Direct reductive amination of aldehydes and ketones with 2,4-ionene-based borohydride exchange resin as a novel polymer-supported reducing agent

Article abstract of DOI:10.1080/00397910801997769

Direct reductive amination of aldehydes and ketones were accomplished efficiently using high-capacity, ionene-based, polymer-supported borohydride reagent in isopropyl alcohol at reflux under neutral conditions. The reagent is easily prepared by mixing aqueous solution of 2,4-ionene bromide with an alkaline solution of sodium borohydride at room temperature. The generality of reaction was established using both aliphatic and aromatic aldehydes, ketones, and amines. Copyright Taylor & Francis Group, LLC.

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Direct Reductive Amination of
Aldehydes and Ketones with
2,4-Ionene-Based Borohydride
Exchange Resin as a Novel
Polymer-Supported Reducing
Agent
Mahmood Tajbakhsh a , Moslem Mansour Lakouraj a
Majid Shabani Mahalli a
&
a Department of Chemistry, Faculty of Basic Science,
Mazandaran University, Babolsar, Iran
Published online: 12 Jun 2008.
To cite this article: Mahmood Tajbakhsh , Moslem Mansour Lakouraj & Majid Shabani
Mahalli (2008) Direct Reductive Amination of Aldehydes and Ketones with 2,4-Ionene-
Based Borohydride Exchange Resin as a Novel Polymer-Supported Reducing Agent,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 38:12, 1976-1983, DOI: 10.1080/00397910801997769
To link to this article: http://dx.doi.org/10.1080/00397910801997769
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Synthetic Communications1, 38: 1976–1983, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801997769
Direct Reductive Amination of Aldehydes and
Ketones with 2,4-Ionene-Based Borohydride
Exchange Resin as a Novel Polymer-Supported
Reducing Agent
Mahmood Tajbakhsh, Moslem Mansour Lakouraj, and
Majid Shabani Mahalli
Department of Chemistry, Faculty of Basic Science, Mazandaran University,
Babolsar, Iran
Abstract: Direct reductive amination of aldehydes and ketones were
accomplished efficiently using high-capacity, ionene-based, polymer-supported
borohydride reagent in isopropyl alcohol at reflux under neutral conditions.
The reagent is easily prepared by mixing aqueous solution of 2,4-ionene bromide
with an alkaline solution of sodium borohydride at room temperature. The gen-
erality of reaction was established using both aliphatic and aromatic aldehydes,
ketones, and amines.
Keywords: 2,4-ionene; Aldehydes; Borohydride exchange resin; Ketones;
Reductive amination
The preparation of amines from aldehydes and ketones is an important
method in organic synthesis because of their versatile utility as intermedi-
ates for synthesis of pharmaceuticals[1] and agrochemicals.[2] For this
transformation, the reductive amination allows the conversion of carbonyl
functionality to an amine by directly treating a mixture of the carbonyl
compound and the amine with suitable reducing agent in a single operation
without preformation of an intermediate imine or iminium salt (Scheme 1).
A variety of reagents, such as NaBH3CN,[3] NaBH(OAc)3,[4]
Ti(OiPr)4–NaBH4,[5] NaBH4–wet clay–microwave,[6] ZnBH4–ZnCl2,[7]
Received in the U.K. May 3 2007
Address correspondence to Mahmood Tajbakhsh, Department of Chemistry,
Faculty of Basic Science, Mazandaran University, Babolsar 47416, Iran. E-mail:
Tajbaksh@umz.ac.ir
1976

Reductive Amination of Aldehydes and ketones
1977
Scheme 1. Reductive amination of aldehydes and ketones.
ZnBH4–SiO2,[8] pyridine–borane,[9] picoline–borane,[10] decaborane,[11]
Et3SiH–CF3CO2H,[12] PhSiH3–Bu2SnCl2,[13] n-Bu3SnH–SiO2,[14] zinc bor-
ohydride N-methyl piperidine (ZBNNMP),[15] Zr(BH4)2(Cl)2(dabco)2,[16]
TiCl(OiPr)3-NaBH(OAc)3,[17] NaBH4-H3PW12O40,[18] and NaBH4 in
micellar media[19] have been reported for this conversion. However, most
of these reagents may have one drawback or another. For example, cyano-
borohydride and tin hydride are highly toxic and generate toxic by-
products such as HCN, NaCN, or organotin compounds[20] upon workup
and may result in the contamination of the product with the toxic com-
pounds. Other hydrides such as sodium triacetoxyborohydride also involve
the use of corrosive acetic acid. Consequently, there is a need for the devel-
opment of a manipulatively easy and an environmentally friendly method
for the reduction of in situ generated Schiff’s bases. On the other hand,
polymer-supported borohydride reagents have received attention in recent
years,[21,22] as they offer several advantages over the other modified boro-
hydrides. The primary advantage is the convenience of use of these materi-
als and the minimal introduction of ionic species or organic by-product
into treated bulk media. Simplified workup of reaction products is another
advantage. One significant limitation of current polymeric reagents
remains their relatively low loading (0.5–2mmol=g) for most commercial
samples, and practically an excess amount is needed to complete the reac-
tion. For example, the classical ion exchange resins prepared from chloro-
methylated styrene and trimethylamine suffer from low loading because of
the weight of the polymer backbone, and the higher loading is restricted
because of Lewis acid–catalyzed cross-linking of chloromethyl groups
within the resin. Furthermore, the molar activity can be decreased con-
siderably during storage because of the chemical lability of the ammonium
salt, which releases the trimethylamine group. Another general problem of
polystyrene-based resins is their chemical lability under oxidation and
strong Lewis acidic conditions.[23] However, high-loading resins would
increase the efficiency and the atom economy[24,25] of the polymeric
reagents considerably and also the concentration of the reactant in poly-
mer would be enhanced, thus reducing the amount of polymer backbone

1978
M. Tajbakhsh et al.
employed. Realizing this, linear poly-2,4-ionene bromide was studied as a
high-capacity polymer-supported borohydride exchange resin (BER)
(Scheme 2).
This report describes the results of utilizing poly-2,4-ionene boro-
hydride (IBER) as a new reducing reagent for reductive amination of a
variety of carbonyl compounds under neutral conditions.
IBER (II) is a stable nonhygroscopic white powder that is not soluble
in most organic solvents. It is prepared quantitatively from aqueous sol-
ution of the corresponding ionene bromide (I)[26] and sodium borohydride
alkali solution at room temperature (Scheme 2). The borohydride capacity
of the IBER was determined by titration to be 6 mmol=g of polymer.[27]
Reductive amination was investigated by treatment of an amine with
an aldehyde followed by addition of IBER at reflux condition in neutral
media (Table 1). The pH of the media was adjusted to neutrality by
addition of 10% aqueous solution of HCl in methanol. A small excess
of resin sufficed to furnish clean products in good to excellent yields.
As indicated in Table 1, aromatic aldehydes having nitro and cyano
groups underwent chemoselective reductive amination to give the corre-
sponding N-phenyl amines in good yields without reduction of other
functional groups (entries 13 and 14). In the case of a,b-unsaturated alde-
hydes, such as cinnamaldehyde, reductive amination was successfully
achieved in excellent yield without reduction of the carbon–carbon dou-
ble bond (entry 24). Similarly, weakly acidic anilines such as 4-nitro and
4-chloroaniline react with aromatic aldehydes in the presence of IBER
to produce their corresponding amines (entries 2 and 3). However, to
examine a greater range of amines to better illustrate the scope and
limitation of the method, we investigated the reaction with allylamine,
benzylamine, propylamine, piperidine, and pyrrolidine using benzalde-
hyde as a representative aldehyde (entries 2–11) and cyclohexanone as
a representative ketone (16–22).
Another interesting feature of this method is that IBER could be
regenerated to its initial activity. For this purpose, the collected spent
polymer was neutralized with HCl (10%) and then treated with fresh
alkaline solution of NaBH4 (Scheme 3).
Scheme 2. Preparation of poly-2,4-ionene borohydride.

1979

1980
M. Tajbakhsh et al.
Scheme 3. Regeneration of poly-2,4-ionene borohydride.
In conclusion, IBER, a stable and versatile benchtop reducing agent,
is easily prepared in almost quantitative yield from commercially avail-
able starting materials. It is so thermally stable and safe that it could
be stored for months without appreciable loss of its reducing ability.
The preparation of the reagent is easy and quite reproducible by different
hands. The high load, low cost, nontoxicity, mildness, easy reaction
workup, efficiency, high reaction rates, and high yields make this new
stabilized polymer-supported tetraborohydrate a useful addition to the
category of reagent used for the reductive preparation of amines.
EXPERIMENTAL
Materials were purchased from Fluka and Merck companies. The
reaction were monitored by thin-layer chromatography (TLC) using
silica-gel plates, and the products were purified by flash column chroma-
tography on silica gel (Merck; 230–400 mesh) and identified by compari-
son of their spectra and physical data with those of authentic samples. 1H
NMR spectra were measured at 300 MHz on a Jeol spectrometer with tet-
ramethylsilane (Me4Si) as an internal reference and CDCl3 as the solvent.
IR spectra were recorded on Pye-unicam SP 1100 spectrophotometer.
Elemental analysis was performed on a Leco 250 instrument.
Preparation of Poly-2,4-ionene Borohydride (IBER)
An alkali solution of sodium borohydride was prepared from NaBH4
(1.51 g, 0.04 mol) in sodium hydroxide solution (5 M, 10 mL). Then, an
aqueous solution of poly 2,4-ionene bromide[26] (molecular weight
1.25 Â 104, 3.32 g in 10 mL of H2O) was added dropwise to the solution
at room temperature and stirred for 2 h. The resulting white solid product
was filtered, washed with ethanol–ether (1:1) twice, and dried in a

Reductive Amination of Aldehydes and ketones
1981
vacuum desiccator over calcium chloride. The content of active reducing
-
agent BH4 was determined by the titrimetric method.[27]
Typical Procedure for Reductive Amination of Aldehydes
and Ketones with IBER
The synthesis of N-phenylbenzylamine is representative of the general
procedure employed. To a stirred solution of benzaldehyde (0.053 g,
0.5 mmol) and aniline (0.056 g, 0.6 mmol) in i-PrOH (5 mL) under reflux,
the reducing agent (0.167 g, 1 mmol) was added and the pH was adjusted
to pH 7 by the addition of 10% aqueous solution of HCl in MeOH. Stir-
ring and reflux were maintained during a period of 1.5 h. The reactions
were monitored by TLC using mixtures of ethyl acetate=n-hexane as
eluent. On completion of the reaction, the spent polymer was removed
by filtration. The solvent was evaporated and the resulting crude mate-
rial was purified by column chromatography on silica gel to afford pure
N-phenylbenzylamine.
ACKNOWLEDGMENT
Financial support of this work from the Research Council of Mazan-
daran University gratefully acknowledged.
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