A critical overview of the kabachnik-fields reactions utilizing trialkyl phosphites in water as the reaction medium: A study of the benzaldehyde- benzylamine triethyl phosphite/diethyl phosphite models

Article abstract of DOI:10.1002/hc.21192

α-Aminophosphonates may be synthesized by the three-component condensation of oxo-compounds, amines, and dialkyl phosphites or trialkyl phosphites. In the latter case, mostly water is the reaction medium and a catalyst is also needed. This approach has been studied critically by us, exploring the background of this version of the Kabachnik-Fields condensation. The possibilities for the Kabachnik-Fields condensation of benzaldehyde, benzylamine, and triethyl phosphite or diethyl phosphite including the accomplishment in water were studied in detail.

Full text of DOI:10.1002/hc.21192

Heteroatom Chemistry
Volume 25, Number 4, 2014
A Critical Overview of the Kabachnik–Fields
Reactions Utilizing Trialkyl Phosphites in Water
as the Reaction Medium: A Study of the
Benzaldehyde-Benzylamine Triethyl
Phosphite/Diethyl Phosphite Models
Gyo¨rgy Keglevich,1 Erika Ba´lint,2 Re´ka Kangyal,1 Ma´ria Ba´lint,3
and Ma´tya´s Milen1,4
1Department of Organic Chemistry and Technology, Budapest University of Technology and
Economics, 1521 Budapest, Hungary
2MTA-BME Organic Chemical Technology Research Group, 1521 Budapest, Hungary
3Ba´lint Analytics, 1116 Budapest, Hungary
4Chemical Research Division, EGIS Pharmaceuticals Plc, 1475 Budapest, Hungary
Received 10 February 2014; revised 6 May 2014
INTRODUCTION
ABSTRACT: α-Aminophosphonates may be synthe-
sized by the three-component condensation of oxo-
compounds, amines, and dialkyl phosphites or trialkyl
phosphites. In the latter case, mostly water is the re-
action medium and a catalyst is also needed. This ap-
proach has been studied critically by us, exploring the
background of this version of the Kabachnik–Fields
condensation. The possibilities for the Kabachnik–
Fields condensation of benzaldehyde, benzylamine,
and triethyl phosphite or diethyl phosphite including
the accomplishment in water were studied in detail.
The synthesis of α-aminophosphonates is of
importance due to their significant biological activ-
ity [1–4]. The classical method for the preparation
of α-aminophosphonates is the Kabachnik–Fields
condensation of an aldehyde, amine, and dialkyl
phosphite [5–8]. A lot of variations were elaborated
during the past decades using different model
compounds and applying different conditions. A
great number of catalyst were described that made
possible carrying out the reactions under mild con-
ditions [9–13], including microwave (MW)-assisted
and solvent-free accomplishments [12,13]. However,
it was found by the senior author of this article that,
in most cases, there is no need to use any catalyst, as
the Kabachnik–Fields reaction takes place efficiently
under catalyst- and solvent-free conditions on MW
irradiation [14–16]. It is a modification of the
classical Kabachnik–Fields reaction, when the Shiff
base (imine) is performed by the condensation of
the aldehyde and the primary amine and the inter-
mediate so formed is reacted with the dialkyl phos-
phite [17]. There were attempts to accomplish the
ꢀC
2014 Wiley Periodicals, Inc. Heteroatom Chem.
25:282–289, 2014; View this article online at wiley-
onlinelibrary.com. DOI 10.1002/hc.21192
Correspondence to: Gyo¨rgy Keglevich; e-mail: gkegle-
vich@mail.bme.hu.
Contract grant sponsor: Hungarian Scientific Research Fund.
Contract grant number: OTKA No. K83118.
Contract grant sponsor: New Sze´chenyi Development Plan.
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282

Critical Overview of the Kabachnik–Fields Reactions Utilizing Trialkyl Phosphites in Water as the Reaction Medium 283
condensations under discussion in water medium
dialkyl phosphites) in water as the reaction medium
may be accomplished efficiently. But what may be
the reason that a few chemists chose water as the
solvent for the reactions under discussion? On the
one hand, these days there are efforts to carry out
reactions in green solvents, such as water. This is,
however, not a right argument here; as it was shown
above, the Kabachnik–Fields condensations may be
best accomplished without any solvent if a dialkyl
phosphite is the P-component [14]. Moreover, water
is not a real solvent here as from among the organic
components applied, only diethyl phosphite and
benzylamine are soluble in water. The other reason
supporting the use of water is that it may have some
role in the course of the reaction. The plausible
mechanism assumed also by other authors is shown
in Scheme 1 [25]. In the original version [25],
the acid is boric acid and the anion is (HO)2BO−
(or in general, a deprotonated acid); however, the
proton may also derive from water. The first step
is the condensation of the aldehyde and primary
amine to provide the imine by dehydration. Then,
a molecule of trialkyl phosphite is added on the
protonated C N bond of the imine. Then, the
adduct is stabilized by an Arbuzov fission to result
in the α-aminophosphonate. One can see that water
has two roles in the course of the reaction. The first
role is to protonate the nitrogen atom of the imine.
The second role is to serve as a counter ion in the
phosphonium salt intermediate before the Arbuzov
stabilization.
In the light of the above mechanism, it is clear
that the presence of water may be advantageous for
the Kabachnik–Fields condensations using trialkyl
phosphites. However, there is no need to add water
to the reaction mixture, as one molecule of water
is formed in the reaction of aldehyde and primary
amine that, basically, may promote further reaction
as a protonating agent and as the source of the
hydroxy counter ion in the phosphonium salt. This
may have been recognized by Karimi-Jaberi and
co-worker, when they reacted aromatic aldehydes,
aromatic amines, and trimethyl phosphite at room
temperature without any solvent. Ten mole percent
of boric acid was used as the catalyst that may also
act a protonating agent and may also provide an
anion. The α-aminophosphonates were obtained
after 15–60 min reaction times in yields of 87–98%
(Scheme 2) [25].
[18,19]. This, however, offers no specific advantage,
as there is no need for solvent at all, and what is
more, if water is used, a catalyst is also needed
[19].
There is another variation for the Kabachnik–
Fields reaction, when a trialkyl phosphite is used in-
stead of the dialkyl phosphite. In these cases, mostly
water was the reaction medium, and it was necessary
to use a catalyst. A few examples are summarized in
Table 1.
If water is used as the solvent, the solubility of
the organic components is problematic. For this rea-
son, surfactants such as scandium tris(dodecyl sul-
fate) and magnesium bis(dodecyl sulfate) were used
to promote the three-component condensation. Us-
ing a variety of aldehydes and amines, along with
triethyl phosphite as the P-reagent at room temper-
ature (or at 30°C), the α-aminophosphonates were
obtained in variable, mostly in good yields (29–84%)
after reaction times of 2–6 h (Table 1, entries 1 and
2) [19,20].
In another method, acyclic and cyclic quaternary
onium salts (ionic liquids) were used as co-solvents
and at the same time as acid catalysts. The conden-
sation of aromatic aldehydes, aromatic amines, and
triethyl phosphite at room temperature gave the cor-
responding α–aminophosphonates in yields of 89–
96% in relatively short reaction times (10–60 min)
(Table 1, entry 3) [18,21].
Mandhane and co-workers reported an
efficient methodology for the synthesis of
α–aminophosphonates using thiamine hydrochlo-
ride (VB1) as the catalyst. The condensations were
carried out not only under conventional stirring,
but under ultrasound. It was found that the reaction
time was reduced to few minutes under ultrasound
(Table 1, entry 4) [22].
The reaction of aromatic aldehydes, amines, and
triethyl phosphite was studied in the presence of
tetramethyl-tetra-3,4-pyridinoporphyrazinato cop-
per (II) methyl sulphate in water at 80°C by Sob-
hani and his research group. The corresponding
α-aminophosphonates were obtained in high yields
(90–98%) after reaction times of 0.5–3 h (Table 1,
entry 5) [23].
In the last case, the reaction of substituted salicy-
laldehydes, aniline derivatives, and triphenyl phos-
phite was investigated at ambient temperature in wa-
ter in the presence of p–toluenesulfonic acid (PTSA)
as the catalyst. The products were obtained in yields
of 82–94% after reaction times of 3–5 h (Table 1,
entry 6) [24].
In other solvent-free variations, an ionic liq-
uid with sulfonic acid function [26] or nano-TiO2
[27] was used as catalysts or TiCl4 was applied in
dichloromethane [28].
It can be seen that the special Kabachnik–Fields
reactions applying trialkyl phosphites (instead of
In overall, the addition of a certain quan-
tity (a few equivalents) of water to the reaction
Heteroatom Chemistry DOI 10.1002/hc

284 Keglevich et al.
TABLE 1 Kabachnik–Fields Reactions Applying Trialkyl Phosphite as the P-Reagent in Water as the Medium
Heteroatom Chemistry DOI 10.1002/hc

Critical Overview of the Kabachnik–Fields Reactions Utilizing Trialkyl Phosphites in Water as the Reaction Medium 285
SCHEME 1
26°C
O
H3BO3 (0.1 equiv)
Ar2NH2
Ar2NH CH P(OMe)2
Ar1
Ar1CHO
(1 equiv)
+
+
P(OMe)3
(1 equiv)
no solvent
(1 equiv)
Ar1 = Ph, 4-MeOC6H4, 4-MeC6H4, 4-HOC6H4, 4-ClC6H4, 4-CNC6H4, 4-NO2C6H4
2 = Ph, 4-ClC6H4
Ar
SCHEME 2
TABLE 2 Hydrolysis of Triethyl Phosphite on Stirring in Wa-
ter at 26°Ca
OEt
OEt
O
OEt
OEt
26°C, t
H2O
EtO
P
P
H
Composition (%)b
TEP
DEP
Entry
Additive
Time
TEP
DEP
SCHEME 3
1/1
1/2
1/3
1/4
2
−
−
5 min
15 min
30 min
1 h
87
32
7
0
0
13
68
93
100
100
−
mixture seems to be reasonable to promote the
Kabachnik–Fields condensation. However, there is
no need to use water in an unlimited quantity, as
it cannot serve as a real solvent. We planned to
study the Kabachnik–Fields condensations in wa-
ter medium ensuring a 2–4 mmol/mL concentra-
tion of the components (0.11 mL (1.0 mmol) of
benzylamine, 0.10 mL (1.0 mmol) of benzaldehyde,
and 1.2 mmol of the P-reagent (0.20 mL of tri-
ethyl phosphite or 0.15 mL of diethyl phosphite), or
2.0 mmol of the P-reagent (0.34 mL of triethyl phos-
phite or 0.26 mL of diethyl phosphite) in 0.5 mL of
water).
−
10% of
PTSA
<10 min
aStirring 0.20 mL TEP in 0.5 mL of water.
bOn the basis of GC.
RESULTS AND DISCUSSION
First of all, we wished to investigate the hydrolysis of
triethyl phosphite (TEP) to diethyl phosphite (DEP)
at 26°C in water (Scheme 3), as this side reaction
may obviously influence the Kabachnik–Fields con-
densation. Our results are summarized in Table 2
and Fig. 1. It was found that the hydrolysis is rela-
tively fast at room temperature. After 30 min, 93%
of triethyl phosphite was hydrolyzed to diethyl phos-
phite (Table 2, entry 1/3). The hydrolysis was com-
pleted after 1 h (Table 2, entry 1/4). In the presence of
FIGURE 1 Hydrolysis of TEP to DEP in the absence of cat-
alyst at 26°C.
10% of PTSA, the hydrolysis was much faster, it was
almost completed within 10 min (Table 2, entry 2).
The 31P NMR shifts of the P-species involved in
our study are listed in Table 3. A small amount (ࣘ3%)
of triethyl phosphate was formed in all reactions as
Heteroatom Chemistry DOI 10.1002/hc

286 Keglevich et al.
TABLE 3 31P NMR Shifts for the Simple P-Species Involved
TABLE 4 Kabachnik–Fields Reaction of Benzaldehyde,
Benzylamine, and Triethyl Phosphite at 26°C in Water
lit
Compound
δP (ppm)
δP (ppm)
Reference
P(OEt)3
(EtO)2P(O)H
138.6
7.31
138.9
8.0
[29]
[30]
Composition (%)a
TEP
Entry Additive (equiv) Time Benzaldehyde Imine AP
1/1
1/2
1/3
1/4
2/1
2/2
2/3
2/4
3/1
−
1.2
3 h
6 h
10 h
1 Day
1 h
3 h
6 h
10 h
1 h
3
3
3
4
3
5
3
4
6
86
81
33
19
90
31
17
4
11
35
64
77b
7
64
80
92b
46
26°C
H2O
PhCH NBn + H2O
PhCHO +
BnNH2
SCHEME 4
−
2
26°C
H2O
P(OEt)3
+
PhCHO + BnNH2
10% of 1.2
PTSA
48
O
PhCH NBn + BnHN CH P(OEt)2
3/2
3/3
3/4
4/1
3 h
4
6
4
4
24
18
10
48
72
76
Ph
AP
10 h
1 Day
1 h
86b
48
10% of
PTSA
2
SCHEME 5
4/2
4/3
3 h
10 h
4
2
13
3
83
95b
a consequence of oxidation of the triethyl phosphite
(δP (CDCl3) –1.3, δP [29] –0.8).
aOn the basis of GC.
bThere was no change for further stirring.
It can be seen that the hydrolysis of the trialkyl
phosphites may be a competent side reaction, when
the Kabachnik–Fields reaction is carried out in wa-
ter. In any case, it is advisable to use the trialkyl
phosphite in an excess to provide an enough quan-
tity of the reactant.
26°C
H2O
BnNH2
+
(EtO)2P(O)H
O
PhCHO +
PhCH NBn + BnHN CH P(OEt)2
In the next part of our work, we studied the
formation of imine from the aldehyde in water.
Our model was the reaction of benzaldehyde with
benzylamine (Scheme 4).
Ph
AP
SCHEME 6
LC-MS analysis revealed that using equimolar
quantities of the reactants (2–2 mmol) in water
(1 mL), the condensation was completed after 6 min.
One can conclude that the formation of an imine is
quite fast under the conditions applied.
Then, we tried to carry out the Kabachnik–Fields
condensation of benzaldehyde, benzylamine, and 1.2
or 2 equiv of triethyl phosphite in water at 26°C
(Scheme 5, Table 4, Fig. 2). Without any catalyst
and using only 1.2 equiv of the phosphite, the reac-
tion was slow and incomplete even after a prolonged
reaction time (Table 4, entry 1/4). Using 2 equiv of
triethyl phosphite, the situation was better and the
reaction was almost complete (Table 4, entry 2/4).
The presence of 10% of PTSA was helpful in the case,
when only 1.2 equiv of phosphite was used (Table 4,
entries 3/4 and 4/3 vs. entries 1/4 and 2/4).
phosphite in the mixture. In case of a higher excess
of the phosphite, there is a bigger chance for the
reaction of imine with the triethyl phosphite. As it
was shown, the PTSA catalyst somewhat accelerated
the process.
On the basis of our experience, the use of triethyl
phosphite in aqueous medium in Kabachnik–Fields
reactions can be questioned due to the hydrolysis of
the reagent to diethyl phosphite. In these condensa-
tions, diethyl phosphite is an in situ formed reagent
concurring with triethyl phosphite, and replacing it
at a certain point.
For this, the condensation was investigated with
diethyl phosphite as well. The reaction conditions
were similar as applied above (Scheme 6, Table 5). It
was found that the condensation with diethyl phos-
phite at 26°C in water took place slower than the
reaction with triethyl phosphite. The increase in the
amount of diethyl phosphite was somewhat helpful,
as the α-aminophosphonate was formed in a big-
ger proportion (Table 5, entries 1/2 and 2/2). In the
presence of PTSA, the bigger amount of DEP had a
It can be said that within a time range of 10
min, triethyl phosphite is the major P-reagent, and
then diethyl phosphite, which is formed from triethyl
phosphite by hydrolysis, becomes the predominant
P-nuchleophile that may react with the protonated
imine. After 40 min, there is practically no triethyl
Heteroatom Chemistry DOI 10.1002/hc

Critical Overview of the Kabachnik–Fields Reactions Utilizing Trialkyl Phosphites in Water as the Reaction Medium 287
100
90
80
70
60
50
1,2 equiv TEP, without any addiꢀve
40
1,2 equiv TEP, in the presence of 10% of PTSA
30
2 equiv TEP, without any addiꢀve
20
2 equiv TEP, in the presence of 10% of PTSA
10
0
0
5
10
15 20
25
Time (h)
FIGURE 2 Time dependence of the relative proportion of aminophosphonate (AP) in the reaction of benzaldehyde,
benzylamine, and triethyl phosphite at 26°C in water.
TABLE 5 Kabachnik–Fields Reaction of Benzaldehyde,
Benzylamine, and Diethyl Phosphite at 26°C in Water
TABLE 6 Temperature Dependence of Kabachnik–Fields
Reaction of Benzaldehyde, Benzylamine, and Diethyl Phos-
phite in Water
Composition (%)a
DEP
Composition (%)a
Entry Additive (equiv) Time Benzaldehyde Imine AP
Entry Additive T (°C) Time Benzaldehyde Imine AP
1/1
1/2
2/1
2/2
3/1
−
−
1.2
2
3 h
1 Day
3 h
1 Day
3 h
9
13
11
16
9
65
33
68
12
63
26
1
2
3
4
−
−
40 1 Day
80 6 h
100 6 h
100 4 h
11
23
11
8
30 51
26 59b
16 73b
12 80b
54b
21
−
72b
28
10% of
PTSA
10% of 1.2
PTSA
aOn the basis of GC.
bThere was no change for further stirring.
3/2
4/1
1 Day
3 h
13
10
24
62
63b
28
10% of
PTSA
2
4/2
1 Day
15
9
76b
10% of PTSA, the reaction was completed after 4 h
at 100°C (Table 6, entry 4).
aOn the basis of GC.
bThere was no change for further stirring.
It can be seen that the Kabachnik–Fields re-
actions with diethyl phosphite in water were not
complete even at higher temperature without cat-
alyst. The aqueous medium inhibited the reaction
of diethyl phosphite. Finally, the reaction of ben-
zaldehyde, benzylamine, and 1.2 equiv of diethyl
phosphite was carried out under solvent-free condi-
tions, first on conventional heating and then under
MW conditions (Scheme 7, Table 7). It was found
that the condensation was complete under both
variations; however, under MW conditions, the re-
action was much faster (Table 7, entries 1 and 2).
In conclusion, in the condensation with diethyl
phosphite, there is no need for any solvent (water)
and catalyst as compared to the reaction with tri-
ethyl phosphite. In addition, the triethyl phosphite
is malodorous and the use of excess of this reagent
means extra cost. Moreover, using water as the sol-
vent in the reaction with triethyl phosphite, it is hy-
drolyzed fast resulting in the formation of diethyl
less effect (Table 5, entries 3/2 and 4/2). While with
triethyl phosphite, the best result was 95% after 10
h and with diethyl phosphite the maximum conver-
sion was 76% after 1 day (Table 4, entry 4/3 and
Table 5, entry 4/2). The reason for the longer reac-
tion time is that the aqueous medium slows down
the bimolecular reaction of diethyl phosphite and
the imine, as water dilutes the reaction components,
and the imine is only slightly soluble in water.
We wished to study the effect of the temperature
on the reaction, thus a few experiments were carried
out with 1.2 equiv of diethyl phosphite without cat-
alyst in water at 40, 80, and 100°C (Table 6). It was
shown that at 26°C after 1 day, 54% of aminophos-
phonate was obtained (Table 5, entry 1/2). At 40,
80, and 100°C, the ratio of the product was 51, 59,
and 73%, respectively. No complete reaction could
be achieved without a catalyst. In the presence of
Heteroatom Chemistry DOI 10.1002/hc

288 Keglevich et al.
Δ or MW
O
100°C
BnNH2
+
(EtO)2P(O)H
BnHN CH P(OEt)2
PhCHO +
no solvent
Ph
AP
SCHEME 7
31P NMR spectra were obtained in CDCl3 solu-
tion on a Bruker AV-300 spectrometer operating at
121.5 MHz. Chemical shifts are downfield relative to
85% H3PO4. In the experiments, distilled water was
used with a pH of 7.0.
TABLE 7 Kabachnik–Fields Reaction of Benzaldehyde,
Benzylamine, and Diethyl Phosphite under Solventless Con-
ditions
Mode of
Heating
Composition
of AP (%)a
Entry
Time
1
2
ꢀ
MW
>1 h
20 min
ꢀ100
100
General Procedure for the Hydrolysis of Triethyl
Phosphite
aOn the basis of GC.
The mixture of 0.20 mL (1.2 mmol) of triethyl phos-
phite, 0.50 mL (28.0 mmol) of distilled water, and
in certain cases 0.019 g (0.1 mmol) of PTSA was
stirred at 26°C for the appropriate time. The re-
action mixture was then washed with 10 mL of
dichloromethane in a separating funnel and 10 mL
of distilled water was also added, then the wa-
ter phase was extracted two times with 10 mL of
dichloromethane and the combined organic phase
dried (Na2SO4). Evaporation of the volatile compo-
nents provided the crude product that was analyzed
by GC and/or GC-MS (see Table 2).
phosphite and, hence resulting in a complicated
reaction mixture, in which both P-reagents may re-
act in a competitive way.
The overall conclusion is that for the preparation
of the desired α-aminophosphonates, the application
of dialkyl phosphites is preferable in the Kabachnik–
Fields reaction, as this reaction can be accomplished
without any catalyst, in a solvent-free manner. How-
ever, together with suitable catalysts, trialkyl phos-
phites may also be used with water as the solvent.
A better alternative is the solvent-free use of trialkyl
phosphites in the presence of suitable catalysts.
General Procedure for the Kabachnik–Fields
Reaction in Aqueous Medium
The mixture of 1.0 mmol (0.11 mL) of benzyl amine,
1.0 mmol (0.10 mL) of benzaldehyde, 1.2 mmol of
phosphite (0.20 mL of triethyl phosphite or 0.15
mL of diethyl phosphite) or 2.0 mmol of phosphite
(0.34 mL of triethyl phosphite or 0.26 mL of diethyl
phosphite), 0.50 mL (28 mmol) of distilled water,
and in certain cases 0.019 g (0.10 mmol) of PTSA was
stirred at appropriate temperature for the appropri-
ate time (see Tables 4 and 5). The reaction mixture
was worked up similarly as above. The crude prod-
ucts were analyzed by GC and/or GC-MS.
EXPERIMENTAL
General
The MW-assisted reaction was carried out in a CEM
Discover (300 W) MW reactor equipped with a pres-
sure controller using 50 W irradiation.
GC was carried out on an HP5890 series 2 GC-
FID chromatograph using a 15 m × 0.18 mm Restek,
Rtx-5 column with a film layer of 0.20 μm. The tem-
perature of the column was initially held at 40°C for
1 min, followed by a 25°C/min program up to 300°C
and a final isothermal period at 300°C for 10 min.
The temperature of the injector was 290°C and of
the FID detector was 300°C. The carrier gas was N2.
GC-MS was carried out on an Agilent 6890 N-
GC-5973 N-MSD chromatograph using a 30 m ×
0.25 mm Restek, Rtx-5SILMS column with a film
layer of 0.25 μm. The initial temperature of column
was 45°C for 1 min, followed by a 10°C/min program
up to 310°C and a final isothermal period at 310°C for
17 min. The temperature of the injector was 250°C.
The carrier gas was He and the operation mode was
splitless.
The reactions at higher temperature (Table 6)
were carried out similarly.
General Procedure for the Kabachnik–Fields
Reaction under Solvent-Free Condition
The mixture of 1.0 mmol (0.11 mL) of benzyl amine,
1.0 mmol (0.10 mL) of benzaldehyde, and 1.2 mmol
(0.15 mL) of diethyl phosphite was heated at 100°C
in a vial in an oil bath or in a CEM Discover MW
reactor for the appropriate time. Then, the water
formed was removed in vacuum. The crude product
Heteroatom Chemistry DOI 10.1002/hc

Critical Overview of the Kabachnik–Fields Reactions Utilizing Trialkyl Phosphites in Water as the Reaction Medium 289
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Heteroatom Chemistry DOI 10.1002/hc