One-Pot Synthesis of α-Amino Phosphonates Using Samarium Diiodide as a Catalyst Precursor

Article abstract of DOI:10.1002/ejoc.200300545

A simple and efficient preparation of α-amino phosphonates under relatively mild conditions by the one-pot reaction of aldehydes with amines and dialkyl phosphites using catalytic amounts of SmI₂ is described. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300545

SHORT COMMUNICATION
One-Pot Synthesis of α-Amino Phosphonates Using Samarium Diiodide as a
Catalyst Precursor
[a]
[a]
[a]
[a]
Fan Xu, Yiqin Luo, Mingyu Deng, and Qi Shen*
Keywords: Samarium / Iodine / Synthetic methods / Lanthanides
A simple and efficient preparation of α-amino phosphonates
under relatively mild conditions by the one-pot reaction of
aldehydes with amines and dialkyl phosphites using catalytic
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
2
amounts of SmI is described.
Introduction
(Scheme 1). The results obtained are summarized in
Table 1. The reaction in acetonitrile worked best at 80 °C;
α-Amino phosphonates are an important class of com- the yield decreased at higher or lower temperature (Entries
pounds widely used in biochemical and pharmaceutical 1Ϫ3). The same reaction in dichloromethane gave a slightly
chemistry. Their synthesis has therefore been the subject of higher yield at 45 °C (Entry 7). The order of addition of
much interest. A variety of methods are available, but the the three reactants to the SmI solution had no effect on
2
nucleophilic addition reaction of phosphites with imines, the yield of the product. For example, stirring a mixture of
usually catalyzed by Lewis acids, is the most direct and ef- benzaldehyde and aniline in advance resulted in a similar
ficient one among them. As many imines are unstable or yield to that obtained by mixing the three substrates simul-
difficult to purify, one-pot reactions (starting from carbonyl taneously (Entries 2 and 4), probably because of instan-
compounds, amines and phosphites) have also received at- taneous imine formation. The reaction proceeded smoothly
[
1,2]
[4]
tention. Several Lewis acids, such as rare earth triflates,
both with and without molecular sieves, giving the product
in similar yields (Entries 2 and 6), indicating that the active
indium() chloride[ and scandium tris(dodecyl sulfate)
3]
have been found to be the most effective catalysts for this species generated from SmI is stable in the presence of the
2
three-component reaction. However, some of them are water generated during imine formation. A slight increase
either expensive or somewhat difficult to prepare.
in the yield of phosphonate was observed when benzylid-
Recently, the use of SmI (which is both cheap and easily eneaniline and diethyl phosphite were used as starting mate-
2
prepared) has received great attention as a precatalyst in rials (Entry 5).
organic reactions such as aldol reactions, Michael ad-
ditions, DielsϪAlder reactions and ring-opening reac-
[
5]
[6,7]
tions. In earlier reports,
we showed that SmI is an
2
efficient Lewis acid-type catalyst for the cyclotrimerization
of nitriles and the condensation of amines with nitriles. As
Scheme 1
a part of our continued studies on SmI -catalyzed CϪN
2
bond-forming reactions, the one-pot synthesis of α-amino
phosphonates from aldehydes, amines and phosphites was
investigated.
The reactions of several carbonyl compounds with am-
ines and dialkyl phosphites were investigated in the pres-
˚
ence of a catalytic amount (10 mol %) of SmI and 4-A
2
Results and Discussion
molecular sieves in acetonitrile at 80 °C for 24 h (Scheme 2);
the results are listed in Table 2. Most of the reactions pro-
The reaction of benzaldehyde with aniline and diethyl ceeded smoothly to give moderate to excellent yields of the
phosphite was carried out in the presence of 10 mol % SmI2 corresponding α-amino phosphonates. Only the reactions
˚
and 4-A molecular sieves under several different conditions of 2-furaldehyde (Entry 8), cinnamaldehyde (Entry 9) and
a ketone (Entry 12) with aniline and diethyl phosphite gave
[
a]
Department of Chemistry, Suzhou University,
rather low yields. However, the reactions of aromatic alde-
hydes with aliphatic amines and diethyl phosphite gave high
yields. For example, the reaction of benzaldehyde with ani-
1
Shizi Street, Suzhou 215006, China
Fax: (internat.) ϩ 86-512-65112371
E-mail: qshen@suda.edu.cn
4728
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300545
Eur. J. Org. Chem. 2003, 4728Ϫ4730

One-Pot Synthesis of α-Amino Phosphonates
SHORT COMMUNICATION
-catalyzed reac- obtain more information on the possible SmIII species, ani-
Table 1. Effect of reaction conditions on the SmI
2
tion of benzaldehyde, aniline and diethyl phosphite
line and benzaldehyde were separately mixed with SmI in
2
THF. The color change from dark blue to yellow was only
Entry[a] Solvent T (°C) Additive
Isolated yield (%)
observed in the latter case. This indicates that the active
III
species may be the pinacolϪSm complex A (Scheme 3)
1[b]
2
CH
CH
CH
CH
CH
CH
CH
CN 60
CN 80
CN 100
CN 80
CN 80
CN 80
4-A mol. sieves 47
˚
˚
˚
˚
3
3
3
3
3
3
2
previously observed in the SmI
-mediated reduction of al-
4-A mol. sieves 60
2
[
9,10]
3
4-A mol. sieves 36
dehydes to pinacols.
To confirm this, the reaction of
[
[
c]
4
5
6
7
4-A mol. sieves 63
benzaldehyde, aniline and diethyl phosphite was carried out
d]
˚
4-A mol. sieves 74
using a 1:1 mixture of SmI and benzaldehyde as a catalyst
2
Ϫ
63
(10 mol %). Indeed, the reaction proceeded smoothly to
˚
Cl
2
45
4-A mol. sieves 66
give product 4a in a similar yield (58%) as that obtained
[
a]
Typical reaction conditions: PhCHO: PhNH
2
: HOP(OEt)
2
ϭ
with SmI alone (Table 2, Entry 1). Due to both the Lewis
2
1
4
:1.1:1.2, 10 mol % SmI relative to PhCHO and 0.05  SmI
2
2
, 24 h,
The
acidic nature of the metal center and its potential for a high
coordination number, coordination of nitrogen and oxygen
is highly favorable. The nucleophilic addition could then
proceed via a transition state B, once the phosphite is added
to the reaction mixture (Scheme 4).
˚
[b]
[c]
-A molecular sieves (MS).
Reaction time was 4 days.
mixture of PhCHO and PhNH
of SmI , followed by the addition of HOP(OEt)
2
was stirred for 2 h in the presence
[
d]
2
2
.
Reaction of
2
PhCHϭNPh and HOP(OEt) .
Scheme 2
Scheme 3
Table 2. One-pot synthesis of α-amino phosphonates catalyzed by
SmI
2
Entry[a] R1
R2 R3
R4 Product Isolated yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
Ph
nBu
tBu
Et 4a
Et 4b
60
88
91
92
Scheme 4
Et 4c
nC
6
H
13 Et 4d
11 Et 4e
C
6
H
96
In conclusion, samarium diiodide has been found to be
an efficient precatalyst in the one-pot synthesis of α-amino
phosphonates from aldehydes, amines and phosphites un-
der mild conditions, giving moderate to excellent yields de-
pending on the structure of the three reactants.
PhCH
Ph
Ph
2
Et 4f
Et 4g
Et 4h
Et 4i
Et 4j
Et 4k
Et 4l
iPr 4m
92 (93[b])
4-CH
PhCHϭCH H
2-furyl
4-CH
PhCH
Ph
Ph
3
Ph
78
39
37
88
H
H
H
CH
H
Ph
0
1
2
3
3
Ph
2
tBu
PhCH
Ph
2
72
18 (29[
b]
)
3
[c]
Ph
42 (59 )
Experimental Section
[
a]
Typical reaction conditions: aldehyde or ketone/amine/dialkyl
phosphite 1:1.1:1.2, 10 mol % SmI
pound (concentration of SmI 0.05  in CH
relative to the carbonyl com- General Remarks: All manipulations were conducted under an at-
CN), 80 °C, 24 h, 4-
mosphere of dry Ar with flame-dried glassware. SmI was synthe-
2 2
A mol. sieves. Solvent CH Cl , 45 °C. 80 °C, 3 days.
2
2
3
2
˚
[b]
[c]
sized by stirring a mixture of Sm metal and I
2
in THF at room
temperature for several hours.[ Aldehydes, amines and aceto-
nitrile were distilled from CaH prior to use. CH Cl was heated
at reflux over P for several hours and then distilled. Dialkyl
phosphites were prepared according to the literature method.
11]
2
2
2
line and diethyl phosphite gave the corresponding phos-
phonate in 60 % yield, but when benzylamine was used, the
yield of product was 92 % (Entries 1 and 6). When diisopro-
pyl phosphite was used instead of diethyl phosphite, the
yield of phosphonate decreased (Entries 1 and 13). This
might be due to a steric effect.
2
O
5
[
12] 1
H
NMR spectra were obtained on a Varian INOVA-400 spectrometer
using tetramethylsilane as an internal reference. Elemental analyses
were determined on a Carlo Erba EA1110-CHNS-O analyzer.
Mass spectra were recorded on a Micromass GCT instrument.
The change in the color of the reaction mixture from
dark blue to yellow and the formation of the solid imine is
observed immediately after the addition of the mixture of
Typical Procedure: A mixture of aldehyde (2 mmol), amine
(
2.2 mmol), phosphite (2.4 mmol) and samarium diiodide (10
˚
mol %) in acetonitrile (4 mL) was stirred with 4-A molecular sieves
(250 mg) at the desired temperature for the given time. The aceto-
nitrile was removed under reduced pressure, water was added to
amine and aldehyde to the solution of SmI . This obser-
2
III
[5,8]
vation suggests that a Sm species,
supposedly the ac-
tive species for this one-pot reaction, is generated during the residue, and the mixture extracted with EtOAc. The combined
the reaction of SmI with aldehyde or amine. In order to organic layers were dried over anhydrous Na SO , concentrated in
2
2
4
Eur. J. Org. Chem. 2003, 4728Ϫ4730
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4729

F. Xu, Y. Luo, M. Deng, Q. Shen
SHORT COMMUNICATION
vacuo and purified by chromatography on silica gel (eluant: ace-
tone/petroleum ether 1:7) to afford the α-amino phosphonate. All
new compounds were fully characterized by 1H NMR, MS and
elemental analysis.
ϩ
OCH
2
), 6.39Ϫ7.62 (m, 10 H, ArH) ppm. MS (EI): m/z ϭ 333 [M ].
C
18
H24NO
3
P: calcd. C 64.85, H 7.26, N 4.20; found C 64.71, H
7.41, N 4.13.
1
Phosphonate 4m: H NMR (400 MHz, CDCl
3
): δ ϭ 0.92 (d, J ϭ
), 1.22 (d, J ϭ 6.4 Hz, 3 H, CH ), 1.26 (d, J ϭ
), 1.32 (d, J ϭ 6.4 Hz, 3 H, CH ), 4.41Ϫ4.49 (m,
H, NCH), 4.66Ϫ4.85 (m, 2 H, 2 ϫ OCH), 6.58Ϫ7.51 (m, 10 H,
Phosphonate 4b: 1H NMR (400 MHz, CDCl
): δ ϭ 0.86 (t, J ϭ
), 1.14 (t, J ϭ 7.2 Hz, 3 H, CH ), 1.28 (t, J ϭ
), 1.32Ϫ1.47 [m, 4 H, (CH ], 2.41Ϫ2.56 (m, 2
), 3.80Ϫ4.09 (m, 5 H, NCH and 2 ϫ OCH ), 7.27Ϫ7.43
P: calcd.
3
5
5
1
.6 Hz, 3 H, CH
.6 Hz, 3 H, CH
3
3
7.2 Hz, 3 H, CH
3
3
3
3
7.2 Hz, 3 H, CH
3
2 2
)
H, NCH
2
2
ϩ
ArH) ppm. MS (EI): m/z ϭ 347 [M ]. C19
3
H26NO P: calcd. C 65.69,
ϩ
(m, 5 H, ArH) ppm. MS (EI): m/z ϭ 299 [M ]. C15
H
26NO
3
H 7.54, N 4.03; found C 65.78, H 7.67, N 4.01.
C 60.18, H 8.76, N 4.68; found C 60.22, H 8.96, N 4.52.
1
Phosphonate 4c: H NMR (400 MHz, CDCl
3
): δ ϭ 1.00Ϫ1.78 (m,
1
7
5 H, 5 ϫ CH
.27Ϫ7.46 (m, 5 H, ArH) ppm. MS (EI): m/z ϭ 299 [M ].
P: calcd. C 60.18, H 8.76, N 4.68; found C 59.97, H
.75, N 4.56.
3
), 3.72Ϫ4.19 (m, 5 H, NCH and 2 ϫ OCH
2
ϩ
), Acknowledgments
The authors thank the National Science Foundation of China
29872031) and State Key Laboratory of Organometallic Chemis-
15 3
C H26NO
8
(
try (Shanghai Institute of Organic Chemistry, Chinese Academy of
Phosphonate 4d: 1H NMR (400 MHz, CDCl
6
1
): δ ϭ 0.86 (t, J ϭ Sciences) for financial support.
), 1.15 (t, J ϭ 7.2 Hz, 3 H, CH ), 1.24Ϫ1.46 [m,
and CH ], 2.40Ϫ2.55 (m, 2 H, NCH ), 3.80Ϫ4.12
), 7.28Ϫ7.43 (m, 5 H, ArH) ppm.
P: calcd. C 62.35, H 9.25,
3
.6 Hz, 3 H, CH
1 H, (CH
3
3
2
)
4
3
2
[1]
C. T. Qian, T. S. Huang, J. Org. Chem. 1998, 63, 4125Ϫ4128.
(m, 5 H, NCH and 2 ϫ OCH
2
[2]
S. Lee, J. H. Park, J. Kang, J. K. Lee, Chem. Commun. 2001,
ϩ
MS (EI): m/z ϭ 327 [M ]. C17
N 4.28; found C 62.32, H 9.33, N 4.15.
H30NO
3
1698Ϫ1699.
[3]
B. C. Ranu, A. Hajra, U. Jana, Org. Lett. 1999, 1, 1141Ϫ1143.
K. Manabe, S. Kobayashi, Chem. Commun. 2000, 669Ϫ670.
J. Collin, N. Giuseppone, P. Van de Weghe, Coord. Chem. Rev.
[4]
1
Phosphonate 4j: H NMR (400 MHz, CDCl
3
): δ ϭ 1.02 (s, 9 H, 3
), 1.29 (t, J ϭ 7.1 Hz, 3 H,
3
), 3.76Ϫ4.17 (m, 5 H, NCH and 2 ϫ
[5]
[6]
ϫ CH
CH ), 2.33 (s, 3 H, ArCH
OCH
C
9
3 3
), 1.13 (t, J ϭ 7.1 Hz, 3 H, CH
1
998, 178Ϫ180, 117Ϫ144.
3
F. Xu, X. H. Zhu, Q. Shen, J. Lu, J. Q. Li, Chin. J. Chem. 2002,
ϩ
2
), 7.12Ϫ7.35 (m, 4 H, ArH) ppm. MS (EI): m/z ϭ 313 [M ].
20, 1334Ϫ1339.
[
[
7]
8]
H28NO
3
P: calcd. C 61.33, H 9.00, N 4.47; found C 61.41, H
F. Xu, J. H. Sun, Q. Shen, Tetrahedron Lett. 2002, 43,
1867Ϫ1869.
W. J. E va n s, Polyhedron 1987, 6, 803Ϫ835.
J. L. Namy, J. Souppe, H. B. Kagan, Tetrahedron Lett. 1983,
24, 765Ϫ766.
J. Souppe, L. Danon, J. L. Namy, H. B. Kagan, J. Organomet.
Chem. 1983, 250, 227Ϫ236.
T. Imamoto, M. Ono, Chem. Lett. 1987, 501Ϫ502.
H. McCombie, B. C. Saunders, G. J. Stacey, J. Chem. Soc.
1945, 380Ϫ382.
16
.16, N 4.42.
Phosphonate 4k: H NMR (400 MHz, CDCl
H, 2 ϫ CH ), 2.93Ϫ3.02 (m, 2 H, CH ), 3.78Ϫ3.92 (m, 3 H,
NCH and CH ), 4.07Ϫ4.35 (m, 4 H, 2 ϫ OCH ), 7.18Ϫ7.35 (m,
0 H, ArH) ppm. MS (EI): m/z ϭ 347 [M ]. C19 P: calcd.
1
): δ ϭ 1.22Ϫ1.39 (m,
[9]
3
6
3
2
[10]
2
2
ϩ
1
H26NO
3
[
[
11]
12]
C 65.69, H 7.55, N 4.03; found C 65.82, H 7.87, N 3.57.
1
Phosphonate 4l: H NMR (400 MHz, CDCl
6
3
): δ ϭ 1.20Ϫ1.28 (m,
), 3.93Ϫ4.02 (m, 4 H, 2 ϫ
H, 2 ϫ CH
3
), 2.00 (s, 3 H, PhCCH
3
Received August 30, 2003
4730
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 4728Ϫ4730