Lithium perchlorate/diethyl ether catalyzed one-pot synthesis of α-hydrazinophosphonates from aldehydes by a three-component reaction

Article abstract of DOI:10.1016/S0040-4039(01)01702-6

Various α-hydrazinophosphonates were prepared on the basis of three-component (aldehydes, N,N-dimethylhydrazine, and dimethyl(trimethylsilyl)phosphite, coupling reactions via LiClO₄-catalyzed tandem reactions.

Full text of DOI:10.1016/S0040-4039(01)01702-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8071–8073
Lithium perchlorate/diethyl ether catalyzed one-pot synthesis of
a-hydrazinophosphonates from aldehydes by a three-component
reaction†
Akbar Heydari,a,* Abdollah Javidanb and Mehdi Schaffiea
aChemistry Department, Tarbiat Modarres University, PO Box 14155-4838, Tehran, Iran
bChemistry Department, Imam Hossein University, PO Box 16575-347, Tehran, Iran
Received 27 June 2001; revised 28 August 2001; accepted 7 September 2001
Abstract—Various a-hydrazinophosphonates were prepared on the basis of three-component (aldehydes, N,N-dimethylhydrazine,
and dimethyl(trimethylsilyl)phosphite, coupling reactions via LiClO4-catalyzed tandem reactions. © 2001 Published by Elsevier
Science Ltd.
The addition of nucleophiles to CꢀN bonds is a syn-
thetically important method of preparing many types of
nitrogen-containing compounds of biological impor-
tance. Among these, a-amino phosphonates are partic-
ularly worth mentioning. As an analog of a-amino-
alkylphosphonic acids, a-hydrazinoalkylphosphonic
acids and their derivatives are of potential biological
importance. For example, several of these compounds
show a good safety effect against the phytotoxic action
of chloroacetanilide herbicides.1 To the best of our
knowledge, only a few examples of the synthesis of
a-hydrazinophosphonic acids have been reported: these
include the base-catalyzed condensation of diethyl
phosphite with aliphatic aldazines followed by subse-
quent acid hydrolysis2 (this method, however, was not
suitable for aryl aldazines), a selective reduction of the
a-hydrazonophosphonic acids with NaBH3CN or
BH3·THF,3 nucleophilic substitution of 1-sulfonyl-
oxyalkylphosphonates by hydrazine,4 and nucleophilic
substitution of 3-methoxy-1,2,3,6-tetrahydropyridazine
derivatives by dimethylphosphite in the presence of
Lewis acid.5
Three-component condensation reactions are interest-
ing and important, not only because two bonds are
formed in one-pot, but also because the methodology is
useful for making a broad variety of compound
libraries. However, it is difficult to extend the Lewis
acid-catalyzed three-component condensation to the
synthesis of amine derivatives because the strong
affinity of many Lewis acids for amino groups does not
allow regeneration of the Lewis acids in the reaction.6
Moreover, the Lewis acids can be decomposed by the
amine and water which are present at the stage of
amine derivative formation.7 It has been reported that
three-component condensation reactions of aldehydes,
Scheme 1.
* Corresponding author.
† In memory of Hans Otto Kalinowski.
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(01)01702-6

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A. Heydari et al. / Tetrahedron Letters 42 (2001) 8071–8073
References
amines or phenylhydroxylamine and nucleophiles such
as O-silylated keteneacetals, trimethylsilylcyanide,
dimethylphosphite and dimethyl trimethylsilyl phos-
phite take place in lithium perchlorate/diethyl ether
solution (5.0 M) to yield, b-aminoesters,8 a-aminoni-
1. Diel, P.; Maier, L. Eur. Pat. Appl. EP 1985, 143078;
Chem. Abstr. 1985, 103, 215544m.
2. (a) Rachon, J.; Wasielewski, C. Rocz. Chem. 1976, 50,
477; (b) Baraldi, P. G.; Guarneri, M.; Moroder, F.;
Pollini, G. P.; Simoni, D. Synthesis 1982, 653.
3. Yuan, C.; Chen, S.; Xie, R.; Feng, H. Phosphorus, Sulfur,
Silicon 1995, 106, 115.
4. Yuan, C.; Li, C. Synthesis 1996, 507.
5. Kaname, M.; Yoshinaga, K.; Arakawa, Y.; Youshifuji, S.
Tetrahedron Lett. 1999, 40, 7993.
6. Niimi, L.; Serita, K-i.; Hiraoka, S.; Yokozawa, T. Tetra-
hedron Lett. 2000, 41, 7075.
triles,9
a-aminophosphonates,10
a-cyanohydroxyl-
amines11 and N-trimethylsilyloxy-a-aminophospho-
nates,12 respectively. Herein, we wish to report that
a-hydrazinophosphonates can be prepared in good
yields by a new multicomponent synthesis in which a
hydrazone (generated in situ from the aldehyde and
N,N-dimethylhydrazine) is reacted with dimethyl
trimethylsilyl phosphite as a nucleophile, in lithium
perchlorate/diethyl ether (LPDE) solution (5.0 M) at
room temperature, within 1 h.13 It should be noted that
a solution of aldehyde the 1, N,N-dimethylhydrazine 2
and dimethyl trimethylsilyl phosphite 3 in diethyl ether
remains unchanged after 4 h at room temperature.
Several examples of the present three component cou-
pling reactions are summarized in Scheme 1.
7. Kobayashi, S.; Akiyama, R.; Kawamura, M.; Ishitani, H.
Chem. Lett. 1997, 1039.
8. Heydari, A.; Ipaktschi, J. Chem. Ber. 1994, 127, 1761.
9. Heydari, A.; Fatemi, P.; Alizadeh, A.-A. Tetrahedron
Lett. 1998, 39, 3049.
10. Heydari, A.; Karimian, A.; Ipaktschi, J. Tetrahedron
Lett. 1998, 39, 5773.
11. Heydari, A.; Larijani, H.; Emami, J.; Karami, B. Tetra-
hedron Lett. 2000, 41, 2471.
12. Heydari, A.; Zarei, M.; Alijanianzadeh, R.; Tavakol, H.
This method seems to be a good route to a-alkyl
hydrazinophosphonates. However, benzaldehyde, p-
methoxy-benzaldehyde, 3-pyridine carbaldehyde and
cinnamaldehyde are inert to nucleophilic addition of
dimethyl trimethylsilyl phosphite in the one-pot three-
component reaction.14 Additionally, we found that
hydrazonophosphonation of an aliphatic aldehyde
rather than an aromatic was performed with more than
99% selectivity. Thus, the reaction of isobutyraldehyde
and 3-pyridine carbaldehyde with N,N-dimethylhy-
drazine and dimethyl trimethylsilyl phosphite in 5.0 M
LPDE solution give a-hydrazinophosphonate 4 and
3-pyridinehydrazone 5, respectively.
Tetrahedron Lett. 2001, 42, 3629.
13. A typical experimental procedure: To a mixture of alde-
hyde (2 mmol) in 5 M LPDE (4 ml) was added N,N-
dimethylhydrazone (2.2 mmol) at room temperature. The
mixture was stirred for 5 min and dimethyl trimethylsilyl
phosphite (2.2 mmol) was added. The mixture was stirred
for 15 min then water was added and the product was
extracted with CH2Cl2. The organic phase was collected,
dried (Na2SO4) and evaporated to afford the crude
product. The product was purified by flash chromatogra-
1
phy (hexan–ethyl acetate). H NMR, 13C NMR, IR and
In conclusion, we report a mild and efficient method
for preparation of a-hydrazinophosphonate derivatives,
that is suitable for a variety of substituted aldehydes.
Applications of this methodology to the preparation of
enantiomerically enriched a-hydrazinophosphonates
and the synthesis of natural products are in progress.
MS spectra were entirely consistent with the assigned
structures. Selected data as follows: 4 (R1=i-propyl): oil
3
1H NMR (500 MHz, CDCl3) l 3.56 (d, JP–H=7 Hz, 3H,
OCH3), 3.54 (d, 3JP–H=7 Hz, 3H, OCH3), 3.1 (bs, 1H,
NH), 2.84 (dd, 2JP–H=14.6 Hz, 2JH–H=4 Hz, 1H, H1),
3
2.24 (s, 6H, NCH3), 1.95 (m, 1H, H2), 0.86 (d, JH–H
=
7Hz, 3H, CH3), 0.81 (d, 3JH–H=7Hz, 3H, CH3); 13C
2
NMR (22.5 MHz, CDCl3) l 59.7 (d, JP–C=146 Hz, C1),
51.56 (d, 3JP–C=7 Hz, OCH3), 50.30 (d, 3JP–C=7 Hz,
Acknowledgements
4
OCH3), 46.25 (s, NCH3), 27.2 (s, CH), 18.77 (d, JP–C
=
11 Hz, CH3), 17.11 (d, JP–C=5 Hz, CH3): 4 (R1=tert-
butyl): oil 1H NMR (90 MHz, CDCl3) l 3.86 (d,
4
Research supported by the National Research Council
of I. R. Iran as a National Research project under the
number 984.
3JP–H=2.7 Hz, 3H, OCH3), 3.72 (d, JP–H=2.7 Hz, 3H,
3
2
CH3), 3.0 (bs, 1H, NH), 2.9 (d, JP–H=18 Hz, 1H, H1),

A. Heydari et al. / Tetrahedron Letters 42 (2001) 8071–8073
8073
2.50 (s, 6H, NCH3), 1.2 (s, 9H, C(CH3)3); 13C NMR (125
MHz, CDCl3): l 65.39 (d, JP–C=141 Hz, C1), 52.25 (d,
(d, 3JP–H=8.8 Hz, 3H, OCH3), 3.69 (d, 3JP–H=8.8 Hz, 3H,
OCH3), 3.41(bs, 1H, NH), 2.95 (dd, 2JP–H=14.6 Hz,
2JH–H=3.5 Hz, 1H, H1), 2.37 (s, 6H, NCH3), 1.76–1.58 (m,
6H), 1.24–1.18 (m, 5H); 13C NMR (125 MHz, CDCl3): l
61.22 (d, 2JP–C=146 Hz, C1), 52.68 (d, 3JP–C=7 Hz,
2
3JP–C=7 Hz, OCH3), 52.20 (d, 3JP–C=7 Hz, OCH3), 47.50
(s, NCH3), 34.38 (d, 3JP–C=3 Hz, C2), 27.82 (d, 4JP–C=6.6
Hz, CH3): 4 (R1=n-propyl): oil 1H NMR (500 MHz,
CDCl3): l 3.67 (d, 3JP–H=5.5 Hz, 3H, OCH3), 3.65 (d,
3JP–H=5.5 Hz, 3H, OCH3), 3.37 (bs, 1H, NH), 2.98 (m, 1H,
H1), 2.34 (s, 6H, NCH3), 1.61–1.34 (m, 4H, CH2-CH2),
0.86 (t, 3H, CH3); 13C NMR (125 MHz, CDCl3): l 55.48
(d, 2JP–C=153 Hz, C1), 52.78 (d, 3JP–C=7 Hz, 3H, OCH3),
52.55 (d, 3JP–C=6.5 Hz, 3H, OCH3), 47.79 (s, 6H, NCH3),
31.31 (s, CH2), 19.66 (d, JP–C=9 Hz, CH2), 14.0 (s, CH3);
3
OCH3), 52.47 (d, JP–C=7 Hz, OCH3), 47.77 (s, NCH3),
38.70 (s, CH), 30.67 (d, JP–C=10 Hz, CH2), 28.9 (d, JP–C=3
Hz, CH2), 26.7 (s, CH2), 26.6 (s, CH2), 26.3 (s, CH2).
14. When a solution of aromatic or heteroaromatic aldehyde
and N,N-dimethylhydrazine was treated with dimethyl
trimethylsilyl phosphite in LPDE solution (5.0 M) at room
temperature for 1 h, the corresponding hydrazone type
product was obtained with high yield.
1
4 (R1=c-hexyl): oil H NMR (500 MHz, CDCl3): l 3.71