Synthesis and applications of Fe3O4- diisopropylaminoacetamide as a versatile and reusable magnetic nanoparticle supported N,N-diisopropylethylamine equivalent

Article abstract of DOI:10.1016/j.tetlet.2012.03.063

A magnetic nanoparticle supported N,N-diisopropylaminoacetamide (Fe ₃O₄-DIPA) was developed for application as a magnetic recoverable, and reusable N,N-diisopropylethylamine equivalent. The Fe ₃O₄ nanoparticles were coated with a silica layer using the sol-gel method, followed by surface modification with 3- aminopropyltriethoxysilane. Subsequent acylation with chloroacetyl chloride and chlorine displacement with diisopropylamine afforded Fe₃O ₄-DIPA in 90% yield with a loading of 0.96 mmol/g. The applicability of Fe₃O₄-DIPA was demonstrated in the synthesis of amine derivatives cv sulfonation, acylation, and N-alkylation reactions. The desired products were obtained in excellent yields and purities after scavenging the residual starting amines by treatment with silica-supported dichlorotriazine. Fe₃O₄-DIPA was readily recovered by separation using a magnet and could be reused several times without significant loss of reactivity.

Full text of DOI:10.1016/j.tetlet.2012.03.063

Tetrahedron Letters 53 (2012) 2689–2693
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and applications of Fe3O4-diisopropylaminoacetamide
as a versatile and reusable magnetic nanoparticle supported
N,N-diisopropylethylamine equivalent
⇑
Parintip Rattanaburi, Bannarak Khumraksa, Mookda Pattarawarapan
Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
A magnetic nanoparticle supported N,N-diisopropylaminoacetamide (Fe3O4-DIPA) was developed for
application as a magnetic recoverable, and reusable N,N-diisopropylethylamine equivalent. The Fe3O4
nanoparticles were coated with a silica layer using the sol-gel method, followed by surface modification
with 3-aminopropyltriethoxysilane. Subsequent acylation with chloroacetyl chloride and chlorine dis-
placement with diisopropylamine afforded Fe3O4-DIPA in 90% yield with a loading of 0.96 mmol/g. The
applicability of Fe3O4-DIPA was demonstrated in the synthesis of amine derivatives cv sulfonation, acyl-
ation, and N-alkylation reactions. The desired products were obtained in excellent yields and purities
after scavenging the residual starting amines by treatment with silica-supported dichlorotriazine.
Fe3O4-DIPA was readily recovered by separation using a magnet and could be reused several times
without significant loss of reactivity.
Received 7 December 2011
Revised 6 March 2012
Accepted 20 March 2012
Available online 24 March 2012
Keywords:
Hünig’s base
N,N-diisopropylethylamine
Magnetic nanoparticles
Solid supported reagent
Ó 2012 Elsevier Ltd. All rights reserved.
N,N-Diisopropylethylamine (Hünig’s base, DIPEA) is a tertiary
amine base used commonly in medicinal chemistry and the
pharmaceutical industry. Due to the presence of a hindered nitro-
gen atom which is shielded by the two bulky isopropyl groups and
an ethyl group, this amine is a good base but a poor nucleophile.
Thus far, DIPEA has been applied successfully as a proton scavenger
in a variety of reactions such as alkylation,1 acylation,2,3 sulfona-
tion,4 and in peptide synthesis5 to prevent undesired side reac-
tions. Direct N-alkylation of secondary amines to generate
tertiary amines can be achieved without formation of a quaternary
ammonium salt.1 In peptide synthesis, DIPEA is used to prevent
racemization of amino acids during peptide coupling.5 Typically,
aqueous work-up and/or column chromatography are required
for removal of Hünig’s base and its ammonium salt. The process
is time-consuming and difficult to carry out in automated solu-
tion-phase parallel synthesis. Moreover, the tendency for product
loss is obviously unavoidable.
One approach to prevent reagent contamination in the final
product is by attachment of reagents to insoluble solid supports
to render their isolation via filtration or centrifugation.6 Cross-
linked polystyrenes7 are frequently used as solid supports, while
inorganic materials such as silica,8–10 alumina,11,12 and clay13 have
also been employed. Nevertheless, due to the low reactivity of such
heterogeneous reagents which is often limited by the substrate dif-
fusion rate, excessive amounts of the supported reagents
O
O
O
Si(OEt)4
APTES
toluene, reflux
Fe3O4
SiO2
Si
NH2
Fe3O4
SiO2
Fe3O4
Aminopropyl-modified Fe3O4
O
O
O
O
O
Cl
Cl
Cl
Fe3O4
Si
N
H
Et3N, CH2Cl2
SiO2
O
O
O
O
iPr2NH
N
Fe3O4
SiO2
Si
Fe3O4-DIPA
Scheme 1. Synthesis of Fe3O4-DIPA.
N
K2CO3, toluene
60 oC
H
(3–6 equiv relative to the limiting agent) are necessary to drive
the reaction to completion.
In continuation of our efforts to develop environmentally be-
nign, economical, and efficient synthetic processes, considerable
attention has been focused on the use of magnetic nanoparticles
(MNPs) as magnetically recoverable supports.14 The superpara-
magnetic property of MNPs is highly useful in that the particles be-
come magnetized only when exposed to an external magnet. In the
absence of a magnetic field, they exhibit no magnetization and can
disperse efficiently in a reaction mixture to allow fast diffusion of
substrate to the nanoparticle surface active sites. On the other
⇑
Corresponding author. Tel.: +66 5394 3341; fax: +66 5389 2277.
E-mail address: mookdap55@gmail.com (M. Pattarawarapan).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.063

2690
P. Rattanaburi et al. / Tetrahedron Letters 53 (2012) 2689–2693
Figure 1. IR spectra of Fe3O4 (a), aminopropyl-modified Fe3O4 (b), Fe3O4-DIPA (c).
Figure 3. The TGA curves of Fe3O4 (a) and Fe3O4-DIPA (b).
hand, they can be readily separated from the media by attachment
to a permanent magnet. The process is inevitably more effective
than filtration and centrifugation in preventing loss of the support.
So far, most reported MNP immobilizations have involved tran-
sition metal catalysts which have been proven to be highly effec-
tive and reusable.14 Recently, a magnetic osmium catalyst was
successfully applied in the dihydroxylation of olefins,15 while sul-
by-products from three model reactions including the sulfonation,
acylation, and N-alkylation of amines was investigated. Fe3O4-DIPA
was synthesized as illustrated in Scheme 1. Magnetite (Fe3O4)
nanoparticles were prepared via
a chemical co-precipitation
method,17 followed by coating with a layer of silica through a
sol-gel method to ensure their stability and provide reactive sites
for further surface functionalization.18 Subsequent condensation
with 3-aminopropyltriethoxysilane (APTES) afforded aminopro-
pyl-modified Fe3O4 with an amino loading of 1.2 mmol gÀ1 as
determined by a quantitative ninhydrin test.19 After acylation of
the supported amino groups with chloroacetyl chloride, and substi-
tution of the chlorine atom with diisopropylamine, Fe3O4-DIPA was
obtained as a dark brown powder in 90% yield. The loading of the
diisopropylamino moiety estimated from elemental analysis was
fonic acid supported on hydroxyapatite-encapsulated-c-Fe2O3
nanocrystallites was shown to be an efficient magnetically separa-
ble catalyst for reductive amination of carbonyl compounds.16 De-
spite the unique features of MNPs, their applications as carriers for
common bases such as DIPEA have yet to be explored.
Herein, MNP supported N,N-diisopropylaminoacetamide, Fe3O4-
DIPA, was synthesized as a Hünig’s base analog. The application of
this recoverable magnetic base as a scavenger for removal of acid
0.96 mmol gÀ1
.
Figure 2. SEM images of Fe3O4 (a), Fe3O4-DIPA (b), and recycled (nine-times) Fe3O4-DIPA (c).

P. Rattanaburi et al. / Tetrahedron Letters 53 (2012) 2689–2693
2691
Table 1
The structures and yields of sulfonamides 1 from the sulfonation reactiona
O
S
O
S
Cl
NRR'
+
NHRR'
a-e
O
O
CH2Cl2
1a-e
Sulfonamide
Isolated yield (%)
Reported yield (%)Ref
Fe3O4
Fe3O4-DIPA
O
8722
9523
7524
S
1a
1b
1c
47
98
Ph
Ph
Ph
Ph
N
Ph
H
O
O
Figure 4. Fe3O4-DIPA in the reaction mixture (a) and its recovery using an external
magnet (b).
S
34
34
98
96
NHPh
O
O
FT-IR was used to further confirm the presence of the N,N-dii-
sopropylaminoacetamide moiety on the surface of the MNP. The
FT-IR spectra of the MNP before and after functionalization are de-
picted inFigure 1. All the samples exhibited a broad band at around
3500–3000 cmÀ1 attributed to adsorbed moisture. The strong
absorption at 580 cmÀ1 was characteristic of the Fe–O stretching
vibration. For the aminopropyl-modified Fe3O4 (Fig. 1b), the Si–
O–Si stretching of the silica layer appeared as a strong peak at
1100 cmÀ1, while the broad band at 3110 cmÀ1 corresponded to
the N–H stretching of the primary amine salt. For Fe3O4-DIPA
(Fig. 1c), the C@O stretch of the amide appeared as a weak band
at 1690 cmÀ1. The weak signals at 2950–2800 and 1239 cmÀ1 cor-
responded to C–H and C–N stretching of the isopropylamino group,
respectively.
S
N
H
O
O
S
1d
1e
56
49
93
97
9225
N
N
O
O
O
S
9525
Ph
O
a
All reactions were carried out with benzenesulfonyl chloride (0.113 mmol),
amine (0.124 mmol), and Fe3O4-DIPA (0.14 g, 0.136 mmol) or Fe3O4 (0.14 g) in
CH2Cl2 at 25 oC.
effectively for reuse by attaching to an external permanent magnet
(Fig. 4). N-benzylbenzenesulfonamide was afforded in quantitative
yield after treating the crude product with silica-supported dichlo-
rotriazine (Si-DCT) as an amine scavenger.19 Neither aqueous
work-up nor column chromatography was necessary.
The size and morphology of Fe3O4 along with those of Fe3O4-
DIPA were investigated by scanning electron microscopy (SEM).
According to Figure 2a, the Fe3O4 nanoparticles exhibited a cluster
of aggregated spherical particles with an average size below 30 nm
in diameter. SEM of the particles after functionalization (Fig. 2b)
revealed agglomerates of spherical particles with larger average
size (ꢀ50 nm) having rather uniform coating of the silane layers.
Thermogravimetric analysis (TGA) was used to study the ther-
mal stability of Fe3O4-DIPA relative to that of Fe3O4 nanoparticles.
The overlaid TGA curves of these materials are shown in Figure 3.
The weight losses below 150 °C in both samples are attributed to
the release of adsorbed water, while the weight loss of about 3%
between 200 and 470 °C for Fe3O4 is attributed to dehydration of
the surface –OH group (Fig. 3a). Thermal decomposition of
Fe3O4-DIPA occurred in two main stages at a broad temperature
range from 200 to 800 °C (Fig. 3b). The approximately 9% weight
loss from 200 to 500 °C is presumably due to decomposition of
the organic spacer group, while relatively slow weight loss at ele-
vated temperature can result from decomposition of the silica
shell. Therefore, Fe3O4-DIPA should function without decomposi-
tion at a temperature below 150 °C.
The applicability of Fe3O4-DIPA was further investigated in
sulfonation, acylation, and N-alkylation of five representative
amines, a–e (Fig. 5).20 All the reactions were performed on milligram
scale in dichloromethane using a 1.5 ml Eppendorf vial as the reac-
tion vessel. A small excess of the amine nucleophile (1.1 equiv)
was used relative to the limiting electrophile. It was found that
nearly all the reactions were complete within 30 min at 25 oC as
monitored by TLC. NMR analyses of the crude mixtures revealed that
without the need for any purification steps, the desired products
were already generated in good purity (>85%) and residual starting
amineswere the onlyobserved impurities. Again, pure sulfonamides
1, amides 2, and amines 3 were isolated after treatment of the crude
products with Si-DCT.21 The yields of these products relative to the
literature yields are listed in Tables 1–3.
The expected sulfonamide, amide, and amine products were ob-
tained in excellent yields. It is also worth mentioning that, in the
N-alkylation, no undesired over alkylated products were observed
according to NMR analysis of the crude product. In particular, a
remarkably improved yield of compound 3a can be accounted for
by the effectiveness of the supported base along with the scaveng-
ing process in reducing the possibility of product loss as was
encountered in the standard work-up protocol. Excess primary
amine was removed selectively from the desired secondary amine
product, presumably due to the steric hindrance of the latter
compound.
To study the efficiency of Fe3O4-DIPA, initially it was used as a
base for the sulfonation of benzylamine (0.124 mmol) with ben-
zenesulfonyl chloride (0.113 mmol). It was found that the reaction
proceeded smoothly within 30 min using only 1.2 mol equiv of
Fe3O4-DIPA. Meanwhile the supported base was collected
NHRR';
O
NH2
NH2
When these reactions were preformed under identical condi-
tions but in the presence of magnetite (Fe3O4) nanoparticles in-
stead of Fe3O4-DIPA, all the reactions were incomplete and yields
of less than 50% were obtained in most cases. These results suggest
that the support itself did not act as a base and further provided
NH2
N
N
H
H
a
b
c
d
e
Figure 5. The structures of the amines used in the representative reactions.

2692
P. Rattanaburi et al. / Tetrahedron Letters 53 (2012) 2689–2693
Table 2
Table 4
The structures and yields of amides 2 from the acylation reactiona
The yield of N-benzylbenzenesulfonamide with reused Fe3O4-DIPA
O
O
Run
1
2
3
4
5
6
7
8
9
Isolated yield (%)
97
96
96
95
95
95
94
87
83
Cl
NRR'
+
NHRR'
a-e
CH2Cl2
2a-e
recoveries. The SEM study of the recovered magnetic base revealed
no obvious changes in the particle size and morphology (Fig. 2c).
The result indicated that Fe3O4-DIPA was highly stable and could
be reused several times without significant loss of reactivity.
In summary, the developed magnetic nanoparticle supported
tertiary amine base (Fe3O4-DIPA) was shown to be highly effective
in place of the equivalent free base, thereby facilitating product
purification and simplifying reagent recovery by magnetic separa-
tion. Only a minimal excess (1.2 equiv) of the supported base was
necessary to drive these solution-phase reactions to completion as
opposed to the larger excess that is typically required on conven-
tional solid supports. When used in conjunction with the amine
scavenger, Si-DCT, the desired products were obtained in excellent
yields and purities without any aqueous work-up and/or column
chromatography. The developed protocol provides a simple, rapid,
yet effective method for milligram-scale synthesis which is poten-
tially useful for high-throughput solution-phase parallel synthesis,
especially when dealing with limited amounts of highly valuable
starting materials.
Amide
Isolated yield (%)
Reported yield (%)Ref
Fe3O4
Fe3O4-DIPA
O
2a
2b
2c
45
93
96
95
9226
9727
9028
Ph
N
H
Ph
O
O
49
55
Ph
Ph
NHPh
N
H
O
O
2d
2e
51
46
98
96
8829
Ph
Ph
N
N
O
9630
Acknowledgements
a
All reactions were carried out with benzoyl chloride (0.142 mmol), amine
(0.156 mmol), and Fe3O4-DIPA (0.18 g, 0.170 mmol) or Fe3O4 (0.18 g) in CH2Cl2 at
The Center of Excellence for Innovation in Chemistry (PERCH-CIC),
the National Research University Project under Thailand’s Office of
the Higher Education Commission, and the Research Professional
Development Project: Under the Science Achievement Scholarship
of Thailand (SAST) are gratefully acknowledged for financial support.
25 oC.
Table 3
The structures and yields of amines 3 from the N-alkylation reactiona
Br
NRR'
+
NHRR'
a-e
Supplementary data
CH2Cl2
3a-e
Supplementary data (experimental procedures and 1H NMR
spectra of sulfonamides 1, amides 2, and amines 3) associated with
this article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2012.03.063.
Amine
Isolated yield (%)
Reported yield (%)Ref
Fe3O4
Fe3O4-DIPA
3a
3b
3c
0
94
93
96
1531
8832
8333
Ph
N
H
Ph
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16
Ph
Ph
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