Synthesis of diphenylphosphoryl enamines, 2-pyridones and 2-pyrrolidones

β -Enamine phosphine oxides were prepared by an one-pot process involving the sequential reaction of triphenylphosphine oxide with methyl lithium and then with alkyl and aryl nitriles. The enamines added regioselectively through the β -carbon to the carbon-carbon triple bond of the DMAD with a stereoselectivity which depended on the substituent of the enamine. Heating the phosphoryl enamines afforded phosphorus substituted, 2-pyridones and 2-pyrrolidones in good to excellent yields. The cyclocondensation could also be performed without isolation of the intermediate adducts. The effects of the solvent and substituents bonded to the enamine moiety on the cyclocondensation process is discussed. The use of bulky substituents promotes alternative pathways for the reaction. Thus, when the enamine containing a tert -butyl group is heated in refluxing toluene, the expected 2-pyridone was not formed but a new 5-dihenylphosporyl-2-hydroxy-3-pyrrolidone was isolated instead.


Introduction
Nitrogen heterocycles containing phosphorus functional groups are compounds of interest in many areas of industrial chemistry such as the textile, the pharmaceutical, the agricultural field, etc. 1 A useful strategy for the preparation of these type of compounds is based on the cyclization of functionalized enamines. 2β-Functionalized enamines or the corresponding imine tautomers derived from phosphonium salts, 3 phosphine oxides, 4 phosphonates, 4b,4d,4f,5 and phosphazenes 6 have been applied to the synthesis of phosphorus substituted three-, five-and six-membered nitrogen heterocycles.The heterocyclic framework available through this methodology includes azirines, pyrazoles, pyrroles, 2-pyrrolones, dihydro-and tetrahydropyridines, 2-pyridones, quinolines and pyrimidin-2,4-diones. Furthermore, phosphorus functionalized enamines are also useful starting materials for the preparation of phosphorus-containing heterocycles. 7e have previously reported the synthesis of 4-(N-acyl)phosphazenyl-2-pyrrolidones 7 and 5-(N-acyl)phosphazenyl-2-pyridones 8 by the intramolecular condensation reaction of polyfunctionalized enamines 6 bearing a (N-acyl)phosphazenyl group on the β-carbon. 6The preparation of the phosphorus-containing enamines 6 precursors of the heterocycles involved five steps (Scheme 1): (i) formation of methyldiphenyl(N-phenyl)phosphazene through the Staudinger reaction of phenylazide with methyldiphenylphosphine, (ii) metallation of the phosphazene with n-BuLi followed by addition of a nitrile to obtain β-[(Nphenyl)phosphazenyl]enamines, (iii) reduction of the P=N linkage of the (Nphenyl)phosphazenylenamines with LiAlH 4 to the corresponding P(III) diphenylphosphinyl derivative 4, 8  Considering the importance of the phosphorus substituted heterocycles we decided to prepare derivatives of 7 and 8 having a P=O group instead of the phosphazenyl moiety.This substituent is a useful surrogate of a carbonyl group in peptidomimetics, 10 which might improve the molecular recognition ability of these compounds.Ogura et al. have recently shown that in the solid state the oxygen of phosphinoylated 2-pyridones is involved in the formation of chiral or achiral one dimensional structures through intermolecular hydrogen bonding with the hydrogen atom of the amide group. 11We report in this paper the synthesis of 4diphenylphosphoryl-2-pyrrolidones 11 and 5-diphenylphosphoryl-2-pyridones 12 in good to excellent yields in four steps starting from triphenylphosphine oxide.The use of the phosphine oxide functional group as the carrier of the phosphorus atom allowed a significant simplification of the synthetic procedure.Heating the adduct of phosphoryl enamines and DMAD in acetonitrile or toluene afforded the heterocycles 11 and 12. Steric effects slowed down the cyclocondensation reaction.The process could be accelerated by performing the transformation in boiling xylene.In the extreme case of a tert-butyl substituent the reaction proceeds through an alternative pathway leading to 5-diphenylphosphoryl-3-pyrrolidone 13.

Synthesis of acyclic polyfunctionalized enamines
Based on the synthesis of 2-pyrrolidones 7 and 2-pyridones 8 shown in Scheme 1 the preparation of the corresponding diphenylphosphoryl derivatives would require the use of βdiphenylphosphoryl enamines 9.These compounds have been previously obtained either by addition of nitriles to methyldiphenylphosphine oxide in the presence of a strong base (LDA or n-BuLi) or through the aza-Wittig reaction of phosphazenylenamines 3 with CO 2 . 12A priori, the synthesis of enamines 9 could be carried out in a one-pot manner by taking into account that the intermediate lithiated phosphine oxide can be obtained almost quantitatively by displacement of a phenyl group of triphenylphoshine oxide with methyl lithium (Seyferth method). 13Indeed, this proved to be the case.The procedure consisted in the formation of lithium methylendiphenylphosphine oxide by treatment of triphenylphosphine oxide with methyl lithium in THF at -30 °C during two hours, followed by the addition of the appropriated nitrile at -70 °C.The reaction was allowed to reach room temperature overnight and was then hydrolyzed with ice-water instead of using diluted hydrochloric acid 13b to avoid the transformation of the enamine moiety into the corresponding carbonyl compound (Scheme 2).The phosphoryl enamines 9 obtained, as well as their yields and 31 P chemical shifts are given in Table 1.As expected, the reaction of DMAD with the phosphoryl enamines 9 in CH 2 Cl 2 showed the same C-regioselectivity observed for the β-[(N-acyl)phosphazenyl]enamines derivatives 6a yielding the aminodienic compounds 10 (Scheme 2, Table 2).The stereoselectivity of the process depended on the substituent R of the enamine.When R represented an aromatic ring, 10a-b, the reaction was stereospecific.The Z geometry around the enamine moiety was retained and a cis-addition of the enamine CH bond to the triple bond in the DMAD took place, affording a conjugated dienic system with a E,Z configuration exclusively.The structural assignment was based on the analysis of the vicinal phosphorus-carbon coupling constants and nuclear Overhauser enhancements (NOE) measured.A magnitude of 3 J PC ≈11 Hz for the ipso-carbon bonded to the enamine clearly established the anti arrangement of the two coupled nuclei around the double bond, which corresponded to a Z configuration. 14This assignment is confirmed by the NOE detected between the methoxycarbonyl group bonded to the quaternary olefinic carbon and the aromatic protons of the p-tolyl substituent in 10a, and the ortho methyl protons in 10b.The E configuration of the double bond conjugated with the enamine is deduced from NOE observed between the olefinic proton and the ortho protons of the aromatic rings bonded to the phosphorus.Interestingly, the saturation of these protons also produced a small NOE enhancement on protons corresponding to the substituent R.These results are consistent with a non planar s-trans conformation of the dienic system, an arrangement already found in the analogous phosphazenyl enamines, Figure 1.When R was aliphatic a mixture of stereoisomers was obtained.Thus, for R= C 6 H 11 the crude reaction mixture contained three aminodienes 10ca:10cb:10cc in a ratio 80:10:10 calculated from the integration of the 31 P NMR spectrum.All attempts to isolate these ARKAT compounds failed and only mixtures of variable composition of the three compounds were obtained.The structural assignment could be carried out by analyzing again the magnitudes of 3 J PC and the NOE data measured from the crude reaction mixture.On this basis, the three structures shown in Figure 2 were identified.Compounds 10ca and 10cc differed from each other in the configuration of the carbon-carbon double bond bearing the two methoxycarbonyl substituents.Both products retained the Z-configuration on the enamine moiety (configurational isomers E,Z and Z,Z, respectively).Compound 10cb was assigned as the Z,E isomer arising from the trans-addition of the enamine to the DMAD and inversion of the stereochemistry of the enamine linkage respect to the starting material.On standing in CHCl 3 solution, compounds 10ca and 10cb isomerized to 10cc, i.e. the product of kinetic control corresponds to the cisaddition of the enamine to the carbon-carbon triple bond of the DMAD, while the Z,Z isomer is the product of thermodynamic control.The reaction between the phosphoryl enamine 9d, R = t-Bu, and DMAD also afforded a mixture of two compounds 10da:10db in a ratio 35:65, which could not be separated because all manipulations of the mixture promoted the cyclization of the components.The structural characterization was carried out from the crude reaction mixture through a combination of NMR experiments including NOE difference and 2D 1 H, 13 C HMQC and HMBC spectra.Compound 10da is the result of the stereospecific cis addition 15 of enamine 9d to DMAD and the isomer 10db was identified as the imino tautomer of the enamine 10da.The correlations observed for the olefinic and methine protons in the HMBC spectrum established the connectivity of the carbon skeleton (Figure 3).The observation in solution of the imine tautomer of an enamine containing a t-butyl substituent is precedented in the literature. 16Moreover, 10db showed a significant broadening of some signals in the 1 H and 13 C NMR spectra.Variable temperature NMR measurements in different solvents (CDCl 3 and THF-d 8 ) combined with the analysis of the ROESY 17 spectrum acquired at -60 °C allowed to identify the existence of a cis-trans equilibrium of the imino moiety. 18Table 2 shows the polyfunctionalized phosphoryl enamines obtained in the reaction of 9 with DMAD.

Synthesis of pyrrolidones and pyridones
The cyclization of the diphenylphosphoryl enamines 10 was achieved thermically.The course of the cyclocondensation was dependent on the reaction temperature and the solvent polarity.Thus, 4-diphenylphosphoryl-2-pyrrolidones 11 were obtained quantitatively by heating enamines 10 in acetonitrile at reflux for 12 h, 19 except for 10b which was recovered unaltered (see below).Fortunately, the mixture of isomeric enamines with cyclohexyl, 10c, and t-butyl substituents, 10d, also lead to the same type of 2-pyrrolidone 11c-d with an E exocyclic double bond (Scheme 3).The synthesis of the heterocycles can be performed in a one pot reaction by adding DMAD to a solution of the enamines 9 in acetonitrile and subsequent reflux of the reaction mixture without isolation of the intermediate product 10.The formation of a five-membered heterocycle and the E configuration of the exocyclic double bond in position 3 were deduced from their NOE difference and HMBC spectra. 6Functionalized pyrrolidones are important compounds because of their biomedical properties. 20n the other hand, refluxing enamines 9 in toluene afforded mixtures of phosphorus substituted 2-pyrrolidones 11 and 2-pyridones 12, i.e., the diphenylphosphoryl derivatives 9 showed the same reactivity as the (N-acyl)phosphazenyl series of enamines (Scheme 3).The heterocycles 11-12 were easily separated by fractional crystallization in hexane/chloroform or column chromatography (eluent: ethyl acetate).The exception in this case was 10d.The new product of the reaction was not the expected pyridone but the diphenylphosphoryl-3-pyrrolidone 13.The structural assignment was carried out based on the HMBC spectrum. 21A possible mechanism for the formation of 13 is shown in Scheme 4. The first step would consist in a proton displacement, either [1,5]  The cyclocondensation of 10b in refluxing toluene deserves some comments.Even after 48 h of heating the conversion was limited to 50% and the crude reaction mixture showed the presence of four products: two acyclic isomers of the starting enamine, 10ba and 10bb, and two heterocyclic, 11b and 12b, in a ratio 27:36:27:10, respectively.The reaction was completed by increasing the reaction time to four days.These conditions allowed to increase the yield of 11b to 70%, while the relative ratio of the other three compounds 10ba:10bb:12b remained similar (11:14:5).The pyrrolidone 11b is very insoluble and precipitated from the reaction medium, which explained the increased yield and facilitated the isolation.The separation of 12b and the mixture 10ba/10bb was achieved by column chromatography using ethyl acetate as eluent.All compounds were identified following the procedure mentioned above for the other members of the series.
The proton spectrum of the mixture of enamines 10ba/10bb showed broad signals which narrowed upon cooling down to -30 °C in CDCl 3 .At this temperature the magnitudes of 3 J PC and the NOE enhancement observed indicated that the configuration of the double bonds of the dienic system was Z,Z for both compounds.Consequently, they must be conformational isomers.Effectively, the proton spectrum of the mixture measured at 60 ºC showed the expected set of signals for a single species although relatively broad because at this temperature the rate of exchange between the rotamers was still relatively slow on the NMR time scale. 22A new set of NOE difference spectra acquired in C 6 D 6 allowed to identify the restricted rotation of the o-tolyl group as the origin of the duplication of the signals (Figure 4).The results above suggest that low polar solvents favored the formation of 2-pyridones vs. 2-pyrrolidones and that the inertia to the cyclocondensation derived from steric effects produced by the substituents on the enamine double bond might be overcome by heating at an appropriated temperature.Therefore, one may assume that the cyclization of 10b could be driven in a shorter time and with increased yield in pyridone by performing the reaction in refluxing xylene.In fact, under these conditions a conversion of 90% was reached in 24 h.However, the yield of 2pyridones was not improved.A large number of natural and synthetic compounds containing the 2(1H)-pyridone structural fragment show valuable biological activities. 23Table 3 shows the heterocycles obtained by cyclocondensation of the enamines 10.In summary, new 4-diphenylphosphoryl-2-pyrrolidones and 5-diphenylphosphoryl-2pyridones have been synthesized by cyclocondensation of adequately functionalyzed enamines under reflux in acetonitrile or toluene.The required enamines have been obtained by addition of DMAD to simple β-diphenylphosphorylenamines.The stereoselectivity of this process depends on the substituents bonded to the enamine moiety.When the substituent is an aromatic ring the reaction is steroespecific whereas with aliphatic substituents a mixture of isomers is obtained.In this case also the isomers formed and their proportions depend on the substituent.The stereoselectivity found in the reaction with DMAD is, however, not essential for the heterocyclization process.Overall, the heterocycles can be obtained in a two step process using commercially available materials.It is also shown that bulky substituents promote alternative pathways for the reaction.Cyclocondensation of o-tolylsubstituted enamines was also achieved in refluxing xylene.Both solvents, toluene and xylene, led to 2-pyridone in similar yields but with the latter a higher conversion was obtained in a shorter time compared with the reaction in toluene.In refluxing toluene the t-butyl enamine afforded a 5-diphenylphosphoryl-2-hydroxy-3pyrrolidone instead of the expected 2-pyridone.A reasonable mechanism for the formation of this product was proposed.

Experimental Section
General Procedures.All reactions were carried out under an atmosphere of nitrogen using dried glassware.THF was distilled from sodium/benzophenone immediately prior use.Commercial reagents were purchased from Sigma-Aldrich Química S.A. and were distilled before use, except LiMe.Triphenylphosphine oxide was commercially available.TLC was performed on Merck plates with aluminium backing and silica gel 60 F 254 .For column chromatography silica gel 60 (40-63 µm) from Scharlau was used.Melting points were recorded on a Büchi-Tottoli apparatus ARKAT and are uncorrected.Infrared spectra were obtained in KBr pellets using a UNICAM Mattson 3020 FT spectrometer.Mass spectra were determined by electron impact on a Hewlett-Packard 5987A.Microanalysis were performed on a Perkin-Elmer 2400.NMR spectra were measured on a Bruker Avance 300DPX or Bruker 400 AMX spectrometer.Chemical shifts are referred to internal tetramethylsilane for 1 H and 13 C, and to external 85% H 3 PO 4 for 31 P. 2D NMR correlation spectra (COSY, NOESY, ROESY, HMQC and HMBC) were acquired using standard Bruker software and processing routines.Compound characterization.Synthesis of β-phosphorylenamines 9. 24 mmol of LiMe were added dropwise to a solution of triphenylphosphine oxide (20 mmol) in dry THF (30 mL) at -30 ºC.After 2h the temperature was lowered at -70 ºC and the desired nitrile (20 mmol) dissolved in 5 mL THF was added.The reaction mixture was stirred for 8 h and allowed to reach room temperature.Addition of water (25 mL) followed by extraction with CH 2 Cl 2 (3x15 mL) and solvent evaporation under vacuum afforded an oil.For compounds 9a, 9b, and 9d, digestion of this oil in diethyl ether yielded the corresponding solid products.They were filtrated, dried and used without further purification.General procedure for the reaction of the phosphorylenamines 9 with DMAD.DMAD (5 mmol) was added to a solution of the corresponding compound 9 (5 mmol) in CH 2 Cl 2 , dried and freshly distilled under N,N-diethylaniline.The mixture was stirred at room temperature during 36 h.After in vacuo solvent evaporation compounds 10 were isolated by recristallization in hexanemethylene chloride.10ba and 10bb).These compounds are two conformers that were obtained as a 43:57 mixture when the enamine 10b was heated in refluxing toluene.The solid mixture (10ba and 10bb) was isolated and purified form the reaction crude that also contain compounds 11b and 12b by means of column chromatography using a mixture of ethyl acetate and methanol ARKAT (1.1)

Figure 3 .
Figure 3. Structures of the compounds obtained in the reaction between the phosphoryl enamine 9d (R = t-Bu) and DMAD showing selected NOEs (dashed arrows) and 1 H 13 C correlations (continuous arrows).

Figure 4 .
Figure 4. Selected NOEs for compounds 10ba and 10bb measured at 300.13 MHz in C 6 D 6 .

Table 2 .
δ 31 P (ppm) and yield (%) for compounds 10 obtained in the treatment of the phosphoryl enamines 9 with DMAD a Relative proportion of compounds in the mixture 10ca:10cb:10cc deduced from the 31 P-NMR spectrum.b Relative proportion of compounds in the mixture 10da:10db deduced from the 31 P-NMR spectrum.