion of the
reaction (monitored by thin-layer chromatography, TLC), the reaction mixture
was triturated with EtOAc (20 mL) and the SiO2-CuI was filtered off. The product
was obtained after removal of the solvent under reduced pressure followed by col-
umn chromatography or crystallization from EtOAc–petroleum. ether. The SiO2-
CuI was washed with distilled water (200 mL) followed by methylene chloride
(3 ꢁ 15 mL) and dried at 110 ꢀC for 2 h. It was used further for carrying out the reac-
tion. The structures of products were confirmed by IR, 1H NMR, mass spectral data
(see supporting information, S4) and comparison with authentic samples obtained
commercially or prepared according to the literature methods.
ACKNOWLEDGMENTS
We are grateful to SAIF, Punjab University, Chandigarh, for SEM, TEM,
and XRD; and the head, Institute Instrumentation Centre, Indian Institute of
Technology, Roorkee, for AAS analysis.
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