Metal-free multicomponent synthesis of (α-aminoalkyl)phosphonates using 2,4,6-trichloro-1,3,5-triazine

Article abstract of DOI:10.1002/hlca.201100037

(α-Aminoalkyl)phosphonates have efficiently been synthesized by multicomponent reaction of aldehydes, amines, and triethyl phosphite in the presence of 2,4,6-trichloro-1,3,5-triazine at room temperature. The products are formed in high yields (83-91%) within 0.5-1h. Copyright

Full text of DOI:10.1002/hlca.201100037

Helvetica Chimica Acta – Vol. 94 (2011)
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Metal-Free Multicomponent Synthesis of (a-Aminoalkyl)phosphonates Using
2,4,6-Trichloro-1,3,5-triazine1)
by Biswanath Das*, Avula Satya Kumar, and Jayprakash Narayan Kumar
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500007, India
(phone: þ 91-40-7193434; fax: þ 91-40-7160512; e-mail: biswanathdas@yahoo.com)
(a-Aminoalkyl)phosphonates have efficiently been synthesized by multicomponent reaction of
aldehydes, amines, and triethyl phosphite in the presence of 2,4,6-trichloro-1,3,5-triazine at room
temperature. The products are formed in high yields (83 – 91%) within 0.5 – 1 h.
Introduction. – (a-Aminoalkyl)phosphonic acid and their derivatives possess
various valuable medicinal properties including anticancer, anti-HIV, and antibacterial
activities [1]. They are also applied as enzyme inhibitors and peptide mimics [2].
Additionally, they are useful as pesticides [3]. Thus, the synthesis of these compounds is
an important goal for the organic chemists, and some methods have been developed for
their preparation [4]. However, application of costly and toxic metal-based reagents,
high temperature, long reaction time, or operational complexity are the drawbacks in
many of these methods. Here, we report a simple synthesis of (a-aminoalkyl)phos-
phonates under metal-free conditions.
Results and Discussion. – In continuation of our work [5] on the development of
useful synthetic methodologies, we have observed that the multicomponent reaction of
aldehydes 1, amines 2, and triethyl phosphite ((EtO)3P) in the presence of 2,4,6-
trichloro-1,3,5-triazine (TCT) yielded the (a-aminoalkyl)phosphonates 3 at room
temperature (Scheme 1).
Scheme 1
A series of (a-aminoalkyl)phosphonates was efficiently prepared from various
aldehydes and amines following the above method (Table). Both aromatic and
aliphatic aldehydes were applied to prepare these compounds. The aromatic aldehydes
1
)
Part 220 in the series, ꢂStudies on Novel Synthetic Methodologiesꢃ.
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 94 (2011)
Table. Synthesis of a-Amino Phosphonates Using Trichloro Triazine (TCT)a)
Entry
R1
R2
Time [min]
Yieldb) [%]
Product
1
2
3
4
5
6
7
8
9
10
11
12
13
Ph
Ph
Ph
4-MeꢀC6H4
35
60
40
50
60
30
35
45
40
40
45
60
60
90
86
87
87
91
88
90
86
91
89
89
84
83
3a
3b
3c
3d
3e
3f
3g
3h
3i
4-HOꢀC6H4
4-BrꢀC6H4
4-MeꢀC6H4
4-HOꢀC6H4
4-EtOꢀC6H4
4-iPrꢀC6H4
2,4-(Cl)2ꢀC6H3
4-Cl,3-FꢀC6H3
2-NO2ꢀC6H4
4-NO2ꢀC6H4
Pr
4-MeOOCꢀC6H4
4-MeOOCꢀC6H4
Ph
Ph
Ph
4-MeꢀC6H4
Ph
Ph
Ph
Ph
3j
3k
3l
Pentyl
3m
a) The structures of the products were deduced from their spectral (IR, 1H- and 13C-NMR, and MS) and
analytical data. b) Yields of isolated pure products after column chromatography.
and the anilines used for this conversion contained electron-donating as well as
electron-withdrawing groups. Various functional groups such as halogen, OH, NO2, and
ester remained unchanged. The conversion was complete within 0.5 – 1 h, and the
products were formed in high yields (83 – 91%). The structures of the products were
1
established from their spectral (IR, H- and 13C-NMR, and MS) and analytical data.
TCT is an inexpensive solid material. It reacts with the H2O generated by the
reaction of aldehydes and amines (during the formation of imines) or with incipient
moisture to release HCl [6]. This acid subsequently activates the ¼C¼Nꢀ bond of the
imines to produce (a-aminoalkyl)phosphonates (Scheme 2).
TCT is easy to handle and is safe to use compared to the direct application of protic
acid. Expensive and toxic metal-based reagents have also been avoided.
Conclusions. – We have developed a simple and efficient method for the synthesis
of (a-aminoalkyl)phosphonates 3 by a one-pot reaction of aldehydes, amines, and
Scheme 2

Helvetica Chimica Acta – Vol. 94 (2011)
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(EtO)3P using TCT at room temperature. The mild reaction conditions, excellent
yields, rapid conversion, and application of a metal-free safe reagent are the notable
advantages of this method.
Experimental Part
General. Column chromatography (CC): silica gel (SiO2; BDH 100 – 200 mesh). Thin layer
chromatography (TLC): silica gel GF 254 (Merck) plates. IR Spectra: Perkin Elmer RX1 FT-IR
spectrophotometer. 1H- and 13C-NMR spectra: Varian Gemini 200 MHz spectrometer; CDCl3 as solvent;
at 200 MHz and 50 MHz, resp. ESI-MS: LC-MSD Trap-SL spectrometer. Elemental analyses: Elementar
Vario EL instrument. Characterization data are provided only for novel compounds.
(a-Aminoalkyl)phosphonates. A mixture of an amine (1.2 mmol) and an aldehyde (1.0 mmol) in
MeCN (5 ml) was stirred for a few min at r.t., and P(OEt)3 (1.5 mmol) and TCT (10 mol-%) were added.
The mixture was stirred for the appropriate time and the progress of the reaction was monitored by TLC.
After completion of the reaction (determined by TLC), the solvent was evaporated, and H2O (10 ml)
was added. The mixture was extracted with AcOEt (3 ꢁ 10 ml), and the extract was dried (anh. Na2SO4)
and concentrated. The residue was purified by CC (SiO2; AcOEt in hexane) to afford a pure (a-
aminoalkyl)phosphonate.
Diethyl {[(4-Methylphenyl)amino](phenyl)methyl}phosphonate (3a). IR (KBr): 3292, 1622, 1504,
1
1243. H-NMR: 7.31 – 7.26 (m, 2 H); 7.10 – 7.01 (m, 4 H); 6.61 (t, J ¼ 8.0, 1 H); 6.51 (d, J ¼ 8.0, 2 H);
4.75 – 4.66 (m, 2 H); 4.15 – 4.02 (m, 2 H); 3.91 – 3.89 (m, 1 H); 3.62 – 3.60 (m, 1 H); 2.31 (s, 3 H); 1.28 (t,
J ¼ 7.0, 3 H); 1.12 (t, J ¼ 7.0, 3 H). 13C-NMR: 144.8; 137.2 (d, J ¼ 10.0); 129.2; 127.9; 126.8; 126.0; 114.2;
63.0 (d, J ¼ 6.0); 55.2 (d, J ¼ 152.0); 23.7; 16.0 (d, J ¼ 10.5). ESI-MS: 351 ([M þ NH4]þ). Anal. calc. for
C18H24NO3P (333.36): C 64.85, H 7.26, N 4.20; found: C 65.34, H 7.20, N 4.27.
Methyl 4-{[(Diethoxyphosphoryl)(4-methylphenyl)methyl]amino}benzoate (3d). IR (KBr): 3310,
1707, 1606, 1523, 1437, 1275. 1H-NMR: 7.80 (d, J ¼ 8.0, 2 H); 7.32 (d, J ¼ 8.0, 2 H); 7.13 (d, J ¼ 8.0, 2 H);
6.60 (d, J ¼ 8.0, 2 H); 5.50 (t, J ¼ 10.0, 1 H); 4.79 (dd, J ¼ 24.0, 10.0, 1 H); 4.15 – 4.06 (m, 2 H); 3.92 – 3.88
(m, 1 H); 3.81 (s, 3 H); 3.63 – 3.61 (m, 1 H); 2.02 (s, 3 H); 1.10 (t, J ¼ 7.0, 3 H); 0.88 (t, J ¼ 7.0, 3 H).
13C-NMR: 166.2; 151.0; 135.9; 133.4 (d, J ¼ 10.0); 129.2; 128.1; 126.8; 118.2; 113.8; 63.1 (d, J ¼ 6.0); 55.9
(d, J ¼ 152.0); 50.5; 24.2; 16.2 (d, J ¼ 10.5). ESI-MS: 392 ([M þ H]þ). HR-ESI-MS: 392.1630 ([M þ
H]þ, C20H27NO5Pþ; calc. 392.1626).
Methyl 4-{[(Diethoxyphosphoryl)(4-hydroxyphenyl)methyl]amino}benzoate (3e). IR (KBr): 3423,
1632, 1495, 1378, 1212. 1H-NMR: 7.80 (d, J ¼ 8.0, 2 H); 7.32 (d, J ¼ 8.0, 2 H); 7.15 (d, J ¼ 8.0, 2 H); 6.60
(d, J ¼ 8.0, 2 H); 5.50 (t, J ¼ 10.0, 1 H); 4.79 (dd, J ¼ 24.0, 10.0, 1 H); 4.20 – 4.09 (m, 2 H); 3.92 – 3.90 (m,
1 H); 3.82 (s, 3 H); 3.63 – 3.61 (m, 1 H); 2.02 (s, 3 H); 1.11 (t, J ¼ 7.0, 3 H); 0.87 (t, J ¼ 7.0, 3 H).
13C-NMR: 166.8; 158.9; 150.4; 137.8 (d, J ¼ 10.0); 130.8; 129.2; 120.1; 118.0; 114.4; 113.1; 110.9; 62.7 (d,
J ¼ 6.5); 55.0 (d, J ¼ 153.0); 51.9; 16.2 (d, J ¼ 10.5). ESI-MS: 394 ([M þ H]þ). HR-ESI-MS: 416.1236
([M þ Na]þ, C19H24NNaO6Pþ; calc. 416.1238).
Diethyl [(4-Ethoxyphenyl)(phenylamino)methyl]phosphonate (3f). IR (KBr): 3289, 1615, 1529,
1
1349, 1238. H-NMR: 7.51 – 7.46 (m, 3 H); 7.34 (d, J ¼ 8.0, 2 H); 7.20 (t, J ¼ 8.0, 1 H); 6.88 – 6.79 (m,
3 H); 5.70 (t, J ¼ 10.0, 1 H); 4.69 (dd, J ¼ 24.0, 10.0, 1 H); 4.20 – 4.09 (m, 2 H); 3.98 (q, J ¼ 7.0, 2 H);
3.91 – 3.89 (m, 1 H); 3.60 – 3.58 (m, 1 H); 1.41 (t, J ¼ 7.0, 3 H); 1.31 (t, J ¼ 7.0, 3 H); 1.11 (t, J ¼ 7.0, 3 H).
13C-NMR: 159.1; 149.2; 147.2 (d, J ¼ 10.0); 130.0; 129.5; 126.2; 120.0; 115.3; 113.3; 108.0; 64.0 (d, J ¼
6.5); 63.4; 63.2 (d, J ¼ 6.5); 55.0 (d, J ¼ 155.0); 16.1 (d, J ¼ 6.0); 16.0 (d, J ¼ 6.0); 14.7. ESI-MS: 363
(Mþ). Anal. calc. for C19H26NO4P (363.16): C 62.80, H 7.21, N 3.85; found: C 62.89, H 7.12, N 3.92.
Diethyl [(2-Nitrophenyl)(phenylamino)methyl]phosphonate (3j). IR (KBr): 3303, 1601, 1499, 1277,
1232. 1H-NMR: 7.09 – 6.98 (m, 4 H); 6.81 – 6.55 (m, 5 H); 5.18 (dd, J ¼ 24.0, 10.0, 1 H); 4.74 (t, J ¼ 10.0,
1 H); 4.21 – 4.10 (m, 2 H); 3.92 – 3.88 (m, 1 H); 3.62 – 3.60 (m, 1 H); 1.32 (t, J ¼ 7.0, 3 H); 1.15 (t, J ¼ 7.0,
3 H). 13C-NMR: 154.1; 151.9; 146.1 (d, J ¼ 14.0); 129.5; 125.8; 118.3; 114.0; 113.2; 111.5; 63.6 (d, J ¼
6.5); 63.2 (d, J ¼ 6.5); 48.1 (d, J ¼ 155.0); 16.5 (d, J ¼ 6.5); 16.1 (d, J ¼ 6.5). ESI-MS: 365 ([M þ
H]þ), 387 ([M þ Na]þ). Anal. calc. for C17H21N2O5P (364.12): C 56.04, H 5.81, N 7.69; found: C 56.16,
H 5.72, N 7.64.

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The authors thank CSIR and UGC, New Delhi, for financial support.
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Received January 26, 2011