Three component coupling catalyzed by TaCl5-SiO2: Synthesis of α-amino phosphonates

Article abstract of DOI:10.1016/S0040-4039(01)01053-X

TaCl₅-SiO₂ has been utilized as an efficient Lewis acid catalyst for the three component coupling of carbonyl compounds, aromatic amines and diethyl phosphite to produce α-amino phosphonates.

Full text of DOI:10.1016/S0040-4039(01)01053-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 5561–5563
Three component coupling catalyzed by TaCl5–SiO2: synthesis of
a-amino phosphonates†
S. Chandrasekhar,* S. Jaya Prakash, V. Jagadeshwar and Ch. Narsihmulu
Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 26 April 2001; accepted 14 June 2001
Abstract—TaCl5–SiO2 has been utilized as an efficient Lewis acid catalyst for the three component coupling of carbonyl
compounds, aromatic amines and diethyl phosphite to produce a-amino phosphonates. © 2001 Published by Elsevier Science Ltd.
Of late, the synthesis and use of a-amino phosphonates
have received attention as structural analogues of the
corresponding a-amino acids. Peptido mimetics1 made
out of this class of compounds have shown promising
pharmacological properties.2 They also play an impor-
tant role in hapten design for antibody generation3 and
We investigated the reaction between p-tolualdehyde
(Table 1, entry 1), aniline and diethyl phosphite by
stirring equimolar quantities in dichloromethane in the
presence of TaCl5–SiO2 for 22 hours and isolated the
desired amino phosphonate in a 92% yield. After this
success, several aldehydes, amines and diethyl phos-
phite were examined in the presence of 10 mol% TaCl5–
SiO2 in dichloromethane. The results are summarized in
Table 1. It is demonstrated for the first time, that the
TaCl5–SiO2 coordinates with the nitrogen of the imine
and facilitates the nucleophilic addition of diethyl phos-
phite to yield the a-amino phosphonate. In all cases,
the three component coupling proceeded smoothly and
the corresponding a-amino phosphonates were isolated.
The examples studied included electron-rich aromatic
aldehydes (entries 1, 2, 3, 6, 7, 8 and 9) and amines
(entries 3, 4, 7, 8, 10 and 13); and electron deficient
aromatic aldehydes (entries 12 and 13) and amines
(entries 9, 11, 15, 16 and 18). Ketones (entries 17 and
18) also gave a-amino phosphonates in good yields at
room temperature. Unlike lanthanide triflate8 and
indium chloride,9 where reflux conditions are required,
enzyme inhibitors.4 Thus,
a variety of synthetic
approaches are desirable to synthesize a-amino phos-
phonates. Of the methods available, the nucleophilic
addition of phosphites to imines is convenient and is
usually activated by an alkali metal alkoxide or by an
acid.5 Lewis acids such as SnCl2, SnCl4 and BF3·OEt2,
ZnCl2 and MgBr2 have also been used to promote the
addition reaction.6 However, the synthesis cannot pro-
ceed in one-pot from a carbonyl compound, an amine
and a phosphite. To address some of the limitations
posed by known reagents, we initiated a programme to
explore the use of TaCl5 and TaCl5–SiO2 for Lewis acid
promoted reactions.7 Herein we disclose the TaCl5-cata-
lyzed three component coupling of carbonyl com-
pounds, amines and diethyl phosphite for the synthesis
of various amino phosphonates (Scheme 1).
Scheme 1.
Keywords: carbonyl compound; amine; diethyl phosphite; a-amino phosphonate; TaCl5.
* Corresponding author. Tel.: +91 40 7170512; fax: 7173387; e-mail: srivaric@iict.ap.nic.in
† IICT Communication No. 4783.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01053-X

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S. Chandrasekhar et al. / Tetrahedron Letters 42 (2001) 5561–5563
following the present protocol the reaction proceeded
at room temperature. The overall yield of this multi-
component coupling was between 81 and 94% irrespec-
tive of the nature of aldehyde or amine. The only
limitation detected was that aliphatic amines gave non-
characterizable products. However, aliphatic aldehydes
(entry 14) and conjugated aldehydes (entries 15 and 16)
reacted well.
Table 1. Tantalum(V) chloride–silica gel catalyzed one-pot synthesis of a-amino phosphonates from aldehydes/ketones and
aminesa

S. Chandrasekhar et al. / Tetrahedron Letters 42 (2001) 5561–5563
5563
In conclusion, it has been demonstrated that TaCl5–
References
SiO2 is an efficient catalyst for the three component
coupling of a carbonyl compound, an amine and
diethyl phosphite to yield a-amino phosphonates, which
can serve as peptide mimetics. The advantages of this
procedure are the operational simplicity, the general
applicability to aldehydes and ketones at room temper-
ature and the high yields obtained. We believe that this
method presents a better and more practical alternative
to existing methodologies for the synthesis of a-amino
phosphonates. Also, it was demonstrated for the first
time that TaCl5 is an efficient coordinating metal for
nitrogen facilitating the nucleophilic addition of diethyl
phosphite.
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A mixture of p-tolualdehyde (100 mg, 1 mmol), aniline
(77 mg, 1 mmol) and diethyl phosphite (114 mg, 1
mmol) was added to a solution of TaCl5–SiO2 (10
mol%,10 29 mg, 0.1 mmol) in dichloromethane (4 mL),
and the mixture was stirred 22 hours at room tempera-
ture under a nitrogen atmosphere. Upon completion
(TLC), the reaction was filtered through Celite, diluted
with H2O (10 mL) and extracted with CH2Cl2 (2×10
mL). The organic layers were washed with brine and
dried over Na2SO4. The solvent was removed in vac-
uum and the crude product was column chro-
matographed on a silica gel column to afford pure
a-amino phosphonate.
Acknowledgements
10. Preparation of TaCl5–silica gel: Tantalum(V) chloride–
silica gel was prepared by mechanically shaking chro-
matography grade silica gel (10 g, 100–200 mesh, dried
overnight at 100°C) and tantalum(V) chloride (3 g) for
20 h.
Three of us (S.J.P., V.J. and C.N.) thank CSIR, New
Delhi for financial support.
.