Novel one-pot synthesis of 3-amino-1-alkenylphophonates by addition of imines to alkynylphosphonate titanium(II) complexes

Article abstract of DOI:10.1021/ol027429a

(Matrix presented) A new method of synthesis of 3-amino-1-alkenylphosphonates is described. It involves the addition of imines to the alkynylphosphonate titanium(II) complexes 2, which are prepared in situ from 1-alkynylphosphonates and Ti(O-i-Pr)₄/2 equiv of i-PrMgCl. Compounds 4a-i were obtained regio- and stereoselectivily in high yields.

Full text of DOI:10.1021/ol027429a

ORGANIC
LETTERS
2003
Vol. 5, No. 3
357-359
Novel One-Pot Synthesis of
3-Amino-1-alkenylphophonates by
Addition of Imines to
Alkynylphosphonate Titanium(II)
Complexes
Abed Al Aziz Al Quntar, Valery M. Dembitsky, and Morris Srebnik*
Department of Medicinal Chemistry and Natural Products, School of Pharmacy,
Hebrew UniVersity in Jerusalem, Jerusalem 91120, Israel
msrebni@md2.huji.ac.il
Received December 8, 2002
ABSTRACT
A new method of synthesis of 3-amino-1-alkenylphosphonates is described. It involves the addition of imines to the alkynylphosphonate
titanium(II) complexes 2, which are prepared in situ from 1-alkynylphosphonates and Ti(O-i-Pr)4/2 equiv of i-PrMgCl. Compounds 4a−i were
obtained regio- and stereoselectivily in high yields.
Vinylphosphonates are compounds that have a wide range
of applications in many areas such as copolymers,1 polymer
additives,2 flame retardants,3 intermediates for drugs,4 agro-
chemicals,5 in further transformations,6 and other applica-
tions.7 Due to their importance, their preparation methods
are varied.8
The presence of a nitrogen atom at any position of
phosphonates in the carbon skeleton enhances the potential
of these types of compounds. Generally, aminophosphonates
are an important class of compounds because of their unique
utilities as antibiotics,9 herbicides,10 antifungal,11 enzyme
inhibitors,12 and pharmacological agents.13 Among the vari-
ous types of aminophosphonates, the 3-aminophosphonates
originally were isolated from microorganisms14 and subse-
quently synthesized to confirm the structures. They were also
prepared from (1-hydroxy-2-alkyl)phosphonates by the reac-
(1) (a) Jin, J., II; Hua, J. C. H. U.S. Patent 3925506, 1975. (b) Fujimatsu,
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S.; Ellis, W. D.; Rowell, R. M. U.S. Patent 5683820, 1997.
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www.delphion.com.
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10.1021/ol027429a CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/16/2003

tion with triphenylphosphine, diethylazidodicarboxylate, and
hydrogen azide, followed by 1,3 rearangement of the allylic
R-azidophosphonates15 or by the addition of diethyl meth-
ylphosphonite to 2-cyclohexenone followed by amino acid
formation.12b Another method involves a seven-stage process
starting from Michael addition of dimethyl methylphospho-
nate to 4-chloro-â-nitrostyrene and catalytic reduction of the
nitro group, followed by hydrolysis of the resulting amine.16
Recently, we reported some interesting reactions of alkynyl-
phosphonates with divalent titanium isopropoxides to produce
various types of di- and trisubstituted vinylphosphonates
(Scheme 1).17 The in situ-generated divalent titanium com-
(O-i-Pr)4 and 2 equiv of i-RrMgX (X ) Cl, Br). It has been
used to synthesize cyclopropanols from esters19 and shown
to add to alkynes or alkenes, which in turn react with various
electrophiles to produce many useful and interesting prod-
ucts.20 Herein, we extend our work to prepare 3-amino-1-
alkenyl-phosphonates by addition of imine to the alkynyl-
phosphonate titanium(II) (Scheme 2).
Scheme 2
Scheme 1
Various types of imines efficiently reacted with the
alkynylphosphonate titanium(II) complex 2, prepared from
1-alkynylphosphonates, and Ti(O-i-Pr)4/2 equiv of i-PrMgCl
to produce the desired 3-amino-1-alkenylphosphonates in
high yields as shown in Table 1. This one-pot reaction is
plex was initially discovered by Kulinkovich.18 It is prepared
from available and inexpensive starting materials, i.e., Ti-
Table 1. 3-Amino-1-alkenylphosphonates 4a-i Obtained from
Addition of Imines to the Alkynylphosphonate Titanacycles
entry
R
R1
R2
31P yielda isolated yield
(8) Wittig-type: (a) Gupta, A.; Sacks, K.; Khan, S.; Tropp, B. E.; Engel,
R. Synth. Commun. 1980, 10, 299. (b) Aboujaoude, E. E.; Lietje, S.;
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C.; Yang, B. Z. Synth. Commun. 1993, 23, 3081. (g) Liu, R.-q.; Schlosser,
M. Synlett 1966, 1197. Dehydration: (h) Semmelhack, M. F.; Tomesch, J.
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Peter, R.; von Itzstein, M. Chem. Ber. 1987, 120, 121. Oxidative elimina-
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Venugopalan, B.; Hamlet, A. B.; Durst, T. Tetrahedron Lett. 1981, 22, 191.
Allylic rearrangements: (p) Principato, B.; Maffei, M.; Siv, C.; Buono,
G.; Peiffer, G. Tetrahedron 1996, 52, 2087. Peterson olefination: (q)
Mikolajczyk, M.; Balczewski, P. Synthesis 1989, 101. (r) Ahlbrecht, H.;
Farnung, W.; Simon, H. Chem. Ber. 1984, 117, 2622. (s) Waschbusch, R.;
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4a
4b
4c
4d
4e
4f
4g
4h
4i
Ph
Ph
p-tolyl
p-MeO-Ph i-Pr
Et
Ph
Ph
Ph
Me
97%
95%
95%
98%
95%
98%
98%
95%
90%
79%
78%
80%
85%
75%
79%
81%
70%
71%
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
Bz
Bz
Ph
i-Pr
p-MeO-Ph i-Pr
1-ClPr Ph
1-ClPr Ph
Ph
Bz
a Determined by 31P NMR of the reaction mixture.
general and proceeds with aliphatic and aromatic substituents
on both the vinylic carbon and the nitrogen atom of the imine,
in high yields.
(9) (a) Kuroda, Y.; Okuhara, T.; Goto, T.; Okamoto, M.; Terano, H.;
Kohaska, M.; Aoki, H.; Imanaka, H. J. Antibiot. 1980, 33, 29. (b) Allen, J.
G.; Atherton, F. R.; Hassel, C. H.; Holmes, S. W.; Nisbet, L. J.; Ringrose,
P. S. Nature 1978, 272, 56. (c) Athreton, F. R.; Hassel, C. H.; Lambert, R.
W.; Ringrose, P. S. Antimicrob. Agent Chemother. 1979, 15, 684.
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Pan, C.; Zhang, Y. X. Heteoatom Chem. 1997, 8, 103-122.(c) Redmore,
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1986, 29, 29. (b) Neda, I.; Melnicky, C.; Vollbrecht, A.; Schmutzler, R.
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(17) Quntar, A. A.; Srebnik, M. Chem. Comm. 2003, 1, 58.
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Pritytskaya, T. S. Zh. Org. Khim. 1989, 25, 2244. (b) Klinkovitch, O. G.;
Sviridov, S. V.; Vasilevskii, D. A. Synthesis 1991, 234.
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358
Org. Lett., Vol. 5, No. 3, 2003

We found that 3 equiv of the freshly distilled imine is
essential for reaching the maximum yield. However, the
excess imine was recovered by silica gel chromatography
during the isolation of the reaction mixture. The course of
the reaction was followed by 31P NMR on aliquots prepared
by quenching with distilled water and extraction with ethyl
acetate. Changing the reaction sequence, i.e., adding the
alkynylphosphonate to imine titanium(II) complex, produced
the 3-amino-1-alkenylphosphonate in much lower yields
(<50%) in addition to many other nonidentified side
products. Only one isomer of the 3-aminovinylphosphonate
was produced, in which carbon-carbon bond formation
occurred on C2 of the titanacycle. This regioselectivity seems
to be controlled by steric factors. The regiochemistry was
Table 2. Selected NMR Data of 4
3J PC (Hz)
3J PC (Hz)
entry allylic amino carbon allylic carbon of R 31P NMR J PH
2
4a
4b
4c
4d
4e
4f
4g
4h
4i
19.2
21.2
19.2
20.3
21.4
20.4
23.8
22.2
20.3
8.1
7.1
7.5
6.9
6.2
6.9
7.1
7.1
6.9
17.98
19.49
18.15
19.59
19.59
20.01
18.10
18.00
20.11
18.6
18.9
18.15
18.6
18.0
18.9
18.6
18.5
19.9
1
determined by H NMR spectroscopy, which showed a
doublet in the region (5.0-6.3 ppm) for the hydrogen on
C1 split by phosphorus, with JPH values (18.0-19.9 Hz).
The stereochemistry of 4 was determined by NMR analysis
of the carbon-phosphorus coupling constant. The large 3JPC
of the amino carbon (19.2-23.8 Hz) compared to the smaller
work all attempts to add imines to alkynylphosphonate
zirconacycles did not succeed.21
3
values of JPC of the vinylic carbon of R (6.2-8.1 Hz) is
In summary, we have developed a new synthetic route
for the preparation of 3-amino-1-alkenylphosphonates by
addition of the imines to the alkynylphosphonate titanacycles.
This methodology has the advantages of being one-pot,
general, and regio- and stereoselective. In addition, it is done
under mild conditions using inexpensive and available
reagents.
consistent with trans arrangement of the amino group to
phosphorus and cis configuration of the vinylic carbon of R
with respect to phosphorus, as shown in Table 2. Previous
methods for the synthesis of 3-aminophosphonates are
multistep, are not general, and suffer from overall low yield.
Finally, the present alkynylphosphonate titanium(II) com-
plexes have proven to be complementary with our work with
phosphonate zirconocene complexes, since in our previous
Acknowledgment. The authors thank the Israeli Science
Foundation and MECC for support of this work.
(20) (a) Sato, F.; Urabe, H.; Okamoto, S. Synlett 2000, 753. (b) Sato,
F.; Okamoto, S. AdV. Synth. Catal. 2000, 343, 759.
(21) (a) Quntar, A. A.; Melman, A.; Srebnik, M. Synlett. 2002, 1, 61.
(b) Quntar, A. A.; Srebnik, M. J. Org. Chem. 2001, 66, 6650. (c) Quntar,
A. A.; Srebnik, M. Org. Lett. 2001, 3, 1379. (d) Quntar, A. A.; Srebnik,
M. J. Org. Chem. 2002, 67, 3769.
Supporting Information Available: Experimental pro-
cedures and full NMR data. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL027429A
Org. Lett., Vol. 5, No. 3, 2003
359