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Synlett 2007(16): 2549-2552  
DOI: 10.1055/s-2007-986654
LETTER
© Georg Thieme Verlag Stuttgart · New York

One-Pot Tandem 1,4- and 1,2-Addition of Phosphites to α,β-Unsaturated Hydrazones

Christian V. Stevens*a, Ellen Van Meenena, Kurt G. R. Masscheleina, Kristof Moonena, Ann De Bliecka, Jozef Drabowiczb
a Research Group SynBioC, Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000 Ghent, Belgium
Fax: +32(9)2646243; e-Mail: chris.stevens@UGent.be;
b Center of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lodz, Poland
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Publication History

Received 25 June 2007
Publication Date:
12 September 2007 (online)

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Abstract

The 1,4- and 1,2-addition of phosphites to α,β-unsaturated hydrazones was investigated. When silylated phosphites and trialkyl phosphites were compared, trialkyl phosphites gave better conversions and subsequently higher yields. A variety of hydrazones were evaluated as substrate in this reaction, which yield 3-phosphonyl-1-hydrazinoalkyl phosphonates.

Key words

phosphorylations - tandem addition - hydrazones - amino acids - Michael additions

    References and Notes

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8

The phosphonylated adduct appears in the 31P NMR spectrum as a major and minor diastereomeric pair. One gives two singlets and the other two doublets (31P coupling).

9

A suitable solvent mixture for flash chromatography is MeCN-CH2Cl2-MeOH (81:17:3).

11

Detailed Description of the Procedure
In an oven-dry flask, hydrazone 2 (2 mmol) is dissolved in abs. EtOH. To this solution, triethyl phosphite (10 mmol, 5 equiv) is added. This mixture is brought to reflux tem-perature under an N2 atmosphere and formic acid (5 equiv) is added by a syringe. The reaction is followed with 31P NMR. When no changes are observed anymore (after several days) the reaction is stopped. The solvent is evaporated and the residue redissolved in Et2O (20 mL). After pouring into 3 N HCl (30 mL) this system is extracted 3 times with Et2O (20 mL). The aqueous phase is made basic with 3 N NaOH and extracted three times with CH2Cl2 (20 mL). The combined organic layers are dried over MgSO4. After filtration, the solvent is evaporated in vacuo. 1H NMR, 13C NMR, IR, and MS spectra were entirely consistent with the assigned structures. Selected example: [1-(N′-Benzoyl-hydrazino)-3-(diethoxyphosphoryl)but-yl]phosphonic acid diethyl ester (3i): Ratio A:B = 47:53 (31P NMR). 1H NMR (300 MHz, CDCl3): δ = 1.19-1.41 [15 H (A) + 15 H (B), m, CHCH 3 (A + B), P(O)OCH2CH 3 (A + B)], 1.67-1.87 [2 H (A), m, CHCH 2CH], 2.10-2.29 [2 H (B), m, CHCH 2CH], 2.32-2.55 [1 H (A) + 1 H (B), m, CHP], 3.27-3.36 [1 H (B), m, NCHP], 3.58-3.67 (1 H (A), m, NCHP], 4.02-4.30 [8 H (A) + 8 H (B), m, P(O)OCH 2CH3], 7.40-7.53 [6 H, m, CH(Ph) (A + B)], 7.80-7.86 [4 H, m, CH(Ph) (A + B)], 8.77 (1 H, br s, NH (B)], 8.79 [1 H, br s, NH (B)], 9.22 [1 H, br s, NH (A)], 9.24 [1 H, br s, NH (A)] ppm. 13C NMR (75 MHz, CDCl3): δ = 13.16 [d, ² J CP = 4.6 Hz, CHCH3 (B)], 15.36 [d, ² J CP = 4.6 Hz, CHCH3 (A)], 16.38, 16.46, 16.54, 16.61 [P(O)OCH2 CH3 (A + B)], 26.61 [dd, ¹ J CP = 140.8 Hz, ³ J CP = 9.2 Hz, CHP (A)], 27.02 [dd, ¹ J CP = 143.1 Hz, ³ J CP = 13.9 Hz, CHP (B)], 28.00 [CHCH2CH (B)], 28.78 [d, ² J CP = 2.3 Hz, CHCH2CH (A)], 55.58 [dd, ¹ J CP = 155.8 Hz, ³ J CP = 6.9 Hz, NCHP (A)], 55.65 [dd, ¹ J CP = 161.5 Hz, ³ J CP = 13.9 Hz, NCHP (B)], 61.79 [d, ² J CP = 6.9 Hz, P(O)OCH2CH3], 61.88 [d, ² J CP = 6.9 Hz, P(O)OCH2CH3], 62.52 [d, ² J CP = 6.9 Hz, P(O)OCH2CH3], 62.71 [d, ² J CP = 6.9 Hz, P(O)OCH2CH3] 62.83 [d, ² J CP = 6.9 Hz, P(O)OCH2CH3], 63.13 [d, ² J CP = 6.9 Hz, P(O)OCH2CH3], 126.97, 128.63, 131.70, 131.81 [CH(Ph) (A + B)], 132.53 [Cq(Ph) (A)], 132.57 [C q(Ph) (B)], 165.64 [C=O (A)], 165.98 [C=O (B)] ppm. 31P NMR (121 MHz, CDCl3): δ = 25.72 [d, J PP = 1.5 Hz (A)], 26.16 [d, J PP = 7.4 Hz (B)], 34.47 [d, J PP = 7.4 Hz (B)], 35.11 [d, J PP = 1.5 Hz (A)] ppm. IR: 3413 (NH), 1648 (C=O), 1229 (P=O), 1052, 1027 (P-O) cm-1. MS: m/z (%) = 465 (100) [M + H]+.