One-pot three-component Kabachnik-Fields synthesis of α- aminophosphonates using H-beta zeolite catalyst

Article abstract of DOI:10.1016/j.tetlet.2010.11.105

One-pot three-component Kabachnik-Fields synthesis of α- aminophosphonates with high yields from the reaction between carbonyl compound, primary amine, and substituted phosphite can be carried out in a short period, using H-beta zeolite as a reusable catalyst.

Full text of DOI:10.1016/j.tetlet.2010.11.105

Tetrahedron Letters 52 (2011) 863–866
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot three-component Kabachnik–Fields synthesis
of a-aminophosphonates using H-beta zeolite catalyst
V. H. Tillu a, D. K. Dumbre b, R. D. Wakharkar a, V. R. Choudhary b,
⇑
a Organic Chemistry Division, National Chemical Laboratory, Pune 411008, India
b Chemical Engineering and Process Development Division, National Chemical Laboratory, Pune 411008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 June 2010
Revised 12 November 2010
Accepted 19 November 2010
Available online 24 November 2010
One-pot three-component Kabachnik–Fields synthesis of
a-aminophosphonates with high yields from
the reaction between carbonyl compound, primary amine, and substituted phosphite can be carried
out in a short period, using H-beta zeolite as a reusable catalyst.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Carbonyl compound
Primary amine
Substituted phosphite
H-beta zeolite
The
a
-aminophosphonic acids and
a
-aminophosphonates exhi-
-amino-
However this method is not devoid of limitations because many
imines are hygroscopic and unstable. The first one-pot synthesis
bit a wide range of intriguing biological activities. The
a
phosphonic acids are potential antibacterial agents besides
of a-aminophosphonate was achieved by the in situ generated
exhibiting neuro-active characteristics and have been employed
reaction of phosphite in the presence of lanthanide triflate as the
as anticancer drugs and pesticides.1
a-Aminophosphonic acid con-
catalyst with imines.12 Since then a number of methods for the
taining compounds have demonstrated their ability to modulate
biochemical processes by enzyme inhibition. Examples of
preparation of diverse
amination of
-hydroxy phosphonate derivatives,13 electrophilic
amination of
-alkylphosphonamides,14 hydrogenation of
a-aminophosphonates, such as nucleophilic
a
a-aminophosphonic acid containing enzyme inhibitors include
a
the therapeutic agent fosinopril, inhibitor of angiotensine convert-
ing enzyme,2 D-Ala:D-Ala ligase,3 HIV-protease,4 glutamine
synthetase,5 and stromelysin-1 (MMP-3) inhibitors.6 Besides
dehydroaminophosphonate,15 Aldol type reactions of (isocy-
anomethyl) phosphonates with aldehyde,16 hydrogenation of azi-
ridinylphosphonates,17 addition of phosphites to sulfimine,18 and
catalyzed Mannich-type one-pot procedure,19 have been reported.
However, these methods suffer from drawbacks, such as long reac-
tion times, low product yields, requirement of the stoichiometric
amounts of catalysts, formation of a large amount of waste and/
or use of toxic catalyst.
antagonists in the metabolism of amino acids, a-aminophosphonic
acid containing compounds have also found novel drug delivery
applications, for example to stabilize peptide drugs during their
intranasal absorption.7
a-Aminophosphonate, the key substrate in the synthesis of
a-aminophosphonic acid, shows a number of interesting activities,
Use of solid catalysts, such as alumina,20 and KSF,21 has also
such as peptidomimetics, enzyme inhibitors, pharmacogenic
agents, herbicides, inhibitors of serine hydrolyses, and inhibitors
of UDP-galactopyranose mutate and anti-tumor agents.8 It is syn-
thesized by the Kabachnik–Fields reaction9,10 which involves a
three-component coupling of a carbonyl, an amine, and a hydro-
phosphonyl compound.
been reported for the synthesis of a-aminophosphonates. How-
ever, the catalyst required was very large and it has a limited reus-
ability. Hence, it is of great practical importance to develop a more
efficient and also an environmentally benign method for the syn-
thesis of
pot synthesis of
a
-aminophosphonates. In this Letter, we report a one-
-aminophosphonates from the reaction between
a
Among the various synthetic approaches to the synthesis of
a
-
carbonyl compound, primary amine, and substituted phosphite,
with a high product yield, using H-beta zeolite as a catalyst in
small amounts as per Scheme 1. The catalyst can be easily sepa-
rated by filtration and reused several times in the reaction.
Results showing the performance of Hb,22 HY,23and HM23 zeo-
aminophosphonate, the acid catalyzed nucleophilic addition of
phosphites to amines is established as the most useful method.11
⇑
Corresponding author. Tel.: +91 20 25902318; fax: +91 20 25902612.
E-mail addresses: vr.choudhary@ncl.res.in, vrc0001@yahoo.co.in (V.R. Choudh-
ary).
lites and also of the Hb modified by its impregnation with Lewis
20–22
acid, such as anhydrous InCl3 and FeCl3
in the one-pot
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.105

864
V. H. Tillu et al. / Tetrahedron Letters 52 (2011) 863–866
synthesis are presented in Table 1. Zeolites are crystalline micropo-
R
1
NHR3
R
1
rous aluminosilicates. Their porous structure can accommodate a
wide variety of cations which can readily be exchanged for other
cations. They differ widely in their cations Si/Al ratios, pore shapes
and sizes, and channel system (1, 2 or 3 dimensional channels).
Among the different acidic zeolites, the Hb (H+-exchanged beta
zeolite) showed the best performance. Moreover, this catalyst
showed excellent reusability. Hence the further synthesis of differ-
H-beta,
MeCN
OR4
OR4
H
P
R3NH2
+
+
O
O
O
P
R2
R
2
OR4
OR4
Scheme 1. H-beta zeolite catalyzed synthesis of a-aminophosphonates.
ent a-aminophosphonates was carried out using the Hb zeolite cat-
Table 1
alyst. The results of the synthesis are given in Table 2. The
preparation and characterization of the Hb, HY, HM, and InCl3 (or
FeCl3)/Hb zeolite catalysts were reported earlier.22–24 The typical
experimental procedure for the synthesis is given in Ref. 25.
The observed better performance of Hb zeolite (Table 1) is ex-
pected because of its higher concentration of acid sites and three
dimensional large size pore system. The impregnation of the Hb
by InCl3 or FeCl3 resulted in a decrease in the product yield. This
may be due to the blockage of some of the zeolite channels and/
or pore openings by the deposited InCl3 or FeCl3 and, thereby,
increasing the diffusion resistance for the reaction species/products
Performance of different zeolite catalysts in the Kabachnik–Fields synthesis from
indole-3-carboxaldehyde, p-anisidine and dibenzyl phoshite
Catalyst
Reaction time (h)
Product yield (%)
H b
H Y
4
4
4
4
5
4
93
81
83
79
61
92
InCl3/Hb
FeCl3/Hb
HM
H ba
a
Fifth reuse of the catalyst.
Table 2
H-beta zeolite catalyzed Kabachnik–Fields synthesis of different
a
-aminophosphonates
Product
Sr. No.
1
Carbonyl compound
2
Amine
3
Reaction time (h)
5
Yield (%)
6
4
CHO
NH2
OCH2Ph
O
P
OCH2Ph
NH
MeO
MeO
1
1
89
CH
OMe
OMe
CHO
NH2
OCH2Ph
O
P
OCH2Ph
NH
O2N
O2N
2
3
4
5
76
90
CH
O2N
NO2
CHO
OCH2Ph
NH2
O
P
OCH2Ph
NH
H
N
NH2
OCH2Ph
OCH2Ph
O
P
MeO
4
1
93
NH
CH
CHO
OMe
N
H
OCH2Ph
P
NH2
NH2
CHO
O
OCH2Ph
5
6
4
2
91
87
NH
O
O
P
OCH2Ph
CH3
OCH2Ph
Ph
NH

V. H. Tillu et al. / Tetrahedron Letters 52 (2011) 863–866
865
Table 2 (continued)
Sr. No.
1
Carbonyl compound
2
Amine
3
Product
4
Reaction time (h)
5
Yield (%)
6
O
O
P
NH2
OCH2Ph
OCH2Ph
7
8
1
1
93
Ph
NH
CHO
NH2
OMe
O
P
OMe
NH
MeO
MeO
78
90
91
CH
OMe
OMe
CHO
NH2
HN
O
9
2
2
OMe
P
OMe
CHO
NH2
NH2
NH2
HN
O
P
10
OMe
OMe
CHO
HN
MeO
O
P
11
12
2
1
90
89
OC2H5
OC2H5
MeO
O
CHO
HN
O
P
OC2H5
OC2H5
O
CHO
O2N
NH2
NO2
MeO
13
3
87
HN
O
P
OC2H5
OC2H5
MeO
CHO
CHO
NH2
Br
MeO
MeO
Br
HN
HN
O
14
15
4
3
80
84
OC2H5
P
OC2H5
MeO
MeO
NH2
O
OC2H5
P
OC2H5
*
Dibenzylphosphite is used in entry Nos. 1–7, Dimethylphosphite is used in entry Nos. 8–10, Diethylphosphite is used in entry Nos. 11–15.
in the zeolite. The lowest performance of the HM zeolite is mostly
because of its one dimensional channels which are prone to block-
age by the large size reaction species.
As shown in Table 2, a wide range of structurally different car-
bonyl compounds and amines were subjected to this procedure
and converted into the corresponding
a-aminophosphonates in

866
V. H. Tillu et al. / Tetrahedron Letters 52 (2011) 863–866
Acknowledgment
O
+
NH2R
C
NR
C
NHR
V.R.C. and D.K.D. are grateful to the National Academy of Sci-
ences, India, for the NASI Senior Scientist Platinum Jubilee Fellow-
ship and Project Assistantship, respectively.
+
HO
HP(O)(OR)2
+HP(O)(OR)2
References and notes
1. Lefebvre, I.; Evans, S. J. Org. Chem. 1997, 62, 7532. and references cited therein.
2. Wyvratt, M.; Patchett, A. Med. Res. Rev. 1985, 5, 483.
3. Parsons, W.; Patchett, A.; Bull, H.; Schoen, W.; Taub, D.; Davidson, J.; Combs, P.;
Springer, J.; Gad Busch, H.; Weiss Berger, B.; Valiant, M.; Mellin, T.; Busch, R. J.
Med. Chem. 1988, 31, 1772.
+NH2R
C
C
P(O)(OR)2
P(O)(OR)2
NHR
OH
4. Peyman, A.; Budt, K. H.; Spanig, J.; Stowasser, B.; Rupert, D. Tetrahedron Lett.
1992, 33, 4549.
Scheme 2. Reaction scheme for the formation of
a-aminophosphonates.
5. Bayer, E.; Gugel, K.; Hagele, K.; Hagen, H.; Jessipow, S.; Konig, W.; Zahner, H.
Helv. Chim. Acta 1972, 55, 224.
6. Goulet, J.; Kinneary, J.; Durette, P.; Stein, R.; Harrison, R.; Martin, M.; Kuo, D.;
Lin, Y.; Hagmann, W. Bioorg. Med. Chem. Lett. 1994, 4, 1221.
7. Hussein, M.; Lim, M.; Raghavan, K.; Rogers, J.; Hidalgo, R.; Kettner, C. Pharm.
Res. 1992, 9, 626.
8. Razaei, Z.; Friouzabadi, H.; Iranpoor, N.; Ghadri, A.; Jafari, M.; Jafari, A.; Zare, H.
Eur. J. Med. Chem. 2009, 44, 4266.
high yields. Both the aromatic and aliphatic aldehydes or
ketones react with aromatic or aliphatic amines quite effectively
for their conversion to open-chain, cyclic, and aromatic imines
and then to the respective
a
-aminophosphonates. No difficulty
9. Kabachnik, M. I.; Medre, T. Y. Dokl. Akad. Nauk SSSR 1952, 83, 689; Chem. Abstr.
1953, 47, 2724b.
10. Fields, E. K. J. Am. Chem. Soc. 1952, 74, 1528.
11. Maghsoodlou, M.; Mustafa, S. Heteroat. Chem. 2009, 20, 5.
12. Sarvari, M. H. Tetrahedron 2008, 64, 5459.
13. Bhagat, S.; Chakraborti, A. K. J. Org. Chem. 2007, 72, 1263.
14. Sobhani, S.; Vafaee, A. Synthesis 2009, 11, 1909.
15. Akbari, J.; Heydari, A. Tetrahedron Lett. 2009, 50, 4236.
16. Sawamura, M.; lto, Y.; Hayashi, T. Tetrahedron Lett. 1989, 30, 2247.
17. Kim, D. Y.; Rhie, D. Y. Tetrahedron 1997, 53, 13603.
18. Lefebvre, I. M.; Evan, S. A. J. Org. Chem. 1997, 62, 7532.
19. Heydari, A.; Karimian, A.; Ipaktschi, J. Tetrahedron Lett. 1998, 39, 6729.
20. Kaboudin, B.; Nazari, R. Tetrahedron Lett. 2001, 42, 8211.
21. Yadav, J.; Subbareddy, B.; Madan, C. Synlett 2001, 1131.
22. Choudhary, V. R.; Jana, S. K.; Patil, N. S.; Bhargava, S. K. Micropor. Mesopor.
Mater. 2003, 57, 21.
was encountered with the reaction of conjugated aldehydes (entry
7). Sensitive functionalities such as OMe, NO2, and C–C double
bond are found to be unaffected under the present reaction condi-
tions. The reactions are fast and the products obtained are clean.
All the products were characterized by usual spectroscopic
methods.
Since
reaction mixture at room temperature, it is believed that the reac-
tion proceeds via -hydroxyphosphonates followed by the substi-
tution of hydroxyl group by amino group. Based on this idea,
Fields10 postulated that
-aminophosphonates are formed via
a-hydroxyphosphonates are found to be present in the
a
a
hemiaminals or imines. The plausible reactions involved in the
23. Choudhary, V. R. Zeolites 1987, 7, 272.
24. Choudhary, V. R.; Jana, S. K.; Mamman, A. S. Micropor. Mesopor. Mater. 2002, 56,
65.
overall synthesis are shown in Scheme 2.
In conclusion, the present procedure using Hb zeolite as the cat-
alyst provides an efficient one-pot synthesis of
25. Typical experimental procedure: For the preparation of (4-methoxy-
phenylamino)-(tetrahydro-1H-indole-3-yl)-methyl]-phosphonic acid dibenzyl
ester uses different catalysts (Table 1): A mixture of indol-3-carboxaldehyde
(1 mmol), p-anisidine (1 mmol), dibenzyl phosphite, and catalyst (10% w/w of
aldehyde) in acetonitrile was refluxed for 4–5 h.
a-aminophospho-
nates from the reaction of a carbonyl compound, primary amine,
and dibenzyl/dimethyl/diethyl phosphite. The notable advantages
of this procedure are (a) operational simplicity, requirement of
no additive, and excellent reusability of the catalyst, (b) general
applicability to aldehydes and ketones, (c) participation of aro-
matic as well as aliphatic amines, (d) reaction conditions tolerant
to a variety of sensitive functional groups, (e) reduced reaction
time, and (f) high product yields. This will be a more practical
For the synthesis of different
a-aminophosphonates using H-beta zeolite catalyst
(Table 2): mixture of aldehyde (1 mmol), amine (1 mmol), dibenzyl/
A
dimethyl/diethyl phosphite, and Hb (10% w/w of aldehyde) in acetonitrile
was refluxed for 4–5 h. The reaction was monitored by TLC.
After completion of reaction, the catalyst was separated by filtration. Then the
filtrate was quenched with water followed by extraction with ethyl acetate to
give the crude product, which was subsequently purified by column
chromatography on silica gel with petroleum ether/ethyl acetate as an
eluent. The catalyst was further washed with acetone, dried, and reused. The
products are known compounds and their spectroscopic data are given
earlier.8,10,12,14–16,19
alternative to existing methodologies for the synthesis of
aminophosphonous acid from their corresponding dibenzyl
-aminophosphonates.
a-
a