Sulfated polyborate catalyzed Kabachnik-Fields reaction: An efficient and eco-friendly protocol for synthesis of α-amino phosphonates

Article abstract of DOI:10.1016/j.tetlet.2017.01.022

An efficient, and environmentally benign protocol for a three-component Kabachnik-Fields reaction of aldehydes, amines, and diethyl phosphite catalyzed by sulfated polyborate has been described to afford α-amino phosphonates under solvent-free reaction conditions. The major advantages of the present method are high yields, short reaction time, simple work-up procedure, inexpensive, eco-friendly and reusable catalyst and solvent-free reaction conditions and tolerance towards various functional groups present in the substrates.

Full text of DOI:10.1016/j.tetlet.2017.01.022

Accepted Manuscript
Sulfated polyborate catalyzed Kabachnik-Fields reaction: An efficient and eco-
friendly protocol for synthesis of α-amino phosphonates
Chetan K. Khatri, Vardhan B. Satalkar, Ganesh U. Chaturbhuj
PII:
S0040-4039(17)30034-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.022
TETL 48525
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
26 November 2016
6 January 2017
8 January 2017
Please cite this article as: Khatri, C.K., Satalkar, V.B., Chaturbhuj, G.U., Sulfated polyborate catalyzed Kabachnik-
Fields reaction: An efficient and eco-friendly protocol for synthesis of α-amino phosphonates, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.01.022
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Graphical Abstract
Sulfated polyborate catalyzed Kabachnik-Fields
reaction: An efficient and eco-friendly protocol
for synthesis of α-amino phosphonates
Chetan K. Khatri, Vardhan B. Satalkar, and Ganesh U. Chaturbhuj*

1
Tetrahedron Letters
Sulfated polyborate catalyzed Kabachnik-Fields reaction: An efficient and eco-
friendly protocol for synthesis of α-amino phosphonates
Chetan K. Khatri, Vardhan B. Satalkar, and Ganesh U. Chaturbhuj
Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology, Mumbai- 400019 India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An efficient, and environmentally benign protocol for a three-component Kabachnik-Fields
reaction of aldehydes, amines, and diethyl phosphite catalyzed by sulfated polyborate has been
described to afford α-amino phosphonates under solvent-free reaction conditions. The major
advantages of the present method are high yields, short reaction time, simple work-up procedure,
inexpensive, eco-friendly and reusable catalyst and solvent-free reaction conditions and
tolerance towards various functional groups present in the substrates.
Available online
Keywords:
2016 Elsevier Ltd. All rights reserved.
Sulfated polyborate
Kabachnik-Fields reaction
Amino phosphonate
Diethyl phosphite
Solvent free
The Kabachnik–Fields reaction is a multi-component organic
reaction forming an α-amino phosphonates from aldehydes,
amines, and dialkyl phosphites.1 Recently, the synthesis of α-
amino phosphonates has attracted much attention in synthetic
organic chemistry as well as in medicinal chemistry due to their
significant biological activities and structural analogy to α-amino
acids.2-5 α-Amino phosphonates has diverse applications such as
antibiotics,6 antithrombotics,7 inhibitors of HIV protease,8 and
peptidases,9 anti-cancer agents,10 antitubercular,11 fungicides,
herbicide and insecticide.12 α-Amino phosphonates have been
used as for the synthesis of valuable actives such as alafosfalin;
an antibacterial agent,6 glyphosate; a herbicide,13 and dufulin; an
anti-viral agent (Fig. 1).14
triflates/magnesium sulfate,37 magnesium dodecylsulphate,38
tartaric acid,39 sulfamic acid,40 silica sulfuric acid,41 xanthan
sulfuric acid,42 sulfated zirconia,43 TfOH/C,44 [H-DABCO]Cl,45
and so on.
However, these methods suffer from various shortcomings
like unsatisfactory yields, longer reaction time, extractive product
isolation with toxic organic solvents, use of expensive, metal-
based, toxic/corrosive catalysts, which limits their use due to
environmental issues. Therefore, the development of a safe,
environmentally benign, mild, efficient, and high yielding rapid
reaction procedure using cost effective and recyclable catalyst
would be valuable.
Pursuit of convenient and practical catalytic methods for the
current interest in organic synthesis and commercial process;
recently we have introduced sulfated polyborate catalyst and
demonstrated its efficiency for catalyzing the Biginelli reaction.46
Its mild acidity, ease of preparation, reusability, and eco-
friendliness have encouraged us to investigate its potential to
catalyze many other useful reactions. Therefore, in continuation
of our previous study, in this paper, we explored the application
of sulfated polyborate catalyst as a rapid and efficient protocol
for the synthesis of α-amino phosphonates via Kabachnik-Fields
reaction of aldehydes, amines and diethyl phosphite under
solvent free condition (Scheme 1).
Kabachnik–Fields reaction is reported using various Bronsted
and Lewis acid catalysts such as InCl3,15 FeCl3,16 LiClO4,17
ZrCl4,18
ZrOCl2.8H2O,19
CeCl3.7H2O,20
BiNO3.5H2O,21
,25
[Cp2Zr(OSO2C4F9)2.2H2O],22 SbCl3/Al2O3,23 TaCl5-SiO2,24 TiO2
HfCl4,26 LnCl3,27 BF3.Et2O,28 M(OTf)n,29 M(ClO4)n,30
NiSO4.6H2O,31 CF3COOH,32 [Cu(3,4-tmtppa)](MeSO4)4,33 β-
cyclodextrine,34 Amberlyst-15,35 Amberlite-IR 120,36 lanthanide
Literature revealed that boric acid catalyzes many important
organic transformations at temperature above 100 °C.47 Boric
acid dehydrates above 100 °C and converts to its polymeric
forms, which presumably is the active species catalyzing the
reaction.48-49 Dehydrative polymerization of boric acid liberates
water molecules which may hamper the progress of the reactions.
Fig. 1 Biologically active molecules.
———
 Corresponding author. Tel.: +91-223-361-2212; fax: +91-222-414-5614; e-mail: gu.chaturbhuj@gmail.com

2
Table 2
Efficiency of sulfated polyborate in comparison with literature reported
catalysts for the Kabachnik-Fields reaction
Entry
Catalyst
Condition
Time
(min)
5
Yielda
(%)
98
Ref.
1.
Sulfated
polyborate
[H-DABCO]Cl
Polyboric acid
solvent free/
90 °C
MeOH/rt
solvent free/
90 °C
This
work
45
2.
3.
10
45
96
96
-
4.
5.
Sulfamic acid
Xanthan sulfuric
acid
solvent free/rt
solvent free/
60 °C
60
60
94
93
40
42
Scheme 1. Schematic representation of sulfated polyborate catalyzed
Kabachnik Fields reaction.
6.
7.
Tartaric acid
solvent free/
50°C
ACN/rt
120
150
83
96
39
22
This inspired us to develop a polymeric boric acid catalyst
with mild Bronsted acidity. To accomplish this boric acid was
dehydrated at 200 °C to convert it into its polymeric Lewis acid
form and then sulfonated to introduce a mild Bronsted acid
character. Boron is an electron deficient element and electron
withdrawing effect of adjacent sulfate enhances its Lewis acidity,
hence it has both Lewis as well as Bronsted acid characters
(Scheme 1).
Zirconocene
bis(perfluorobuta
nesulfonate)
TfOH/C
Silica sulfuric
acid
Sulfated zirconia
Trifluoro acetic
acid
8.
9.
solvent free/rt
ACN /rt
180
300
97
87
44
41
10.
11.
ACN/rt
solvent free/rt
480
1440
95
96
43
32
a Isolated yield.
For initial screening, the study was structured to investigate
the suitability of sulfated polyborate as a catalyst at different
reaction conditions. For the preliminary experiment, a mixture of
benzaldehyde; a model substrate, aniline, and diethyl phosphite
were used (Scheme 2). The results are summarized in Table 1.
polyborate (Table 1, entry 4 and 6-8). The reaction proceeded at
room temperature but took longer time with a relatively lower
yield (Table 1, entry 6). An increase in the temperature to 90 °C
resulted in significantly increased product yield in shorter
reaction time (Table 1, entries 4). Therefore, 90 °C was chosen as
optimum temperature for the reaction.
The effect of the catalyst loading on time and yields of the
reaction was assessed (Table 1, entries 2-5). In absence of a
catalyst, the reaction proceeded at 90 °C and took longer reaction
time with a lower yield (Table 1, entry 1). An increase in the
catalyst loading increased the product yield with significate
reduction in the reaction time was observed (Table 1, entries 2-
5). The catalyst loading beyond 5 wt % was not advantageous
(Table 1, entries 4 and 5). Hence, 5 wt % catalyst loading was
chosen for further study.
The effect of various solvents on time and yield of the
reaction was ascertained (Table 1, entries 9-14). None of the
solvents have shown advantage over solvent free condition.
Hence, the solvent free condition was regarded as best for the
cost and environmental acceptability.
Various catalysts are reported for the synthesis of α-amino
phosphonates via Kabachnik-Fields reaction. Herein, in
comparison with other acid catalysts sulfated polyborate catalyst
showed an advantage with respect to reaction conditions, workup
procedure, time and yields (Table 2, entry 1-11).
Temperature played an important role for Kabachnik-Fields
reaction. The temperature effect was examined at ambient, 50 °C,
70 °C, and 90 °C under solvent free condition using sulfated
To study the generality and scope, optimized reaction
conditions54 were applied to various aldehydes. All the aromatic,
heterocyclic and alicyclic aldehyde variants reacted well and
afforded higher yields of the corresponding α-amino
phosphonates in shorter reaction time (Table 3, entry 1-16).
Various electron donating or electron withdrawing substituents at
the ortho, meta and para position of aromatic aldehydes have
been examined. The nature of substitutions on aromatic
aldehydes has no significant effect on the reaction time and
yields (Table 3, entries 2-12). The protocol was also extended to
heterocyclic and alicyclic aldehyde variants, resulted in
corresponding α-amino phosphonates in shorter reaction time
with good yields (Table 3, entries 13-16). Further the substrate
scope was evaluated for various aromatic amines and benzyl
amine, which also resulted in higher yields of the corresponding
α-amino phosphonates in shorter reaction time. Various electron
donating or electron withdrawing substituents at the para
position of aromatic amines have been examined. The nature of
substitutions on aromatic amines has no significant effect on the
reaction time and yields (Table 3, entries 17-21). This protocol
tolerated a variety of substituents on aromatic aldehydes and
amines, whereas, found to be unsuitable for aliphatic aldehydes
and amines.
Scheme 2. Kabachnik-Fields reaction of benzaldehyde, aniline and
diethyl phosphite.
Table 1
Results of optimization studies
Entry
Catalyst
Solvent
Temperature Time
Yielda
(%)
51
88
94
98
98
88
93
97
91
90
88
Traces
81
94
(wt %)
(°C)
90
90
90
(min)
360
30
15
5
1.
2.
3.
4.
5.
6.
7.
8.
0
1
2.5
5
7.5
5
5
5
5
solvent free
solvent free
solvent free
solvent free
solvent free
solvent free
solvent free
solvent free
EtOH
90
90
5
rt
50
70
reflux
reflux
reflux
90
90
90
60
30
15
30
30
30
30
30
30
9.
10.
11.
12.
13.
14.
5
5
5
5
ACN
THF
water
toluene
The reusability of the catalyst in the model reaction of
benzaldehyde, aniline and diethyl phosphite under solvent free
5
DMF
a Isolated yield.

3
Aldehydes (R1)
Amines (R2)
Time
(min) (%)
10 94
Yielda
Entry
21.
Table 3
Substrate scope for the Kabachnik-Fields reaction using sulfated polyborate
catalyst
a Isolated yield.
Aldehydes (R1)
Amines (R2)
Time
(min) (%)
Yielda
Entry
1.
2.
3.
4.
5.
6.
7.
8.
5
98
10
10
5
94
95
95
93
10
10
5
Fig. 2. Reusability of the catalyst.
94
94
92
conditions at 90 °C was evaluated. After completion of each
reaction cycle, water was added and the product was filtered off.
The filtrate was evaporated in vacuum rotary evaporator to
recover the catalyst quantitatively. The recovered catalyst was
recycled for four times with no significant loss in a catalytic
activity (Fig. 2).
The plausible mechanism of the Kabachnik-Fields reaction
catalyzed by sulfated polyborate is as depicted in Fig. 3. A
nucleophilic attack of aniline on sulfated polyborate activated
aldehydes results in formation of imine intermediate50,51 followed
by a nucleophilic attack of phosphite on sulfated polyborate
activated imine leads to the formation of α-amino
phosphonates.52
10
9.
10
10
10
10
10
10
94
95
94
93
93
95
10.
11.
12.
13.
14.
Conclusion
In conclusion, the present procedure is a rapid, efficient and
eco-friendly protocol for Kabachnik-Fields reaction of various
aldehydes, amines, and diethyl phosphite under optimized
conditions. Mild reaction conditions, easy of workup procedure,
shorter reaction time, high yields, and recyclability of the catalyst
are the key features of this procedure. Moreover, this protocol
has the ability to tolerate a wide variety of substituents along
with enhanced product purity which promises economical as well
as ecological rewards.
15.
16.
17.
10
5
90
95
97
10
18.
19.
20.
10
10
10
95
93
97
Fig. 3. The plausible mechanism of the Kabachnik-Fields reaction
catalyzed by sulfated polyborate.

4
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5
Highlights:
 Solvent free, efficient, rapid and
environmentally benign Kabachnik-Fields
reaction.
 High yields, short reaction time and simple
work-up procedure.
 Recyclable catalyst with no significant loss
in activity.
 Method tolerates a variety of functional
groups with wide substrate scope.