Tartaric acid-catalyzed synthesis of α-aminophosphonates under solvent-free conditions

Article abstract of DOI:10.1080/00397911.2010.515358

A facile procedure is developed for the synthesis of α- aminophosphonates, using tartaric acid as a stable, environmentally benign, low cost, and easily available organocatalyst. In the presence of tartaric acid (10 mol%), triethyl phosphite reacts with imines (generated in situ from an aldehyde and an amine) to yield the corresponding α-aminophosphonates. The organocatalyst tartaric acid is more stable during reaction. The catalyst provides easier workup, affords better yields, and takes less reaction time in comparison to generally used Lewis acid catalysts. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.515358

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Tartaric Acid–Catalyzed Synthesis of α-
Aminophosphonates Under Solvent-Free
Conditions
Nidhi Gangwar a & Virendra Kumar Kasana a
a Department of Chemistry, College of Basic Sciences and
Humanities, G. B. Pant University of Agriculture and Technology,
Pantnagar, Uttarakhand, India
Published online: 29 Jun 2011.
To cite this article: Nidhi Gangwar & Virendra Kumar Kasana (2011): Tartaric Acid–Catalyzed Synthesis
of α-Aminophosphonates Under Solvent-Free Conditions, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 41:18, 2800-2804
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Synthetic Communications1, 41: 2800–2804, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.515358
TARTARIC ACID–CATALYZED SYNTHESIS
OF a-AMINOPHOSPHONATES UNDER
SOLVENT-FREE CONDITIONS
Nidhi Gangwar and Virendra Kumar Kasana
Department of Chemistry, College of Basic Sciences and Humanities,
G. B. Pant University of Agriculture and Technology, Pantnagar,
Uttarakhand, India
GRAPHICAL ABSTRACT
Abstract A facile procedure is developed for the synthesis of a-aminophosphonates, using
tartaric acid as a stable, environmentally benign, low cost, and easily available
organocatalyst. In the presence of tartaric acid (10 mol%), triethyl phosphite reacts with
imines (generated in situ from an aldehyde and an amine) to yield the corresponding a-
aminophosphonates. The organocatalyst tartaric acid is more stable during reaction. The
catalyst provides easier workup, affords better yields, and takes less reaction time in
comparison to generally used Lewis acid catalysts.
Keywords a-Aminophosphonates; organocatalyst; tartaric acid; triethyl phosphite
INTRODUCTION
Because of their structural analogy to a-amino acids, a-aminophosphonates
have been the subject of considerable interest. They function as inhibitors of enzymes
involved in the metabolism of proteins and amino acids. These compounds have
already been found to act as antibacterial agents, neuroactive compounds, anti-
cancer drugs, and pesticides, with some of them being commercialized. The altered
activity of such enzymes has been associated with HIV infections and several patho-
logical disorders, including cancer and cataracts.[1]
Organophosphorous compounds have been known for more than 50 years.[2]
Many of them exhibit biological activity and are widely used as potent herbicides.
Received May 6, 2010.
Address correspondence to Nidhi Gangwar, Department of Chemistry, College of Basic Sciences
and Humanities, G. B. Pant University of Agriculture and Technology, Pantnagar 263145,
Uttarakhand, India. E-mail: gangwar.nidhi@gmail.com
2800

a-AMINOPHOSPHONATES SYNTHESIS
2801
Perhaps the best known are glyphosate,[3] trakephon,[4] and amino phosphonic acid
derivatives of fluorine.[5] It was suggested that the biological activity of these are
correlated to their lipophilicity.[6]
Nucleophilic addition of phosphate onto imines, catalyzed by a base or an acid,
has emerged as an important alternative for the synthesis of a-aminophosphonates
derivatives. Generally, Lewis acids such as SnCl2, SnCl4, BF3 ꢀ OEt2, ZnCl2, MgBr2,
and InCl3 have been used as catalysts.[7]
However, these reactions could not be carried out efficiently in a single-step
operation with the carbonyl, amine, and phosphite functionalities because water
formed during imine formation can decompose or deactivate these Lewis acids.
There is a need to develop a one-pot synthesis of a-aminophosphonates catalyzed
by a water-tolerant Lewis acid.[8]
Organocatalysis has emerged as an important area of research over recent dec-
ades.[9] It is well known that organocatalyst tartaric acid is a relatively stable,
easy-to-handle solid that is insensitive to small amounts of air and moisture. Herein,
a mild and efficient protocol for the synthesis of a-aminophosphonates was under-
taken using a catalytic amount of organocatalyst tartaric acid under solvent-free
conditions.
RESULTS AND DISCUSSION
We explored the effectiveness and compativility of tartaric acid as a catalyst for
the generation of a-aminophosphonates. Thus, the reaction of triethyl phosphite
with imines generated in-situ from substituted benzaldehyde and aniline or p-anisi-
dine at 50 ꢁC in the presence of 10 mol% of tartaric acid without using any solvent
afforded the corresponding a-aminophosphonate in good yield (Table 1). The reac-
tion was completed in 2 h, and the product was isolated by extraction with water and
dichloromethane in high purity. To the best of our knowledge, this is the first dem-
onstration of tartaric acid–catalyzed synthesis of a-aminophosphonates.
Several aromatic aldehydes were examined using different amounts of tartaric
acid. Finally, it was found that 10 mol% of tartaric acid was optimum to catalyze the
Table 1. Synthesis of a-aminophosphonate derivatives
Compound
R1
R2
Yield (%)
A
B
C
D
E
F
G
H
I
H
H
83
89
77
62
78
71
81
71
78
65
74
78
4-OCH3
2-Cl
H
H
4-OH
4-CH3
4-F
H
H
H
2-OCH3
3-OCH3
4-Cl
H
H
H
J
H
4-OCH3
4-OCH3
4-OCH3
K
L
4-OCH3
2-Cl

2802
N. GANGWAR AND V. K. KASANA
Scheme 1. Mechanism of synthesis of a-aminophosphonate.
reaction efficiently. The results are shown in Table 1. In all cases, the reaction
proceeded smoothly to give the corresponding a-amino phosphonates in good yields.
Most important, aromatic aldehydes carrying either electron-donating or electron-
withdrawing substituents including hydroxy groups reacted efficiently, giving
excellent, yields. The mechanism of this reaction is believed to involve, at first, the
formation of the activated imine so that addition of phosphite is facilitated to afford
phosphonium intermediate, which then undergoes reaction with water generated
during formation of imine to give a-amino phosphonates and ethanol as shown
in Scheme 1.[10]
CONCLUSIONS
We have successfully demonstrated the use of tartaric acid as a catalyst, for the
first time, to the three-component, high-yielding synthesis of a-aminophosphonates.
The tartaric acid is stable and does not show any decrease in its catalytic activity due
to in-situ generated water during the course of the reaction.
EXPERIMENTAL
A mixture of benzaldehyde (10 mmol), tartaric acid (10 mol%), aniline (10 mm),
and triethyl phosphite (11 mm) was stirred vigorously on a magnetic stirrer at 50 ꢁC
for approximately 2 h (Scheme 2).
The reaction was monitored from time to time by running reaction mixtures on
silica-gel thin-layer chromatography (TLC) plates using a hexane and ethyl acetate
(80:20) solvent system. After completion of the reaction, the reaction mixture was
quenched with aqueous saturated NaHCO3 and then extracted with dichloro-
methane. The organic layer was washed with water and brine. The organic extracts
were combined, dried over sodium sulfate or magnesium sulfate, and concentrated
under reduced pressure to give the crude products. The residue was purified by
recrystallization with chloroform.

a-AMINOPHOSPHONATES SYNTHESIS
2803
Scheme 2. Synthesis of a-aminophosphonate derivatives using tartaric acid.
Diethyl(phenylamino)(phenyl)methylphosphonate (A)
IR (KBr), 3392, 1235, 1018, 759 cmꢂ1. 1H NMR (CDCl3, TMS): d 1.138 (t, 3H,
J ¼ 7 Hz, OCH2CH3), 1.310 (t, 3H, J ¼ 7 Hz, OCH2CH3), 3.962 (q, 2H, J ¼ 7 Hz,
OCH2CH3), 4.139 (q, 2H, J ¼ 7 Hz, OCH2CH3), 4.186 (bs, 1H, NH), 4.793 (d, 1H,
CH), 6.610–7.304 (m, 10H, C6H5); 13C NMR (CDCl3, TMS): d 56.67, 63.28,
76.81, 77.06, 77.32, 113.87, 118.41, 127.89, 128.60, 129.18.
Diethyl(phenylamino)(4-ethoxyphenyl)methylphosphonate (B)
IR (KBr), 3373, 1234, 1022, 757 cmꢂ1. 1H NMR (CDCl3, TMS): d 1.152 (t, 3H,
J ¼ 7 Hz, OCH2CH3), 1.343 (t, 3H, J ¼ 7 Hz, OCH2CH3), 3.739 (q, 2H, J ¼ 7 Hz,
OCH2CH3), 3.829 (s, 3H, OCH3), 4.135 (q, 2H, J ¼ 7 Hz, OCH2CH3), 4.769 (d,
1H, CH), 4.165 (bs, 1H, NH), 6.609–7.29 (m, 10H, C6H5); 13C NMR (CDCl3,
TMS): d 16.24, 16.29, 16.43, 16.47, 54.82, 55.24, 56.03, 63.21, 63.25, 77.03, 113.91,
114.06, 118.36, 127.72, 128.98, 146.45, 159.34.
Diethyl(phenylamino)(2-chlorophenyl)methylphosphonate (C)
IR (KBr), 3236, 1235, 1016, 754 cmꢂ1. 1H NMR (CDCl3, TMS): d 1.090 (t, 3H,
J ¼ 7 Hz, OCH2CH3), 1.362 (t, 3H, J ¼ 7 Hz, OCH2CH3), 3.923 (q, 2H, J ¼ 7 Hz,
OCH2CH3), 4.230 (q, 2H, J ¼ 7 Hz, OCH2CH3), 5.00 (bs, 1H, NH), 5.410 (d, 1H,
CH), 6.605–7.603 (m, 10H, C6H5); 13C NMR (CDCl3, TMS): d 16.32, 51.01,
52.23, 63.45, 77.02, 113.56, 118.54, 127.37, 129.09, 134.21, 145.80.
ACKNOWLEDGMENT
The authors thank the Instrumentation Centre, Indian Institute of Technology,
Roorkee, India, for obtaining NMR and IR spectra.
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2804
N. GANGWAR AND V. K. KASANA
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