Solvent and catalyst free three-component coupling of carbonyl compounds, amines and triethylphosphite; A new synthesis of α-aminophosphonates

Article abstract of DOI:10.1055/s-2003-37508

The first solvent and catalyst free three-component coupling of carbonyl compounds, amines and triethylphosphite is achieved producing α-aminophosphonates at ambient temperature in very high yields.

Full text of DOI:10.1055/s-2003-37508

LETTER
505
Solvent and Catalyst Free Three-component Coupling of Carbonyl
Compounds, Amines and Triethylphosphite; a new Synthesis of a-Amino-
phosphonates
A
new Synthe
.
sis of
α
-Ami
C
nophosphonateshandrasekhar,* Ch. Narsihmulu, S. Shameem Sultana, B. Saritha, S. Jaya Prakash
Indian Institute of Chemical Technology, Hyderabad, 500007, India
Fax +91(40)27160512; E-mail: srivaric@iict.ap.nic.in
Received 24 January 2001
Abstract: The first solvent and catalyst free three-component
coupling of carbonyl compounds, amines and triethylphosphite is
achieved producing α-aminophosphonates at ambient temperature
in very high yields.
Key words: three-component coupling, carbonyl compounds,
amines, triethyl phosphite, α-aminophosphonates
Scheme 1
The development of efficient methodologies involving
novel reaction media including ‘solventless’ chemistry is
gaining prominence.1–5 Our group has been involved in
this research area and we serendipitously observed that a
three-component coupling between the carbonyl com-
pound, an aliphatic/aryl amine and triethyl phosphite was
facile in the absence of solvent as well as an external cat-
alyst. This reaction in presence of solvent (diethyl ether/
dichloromethane) always required external Lewis acid
catalyst. The products obtained, namely α-aminophos-
phonates, have major roles to play in peptidomimetics,6
hapten design in antibody generation7 and also in enzyme
inhibitory activity.8 A few of the one-pot literature proce-
dures for α-aminophosphonate synthesis involve catalysis
tion of benzaldehyde with benzylamine (entry 3) required
longer reaction time (8 h) and the product yield was 93%.
In the case of the coupling of (S)-(–)-phenylethylamine
with benzaldehyde and triethyl phosphite (entry 4) the
product yield was 85% with 86% diastereomeric excess
(in favorr of S,R-diasteromer), whereas the reported de
with the Lewis acid catalyzed procedure was only 66%.
The efficiency of the reaction was examined with several
aromatic aldehydes including normal (entry 5), electron
rich (entry 6), electron deficient (7, 8 and 9) and hetero-
cyclic aldehydes (entry 10). Further generality of this
method was demonstrated by 3-component coupling reac-
tions between aliphatic aldehydes and aromatic/aliphatic
amines (entries 11–18) and triethyl phosphite. More im-
portantly ketones (entries 19, 20) also underwent smooth
3-component coupling albeit requiring longer reaction
times.
10
by lithium perchlorate,9 BF3⋅OEt2, SnCl2 and SnCl4,
ZnCl2 or MgBr2,11 lanthanide triflates,12 TaCl5–SiO2,13 in-
dium chloride,14 montmorillonite clay and ZrCl4.15 Most
of these procedures involve diethylphosphite as the phos-
phonate source.
In conclusion the present protocol describes the first
simple and efficient method for solvent free synthesis of
α-aminophosphonates. The reaction proceeds using nei-
ther solvent nor any catalyst at room temperature, which
leads to an ecologically and economically advantageous
process.
We first investigated the reaction between benzaldehyde
(entry 1, 5 mmol), aniline (5 mmol) and triethylphosphite
(5 mmol) by stirring all the reactants together.16 After 15
minutes, the reaction mixture was adsorbed on silicagel
and eluted with petroleum ether–ethyl acetate to obtain
the product in 95% yield. The product obtained was com-
parable with a known sample in all respects including Acknowledgement
spectral data. Similarly, the three-component coupling of
We CN, SSS, BS and SJP thank CSIR, New Delhi for financial
assistance.
a variety of carbonyl compounds and amines with trieth-
ylphosphite was studied systematically, the results of
which are summarized in Table 1 (Scheme 1).
References
The coupling of benzaldehyde with an electron rich amine
(entry 2) and triethyl phosphite proceeded smoothly pro-
viding the α-aminophosphonate in 93% yield. The reac-
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506
S. Chandrasekhar et al.
LETTER
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(16) Representative Procedure: Benzaldehyde (5 mmol),
aniline (5 mmol) and triethyl phosphite (5 mmol) were added
successively and the mixture was stirred for 15 min at r.t.
After completion of the reaction (monitored by TLC), the
reaction mixture was adsorbed on silicagel and eluted with
petroleum ether–EtOAc (7:3) to give (phenyl-phenylamino-
methyl)-phosphonic acid diethylester. 1H NMR (200 MHz,
CDCl3): δ = 7.45 (d, J = 7.4 Hz, 2 H), 7.35–7.20 (m, 3 H),
7.04 (t, J = 8.2 Hz, 2 H), 6.68–6.50 (m, 3 H), 4.98 (d, J = 8.2
Hz, 2 H), 4.78 (d, J = 6.7 Hz, 2 H), 4.66 (d, J = 7.4 Hz, 2 H),
4.18–3.98 (m, 2 H), 3.92–3.82 (m, 1 H), 3.70–3.54 (m, 1 H),
1.26 (t, J = 7.4 Hz, 3 H), 1.08 (t, J = 6.7 Hz, 3 H). MS (FAB):
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3310, 2924, 1452, 1239, 1029 cm–1.
18
19
60
84
80
12b
20
12b
85
a Isolated after column chromatography and characterised by 1H NMR
and Mass spectroscopy.
b Time in hours.
c 86% de (HPLC).
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