Polymer-supported triacetoxyborohydride: A novel reagent of choice for reductive amination

Article abstract of DOI:10.1016/S0040-4039(03)01167-5

A novel polymer-supported triacetoxyborohydride reagent for reductive amination of aldehydes and ketones is reported. The bound reagent was found to be shelf-stable and provided broad scope and reactivity in reductive amination reactions under mild reacti

Full text of DOI:10.1016/S0040-4039(03)01167-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4957–4960
Polymer-supported triacetoxyborohydride: a novel reagent of
choice for reductive amination
Sukanta Bhattacharyya,* Sunil Rana, Owen W. Gooding and Jeff Labadie
Argonaut Technologies, 1101 Chess Drive, Foster City, CA 94404, USA
Received 19 April 2003; accepted 12 May 2003
Abstract—A novel polymer-supported triacetoxyborohydride reagent for reductive amination of aldehydes and ketones is
reported. The bound reagent was found to be shelf-stable and provided broad scope and reactivity in reductive amination
reactions under mild reaction conditions. Streamlined protocols for its application in reductive amination reactions using both
primary and secondary amines are described. © 2003 Elsevier Science Ltd. All rights reserved.
The use of polymer-supported reagents and scavengers1
is a powerful tool for integrated organic synthesis and
purification. By using bound reagents and scavengers
the reaction by-products and excess starting materials
can be selectively removed from the crude reaction
mixture by simple filtration of resin. Immobilized
reagents on polymer supports are particularly useful in
high throughput parallel synthesis due to their well-
known attributes for dispensing and removal from reac-
tion mixtures. Moreover, polymer-supported reagents
can provide unique advantages relative to their soluble
counterparts including selectivity, isolable reactive
intermediates and the ability to simultaneously use
incompatible reagents, or perform multiple transforma-
tions in a single flask. In addition, they are adaptable to
automated parallel synthesis and continuous flow
reactors.2
emerged as one of the most commonly employed
reagents.6 This reagent has gained preference relative to
other reducing agents due to mild reaction conditions
that are compatible with a variety of functional groups,
and a broad scope of reactivity. However, sodium
triacetoxyborohydride is moisture-sensitive and has
poor solubility in most of the commonly used organic
solvents. The reagent is therefore dispensed as a solid
or slurry, thereby limiting its use in automated plat-
forms. Following a reaction, product isolation requires
an aqueous quench followed by liquid–liquid extraction
and column chromatography further limiting the
throughput in parallel synthesis.
In the context of our program on the development of
polymer-supported reagents and scavengers for expe-
dited organic synthesis, we envisioned a polymer-bound
triacetoxyborohydride. Polymer-bound borohydride
and cyanoborohydride reagents are known in the litera-
ture,7 however, triacetoxyborohydride reagent on poly-
mer support is unknown. Nonetheless, the scope and
reactivity of bound borohydride and cyanoborohydride
reagents in reductive amination reactions are limited in
comparison to sodium triacetoxyborohydride. For
example, bound cyanoborohydride requires moderately
strong acidic reaction conditions7,8 that are incompat-
ible with acid-labile functional groups. The use of poly-
mer-bound borohydride in reductive amination
reactions is restricted as it lacks chemoselectivity. The
reagent readily reduces carbonyl compounds along with
imines and, therefore, is only suitable for reactions with
preformed imines.9 We describe here the first synthesis
of an immobilized triacetoxyborohydride reagent10 and
demonstrate that it is a powerful reducing system for
reductive amination reactions. The bound reagent
Amines and their carboxamide derivatives comprise the
most abundant structural moieties present in the com-
prehensive medicinal chemistry database.3 The reduc-
tive amination of carbonyl compounds provides an
expedient access to structurally diverse amines and has
wide applications in synthetic organic chemistry.4,5 The
sequence proceeds through the formation of an imine
or iminium intermediate upon reaction of a carbonyl
compound with ammonia, primary amine or secondary
amine followed by in situ reduction to an amine of
higher order. A variety of borohydride-based reducing
systems5 have been developed for this transformation.
Among these, sodium triacetoxyborohydride has
* Corresponding author. Tel.: +650-655-4229; fax: +650-655-4329;
e-mail: sbhattacharyya@argotech.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01167-5

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S. Bhattacharyya et al. / Tetrahedron Letters 44 (2003) 4957–4960
offers broad scope and reactivity under mild reaction
conditions, combined with the well-known attributes of
triacetoxyborohydride, no acetic acid was required
(Scheme 2). THF was found to be preferred to
dichloroethane (DCE) due to the incompatibility of
reactive amines with chlorinated solvents. Polar aprotic
solvents, e.g. N,N-dimethylformamide (DMF) or N-
methylpyrrolidinone (NMP), were effective solvents for
substrates with low solubility in THF.
a
polymer-supported reagent for handling and
purification.
Polymer-bound borohydride and cyanoborohydride
resins have been prepared7 by straightforward anion
exchange reactions on quaternary ammonium chloride
resins using aqueous solutions of the corresponding
borohydrides. However, attempts to immobilize triace-
toxyborohydride by anion exchange reaction on resin
bound tetraalkylammonium chloride failed, as sodium
triacetoxyborohydride is sparingly soluble in, or incom-
patible with, solvents used for ion exchange.
For synthesis of secondary amines, the starting primary
amine was used in 20% excess in order to control
selectivity toward monoalkylation. After the reaction
was complete a bound aldehyde, PS-Benzaldehyde,12
was added to the reaction mixture to selectively scav-
enge the excess primary amine. Products were then
isolated in pure form by simple filtration and evapora-
tion of solvent. The results are summarized in Table 1.
The product amines were characterized by GC and
NMR analysis.13 Acid sensitive functional groups were
tolerated, as exemplified by successful reductive amina-
tion of 1,4-cyclohexanedione mono-ethylene ketal
(entries 2, 3 and 8, Table 1). Acetophenone underwent
reductive amination consistent with sodium triacetoxy-
borohydride (entry 4, Table 1). Reductive amination
using secondary amines was carried out with carbonyl
compounds as the limiting reagent.14 Upon completion
of the reaction a bound isocyanate, PS-Isocyanate,12
was added to the reaction mixture to selectively scav-
enge excess secondary amine. Cyclic and acyclic sec-
ondary amines were effective substrates (entries 8–10,
Table 1). These reactions may also be carried out with
the secondary amine as the limiting reagent to drive the
reaction to completion. In these cases, the product
amines were purified from non-basic impurities by
‘catch and release’ using a polymer-bound sulfonic acid,
MP-TsOH.12
In an alternative approach, the polymer-bound triacet-
oxyborohydride reagent was conveniently synthesized
in one-step from MP-Borohydride11 (Scheme 1). Treat-
ment of MP-Borohydride (capacity, 3 mmol/g) with 3
equiv. of glacial acetic acid in anhydrous THF afforded
the supported triacetoxyborohydride in nearly quantita-
tive yield, as revealed by the mass increase of the
isolated resin. The active hydride content of the result-
ing resin was determined by measuring the volume of
hydrogen gas evolved upon treatment of a resin sample
with aqueous hydrochloric acid. The capacity was
found to be 2.0 mmol/g or 99% of the theoretical value,
indicating quantitative formation of the triacetoxyboro-
hydride. The isolated resin typically contained about
10% (w/w) THF as calculated from the 1H NMR
spectrum of a CDCl3 extract. In the process of synthesis
and isolation of the triacetoxyborohydride resin, we
discovered that the residual THF was critical to retain
the activity of the resin. When all THF was removed by
vacuum drying at the end of the synthesis, as normally
done in resin isolation, the dried resins showed little or
no activity within a few days. This is an unusual finding
since
a
similar effect with sodium or tetra-
Reductive amination using hydrochloride salts of
amino esters was carried out using DMF in the pres-
ence of 3.5 equiv. of MP-Triacetoxyborohydride with
amine as the limiting reagent (entries 5–7, Table 1).15
The additional equivalent of resin was used to neutral-
ize the HCl present in the form of amine hydrochloride.
Notably, overalkylation was not observed even in the
presence of excess carbonyl compound. DMF and
NMP were equally effective. Since carbonyl compounds
were used in excess, the products were purified by
‘catch and release’ using MP-TsOH.12 This method
effected convenient DMF separation from the product
by elution with MeOH prior to product release with
ammonia/methanol.
alkylammonium triacetoxyborohydride is unknown.
The THF imbibed reducing polymer remained stable
towards storage without any loss of activity and
behaved like free-flowing dry beads in their handling
rather than like a wet solid. This novel reducing system,
further referred to as MP-Triacetoxyborohydride,
proved to be a highly effective reagent for reductive
amination reactions.
The scope and reactivity of MP-Triacetoxyborohydride
have been evaluated for the synthesis of secondary and
tertiary amines (Table 1). Typical conditions for reduc-
tive amination required 2.5 equiv. of MP-Triacetoxy-
borohydride relative to the limiting reagent. The
reactions proceeded overnight at room temperature in
tetrahydrofuran (THF) and unlike the case of sodium
Scheme 2. Reductive amination using primary and secondary
amines. Reagents: (a) MP-BH(OAc)3, 2.5 equiv., THF; (b)
PS-Benzaldehyde (R2=H) or PS-NCO (R2=alkyl) or MP-
TsOH.
Scheme 1. Synthesis of MP-Triacetoxyborohydride.

S. Bhattacharyya et al. / Tetrahedron Letters 44 (2003) 4957–4960
4959
Table 1. Examples of reductive amination reactions using MP-Triacetoxyborohydride
In summary, we have described the first synthesis of
polymer-bound triacetoxyborohydride. The novel
reagent system was isolated with a high capacity of 2
mmol/g and found to be shelf-stable in the presence of
residual THF. MP-Triacetoxyborohydride displayed
wide scope in reductive amination chemistry along with
the benefits of integrated synthesis and purification
associated with immobilized reagents. Further studies
expanding the scope of this reagent are underway and
will be reported shortly.

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S. Bhattacharyya et al. / Tetrahedron Letters 44 (2003) 4957–4960
Meeting of the American Chemical Society, Chicago, IL;
References
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11. MP-Borohydride,
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13. Reductive amination using primary amine (entry 2, Table
1): A THF solution of N-(3-aminopropyl)morpholine
(1.2 mL, 0.6 mmol, 0.5 M) was added to a THF solution
of 1,4-cyclohexanedione mono-ethylene ketal (1 mL, 0.5
mmol, 0.5 M). MP-Triacetoxyborohydride (2 mmol/g,
0.625 g, 1.25 mmol) was then added and the mixture was
agitated for 16 h at room temperature. After which
PS-Benzaldehyde12 (0.42 g, 0.5 mmol) and THF (3 mL)
were added and the mixture was further agitated for a
period of 6 h. The solution was filtered and the resin was
washed with THF. The combined solution was concen-
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14. Reductive amination using secondary amines (entry 8,
Table 1): A THF solution of N-methylpiperazine (1.2
mL, 0.6 mmol, 0.5 M) was added to a THF solution of
1,4-cyclohexanedione mono-ethylene ketal (1 mL, 0.5
mmol, 0.5 M). MP-Triacetoxyborohydride (2 mmol/g,
0.625 g, 1.25 mmol) was then added and the mixture was
agitated for 16 h at room temperature. After which
PS-Isocyanate12 (0.4 g, 0.5 mmol) and THF (2 mL) were
added and the mixture was further agitated for a period
of 6 h. The solution was filtered and the resin was washed
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15. Reductive amination of amine hydrochloride (entry 7,
Table 1): A DMF solution of HCl-Tyr(OBn)-OMe (2
mL, 0.5 mmol, 0.25 M) was added to a DMF solution of
cyclohexylcarboxaldehyde (1.2 mL, 0.6 mmol, 0.5 M).
MP-Triacetoxyborohydride (2 mmol/g, 0.875 g, 1.75
mmol) was then added and the mixture was agitated for
16 h at room temperature. The resin was filtered and
washed with DMF. The combined filtrate was agitated
with MP-TsOH12 (1 g, 1.5 mmol) for 45 min. The MP-
TsOH resin was filtered and washed with MeOH (4×8
mL) to remove non-basic impurities. The amine product
was released from MP-TsOH by washing with 2 M
NH3/MeOH, and MeOH (2×8 mL). The combined solu-
tion was concentrated to afford the secondary amine
product in 74% yield and 98% purity. The secondary
amine was characterized by GC and 1H NMR (300 MHz,
CDCl3).