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

Christian V. Stevens; Ellen Van Meenen; Kurt G. R. Masschelein; Kristof Moonen; Ann De Blieck; Jozef Drabowicz

doi:10.1055/s-2007-986654

LETTER

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

Christian V. Stevens*^a, Ellen Van Meenen^a, Kurt G. R. Masschelein^a, Kristof Moonen^a, Ann De Blieck^a, Jozef Drabowicz^b
^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

Abstract

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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

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References

References and Notes

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<A NAME="RG16607ST-3">3</A> Moonen K. Laureyn I. Stevens CV. Chem. Rev. 2004, 104: 6177

<A NAME="RG16607ST-4">4</A> Moonen K. Van Meenen E. Verwée A. Stevens CV. Angew. Chem. Int. Ed. 2005, 44: 7401

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The silylated diethyl phosphite was prepared in a separate reaction. Triethylammonium salts were removed from the reagent.

<A NAME="RG16607ST-7A">7a</A> Quin LD. A Guide to Organophosphorus Chemistry J. Wiley and Sons; New York: 2000. Chap. 2. p.394

<A NAME="RG16607ST-7B">7b</A> Wozniak L. Chojnowski J. Tetrahedron 1989, 45: 2465

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).

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

<A NAME="RG16607ST-10">10</A> Teulade M.-P. Savignac P. Synth. Commun. 1987, 19: 1037

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 [C_q(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]⁺.