Microwave-assisted one-pot synthesis of α-amino phosphonates via three component coupling on a silica gel support

Article abstract of DOI:10.1246/cl.2005.1042

A fast, highly efficient, general procedure under microwave irradiation, using silica gel-supported reagents for the synthesis of α- aminophosphonates is developed through a one-pot reaction of aldehydes and ketones with amines. Copyright

Full text of DOI:10.1246/cl.2005.1042

1042
Chemistry Letters Vol.34, No.7 (2005)
Microwave-assisted One-pot Synthesis of ꢀ-Amino Phosphonates via Three Component
Coupling on a Silica Gel Support
Zhuang-Ping Zhan,ꢀ Rui-Feng Yang, and Jun-Ping Li
Department of Chemistry and The Key Laboratory for Chemical Biology of Fujian Province,
College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, P. R. China
(Received April 19, 2005; CL-050537)
A fast, highly efficient, general procedure under microwave
nates from aliphatic aldehydes are obtained in moderate yields.
Thus, a fast, efficient, and general method is desirable for the
synthesis of ꢀ-aminophosphonates from both aldehydes and
ketones with aromatic as well as aliphatic amines.
irradiation, using silica gel-supported reagents for the synthesis
of ꢀ-aminophosphonates is developed through a one-pot reac-
tion of aldehydes and ketones with amines.
Herein we report an efficient and rapid microwave-assisted
one-pot synthesis of ꢀ-aminophosphonates from both aldehydes
and ketones on a silica gel support.
In a typical procedure, a mixture of carbonyl compound, an
amine, and a dialkyl phosphite absorbed on silica gel was irradi-
ated in a microwave oven for a certain period of time as required
to complete the reaction (TLC). A wide range of structurally var-
ied carbonyl compounds were used as substrates and converted
to the corresponding ꢀ-aminophosphonates in good to excellent
yields. The results are reported in Table 1.
Recently, solvent-free reactions using either organic or
inorganic solid supports have received increasing attention.1
There are several advantages to perform synthesis in dry media:
(i) short reaction times, (ii) increased safety, (iii) economic
advantages due to the absence of solvent. Silica gel is effective
because the end products can easily be separated. Moreover,
silica gel can function as a convenient medium and also act as
a mild acidic catalyst.2
Not only benzaldehydes but also electron rich aromatic
aldehydes, electron deficient aromatic aldehydes and aliphatic
The application of microwave (MW) irradiation as a non-
conventional energy source for activation of reactions, in general
and on inorganic solid supports in particular, have gained popu-
larity over the usual homogeneous and heterogeneous reactions,
as they can be performed rapidly to give pure products in high
yields under solvent-free conditions with several eco-friendly
advantages in the context of green chemistry.3,4
Table 1. Synthesis of ꢀ-aminophosphonates from aldehydes/
ketones and amines using silica gel-supported reagents under
MW
R2
O
MW
+ R3NH2 + HOP(OR4)2
R2
R1
C
R1
O
C
NHR3
ꢀ-Aminophosphonates are an important class of compounds
in modern pharmaceutical chemistry. The potential of ꢀ-amino-
phosphonates as peptide mimetics,5 haptens of catalytic antibod-
ies,6 enzyme inhibitors,7 and antibiotics and pharmacologic
agents8 has been established. Thus, how to efficiently synthesize
ꢀ-aminophosphonates has been explored. Of the methods avail-
able, the nucleophilic addition of phosphites to imines is most
convenient. These reactions are usually promoted by a base or
Silica gel Support
P(OR4)2
4
1
2
3
Entry
R1
R2
R3
R4 Time 4a/%b
1
2
3
4
5
Ph
Ph
Ph
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Et 15 min 4a/94
Me 15 min 4b/92
i-Pr 15 min 4c/80
Et 15 min 4d/95
Et 15 min 4e/93
9
.
p-MeO-Ph
o-MeO-Ph
2,4-Dichloro-
C6H4
an acid. Lewis acids such as SnCl2, SnCl4, BF3 OEt2, ZnCl2,
and MgBr2 have been found to be effective.10 However, these re-
actions cannot be carried out in a one-pot operation with carbon-
yl compound, amine and phosphite, because amine and water
produced during imine formation can decompose or deactivate
these Lewis acids. Recently, it has been reported that using lan-
thanide triflate,11 samarium diiodide,12 scandium tris(dodecyl
sulfate),13 indium(III) chloride,14 TaCl5-SiO2,15 and (Bromodi-
methyl)sulfonium bromide16 as catalysts, one-pot reactions can
proceed smoothly. However, these catalysts have some draw-
backs: For instance, reactions require a long time,11,12,14,15 when
carbonyl compounds are ketones, many of these catalysts proved
to be less effective,11–13,16 and when starting materials contain
aliphatic amines, reactions gave noncharacterizable products.15
In addition, some of these catalysts are either expensive or some-
what difficult to prepare. Of late, Kaboudin reported that micro-
wave-assisted one-pot synthesis of ꢀ-aminophosphonates using
alumina-supported reagents.17 However, although this approach
is satisfactory for reactions with aromatic aldehydes, the reaction
of ketones has not been reported. In addition, aminophospho-
6
H
Ph
Et 10 min 4f/85
7
8
9
10
11
12
p-MeO-Ph
o-HO-Ph
p-NO2-Ph
Cyclohexyl
Ph
Ph
PhCH=CH
(trans)
H
H
H
H
H
H
n-Pr
Ph
Ph
Ph
Et 10 min 4g/91
Et 15 min 4h/83
Me 10 min 4i/81
Et 15 min 4j/88
PhCH2 Et 15 min 4k/95
PhCH2 Me 10 min 4l/91
13
H
PhCH2 Et 10 min 4m/88
14
15
16
Cyclohexanone
Cyclohexanone
CH3
PhCH2 Et
n-Pr Et
PhCH2 Et
n-Pr Et
5 min 4n/88
5 min 4o/87
5 min 4p/87
3 min 4q/83
CH3
17 Cyclopentanone
18 CH3
isobutyl PhCH2 Et 10 min 4r/85
aAll products gave satisfactory spectral and analytical data. For
a general procedure, see Ref. 18 bIsolated yields after column
chromatography.
Copyright Ó 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.7 (2005)
1043
aldehydes react with aromatic as well as aliphatic amines to give
the ꢀ-aminophosphonates in high yields. This procedure is
equally effective for conversion of ketone to the respective
dialkyl phosphonates. The reaction from ketones gave a high
yield of the desired product in 3–10 min and a prolonged reaction
time will lead to the decomposition of the product. Several
sensitive functionalities such as NO2, OMe, OH, and Cl and
the C–C double bond are unaffected in the reaction. It should
be noted that silica gel was easily recovered by filtration, washed
with methanol, and reused after activation at 100 ꢁC for 1 h.
Microwave assisted rapid synthesis of a variety of organic
compounds because of the selective absorption of microwave
energy by polar molecules.19 We envisioned that our three-com-
ponent coupling was accelerated by microwave energy because
of reactants’ polar nature. The role of silica gel may be two-fold:
(1) Physisorption of reactants on the silica surface leading to an
increase in local concentration, which in turn enhances the
rate of the reaction. (2) The acidic nature of the silica surface
promotes our three-component coupling.
In conclusion, the present procedure provides an efficient
one-pot synthesis of ꢀ-aminophosphonates from the reaction
of a carbonyl compound, amine and dialkyl phosphite. The no-
table advantages of this procedure are (1) general applicability
to aldehydes and ketones, (2) high yields of products, (3) very
short reaction times, (4) operational simplicity, (5) solvent-free
conditions, (6) silica gel is cheap and can be reused. We believe
that all these advantages make this method an attractive and a
useful contribution to present methodologies.
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18 A typical experimental procedure for the synthesis of ꢀ-
aminophosphonate 4d is as follows: A mixture of p-anis-
aldehyde (136 mg, 1 mmol), aniline (93 mg, 1 mmol), and
diethyl phosphite (138 mg, 1 mmol) absorbed on 0.25 g silica
gel (99% SiO2, 300–400 mesh, Surface area 300–400 m2/g)
was mixed thoroughly by grinding into a fine, homogeneous
powder. Then the mixture was taken in a 5 mL conical flask
and was placed in a microwave oven (cooking type, Galanz
WP 700P 21-6) and irradiated for 15 min at 680 W. After
completion of the reaction indicated by TLC, the
reaction mixture was diluted with EtOAc and followed by
filtration. The filtrate was evaporated under reduced pressure
and the residue was purified by column chromatography to
afford the pure ꢀ-aminophosphonate 4d (331 mg, 95%). IR
References and Notes
1
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2
3
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(film) ꢁmax: 3301, 1603, 1510, 1245, 1025, 751 cmꢂ1
.
1H NMR (500 MHz, CDCl3): ꢂ 1.14 (t, J ¼ 7:0 Hz, 3H,
OCH2CH3), 1.28 (t, J ¼ 7:0 Hz, 3H, OCH2CH3), 3.66–
4
3.73 (m, 1H, OCH2), 3.77 (s, 3H, OCH3), 3.92–3.98 (m,
2
1H, OCH2), 4.06–4.17 (m, 2H, OCH2), 4.72 (d, JPH
¼
24:0 Hz, 1H, PCH), 6.58–6.60 (m, 2H, ArH), 6.67–6.71
(m, 1H, ArH), 6.85–6.88 (m, 2H, ArH), 7.08–7.12 (m, 2H,
ArH), 7.37–7.40 (m, 2H, ArH). 13C NMR (125 MHz,
3
CDCl3): ꢂ 16.15 (d, JPC ¼ 5:5 Hz, OCH2CH3), 16.33 (d,
1
5
6
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¼
2
151:3 Hz, PCH), 63.07 (d, JPC ¼ 7:4 Hz, OCH2), 63.13 (d,
2JPC ¼ 7:4 Hz, OCH2), 113.79, 113.94, 118.23, 127.58,
2
128.86 (d, JPC ¼ 5:5 Hz, CHCAr), 129.03, 146.28 (d,
3JPC ¼ 14:9 Hz, NHCAr), 159.21. ESI-MS: m=z (%) = 350
(100) [M þ Hþ]. Anal. Calcd for C18H24NO4P: C, 61.88;
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8
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Published on the web (Advance View) June 18, 2005; DOI 10.1246/cl.2005.1042