A catalyst-free synthesis of α-aminophosphonates in glycerol

Article abstract of DOI:10.1016/j.tetlet.2014.11.057

A simple and efficient method is described using glycerol as a solvent in the catalyst-free synthesis of α-aminophosphonates in high purity. Products are prepared by the Kabachnik-Fields reaction from amines, phosphites, and carbonyl compounds. The method does not require a toxic catalyst.

Full text of DOI:10.1016/j.tetlet.2014.11.057

Accepted Manuscript
A catalyst-free synthesis of α-aminophosphonates in glycerol
Kobra Azizi, Meghdad Karimi, Akbar Heydari
PII:
S0040-4039(14)01950-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.11.057
TETL 45441
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
30 June 2014
31 October 2014
13 November 2014
Please cite this article as: Azizi, K., Karimi, M., Heydari, A., A catalyst-free synthesis of α-aminophosphonates in
glycerol, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.11.057
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α-aminophosphonates in glycerol
Kobra Azizi, Meghdad Karimi, Akbar Heydari *

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A catalyst-free synthesis of α-aminophosphonates in glycerol
Kobra Azizi, Meghdad Karimi, Akbar Heydari
Chemistry Department, Tarbiat Modares University, Tehran, Iran
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple and efficient method is described using glycerol as a solvent in the catalyst-free
synthesis of α-aminophosphonates in high purity. The products are prepared by the Kabachnik–
Fields reaction from amines, phosphites, and carbonyl compounds. The method is does not
require a toxic catalyst.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
α-Aminophosphonates
Glycerol
Kabachnik–Fields
Phosphites
Carbonyl compounds
α-Aminophosphonic acids and their derivatives exhibit a wide
range of biological properties,1 and are able to function as α-
aminocarboxylic acid surrogates.2 α-Aminophosphonate esters
have attracted attention because not only are they biologically
attractive peptide mimics of α-amino acids, but they also exhibit
intriguing biological activities.3 α-Aminophosphonates play a
significant role in hapten design for antibody generation.4
α-Aminophosphonic acids act as herbicides,5 and antibacterial,1,6
antiviral and antitumor agents.7 Owing to their widespread
applications, different strategies for the synthesis of these
compounds have been designed. One known approach in this
field is Kabachnik–Fields reaction.8 In this reaction, a carbonyl
compound (aldehyde or ketone), an amine and a di- or trialkyl
phosphite react in a one-pot fashion in the presence of either a
Lewis acid or a Brønsted acid. A variety of acid catalysts such as
CAN,9 Mg(ClO4)2,10 TaCl5–SiO2,11 an ethereal solution of LiClO4
12 and other catalysts such as quinine,13 and a bis(8-quinolinolato)
(TBOx) aluminum(III) complex14 have been used in methylene
chloride or other organic solvents to promote this addition. Since
the amines and the water that form during imine formation can
decompose or deactivate some of the catalysts, these reactions
cannot be carried out in a ‗one-pot‘ operation.
trifluoroethanol (TFE)15 and deep eutectic solvents (DES)16 for
chemical synthesis.
Glycerol is produced as a co-product during the production of
long-chain carboxylate salts used as soaps, and because of the
presence of three hydroxyl groups that are responsible for its
solubility in water and its hygroscopic nature, it can act as a
hydrogen bond donor and water attracting agent. Glycerol is a
simple polyol, and a colorless, odorless, viscous liquid that is
widely used in pharmaceutical formulations, and is one of the
most important biomass-derived materials. It is the simplest
trihydric alcohol and its chemical nature is similar to that of other
alcohols. Glycerol is widely used as a solvent because it can
accelerate considerably the rate of an organic reaction. The
primary hydroxyls are usually more reactive than the secondary
group, and the first OH to react does so more readily than the
second.17 Glycerol can be considered as ―organic water‖ since,
like water, it is abundant, biodegradable, inexpensive, non-toxic,
highly polar, immiscible with hydrocarbons, is able to form
strong hydrogen-bond networks and can dissolve a wide range of
organic and inorganic compounds, including transition metal
catalysts.18
In addition, compared to water, it has the advantage of a higher
boiling point, lower vapor pressure, and is able to dissolve
organic compounds usually immiscible with water.19
However,
organic
solvents,
particularly
chlorinated
hydrocarbons, are high on the list of damaging chemicals because
of their volatile nature, considerable toxicity, and their use in
large quantities. Additionally, the metal halides utilized as
catalysts in these procedures are not all ecofriendly, and often
entail severe environmental pollution during the waste disposal
process. These problems encourage researchers to design new
green and catalyst-free strategies, such as solvent-free methods or
One of the possible uses of glycerol and its derivatives is as a
solvent. Just like the majority of organic substances, organic
solvents are petroleum-derived, and many are volatile, toxic, and
harmful compounds. Glycerol has previously been used as a
solvent for the aza-Michael addition of aromatic amines to
electron-deficient α,β-unsaturated ketones.
use of media with dual solvent/catalyst roles, e.g.
t—he——
Based on these reports,8, 20 we decided to explore the possibility
 Corresponding Author: Tel.: (+98)-21-82883444; fax: (+98)-21- 82883455; e-mail: heydar_a@modares.ac.ir (A. Heydari)

2
Tetrahedron
of executing a three-component Kabachnik–Fields reaction for
give good yields of the desired products. Both aromatic and aliphatic
amines provided excellent yields of products (70–95%) in short
reaction times. Also, cyclohexanone gave the corresponding
phosphonate in good yield (80%). Furthermore, diethyl phosphite
and diphenyl phosphite demonstrated good activity.
the preparation of α-aminophosphonates from amines,
phosphites, and carbonyl compounds in glycerol (Scheme 1).
Glycerol has been described as an effective promoting medium
for these kinds of reactions which are conventionally carried out
using acid catalysts.21
Scheme 1: Non-catalyzed Kabachnik–Fields reaction in
glycerol
In order to establish the optimum conditions for the reaction, the
results of the model reaction between aniline, benzaldehyde and
dimethyl phosphite in conventional solvents were compared with
glycerol (Table 1). The use of glycerol led to a much better result
than with conventional organic solvents including toluene, THF,
CH2Cl2, CHCl3, CH3CN, methanol, ethanol and water at room
temperature for 10 hours. Glycerol has been used as a green solvent
in the synthesis of phosphonates in examples where it facilitated the
solubility of the organic reagent.
Table 1: Comparison of the results of the synthesis of
α-aminophosphonates in different solvents a
Entry
Solvent
toluene
CHCl3
THF
CH2Cl2
CH3CN
MeOH
EtOH
Yield (%)b
1
2
3
4
5
6
7
8
9
0
0
0
0
trace
trace
25
40
70
H2O
glycerol
a Reaction conditions: benzaldehyde (1 mmol), aniline (1 mmol),
dimethyl phosphite (1.1 mmol), solvent, room temperature, 10 h.
b Yield of isolated pure product
Figure 2: Products of the Kabachnik–Fields reactions of various carbonyl
compounds, amines and phosphites in glycerol
In this case, the hydrogen-bonding activation of glycerol resulted in
catalysis of the Kabachnik–Fields reaction (Scheme 2). According to
this mechanism, glycerol catalyzed the in situ formation of the imine
intermediate through generation of hydrogen bonds between the
hydroxyl groups and the oxygen atom of the carbonyl group. In the
presence of glycerol, the imine carbon is attacked by dimethyl
phosphite to give the product.24
Subsequently we determined the optimum temperature for this model
reaction.
Temperature
optimization
revealed
that
60-80 °C was suitable to provide the best yield of
the α-aminophosphonate (Figure 1).
Figure 1: Effect of the reaction temperature on aminophosphonate yield
Several α-aminophosphonates were prepared using the optimized
reaction conditions (Figure 2). Aromatic aldehydes generated
phosphonate derivatives in good to excellent yields and the products
were characterized by comparison of their physical data with those
of known compounds.22,23 Acid-sensitive aldehydes such as
thiophene-2-carbaldehyde and cinnamaldehyde underwent the
reaction with aniline and dimethyl phosphite to produce the
corresponding α-aminophosphonates. Several other aniline
derivatives were coupled with aldehydes and phosphite derivatives to
Scheme 2: A plausible mechanism for the one-pot synthesis
of α-aminophosphonates in glycerol

3
4. R. Hirschmann, A. B. Smith III, C. M. Taylor, P. A. Benkovic,
S. D. Taylor, K. M. Yager, P. A. Sprengeler, S. J. Benkovic,
Science 994, 265, 234.
5. G.C.S. Reddy, S. Annar, K.U.M. Rao, A. Balakrishna, C.S.
Reddy, Pharm. Chem. 2010, 2, 177.
The recyclability of glycerol was investigated in the case of
the reaction of aniline, benzaldehyde and
dimethyl phosphite. Upon completion of the reaction, the mixture
was extracted with hexane–ethyl acetate. The glycerol phase
(glycerol is insoluble in hydrocarbons) was dried and reused up
to four more times without any significant reduction in the
product yield (from 90% on the first use to 80% on the fourth)
(Table 2).
6. R. F. Pratt, Science 1989, 246, 917.
7. (a) J. Huang and R. Chen, Heteroatom Chem. 2000, 480; (b) G.
Lavielle, P. Hautefaye, C. Schaeffer, J. A. Boutin, C. A.
Cudennec, and A. Pierré, , J. Med. Chem. 1991, 34, 1998.
8. (a) M. J. Kabachnik, T. Medved. Izv. Akad. Nauk SSSR 1953,
1126; (b) M. J. Kabachnik, T. Medved. Izv. Akad. Nauk SSSR
1954, 1024; (c) E. K. Fields, J. Am. Chem. Soc. 1952, 74, 1528.
9. M. Kasthuraiah, K. A. Kumar, C. S. Reddy, C. D. Reddy
Heteroatom Chem. 2007, 18, 2.
Table 2: Reusability of glycerol in the
Kabachnik–Fields reactiona
Run
1
2
3
4
Isolated Yield (%)b
90
87
82
80
10. S. Bhagat A. K. Chakraborti, J. Org. Chem. 2007, 72, 1263.
11. S. Chandrasekhar,S. Jaya Prakash, V. Jagadeshwar, Ch.
Narsihmulu, Tetrahedron Lett. 2001, 42, 5561.
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a
39, 6729.
Reaction conditions: benzaldehyde (1 mmol),
13. D. Pettersen, M. Marcolini, L. Bernardi, F. Fini, R. P. Herrera, V.
Sgarzani, A. Ricci, J. Org. Chem. 2006, 71, 6269.
aniline
(1.1
mmol),
dimethyl
phosphite
(1 mmol), 20 min. b Yield of isolated pure product
14. J. P. Abell, H. Yamamoto, J. Am. Chem. Soc. 2008, 130, 10521.
15. (a) A. Heydari, S. Khaksar, M. Tajbakhsh, H. R. Bijanzadeh, J.
Fluorine Chem. 2009, 130, 609; (b) S. Khaksar, A. Heydari, M.
Tajbakhsh, S. M. Vahdat, J. Fluorine Chem. 2010, 131, 1377.
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Lett. 2012, 53, 5151; (b) B. Singh, H. Lobo, G. Shankarling,
Catal. Lett. 2011, 141,178.
Finally, a comparative study of this system with our recent
report on the one-pot synthesis of α-aminophosphonates in the
presence of dehydroascorbic acid (DHAA) capped magnetite
nanoparticles24 revealed that this system is comparable in terms
of the reaction time and catalyst-free conditions.
17. K.Weissermel, H. J. Arpe, Industrial Organic Chemistry John
Wiley & Sons, 2008.
Glycerol is one of the renewable resources produced as a
waste chemical during the production of fatty acids, biofuels and
biolubricants in quantities greater than the current demand. The
abundant availability of glycerol as a waste at low cost has drawn
much attention aimed toward its use in academia and industry.
18. Y. Gu, J. Barrault, F. Jérôme, Adv. Synth. Catal. 2008, 350, 2007.
19. A. E. Díaz-Álvarez, J. Francos, P. Crochet, V. Cadierno, Curr.
Green Chem. 2014, 1, 51.
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Reddy, B. S. Kumar, A. Balakrishna,C. S. Reddy, S. K. Nayak, C.
D. Reddy, Arkivoc 2007, xv, 246.
In conclusion, we have shown that glycerol combines the
advantages of water (low toxicity, low cost, ready availability,
renewability) and ionic liquids (high boiling point, low vapor
pressure). The advantages of glycerol for this synthesis of -
aminophosphonates include: (i) the non-assistance of acid
catalysts, which not only simplifies the work-up procedure and
minimizes the generation of waste, but also allows the use of
acid-sensitive substrates; (ii) easy separation of the reaction
products; and (iii) no volatile organic solvent was required for the
reaction to occur.
21. (a) H. M. Bachhav, S. B. Bhagat, V. N. Telvekar, Tetrahedron
Lett. 2011, 52, 5697; (b) V. B. Jagrut, D. L. Lingampalle, P.D.
Netankar, W. N. Jadhav, Pharma Chem. 2013, 5, 8.
22. General procedure for the synthesis of α-aminophosphonates in
glycerol: A mixture of carbonyl compound (1 mmol), amine (1
mmol) and phosphite (1.1 mmol) was stirred at 60-80 °C in
glycerol (4 mmol) for 5-30 min. After completion of the reaction
as indicated by TLC, the mixture was extracted with EtOAc. The
combined organics were dried and evaporated under reduced
pressure. The residue was purified by recrystallization from
CH2Cl2/n-hexane. The identity of the products was confirmed by
comparison of their spectroscopic data with literature data.
23. Dimethyl 1-(phenylamino)cyclohexylphosphonate: yellow solid,
1H NMR (400 MHz, CDCl3): δ = 1.30–1.51 (m, 6H), 1.55–2.12
(4H, m), 3.63 (d, J = 10.4 Hz, 3H), 3.65 (d, J = 10.4 Hz, 3H), 4.50
(br s, 1 H), 7.01 (t, J = 7.1 Hz, 1H), 7.14 (d, J = 8.1 Hz, 2H), 7.17
(t, J = 8.1 Hz, 2H). 13C NMR (100 MHz, CDCl3): δ = 19.8, 26.6,
26.1, 53.2 (d, J = 7.4 Hz), 54.1 (d, J = 7.4 Hz), 66.8 (d, J = 155.1
Hz), 118.4, 118.5, 130.1, 146.7.
Acknowledgments
We are thankful to Tarbiat Modares University for partial support of
this work.
References and notes
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