Sulfated polyborate: A dual catalyst for the reductive amination of aldehydes and ketones by NaBH4

Article abstract of DOI:10.1016/j.tetlet.2021.153143

An efficient, quick, and environment-friendly one-pot reductive amination of aldehydes or ketones was developed. In ethanol at 70 °C, a imination catalyzed by sulfated polyborate and further reduced by sodium borohydride yields various amines. The present method has many significant benefits, including a shorter reaction time, excellent yields, and a hassle-free, straightforward experimental process. The reaction has a wide range of applications due to its flexibility, including secondary amine for reductive amination.

Full text of DOI:10.1016/j.tetlet.2021.153143

Tetrahedron Letters xxx (xxxx) xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Sulfated polyborate: A dual catalyst for the reductive amination of
aldehydes and ketones by NaBH4
⇑
Prerna Ganwir, Ganesh Chaturbhuj
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai 400019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, quick, and environment-friendly one-pot reductive amination of aldehydes or ketones was
developed. In ethanol at 70 °C, a imination catalyzed by sulfated polyborate and further reduced by
sodium borohydride yields various amines. The present method has many significant benefits, including
a shorter reaction time, excellent yields, and a hassle-free, straightforward experimental process. The
reaction has a wide range of applications due to its flexibility, including secondary amine for reductive
amination.
Received 20 February 2021
Revised 24 April 2021
Accepted 28 April 2021
Available online xxxx
Keywords:
Ó 2021 Elsevier Ltd. All rights reserved.
Reductive amination
Sulfated polyborate
NABH4
One-pot
Amines and analogues constitute an important class of organic
compounds with versatile utility due to their role as intermediate
for the synthesis of pharmaceuticals [1] and agrochemicals.[2]
Amines as intermediate compounds have been identified as having
the capacity to treat various types of diseases like depression, [3]
arrhythmias, [4], and haemorrhage. [5] The primary and secondary
amine in drugs include oxprenolol hydrochloride, [6] fluoxetine
hydrochloride, [7] etamsylate, [8] ranitidine. [9] Various methods
have been developed for direct reduction amination. Borohydride
reagents used are NaBH3CN, [10] LiBH3CN. [11] However, these
have the disadvantage of producing cyanide ions, which may lead
to toxicity by leaching during the workup. Their variants developed
are NaBH(OAc)3, [12] NaBH3CN–ZnCl2, [13] NaBH3CN–Ti(OiPr)4,
[14] (n-Bu)4NBH3CN, [15] NaBH3CN–Mg(ClO4)2. [16] Other borohy-
drides include ZnBH4–ZnCl2, [17] ZnBH4, [18] ZnBH4–SiO2, [19]
nickel borohydride may not reduce imines chemoselectively in
the presence of other functional groups like ketones, nitro, ester,
carboxylic acid. [20–22] The most efficient borohydride reagent
NaBH4 [23] is relatively inexpensive and efficient. Few reagent sys-
tems have been developed using NaBH4 include NaBH4–NiCl2, [24]
Ti(OiPr)4–NaBH4, [25] NaBH4–H2SO4,[26] NaBH4–wet clay-micro-
wave, [27] NaBH4–ZrCl4, [28] NaBH4–ZnCl2, [29] but the use of
metal or highly acidic condition are the major limitation of possi-
ble contamination and byproducts. Catalytic hydrogenation also
have been reported PhSiH3–Bu2SnCl2, [30] PhMe2SiH(C6F6)3, [31]
(n-Bu)3SnH–DMF, [32] polymethyl-hydro siloxane (PMHS)–Ti
(OiPr)4, [33] PMHS–ZnCl2, [34] PMHS–BuSn(OCOR)3, [35] Et3SiH–
CF3CO2H, [36] (n-Bu)2-SnClH, [37] tin hydride may produce toxic
by-products. Other methods include decaborane, [38] diborane–
MeOH, [39] picoline–borane, [40] pyridine–borane. [41] Inspired
by our previous work on applying sulfated polyborate for various
name reactions such as Kindler reaction, [42] Willgerodt-kindler,
[43] Quinoxaline, [44] Strecker reaction, [45] Betti reaction, [46]
Kabachnik Fields, [47] which primarily involved imination of vari-
ous aldehydes and ketones followed by addition of a nucleophile.
The literature searches revealed that NaBH4 is a cheap and safe
reducing agent to use. The sulfated polyborate was synthesized
from readily available boric acid as a cost-effective and non-toxic
starting material, then characterized and used in various organic
transformations. [42–58] As a result, in search of a more broad, fea-
sible, safe, effective, and high-yielding direct reductive amination
protocol, we propose sulfated polyborate as a dual catalyst for
the imination of aldehyde/ketones with amines and as a NaBH4
activator in the greener solvent ethanol.
The initial experiment was planned to investigate the suitability
of sulfated polyborate as a catalyst for the synthesis of N-benzy-
laniline by the reaction of an equimolar mixture of benzaldehyde,
aniline, and 2 equivalents of NaBH4. In the absence of a catalyst, no
reductive amination was observed after 12 h at 70 °C (Table 1,
entry 1), while complete reductive amination was observed in a
shorter reaction period with sulfated polyborate. The results from
the model reaction laid the foundation to evaluate the effect of the
catalyst loading on the time and yield of the reaction (Table 1,
entries 1–7)
⇑
Corresponding author.
E-mail addresses: gu.chaturbhuj@ictmumbai.edu.in, gu.chaturbhuj@gmail.com
(G. Chaturbhuj).
https://doi.org/10.1016/j.tetlet.2021.153143
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.
Please cite this article as: P. Ganwir and G. Chaturbhuj, Sulfated polyborate: A dual catalyst for the reductive amination of aldehydes and ketones by NaBH4,
Tetrahedron Letters, https://doi.org/10.1016/j.tetlet.2021.153143

P. Ganwir and G. Chaturbhuj
Tetrahedron Letters xxx (xxxx) xxx
The reaction takes 60 min in the presence of the catalyst
(Table 1, entry 2). The increased catalyst loading increased the pro-
duct yield with reduced reaction time (Table 1, entries 3–5). The
catalyst loading greater than 5 wt% was ineffective (Table 1, entry
3); hence, a 5 wt% catalyst loading was chosen for further
investigation.
The temperature has a vital role in reductive amination. The
temperature effect was examined at ambient, 50, and 70 °C in
ethanol. The reaction does proceed at room temperature in the
presence of a catalyst with a lower yield while increasing temper-
ature to 70 °C resulted in increased product yield in shorter reac-
tion time (Table 1, entries 3, 6, and 7). Following that, solvent
optimization experiments in polar and nonpolar solvents were car-
ried out. In polar and nonpolar solvents, including ethanol, metha-
nol, toluene, and DMF, the reaction proceeds smoothly. While both
solvent groups resulted in the successful formation of target pro-
duct, the reaction time was significantly longer in nonpolar sol-
vents Table 2. As a result, ethanol was the solvent of choice due
to cost-effectiveness and environment-friendliness. The current
sulfated polyborate-catalyzed protocol for the synthesis of N-ben-
zylaniline compared with other published acid-catalyzed methods
(Table 3). The present protocol outperforms the reaction men-
tioned above conditions and yields, as evidenced by the results.
Some methods although produce similar results, however used
highly corrosive chemicals such as H2SO4 (Table 3, entry 7)
The optimized reaction condition was applied to various aro-
matic, aliphatic, alicyclic, and heterocyclic aldehydes/ketones with
aromatic, aliphatic, alicyclic as well as heterocyclic amines to
determine the substrate scope and applicability (Table 4). [67]
Various aromatic aldehydes with electron-withdrawing and
electron-donating substituents, including
were investigated. Except for the o-hydroxy and p-methoxyben-
zaldehyde (Table 4, entries and 4), all aldehyde variants
a,b-unsaturated ones,
3
responded well, resulting in higher product yields in less time
(Table 4, entries 1,2,5–8). Various aromatic amines with electron-
withdrawing and electron-donating substituents, benzylamine, ali-
phatic amines, heterocyclic amines, and secondary amines were
also attempted. All aromatic amines reacted well resulted in excel-
lent yields (Table 4, entries 9–11). All aliphatic, alicyclic, hetero-
cyclic, and secondary amines reacted well (Table 4, entries 12–
16) except butylamine, which took a longer reaction time (Table 4,
entry 13). It is worth noting that the procedure equally effective for
the reductive amination of secondary amine with benzaldehyde
catalyzed by sulfated polyborate. Our previous work demonstrated
the formation of the iminium ion in secondary amine. [42–46]
The protocol yielded modest yields in a relatively long reaction
time for acetophenone (Table 4, entry 18) and alicyclic and alipha-
tic ketones (Table 4 entries 19 to 21).
Table 1
Effect of catalyst loading and temperature for the synthesis of N-benzylanilinea.
Entry
Catalyst
(wt %)
Temperature
(°C)
Time
Yieldb
(%)
1
2
3
4
5
6
7
–
2.5
5
7.5
10
5
70
70
70
70
70
r.t.
50
120 min.
60 min.
5 min.
5 min.
5 min.
12 h
NPc
20
96
95
95
40
70
5
12 h
Proposed mechanism
a
Reaction condition: benzaldehyde (1 mmol), aniline (1 mmol), NaBH4 (2 mmol),
EtOH,
b
Isolated yield, cNo desired product but alcohol and aniline observed.
Scheme 1 depicts a plausible mechanism for the sulfated polyb-
orate-catalyzed reductive amination reaction. Sulfated polyborate
may have activated aldehyde/ketone (1) by protonating the oxygen
atom in response to the nucleophilic attack of amine (2), resulting
in the formation of imine. Additionally, sulfated polyborate proto-
nates imine and activates borohydride for the nucleophilic attack,
resulting in the formation of the desired amine (3). Sulfated polyb-
orate recycles for further catalysis.
Table 2
Effect of the solvents for the synthesis of N-benzylanilinea.
Entry
Solvent
Temperature
Time
Yieldb (%)
00
(°C)
(min.)
1
Solvent-
freec
70
240
2
3
4
6
7
EtOH
MeOH
THF
Toluene
DMF
70
70
70
70
70
5
7
30
30
30
96
80
Conclusion
NRc
55
60
We have shown that sulfated polyborate is a dual catalyst that
facilitates quick imination and acts as an efficient NaBH4 activator
in this study. Secondary amines were produced successfully by
reductive amination of various aldehydes/ketones with a variety
of primary and secondary amines, including aliphatic and
a
Reaction condition: benzaldehyde (1 mmol), aniline (1 mmol), NaBH4 (2 mmol),
and sulfated polyborate (5 wt%),
b
c
Isolated yield, No reaction.
Table 3
Comparison of the efficiency of sulfated polyborate with literature reported acid catalysts for the synthesis of N-benzylanilinea.
Entry
Catalyst
Hydride source
Reaction condition
Time
Yield (%)
Ref.
1
2
3
5
6
7
8
9
Sulfated polyborate
CoCl2-MeOH
Borane- Pyridine
H2SO4
Silica gel
Silica gel Supported H2SO4
CHCl/ Urea
Acetic acid
Carbon- based solid acid
H3BO3
NaBH4
NaBH4
Borane
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
EtOH/ 70 °C
THF/ À10 °C
AcOH/ r.t.
THF/r.t.
THF
THF
MeOH
Neat/r.t.
H2O/r.t.
Neat, Grinding /r.t.
Neat/ACN
5 min.
3 h
2 h
2 h
2 h
7 min.
45 min.
1.5 h
25 min.
10 min.
10 min.
96
80
93
60
51
95
92
60
94
94
95
This work
[57]
[59]
[60]
[60]
[60]
[61]
[62]
[63]
10
11
12
[64]
[65]
B(OSO3H)3/SiO2(SBSA)
a
Reaction condition: benzaldehyde (1 mmol), aniline (1 mmol), and NaBH4 (2 mmol).
2

P. Ganwir and G. Chaturbhuj
Tetrahedron Letters xxx (xxxx) xxx
Table 4
Sulfated polyborate catalyzed synthesis of aminesa, [66]
Entry
1
Aldehyde/Ketone, 1
Amines, 2
Products
Time (min.)
Yieldb(%)
96
3a
5
2
3
4
5
6
7
8
9
3b
3c
3d
3e
3f
4
97
91
84
95
95
92
96
95
15
4
7
10
5
3g
3h
3i
HCHO
10
10
10
11
3j
15
15
95
97
3k
12
13
14
3l
5
99
91
92
3m
3n
60
15
15
16
3o
3p
15
10
95
97
17
18
3q
3r
15
30
75c
95
19
20
3s
3t
45
60
82
85
21
3u
60
80
a
c
Reaction condition: aldehyde/ketone (1 mmol), amine (1 mmol), NaBH4 (2 mmol) and sulfated polyborate (5 wt%) in ethanol at 70 °C, bIsolated yield,
Mixture of benzyl alcohol and product separated by dil. HCl wash as Rf values were too close to be separated by column chromatography.
3

P. Ganwir and G. Chaturbhuj
Tetrahedron Letters xxx (xxxx) xxx
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Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
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Acknowledgment
The authors are thankful to the Department of Science and
Technology WOS-A scheme for their financial support.
Appendix A. Supplementary data
Full experimental details and 1H NMR spectra can be found in
the Electronic Supplementary Information section of this article’s
webpage. Supplementary data to this article can be found online
at https://doi.org/10.1016/j.tetlet.2021.153143.
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[66] General procedure for the synthesis of amines: To an equimolar mixture of
benzaldehyde (0.5 g, 4.7 mmol, 1 equiv.), aniline (0.44 g, 4.7 mmol, 1 equiv.), in
5 mL ethanol was added sulfated polyborate (5wt%, 0.025 g) and stirred in an
oil bath preheated to 70 °C after 1 minute/TLC monitored for imines, added
NaBH4 (0.36 g, 9.4 mmol, 2 equiv.) and completion of the reaction monitored
by thin-layer chromatography. Upon completion of the reaction, cooled to
room temperature and quenched in water/NaHCO3, and the product extracted
by ethyl acetate; The organic layer was dried over sodium sulfate and
evaporated under vacuum to get pure product. The products obtained were
known compounds identified by 1H NMR spectroscopy, and the analytical
data compared with the literature values.
4