A study on the Kabachnik-Fields reaction of benzaldehyde, propylamine, and diethyl phosphite by in situ Fourier transform IR spectroscopy

Article abstract of DOI:10.1002/hc.20676

The phospha-Mannich condensation of benzaldehyde, n-propylamine, and diethyl phosphite carried out at 80°C in acetonitrile takes place via the imine (PhC=N-Pr) intermediate as suggested by in situ FT-IR spectroscopy. Copyright

Full text of DOI:10.1002/hc.20676

Heteroatom Chemistry
Volume 22, Number 5, 2011
A Study on the Kabachnik–Fields Reaction
of Benzaldehyde, Propylamine, and Diethyl
Phosphite by In Situ Fourier Transform IR
Spectroscopy
Gyo¨rgy Keglevich, Andra´s Fehe´rva´ri, and Istva´n Csontos
Department of Organic Chemistry and Technology, Budapest University of Technology
and Economics, 1521 Budapest, Hungary
Received 15 December 2010; revised 24 January 2011
phorus chemistry [5,10,11]. We wished to study
ABSTRACT: The phospha-Mannich condensation of
the Kabachnik–Fields (phospha-Mannich) reaction
[12,13] by in situ FT-IR spectroscopy to obtain in-
formation on the course of the three-component
condensation reaction of an oxo compound, a pri-
mary or secondary amine, and a dialkyl phosphite.
The resulting α-aminophosphonates are important,
potentionally biologically active substrates [14–17].
benzaldehyde, n-propylamine, and diethyl phosphite
carried out at 80◦C in acetonitrile takes place via the
imine (PhC N Pr) intermediate as suggested by in
ꢀ
C
situ FT-IR spectroscopy. 2011 Wiley Periodicals, Inc.
Heteroatom Chem 22:599–604, 2011; View this article on-
line at wileyonlinelibrary.com. DOI 10.1002/hc.20676
In our laboratory, the microwave(MW)-assisted syn-
thesis of heterocyclic α-aminophosphates and α-
INTRODUCTION
aminophosphine oxides was investigated [18,19].
It was found that, in general, the simplest pro-
cedure involves solventless MW conditions, and
there is no need for special (expensive and environ-
ment unfriendly) catalysts [20]. The course of the
Kabachnik–Fields reaction is also of continuing in-
terest. Cherkasov and Galkin studied the mechanism
of the Kabachnik–Fields reaction in detail [21]. One
possibility is that an imine is formed from the car-
bonyl compound and the (primary) amine, and then
the dialkyl phosphite is added onto the C N moiety
of the imine. The other route that they considered in-
volves the formation of an α-hydroxyphosphonate by
the addition of the phosphite to the carbonyl group
of the oxo component. Then the hydroxyphospho-
nate may undergo substitution by the amine to af-
ford the α-aminophosphonate. Mainly on the basis of
kinetic studies, it was thought that the mechanism is
dependent on the nature of the reactants. For exam-
ple, the condensation of aniline, benzaldehyde, and
a dialkyl phosphite was shown to follow the “imine”
In situ Fourier transform infra-red (FT-IR) spec-
troscopy is a useful tool in environment friendly
chemistry, as it allows optimization of the reaction
conditions via monitoring the concentration pro-
file of the components [1–5]. The time-dependent
IR spectra also allow the establishment of formal
kinetics or equilibrium constants [6,7] as well as
detection of intermediates [8,9]. In situ FT-IR spec-
troscopy has been applied only rarely in organophos-
Correspondence to: Gyo¨rgy Keglevich; e-mail: gkeglevich@
mail.bme.hu.
Contract grant sponsor: Hungarian Scientific Research Fund
(OTKA).
Contract grant numbers: K067679 and K83118.
This work is connected to the scientific program of the “Devel-
opment of quality-oriented and harmonized R+D+I strategy and
functional model at BME” project. This project is supported by
´
the New Hungary Development Plan (Project ID: TAMOP-4.2.1/
B-09/1/KMR-2010-0002).
c
ꢀ
2011 Wiley Periodicals, Inc.
599

600 Keglevich, Fehe´rva´ri, and Csontos
a hard nucleophile, that is the amine, compete for
the electrophilic carbonyl compound. The softer the
carbonyl compound is, the faster it reacts with
the softer P-nucleophile and the slower it reacts with
the harder amine nucleophile [28].
δ
+
δ−
PhCHO
(RO)2P(O)H + PhNH2
(RO)2P
O
H N Ph
−
H2O
H
H
O
NHPh
+
PhN CHPh
(RO)2P(O)H
(RO)2P CHPh
We wished to study the course of the phospha-
Mannich reactions involving a primary aliphatic
amine, an aromatic aldehyde, and a dialkyl phos-
phite as the reactants. In situ FT-IR spectroscopy
seemed to be an appropriate tool in monitoring the
target reaction.
SCHEME 1 [21,22]
mechanism. Interestingly, it was found that before
the condensation of the aniline and the benzalde-
hyde, an H-bond is formed between the P O func-
tion of the phosphite and the NH unit of the amine
(Scheme 1) [21,22].
RESULTS AND DISCUSSION
In another example, Cherkasov and Galkin sug-
gested that the reaction of the more nucleophilic
cyclohexylamine, benzaldehyde, and a dialkyl phos-
phite takes place via the “hydroxyphosphonate”
route [21,23].
Later, however, Matveeva and Zefirov proved
that the condensation of cyclohexylamine, benzalde-
hyde, and dialkyl phosphite follows the “imine route”
and concluded that there is no experimental ev-
idence for the hydroxyphosphonate route being
involved [24].
It is worthy of mention that the reaction of
cyclohexylamine, benzaldehyde, and dibutylphos-
phine oxide, which can be regarded as an extended
Kabachnik–Fields condensation, was shown to pro-
ceed according to the “imine” mechanism [21,25]. It
seems to be probable that the actual mechanism is
dependent on the components of the reaction, but
the “imine” route is more general, than the pathway
involving an “α-hydroxyphosphonate” intermediate
[26]. Gancarz observed that a reversible formation
of the α-hydroxyphosphonate may also occur, and
at the same time if it is rearranged to the corre-
sponding phosphate this is a “dead-end” route [27].
It can be said that in the Kabachnik–Fields reaction,
a soft nucleophile, that is the dialkyl phosphite, and
The model reaction to be studied was the con-
densation of n-propylamine, benzaldehyde, and di-
ethyl phosphite affording diethyl α-propylamino-
α-phenyl-methylphosphonate (3) either via imine
(Schiff base)
(Scheme 2).
1
or α-hydroxyphosphonate
2
According to earlier experiences, in most cases,
“Route A” is the preferred pathway. For this, we
wished to evaluate first the possibility of the imine
pathway.
Schiff base 1 and α-aminophosphonate 3 were
prepared in separate experiments, and the IR spec-
tra of benzaldehyde, diethyl phosphite, imine 1, and
aminophosphonate 3 were recorded in acetonitrile
solution. The spectra are shown in Fig. 1. Owing
to its lack of IR absorption in the region of 800–
1700 cm−1, the spectrum of n-propylamine was not
included.
The reagents benzaldehyde and diethyl phos-
phite revealed intense absorptions at 1702 or 980,
1042 and 1258 cm−1, respectively. The peaks at 1702,
980/1042, and 1258 cm−1 are due to νC=O, νP–O–C , and
νP=O stretching vibrations, respectively. The imine (1)
showed intense signals at 973 and 1648 cm−1. As the
first one overlaps with the peak of (EtO)2P(O)H at
980 cm−1, the absorption at 1648 cm−1 that is due
Route A
CH NPr
PrNH2
(EtO)2P(O)H
O
NHPr
(EtO)2P
O
1
H
(EtO)2P
O
PrNH2
OH
(EtO)2P(O)H
Route B
3
2
SCHEME 2
Heteroatom Chemistry DOI 10.1002/hc

A Kabachnik–Fields Reaction Monitored by FT-IR Spectroscopy 601
FIGURE 3 Concentration profile for the reaction of ben-
zaldehyde with n-propylamine at 0◦C in acetonitrile.
FIGURE 1 IR spectra of the reaction components measured
in acetonitrile solution.
to evaluate the temperature at which the addition
commences. For this, the acetonitrile solution of the
reactants was heated gradually from room temper-
ature to 80◦C. The reaction started at 75◦C, as was
shown by the appearance of the absorbances at 1027
and 1054 cm−1 belonging to the νP–O–C vibration of
aminophosphonate 3. At the same time, the signals
at 980, 1042, and 1258 cm−1 characteristic of diethyl
phosphite and at 1648 cm−1 belonging to the imine
(1) started decreasing when the temperature reached
75◦C. The three-dimensional (3D) diagram of the
above transformation is shown in Fig. 4. It can be
concluded that the imine (1) and diethyl phosphite
react at a temperature ≥75◦C.
to the νC=N vibration remains for identification. The
aminophosphonate 3 can be recognized from the
signals at 1027 and 1054 cm−1 (both due to νP–O–C
stretching vibration) and 1243 cm−1 (νP=O).
In the first experiment, the formation of imine 1
was studied. Benzaldehyde and n-propylamine were
reacted in acetonitrile at 0◦C. On the basis of the de-
creasing absorption at 1702 cm−1 and the increasing
signal at 1648 cm−1, the change in the concentration
of benzaldehyde and imine 1 could be followed well
(Fig. 2).
The concentration profile for the reaction com-
ponents, benzaldehyde, and imine 1 is shown in
Fig. 3. The curves were obtained by deconvolution,
which is the separation of the (overlapping) absorp-
tion bends of the reaction components. The for-
mation of imine 1 was practically complete after
20 min.
The next experiment was on a three-component
equimolar reaction mixture and was carried out in
two stages. The first spectrum was obtained on the
acetonitrile solution of diethyl phosphite at 26◦C. Af-
ter recording of 3 and 11 spectra, the n-propylamine
and benzaldehyde, respectively, were added. After
the addition of benzaldehyde, the temperature rose
The next experiment involved the reaction of
Schiff base 1 with diethyl phosphite. We wished
FIGURE 2 A segment of the time-dependent IR spectrum
for the reaction of benzaldehyde with n-propylamine in ace-
tonitrile at 0◦C.
FIGURE 4 A segment of the time-dependent IR spectrum for
the reaction of imine 1 with diethyl phosphite in acetonitrile.
Heteroatom Chemistry DOI 10.1002/hc

602 Keglevich, Fehe´rva´ri, and Csontos
FIGURE 5 A segment of the time-dependent IR spec-
trum for the Kabachnik–Fields reaction of diethyl phosphite,
n-propylamine, and benzaldehyde in acetonitrile carried out
in two stages.
FIGURE 7 Concentration profile for the Kabachnik–Fields
reaction studied at 80◦C in acetonitrile.
from 26 to 36◦C. Simultaneously, the benzaldehyde
was consumed and the imine appeared as shown by
the peak at 1648 cm−1. The temperature was then
gradually increased by heating. At 75◦C, the imine
(1) gradually disappeared, but the aminophospho-
nate appeared as suggested by the signals at 1027
and 1054 cm−1. The 3D diagram obtained is shown
in Fig. 5.
Finally, an acetonitrile solution of diethyl phos-
phite and n-propylamine was heated to 80◦C, and
benzaldehyde was then added. Collection of the
spectra was started when all the three components
were in the flask. The benzaldehyde could not be de-
tected as it was converted instantly to Schiff base
1, which, in turn, was transformed to aminophos-
phonate 3 by reaction with diethyl phosphite. The
intermediate (1) appearing at 1648 cm−1 could be
seen clearly for ca. 3 h. The maximum concentra-
tion could be seen after 10 min. The 3D diagram for
the phospha-Mannich reaction carried out in ace-
tonitrile at 80◦C is shown in Fig. 6. No absorption
at 3268 cm−1 characteristic to the stretching vibra-
tion of the hydroxy group of α-hydroxyphosphonate
2 could be detected during the course of the reaction.
The above experiment serves as direct evidence
for the pathway via Schiff base 1 (“Route A” in
Scheme 2) in the case of the three-component con-
densation under discussion. So far, only kinetic stud-
ies have been published in respect of the mechanism
of other Kabachnik–Fields reactions [21]. The course
of the phospha-Mannich reactions may obviously de-
pend on the nature of the starting materials [21–24].
The relative concentration–time diagram ob-
tained after deconvolution is shown in Fig. 7. The
intermediacy of imine 1 can be seen clearly, and it
can be established that the reaction time is approxi-
mately 4 h.
It was also possible to reproduce the IR spectra
of the reaction components, such as diethyl phos-
phite, Schiff base 1, and aminophosphonate 3 (Fig. 8
and Table 1). It can be seen that the real IR spectra
FIGURE 6 A segment of the time-dependent IR spec-
trum for the Kabachnik–Fields reaction of diethyl phosphite,
n-propylamine, and benzaldehyde at 80◦C in acetonitrile.
FIGURE 8 IR spectra for the reaction components obtained
from the 3D diagram after deconvolution.
Heteroatom Chemistry DOI 10.1002/hc

A Kabachnik–Fields Reaction Monitored by FT-IR Spectroscopy 603
TABLE 1 IR Absorptions Measured and Obtained from the 3D Diagram after Deconvolution (in cm−1
)
(EtO)2P(O)H
Measured
C6H5CH NPr
Calculated
(EtO)2P(O)CH(Ph)NHPr
Calculated
Measured
1648
Calculated
Measured
1648
1262
1073
1046
980
1258
1077
1042
980
1243
1054
1027
969
1243
1053
1027
969
988
973
are almost identical to those obtained by deconvolu-
tion (Fig. 1 vs. Fig. 8).
Synthesis of Diethyl α-Phenyl-α-propylamino-
methylphosphonate (3)
In summary, the Kabachnik–Fields reaction of
benzaldehyde, n-propylamine, and diethyl phosphite
carried out at 80◦C in the acetonitrile solution could
be monitored successfully by in situ FT-IR spec-
troscopy, and the intermediacy of the correspond-
ing Schiff base was pointed out suggesting that ben-
zaldehyde and n-propylamine react with each other
in the first step. We plan to study phospha-Mannich
condensations of other types as well.
6.1 mL (60.0 mmol) of benzaldehyde, 5.0 mL
(61.0 mmol) of n-propylamine, and 7.7 mL (60.0
mmol) of diethyl phosphite was heated at 80◦C for
22 h. The mixture was passed through a short silica
gel column using 3% methanol in chloroform as the
eluant to furnish 12.8 g (75%) of aminophosphonate
3. 31P NMR δ (CDCl3) 23.7, δP[30] 24.1; IR (neat) 700,
966, 1028, 1057, 1243, 1454, 2970 cm−1.
Monitoring the Reaction of Benzaldehyde with
n-Propylamine
EXPERIMENTAL
Equipment
To 5.1 mL (50.0 mmol) of benzaldehyde in 25 mL
of acetonitrile, 4.1 mL (50 mmol) of n-propylamine
was added dropwise at 0◦C over a period of 2 min
with external ice-cooling and vigorous stirring. The
reaction was complete after 15 min. The reaction
took place as shown in Fig. 2.
In situ FT-IR measurements were carried out using
a ReactIR 1000 equipment. The diamond measur-
ing head was placed in a 100-mL four-necked flask
equipped with a dropping funnel, a condenser, a
thermometer, and a magnetic stirrer. The temper-
ature was maintained by using an appropriately ad-
justed water bath.
Monitoring the Reaction of Schiff Base 1 with
Diethyl Phosphite
Synthesis of Imine 1
To 7.4 g (50.0 mmol) of imine 1 in 25 mL of acetoni-
trile, 6.4 mL (50.0 mmol) of diethyl phosphite was
added dropwise at 26◦C on intensive stirring. After
complete addition, the mixture was heated gradually
from 26◦C by a water bath. The addition reaction
commenced at 75◦C, as shown in Fig. 4.
10.2 mL (100.0 mmol) of benzaldehyde and 8.2 mL
(100.0 mmol) of n-propylamine was measured to-
gether at 26◦C, and the mixture was stirred for 24 h.
Then the mixture was kept under vacuum to afford
14.2 g (96%) of Schiff base 1. IR (neat) 693, 969,
1451, 1647, 2961 cm−1.
Monitoring the Phospha-Mannich Reaction
Synthesis of α-Hydroxyphosphonate 2
Carried Out at 26 → 75◦C
A mixture of 3.0 mL (29.5 mmol) of benzalde-
hyde, 3.8 mL (29.5 mmol) of diethyl phosphite, and
2.8 g Na2CO3 (as the catalyst) in 30 mL of toluene was
heated at 110◦C for 6 h. Then the solid was filtered
off, and the filtrate was evaporated. The residue was
washed with 2 × 10 mL of ether to give 6.2 g (86%) of
α-hydroxyphosphonate 2. 31P NMR δ (CDCl3) 21.5,
δP[29] 22.0; IR (KBr) 701, 962, 1026, 1050, 1228,
1451, 2989, 3268.
To the mixture of 7.7 mL (60.0 mmol) of di-
ethyl phosphite in 30 mL of acetonitrile, 5.0 mL
(61.0 mmol) n-propylamine and 6.1 mL (60.0 mmol)
of benzaldehyde were added, whereupon the temper-
ature increased from 26 to 36◦C due to the formation
of imine 1. The mixture was then heated with a water
bath until the temperature reached 75◦C. At this tem-
perature, the addition reaction took place gradually
as shown in Fig. 5.
Heteroatom Chemistry DOI 10.1002/hc

604 Keglevich, Fehe´rva´ri, and Csontos
[13] Kabachnik, M. I.; Medved, T. Y. Dokl Akad Nauk
SSSR 1952, 83, 689.
[14] Kafarski, P.; Lejczak, B. Curr Med Chem Anti-Cancer
Agents 2001, 1, 301.
[15] Sienczyk, M.; Oleksyszyn, J. Curr Med Chem 2009,
16, 1673.
[16] Liu, W.; Rogers, C. J.; Fisher, A. J.; Toney, M. D. Bio-
chemistry 2002, 41, 12320.
Monitoring the Phospha-Mannich Reaction
Carried Out at 75◦C
The above reaction was repeated by adding the ben-
zaldehyde to the mixture of diethyl phosphite and
n-propylamine in acetonitrile at 80◦C. The resulting
3D diagram is shown in Fig. 6.
[17] Grembecka, J.; Mucha, A.; Cierpicki, T.; Kafarski, P.
J Med Chem 2003, 46, 2641.
[18] Prauda, I.; Greiner, I.; Luda´nyi, K.; Keglevich, G. Syn-
thetic Commun 2007, 37, 317.
[19] Keglevich, G.; Szekre´nyi, A.; Sipos, M.; Luda´nyi, K.;
Greiner, I. Heteroatom Chem 2008, 19, 207.
[20] Keglevich, G.; Szekre´nyi, A. Lett Org Chem 2008, 5,
616.
[21] Cherkasov, R. A.; Galkin, V. I. Russ Chem Rev 1998,
67, 857 (Usp Khim 1998, 67, 940; in Russian).
[22] Galkin, V. I.; Zvereva, E. R.; Sobanov, A. A.; Galkina,
I. V.; Cherkasov, R. A. Zh Obshch Khim 1993, 63,
2225.
[23] Galkina, I. V.; Sobanov, A. A.; Galkin, V. I.;
Cherkasov, R. A. Russ J Gen Chem 1998, 68, 1398
(Zh Obshch Khim 1998, 68, 1465; in Russian).
[24] Matveeva, E. D.; Zefirov, N. S. Doklady Chem 2008,
420, 137 (Dokl Akad Nauk 2008, 420, 492; in
Russian).
REFERENCES
[1] Ende, D. J.; Preigh, M. J. Curr Opin Drug Disc 2000,
3, 699.
[2] Pintar, A.; Batista, J.; Levec, J. Analyst 2002, 127,
1535.
[3] Rein, A. J. SPIE—Optically Based Methods Process
Anal 1992, 1681, 49.
[4] Sheridan, R. E.; Rein, A. J. Res Dev 1991, 33, 100.
[5] Yamagiwa, N.; Abiko, Y.; Sugita, M.; Tian, J.;
Matsunaga, S.; Shibasaki, M. Tetrahedron:
Asymmetry 2006, 17, 566.
[6] Keglevich, G.; Csontos, I.; Nova´k, T.; Mucsi, Z.;
Marosi, G.; Greiner, I. Hung Chem J 2006, 112, 114.
[7] Sallay, P.; Szila´gyi, N.; Csontos, I.; Keglevich, G. Per
Politechn Chem Eng 2009, 53, 9.
[25] Galkina, I. V.; Galkin, V. I.; Cherkasov, R. A. Zh Ob-
shch Khim 1998, 68, 1469.
[26] Zefirov, N. S.; Matveeva, E. D. ARKIVOC 2008, (i), 1.
[27] Gancarz, R.; Gancarz, I. Tetrahedron Lett 1993, 34,
145.
[28] Gancarz, R. Tetrahedron 1995, 51, 10627.
[29] Nesterov, V. V.; Kolodyazhnyi, O. I. Russ J Gen Chem
2005, 75, 1161 (Zh Obshch Khim 2005, 75, 1225; in
Russian).
[8] Keglevich, G.; Csontos, I.; Szila´gyi, N.; Greiner, I.
Chem Eng Technol 2008, 31, 421.
[9] Keglevich, G.; Csontos, I.; Szila´gyi, N. Spec Lett 2009,
42, 67.
[10] Keglevich, G.; Puska´s, R. E.; Gru¨n, A.; Csontos, I.;
Phosphorus, Sulfur, Silicon 2010, 185, 832.
[11] Keglevich, G.; Puska´s, R. E.; Gru¨n, A.; Csontos, I.;
Greiner, I. Phosphorus, Sulfur, Silicon 2010, 185,
2333.
[30] Qian, C.; Huang, T. J Org Chem 1998, 63, 4125.
[12] Fields, L. K. J Am Chem Soc 1952, 74, 1528.
Heteroatom Chemistry DOI 10.1002/hc