Maghsoodlou M. T, Hazeri N, Khorassani S. M. H, Milani F. J, Kazemian M. A, Shahraki M. Diastereoselective Synthesis of Phosphonate Ester through the Reaction Between Activated Acetylenic Ester and Heterocyclic NH Compounds with Biological Activity in the Presence of Triphenylphosphite. Biomed. Pharmacol. J.2008;1(2)

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Malek Taher Maghsoodlou^*, Noroullah Hazeri, Sayyed Mostafa Habibi Khorassani, Forough Jalili Milani, Mohammad Amin Kazemian and Mahdi Shahraki

Department of Chemistry, The University of Sistan and Balouchestan, Zahedan (Iran).

Corresponding Author E-mail:smhabibius@ yahoo.com

Abstract

The reaction between dimethyl acetylenedicarboxylate and biological active heterocyclic NH compounds such as 3-methylpyrazole and 3,6-diboromocarbazole in the presence of triphenylphosphite at room temperature led to phosphonate ester 4a-b. The configuration of compounds 4a-b (2S*,3R*)-were determined on the basis of coupling constants emerged from the Karplus equation.

Keywords

Diastereo selectivity; Heterocyclic NH compounds; biological activity; Activated acetylenic ester

Introduction

Phosphorus-carbon bond formation^1-15 is an active and important research area, as new reactions are continuously being developed for the preparation of organophosphorus compounds such as phosphinates and phosphonates.^16-24 Over the last few years, the quest for the synthetic efficiency has gained remarkable importance, partly due to the need reduce waste.²⁵ Given the increasing industrial, biological and synthetic impact of organophosphorus compounds.^26-30 The successful attack by nucleophilic trivalent phosphorus on a carbon atom is facilitated when the latter is part of, or conjugated with, a carbonyl group, or when it is part of an unsaturated bond otherwise activated.^27-29 There are many studies on the reaction between trivalent phosphorus nucleophiles and α, β–unsaturated carbonyl compounds in the presence of a proton source such as alcohol or phenol.^31,32 Previously, the pyrazole and thiazole moieties and their derivatives have been used commercially as pharmaceuticals, pesticides and dyestuffs.³³ Here we wish to report on a simple one-pot synthesis of diastereoselective phosphonate esters 4 through the reaction of biological active heterocyclic NH compounds 3 and dimethyl acetylenedicerboxylate 2 in the presence of triphenylphosphite 1

Scheme 1:   Click here to View Scheme

Results and Discussion

In the current work, we wish to report a simple, short time, neutral, room temperature and high diastereoselective synthesis of phosphonate esters from reaction between triphenylphosphite 1 and acetylenic ester 2 in the presence of heterocyclic NH compounds, such as 3-methylpyrazole and 3,6-diboromocarbazole 3 led to 4 in fairly high yield (see Scheme 1). These reactions were carried out in the mixture of diethyl ether and hexan (2 : 1) as solvent at room temperature and were finished within a few hours. The ¹H and ¹³C NMR spectrum of the crude product clearly indicated the formation of phosphonate esters 4a-b. Any products other than 4a-b could not be detected by NMR spectroscopy. The structures of compounds 4a-b were confirmed by ¹H, ¹³C, ³¹P NMR, mass spectrometry, IR and elemental analysis. The mass spectra of compounds 4a-b displayed molecular ion peaks at appropriate values, which were consistent with 1:1:1 adducts of heterocyclic NH compounds, DMAD and triphenylphosphite. The 300 MHz ¹H NMR spectra of compound 4a displayed three sharp lines (δ= 2.23, 3.74 and 3.80) arising from methyl and methoxy protons along with signals for methine protons at δ= 4.64 ppm (1H, ²J_PH=21.2 Hz, ³J_HH=10.9 Hz) and δ= 5.74 ppm (1H, ³J_PH=8.7 Hz, ³J_HH=10.9 Hz) which appear as two doublet of doublet, respectively, for the O=P-CH-CH and O=P-CH-CH groups. The vicinal proton-proton coupling constant (³J_HH) as a function of the torsion angle can be obtained from the Karplus equation.³⁴ Typically, J_gauche varies between 1.5 and 5 Hz and J_anti between 10 and 14 Hz. Observation of ³J_HH=10.9 Hz for the vicinal protons in compound 4a (see Experimental section) indicates an anti arrangement for these protons. Since compound 4a possess two stereogenic center, two diastereoisomers with anti HCCH arrangements are possible. The three-bond carbon-phosphorus coupling, ³J_CP, depends on configuration, as expected, transoid coupling being larger than cisoid ones. The Karplus relation can be derived from the data for organophosphorus compound with tetra and pentavalent phosphorus.³⁵ The observation of ³J_CP of 18.3 Hz for the ester  C=O group (see Experimental section), is in a good agreement with the 2S,3R-4a and its mirror image 2R,3S-4a geometries (see Scheme 2). Although the presence of the ³¹P nucleus complicates both the ¹H and ¹³C NMR spectra of 4a, it helps in assignment of the signals by long-range couplings with the ¹H and ¹³C nuclei (see Experimental section). The ¹H and ¹³C NMR  spectra of 4b is similar to those of 4a, except for the ester groups, which exhibited characteristic resonances with appropriate chemical shifts (see Experimental section). The structural assignments made on the basis of the ¹H and ¹³C NMR spectra of compounds 4a-b were supported by the IR spectra. (see Experimental section).

In conclusion, we have prepared novel diastereoselective phosphonate esters using a one-pot reaction between triphenylphosphite and dimethyl acetylenedicarboxylate in the presence of heterocyclic NH compounds such as 3-methylpyrazole and 3,6-diboromocarbazole. The present method, carries the advantage that, not only the reaction is performed under neutral conditions, but also the substances can be mixed without any activation or modifications.

Scheme 2:   Click here to View Scheme

Experimental

Melting points and IR spectra of all compounds were measured on an Electrothermal 9100 apparatus and a Shimadzu IR-460 spectrometer respectively.  Also, the ¹H, ¹³C, and ³¹P NMR spectra were obtained from a BRUKER DRX-300 AVANCE instrument with CDCl₃ as solvent at 300.1, 121.5, and 75.5 MHz respectively. In addition, the mass spectra were recorded on a Shimadzu QP 1100 EX mass spectrometer operating at an ionization potential of 70 eV. Elemental analysis for C, H and N were performed using a Heraeus CHN-O-Rapid analyzer. Dimethyl acetylenedicarboxylate, triphenlphosphite, 3-methylpyrazole and 3,6-diboromocarba- zole were purchased from Fluka, (Buchs, Switzerland) and used without further purifications.

Preparation of (2S,3R)-Dimethyl-2-(3-methylpyrazole-1-yl)-3-(diphenoxyphosphonato)-butanedioate (4a)

To a magnetically stirred solution of triphenylphosphite (0.31g, 1mmol) and 3-methylpyrazole (0.08g, 1mmol) in diethyl ether/ hexan (10ml) was added dropwise a mixture of dimethyl acetylenedicarboxylate (0.14g, 1mmol) in diethyl ether (5ml) at -10 °C over 10 min.  After approximately 10 hours stirring at room temperature, the solvent was removed under reduced pressure and product washed with cold diethyl ether (2×5mL).

White powder, %93, m.p 125-127 ^oC, IR (KBr) (ν_max, cm^-1): 1740 and 1715 (C=O), 1270 (P=O). Ms, (m/z, %):   458 (M⁺, 3), 427 (M-OCH_3, 33), 399 (M-CO₂CH₃, 45), 365 (M-Ph, 19), 377 (M-C₄H₅N₂, 9), 93 (OPh, 15), 77 (Ph, 100).  Anal. Calcd for C₂₁H₂₁N₂O₇P (458): C, 57.64; H, 5.02; N, 6.11, Found: C, 57.56; H, 4.95; N, 6.18. ¹H NMR (300.1 MHz, δ, CDCl₃): 2.23 (CH₃), 3.73 and 3.80 (6H, 2s, 2OCH₃), 4.64 (1H, dd, ²J_PH=21.2 Hz, ³J_HH=10.9 Hz, P-CH-CH), 5.74 (1H, dd, ³J_PH=8.7 Hz, ³J_HH=10.9 Hz, P-CH-CH), 6.05 -7.56 (13H, m, H_aro). ¹³C NMR (75.5 MHz, δ, CDCl₃): 13.60 (CH₃), 47.93 (d, ¹J_CP=134.6 Hz, P-CH), 53.28 and 53.42 (2S, 2OCH₃), 61.72 (d, ²J_CP=3.5 Hz, P-C-CH), 106.06 (1C, C₃H₃N₂), 120.16 and 120.37 (2d, ³J_PC= 4.8 Hz C_ortho of 2C₆H₅ ), 125.40 and 125.49 (C_para of 2C₆H₅), 129.69 and 129.80 (C_meta of 2C₆H₅), 132.98 (1C , C₃H₃N₂),  149.70 and 150.45 (2d, ²J_CP=9.6 Hz ,C_ipso of 2C₆H₅), 150.46 (1C, C₃H₃N₂), 166.85 (d, ²J_CP=6.0 Hz, C=O), 167.74 (d, ³J_CP=18.3 Hz, C=O). ³¹P NMR (121.5 MHz, δ, 10.38 [s, (PhO)₂P(=O)].

(2S,3R)-Dimethyl-2-(3,6-diboromocarbazole-1-yl)-3-(diphenoxyphosphonato)- butanedioate (4d)

White powder, %95, m.p 163-165 ^oC, IR (KBr) (ν_max, cm^-1): 1748 and 1720 (C=O), 1271 (P=O).MS, (m/z, %):   701 (M⁺, 33), 642 (M-CO₂CH_3, 38), 608 (M-OPh, 29), 377 (M-C₁₂H₆Br₂N₂, 15), 77 (Ph, 100).  Anal. Calcd for C₂₅H₂₃N₂O₇P (701): C, 51.36; H, 3.42; N, 1.99, Found: C, 51.49; H, 3.36; N, 2.07. ¹H NMR (300.1 MHz, δ, CDCl₃): 3.61 and 3.89 (6H, 2s, 2OCH₃), 4.73 (1H, dd, ²J_PH=21.1 Hz, ³J_HH=11.8 Hz, P-CH-CH), 6.27 (1H, dd, ³J_PH=7.9 Hz, ³J_HH=11.8 Hz, P-CH-CH), 6.38 -8.08 (16H, m, H_aro). ¹³C NMR (75.5 MHz, δ, CDCl₃): 45.55 (d, ¹J_CP=136.9 Hz, P-CH), 53.56 and 53.64 (2S, 2OCH₃), 55.80 (d, ²J_CP=3.9 Hz, P-C-CH), 111.30, 111.99, 112.41, 113.46 and 113.66 (5C, C₁₂H₆Br₂N),   119.07 and 119.77 (2d, ³J_PC= 3.5 Hz C_ortho of 2C₆H₅ ), 123.04, 123.09, 123.72. 123.85 and 125.12 (5C , C₁₂H₆Br₂N), 125.40 and 125.33 (C_para of 2C₆H₅), 129.40 (1C , C₁₂H₆Br₂N), 129.57 and 129.60 (C_meta of 2C₆H₅), 129.64 (1C , C₁₂H₆Br₂N),   149.12 and 149.58 (2d, ²J_CP=9.1 Hz ,C_ipso of  2C₆H₅), 166.72 (d, ²J_CP= 6.3 Hz, C=O), 168.84 (d, ³J_CP=19.5 Hz, C=O). ³¹P NMR (121.5 MHz, δ, 9.83 [S, (PhO)₂P=O].

Acknowledgements

We gratefully acknowledge financial support from the Research Council of University of Sistan and Balouchestan

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