Unexpected course of Kabachnik-Fields reaction in the microwave synthesis of quinoline-based α-aminophosphonates

Article abstract of DOI:10.2174/157017809787003142

The course of kabachnik-fields reaction in the synthesis of 3-substituted quinoline-based α-aminophosphonates under microwave irradiation has been investigated. some unexpected monoester hydrogen phosphonate derivativeso btained along with diethyl phospho

Full text of DOI:10.2174/157017809787003142

Letters in Organic Chemistry, 2009, 6, 11-16
11
Unexpected Course of Kabachnik-Fields Reaction in the Microwave
Synthesis of Quinoline-Based ꢀ-Aminophosphonates
Marina Juribaꢀiꢁ*,1, Laura Stella2, ꢂeljko Mariniꢁ1, Marijana Vinkoviꢁ1, Pietro Traldi2 and
Ljerka Tuꢀek-Boꢃiꢁ*,1
1Ruꢀer Boꢁkoviꢂ Institute, Bijeniꢃka c. 54, HR-10002 Zagreb, Croatia
2CNR, Istituto di Scienze e Tecnologie Molecolari, Sezione di Padova, Corso Stati Uniti 4, 35100 Padova, Italy
Received June 06, 2008: Revised October 22, 2008: Accepted October 22, 2008
Abstract: The course of Kabachnik-Fields reaction in the synthesis of 3-substituted quinoline-based ꢀ-amino-
phosphonates under microwave irradiation has been investigated. Some unexpected monoester hydrogen phosphonate de-
rivatives, obtained along with diethyl phosphonates by reaction of quinoline-3-carboxaldehyde and aniline as well as 3-
aminoquinoline and benzaldehyde, respectively, with diethyl phosphite, have been analyzed and discussed.
Keywords: ꢀ-Aminophosphonate, quinoline, microwave-assisted reaction, Kabachnik-Fields reaction.
INTRODUCTION
shorter reaction times usually giving products in high yields
under eco-friendly solvent-free conditions [18]. Thus, a few
examples of microwave-assisted Kabachnik-Fields reactions
have recently been reported [19-23]. Some procedures were
performed on the solid surface such as Montmorillonite clay
[21], alumina [22] or silica gel [23]. It is noteworthy that
among the prepared compounds there are no phosphonates
with the nitrogen containing heterocyclic aromatic ring. In
addition, there are generally only few synthetic routes that
yield such kind of compounds [20, 24, 25].
The synthesis of ꢀ-aminophosphonate derivatives has at-
tracted current interest in the organic and medicinal chemis-
try due to important biological and pharmacological proper-
ties of these organophosphorus compounds [1]. As structural
analogues of amino acids, their biological activity is mainly
displayed through metabolic regulation and ability to inhibit
various metalloenzymes having an amino acid as substrate
[2]. In addition, a number of these compounds may act as
antibiotic [3], antimicrobial [4], antitumor [5] and antiviral
agents [6]. In agrochemistry some derivatives are used as
fungicidal [7] and herbicidal agents [8]. Another aspect re-
garding this kind of compounds arises from their ability of
forming various types of metal complexes, which are also
interesting because of their biological activity [9]. Thus,
some complexes of platinum group metals have shown re-
markable antitumor activity [10,11]. The high phosphonate
affinity to bone and other calcified tissues may be utilized
for the drug design against bone diseases [12].
In search for the appropriate method for preparation of
quinoline-based ꢀ-aminophosphonates, we recently de-
scribed the preparation of dialkyl [ꢀ-anilino-N-(2-
quinolylmethyl)]phosphonates and [ꢀ-(3-quinolylamino)-N-
benzyl]phosphonates by various conventional and micro-
wave-assisted one- and two-steps reactions of the corre-
sponding aromatic aldehyde, amine and dialkyl phosphite
carried out without or in the presence of solvent and catalyst
[20]. It is noteworthy that in the microwave-assisted synthe-
sis of 2-substututed derivatives, the yield of the aminophos-
phonates was in the best case only ca. 20% and an unusual
main product, quinoline-2-carboxanilide, was isolated.
Moreover, under a number of applied reaction conditions
aminophosphonate was not detected at all. Taken into ac-
count these results, presently we have directed out attention
to investigations on the course of microwave-assisted one-
pot three-component reaction of quinoline-3-carboxaldehyde
and aniline as well as 3-aminoquinoline and benzaldehyde,
respectively, with diethyl phosphite. Some unexpected
monoester hydrogen phosphonate derivatives, which were
isolated along with diethyl phosphonates, have been ana-
lyzed and discussed with respect to the previously described
studies on the Kabachnik-Fields reaction of different types of
carbonyl and amine reactants with dialkyl phosphites.
Various synthetic methods have been developed for the
synthesis of ꢀ-aminophosphonates [13-17]. Among them,
the classical Kabachnik-Fields reaction, a three-component
one-pot reaction of amine, carbonyl compound (aldehyde or
ketone) and hydrophosphoryl compound, has proven its great
synthetic potential and significance as one of the simplest
approaches to these important organophosphorus compounds
[15-17]. The reaction can be carried out with or without sol-
vent or catalyst and mostly are used dialkyl phosphites as a
hydrophosphoryl reagent.
The use of microwave irradiation as a non-conventional
energy source for activation of reactions in recent years has
become a very popular method to simplify and improve
some classic organic reactions. They are performed with
RESULTS AND DISCUSSION
*Address correspondence to these authors at the Institute, Division of
Physical Chemistry, Bijeniꢄka c. 54, HR-10002 Zagreb, Croatia; Tel: +385-
1-4571217;Fax: +385-1-4680245;E-mail:tusek@irb.hrand mjuribas@irb.hr
The basic problem in the synthesis of ꢀ-aminopho-
sphonates is the formation of the aminoalkylphosphonate
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

12 Letters in Organic Chemistry, 2009, Vol. 6, No. 1
Juribaꢀiꢁ et al.
framework P(O)-C-N. Investigations on the mechanism of
the Kabachnik-Fields reaction have shown that depending on
the nature of the reactants two main reaction pathways with
different sequence of separate steps that lead to formation of
aminophosphonate could occur (Scheme 1) [16, 26]. Car-
bonyl compound can react first with amine forming imine, or
in the other case, with hydrophosphoryl compound can give
ꢀ-hydroxyphosphonate. In the second step hydrophosphory-
lation of imine and amination of ꢀ-hydroxyphosphonate,
respectively, forms ꢀ-aminophos-phonate. In our studies we
used only dialkyl phosphite as the hydrophosphoryl reactant.
It should be noted that this reaction of three components
is a very complex system with possibilities of various bimol-
ecular processes between reactants and the intermediate
products, and may yield some unexpected products, espe-
cially in the microwave assisted reactions. Thus, in some
cases an imine, ꢀ-hydroxyphosphonate, bisphosphonate,
phosphate or enamine along with an ꢀ-aminophosphonate
derivate were isolated [27] or only detected by spectroscopic
studies [26, 28]. To the best of our knowledge there are no
reports that hydrogen phosphonate derivate or simple amino-
phosphonate monoester was obtained in the course of
Kabachnik-Fields reaction, as we obtained in the present
work. We have investigated one-pot three-component reac-
tion of quinoline-3-carboxaldehyde and aniline as well as 3-
aminoquinoline and benzaldehyde, respectively, with diethyl
phosphite under microwave irradiation (Scheme 2, Table 1).
In the first case the reaction proceeds in the formation of
diethyl [ꢀ-anilino-(3-quinolylmethyl)]phosphonate 1 with
the relative good yield of about 80%. Unexpectedly, the cor-
responding monoester 2 (3%) and very interesting three-
phosphorus compound that proved to be a bis(hydrophos-
phonate)-phosphate monoester derivative 3 (7%) were iso-
lated as by-products.
P(O)H
C
N
imine
P(O)H
O
C
NH2
+
+
O
P
C
N
aminophosphonate
NH2
- H2O
O
P
C
OH
hydroxyphosphonate
Our recent study has shown that under the same reaction
conditions with 2-quinolinecarboxaldehyde as the carbonyl
reactant, the main product was quinoline-2-carboxanilide,
while the yield of the corresponding diethyl [ꢀ-anilino-(2-
Scheme 1. Two pathways of formation of ꢀ-aminophosphonates in
Kabachnik-Fields reaction (>P(O)H, hydrophosphoryl compound;
O=C<, carbonyl compound; –NH2, amine).
EtO
O
OEt
O
H
H
P
P
OEt
O
O
O
P
OR
2' 3'
5
8
4
HO
P
OEt
10
9
3
1'
6
7
CH
NH
4'
+
CH NH
2
6' 5'
N
N
1: R=Et; 2: R=H
3
R1CHO + R2NH2 + HPO(OEt)2
OEt
P
R1 = 3-quinolyl, phenyl
R2 = phenyl, 3-quinolyl
O
OH
P
O
EtO
4
2' 3'
5
8
10
9
NH
P
OEt
N
OEt
3
6
7
NH
CH
4'
+
1'
H
H
N
N
2
6' 5'
N
4
5
Scheme 2. Kabachnik-Fields reaction with quinoline-3-carboxaldehyde (up) and with 3-aminoquinoline (down).
Table 1. Results of Kabachnik-Fields Microwave Solvent-Free Reactions at Given Temperature
Yield
Carbonyl Compound
Amine
Phosphite
Product
90 ºC
115 ºC
1
2
3
86
*
78
3
O
C
NH2
HP(O)(OEt)2
H
4
7
N
4
5
64
9
66
*
O
H
NH2
HP(O)(OEt)2
C
N
*Product was not isolated.

Microwave Synthesis of Quinoline-Based ꢁ-Aminophosphonates
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
13
H
H
P
H
N
H
H
N
H
P
OEt
OEt
ꢁꢀ ꢁ+
OEt
OEt
- EtOH
QNH2 + HPO(OEt)2
Q
N
H
Q
P
Q
OEt
OH
O
O
Scheme 3. Proposed mechanism for formation of 5 (Q=quinoline).
1
quinolylmethyl)]phosphonate was only ca. 20% [20]. Fa-
vored formation of amide and not imine by reaction of qui-
noline-2-carboxaldehyde and aniline may arise from proxim-
ity of the acidic aldehyde hydrogen with respect to the qui-
noline nitrogen. This assumption is supported by the present
study with the 3-quinoline-substituted aldehyde, where, as
expected, formation of amide compound was not detected. It
is worth noting that when this reaction was performed at
lower temperature (90 °C), only diester 1 (86%) and the
three-phosphorus compound 3 (4%) were isolated. Mono-
ester 2 was not obtained.
The complete H, 13C and 31P NMR resonance assign-
ments of compounds 1-5 in DMSO-d6, based on 1D and 2D
homo- and heteronuclear NMR analyses, are in agreement
with their structure. In diesters 1 and 4 two sets of separate
H/C resonances have been observed for the diastereotopic
ethyl groups of the P(O)(OEt)2 moiety. The monoesters 2
and 5 show H/C absorption ascribed to one ethyl ester group,
while 3 shows two ethyl absorptions in the ratio 1:2. The
first one is from the quinolylmethylphosphate part of the
molecule, while the second one could be ascribed to the two
ethyl hydrophosphonate moieties. The presence of two PH
protons in this monoester and one in 5 is confirmed by a
doublet at 6.56 and 6.70 ppm, respectively, with one-bond
PH coupling of ca. 590 and 650 Hz, respectively. In all
monoester derivatives the signal of NH proton appears as a
broad singlet, indicating its involving in hydrogen bonding
observed in these compounds. The valuable structural infor-
mation about all phosphorus compounds could be obtained
by their 31P NMR spectra (Fig. (1)). As expected, diesters 1
and 4 as well as monoester 2 show one signal at about 23
and 18.6 ppm, respectively, with heteronuclear correlation
with the PCH, NH and methylene POCH2 protons, character-
istic for such kind of phosphonate compounds [32, 33]. The
spectra of compound 3 confirm the presence of three phos-
phorus atoms. There are two singlets in the ratio 1:2, a broad
one at 11.68 and a rather sharp absorption arisen from two
equivalent hydrophosphonate phosphorus atoms at 0.37 ppm.
In the course of reaction of 3-aminoquinoline and ben-
zaldehyde as the amino and carbonyl reactants, besides the
corresponding diethyl ester 4 (66%), again one hydrogen
phosphonate derivative, ethyl N-(3-quinolyl)phosphon-
amidate 5 (9%) was isolated as by-product. The plausible
mechanism for its formation through a pre-reaction complex
between aminoquinoline and phosphite is shown in Scheme
3. In this compound, for which the amide – imide tautomer-
ism could be proposed, the phosphorus is bonded to the qui-
nolylamino nitrogen.
All prepared quinoline-based phosphonate compounds
are stable compounds very soluble in alcohols, DMF and
DMSO, soluble (1,4) or slightly soluble (2, 3 and 5) in other
common organic solvents and apart 3 and 5 insoluble in wa-
ter. The molar conductance in methanol of 1 and 4 (ꢀM~1 S
cm2 mol-1) and those of 2, 3 and 5 (ꢀM=13-30 S cm2 mol-1)
are consistent with the structure of diester and monoester
organophosphorus derivatives, respectively [29]. The new
In the heteronuclear H-31P spectrum, correlations of these
1
phosphorus atoms with the PH and methylene POCH2 pro-
tons are clearly visible. The tautomeric structure of mono-
ester 5 is confirmed by the presence of two phosphorus sig-
nals at 4.83 and 1.95 ppm. Their intensity ratio is 1:13, simi-
1
compounds were fully characterized on the basis of IR, H,
13C and 31P NMR and mass spectroscopic studies. All mono-
ester derivatives (2, 3 and 5) are hydrated compounds which
were supported by the thermogravimetric analyses.
The IR spectra of diesters 1 and 4 are characterized by
the absorptions around 3300 cm-1, those between 1060 and
1020, and about 1235 and 970 cm-1, ascribed to the ꢄ(NH),
ꢄ(PO-C), ꢄ(P=O) and ethyl C-C vibrations, respectively. In
the monoester 2 three typical broad shallow bands between
2500 and 1840 cm-1 arise from the intermolecular hydrogen
bonded P(O)OH group [29-31], The superimposed ꢄ(PO-H)
ꢄ(PO-C) vibrations give a broad and very strong band at
1046 cm-1, while the ꢄ(P=O) absorption at 1218 cm-1 is ac-
companied by shoulders on the lower frequency side due to
involving of this group in the hydrogen bonding. The ꢄ(P=O)
vibration of the hydrophosphonate and phosphate groups in
the compound 3 give a broad and very strong absorption
around 1200 cm-1, indicating a strong intramolecular hydro-
gen bonding in this phosphorus compound. The presence of
the PH bond is supported by the characteristic absorption at
2385 cm-1, while bands between 1000 and 950 cm-1 arise
from the P-O-P and ethyl C-C vibrations. The PH absorption
in monoester 5 appears at 2332 cm-1 and a series of bands in
the range 1200-1000 cm-1 could be ascribed to the P=O, P-
NH, P-OC and P-OH vibrations [30].
Fig. (1). 31P NMR spectra of compounds 1-5.

14 Letters in Organic Chemistry, 2009, Vol. 6, No. 1
Juribaꢀiꢁ et al.
larly as that for the PH signal in the 1H NMR spectrum. After
staying the amide-imide ratio is changed to 1:7 after two
weeks, while at elevated temperatures of 388 K it is about
1:2 (Fig. (1) d,e). It may be presumed that the amide form
predominates in DMSO solution at room temperature.
XWINNMR software Version 3.5. The ESI mass measure-
ments were performed on a LCQDeca ion trap instrument
(Thermo, San Jose, CA, USA) operating in the positive ion
mode. Compounds were dissolved in MeCN (1,4),
MeOH/0.1% HCOOH (2,3) or MeOH (5) (10-6 M solutions)
and directly injected into the ESI source via a syringe pump
at a flow rate of 10 μL min-1. Structural identification of the
ions produced by ESI was performed by means of multiple
mass spectrometry experiments. Elemental analyses (CHN)
were performed on a Perkin-Elmer Analyser PE 2400 Series
2. Conductance measurements were carried out at room tem-
perature using a CD 7A Tacussel conductance bridge for 10-3
mol dm-3 solutions in MeOH. Thermogravimetric measure-
ments were carried out using a Shimadzu DTG-60H ana-
lyzer, with a heating rate of 10 °C min–1 in a stream of syn-
thetic air.
The structure of the investigated compounds was also
supported by the ESI mass spectra. The compounds 1-4
show the protonated molecular ion [M+H]+ at m/z 371, 343,
544 and 371, respectively, as well as fragment ions obtained
by dissociation (C2H4 loss) or complete loss of the phospho-
nate ethyl ester groups by cleavage of the C-P bond (see Ex-
perimental). This fragmentation pathway is characteristic for
this type of organophosphorus compounds [29, 34]. In the
spectrum of monoester 5, the [M+H]+ species is absent and
the base peak is fragment ion at m/z 145 obtained by cleav-
age of the N-P bond, which corresponds to the protonated
aminoquinoline ion.
A. Preparation of Quinoline-3-carboxaldehyde Deriva-
tives
Decomposition of derivative 3 was investigated also by
TG-DTA measurements. It takes place through a multistep
process, which begins with a broad dehydration step at 40-
130 °C and the mass loss of one molecule of water (found
mass loss: ca. 3.9%; calc. 3.2%), visible in the DTA curve as
a broad endothermic effect around 90 °C. The followed deg-
radation processes occur in two steps accompanied by exo-
thermic effects at ca. 260, 500 and 800 °C. The first rela-
tively sharp step up to 280 °C could be ascribed to deesteri-
fication process, and the second broad step arises from the
other degradation processes. The pyrolytic residue is P2O5
and difference obtained between the calculated and (37.8%)
and found (ca. 34%) residue value could be ascribed to par-
tial sublimation of P2O5, which takes place at higher tem-
peratures [35].
Equimolar amounts of quinoline-3-carboxaldehyde and
aniline (ca. 1.5 mmol) were mixed and diethyl phosphite (ca.
10% molar excess) was added. Reaction mixture was quickly
stirred, irradiated for 10 minutes on 90 or 115 °C and chro-
matographed on silica gel column using first pure EtOAc
and then gradually changing eluens to pure EtOH. First di-
ester 1 was eluted from the column with pure EtOAc, then 2
upon change of eluens to EtOAc:EtOH=1:1. Monoester 3
was eluted last using pure EtOH. Solid products 1, 2 and 3
were obtained by evaporation of solvent in vacuo. Reaction
on 90 °C yielded products 1 (86%) and 3 (4%), while that on
115 °C yielded products 1 (78%), 2 (3%) and 3 (7%).
Diethyl [ꢁ-anilino-N-(3-quinolylmethyl)]phosphonate (1)
Pale ochre powder. M.p. 83-85 ºC; IR (KBr, cm-1): 3300
m [ꢄ(N-H)], 1602 s, 1498 s [ꢄ(C=N), ꢄ(C=C), ꢂ(NH)], 1235
s [ꢄ(P=O)], 1050 vs, 1023 vs [ꢄ(PO-C)], 972 s [ꢄaliph(C-C)],
EXPERIMENTAL
All reagents and solvents were high purity products and
used without additional purification. The MW irradiation
experiments were carried out in sealed MW process vials (5
mL) with magnetic stirring using CEM Discover® Lab-
1
751 s [ꢄ(P-C)]; H NMR (600.13 MHz, DMSO-d6): ꢅ (ppm)
= 9.07 (s, H-2), 8.44 (s, H-4), 8.00 (d, JHH=8.4 Hz, H-8),
7.92 (d, JHH=8.0 Hz, H-5), 7.74 (t, JHH=7.5 Hz, H-7), 7.60 (t,
JHH=7.5 Hz, H-6), 7.02 (t, JHH=7.9 Hz, H-3',5'), 6.87 (t,
mateTH/ExplorerPLS monomode reactor. Reaction times un-
®
3
JHH=7.9 Hz, H-2',6'), 6.56 (dd, JPH=9.6 Hz, JHH=5.9 Hz,
der MW irradiation correspond to actual reaction times at
given temperature without ramp time needed to reach desired
temperature (ca. 70 s). Maximum power used for all the re-
actions was 50 W. Completion of reaction was indicated by
TLC (silica gel 60 F254, Merck) and products were purified
by column chromatography performed on silica gel (130-270
mesh, 60 Å, Aldrich). Melting points were determined on a
hot stage microscope and are uncorrected. Infrared spectra
were recorded on an ABB Bomem MB102 spectrometer
using KBr pellets. The one- and two-dimensional 1H, 13C and
31P NMR spectra were recorded with Bruker XWIN-600
Fourier-transform spectrometer operating at 600.13 MHz,
2
NH), 6.54 (t, JHH=7.2 Hz, H-4'), 5.40 (dd, JPH=25.0 Hz,
JHH=10.1 Hz, PCH), 4.11 (m, 2H, OCH2), 3.96, 3.85 (two m,
2H, OCH2'), 1.20 (t, JHH=7.1 Hz, CH3), 1.05 (t, JHH=7.0 Hz,
CH3'); 13C NMR (150.92 MHz, DMSO-d6): ꢅ (ppm) = 151.0
3
3
(d, JPC=4.0 Hz, C-2), 146.8 (C-9), 146.8 (d, JPC=13.6 Hz,
3
C-1'), 134.5 (d, JPC=6.4 Hz, C-4), 130.4 (C-3), 129.4 (C-7),
128.7 (C-3',5'), 128.6 (C-8), 127.7 (C-5), 127.1 (C-10), 126.8
2
(C-6), 117.2 (C-4'), 113.6 (C-2',6'), 62.8 (d, JPOC=6.8 Hz,
2
1
OCH2), 62.3 (d, JPOC=6.9, OCH2'), 52.0 (d, JPC=152.8 Hz,
PCH), 16.2 (d, JPOCC=5.0 Hz, CH3), 16.0 (d, 3JPOCC=5.3 Hz,
3
CH3'); 31P NMR (242.92 MHz, DMSO-d6): ꢅ (ppm) = 22.99;
MS (+ESI): m/z 393 ([M+Na]+, 11%), 371 ([M+H]+, 100%),
343 ([(M+H)-C2H4]+, 9%), 233 ([(M-PO(OEt)2]+, 44%);
C20H23N2O3P (370.39) Calc. C 64.85, H 6.26, N 7.56; found
C 64.69, H 5.76, N 7.60.
150.92 MHz and 242.92 MHz for H, 13C and 31P nucleus,
respectively. Spectra were recorded in DMSO-d6 at ambient
1
1
temperature containing SiMe4 as an internal standard for H
and 13C spectra or 85% H3PO4 as an external standard for 31
P
spectra. The following techniques were used: H, 13C, 31P,
1
Ethyl [ꢁ-anilino-N-(3-quinolylmethyl)]phosphonate mono-
hydrate (2)
1
1
1
1
APT, H-1H COSY, H-13C COSY, H-13C HMQC, H-13C
HMBC, 31P gated proton decoupling, 1H-31P HMQC and H-
1
Green powder. M.p. 95-98 ºC; IR (KBr, cm-1): 3370 m br
[ꢄ(N-H), ꢄ(O-H)], 2700-2300 w br, 2110 w br, 1970 w br,
31P HMBC. All two-dimensional experiments were per-
formed by standard pulse sequences, using Bruker

Microwave Synthesis of Quinoline-Based ꢁ-Aminophosphonates
Letters in Organic Chemistry, 2009, Vol. 6, No. 1
15
1840 w br [ꢄ(P(O)OH)], 1645 w [ꢂ(OH, H2O)], 1602 vs,
1499 s [ꢄ(C=N), ꢄ(C=C), ꢂ(NH)], 1218 m br, 1190 sh
[ꢄ(P=O)], 1046 s br [ꢄ(PO-C), ꢄ(PO-H)], 949 m [ꢄaliph(C-C)],
tor, product 5 was precipitated, filtered, washed with cold
THF:hexane=2:1 and dried in vacuo. Yield 9%.
Diethyl [ꢁ-(3-quinolylamino)-N-benzyl]phosphonate (4)
1
750 s [ꢄ(P-C)]; H NMR (600.13 MHz, DMSO-d6): ꢅ (ppm)
White powder. M.p. 143-145 ºC; IR (KBr, cm-1): 3273 s
[ꢄ(N-H)], 1614 s, 1575 w, 1536 m-s [ꢄ(C=N), ꢄ(C=C),
ꢂ(NH)], 1242 s, 1223 vs [ꢄ(P=O)], 1054 s, 1021 vs [ꢄ(PO-
= 9.03 (s, H-2), 8.36 (s, H-4), 7.97 (d, JHH=8.4 Hz, H-8),
7.88 (d, JHH=8.0 Hz, H-5), 7.70 (t, JHH=7.6 Hz, H-7), 7.56 (t,
JHH=7.5 Hz, H-6), 6.98 (t, JHH=7.9 Hz, H-3',5'), 6.77 (d,
JHH=7.9 Hz, H-2',6'), 6.49 (t, JHH=7.3 Hz, H-4'), 6.30 (s,
1
C)], 965 s, 953 s [ꢄaliph(C-C)], 751 m [ꢄ(P-C)]; H NMR
2
(600.13 MHz, DMSO-d6): ꢅ (ppm) = 8.78 (d, JHH=2.8 Hz, H-
2), 7.75 (d, JHH=8.0 Hz, H-8), 7.61 (d, JHH=7.0 Hz, H-2',6'),
7.54 (d, JHH=8.1 Hz, H-5), 7.37 (t, JHH=6.8 Hz, H-6), 7.34 (t,
JHH=7.6 Hz, H-3',5'), 7.32 (t, JHH=7.0 Hz, H-7), 7.26 (t,
JHH=7.3 Hz, H-4'), 7.25 (d, JHH=2.6 Hz, H-4), 7.10 (dd,
NH), 5.07 (d, JPH=24.1 Hz, PCH), 3.93 (m, OCH2), 1.11 (t,
JHH=7.0 Hz, CH3); 13C NMR (150.92 MHz, DMSO-d6): ꢅ
(ppm) = 151.2 (d, 3JPC=3.2 Hz, C-2), 147.3 (d, 3JPC=12.3 Hz,
3
C-1'), 146.6 (C-9), 134.2 (d, JPC=6.0 Hz, C-4), 132.1 (C-3),
129.0 (C-7), 128.7 (C-3',5'), 128.5 (C-8), 127.7 (C-5), 127.3
(C-10), 126.6 (C-6), 116.7 (C-4'), 113.3 (C-2',6'), 53.0 (d,
1JPC=145.7 Hz, PCH), 61.4 (d, 2JPOC=6.1 Hz, OCH2), 16.4 (d,
3JPOCC=5.6 Hz, CH3); 31P NMR (242.92 MHz, DMSO-d6): ꢅ
(ppm) = 18.61; MS (+ESI): m/z 343 ([M+H]+, 12%), 315
([(M+H)-C2H4]+, 12%), 297 ([(M+H)-EtOH]+, 70%), 250
([(M+H)-PhNH2]+, 62%), 233 ([M-PO(OEt)(OH)]+, 100%).
3
3JPH=10.0 Hz, JHH=5.9 Hz, NH), 5.23 (dd, JPH=24.0 Hz,
JHH=9.9 Hz, PCH), 4.08 (m, 2H, OCH2), 3.91, 3.76 (two m,
2H, OCH2'), 1.18 (t, JHH=7.0 Hz, CH3), 1.06 (t, JHH=7.0 Hz,
CH3'); 13C NMR (150.92 MHz, DMSO-d6): ꢅ (ppm) = 144.1
3
(C-2), 141.3 (C-9), 141.0 (d, JPC=13.3 Hz, C-3), 136.1 (C-
3
1'), 128.9 (C-10), 128.4 (C-8), 128.3 (d, JPC=5.5 Hz, C-
4
5
2',6'), 128.1 (d, JPC=1.5 Hz, C-3',5'), 127.6 (d, JPC=2.7 Hz,
Bis(hydroethoxyphosphoryl)
quinolylmethyl)]phosphate monohydrate (3)
ethyl
[ꢁ-anilino-N-(3-
C-4'), 126.5 (C-6), 125.8 (C-5), 124.4 (C-7), 110.1 (C-4),
2
2
62.5 (d, JPOC=6.7 Hz, OCH2), 62.3 (d, JPOC=7.2 Hz,
Yellow powder. M.p. >175 ºC decomp.; IR (KBr, cm-1):
3376 m br [ꢄ(N-H), ꢄ(O-H)], 2385 w-m [ꢄ(P-H)], 1650 sh
[ꢂ(OH, H2O)], 1603 s, 1500 s [ꢄ(C=N), ꢄ(C=C), ꢂ(NH)],
1230 sh, 1206 vs br [ꢄ(P=O)], 1085 vs, 1054 vs [ꢄ(PO-C),
ꢄ(PO-H)], 998 m, 949 s [ꢄaliph(C-C), ꢄ(P-O-P)], 749 s [ꢄ(P-
OCH2'), 53.4 (d, JPC=152.5 Hz, PCH), 16.3 (d, JPOCC=4.9
1
3
Hz, CH3), 16.0 (d, JPOCC=5.6 Hz, CH3'); 31P NMR (242.92
3
MHz, DMSO-d6): ꢅ (ppm) = 23.17; MS (+ESI): m/z 393
([M+Na]+, 17%), 371 ([M+H]+, 92%), 341 ([(M+H)-C2H4]+,
10%), 233 ([M-PO(OEt)2]+, 100%); C20H23N2O3P (370.39)
Calc. C 64.85, H 6.26, N 7.56; found C 64.29, H 5.89, N
7.63.
1
C)]; H NMR (600.13 MHz, DMSO-d6): ꢅ (ppm) = 9.02 (s,
H-2), 8.27 (s, H-4), 7.87 (d, JHH=8.1 Hz, H-5), 7.94 (d, J-
HH=8.4 Hz, H-8), 7.64 (d, JHH=7.6 Hz, H-7), 7.51 (t, JHH=7.4
Hz, H-6), 6.94 (t, JHH=7.8 Hz, H-3',5'), 6.57 (d, JHH=8.1 Hz,
H-2',6'), 6.56 (d, 1JPH=592.9 Hz, 2H, 2xPH), 6.44 (t, JHH=7.2
Hz, H-4'), 5.90 (s, NH), 4.58 (dd, 2JPH=22.1 Hz, JHH=4.1 Hz,
PCH), 3.70 (m, 6H, 3xOCH2), 1.12 (t, JHH=7.0 Hz, 6H,
2xCH3), 0.95 (t, JHH=6.9 Hz, 3H, 1xCH3); 13C NMR (150.92
Ethyl N-(3-quinolyl)phosphonamidate Monohydrate / ethyl
N-(3-quinolyl)phosphonimidate monohydrate (5)
Yellow powder. M.p. 102-104 ºC; IR (KBr, cm-1): 3396
w-m, 3336 w-m, 3190 m [ꢄ(N-H), ꢄ(O-H)], 2333 w-m [ꢄ(P-
H)], 2079 w-m br, 1967 w-m br, 1650 m [ꢄ(P(O)OH), ꢂ(OH,
H2O)], 1588 vs [ꢄ(C=N), ꢄ(C=C), ꢂ(NH)], 1205 vs [ꢄ(P=O)],
1074 m, 1049 s, 1024 m, 1005 s [ꢄ(PO-C), ꢄ(P-OH), ꢄ(P-
3
MHz, DMSO-d6): ꢅ (ppm) = 151.8 (d, JPC=1.9 Hz, C-2),
148.1 (d, 3JPC=12.3 Hz, C1'), 146.4 (C-9), 134.8 (d, 2JPC=2.2
Hz, C-3), 133.0 (C-4), 128.6 (C-3',5'), 128.5 (C-8), 128.1 (C-
7), 127.6 (C-10), 127.6 (C-5), 126.0 (C-6), 115.8 (C-4'),
1
NH)], 949 s [ꢄaliph(C-C)]; H NMR (600.13 MHz, DMSO-
d6): ꢅ (ppm) = 8.46 (d, JHH=2.7 Hz, H-2), 7.79 (d, JHH=8.3
Hz, H-8), 7.64 (d, JHH=8.1 Hz, H-5), 7.40 (t, JHH=7.5 Hz, H-
2
112.9 (C-2',6'), 59.8 (d, JPOC=4.6, 1xOCH2), 57.9 (d,
3
1
2JPOC=3.7 Hz, 2xOCH2), 55.0 (d, JPC3=134.8 Hz, PCH), 16.7
6), 7.35 (t, JHH=7.6 Hz, H-7), 7.21 (d, JHH=2.6 Hz, H-4),
1
6.74 (d,1JPH=639.8 Hz, PHminor), 6.70 (d, JPH=652.5 Hz,
3
(d, JPOCC=5.9 Hz, 1xCH3), 16.6 (d, JPOCC=6.6 Hz, 2xCH3);
31P NMR (242.92 MHz, DMSO-d6): ꢅ (ppm) = 11.68 (2P),
0.37 (1P); MS (+ESI): m/z 544 ([M+H]+, 52%), 444
([(M+Na)-2O-2EtO]+, 41%), 381 ([(M+Na)-HPO(OEt)-
PO(OEt)]+, 64%), 365 ([(M+Na)-HPO2(OEt)-HPO(OEt)]+ ꢅ
[2+Na]+, 50%), 343 ([2+H]+, 100%), 315 ([(2+H)-C2H4]+,
15%), 261 ([(2-PO(OH)2]+, 28%), 233 ([2-PO(OEt)(OH)]+,
76%); C22H33N2O9P3 (562.44) Calc. C 46.98, H 5.91, N 4.98;
found C 46.85, H 5.60, N 4.99.
PHmajor), 4.94 (br, NH, OH overlap with H2O from DMSO),
3.93, 3.91 (two q, JHH=7.1 Hz, 2H, OCH2(major)), 3.45 (q,
JHH=7.0 Hz, OCH2(minor)), 1.22 (t, JHH=7.0 Hz, CH3(major)),
1.06 (t, JHH=7.0 Hz, CH3(minor)); 13C NMR (150.92 MHz,
DMSO-d6): ꢅ (ppm) = 142.6 (C-2), 142.5 (C-3), 140.0 (C-9),
129.5 (C-10), 127.7 (C-8), 126.7 (C-6), 125.6 (C-5), 124.3
2
(C-7), 112.4 (C-4), 59.9 (d, JPOC=5.0 Hz, OCH2), 16.2 (d,
3JPOCC=6.5 Hz, CH3); 31P NMR (242.92 MHz, DMSO-d6): ꢅ
(ppm) = 4.83 (major), 1.95 (minor); MS (+ESI): m/z 145
([(M+H)-PO(OEt)]+, 100%); C11H15N2O3P (254.23) Calc. C
51.97, H 5.95, N 11.02; found C 52.04, H 5.99, N 10.78.
B. Preparation of 3-Aminoquinoline Derivatives
Equimolar amounts of benzaldehyde and 3-
aminoquinoline (ca. 1.5 mmol) were mixed and diethyl
phosphite (ca. 10% molar excess) was added. Reaction mix-
ture was quickly stirred and irradiated for 10 minutes on 90
or 115 °C. Upon addition of THF:hexane=2:1 to the reaction
mixture diester 4 immediately percipitated, separated by fil-
tration, washed with cold THF:hexane=2:1 and dried in
vacuo. Yield 64 and 66% for 90 and 115 °C, respectively.
From the filtrate that was cooled overnight in the refrigera-
CONCLUSIONS
In summary, it could be concluded that the microwave-
assisted Kabachnik-Fields reaction is efficient method for
synthesis
of
diethyl
3-quinoline-substituted
ꢀ-
aminophosphonates. In addition, it was confirmed that effi-
ciency of this method greatly depends on the quinoline (al-
dehyde and amine) reactant. Comparative studies have

16 Letters in Organic Chemistry, 2009, Vol. 6, No. 1
Juribaꢀiꢁ et al.
[6]
[7]
[8]
De Clercq, E. Clin. Microbiol. Rev., 2003, 16, 569.
shown that the aminoquinoline is less reactive than the qui-
nolylaldehyde, what could be ascribed to the relatively low
basicity of the quinolylamino group, resulting from its par-
ticipation in resonance structure with the adjacent heteroaryl
ꢀ-system. In the synthesis of both types of aminophospho-
nates described in this work, some unexpected hydrophos-
phonate derivatives were isolated as byproducts. This is the
first example of obtaining monoester hydrogen phosphonate
compounds in the course of synthesis of dialkyl ꢀ-
aminophosphonates by using either Kabachnik-Fields
method or any other known procedure for synthesis of this
kind of organophosphorus compounds. It should be pointed
out that a three-component reaction mixture of carbonyl
compound, amine and phosphite is a very complex system
with possibilities of various bimolecular processes between
reactants and the intermediate products. This may yield to
some unusual products, especially in the microwave assisted
reactions. In our systems there are at least the possibilities of
bimolecular processes in the following pairs: amine-
aldehyde, diethyl phosphite-amine and diethyl phosphite-
imine that all yielded isolable products.
Maier, L. ; Diel, P.J. Phosphorus Sulphur Silicon, 1991, 57, 57.
(a) Kozlowski, H.; Pusino, A.; Swiatek, J.; Spychala, J.; Glowiak,
T.; Micera, G.; Gessa, C. J. Agric. Food Chem., 1990, 38, 1989; (b)
Nska, H.; Bonarska, D.; Bielecki, K.; Sarapuk, J. Cell. Mol. Biol.
Lett., 2002, 7, 929.
[9]
Kafarski, P.; Lejczak, B. Curr. Med. Chem.-Anti-Cancer Agents,
2001, 1, 301.
[10]
(a) Klenner, T.; Valenzuela-Paz, P.; Amelung, F.; Münch, H.;
Zahn, H.; Keppler, B.K.; Blum, H. Platinum phosphonato
complexes with particular activity against bone malignancies. An
evaluation of an experimental model highly predictive for the clini-
cal situation, in Metal Complexes in Cancer Chemotherapy; Kep-
pler, B.K., Ed.; VCH: Weinheim, 1993; pp. 85-127; (b) Brzezin-
ska-Blaszczyk, E.; Mincikiewicz, M.; Ochocki, J. Eur. J. Pharma-
col., 1996, 298, 155; (c) Bloemink, M.J.; Diederen, J.H.; Dorenbos,
J.P.; Heeterbij, R.J.; Keppler, B.K.; Reedijk, J. Eur. J. Inorg.
Chem., 1999, 10, 1655.
(a) Tuꢀek-Boꢃiꢁ, Lj.; Matijaꢀiꢁ, I.; Bocelli, G.; Calestani, G.; Fur-
lani, A.; Scarcia, V.; Papaioannou, A. J. Chem. Soc. Dalton. Trans.,
1991, 195; (b) Tuꢀek-Boꢃiꢁ, Lj.; Furlani, A.; Scarcia, V.; De
Clercq, E.; Balzarini, J. J. Inorg. Biochem., 1998, 72, 201; (c)
Tuꢀek-Boꢃiꢁ, Lj.; Frausin, F.; Scarcia, V.; Furlani, A. J. Inorg. Bio-
chem., 2003, 95, 259; (d) Tuꢀek-Boꢃiꢁ, Lj.; Cmreꢄki, V.; Balzarini,
J.; De Clercq, E. Lett. Drug Des. Discov., 2006, 3, 528.
Lipton, A. Curr. Cancer Ther. Rev., 2005, 1, 217.
(a) Pudovik, A.N. Dokl. Akad. Nauk SSSR, 1952, 83, 865; (b) Las-
chat, S.; Kunz, H. Synthesis, 1992, 90; (c) Zon, J. Pol. J. Chem.,
1981, 55, 643; (d) Yokomatsu, T.; Yoshida, Y.; Shibuya, S. J. Org.
Chem., 1994, 59, 7930.
(a) Jagodiꢁ, V. Chem. Ber. 1960, 93, 2308; (b) Jagodiꢁ, V.; Tuꢀek,
Lj. J. Org. Chem., 1972, 37, 1222.
(a) Fields, F.K. J. Am. Chem. Soc., 1952, 74, 1528; (b) Kabachnik,
M.I.; Medved, T.Y. Dokl. Akad. Nauk SSSR, 1952, 83, 689.
Cherkasov, R.A.; Galkin, V.I. Russ. Chem. Rev., 1998, 67, 857.
(a) Bhagat, S.; Chakraborti, A.K. J. Org. Chem., 2007, 72, 1263;
and references therein; (b) Azizi, N.; Rajabi, F.; Saidi, M.R. Tetra-
hedron Lett., 2004, 45, 9233.
Kappe, C.O.; Stadler, A. Microwaves in Organic and Medicinal
Chemistry, in Methods and Principles in Medicinal Chemistry;
Mannhold, R.; Kubinyi, H.; Folkers, G., Series, Eds.; Wiley-VCH:
Weinheim, 2005; Vol. 25.
[11]
[12]
[13]
It is worth noting here a need for the development of new
synthetic approaches in design of specific aminophospho-
nates such as quinolylaminophosphonates, which may be
interesting not only because of their potential biological
properties, but also of their complexation capability towards
various metal ions. The possibility of chelate formation in-
volving quinoline ring, aminoquinoline or aniline nitrogen
donor atoms and phosphoryl or phosphonic acid oxygen
donor atoms, makes these compounds very attractive as the
complex-forming agents.
[14]
[15]
[16]
[17]
[18]
[19]
ACKNOWLEDGEMENTS
(a) Mu, X.-J.; Lei, M.-Y.; Zou J.-P.; Zhang, W. Tetrahedron Lett.,
2006, 47, 1125; (b) Kabachnik, M.M.; Zobnina E.V.; Beletskaya,
I.P. Synlett, 2005, 1393; (c) Zhang, G.; Song, B.; Xue, W.; Jin, L.;
Hu, D.; Wan, Q.; Lu, P.; Wang, H.; Yang, S.; Li Q.; Liu, G. J.
Fluor. Chem., 2006, 127, 48.
Tuꢀek-Boꢃiꢁ, Lj.; Juribaꢀiꢁ, M.; Komac, M.; Cmreꢄki, V.; Zrinski,
I.; Balzarini, J.; De Clercq, E. Lett. Org. Chem., 2007, 4, 332.
Yadav, J.S.; Reddy, B.V.S.; Madan, C. Synlett, 2001, 1131.
Kaboudin, B.; Nazari, R. Tetrahedron Lett., 2001, 42, 8211.
Zhan, Z.-P.; Yang, R.-F.; Li, J.-P. Chem. Lett., 2005, 34, 1042.
Ranu, B.C.; Hajra, A. Green Chem., 2002, 4, 551.
The financial support granted by the Croatian Ministry of
Science, Education and Sports (Grant Nos. 098-0982915-
2950 and 098-0982929-2917) is gratefully acknowledged.
The authors would like to thank Laboratory for Physical-
Organic Chemistry in the Ruꢆer Boꢀkoviꢁ Institute for using
[20]
the CEM Discover® LabmateTH/ExplorerPLS monomode
®
[21]
[22]
[23]
[24]
[25]
reactor and Mr. Ernest Sanders for recording the TG/DTA
measurements.
Failla, S.; Finocchiaro, P.; Consiglio, G.A. Heteroatom Chem.,
2000, 11, 493; and references therein.
[26]
[27]
Gancarz, R. Tetrahedron, 1995, 51, 10627.
Matveeva, E.D.; Podrugina, T.A.; Prisyajnoy, M.V.; Zefirov, N.S.
Russ. Chem. Bull. Int. Ed., 2006, 55, 1209.
Gancarz, R.; Gancarz, I. Tetrahedron. Lett., 1993, 34, 145.
Tuꢀek-Boꢃiꢁ, Lj.; D’Alpaos, M. Polyhedron, 1998, 17, 1482.
Thomas, L.C. Interpretation of Infrared Spectra of Organophos-
phorus Compounds; Plenum: New York, 1974; pp. 39-45.
Tuꢀek-Boꢃiꢁ, Lj. Vib. Spectrosc., 2002, 28, 235; and references
therein.
Tuꢀek-Boꢃiꢁ, Lj.; Komac, M.; ꢇuriꢁ, M.; Lyꢄka, A.; D'Alpaos, M.;
Scarcia, V.; Furlani, A. Polyhedron, 2000, 19, 937.
Berger, S.; Braun, S. Kalinowski, H.-O. In NMR-Spektroskopie von
Nichtmetallen, 31P-NMR-Spektroskopie; Georg Thieme Verlag:
Stuttgart, 1993; Vol. 3.
(a) Caliceti, P.; Veronese, F.M.; Marsilio, F.; Lora, S.; Seraglia, R.;
Traldi, P. Org. Mass Spectrom., 1992, 27, 1199; (b) Ma, Y.; Lui,
W.; Zhao, Y. Int. J. Mass Spectrom., 2007, 263, 185.
(a) Handbook of Chemistry and Physics; Lide, D.R., Ed.; The
Chemical Rubber Co.: Boca Raton, Florida, 1998-1999; p. 76; (b)
Tuꢀek-Boꢃiꢁ, Lj.; Trojko, R. J. Therm. Anal. Cal., 2005, 81, 153.
REFERENCES
[1]
(a) Kafarski, P.; Lejczak, B. In Aminophosphonic and Amino-
phosphinic Acids. Chemistry and Biological Activity; Kukhar, V.P.;
Hudson, H.R., Eds.; John Wiley & Sons: Chichester, 2000; pp.
407-442; (b) Atherton, F.R.; Hassall, C.H.; Lambert, R.W. J. Med.
Chem., 1986, 29, 29; (c) Du, S.; Faiger, H.; Belakhov, V.; Baasov,
T. Bioorg. Med. Chem., 1999, 7, 2671.
[28]
[29]
[30]
[31]
[32]
[33]
[2]
(a) Giannousis, P.P.; Barlett, P.A. J. Med. Chem., 1987, 30, 1603;
(b) Grembecka, J.; Mucha, A.; Cierpicki, T.; Kafarski, P. J. Med.
Chem., 1989, 32, 2461.
[3]
[4]
Atherton, F.R.; Hassall, C.H.; Lambert, R.W. J. Med. Chem., 1986,
29, 20.
Zomova, A.M.; Molodykh, Zh.V.; Kudryavtseva, L.A.;
Teplyakova, L.V.; Fedorov, S.B.; Ivanov, B.E. Pharm. Chem. J.,
1986, 20, 774.
[34]
[35]
[5]
(a) Pierre, A.; Lavielle, G.; Hautefaye, P.; Seurre, G.; Leonce, S.;
Saint-Dizier, D.; Boutin, J.A.; Cudennec, C.A. Anticancer Res.,
1990, 10, 139; (b) Jin, L.H.; Song, B.A.; Zhang, G.P.; Xu, R.Q.;
Zhang, S.M.; Gao, X.W.; Hu, D.Y.; Song Yang, S. Bioorg. Med.
Chem. Lett., 2006, 16, 1537.