β,γ-Unsaturated α-aminophosphonates: Synthesis and reactivity

Article abstract of DOI:10.1016/S0040-4039(00)00922-9

Vinylogous iminium salts from γ-aminoenamines react with triethylphosphite to afford amino phosphonates in moderate to good yields. The latter are easily converted to α-substituted aminoallylphosphonates that can yield α-substituted aminoallylphosphonates on reaction with butyllitium and a series of electrophiles. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00922-9

Tetrahedron Letters 41 (2000) 6045±6048
b,g-Unsaturated a-aminophosphonates:
synthesis and reactivity
A. Atmani,a,* J.-C. Combret,a C. Malhiaca and J. Kajima Mulengib
a
 Â
Â
Laboratoire d'Heterochimie Organique, Universite de Rouen, B.P.118/76.134, Mont-St Aignan, France
Á Â
Laboratoire de Synthese Organique, Institut de Chimie, Universite de Tlemcen, B.P. 119, Tlemcen 13000, Algeria
b
Received 22 April 2000; accepted 1 June 2000
Abstract
Vinylogous iminium salts from g-aminoenamines react with triethylphosphite to a€ord amino phos-
phonates in moderate to good yields. The latter are easily converted to a-substituted aminoallylphos-
phonates that can yield a-substituted aminoallylphosphonates on reaction with butyllitium and a series of
electrophiles. # 2000 Elsevier Science Ltd. All rights reserved.
a-Aminophosphonic acids and their esters represent an interesting class of chemical compounds
as they are endowed with interesting biological and chemical properties.1 4 The synthesis of the
title substances of type 1 has received little attention since preparative methods already described
in the literature start generally from unsaturated imines.5,6
In this work we deal with a new synthetic way leading to a-amino b,g-ethylenic phosphonates
starting from unsaturated iminiums salts 2.7 We describe, for the ®rst time, the use of such
unsaturated compounds as a source of carbanions and the reaction of the latter with a series of
electrophiles. Iminium salts were quantitatively prepared by the reaction of an acid chloride such
as acetyl chloride with g-aminoenamines or by the reaction of methyl iodide with the same
enamines (Scheme 1).
* Corresponding author.
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00922-9

6046
Scheme 1.
This procedure is advantageous, compared to that of Bohme et al.8 The reaction takes place
under mild working conditions and the isolation and puri®cation of salts 2 just requires their
®ltration and washing with the appropriate solvent. However, when R1 is a methyl group, the
iminium salt cannot be isolated and it is engaged in situ in the synthesis of the aminophosphonate.
In each case, we have investigated the reaction of 2 with alkylphosphites. The reaction a€orded
a-dialkylamino b,g-ethylenic phosphonates 1 in good yields (Scheme 2).
Scheme 2.
Hetero-substituted phosphonates have been extensively used as a source of carbanions in the
Wittig±Horner or Horner±Wadsworth±Emmons reactions.9,10 However, the ease of carbanion
formation is not always clear and some discrepancies are found in the literature.11 15
In recent years, b,g-unsaturated phosphonates have been used as a source of carbanions.16 18
To our best knowledge, b,g-ethylenic a-aminophosphonates 1 have not been tried for the same
target yet. Scheme 3 shows our results on the treatment of 1 with butyllithium and the reaction of
the resulting carbanions with a series of electrophiles to a€ord a-substituted b,g-unsaturated
aminophosphonates 2.
Scheme 3. R1=CH3, C2H5; i=R0CHO, PhCH2Br, CH3I; R0=CH3, Ph, (CH3)2CH, Furyl
1. Experimental
1H, 13C and 31P NMR spectra were recorded at 200 MHz on an AC 200 Bruker or a WP 80
Bruker (80 MHz) instrument using TMS as an internal standard for 1H and 13C analyses; phosphoric
acid was used for 31P spectra. Chemical shifts are expressed in ppm. Mass spectra were recorded
by coupling a HP 5890 Hewlett Packard gas chromatography instrument with a 70 eV electronic
impact HP 5970 mass spectrometer. All commercial solvents were puri®ed and dried prior to
use.

6047
1.1. Iminium salts: general procedure (example: 2a)
1,3-dimorpholino 3-phenylpropene (14.4 g, 50 mmol) was dissolved in dry ether (250 ml) and
the resulting solution was cooled at ^5ꢀC. Acetyl chloride (3.9 g, 50 mmol) in dry ether (100 ml)
was slowly added with stirring to the propene solution keeping the temperature at ^5ꢀC during
the addition. Stirring was maintained for 30 min during which the temperature rose to room
temperature. The solid 2a was ®ltered and washed several times with dry ether in order to get rid
of acetmorpholide and was ®nally dried.
ꢀ
0
1
Yield 96%. mp 180 C. H NMR (80 MHz,CD3CN): 2.3±3 (m, 6H, Hb, Hb , Hc), 3.4±3.7 (m,
4H, Ha, Ha0), 7.5±8 (m, 2H, Hb, Hg), 8.7 (d, J=11 Hz, 1H, Ha). IR: 1650 cm^1. Other salts were
prepared from piperidine with XˆCl (yield 95%, mp 185ꢀC, ꢀ Ha=8.8, J=11 Hz); from morpholine
with XˆI (yield 95%, mp 210ꢀC, ꢀ Ha=8.7, J=10 Hz); from dimethylamine with XˆI (yield
95%, mp 194ꢀC, ꢀ Ha=8.8, J=10 Hz).
1.2. ꢁ-Aminophosphonates: general procedure
Iminium salt (5 mmol) in dry acetonitrile (10 ml) was placed in a 50-ml three-necked ¯ask
under dry nitrogen. Freshly distilled trialkylphosphite (5.1 mmol) was then added and the mixture
was stirred overnight. After removal of the solvent, the residue was dissolved in ether (20 ml) and
washed with 2 M HCl (10 ml). The organic layer was washed with further 2 M HCl (3Â5 ml).
The aqueous phase was adjusted at pH 11 with a 5 M NaOH solution and extracted with ether.
The combined organic phases were dried over magnesium sulfate and the solvent was removed to
a€ord the phosphonate as an oil.
1a: Yield: 40%. MS (EI, 70 eV): m/z 247 (6) M+, 138 (100), M-109. 31P NMR (200 MHz,
CDCl3): 24.2. 1H NMR (200 MHz, CDCl3): 1.34 (m, 2H, Hc), 1.46±1.52 (m, 4H, Hb),1.71(d, 3H,
J=4.6 Hz, CH3 CHˆ), 2.46±2.75 (m, 4H, Ha), 3.30 (dd, J=8, 18 Hz, 1H, ˆCH CH P), 3.67±
3.78 [2d, J=9.33, 9.90 Hz, 6H, P(OCH3)2], 5.63 (m, 2H, CH3 CHˆCH). 13C NMR (200 MHz,
CDCl3): 18(s), 23.3(s, c), 26.5(s, b, b0), 51.5 (d, J=8.4 Hz, a, a0), 52.5 [d, J=7.3 Hz, (CH3O)2P], 53
[d, J=7.1 Hz, (CH3O)2P], 67.5 (d, J=156.6 Hz, ˆCH CH CH3), 121 (s, ˆCH CH), 132 (d,
J=15.5 Hz, CH3 CHˆ). 1b: Yield: 87%. MS(EI): 269(4), M+, 160 (100), M-109. 31P NMR (200
1
MHz, CDCl3): 23.6; H NMR (200 MHz, CDCl3): 2.5 (s, 6H, N(CH3)2), 3.50 (dd, J=8.8, 17.7
Hz, 1H, ˆCH CH P) 3.75, (d, J=11 Hz, 3H, P(OCH3)2), 3.85 (d, J=11 Hz, 3H, P(OCH3)2),
6.35 (ddd, J=6.7, 9.8, 15 Hz, 1H, CH=CH), 6.7 (dd, J=2.8, 16 Hz, 1H, CH=CH), 7.4 (m, 5H,
C6H5). 13C NMR (200 MHz, CDCl3): 43 [d, J=9.1 Hz, N(CH3)2], 52 (m, P(OCH3)2) 65 (d,
J=159.4 Hz, ˆCH CH P), 120 (s, CHˆCH), 138 (d, J=15.4 Hz, CHˆCH), 126, 128, 136 (Ph).
1c: Yield 84%. MS (EI): m/z 339 (4) M+, 202 (100), M-137. 31P NMR (200 MHz, CDCl3): 20.3.
1H NMR (200 MHz, CDCl3): 1.28 [dt, J=6, 16 Hz, 6H, P(OCH2CH3)2], 2.62±2.94 (m, 4H, Ha),
3.45 (dd, J=8, 20 Hz, 1H, CH CH P), 3.66±3.70 (m, 4H, Hb), 4.11 [(m, 4H, P(OCH2CH3)2],
6.20 (dd, J=3, 12, 16 Hz, 1H, Ph CHˆCH), 6.50 (dd, J=4, 16 Hz, 1H, C6H5 CHˆCH), 7.20
(m, 5H, C6H5 ). 13C NMR (200 MHz, CDCl3): 18 [m, P(OCH2CH3)2], 52 (d, J=8.2 Hz, a, a0),
62 [2d, J=7 Hz, P(OCH2CH3)2], 65 (d, J=157.9 Hz, ˆCH CH P), 120 (s, C6H5 CHˆCH),
126, 127, 128, 136 (Ph), 138 (d, J=15 Hz, PhCHˆ). 1d: Yield: 89%, MS (EI): 295 (7) M+, 186
1
(100), M-109. H NMR (200 MHz, CDCl3): 1.72 (m, 4H, Hb), 2.74 (m, 4H, Ha), 3.71 and 3.73
[2d, J=7.31, 6H, P(OCH3)2], 3.59 (dd, J=9.93, 13.4 Hz, 1H, ˆCH CH P), 6.29 (dd, J=4, 6, 16
Hz, 1H, PhCHˆCH), 6.58 (dd, J=5, 15 Hz, 1H, PhCHˆCH), 7.32 (m, 5H, Ph).

6048
1.3. Alkylation of ꢂ,ꢃ-unsaturated ꢁ-aminophosphonates: general procedure
To a cooled solution (^78ꢀC) of 1 (5 mmol) in THF (5 ml) was added butyllithium in THF (5
mmol), dropwise under argon, and the resulting solution was stirred for 1 h. A solution of the
required aldehyde (5 mmol) in THF(5 ml) was then added. After 30 min stirring, Me3SiCl (5
mmol) was added and stirring was continued for a further 2 h. At the end, the solvent was
removed under reduced pressure and the residue was dissolved in CH2Cl2. The resulting solution
was washed with a saturated aqueous solution of NH4Cl (3Â5 ml) and dried over MgSO4. After
removal of the solvent, the residue was puri®ed on a silica gel column chromatography eluted
with ether/methanol (9:1).
All compounds gave satisfactory analytical data. 2a: R1ˆC2H5, R2ˆCH3. Yield 80%. MS(EI,
1
70 eV), m/z: 353 (20) M+, 322 (100). 31P NMR: 14.5. H NMR (200 MHz,CDCl3) 1.10 (s,3H,
C CH3), 1.30 (dt, J=7.48, 14.18 Hz, 6H, P[(OCH2CH3)2], 2.80 (m, 4H, Ha, Ha0), 3.69 (m, 4H,
Hb, Hb0), 4.03 (m, 4H, P[(OCH2CH3)2]), 6.40±6.54 (2d, J=11.89, 12.43 Hz, 2H, PhCHˆCH),
7.18 (m, 5H, C6H5). 2f: R1ˆi-C3H7CHOTMS. Yield 85%. MS (EI, 70eV), m/z: 483, M+, 411 (7)
1
M-73, 338 (100). 31P NMR: 14.1. H NMR (200 MHz,CDCl3) 0.06 (s, 6H, OSiMe3), 0.89 (d,
J=2.9 Hz, 6H, [(H3C)2CH]), 1.28 (dt, J=3.7, 7.17 Hz, 6H, [(OCH2CH3)2]), 1.50 (m, 1H,
[CH3)2CH]), 2.60±2.80 (m, 4H, Ha), 4.08 (m, 4H, P[(0CH2CH3)2]), 6.75 (d, J=10 Hz, 1H,
PhCHˆCH), 6.80 (d, J=10 Hz, 1H, PhCHˆ) 7.18 (m, 5H, C6H5).
References
1. Kase, K.; Yamamoto, M.; Koguchi, T.; Okachi, R.; Kasai, M.; Shirata, K.; Kawamoto, I.; Shuto, K.; Karasawa,
A. Eur. Pat. Appl., Ep 61, 172, 1982., Chem. Abstr. 1983, 98, 107793.
2. (a) Maier, L. Phosphorus, Sulfur and Silicon 1990, 53, 43±46. (b) Dhawan, B.; Redmore, D. Phosphorus, Sulfur and
Silicon 1987, 32, 119. (c) Jacobson, N. E.; Bartlett, P. A. J. Am. Chem. Soc. 1981, 103, 654±657. (d) Lukszo, J.;
Tyka, R. Synthesis 1977, 239±240. (e) Pudovik, A. N.; Konovalova, I. V. Synthesis 1979, 81±93. (f) Bartlett, P. A.;
Hanson, J. E.; Giannousis, P. P. J. Org. Chem. 1990, 55, 6268±6274.
3. Kabachnik, M. I.; Medved, T. Y.; Dyatlova, N. M.; Arkhipova, O. G.; Rudomino, M. V. Chem. Abstr. 1969, 7c,
20101g. Usp. Khim. 1968, 37, 1161±1191.
4. Wadsworth, W. S.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83, 1733±1738.
5. Sobanov, A. A.; Bathtiyarova, I. V.; Badeeva, E. K.; Zimin, M. G.; Pudovik, A. N. Zh. Obsch. Khim. 1985, 55,
22±26.
6. (a) Afarinkia, K.; Cadogan, J. I. G.; Rees, C. W. Synlett 1992, 123. (b) Afarinkia, K.; Cadogan, J. I. G.; Rees,
C. W. Tetrahedron 1990, 46, 7175±7196.
7. Jahn, U.; Andersch, J.; Schroth, W. Synthesis 1997, 573±588.
8. Bohme, H.; Viehe, H. G. Iminium Salts in Organic Chemistry. Adv. Org. Chem.; Taylor, E. C., Ed. Vol 9. John
Wiley: New York, 1975±1979; pp. 107±223.
9. (a) Martin, S. F.; Gomper, R. J. Org. Chem. 1974, 39, 2814±2815. (b) Martin, S. F. J. Org. Chem. 1976, 41, 3337±
3338. (c) Martin, S. F.; Chou, F. S.; Payne, C. W. J. Org. Chem. 1977, 42, 2520±2523.
10. Ahlbrecht, H.; Farnung, W. Synthesis 1977, 336±338.
11. Broekhof, N. J.; Van der Gen, A. Tetrahedron Lett. 1980, 21, 2671±2674.
12. Zimmer, H.; Bercz, J. P. Liebigs Ann. Chem. 1965, 686, 107±114.
13. Gross, H.; Costisella, B. Angew. Chem. 1968, 80, 364±365.
14. Schindler, N.; Ploger, W. Chem. Ber. 1971, 104, 2021±2022.
15. Fukuda, M.; Kan, K.; Okamoto, Y.; Sakurai, H. Bull. Chem. Soc. Jpn. 1975, 2103±2105.
16. Gerber, J. P.; Modro, T. A. Phosphorus, Sulfur and Silicon 1994, 88, 99±111.
17. Gross, H.; Costisella, W. Angew. Chem., Int. Ed. 1968, 7, 391±392.
18. (a) Ahlbrecht, H.; Farnung, W. Chem. Ber. 1984, 117, 1±22. (b) Ahlbrecht, H.; Farnung, W.; Simon, H. Chem.
Ber. 1984, 117, 2622±2643.