Organic reactions in water: A distinct novel approach for an efficient synthesis of α-amino phosphonates starting directly from nitro compounds

Article abstract of DOI:10.1021/jo901765s

(Chemical Equation Presented) A distinct approach for high-yielding synthesis of α-amino phosphonates has been discovered through three-component reaction of nitro compounds, aldehydes, or ketones and dialkyl or trialkyl phosphites using indium in dilute

Full text of DOI:10.1021/jo901765s

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SCHEME 1. Synthesis of R-Amino Phosphonates Directly
Starting from Nitro Compounds
Organic Reactions in Water: A Distinct Novel
Approach for an Efficient Synthesis of r-Amino
Phosphonates Starting Directly from Nitro
Compounds†
Biswanath Das,* Gandham Satyalakshmi,
Kanaparthy Suneel, and Kongara Damodar
TABLE 1. Synthesis of R-Amino Phosphonates Using Different
Organic Chemistry Division-I, Indian Institute of Chemical
Technology, Hyderabad 500 007, India
Metalsa
entry
metal
time (h)
yield (%)b
biswanathdas@yahoo.com
Received August 18, 2009
1
2
3
4
Zn
Sn
Fe
In
5
6
4
0.5
62
68
61
96
aReaction conditions: nitrobenzene (1 mmol), 1 N aqueous HCl
(1 mL), benzaldehyde (1 mmol), triethyl phosphite (1.3 mmol), and
5 mL of water at room temperature. bYields of isolated pure compound
after column chromatography.
reaction times, and high temperatures are the problems in
many of these methods. Herein we report a distinct approach
for the synthesis of R-amino phosphonates starting directly
from the nitro compounds.
In continuation of our work7 on the development of useful
synthesis methodologies, we have discovered that R-amino
phosphonates can be synthesized efficiently through the
three-component reaction of nitro compounds, aldehydes,
or ketones and dialkyl or trialkyl phosphites using indium in
dilute aqueous HCl at room temperature (Scheme 1).
Initially, the reaction of nitrobenzene, benzaldehyde, and
triethyl phosphite was conducted using different metals such
as Zn, Fe, Sn, and In in aqueous HCl at room temperature
(Table 1). Indium was found to be most effective in respect to
the reaction time and yield at room temperature. Recently,
indium has been utilized efficiently in various organic synth-
eses.8 The advantage with this metal is that it generally does
not affect oxygen- and nitrogen-containing functionalities.
Considering all of the benefits of using indium, subse-
quently, it was applied to prepare a series of R-amino
phosphonates from different nitro compounds, aldehydes,
or ketones and phosphites (Table 2). The conversion re-
quired only 30 min to 1.5 h to form the desired products
in excellent yields (88-96%). Various derivatives of
A distinct approach for high-yielding synthesis of
R-amino phosphonates has been discovered through three-
component reaction of nitro compounds, aldehydes, or
ketones and dialkyl or trialkyl phosphites using indium in
dilute aqueous HCl at room temperature. This one-pot
conversion consists of the following steps: (i) reduction of
nitro compounds to amines, (ii) formation of imines from
amines and carbonyl compounds, and (iii) hydrophospho-
nylation of imines.
R-Amino phosphonates are biologically and industrially
important compounds. They possess anticancer,1a anti-
HIV,1b antithrombotic,1c and antibacterial properties.1d
They are also employed as enzyme inhibitors2 and peptide
mimics.3 Additionally, they are utilized as insecticides,4a
herbicides,4b and fungicides.4c They are also applied as fire
retardants for cotton.5 Several methods have been developed
for the synthesis of these useful compounds both in racemic
and in optically active forms.6 In general, R-amino phospho-
nates are prepared from amines and carbonyl compounds or
directly from the imines. However, expensive reagents, long
(6) (a) Allen, J. G.; Atherton, F. R.; Hall, M. J.; Hassal, C. H.; Holmes,
S. W.; Lambert, R. W.; Nisbet, L. J.; Ringrose, P. S. Nature 1978, 272, 56–58.
(b) Changtao, Q.; Taishing, H. J. Org. Chem. 1998, 63, 4125–4128. (c) Ramu,
B.; Hajra, A.; Jana, H. Org. Lett. 1999, 1, 1141–1143. (d) Manabe, K.;
Kobayashi, S. Chem. Commun. 2000, 669–670. (e) Lee, S.; Park,
J. K.; Lee, J. K. Chem. Commun. 2001, 1698–1699. (f) Yadav, J. S.; Reddy,
B. V. S.; Sreedhar, P. Green Chem. 2002, 4, 436–438. (g) Joly, G. D.;
Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 4102–4103. (h) Kaboudin,
B.; Moradi, K. Tetrahedron Lett. 2005, 46, 2989–2991. (i) Pawar, V. D.;
Bettigeri, S.; Wang, S.-S.; Kan, J.-Q.; Chen, C.-T. J. Am. Chem. Soc. 2006,
128, 6308–6309. (j) Bhagat, S.; Chakraborti, A. K. J. Org. Chem. 2007, 72,
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1978–1986. (l) Bhanushali, M. J.; Nandurkar, N. S; Jagtap, S. P.; Bhanage,
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† Part 195 in the series “Studies on Novel Synthetic Methodologies”.
(1) (a) PCT Int. Appl. WO 2007045496, 2007. (b) Alonso, E.; Alonso, E.;
Solis, A.; del Pozo, C. Synlett 2000, 698–700. (c) Meyer, J. H.; Barlett, P. A.
J. Am. Chem. Soc. 1998, 120, 4600–4609. (d) Atherton, F. R.; Hasall, C. H.;
Lambert, R. W. J. Med. Chem. 1986, 29, 29–40.
(2) (a) Allen, M. C.; Fuhrer, W.; Tuck, B.; Wade, R.; Wood, J. M. J. Med.
Chem. 1989, 32, 1652–1661. (b) Bartlett, P. A.; Hanson, J. E.; Giannousis,
P. G. J. Org. Chem. 1990, 55, 6268–6274.
(3) Kafarski, P.; Lejezak, B. Phosphorus, Sulfur Silicon Relat. Elem 1991,
63, 193–215.
(4) (a) Emsley, J.; Hall, D. The Chemistry of Phosphorus; Harper and Row:
London, 1976. (b) Klesezynska, H.; Bornarska, D.; Bielecki, K.; Sarapak J. Cell
Mol. Biol. Lett. 2002, 7, 929–935. (c) Smith, W. W.; Bartlett, P. A. J. Am. Chem.
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(7) (a) Das, B.; Damodar, K.; Bhunia, N.; Kanth, B. S. Tetrahedron Lett.
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Published on Web 09/23/2009
DOI: 10.1021/jo901765s
r
2009 American Chemical Society

Das et al.
JOCNote
TABLE 2. Synthesis of R-Amino Phosphonates Using Indium in Dilute
SCHEME 2. Derived Mechanism for Synthesis of R-Amino
Phosphonates Directly Starting from Nitro Compounds
Aqueous HCl at Room Temperaturea
dinitrobenzeneproducedonly a mono-R-amino phosphonate
containing an unchanged nitro group. However, with an
alkyl nitrate, a mixture of products was obtained. It was
difficult to identify the desired product in this mixture by
1H NMR spectrum though ESIMS indicated the presence of
this product. The present conversion was found to be general
for aldehydes and ketones. Both aliphatic and aromatic car-
bonyl compounds afforded the corresponding R-amino phos-
phonates smoothly. The aromatic carbonyl compounds con-
tained electron-donating as well as electron-withdrawing
groups. An acid-sensitive aldehyde such as cinnamaldehyde
or furfuraldehyde and a sterically hindered aldehyde such as
2-naphthaldehyde furnished the desired products in impress-
ive yields. Even with ketones, the reaction was accomplished
at room temperature. The methods for the preparation of
R-amino phosphonates from both aldehydes and ketones are
limited.6c,j Moreover, with ketones, the reaction was gener-
ally conducted under reflux.6c In some methods, only aro-
matic aldehydes have been used.6e,h The present conversion
also proceeded equally with dialkyl and trialkyl phosphites.
In some earlier methods, the formation of R-amino phospho-
nates required much longer reaction times when dialkyl phos-
phites were used instead of trialkyl phosphites.6e Even in some
cases, the conversions scarcely proceeded with dialkyl phos-
phites.6d Following our present method, 26 R-amino phos-
phonates have been successfully prepared using both dialkyl
and trialkyl phosphites. The structures of the products were
settled from their spectral (IR, 1H, 13C NMR, and MS) data.
The present synthesis of R-amino phosphonates consists
of three steps in one pot. Initially, the nitro compounds
on treatment with In/HCl reduce to amines,9 which then
react with carbonyl compounds to produce the correspond-
ing imines. Finally, the imines undergo hydrophosphoryla-
tion with phosphites to form the R-amino phosphonates
(Scheme 2). When the conversion was conducted with an
amine, a carbonyl compound, and phosphite under the present
reaction conditions, the corresponding R-amino phosphonate
was also obtained in high yield and in short reaction time.
In conclusion, we have developed a novel efficient method
for the one-pot synthesis of R-amino phosphonates through
a distinct approach involving the reaction of nitro com-
pounds, aldehydes, or ketones and phosphites using indium
in dilute aqueous HCl at room temperature. The direct
application of nitro compounds, reaction in water, mild
experimental conditions, rapid conversion, and impressive
yields are the advantages of the present method. The method
is general for aliphatic and aromatic aldehydes and ketones
and for dialkyl and trialkyl phosphites.
aThe structures of the products were settled from their spectral (IR,
1H, 13C NMR, and MS) data. bYields of isolated pure compounds after
column chromatography. cTriethyl phosphite. dDiethyl phosphite. eTri-
methyl phosphite. fDimethyl phosphite.
Experimental Section
General Experimental Procedure: To a mixture of nitro
compound 1 (1.0 mmol) were added indium powder (325 mesh,
nitrobenzene were applied to prepare R-amino phospho-
nates. Different functional groups including hydroxyl, ether,
amine, and halogen remained intact. The reaction with a
(9) Lee, J. C.; Choi, K. II; Koh, H. Y.; Kang, Y.; Kim, Y.; Kang, Y.; Cho,
Y. S. Synthesis 2001, 81–84.
J. Org. Chem. Vol. 74, No. 21, 2009 8401

Das et al.
JOCNote
2 mmol), 1 N aqueous HCl (1 mL), aldehyde 2 (1.0 mmol), alkyl
phosphite 3 (1.3 mmol), and water (5 mL). The mixture was
stirred at room temperature, and the reaction was monitored by
TLC. After completion, the reaction mixture was washed with
saturated NaHCO3 solution (3 ꢀ 5 mL) and water (3 ꢀ 5 mL)
and extracted with EtOAc (3 ꢀ 5 mL). The extract was con-
centrated, and the residue was subjected to column chromatog-
raphy (silica gel, hexane/EtOAc) to obtain pure R-amino
phosphonate.
J=14.0 Hz), 130.2, 129.8, 128.2, 119.1, 113.5, 96.2, 63.4 (d, J =
6.5 Hz), 63.2 (d, J = 6.5 Hz), 51.6 (d, J = 155.2 Hz), 16.6 (d, J =
6.5 Hz), 16.2 (d, J = 6.5 Hz); ESIMS m/z 387 [M]þ, 388, 390, 392
[M þ H]þ; HRMS (ESI) m/z 410.0459 [M þ Na]þ (calcd for
C17H20Cl2NO3PNa m/z 410.0455).
Acknowledgment. The authors thank CSIR, New Delhi,
for financial assistance. They are also thankful to the NMR,
Mass and IR Divisions of IICT for recording the spectra.
Diethyl(2,4-dichlorophenyl)(phenylamino)methyl phosphonate
1
(Table 2, entry 3): IR νmax 3309, 1607, 1508, 1247 cm-1; H
Supporting Information Available: General information,
general experimental procedure, the spectral (IR, 1H, and
13C NMR, ESIMS and ESIHRMS) data and copies of NMR
(1H and 13C) and HRMS (ESI) spectra of the new R-amino
phosphonates (entries 3-10 and 21-24 in Table 2). This material
is available free of charge via the Internet at http://pubs.acs.org.
NMR (200 MHz, CDCl3) δ 7.51 (1H, d, J = 8.0 Hz), 7.40 (1H, d,
J = 2.0 Hz), 7.22 (1H, dd, J = 8.0, 2.0 Hz), 7.06 (2H, t, J = 8.0
Hz), 6.64 (1H, t, J = 8.0 Hz), 6.48 (2H, d, J = 8.0 Hz), 5.23 (1H,
dd, J = 24.0, 10.0 Hz), 4.82 (1H, t, J = 10.0 Hz), 4.25-4.12 (2H,
m), 3.91 (1H, m), 3.67 (1H, m), 1.35 (3H, t, J = 7.0 Hz), 1.11
(3H, t, J = 2.0 Hz); 13C NMR (50 MHz, CDCl3) δ 146.2 (d,
8402 J. Org. Chem. Vol. 74, No. 21, 2009