A new protocol for a one-pot synthesis of α-amino phosphonates by reaction of imines prepared in situ with trialkylphosphites

Article abstract of DOI:10.1055/s-2002-32957

Imines prepared in situ by reaction of aldehydes and ketones with primary amines in ethereal solution of LiClO₄ react readily at ambient temperature with trialkylphosphite to give high yields of α-amino phosphonates.

Full text of DOI:10.1055/s-2002-32957

LETTER
1347
A New Protocol for a One-pot Synthesis of -Amino Phosphonates by Reaction
of Imines Prepared In Situ with Trialkylphosphites
One-pot
Synthesis of
o
-Amino Phos
h
phonates ammad R. Saidi,* Najmedin Azizi
Department of Chemistry, Sharif University of Technology, P. O. Box 11365-9516 Tehran, Iran
Fax +98(21)6012983; E-mail: saidi@sharif.edu
Received 23 May 2002
ethereal solution of lithium perchlorate in one-pot with a
short reaction time (Scheme 1, Table).
Abstract: Imines prepared in situ by reaction of aldehydes and ke-
tones with primary amines in ethereal solution of LiClO4 react
readily at ambient temperature with trialkylphosphite to give high
yields of -amino phosphonates.
R
R'
R
LiClO4 / ether
r. t.
Key words: amino phosphonate, imine, trialkylphosphite, lithium
perchlorate
R"NH2
2
+
R"
O
TMSCl,
N
R'
1
3
LiClO4 / ether
30 min, r. t.
R
NHR"
PO(OR''')2
3
P(OR''')3
-Amino phosphonates are an important class of com-
pounds since they are considered as structural analogues
of the corresponding -amino acids, and their utilities as
enzyme inhibitors, antibiotics, pharmacological agents
and many other applications are well documented.1 Syn-
thesis of -amino phosphonate has drawn considerable at-
tention over the past few years and a large number of
modified conditions,2–7 as well as the preparation of a
three component reaction between triethyl phosphite8
with a secondary amine and an aldehyde in the presence
of a Lewis acid have been reported in the literature. Here
we would like to report a one-pot three-component reac-
tion of trialkylphosphite with imines prepared in situ in
the presence of trimethylsilyl chloride, TMSCl, in ethere-
al solution of LiClO4.
+
R'
R''' = Me or Et
Scheme 1
4
The reactions are clean and the products are obtained in
high yield even for the reaction with enolizable aldehyde
or ketone, such as isopropyl aldehyde and cyclohexanone.
As it was reported before,10 the yield of the LiClO4-medi-
ated amioalkylation reaction is lower for the enolizable al-
dehydes due to the formation of enamines as side
products. But with this procedure, aminophosphonation
of enolizable aldehydes or ketones proceeds with high
yields and in short time. In addition, the reaction condi-
tions are mild so that no side products or decomposition
of the products are observed.11,12 To demonstrate the effi-
ciency of lithium perchlorate, a mixture of 1, 2 and trime-
thylphosphite were stirred in diethyl ether at ambient
temperature for several hours in the absence of lithium
perchlorate. After aqueous work-up, in contrast to the
above results, no -amino phosphonate 4 could be detect-
ed as the product.
During the course of our efforts towards the aminoalkyla-
tion of aldehydes mediated by lithium perchlorate in di-
ethyl ether,9 we found that an imines prepared in situ react
very effectively with trimethylphosphite or triethylphos-
phite as nucleophile to produce -amino phosphonates. In
the present work, we attempted to develop a novel one-pot
and fast procedure for the preparation of -amino phos-
phonates at ambient temperature. It was found that the re-
action of aldehydes or ketones 1 (1 equiv) with an excess
of a primary amine 2 (1.25 equiv), forms the imine 3 in the
presence of TMSCl in a concentrated ethereal solution of
lithium perchlorate.10 By the addition of trimethylphos-
phite or triethylphosphite in the same flask, without any
further purification of the intermediate imines, -amino
phosphonates 4 were formed in very short time with
high yields, (Scheme 1). The reaction can be applied for
both enolizable and non-enolizable aldehydes and ketones
with a range of substituted starting materials. All trans-
formations were carried out at room temperature in a 5 M
In order to examine the diastereoselectivity in aminophos-
phonation of aldehyde with the chiral amine, enantiopure
(R)-1-phenylethylamine, very accessible in both the enan-
tiopure forms, was used. Upon addition of trimethylphos-
phite to the imines prepared in situ by reaction of
aldehydes with primary chiral amine, -amino phospho-
nates 5 were formed with high yields and with diastereo-
selectivity (dr) from 70% to more than 80% (Scheme 2).
The structure and the ratio of the major and minor diaste-
reomers were determined by 1H NMR spectra of the crude
product and by comparison of the chemical shift and
coupling constant of proton attached to the carbon bearing
the phosphonate group with similar compound reported in
the literature.6b,7b Each diasereomers show a doublet with
different chemical shift and coupling constant. The up-
field doublet was assigned for the major diasereomer
Synlett 2002, No. 8, Print: 30 07 2002.
Art Id.1437-2096,E;2002,0,08,1347,1349,ftx,en;G11102ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1348
M. R. Saidi, N. Azizi
LETTER
Table Synthesis of -Amino Phosphonates from Aldehydes and Ketones Mediated by LPDE
R
R'
R'
R
NHR''
LiClO4 / ether
P(OR''')3
R''NH2
+
+
r. t.
TMSCl,
PO(OR''')2
O
4
Entry
1
R
R′
H
H
H
H
H
H
H
H
H
H
H
H
R′′
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
R′′′
Product
4a
Yield
98
98
98
97
93
95
98
98
85
85
85
85
Ph
Me
Et
2
Ph
4b
4c
3
p-Cl-Ph
p-Cl-Ph
PhCH=CH
PhCH=CH
m-NO2-Ph
m-NO2-Ph
Me2CH
Me2CH
p-OMe-Ph
p-OMe-Ph
Me
Et
4
4d
4e
5
Me
Et
6
4f
7
Me
Et
4g
8
4h
4i
9
Me
Et
10
11
12
4j
Me
Et
4k
4l
13
14
Ph
Ph
Me
Et
4m
4n
97
97
CHO
15
16
17
18
19
Ph
H
H
H
H
H
p-Br-Ph
n-Bu
Me
Me
Et
4o
4p
4r
4s
4t
97
95
94
94
96
Ph
Ph
n-Bu
p-Cl-Ph
m-NO2-Ph
n-Bu
Me
Me
n-Bu
20
21
Ph
Ph
Me
Et
4u
4v
90
88
O
H
N
Me
Me
PO(OMe)2
Ar
H
Ph
+
Me
+
NH2
LiClO4 / ether
r. t.
Ar H
(R,S)-5
Ph
Ph
P(OMe)3
dr
H
TMSCl,
O
N
PO(OMe)2
Ar
Ph
Yield(%)
H Ar
(R,R)-5
95
97
75/25
78/22
80/20
70/30
p-Cl-Ph
m-NO2-Ph 96
PhCH=CH 93
Scheme 2
Synlett 2002, No. 8, 1347–1349 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
One-pot Synthesis of -Amino Phosphonates
1349
(3.0 mmol) and TMSCl (2.0 mmol) were added via a
syringe. After 10 min, trimethyl-phosphite or triethyl-
(R,S)-5 and the downfield doublet was assigned for the
minor diastereomer (R,R)-5.
phosphite (2.5 mmol) was added and the mixture was stirred
at r.t. for about 15 min. Then water (20 mL) and CH2Cl2 (20
mL) were added. The organic phase was separated, dried
over MgSO4, and the solvent was removed. Almost pure
crude product obtained. Further purification was carried out
by column chromatography on basic alumina eluting with
petroleum ether/EtOAc, if needed. All compounds were
characterized on the basis of spectroscopic data (IR, NMR,
MS) and comparison with those reported in the literature.
Caution: Although we did not have any accident while
using LiClO4, it is advisable to dry lithium perchlorate in a
fume hood using a suitable lab-shield.
In summary, we have reported that in situ prepared imines
in a concentrated ethereal solution of lithium perchlorate
can react with trimethylphosphite or triethylphosphite in
excellent yields. The procedure for the reaction is mild
and operationally simple. With enantiopure (R)-1-phenyl-
ethylamine, a mixture of two diastereomers formed with
dr from 70% to 80%.
Acknowledgement
(12) Selected spectral data. 4a: IR (KBr): 3304 cm–1 (NH).
1H NMR (CDCl3, 500 MHz): = 3.48 (d, 3 H, J = 6.1 Hz),
3.78 (d, 3 H, J = 10.7 Hz), 4.50 (br s, 1H, NH), 4.83 (d, 1 H,
J = 24.3), 6.61–6.72 (m, 3 H), 7.28–7.50 (m, 7 H). 13C NMR
(CDCl3, 125 MHz): = 53.68 (d, 2JPC = 6.6 Hz), 54.2 (d,
2JPC = 7.6 Hz), 55.6 (d, 1JPC = 150.6 Hz), 114.2, 119.2,
123.4, 129.0, 129.8 (d, JPC = 4.5 Hz), 130.2, 135.9 (d,
We are grateful to the Research Council, Ministry of Science, Rese-
arch and Technology for financial support of this research (GN
503495). We also thank ‘Volkswagen-Stiftung, Federal Republic of
Germany’ for financial support towards the purchase of equipment
and chemicals.
References
JPC = 2.5 Hz), 146.4 (d, JPC = 14.7 Hz). 4c: IR (KBr): 3314
cm–1 (NH). 1H NMR (CDCl3, 500 MHz): = 3.55 (d, 3 H,
J = 10.6 Hz), 3.78 (d, 3 H, J = 10.7), 4.83 (d, 1 H, J = 24.6
Hz), 4.85 (br s, 1 H, NH), 6.62–7.46 (m, 9 H). 13C NMR
(CDCl3, 125 MHz): = 53.70 (d, 2JPC = 6.6 Hz), 54.2 (d,
2JPC = 6.0 Hz) 55.02 (d, 1JPC = 154 Hz), 114.0, 119.1, 129.0,
129.6 (d, JPC = 8.1), 129.9, 130.2, 134.2 (d, JPC = 3.9 Hz),
146.4 (d, JPC = 15.0 Hz). 4g: IR (KBr): 3325 cm–1 (NH). 1H
NMR (CDCl3, 500 MHz): = 3.64 (d, 3 H, J = 10.7 Hz),
3.83 (3 H, J = 10.7 Hz), 4.99 (d, 1 H, J = 25.0 Hz), 5.12 (br
s, 1 H, NH), 6.62–6.73 (m, 3 H), 7.11–7.13 (m, 2 H), 7.88–
8.40 (m, 4 H). 13C NMR (CDCl3, 125 MHz): = 54.1 (d,
2JPC = 6.8 Hz), 54.6 (d, 2JPC = 5.9 Hz), 54.8 (d, 1JPC = 155.0
Hz), 114.2 (d, JPC = 11.2 Hz), 119.3 (d, JPC = 11.4 Hz),
123.2, 129.7 (d, JPC = 4.5 Hz), 130.0 (d, JPC = 11.2 Hz),
134.3 (d, JPC = 3.9 Hz), 139.9, 145.9 (d, JPC = 13.8 Hz),
148.9 (d, JPC = 2.5 Hz). 4n: IR (KBr): 3300 cm–1 (NH). 1H
NMR (CDCl3, 500 MHz): = 0.77 (t, 3 H, J = 6.9 Hz), 1.37
(t, 3 H, J = 7.0 Hz), 3.26 (m, 1 H), 3.79 (m, 1 H), 4.26 (m, 2
H), 5.01 (br s, 1 H, NH), 5.75 (d, 1 H, J = 24.1 Hz), 6.63–
6.70 (m, 3 H), 7.06–7.09 (m, 2 H), 7.45–7.93 (m, 6 H), 8.33–
8.35 (m, 1 H). 13C NMR (CDCl3, 125 MHz): = 16.3 (d,
3JPC = 2.3 Hz) 17.0 (d, 3JPC = 5.8 Hz), 51.8 (d, 1JPC = 151
Hz), 63.6 (d, 2JPC = 6.5 Hz), 63.9 (d, 2JPC = 5.8 Hz), 113.9,
114.1, 118.6, 123.4 (d, JPC = 6.6 Hz), 126.2, 126.2, 126.7,
128.8, 129.0, 129.4, 129.6 (d, JPC = 10.6 Hz), 132.0 (d,
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(11) General Procedure for the Preparation of -Amino
Phosphonates 4. The aldehyde (2 mmol)and 4 mL of 5 M
LiClO4 in diethyl ether were placed in a 50 mL flask under
argon and stirred for 5 min. Then a primary amine
J
PC = 5.0) 134.3, 146.6 (d, JPC = 14.5 Hz). 4u: IR (KBr):
3320 cm–1 (NH). 1H NMR (CDCl3, 500 MHz): = 1.13-2.13
(m, 10 H), 3.45(br s, NH), 3.54 (d, 6 H, J = 10.2 Hz), 6.66–
7.05 (m, 5 H). 13C NMR (CDCl3, 125 MHz): = 20.2 (d,
J
J
PC = 10.5 Hz), 25.6, 30.5, 53.3 (d, JPC = 7.7 Hz), 58.1 (d,
PC = 159.0 Hz), 118.6 (d, JPC = 10.5 Hz), 119.6 (d,
JPC = 13.2 Hz), 129.0 (d, JPC = 6.7 Hz), 146.1.
Synlett 2002, No. 8, 1347–1349 ISSN 0936-5214 © Thieme Stuttgart · New York