One-pot synthesis of benzyltriphenylphosphonium acetates from the corresponding activated benzyl alcohols

A simple synthetic methodology for the preparation of benzyltriphenylphosphonium acetates is described. The reaction, using different benzyl alcohols substituted with an electron-donating group, involves the generation of a good leaving group and substitution with triphenylphosphine. In these cases the reactions take place with good yields. Furthermore, the obtained salts ( 16 and 17 ) have been used for the synthesis of 5-substituted benzofuroxan derivatives.


Introduction
Recently, therapeutically active benzofuroxans, such as 1 and 2 (Scheme 1), have emerged as an important class of anti-T.cruzi agents. 1 The relevance in the activity of the phenylethenyl substituent and the N-oxide group to this activity was identified through QSAR studies. 2 The synthetic routes that have been considered for the production of the phenylethenyl moiety are shown in Scheme 1.Among the various methods reported for the Wittig reaction we selected the mild conditions, promoted by crown ether catalysis, of the Bodens methodology. 3ontinuing with this research we tried to prepare and evaluate as new anti-T.cruzi agents some analogs of 1 and 2, with R an electron-donating substituent.Our first approach involved the preparation of compound 6 (Scheme 2).In order to synthesize this derivative we planned the synthetic methodology shown in Scheme 2 where we used the conventional synthesis of the phosphonium salt 5 that involves halide nucleophilic substitution with triphenylphosphine.

Scheme 2
However, compound 4 was not generated under any of the conditions tried by us. 4 Alcohol 3 proved to be significantly reactive during its purification (silica gel chromatographic column, petroleum:ethyl acetate (9:1)), and while attempting to prepare the chloride (SOCl 2 , room ARKAT temperature) it afforded an unexpected product, compound 7 (Scheme 3).Product 7 was characterized by NMR ( 1 H-, 13 C-, HMQC, and HMBC), IR and MS analysis. 5Single crystals of 7 adequate for structural X-ray diffraction studies 6 were obtained by slow evaporation from a petroleum solution.Figure 1  The generation of compound 7 could be the result of the presence, in 3 and possibly in 4, of a good leaving group and a nucleophilic moiety in the same structure.This combination promotes the formation of intermediate 8 that could react as indicated in Scheme 4. Assuming these processes, an acidic medium that reduces the nucleophilicity of the amine could avoid the formation of secondary product 7.This option, the use of an acidic medium, provides the possibility of carrying out the preparation of the phosphonium salt in a one-pot process from the ARKAT corresponding alcohol and avoids isolation of the halide intermediate.10] Herein, we report our research on the development of a new efficient synthetic methodology to prepare phosphonium salts from the corresponding benzyl alcohols substituted with an electron-donating group.This procedure was inspired by some previous reports with disadvantages such as prolonged reaction times, 11 lack of generality, 12 or use of deprotectinggroups as reagents. 13In our case, neither the aliphatic alcohols studied nor benzyl alcohols substituted with mesomeric electron-withdrawing groups gave the expected salts.

Results and Discussion
In our research, the preparation of phosphonium salts from benzyl alcohols substituted with an electron-donating group was explored as shown in Table 1.For instance, a mixture of the appropriate alcohol (1 equivalent), triphenylphosphine (1 equivalent) and dry toluene as solvent was heated at reflux, under an inert atmosphere, and then glacial acetic acid (2 equivalents) was added dropwise over 30 minutes.Then, the mixture was heated at reflux until the benzyl alcohol could no longer be detected (Table 1).The corresponding acetates (16-21), as oils, were treated successively with hexane in order to eliminate excess triphenylphosphine.Products 16-21 were characterized by NMR ( 1 H-, 13 C-, HMQC, and HMBC) and IR spectroscopy.

ARKAT
The anhydrous conditions of the reactions were ensured using adequate solvent quality and a nitrogen atmosphere to minimize the formation of triphenylphosphine oxide, the main product of reaction when undried toluene was employed.Table 1.Conditions and results in the preparation of the phosphonium acetates 16-21 OH Ph 3 P (1 eq.) / toluene reflux AcOH (2 eq.) 4.97 14.6 In the cases of alcohols 10 and 11, entries c and d (Table 1), respectively, the acidic conditions produced side reactions.On one hand, the integrity of the methylenedioxy moiety in product 18 was low, giving the desired phosphonium salt in low yield (entry d).On the other hand, the acetyl group (entry c) was lost, maybe as was previously reported, 13 by reaction of the benzyl alcohol with the ester in acid medium, producing product 17 from the alcohol 10.
It was clear that the substituent electron-donor capabilities in the different benzyl alcohols affected the yield and the time of the reactions.The best results were obtained with the activated alcohols 3, 9, 10 and 12, while an inductive electron-withdrawing substituent, in alcohol 14, gave the worst result.On the other hand, in contrast with an earlier report 13a phosphonium salt 20 was obtained after 48 h of reflux.No formation of the desired salt was observed after prolonged reaction time of alcohol 15, the benzyl alcohol with a strong electron-withdrawing substituent.
In order to extend this methodology to other alcohols we tried this procedure with the aliphatic alcohols 22 and 23 (Scheme 5).However, after prolonged reaction times neither of the desired products was generated.Other conditions were examined in order to obtain the phosphonium salts, i.e. microwave irradiation in the case of alcohol 23, 14 but without success.Moreover, the acetate counteranion did not show any deleterious effect in the following Wittig reaction.The phosphonium acetates 16 and 17 were submitted successfully to the Bodens modification with 5-formylbenzofuroxan and 4-chloro-3-nitrobenzaldehyde, respectively.

Conclusions
In summary, the present methodology describes a simple, convenient and efficient procedure for the preparation of phosphonium salts in one-pot procedure from the corresponding benzyl alcohol.The procedure is adequate for benzyl alcohols substituted with an electron-donating group that favors formation of the electrophilic benzyl carbocation for attack by triphenylphosphine.The experimental procedure is simple, convenient and does not require any special precautions for the isolation of salts.

Experimental Section
General Procedures.The alcohols 13 and 22 are commercially available.The alcohols 3, 15 9-12, 14 and 15 were prepared by reduction with NaBH 4 from the corresponding aldehyde 16 and 23 as previously reported. 17Elemental analyses were obtained from vacuum-dried samples (over phosphorous pentoxide at 3-4 mm Hg, 24 h at room temperature) and performed on a Fisons EA ARKAT 1108 CHNS-O analyzer.NMR spectra were acquired with a Bruker DPX-400 instrument at 303 K, in approximately 10 % w/v solution, using the standard sequences for the HMQC and HMBC experiments and samples were dissolved in the indicated deuterated solvents.TMS (tetramethylsilane) was used as internal reference.FTIR spectra were recorded with a resolution of 4 cm -1 , on a Perkin-Elmer 1310 spectrometer, using KBr wafers containing 1% of the sample.Electron impact (EI) mass spectra were obtained at 70 eV on a Shimadzu GC-MS QP 1100 EX instrument.
General experimental procedure.To a solution of the appropriate benzyl alcohol (3.3 mmol) and Ph 3 P (870 mg, 3.3 mmol) in dry toluene (5.0 mL) heated at reflux were added, dropwise, HOAc (0.38 mL, 6.6 mmol) in dry toluene (3.0 mL) as solvent.The mixture was heated at reflux for 4-73 h (see Table 1).The solvent was evaporated in vacuo and the residue was treated with petroleum (10.0 mL) and after heating at reflux for 1 h, the solvent was discarded.This procedure was repeated until absence of Ph 3 P in the organic solvent (checked by TLC).The resulting syrup is the product.two-fold axis that symmetry relates the two molecular halves hence resembling a two-bladed propeller.As expected, each half is planar [rms deviation of atoms from the least-squares plane of 0.042 Å].Because of the small anomalous atomic dispersion, the correct molecular stereoisomer in the lattice could not be determined.Crystal data, data collection procedure, structure determination method and refinement results for the compound are summarized in Table S1 (Supplementary material).Atomic fractional coordinates and equivalent isotropic displacement parameters are given in Table S2.Interatomic bond distances and angles are in Table S3.Listings of atomic anisotropic displacement parameters (Table S4), hydrogen atoms positions and isotropic displacement parameters (Table S5), and calculated and observed structure factor amplitudes (Table S6) are also given. 7 Scheme 1

a
Isolated yields are unoptimised.b 1 H-NMR signal of methylene group bonded to phosphorus.Solvent: DMSO-d 6 .c In ppm.d In Hertz.e The formation of 7 was observed chromatographically. f Solvent: acetone-d 6 .g No presence of phosphonium salt and no disappearance of the corresponding alcohol were observed after 48 h of reaction.

Ph 3 P
Scheme 5 Crystallographic data (excluding structure factors) for the structure in this paper have been deposited at the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC 601663.Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: 144-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].