This article was downloaded by: [Linnaeus University]On: 15 October 2014, At: 15:26Publisher: Taylor & FrancisInforma Ltd Registered in England and Wales Registered Number: 1072954 Registeredoffice: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK

Journal of Sulfur ChemistryPublication details, including instructions for authors andsubscription information:http://www.tandfonline.com/loi/gsrp20

γ-Alkylsulfide phosphonates throughthe thia-Michael strategyAbderrahmen Abdelliab, Hedi M'rabeta, Mohamed Lotfi Efrita, AnneGaucherb & Damien Primb

a Laboratoire de Synthèse Organique et Hétérocyclique,Université de Tunis El Manar-2092-Tunis, Tunisieb Institut Lavoisier de Versailles-UMR CNRS 8180, Université deVersailles-Saint-Quentin-en-Yvelines, 45, avenue des Etats-Unis,78035 Versailles Cedex, FrancePublished online: 01 Sep 2014.

To cite this article: Abderrahmen Abdelli, Hedi M'rabet, Mohamed Lotfi Efrit, Anne Gaucher &Damien Prim (2014) γ-Alkylsulfide phosphonates through the thia-Michael strategy, Journal of SulfurChemistry, 35:6, 674-682, DOI: 10.1080/17415993.2014.951856

To link to this article: http://dx.doi.org/10.1080/17415993.2014.951856

PLEASE SCROLL DOWN FOR ARTICLE

Taylor & Francis makes every effort to ensure the accuracy of all the information (the“Content”) contained in the publications on our platform. However, Taylor & Francis,our agents, and our licensors make no representations or warranties whatsoever as tothe accuracy, completeness, or suitability for any purpose of the Content. Any opinionsand views expressed in this publication are the opinions and views of the authors,and are not the views of or endorsed by Taylor & Francis. The accuracy of the Contentshould not be relied upon and should be independently verified with primary sourcesof information. Taylor and Francis shall not be liable for any losses, actions, claims,proceedings, demands, costs, expenses, damages, and other liabilities whatsoever orhowsoever caused arising directly or indirectly in connection with, in relation to or arisingout of the use of the Content.

This article may be used for research, teaching, and private study purposes. Anysubstantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-and-conditions

Dow

nloa

ded

by [

Lin

naeu

s U

nive

rsity

] at

15:

26 1

5 O

ctob

er 2

014

Journal of Sulfur Chemistry, 2014Vol. 35, No. 6, 674–682, http://dx.doi.org/10.1080/17415993.2014.951856

γ -Alkylsulfide phosphonates through the thia-Michael strategy

Abderrahmen Abdellia,b, Hedi M’rabeta∗, Mohamed Lotfi Efrita, Anne Gaucherb andDamien Primb∗

aLaboratoire de Synthèse Organique et Hétérocyclique, Université de Tunis El Manar-2092-Tunis, Tunisie;bInstitut Lavoisier de Versailles-UMR CNRS 8180, Université de Versailles-Saint-Quentin-en-Yvelines, 45,avenue des Etats-Unis, 78035 Versailles Cedex, France

(Received 1 July 2014; accepted 2 August 2014 )

The formation of γ -alkylsulfide phosphonates is described from allylphosphonates under mild condi-tions using thiols through the thia-Michael strategy. A series of new phosphonates, bisphosphonates werecleanly prepared in high yields. The methodology developed allowed further preparing γ -alkylsulfidephosphonates bearing valuable esters groups in β and δ positions with respect to the phosphonate moiety.

Keywords: allylphosphonates; γ -alkylsulfide phosphonates; bis-(γ -alkylsulfide phosphonates); thiols;thia-Michael

1. Introduction

Alkylsulfide phosphonates belong to the large functionalized-thioether family which has beenextensively studied for a wide range of applications and properties.[1–4] The combination ofalkylsulfides and other organic functions may generate interesting issues. Indeed, the presenceof alkoxycarbonyl groups at the alkylsulfide skeleton is known to significantly alter flavors ofseveral tropical fruits.[5] The joint presence of a thioether and a phosphonate moiety renderssuch molecular architectures attractive in domains related to the treatment of various skele-tal disorders [6] such as osteoporosis, arthritis,[7] osseous resorption, solid tumor metastasesor myeloma.[8,9] Among the latter, γ -alkylsulfide phosphonates recently emerged as potentialbetaine homocysteine S-methyltransferase [10] and metallo-β-lactamases inhibitors.[11] Simi-larly, Pt complexation using mono-or bidentate ligands advantageously combining sulfides or

∗Corresponding author. Email: damien.prim@uvsq.frThis article makes reference to supplementary material available on the publisher’s website at http://dx.doi.org/10.1080/17415993.2014.951856.

c© 2014 Taylor & Francis

Dow

nloa

ded

by [

Lin

naeu

s U

nive

rsity

] at

15:

26 1

5 O

ctob

er 2

014

Journal of Sulfur Chemistry 675

bis-sulfides and phosphonates has been recently explored.[12] (For transition and heavy metalcomplexation studies using bis-sulfides see [13–15].) However, the preparation of such com-pounds is scarcely reported being obtained through multistep processes characterized by theinstallation of the ‘P-based’ group in the last step.[16] The development of alternative method-ologies allowing an easy preparation of γ -alkylsulfide phosphonates, introduction of additionalfunctional groups and generalization to bis-sulfide analogues remains a subject of interest. In thiscontext, we describe the preparation of new γ -alkylsulfide phosphonates bearing an additionalalkoxycarbonyl group from allylphosphonates and various thiols under soft thia-Michael reactionconditions. This methodology could be further extended to the preparation of bis-(γ -alkylsulfidephosphonates).

2. Results and discussion

We first examined the formation of C–S bond from allylphosphonate 1 and ethane thiol. Sincerecent examples of addition of thiols to activated alkenes required the presence of additivessuch as tetrabutylammonium bromide,[17] 1-pentyl-3-methylimidazolium bromide,[18] potas-sium phosphate,[19] silica gel [20] or rhenium complexes,[21] we initially studied the simplethiol addition on allylphosphonates 1 under basic conditions (Scheme 1). Table 1 gathers resultsobtained using various bases and solvents for the preparation of alkylsulfides 2–4.

Scheme 1. Strategy toward γ -alkylsulfide phosphonates 2–4.

Control experiment realized without the presence of a base led the starting material unchangedeven after prolonged reaction courses and increase in the reaction temperature. The use of sodiumethoxide (1.2 eq.) at room temperature afforded the expected alkylsulfide 2 in 45% yield (Entry2). Increasing the reaction temperature (Entry1) to reflux (Entry 3) or using tBuOK(1.2) in THF(Entries 4 and 5) led to similar results.

Interestingly, moving from alkoxides as bases to triethylamine in EtOH at 25◦C for 16 h ledto clear enhancement of both conversions and yields. Indeed, under such optimized conditions

Table 1. Preparation of alkylsulfides (2–4).

Entry R′ R Base (eq.) Solvent (T ◦C) Product Yield (%)

1 Et Me 1a – EtOH (25-reflux) 2 –2 Et Me 1a EtONa (1.2) EtOH (25) 2 453 Et Me 1a EtONa (1.2) EtOH (reflux) 2 404 Et Me 1a tBuOK (1.2) THF (reflux) 2 465 Et Me 1a tBuOK (1.2) THF (25) 2 536 Et Me 1a Et3N (1.2) EtOH (25) 2 887 Bu Me 1a Et3N (1.2) EtOH (25) 3 928 Bu Et 1b Et3N (1.2) EtOH (25) 4 90

Dow

nloa

ded

by [

Lin

naeu

s U

nive

rsity

] at

15:

26 1

5 O

ctob

er 2

014

676 A. Abdelli et al.

various γ -alkylsulfide phosphonates were smoothly prepared in yields ranging from 88% to 92%(Entries 6–8). The use of triethylamine revealed beneficial to the transformation, avoiding theuse of large excesses of mercaptan to ensure completion of the reaction. 31P NMR revealedindicative of the chemical transformation. Indeed, if the P atom of the starting phosphonates 1aand 1b resonate at 27.7 and 24.9 ppm, respectively, shieldings ranging from 3.5 to 3.7 ppm wereobserved after formation of the C–S bond in alkylsulfides 2, 3 and 4.

We next examined the reaction of dithiols with allylphosphonates 1. Double Michael additionof dithiols usually required the use of additives such as Al2O3,[22] n-Bu3P,[23] MeONa [24]and ionic liquids [25–27] in order to obtain the desired product in good yields. In our case,dithioethers 5–7 could be obtained in good yields without any additional promoter (Scheme 2).

Scheme 2. Access to bis(γ -alkylsulfide phosphonates).

Dithia-Michael adducts were smoothly prepared using one equivalent of ethanedithiols orpropanedithiols, two equivalents of allylphosphonates 1 and two equivalents of base. Interest-ingly, our procedure revealed highly selective in EtOH at room temperature. Mono adduct Aas well as 1,4-dithiepan-5-one B potentially arising from a mono thia-Michael addition understoichiometric conditions and a further intramolecular addition at the ester group, respectively,were not detected. Bisalkylsulfides 5–7 were obtained as mixtures of diastereomers. In fact, aset of two 31P signals resonating at 28.32 and 28.35 ppm has been observed for compound 5 thataccount for the presence of two diastereomers. In the case of products 6 and 7, we were ableto recover only one diastereomer after silica gel chromathography purification in nearly 40%yield each. Interestingly, 31P signals resonated at 30.85 and 29.3 ppm for compound 6 and 7,respectively.

As our goal was the preparation of new functionalized sulfide adducts, our methodologywas further extended to alkyl thioglycolate. The selective formation of C–S bonds using alkylthioglycolate in thia-Michael additions is known to be impacted by retro-Michael side reac-tions. To avoid the latter reaction, several groups mentioned the use of additives such asN ,N’-tetrahydroisoquinoline dioxide [28] or catalysts such as lanthanium complexes like L/La(OTf)3.[29] Since the reaction of alcoholates or NaH under various conditions did not afford theexpected product, the aforementioned mild conditions EtOH, Et3N at room temperature allowedus to cleanly and selectively isolate the expected functionalized γ -alkylsulfide phosphonates8–11 (for the use of amines in the formation of C–S bonds through conjugate addition see [30,31])in high yields ranging from 71% to 89% (Scheme 3, Table 2).

Yields are crucially depending on the reaction time. Indeed, prolonged reaction times from16 h to over 72 h led to the appearance of transesterification side-products due to the presence

Dow

nloa

ded

by [

Lin

naeu

s U

nive

rsity

] at

15:

26 1

5 O

ctob

er 2

014

Journal of Sulfur Chemistry 677

Scheme 3. Access to functionalized γ -alkylsulfide phosphonates.

Table 2. Preparation of functionalized alkylsulfides (8–11).

Entry R R′ γ−Alkylsulfide phosphonates δ31P (ppm) Yield (%)

1 Et Me 8 28.1 712 Et Et 9 27.7 703 Me Me 10 30.8 734 Me Et 11 30.8 89

of EtOH as the solvent. The installation of a functionalized alkylsulfide fragment at the phos-phonate core in compounds 8–11 again resulted in shieldings ranging from 2.9 to 3.1 ppm withrespect to the parent allylphosphonates. Although lower, the latter �δ 31P are consistent withthose observed for alkylsufides 2–4.

3. Conclusion

In conclusion, we succeeded in the functionalization of allylphosphonates 1 with various thiolsleading to new γ -alkylsulfide phosphonates. The formation of the C–S bonds could be selectivelyachieved through thia-Michael addition under smooth reaction conditions involving Et3N as thebase and EtOH as the best solvent. The electrophilic character of allylphosphonates was shownbeneficial to the selective introduction of both thiols and dithiols derivatives. Our methodologycan be extended to the preparation of γ -alkylsulfide phosphonates bearing valuable esters groupsin β and δ positions with respect to the phosphonate moiety.

4. Experimental section

4.1. General

Unless otherwise noted, all starting materials were obtained from commercial suppliers and usedwithout purification. Ethanol was distilled over magnesium turnings in the presence of iodine.Triethylamine was distilled from calcium hydride and stored over KOH. The allylphosphonates1 were prepared according to reference.[32] NMR spectra were recorded on a 300 and 200 MHzBrucker spectrometers. Chemical shifts were reported in ppm relative to the residual solvent peak(7.27 ppm for CHCl3) for 1H spectra (77.00 ppm for CDCl3) for 13C spectra and the 85% H3PO4

as an external reference is used for the 31P NMR. Coupling constants (J) are expressed in hertz(Hz). The multiplicity of the signals is coded as follows: s: singlet; d: doublet; t: triplet; q: quadru-plet; m: multiplet. High-resolution mass spectroscopy data were recorded on an Autospec Ultima(Waters/Micromass) device with a resolution of 5000 RP at 5%. Analytical chromatography

Dow

nloa

ded

by [

Lin

naeu

s U

nive

rsity

] at

15:

26 1

5 O

ctob

er 2

014

678 A. Abdelli et al.

(TLC) was performed on plates coated with silica gel, 0.2-mm thick aluminum with fluorescentindicator 254 nm and was revealed using a UV lamp. Column chromatography separations wereperformed using silica gel (0.040–0.060 mm). The procedure is general; the various reactions ofconjugated additions are followed and monitored by TLC.

Representative experimental details are given below for compounds 2, 6, 8 and full character-ization as well as 1H, 13C, 31P spectra are given in the supplementary material (http://dx.doi.org/10.1080/17415993.2014.951856).

4.2. Synthesis of compounds (2–4)

To a solution of allylphosphonate (5 mmol) in 5 mL of ethanol and triethylamine (6 mmol), 1.2eq. of mercaptan was added dropwise. The reaction mixture was stirred for 8 h at room tempera-ture. The solvent was then removed, the residue diluted in 20 mL of chloroform and the organicphase is washed twice with 15 mL of distilled water. The solvent was next removed and the reac-tion residue purified by silica gel column chromatography using ethyl acetate/petroleum ethermixture (1/1) as the eluent.

4.2.1. Ethyl 3-(dimethoxyphosphoryl)-2-((ethylthio)methyl)propanoate (2)

Yield = 88%; viscous; 1H NMR (300 MHz, CDCl3): 1.25 (t, 3JHH = 6.0 Hz, 3H), 1.29 (t, 3JHH =6.0 Hz, 3H), 2.21 (m, 2H), 2.55 (q, 3JHH = 6.0 Hz, 2H), 2.76 (m, 2H), 2.89 (m, 1H), 3.74(d, 3JHP = 9.0 Hz, 6H), 4.19 (q, 3JHH = 6.0 Hz, 2H); 13C NMR (75 MHz, CDCl3) : 14.18(CH3), 14.62 (CH3), 25.68 (CH2−P(O), 1JPC = 142.6 Hz), 26.06 (CH2−S), 34.43 (CH−CO2Et,2JPC = 13.5 Hz), 40.18 (CH2−S, 3JPC = 3.77 Hz), 52.50 (CH3−O−P(O), 2JPC = 11.3 Hz),61.15 (CH2−O−C(O)), 173.12 (C(O), 3JPC = 8.3 Hz); 31P NMR (300 MHz,CDCl3): 31,25;HRMS Calcd for C10H22O5SP 285.0926, found 285.0922.

4.2.2. Ethyl 3-(benzylthio)-2-((dimethoxyphosphoryl)methyl)propanoate (3)

Yield = 92%; viscous; 1H NMR (300 MHz, CDCl3): 1.26 (t, 3JHH = 6.0 Hz, 3H), 2.13 (m, 2H),2.66 (m, 2H), 2.89 (m, 1H), 3.62 (d, 3JHP = 9 Hz, 6H), 3.70 (s, 2H), 4.16 (q, 3JHH = 6.0 Hz,4H), 7.26 (m, 5H); 13C NMR (300 MHz, CDCl3): 14.14 (CH3), 25.68 (CH2−P(O), 1JPC =141.8 Hz), 33.96 (CH−CO2Et, 2JPC = 14.3 Hz), 36.00 (CH2–S), 39.74 (CH2−S, 3JPC = 3.7 Hz),52.44 (CH3−O−P(O), 2JPC = 11.3 Hz), 61.12 (CH2−O−C(O)), 127.11–137.72 (CAr), 172.98(C(O), 3JPC = 7.54 Hz); 31P NMR (300 MHz, CDCl3): 31.23; HRMS Calcd for C15H24O5SP347.1082, found 347.1084.

4.2.3. Ethyl 3-(butylthio)-2-((diethoxyphosphoryl)methyl)propanoate (4)

Yield = 90%; viscous; 1H NMR (300 MHz, CDCl3): 0.75 (t, 3JHH = 6.0 Hz, 3H), 1.15 (m, 9H),1.26 (m, 2H), 1.39 (m, 2H), 2.03 (m, 2H), 2.36 (t, 3JHH = 6.0 Hz, 2H), 2.65 (m, 2H), 2.76(m, 1H), 3.93 (m, 4H), 4.02 (q, 3JHH = 6.0 Hz, 2H); 13C NMR (300 MHz, CDCl3): 13.43 (CH3),13.96 (CH3), 16.22 (CH3), 21.67 (CH2), 26.50 (CH2−P(O), 1JPC = 143.3 Hz), 31.35 (CH2),31.74 (CH2−S), 34.74 (CH−CO2Et, 2JPC = 12.8 Hz), 40.17 (CH2−S, 3JPC = 3.0 Hz), 60.85(CH2−O−P(O)), 61.62 (CH2−O−C(O)), 173.01 (C(O), 3JPC = 8.3 Hz); 31P NMR (300 MHz,CDCl3): 28.62; HRMS Calcd for C14H30O5SP 341.1552, found 341.1561.

Dow

nloa

ded

by [

Lin

naeu

s U

nive

rsity

] at

15:

26 1

5 O

ctob

er 2

014

Journal of Sulfur Chemistry 679

4.3. Synthesis of compounds (5–7)

To a solution of allylphosphonate (5 mmol) in 7 mL of ethanol and dithiol (2.5 mmol), triethy-lamine (5 mmol) was added portionwise. The reaction mixture was stirred at room temperaturefor 4 h. The solvent was next removed in vacuo, the residue diluted in 10 mL of dichloromethaneand the resulting organic phase washed twice with 15 mL of water. The solvent was removed andthe crude material as purified by silica gel column chromatography using ethyl acetate as eluent.

4.3.1. Diethyl 3,3’-(ethane-1,2-diylbis(sulfanediyl))bis(2-((diethoxyphosphoryl)methyl)propanoate) (5)

Yield = 82%; viscous; 1H NMR (300 MHz, CDCl3): 1.30 (m, 18H), 2.15 (m, 4H), 2.73 (s, 2H),2.85 (m, 6H), 2.96 (m, 2H), 4.14 (m, 12H); 13C NMR (300 MHz, CDCl3): δ1 = 14.15/δ2 = 14.16(CH3), δ1 = 16.34/δ2 = 16.42 (CH3), 26.67 (CH2−P(O), 1JPC = 142.6 Hz), 31.57 (CH2−S),32.13 (CH2−S), 34.69 (CH−CO2Et, 2JPC = 12.8 Hz), 40.40 (CH2−S, 3JPC = 3.0 Hz), δ1 =61.16/δ2 = 61.19 (CH2−O−P(O)), δ1 = 61.92/δ2 = 61.94 (CH2−O−C(O)), 172.93 (C(O),3JPC = 9.0 Hz); 31P NMR (300 MHz, CDCl3): δ1 = 28.32/δ2 = 28.35.

4.3.2. Diethyl 3,3’-(methylenebis(sulfanediyl))bis(2-((dimethoxyphosphoryl)methyl)propanoate) (6)

Yield = 41%; viscous; 1H NMR (200 MHz, CDCl3): 1.03 (t, 3JHH = 6.0 Hz, 6H), 1.58 (qun,3JHH = 6.0 Hz, 2H), 1.95 (m, 4H), 2.36 (t, 3JHH = 6.0 Hz, 4H), 2.53 (m, 4H), 2.69 (m, 2H), 3.47(d, 3JHP = 10.0 Hz, 12H), 3.93 (q, 3JHH = 6.0 Hz, 4H); 13C NMR (300 MHz, CDCl3): 13.96(CH3), 25.42 (CH2−P(O), 1JPC = 142.6 Hz), 28.59 (CH2), 30.56 (CH2−S), 34.47 (CH−CO2Et,2JPC = 13.5 Hz), 39.93 (CH2−S, 3JPC = 4.5 Hz), 52.24 (CH3−O−P(O), 2JPC = 11.3 Hz), 60.9(CH2−O−C(O)), 172.69 (C(O), 3JPC = 9.0 Hz); 31P NMR (200 MHz, CDCl3): 30.85; HRMSCalcd for C19H39O10S2P2 553.1460, found 553.1459.

4.3.3. Diethyl 3,3’-(propane-1,3-diylbis(sulfanediyl))bis(2-((diethoxyphosphoryl)methyl)propanoate) (7)

Yield = 40%; viscous; 1H NMR (300 MHz, CDCl3): 1.26 (m, 18H), 1.79 (qun, 3JHH = 6.0 Hz,2H), 2.07 (m, 4H), 2.57 (t, 3JHH = 6.0 Hz, 4H), 2.74 (m, 4H), 2.90 (m, 2H), 4.08 (m,12H); 13C NMR (300 MHz, CDCl3): 14.10 (CH3), 16.35 (CH3), 26.62 (CH2−P(O), 1JPC =143.3 Hz), 28.78 (CH2), 30.84 (CH2−S), 34.71 (CH−CO2Et, 2JPC = 12.8 Hz), 40.24 (CH2−S,3JPC = 3.01 Hz), 61.08 (CH2−O−P(O)), 61.79 (CH2−O−C(O)), 173.05 (C(O), 3JPC = 9.0 Hz);31P NMR (300 MHz, CDCl3): 29.34; HRMS Calcd for C23H46O10S2P2Na 631.1910, found631.1905.

4.4. Synthesis of compounds (8–11)

To a solution of allylphosphonate (5 mmol) in 5 mL of ethanol and triethylamine (6 mmol), alkylthioglycolate (6 mmol) was added portionwise. The reaction mixture is stirred at room temper-ature for 16 h. The solvent was removed in vacuo, the residue diluted in 10 mL of chloroformand the organic phase washed twice with 15 mL of water. The solvent was removed and thecrude material was purified by silica gel column chromatography using a mixture of diethylether/petroleum ether (2/1) as the eluent.

Dow

nloa

ded

by [

Lin

naeu

s U

nive

rsity

] at

15:

26 1

5 O

ctob

er 2

014

680 A. Abdelli et al.

4.4.1. Ethyl 3-(diethoxyphosphoryl)-2-(((2-methoxy-2-oxoethyl)thio)methyl)propanoate (8)

Yield = 71%; viscous; 1H NMR (200 MHz, CDCl3): 1.20 (m, 9H), 2.12 (m, 2H), 2.83 (m, 2H),2.90 (m, 1H), 3.14 (s, 2H), 3.62 (s, 3H), 4.01 (m, 6H); 13C NMR (300 MHz, CDCl3): 14.01(CH3), 16.20 (CH3), 26.67 (CH2−P(O), 1JPC = 143.3 Hz), 33.29 (CH2−S), 34.98 (CH−CO2Et,2JPC = 12.8 Hz), 39.77 (S−CH2–CO2Et), 52.30 (CH3−O−C(O)), 61.08 (CH2−O−P(O)), 61.77(CH2−O−C(O)), 170.38 (C(O)), 172.75 (C(O), 3JPC = 9.0 Hz); 31P NMR (200 Mhz, CDCl3):28.88; HRMS Calcd for C13H26O7PS 357.1137, found 357.1140.

4.4.2. Ethyl 3-(diethoxyphosphoryl)-2-(((2-ethoxy-2-oxoethyl)thio)methyl)propanoate (9)

Yield = 70%; viscous; 1H NMR (300 MHz, CDCl3): 1.32 (m, 12H), 2.20 (m, 2H), 2.96 (m, 2H),3.01 (m, 1H), 3.25 (s, 2H), 4.13 (m, 8H); 3C NMR (300 MHz, CDCl3): 14.16 (CH3), 16.35(CH3), 16.37 (CH3), 26.92 (CH2−P(O), 1JPC = 142.6 Hz), 33.73 (CH2−S), 35.19 (CH−CO2Et,2JPC = 12.8 Hz), 40.01(S−CH2−CO2Et), 61.12 (CH2−O−P(O)), 61.81 (CH2−O−C(O)), 61.84(CH2−O−C(O)), 169.95 (C(O)), 172.82 (C(O), 3JPC = 8.30 Hz); 31P NMR (300 MHz, CDCl3):δ = 27.69.

4.4.3. Ethyl 3-(dimethoxyphosphoryl)-2-(((2-methoxy-2-oxoethyl)thio)methyl)propanoate (10)

Yield = 73%; viscous; 1H NMR (300 MHz, CDCl3): 1.30 (t, 3JHH = 6.0 Hz, 3H), 2.18 (m, 2H),2.92 (m, 2H), 3.01 (m, 1H), 3.27 (s, 2H), 3.75 (m, 9H), 4.19 (q, 3JHH = 6.0 Hz, 4H); 13CNMR (300 MHz, CDCl3): 14.16 (CH3), 25.83 (CH2−P(O), 1JPC = 142.6 Hz), 33.46 (CH2−S),35.15 (CH−CO2Et, 2JPC = 13.5 Hz), 39.88 (S−CH2−CO2Me), 52.44 (CH3−O−C(O)), 52.57(CH3−O−P(O), 2JPC = 10.5 Hz), 61.31 (CH2–O–C(O)), 170.54 (C(O)), 172.81 (C(O), 3JPC =9.0 Hz); 31P NMR (300 MHz, CDCl3): 30.81; HRMS Calcd for C11H22O7SP 329.0824, found329.0822.

4.4.4. Ethyl 3-(dimethoxyphosphoryl)-2-(((2-ethoxy-2-oxoethyl)thio)methyl)propanoate (11)

Yield = 89%; viscous; 1H NMR (300 MHz, CDCl3): 1.30 (t, 3JHH = 6.0 Hz, 6H), 2.15 (m, 2H),2.92 (m, 2H), 3.00 (m, 1H), 3.25 (s, 2H), 3.74 (d, 3JHP = 9.0 Hz, 6H), 4.19 (q, 3JHH = 6.00 Hz,4H); 13C NMR (CDCl3): 14.14 (CH3), 14.16 (CH3), 25.78 (CH2−P(O), 1JPC = 142.6 Hz), 33.59(CH2−S), 35.11 (CH−CO2Et, 2JPC = 13.5 Hz), 39.81 (S−CH2−CO2Et), 52.56 (CH3−O−P(O),2JPC = 11.3 Hz), 61.28 (CH2−O−C(O)), 61.44 (CH2−O−C(O)), 170.07 (C(O)), 172.83(C(O), 3JPC = 8.3 Hz); 31P NMR (300 MHz, CDCl3): 30.82; HRMS Calcd for C12H24O7SP343.0980, found 343.0988.

Funding

The authors are grateful to the Tunisian Ministry of Higher Education and Scientific Research, to the University of TunisEl Manar, to the CNRS and the University of Versailles-St Quentin-en-Yvelines for financial support.

Supplemental data

Supplemental data for this article can be accessed at 10.1080/17415993.2014.951856.

Dow

nloa

ded

by [

Lin

naeu

s U

nive

rsity

] at

15:

26 1

5 O

ctob

er 2

014

Journal of Sulfur Chemistry 681

References

[1] Xu W, Li S, He M, Yang S, Li X, Li P. Synthesis and bioactivities of novel thioether/sulfone derivatives containing1,2,3-thiadiazole and 1,3,4-oxadiazole/thiadiazole moiety. Bioorg Med Chem Lett. 2013;23:5821–5824.

[2] Reedijk JJ. Plasticity in the copper–thioether bond: manifestation in blue Cu proteins and in synthetic analogs. InorgBiochem. 2012;115:182–185.

[3] Sharma G, Kumar R, Chakraborti KA. A novel environmentally friendly process for carbon–sulfur bond formationcatalyzed by montmorillonite clays. J Mol Catal A: Chem. 2007;263:143–148.

[4] Nishimura K, Tomioka K. Chiral amino ether-controlled catalytic enantioselective arylthiol conjugate additionsto α,β-unsaturated esters and ketones: scope, structural requirements, and mechanistic implications. J Org Chem.2002;67:431–434.

[5] Gunther CS, Matich AJ, Marsh KB, Nicolau L. (methylsulfanyl)alkanoate ester biosynthesis in Actinidia chinensiskiwifruit and changes during cold storage. Phytochemistry. 2010;71:742–750.

[6] Monteil M, Migianu-Griffoni E, Sainte-Catherine O, Benedetto MD, Lecouvey M. Bisphosphonate prodrugs:synthesis and biological evaluation in HuH7 hepatocarcinoma cells. Eur J Med Chem. 2014;77:56–64.

[7] Francis MD, Kaas SM, Ebetino FH. Sulfur-containing phosphonate compounds, pharmaceutical compositions, andmethods of treating abnormal calcium and phosphate metabolism. United States patent US 5,824,661 A. 1998Oct 20.

[8] Russell RG, Watts NB, Ebetino FH, Rogers MJ. Mechanisms of action of bisphosphonates: similarities anddifferences and their potential influence on clinical efficacy. Osteoporos Int. 2008;19:733–759.

[9] Rogers MJ, Crockett JC, Coxon FP, Mönkkönen J. Biochemical and molecular mechanisms of action ofbisphosphonates. Bone. 2011;49:34–41.

[10] Pícha J, Vanìk V, Budìšínský M, Mládková J, Garrow TA, Jiráèek J. The development of a new class of inhibitorsfor rbetaine-homocysteine S-methyltransferase. Eur J Med Chem. 2013;65:256–275.

[11] Lassaux P, Hamel M, Gulea M, Delbrück H, Mercuri PS, Horsfall L, Dehareng D, Kupper M, Frère J-M,Hoffmann K, Galleni M, Bebrone C. Mercaptophosphonate compounds as broad-spectrum inhibitors of theMetallo-β-lactamases. J Med Chem 2010;53:4862–4876.

[12] Hamel M, Lecinq M, Gulea M, Kozelka J. Ortho-(methylsulfanyl)phenylphosphonates and derivatives: synthesisand applications as mono- or bidentate ligands for the preparation of platinum complexes. J Organomet Chem.2013;745–746:206–213.

[13] Yoon I, Park KM, Jung JH, Kim J, Park SB, Lee SS. Synthesis and crystal structures of S2O2 Macrocycle L, andits silver(I) and platinum(II) complexes (where L = 5,8-dioxa-2,11-dithia-[12] -o-cyclophane). J Inclusion PhenomMol Recognit Chem. 2002;42:45–50.

[14] Arnesano F, Scintilla S, Natile G. Interaction between platinum complexes and a methionine motif found in coppertransport proteins. Angew Chem Int Ed. 2007;46:9062–9064.

[15] Yoon I, Yoo BS, Lee SS, Kim BG. cis-Dichloro(5,8-dioxa-2,11-dithia[12]-o-cyclophane)palladium(II). ActaCrystallogr Sect C: Cryst Struct Commun. 2000;56:758–759.

[16] Abrunhosa I, Drabowicz J, Grach G, Gulea M, Hamel M, Masson S, Mikolajczyk M, Vazeux M. New chiral ortho-P,S-difunctionalized aromatic compounds. Phosphorus Sulfur Silicon Relat Elem. 2005;180:1267–1272.

[17] Ranu BC, Dey SS, Hajra A. Catalysis by an ionic liquid: efficient conjugate addition of thiols to electrondeficient alkenes catalyzed by molten tetrabutylammonium bromide under solvent-free conditions. Tetrahedron.2003;59:2417–2421.

[18] Ranu BC, Dey SS. Catalysis by ionic liquid: a simple, green and efficient procedure for the Michael addition ofthiols and thiophosphate to conjugated alkenes in ionic liquid, [pmIm]Br. Tetrahedron. 2004;60:4183–4188.

[19] Pore DM, Soudagar MS, Desai UV, Thopate TS, Wadagaonkar PP. Potassium phosphate or silica sulfuric acidcatalyzed conjugate addition of thiols to α,β-unsaturated ketones at room temperature under solvent-free conditions.Tetrahedron Lett. 2006;47:9325–9328.

[20] Firouzabadi H, Iranpoor N, Jafarpour M, Ghaderi A. Silica gel catalyzed highly selective C-S bond formationvia Michael addition of thiols to α,β-unsaturated ketones under solvent-free conditions. J Mol Catal A: Chem.2006;249:98–108.

[21] Peng A, Rosenblatt R, Nolin K. Conjugate addition of unactivated thiols to α,β-unsaturated ketones catalyzed by abifunctional rhenium(V)–oxo complex. Tetrahedron Lett. 2012;53:2712–2714.

[22] Ranu BC, Bhar S, Chakraborti R. Synthesis of .rbeta.-keto 1,3-dithianes from acetylenic ketones. J Org Chem.1992;57:7349–7352.

[23] Paterson I, Price LG. O-silylated enolates in organic synthesis: α-alkylation of carbonyl compounds by 1,3-dithienium fluoroborate. Tetrahedron Lett. 1981;22:2829–2832.

[24] Choi EB, Youn IK, Pak CS. Preparation of protected β-keto aldehydes from β-keto esters via selective reduction ofacyl(alkoxycarbonyl)ketene dithioacetals. Synthesis. 1988;1988(10):792–794. doi:10.1055/s-1988-27709.

[25] Xu C, Bartley JK, Enache DI, Knight DW, Lunn M, Lok M, Hutchings GJ. On the synthesis of β-keto-1,3-dithianesfrom conjugated ynones catalyzed by magnesium oxide. Tetrahedron Lett. 2008;49:2454–2456.

[26] Sneddon HF, van den Heuvel A, Hirsch AKH, Booth RA, Shaw DM, Gaunt J, Ley SV. Double conjugate addi-tion of dithiols to propargylic carbonyl systems to generate protected 1,3-dicarbonyl compounds. J Org Chem.2006;71:2715–2725.

[27] Ranu BC, Banerjee S, Jana R. Ionic liquid as catalyst and solvent: the remarkable effect of a basic ionic liquid,[bmIm]OH on Michael addition and alkylation of active methylene compounds. Tetrahedron. 2007;63:776–782.

Dow

nloa

ded

by [

Lin

naeu

s U

nive

rsity

] at

15:

26 1

5 O

ctob

er 2

014

682 A. Abdelli et al.

[28] Chakka SK, Cele ZED, Sosibo SC, Francis V, Arvidsson PI, Kruger HG, Maguire GEM, Govender T. Asymmet-ric conjugate addition of thioglycolate to a range of chalcones using tetrahydroisoquinoline (TIQ) N , N ′-dioxideligands. Tetrahedron: Asymmetry. 2012;23:616–622.

[29] Hui Y, Jiang J, Wang W, Chen W, Cai Y, Lin L, Liu X, Feng X. Highly Enantioselective conjugate addition of thio-glycolate to chalcones catalyzed by lanthanum: low catalyst loading and remarkable chiral amplification. AngewChem Int Ed. 2010;49:4290–4293.

[30] Juarez E, Garcia A, Hommer H, Salas M, Gordillo B. Stereoselective synthesis and conformational analysis ofaromatic C-thionucleosides. Heteroat Chem. 2006;17:289–298.

[31] Dridi K, El Efrit ML, Zantour H. Condensation de mercaptoacétates et de mercaptopropionates d’alkyle sur les2-dialkylaminométhylpropènenitriles. J Soc Chim Tunisie. 2005;7:43–50.

[32] Mrabet H, Zantour H. Nouvelles voies d’accès aux 2-ethoxycarbonylallylphosphonates. Phosphorus Sulfur SiliconRelat Elem. 2004;179:25–33.

Dow

nloa

ded

by [

Lin

naeu

s U

nive

rsity

] at

15:

26 1

5 O

ctob

er 2

014