Phosphomolybdic acid promoted Kabachnik-Fields reaction: An efficient one-pot synthesis of α-aminophosphonates from 2-cyclopropylpyrimidine-4- carbaldehyde

Article abstract of DOI:10.1016/j.tetlet.2014.04.053

2-Cyclopropylpyrimidin-4-yl-aryl/benzothiazole derived α- aminophosphonates were synthesized in a simple and efficient method from a three-component condensation reaction of 2-cyclopropylpyrimidin-4-carbaldehyde, various anilines/benzothiazole amines, and different phosphites by using 0.5 mol % of phosphomolybdic acid (PMA, H₃PMo₁₂O₄₀) in dichloromethane at room temperature in good to excellent yields with short reaction times.

Full text of DOI:10.1016/j.tetlet.2014.04.053

Accepted Manuscript
Phosphomolybdic acid promoted Kabachnik–Fields reaction: an efficient one-
pot synthesis of α-aminophosphonates from 2-cyclopropylpyrimidine-4-carbal-
dehyde
Pogula Sreekanth Reddy, Peddiahgari Vasu Govardhana Reddy, Sura
Mallikarjun Reddy
PII:
S0040-4039(14)00665-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.053
TETL 44515
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 February 2014
10 April 2014
15 April 2014
Please cite this article as: Reddy, P.S., Vasu Govardhana Reddy, P., Reddy, S.M., Phosphomolybdic acid promoted
Kabachnik–Fields reaction: an efficient one-pot synthesis of α-aminophosphonates from 2-
cyclopropylpyrimidine-4-carbaldehyde, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.
2014.04.053
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Tetrahedron Letters
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α-aminophosphonates from 2-cyclopropylpyrimidine-4-carbaldehyde
Pogula Sreekanth Reddya, Peddiahgari Vasu Govardhana Reddya* and Sura Mallikarjun Reddyb
2-Cyclopropylpyrimidin-4-yl-aryl/benzothiazole derived α-aminophosphonates were synthesized in a simple and efficient method from
the three-component condensation reaction of 2-cyclopropylpyrimidin-4-carbaldehyde, various anilines/ benzothiazole amines and
different phosphites by using 0.5 mol % of phosphomolybdic acid.
N
N
H
N
0.5 mol%PMA
DCM,RT
Ar-NH2/Bt-NH2
N
CHO
+
N
Ar/Bt
RO
P
O
RO
RO
O
H
P
OR
14 examples

Tetrahedron Letters
1
Tetrahedron Letters
journal homepage: www.els evier.com
Phosphomolybdic acid promoted Kabachnik–Fields reaction: an efficient one-pot
synthesis of α-aminophosphonates from 2-cyclopropylpyrimidine-4-carbaldehyde
Pogula Sreekanth Reddya, Peddiahgari Vasu Govardhana Reddya∗ and Sura Mallikarjun Reddyb
a Department of Chemistry, Yogi Vemana University, Kadapa-516003, Andhra Pradesh, India.
b Department of Chemistry, Vellore Institute of Technology, Vellore-632014, Tamil Nadu, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
2-Cyclopropylpyrimidin-4-yl-aryl/benzothiazole derived α-aminophosphonates were
synthesized in a simple and efficient method from a three-component condensation
reaction of 2-cyclopropylpyrimidin-4-carbaldehyde, various anilines/ benzothiazole
amines and different phosphites by using 0.5 mol % of phosphomolybdic acid (PMA,
H3PMo12O40) in dichloromethane at room temperature in good to excellent yields with
short reaction times.
Received in revised form
Accepted
Available online
Keywords:
Phosphomolybdic acid
2014 Elsevier Ltd. All rights reserved
2-Cyclopropylpyrimidine 4-carbaldehyde
α-Aminophosphonates
Kabachnik-Fields reaction
Significant efforts have been made to improve the biological
features of α-
organophosphorus compounds1-4 wherein
act as bifuncional catalysts in homogeneous as well as
heterogeneous conditions.8a-cAmong various heteropoly acids,
phosphomolybdic acid (PMA, H3PMo12O40) is one of the less
expensive and commercially available solid acid catalysts.
aminophosphonates constitutes an important class of compounds
in pharmaceutical chemistry with potential biological effectives
and medicinal importance due to structure analogues of amino
acid.5 Apart from this, their potential usage as anticancer
agents,6a-c herbicides,6d peptide mimetics,6e enzyme inhibitors,6f
fungicides,6g bactericides,6h and antiviral agents6i,6j is of
significant importance. Because of their versatile biological
activities, a number of methods for the synthesis of α -
aminophosphonates have been developed during the past two
decades. Of these methods, three-component Kabachnik- Fields
reaction starting from aldehydes, amines and phosphites
catalyzed by nano catalysts,7a-c heterogeneous catalysts,7d metal
Though several works focused on the synthesis and biological
tests of α-aminophosphonates have been reported, the preparation
of α-aminophosphonates from the reaction of heterocyclic
aldehydes and heterocyclic amines is limited. Owing to their
synthetic and biological values, there is a need to find new,
accessible, cheaper, and more efficient approaches to the
synthesis of α-aminophosphonates. Heterocyclic skeletons serve
as ideal scaffolds on which pharmacophores can be appended to
yield potent and selective drugs. Among them, pyrimidine
derivatives play an important role in several biological and
pharmacologically active substances such as antimicrobial and
antitumor agents.9a-c, 10 In view of this research and our desire to
develop α-aminophosphonate structures, we have designed and
synthesized a series of new α-aminophosphonates containing 2-
cyclopropylpyrimidine moiety. Herein, we report for first time
the finding of our investigations for the synthesis of new α-
aminophosphonates by three-component coupling (3CC) of 2-
7f
triflates,7e, Lewis acids,7g-i and Brønsted acids7j are common
strategic catalytic systems for the synthesis of
α
-
aminophosphonates. But most of them suffer from at least one of
the following disadvantages: harsh reaction conditions, air
sensitivity, use of stoichiometric, toxic and relatively expensive
reagents or catalysts, poor product yields, long reaction times and
tedious separation procedures. To compensate for these
deficiencies, numerous endeavors have been made giving rise to
satisfactory results in terms of efficiency and rate of the reaction.
Therefore, the development of a simple, convenient, and an
efficient protocol using inexpensive and readily available
reagents would extend the scope of the synthesis of α-amino
phosphonates. Recently, the use of heteropoly acids (HPAs) has
received great attention in organic synthesis, owing to their
commercial viability, high catalytic activity and ease of handling.
They are low-toxic and allow cleaner reactions when compared
to conventional catalysts, hence they are regarded as green
catalysts. Moreover, heteropoly acids are potent solid acids and
cyclopropylpyrimidin-4-carbaldehyde
with
amines
and
phosphites in the presence of phosphomolybdic acid
(H3PMo12O40), further the reaction conditions like optimization of
catalyst and solvent were carried out and listed in the Table 1.
Initially, we have examined the preparation of 2-cyclopropyl
pyrimidine-4-carbaldehyde (4) by following the reported
literature with some modifications in order to introduce
cyclopropyl moiety to pyramidine-4-carbaldehyde at second
position.10 In this connection, the reaction of cyclopropane
carboxamidine hydrochloride (1)11 and (E)-4-(dimethylamino)-
———
∗ Corresponding Author. Tel:+91-8562-225410, e-mail: pvgr@yogivemanauniversity.ac.in (P. V. G. Reddy)

Tetrahedron Letters
2
1,1-dimethoxybut-3-en-2-one (2)10 in the presence of Et3N base
resulted in the production of 2-cyclopropyl-4-
(dimethoxymethyl)pyrimidine (3). It was later treated with 3N
hydrochloric acid to obtain the 2-cyclopropyl pyrimidine 4-
carbaldehyde (4) (Scheme 1).
provides a wide range of α-aminophosphonate derivatives from 2-
cyclopropylpyrimidin-4-carbaldehyde in good to excellent yields.
We observed that the physical state of the title compounds (7a-n), in
which some of them (7a-f) obtained as solids when the aromatic
phosphite moiety is attached to the system while the other
compounds (7g-n) were obtained as liquids since the system has
alkyl phosphite moiety.
O
NH
N
Et3N, EtOH
.HCl
NH2
O
N
+
Table1: Influence of the catalyst and solvent on the synthesis of α-
minophosphonate (7a)a
O
N
O
O
1
2
3
N
Entry
Catalyst (mol %)
Solvent
Time
(min)
180
150
180
120
90
Yield
(%)b
60
3NHCl
N
CHO
4
a
b
c
d
e
f
AlCl3(10)
FeCl3(10)
ZnCl2(10)
Amberlyst-15c
CellSAc
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
MeOH
Scheme1: Synthesis of 2-cyclopropyl pyrimidine-4-carbaldehyde
63
62
In this article, we report an efficient and environmentally benign
protocol for the synthesis of α-aminophosphonates via Kabachnik-
Fields reaction approach from 2-cyclopropylpyrimidin-4-
carbaldehyde, anilines/ benzothiazole amines, and aromatic and
alkylphosphites in the presence of catalytic amount (0.5 mol %) of
PMA in dichloromethane at room temperatures (Scheme 2).
68
70
c
Al2O3-SiO2
90
75
g
h
I
H3PWo12O40(2)
H3PMo12O40(2)
H3PMo12O40(1)
H3PMo12O40(0.5)
H3PMo12O40(0.5)
H3PMo12O40(0.5)
H3PMo12O40(0.5)
60
90
N
N
25
92
H
N
0.5 mol%PMA
DCM,RT
Ar-NH2/Bt-NH2
5a-f
N
CHO
+
25
92
N
Ar/Bt
RO
P
O
4
RO
RO
O
H
J
25
92
P
7a-n
OR
k
l
25
88
6a-d
R=Ph, Bu, Et and Me
Ar=Ph, Cl-Ph, Br-Ph and CH3-Ph
Bt=Benzothiazole
CH3CN
DCM
25
82
m
20
95
Scheme 2. Synthesis of α-aminophosphonates from 2-cyclopropyl
pyrimidine-4-carbaldehyde.
aReaction of 2-cyclopropylpyrimidin-4-carbaldehyde (4) (1 mmol), aniline
(5a) (1 mmol) and diphenyl phosphate (6a) (1 mmol) in various solvents.
bIsolated yields.
We also screened different common Lewis acids for their ability to
catalyze the three-component Kabachnik–Fields reaction and 2-
cyclopropylpyrimidin-4-carbaldehyde, aniline, and diphenyl
phosphite were selected as models. As shown in Table 1, the
common Lewis acids such as AlCl3, FeCl3 and ZnCl2 afforded the
desired product 7a but only in moderate yield (Table 1, entries a–c).
Encouraged by these initial findings, we began a systematic
screening of various catalysts in order to improve the conversion.
The results reveal that, solid acids such as Amberlyst-15, cellulose
sulfuric acid and Al2O3-SiO2 also afforded the product 7a with
moderate yield (Table 1, entries d−f). After screening several
catalysts, the best conversions were achieved with 2 mol % of
phosphomolybdic acid (H3PMo12O40) (Table 1, entry m). No change
was observed when we decreased the amount of catalyst from 2 to
0.5 mol %. The results are summarized in Table 1. Subsequently, we
examined the effect of various solvents such as dichloromethane,
methanol, toluene and CH3CN. Of these, dichloromethane appeared
to give the best results.
cCatalyst loaded by 20 mg
The reusability of the phosphomolybdic acid (PMA) catalyst was
also examined. After each run, the product was filtered, the solvent
was evaporated, and the catalyst residue was washed with
dichloromethane and reused. For example, the reaction of 2-
cyclopropylpyrimidin-4-carbaldehyde,
aniline
and
diphenyl
phosphite in the presence of PMA gave the corresponding α-
aminophosphonate 7a in 95%, 93%, 92%, and 90% yields over four
cycles. These results indicate that the PMA catalyst is highly
efficient for the synthesis of α-aminophosphonates and could avoid
the necessity of anhydrous conditions, highly expensive and toxic
reagents, and moisture sensitive Lewis acids. The developed
methodology is simple and a substantial contribution in the field of
α-aminophosphonates.
2-Cyclopropylpyrimidin-4-yl-aryl/
aminophosphonates were obtained as racemates as evidenced by 1:1
ratio peaks in chiral HPLC (7f).
benzothiazole derived α-
Inspired by the above results, we further extended this process for
other amines and phosphites. The scope of the reaction is illustrated
with respect to various amines and phosphites and the results are
summarized in Table 2. Interestingly, diphenyl phosphite (6a)
In summary, we have demonstrated promising ability of heteropoly
acid as
underwent
a smooth coupling with 2-cyclopropylpyrimidin-4-
a solid catalyst for the synthesis of potent α-
carbaldehyde (4) under similar conditions to afford the
corresponding α-aminophosphonate (7g) in 96 % yield (entry g,
Table 2). Similarly, effective reaction was observed with other
phosphites such as dibutyl, diethyl and dimethyl phosphites in the
combination of 2-cyclopropylpyrimidin-4-carbaldehyde (4) and
various amines to obtain the respective α-amino phosphonates in
good yields (Table 2). The reaction works not only with aniline but
also with chloroaniline, p-toulidine, benzo[d]thiazol-5-amine and
benzo[d]thiazol-6-amine. All the products were characterized by IR,
(1H, 13C{1H} &31P) NMR and mass spectral analysis. This method
aminophosphonates by the Kabachnik-Fields reaction of 2-
cyclopropylpyrimidin-4-carbaldehyde, amines and phosphites. The
salient features of PMA-promoted Kabachnik-Fields reaction are
short reaction times, high conversions, and the use of easily
recyclable catalyst without loss of considerable catalytic activity.
Moreover, the use of phosphomolybdic acid (H3PMo12O40) makes
this method simple, convenient, and may be practical for the large
scale synthesis. Furthermore, studies are under progress on the
synthesis of chiral α-aminophosphonates by our newly synthesized
chiral Brønsted acids from the camphor for the same racimates.

Tetrahedron Letters
3
Table 2: Synthesis of α-aminophosphonates from 2-cyclopropyl pyrimidine-4-carbaldehyde in the presence of 0.5 mol% of PMA in dichloromethane.
Entry
a
Amine (5a-f)
Phosphite (6a-d)
Product (7a-n)
Yield (%)d Mp (°C)
N
H
N
O
NH2
N
CH
P
95
76-78
C6H5O
P
H
C6H5O
O
OC6H5
OC6H5
N
H
N
O
Cl
NH2
N
CH
b
c
92
93
80-82
78-80
C6H5O
P
H
C6H5O
P
O
OC6H5
Cl
OC6H5
N
H
N
O
Br
NH2
N
CH
P
C6H5O
P
H
C6H5O
O
OC6H5
Br
OC6H5
N
H
N
O
H3C
NH2
N
CH
d
e
92
94
76-78
C6H5O
P
H
C6H5O
P
O
OC6H5
CH3
OC6H5
N
H
N
O
H2N
N
N
N
CH
134-136
C6H5O
P
H
S
C6H5O
P
O
S
OC6H5
OC6H5
N
H
N
O
N
S
N
CH
f
92
96
130-132
C6H5O
P
H
N
C6H5O
P
O
H2N
OC6H5
S
OC6H5
N
H
N
O
NH2
N
CH
g
h
oil
C2H5O
P
H
C2H5O
P
O
OC2H5
OC2H5
N
H
N
O
N
CH
P
Cl
NH2
91
93
oil
oil
C2H5O
P
H
C2H5O
O
Cl
OC2H5
OC2H5
N
H
N
O
N
CH
P
H3C
H2N
NH2
i
j
C2H5O
P
H
C2H5O
O
CH3
OC2H5
OC2H5
O
N
S
N
H
N
N
S
C4H9O
P
H
N
CH
89
93
oil
oil
OC4H9
C4H9O
P
O
OC4H9
N
H
N
O
N
S
H2N
N
S
N
CH
k
C2H5O
P
H
C2H5O
P
O
OC2H5
OC2H5
N
H
N
CH
O
N
S
N
l
87
91
oil
oil
N
C2H5O
P
H
C2H5O
P
O
H2N
H2N
OC2H5
S
OC2H5
m
O
N
N
H
N
N
S
H3CO
P
H
N
CH
S
OCH3
H3CO
P
O
OCH3

Tetrahedron Letters
4
N
H
O
P
N
S
N
N
CH
H3CO
H
n
94
oil
N
H3CO
P
O
OCH3
H2N
S
OCH3
dIsolated yields
Subba Reddy, B. V.; Chaya, D. N.; Narayana Kumar, G.
G. K. S.; Naresh, P.; Jagadeesh, B. Tetrahedron Lett.
2009, 50, 1799–1802; (c) Yadav, J. S.; Subba Reddy, B.
V.; Pandurangam, T.; Raghavendra Rao, K. V.; Praneeth,
K.; Narayana Kumar, G. G. K. S.; Madavi, C.; Kunwar.
A. C. Tetrahedron Lett. 2008, 49, 4296-4301.
Acknowledgements
This project was supported by the Department of Science and
Technology (DST), New Delhi, India (grant SR/FT/CS-013/2010)
and is gratefully acknowledged.
9. (a) Talukdar, A.; Breen, M.; Bacher, A.; Illarionov, B.;
Fischer, M.; Georg, G.; Ye, Q.-Z.; Cushman, M. J. Org.
Chem. 2009, 74, 5123-5134; (b) Chen, X.; Adrian, J.;
Cushing, T. Di Maio, H.; Liang L.; Mayorga, V.; Miao,
S.; Peterson, M. G.; Powers, J. P.; Spector, F.; Stein, C.;
Wright, M.; Xu, Ye, D. Q.; Jaen, J. Bio Org. Med. Chem.
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Supplementary Material
Supplementary material of all experimental data, 1H, 13C {1H} & 31
NMR, HRMS spectra and chiral HPLC (7f) associated with this
article can be found in the online version, at
P
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