Bogdan Iorga

Frédéric Eymery

Virginie Mouriès

Philippe Savignac

Phosphorylated Aldehydes : Preparations and Synthetic Uses*

). Use of a

 However, it is limited to 1-formylmethylphosphonates unsubstituted at the α-carbon. Fig. 3. Synthesis of diethyl 1-formylmethylphosphonate via the MA reaction 17 .

). According to the conditions employed, either one or two molecules of ethanol can be added across the triple bond to give, respectively, diisopropyl 2-ethoxyvinylphosphonate 9 and 2,2-diethoxyethylphosphonate 8. As above both compounds give 10 on acid hydrolysis. However,

EtO) 2 P O CH 2 CH(OEt) 2 (EtO) 2 P O CH 2 C O H (EtO) 2 P O CH CH OEt (EtO) 3 P Br CH 2 CH(OEt) 2 4 5 6 HCl 1M 80-90°C 150-160°C t >180°C 81%

INTRODUCTION

Aldehydes are among the most fundamental chemical functionalities in organic chemistry. In turn, phosphorylated aldehydes are popular reagents which occupy a unique position in organic chemistry and the specific properties of these compounds have given rise to a large number of developmental and synthetic applications. 1 Since the review on the subject written by Razumov et al. 1 in 1973, these compounds have received considerably more attention than during the 21 years following their first preparation by Dawson and Burger 2 in 1952. The number and diversity of papers in the literature attest to the wide acceptance and general utility of these reagents. The intervening 25 years have seen decisive progress in the development of the chemistry of these compounds: the blossoming of research on phosphonate carbanions, including their use in intermolecular and intramolecular Horner-Wadsworth-Emmons reactions; the discovery of phosphonoacetaldehyde in nature; and the application of phosphorylated aldehydes to the preparation of aminophosphonic acids. So much knowledge has been accumulated that the time seemed appropriate to gather the results of phosphorylated aldehyde research in a review. In this review, the various methods for the preparation of phosphonates containing a formyl group in the alkyl substituent linked to phosphorus, the types of reaction they undergo, their use as synthetic intermediates and their conversion into biologically active compounds are summarised.

SYNTHESIS OF PHOSPHORYLATED ALDEHYDES

One of the advantages of phosphorylated aldehydes is their synthetic accessibility. In principle, the formyl group can be introduced at any position relative to the phosphorus, and compounds with formyl group in positions 1 to 16 are known (Fig. 1). The methods for the preparation of phosphorylated aldehydes are generally a combination of phosphorus and carbon chemistry. To this end either a trivalent phosphorus compound reacts with an alkyl halide attached at a masked formyl group, or the formyl group is introduced into the alkyl substituent linked to the phosphoryl group using organometallic coupling methods (C-C bond formation) or functional group transformations. The choice of method, P-C versus C-C bond formation, depends on the relative position of the formyl group to phosphorus. The selected preparations here described include compounds containing alkoxy groups on the phosphorus atom. Compounds containing the formyl group attached directly to the phosphoryl group are somewhat controversial and information on their synthesis is extremely limited and to some extent doubtful. In 1973 it was written "possibly they cannot exist at all". 1,3 In 1974 the preparation of the dimethyl formylphosphonate was briefly reported in a patent providing a method for the production of fosfomycin. 4 In 1982 the reaction of the sodium derivative of dimethylphosphite with formic acetic anhydride in Et 2 O at -10°C was reproduced on laboratory scale to give what appeared to be a mixture containing the desired dimethyl formylphosphonate and presumably oligomers. 5 In 1987 it was shown that diethyl formylphosphonate 1 decomposes at -10°C into diethylphoshite and carbon monoxide (Fig. 2). As diethylphosphite accumulates in the reaction mixture the addition reaction of diethylphosphite to the carbonyl group of the formylphosphonate takes place leading to the formation of tetraethyl (hydroxymethylene)diphosphonate 2, which isomerizes into (diethoxyphosphinyl) methyl diethyl phosphate 3 (79%). 6 The difficulty in isolating 1 by hydrolysis of an iminium salt has been reported. 187 Fig. 2. Formation and decomposition of diethyl formylphosphonate.

On the other hand, acetals, hemithioacetals and thioacetals of formylphosphonates are known and readily available. 7 In contrast to the parent compound, acetals and thioacetals are chemically stable. They can be obtained in two ways. Condensation of dialkylphosphites with orthoformic esters at 182°C for 5h provides formylphosphonates with satisfactory yields (60 to 80%). 8 The second route, from either chlorophosphites and orthoformic esters, or trialkylphosphites and chloroacetals, is more general. 9 For example, the synthesis of thioacetals is usually accomplished in high yields by reaction between the appropriate chlorodithioacetals and trivalent phosphorus compounds. 7 A recent method for the synthesis of thioacetals involves the reaction between a dialkyl 1-lithioalkylthiophosphonate and a disulfide. The mixed thioacetals, obtainable in 70-90% yields from PhS-SPh, are accompanied by 5-20% of symmetrical thioacetals. 10 The hydrolysis of diethyl formylphosphonates acetals with HCl 2M at 117°C for 3h does not lead to the corresponding aldehydes but involves the dissociation of the C-P bond with formation of the initial diethylphosphite, EtOH and HCO 2 Et. 11 2.2. n=1.

development of the method remains limited by the availability of diisopropyl ethynylphosphonate 7 on large scale. 24 Fig. 4. Synthesis of diisopropyl 1-formylmethylphosphonate from ethynylphosphonate 24 .

A variation of the MA reaction utilized the chloromethyloxazine as masked formyl group instead of diethyl acetal (Fig. 5). Chloromethyloxazine underwent a smooth reaction with trialkyl phosphites at reflux for 24h to furnish the oxazine phosphonates 11 (R=Me, 40% and R=Et, 80%). 25 Fig. 5. Synthesis of oxazine phosphonates 25 Employing the oxazine phosphonates 11 provided a route to α-substituted phosphonoacetaldehydes. For instance the 1,1-dimethyl oxazine phosphonate 12 was obtained in high yield (93%) by treating the sodium derivative of 11 (R=Et) in DME with methyl iodide in excess. The conversion of 12 into the diethyl 1,1-dimethyl-1-formylmethylphosphonate 13 was accomplished in 62% overall yield by the standard reductionhydrolysis technique using sodium borohydride at -45°C followed by heating in oxalic acid (Fig. 6). Thus the use of oxazine phosphonates 11 constitutes an entry into α-substituted phosphonoacetaldehydes. 25 Fig. 6. Synthesis of diethyl 1,1-dimethyl-1-formylmethylphosphonate using the oxazine phosphonate 25 .

Another variation of the protecting reagent for the formyl group utilizes vinyl acetates. Thus diethyl 1-formylmethylphosphonate 4 was obtained in 66% yield through the hydrolysis of diethyl 2-acetoxy-2-chloroethylphosphonate 14. Preparation of 14 was achieved by successive reaction of vinyl acetate with phosphorus pentachloride at 7-8°C in CCl 4 , treatment of the unisolated adduct at the same temperature with SO 2 and alcoholysis of the (2-acetoxy-2-chloroethyl)phosphonic dichloride with ethanol at 0°C in Et 2 O in the presence of pyridine (Fig. 7). Deprotection of the formyl group, in acetone or dioxane, was a slow operation. 26 (i-PrO)

2) 2.5 eq. MeI 1)NaBH 4

2)H 3 O + 62% Fig. 7. Synthesis of diethyl 1-formylmethylphosphonate from vinyl acetates 26 A recently introduced method is the palladium-catalysed MA reaction of allyl acetates with (EtO) 3 P, which provided diethyl allylphosphonates in reasonable yield (65%). This reaction was been applied to the synthesis of diethyl 1-formylmethylphosphonate 4 on a preparative scale (crude 78%, pure 52%) by reductive ozonolysis of diethyl allylphosphonate in CH 2 Cl 2 at -70°C over 4h (Fig. 8). 27 Fig. 8. Synthesis of diethyl 1-formylmethylphosphonate by reductive ozonolysis 27 The preparation on a large scale of dialkyl 1-formylethylphosphonates was achieved in good yield (66%) by hydroformylation of several dialkyl vinylphosphonates in the presence of catalytic amounts of Rh(COD)Cl dimer in toluene with 1:1 CO-H 2 ratio. 188 Decisive progress was made with the formylation of organophosphorus compounds containing an active methylene group. This methodology is the procedure of choice for preparing both unsubstituted and αsubstituted phosphonoacetaldehydes with or without a functional group next to the formyl group. The aldehydes synthesised include, together with the phosphorus-containing groups, alkyl, aryl and electron withdrawing groups in the α-position.

Two complementary procedures have been successfully developed. One employs a carbanionic route with HCO 2 Et, 28,29,30,33b DMF, 31,149 N-formylmorpholine 32 or orthoformic esters 33a,42,43 as formylating agents, the other employs a thermal route with dimethylformamide dialkyl acetal or aminals. 34,35 In the carbanionic procedure, n-BuLi deprotonated the methylene group of 15 to give α-lithioalkylphosphonates 16, which reacted with DMF or N-formylmorpholine to give a transient lithium β-aminoalkoxide 17. After treatment of the reaction mixture by aqueous acid (3M HCl) the dialkyl 1-formylalkylphosphonates 18 were isolated in near quantitative yield (Fig. 9). 31,32 By a similar procedure 16 reacted with HCO 2 Et to give 18 in comparable yield. This formylation reaction using lithio anions and HCO 2 Et has been applied to the synthesis of several phosphonates containing an active methylene group including allyl-, 36 benzyl-, 30 chloromethyl-, 37 bromomethyl-, 29 3,3-diethoxybutyl-38 and thioethylmethylphosphonate. 30 Yields of functional dialkyl 1-formyl-alkylphosphonates 18 were high and the only byproduct was the unreacted starting phosphonate. Fig. 9. Synthesis of 1,1-dialkyl-1-formylmethylphosphonates by the carbanionic route 31,32 .

The ethyl formate approach was combined with the phosphate-phosphonate conversion reaction to provide a useful one-pot transformation of triethylphosphate to the corresponding diethyl 1formylalkylphosphonates 19 in good overall yield (94% with R=n-Pr) (Fig. 10). 39,40 Generation of 19 from triethylphosphate renders this methodology a viable alternative to methods which require the preparation of diethyl alkylphosphonates (EtO) 2 P(O)CH 2 R. Thus, triethylphosphate serves as a reagent for the direct phosphorylation of alkyl groups. Fig. 10. One pot synthesis of diethyl 1-formylalkylphosphonates from triethylphosphate 39,40 .

Through a halogen-metal exchange reaction, the diethyl trichloromethylphosphonate 20 proved to be a useful reagent for the one-pot synthesis of diethyl 1-formylalkylphosphonates 19 (Fig. 11). In the presence of n-BuLi (2 eq.), 20 reacted readily at low temperature with TMSCl to give the 1-lithio-1-chloro-1-(trimethylsilyl)-methylphosphonate 21, which provided 22 on treatment with alkyl halides. A third halogenmetal exchange reaction gaves the 1-lithio-1-(trimethylsilyl)alkylphosphonates 23, which were converted into the mixed acetals 24 by treatment with HCO 2 Et and an excess of TMSCl. Hydrolysis with 2M HCl to diethyl 1-formyl-alkylphosphonates 19 usually as a mixture of aldehyde and enol in a good overall yield (70%). 41 (R

1 O) 2 P O CH R 2 R 3 n-BuLi (R 1 O) 2 P O C R 2 R 3 CH O Li N(R 4 ) 2 (R 1 O) 2 P O C R 2 R 3 C O H HCl 2M (R 1 O) 2 P O CLi R 2 R 3 (R 4 ) 2 N-CHO 1 6 1 7 1 8 1 5 -78°C, THF HCO 2 Et 2M HCl R 4 = Me, O 45-88% 51-94% R 1 =Me, Et, i-Pr R 2 =H, Me, Et, Ph, Cl, SEt R 3 =H, Me (EtO) 2 P O OEt R = Me, Et, n-Pr, i-Pr, n-Bu, i-Bu 2 R-CH 2 Li (EtO) 2 P O CH R C O H 1 9 1) HCO 2 Et (EtO) 2 P O CH R Li -78°C, THF
2) 3M HCl 90-94% Fig. 11. Synthesis of diethyl 1-formylalkylphosphonates from diethyl trichloromethylphosphonate 41 Formylation of methylene group with orthoformic esters is a more limited reaction. In the presence of sodium in Et 2 O at room temperature, orthoformic esters effect a formylation reaction with a number of relatively acidic (Z=Cl, 33a Br, 33a Ph 33a,42 ) or very acidic phosphonates 25 (Z=CN, 33b CO 2 R, 33b COR 29,33a,43 ). Yields of functionalized diethyl 1-formylmethylphosphonates 27, after aqueous acid treatment of the diethyl acetals or enol ethers, are relatively modest (32 to 50%), which renders this methodology not competitive with methods that use formylating agent at low temperature.

When phosphonates 25 containing powerful electron withdrawing groups Z are subjected to formylation by HCO 2 Et, the corresponding phosphorylated aldehydes 27 are obtained in low yields (25 to 30%). 28,29,30 Full utilization of this carbanionic route is handicapped by the Z groups, which promote a stabilisation of the anionic form unfavourable to the reaction. This may be overcome by use of a thermal route (Fig. 12). In the thermal procedure, an aminomethylene fragment is introduced on the methylene group by the reaction of the phosphonates 25 with a N,N-dimethylformamide dialkyl acetal to produce phosphorylated enamines 26 in pure form. The phosphorylated enamines 26 are then converted to the 1-formyl-methylphosphonates 27 by further acid or basic hydrolysis. 34,35 By contrast to the carbanionic route, the electron withdrawing effect of the Z group appears as a favourable factor in the thermal route. Fig. 12. Synthesis of diethyl 1-formylalkylphosphonates by thermal route 35 A large variety of N,N-dimethylformamide dialkyl acetals are commercially available. They have a greater reactivity than the orthoformate esters and they offer the advantages of neutral conditions and greater yields than those obtained by other methods. The N,N-dimethylformamide dimethyl acetal and tert-butoxybis-(dimethylamino)methane have been shown to be useful in reaction with phosphonates bearing a good electron withdrawing group Z. On reaction with functionalized phosphonates 25, N,N-dimethylformamide dimethyl acetal undergoes spontaneous elimination of methanol at room temperature when Z=CN and CO-CO 2 R; with Z=CONR 2 , CO 2 R and COR the reaction requires 2h at reflux and when Z=C 6 H 4 NO 2 8h at reflux is necessary.

The enamine phosphonates 26 are always obtained in nearly quantitative yield. However, the number of compatible functional groups is limited since phosphonates with Z=CH(OEt) (83-90%) and the phosphonates containing a formyl group next to the Z group are isolated mainly in the enol form. 35 Another attractive preparation of 1-formylphosphonates includes the rearrangement of epoxides to carbonyl compounds, which is a well established reaction offering a true synthetic utility. An advantageous synthesis of diethyl 1,1-disubstituted 1-formylmethylphosphonates 29 has been developed using readily available diethyl 1,2-epoxyphosphonates 28 and catalytic isomerisation induced by Lewis acids (Fig. 13). The boron trifluoride etherate is an effective catalyst in the rearrangement of 28. The [1,2] migration of the phosphoryl group is conducted with high selectivity and in good yield. Both symmetrical and unsymmetrical aliphatic and cyclic phosphorylated aldehydes 29 can be obtained by this way. [44][45][46][47][48] Fig. 13. Synthesis of diethyl 1,1-dialkyl-1-formylmethylphosphonates from 1,2-epoxyphosphonates 48 . It has been found that there are limitations in this rearrangement. For example, the 1,2-epoxyphosphonates prepared from cyclic ketones (m=1-3, Fig. 14), upon treatment with boron trifluoride etherate undergo a competing proton migration and consequently give a mixture of diethyl 1,1-disubstituted-1formylphosphonates 30 (major product, 25-71%) and diethyl 1-hydroxyallylphosphonates 31 (minor product, 10-15%) (Fig. 14). 48 Fig. 14. Side reactions in the rearrangement of 1,2-epoxyphosphonates 48 .

Z Z P O C C O R 1 R 2 P O C C R 2 R 1 O H BF 3 .Et 2 O H (EtO) 2 (EtO) 2 P O CH C O R 1 R 2 (EtO) 2 + 0°C,
In some cases 1,2-epoxyphosphonates undergo thermal isomerisation at high temperature (170-300°C) to produce, as a result of the phosphoryl group migration, substituted 1-formylmethylphosphonates. In fact, the rearrangement products themselves can be thermally labile undergoing dephosphorylation. 44,49 The ring opening of diethyl 1,2-epoxyphosphonates 32 has been effected by refluxing 32 with an ethanolic solution of sodium dialkylphosphite (Fig. 15), which attacks the β-carbon atom of the epoxide via the equilibrium sodium phosphite salt-alcoholate intermediate. The ring opened compound easily undergoes a phosphite anion elimination producing dialkyl 1-formylethylphosphonates 33 in 50-85% yields. 50 Fig. 15. Rearrangement of dialkyl 1,2-epoxyphosphonates in basic medium 50 .

The treatment with singlet oxygen of a methanolic solution of dimethyl 2-nitroethylphosphonate also containing MeONa and a sensitizer, Rose Bengal, affords dimethyl 1-formylalkylphosphonates in yields ranging from 64 to 90%. Temperature dependence of the yield has been observed. The higher yield at low temperature may be attribuable to increasing stability of the intermediate dioxazetidine. 51

n = 2.

The conventional MA reaction of (EtO) 3 P and halogenoacetals has been applied to the synthesis of diethyl 3,3-diethoxypropylphosphonates 34. 14a,17a,18a,c The reaction can be realized in good yield (65%) with linear or branched primary halogenoacetals (Fig. 16). Of significant synthetic importance is the easy formation Reaction of (EtO) 3 P with dihalogenoalkenes at 120-140°C provides the diethyl 3-halogeno-propen-2ylphosphonates 37 (56 to 90% yield) which upon treatment with alcoholates or thiolates in ethanol at room temperature results in the only formation of the substitution products in the γ-position (Fig. 17). The enol-38 and thioenolether 39 were converted by hydrolysis with 5M HCl at reflux to the corresponding diethyl 2-alkyl-2-formylethylphosphonate 36 (R 1 ≠H) or 2-formylethylphosphonate 36 (R 1 =H) thus giving an entry into βsubstituted phosphonopropionaldehydes. 52 Fig. 17. Synthesis of diethyl 2-alkyl-2-formylethylphosphonates via the MA reaction 52 .

Unsaturated dialkyl 2-formylphosphonates have been obtained via alkoxyacetals 41. These were prepared from the reaction of PCl 5 with alkyl allyl ethers at 7°C in C 6 H 6 . On treatment with RONa in Et 2 O, the (3-alkoxy-3-chloropropenyl)phosphonic dichlorides 40 resulting from decomposition of the adduct with SO 2 (41% yield for R 1 =Et and 24% for R 1 =n-Pr) produced a number of dialkyl 3,3-dialkoxy-propenylphosphonates 41 in yields ranging from 56 to 82% (Fig. 18). However, in experiments aimed at the isolation of the corresponding dialkyl 2-formylvinylphosphonates by hydrolysis of 41, only clear viscous, undistillable resins were obtained. In view of their instability, phosphonoacroleins were not isolated in a free state but were identified as their 2,4-dinitrophenylhydrazones derivatives. 54 (EtO In contrast, the diethyl 2-formylethynylphosphonate 43 is a distillable colorless liquid, which proved to be stable when stored for several months at 0°C. It is obtained on preparative scale in high yield by hydrolysis with 97% HCO 2 H of the diethyl 3,3-diethoxypropynylphosphonate 42. Catalytic hydrogenation of 42 (5% Pd/CaCO 3 ) gave a mixture Z-and E-of acetals, from which the Z-isomer 44 was isolated in 60% yield. Formolysis of pure 44 using 97% HCO 2 H gave a mixture of Z-and E-aldehydes from which the Z-diethyl 2-formylvinylphosphonate 45 Z-was isolated in 60% yield by distillation (Fig. 19). 55 Fig. 19. Synthesis of diethyl 2-formylethynyl-and Z-2-formylvinylphosphonates 55 .

) 2 P O (EtO) 2 P O CH C O H (EtO) 3 P Br CH 2 CH CH(OEt) 2 R 1 CH 2 CH CH(OEt) 2 R 1 CH 2 R 1 (EtO) 2 P O CH CH 2 CH(OEt) 2 R 1 = H 1) n-BuLi / THF 2) R 2 X R 2 = Me, Et, CH 2 =CH-CH 2 R 1 = H, Me 3 4 3 5 3 6 R 2 1M HCl R 1 Δ 50-85% 62-70% (EtO) 2 P O (EtO) 2 P O CH C H (EtO) 3 P X CH 2 C CH R 1 CH 2 C CH R 1 CH 2 R 1 (EtO) 2 P O CH 2 C CH R 1 R 1 = H, Me X X (EtO) 2 P O CH 2 C CH
Preparation of pure E-diethyl 2-formylvinylphosphonate 45 in 52% yield involved the oxidation with pyridinium chlorochromate (PCC) in CH 2 Cl 2 at room temperature of diethoxyphosphinylallyl alcohol 47, which was prepared from the diethyl 2,3-epoxyprop-1-ylphosphonate 46. Compound 46 underwent ring opening at 0°C with sodium methoxide in methanol followed by treatment with Dowex (H + ) resin to give the crude allylic alcohol in quantitative yield (Fig. 20). 56 Fig. 20. Synthesis of E-diethyl 2-formylvinylphosphonate 56 .

Very recently the preparation of diethyl 3,3-diethoxy-2-hydroxypropylphosphonate 48 was reported with 38% yield through the condensation of lithium diethylphosphite with D-glycidaldehyde diethyl acetal at -80°C in THF in the presence of BF 3 . Et 2 O (Fig. 21). Deprotection of the aldehyde was accomplished with 0.1M HCl at 40°C to give 49. 57,58 Fig. 21. Synthesis of diethyl 2-formylphosphonate by epoxide ring opening 57 .

1) 2 PCl 5 2) SO 2 2 R 2 ONa Et 2 O R 1 = Et, n-Pr R 2 = Me, Et, n-Pr, n-Bu 4 0 4 1 Cl 2 P O CH OR 1 Cl (R 2 O) 2 P O CH CH CH OR 1 OR 2 CH 2 OR 1 CH CH CH 2 CH 56-82% (EtO) 2 P O CH CH CH(OEt) 2 (EtO) 2 P O CH(OEt) 2 H 2 , Pd, CaCO 3 HCO 2 H HCO 2 H (EtO) 2 P O C C C H (EtO) 2 P O C C CHO O 4 2 4 3 4 4 4 5 H H C C 60% 60% (EtO) 2 P O (EtO) 2 P O C C CHO H H (EtO) 2 P O C C CH 2 OH H H CH 2 CH CH 2 O 4 5 4 7 4 6 1) MeONa/MeOH 2) Dowex (H + ) PCC CH 2 Cl 2 , r.t. 52% (EtO) 2 P O C CH(OEt) 2 (EtO) 2 P CH 2 O H O CH(OEt) 2 H OH (EtO) 2 P O C C O H CH 2 OH 0.1M HCl 4 8 4 9
1) n-BuLi, Et 2 O.BF 32)

H H

The method of converting vinyl to carbonyl groups by reductive ozonolysis has received much attention and has been applied with success to a variety of phosphonates containing homoallyl groups, including α-functionalized phosphonates. [59][60][61] The homoallyl group is often introduced by condensation of allylbromide with diethyl 1-lithioalkylphosphonates. 60,61 For instance, a convenient preparation of 52 (Fig. 22) was achieved by ozonolysis of diethyl 1-allyl-1,1-difluoromethylphosphonate 51, which itself was prepared in 64% yield from 50 after treatment of diethyl difluoromethylphosphorylcadmium bromide intermediate with allyl bromide. 62 Fig. 22. Synthesis of diethyl 1,1-difluoro-2-formylethylphosphonate by reductive ozonolysis 62 .

Lactols have appeared as effective precursors in the synthesis of phosphorylated aldehydes. They have been utilized as starting materials for the conversion of phosphorylated 1,2-glycols to corresponding aldehydes via an oxidation with NaIO 4 in basic medium (Malaprade reaction). The lactol oxidative opening provided the diethyl 2-formyl-2-(hydroxymethyl)ethylphosphonate, which eliminated water during purification by chromatography on silica to produce diethyl 2-methylene-2-formylethylphosphonate. 63 A reaction of significant synthetic importance for the generation of dialkyl 2-formylethylphosphonates 36 (R 1 =H) is the addition of trivalent phosphorus reagents to α,β-unsaturated aldehydes. [START_REF] Engel | Synthesis of Carbon-Phosphorus Bonds[END_REF] This Michael / Michaelis-Arbuzov strategy (Fig. 23) is the method of choice for incorporating substituents at any position between the phosphoryl and formyl groups. Addition was observed to occur under quite mild conditions in a conjugate manner with a wide range of Michael type substrates. 53,[START_REF] Kamai | [END_REF] The reaction of (EtO) 3 P with α,β-unsaturated aldehydes in the presence of a proton source was first investigated. The use of a protic solvent such as an alcohol or a phenol provides not only a source of a proton for the anionic site of the zwitterionic adduct, but also a nucleophile for the required dealkylation step. Further efforts demonstrated that better yields were obtained using phenol (82% with crotonaldehyde) rather than simple alcohols. 66 Besides alcohol or phenol, a variety of associated reagents including dialkyl chlorophosphates 67 and silyl halides 68 have also been added as a trap in the reaction medium. Frequently, the use of these different reagent systems gave conjugate addition products. [START_REF] Engel | Synthesis of Carbon-Phosphorus Bonds[END_REF] In recent years, some striking developments with conjugate addition reactions have been accomplished using either phosphorus reagents bearing silyl ester

(EtO) 2 P O C 1) Cd, 65°C,THF (EtO) 2 P O CH 2 C O H C BrCH 2 CH CH 2 (EtO) 2 P O C CH 2 CH CH 2 O 3 F F F F F F 5 1 5 2 5 0 2) MeOH CH 2 Cl 2 Br (EtO) 3 P + EtOH EtO -EtOEt CH C O CH (EtO) 3 P + CH 2 C H O CH (EtO) 3 P + CH 2 C H O CH (EtO) 2 P O R R R R = Me, Ph H CH CH C O H R
linkages such as X 2 POSiR 3 or X 2 POR and R 3 SiCl. Reactions with α,β-unsaturated aldehydes were carried out with 1 equivalent of each reagent either neat or in a solvent at ambient temperature (Fig. 24). A comparison of different reagents reveals that the reaction of acrolein, methacrolein and cinnamaldehyde proceeds quite readily, but with some complications. Although in certain instances low yield of conjugate addition products can be isolated, the major product formed is the product of addition at the carbonyl carbon (Abramov product). 68 The conjugate addition has been observed in the reaction of arylmethylenemalonaldehydes with trimethylphosphite. The reaction proceeds via an unstable intermediate, whose existence has been proven on the basis of spectral and chemical evidence, and which is easily hydrolysed to give a phosphonomethylenemalonaldehyde. 69 Full utilization of α,β-unsaturated aldehydes is often handicapped by the complications reported above. These disadvantages are overcome when the unprotected α,β-unsaturated aldehyde is replaced with an aldimine 53, which is activated as an imminium salt (Fig. 25). (EtO) 3 P does not react with aldimines in ethanol. By contrast, the addition of 1 equivalent of HCO 2 H to the mixture (EtO) 3 P/EtOH/aldimine induces an exothermic reaction resulting in the exclusive formation of 54. Undoubtedly, the 1,4-addition of (EtO) 3 P is promoted by initial protonation at nitrogen thus activating the double bond (Michael addition) and generating the formate for the dealkylating step (MA reaction). The dialkyl-substituted formylphosphonates 55 are obtained by hydrolysis of the imine function with 6M HCl or 1M oxalic acid. The method provides a ready and convenient access to a broad range of substituted diethyl 2formylalkylphosphonates 55 in satisfactory yields (45-80%). 70 2.4. n=3.

CH CH 3 + (RO) 3 P Me 3 SiCl CH C H OSiMe 3 CH (RO) 2 P CH 3 O CH CHO (EtO) 3 P/EtOH R 1 R 2 R 3 N t-Bu -HCO 2 Et (EtO) 2 P R 2 R 3 N t-Bu R 1 O (EtO) 2 P R 2 R 3 R 1 O O H 6M HCl R 1 R 2 R 3 CHO (EtO) 3 P R 2 R 3 N t-Bu R 1 + HCO 2 H 5 3 5 4 5 5 HCO 2 H EtOH t-BuNH 2 or (CO 2 H) 2 45-80% R 1 =Me, Et, n-Pr, n-Bu, Ph R 2 =H, Me R 3 =H, Me, Et, n-Pr, n-Pent, n-Hex
The MA reaction for the synthesis of diethyl 3-formylpropylphosphonate has been realized from 4bromobutyraldehyde diethyl acetal and 2-(3-bromopropyl)-1,3-dioxolane (Fig. 26). The latter reacts with (EtO) 3 P at 110°C for 10h to give the cyclic acetal 56 in 83% yield. Hydrolysis of acetal with 0.35M HCl in dioxane at 100°C for 2h produces the diethyl 3-formylpropylphosphonate 57 in nearly quantitative yield. 18a Fig. 26. Synthesis of diethyl 3-formylpropylphosphonate via the MA reaction 18a .

Since the double bond is an ideal precursor for the generation of a cyclopropyl ring an attractive procedure involving the addition of the carbenoid followed by transformation of an ester group into an aldehyde has been developed (Fig. 27). For example, the CuSO 4 -induced addition of ethyl diazoacetate to diethyl allylphosphonate in cyclohexane at reflux produced diethyl cyclopropylmethylphosphonate 58 in 30% yield as a 1:3 mixture of cis-and trans-isomers. The ester was hydrolysed to the acid which was treated with borane to give the alcohol 59. Subsequent oxidation of the intermediate 59, using PCC, afforded the aldehyde 60 in 83-86% yields respectively. 71 The method has been extended (vide infra) to the preparation of higher analogs (n=4 and 5). 71 Fig. 27. Synthesis of diethyl 3-formylalkylphosphonate via addition of carbenoid to allylphosphonate 71 . Unsaturated 3-formylphosphonates have been obtained by a MA reaction using 1,1-diethoxy-4-bromo-2-butene 72a or 1-acetoxy-4-chloro-2-butene 72b,c as masked formyl group (Fig. 28). The former reacts with (EtO) 3 P at 135°C to give the diethyl 4,4-diethoxy-2-butenylphosphonate in 50% yield; deprotection was accomplished in 98% using a cold-saturated aqueous solution of tartaric acid. 72a The latter reacts with (EtO) 3 P or (i-PrO) 3 P at 125-140°C in the presence of catalytic amount of NaI to give the corresponding phosphoryl acetates 61 in 81% (R=Et) and 54% (R=i-Pr) with E:Z=90:10 in both cases. By refluxing 61 for 20h in ethanol or methanol with a catalytic amount of p-toluenesulfonic acid, the alcohols 62 were smoothly obtained in almost quantitative yield (95-97%) E:Z=90:10. The Jones reagent proved to be the best reagent (65-68% yield) for the oxidation of the alcohols 62 to the aldehydes 63. The dialkyl 3-formylallylphosphonates 63 are reasonably stable if stored under argon at -20°C. 72c Preparation of diethyl 3-formyl-2-methyl-allylphosphonate 64 is an example of the above process using the 1-bromo-2-methyl- By contrast, the 3-formyl-3-methyl-allylphosphonate 67 was prepared from diethyl crotylphosphonate 65, incorporating the formyl group by a carbanionic route (Fig. 29). Compound 65, on treatment with 3 equivalents of LDA, underwent successively silylation with TMSCl and formylation with HCO 2 Et to give the oxoanion 66, which after acid hydrolysis lead exclusively to the E-diethyl 3-formyl-3-methyl-allylphosphonate 67 in 78% yield. 73 Fig. 29. Synthesis of diethyl 3-formyl-3-methyl-allylphosphonate 73 .

The synthetically useful diethyl 2-oxopropylphosphonate 68 is known to give a stable dianion 69 at ambient temperature. In the presence of 2 equivalents of LDA this dianion was smoothly reacted at low temperature with HCO 2 Et to provide a stabilized bis-enolate 70, which was soluble in water. Acidification with 4M HCl produced the diethyl 3-formyl-2-oxo-propylphosphonates 71 in high yields (81-89%). This "one-pot" procedure offers a short and efficient means for obtaining a variety of compounds from readily available starting materials 68 (Fig. 30). 74 Recently, another preparation of 71 (R 1 =R 2 =H) was reported and involves a multi-step route using diethyl 2-oxo-propylphosphonate 68 (R 1 =R 2 =H) as starting material.

78%

Fig. 30. Synthesis of diethyl 3-formyl-2-oxo-propylphosphonate 74 .

The ring opening reaction of D-glycidaldehyde diethyl acetal at -80°C in THF by the diethyl 1-lithiomethylphosphonate in the presence of boron trifluoride etherate provided a convenient preparation of diethyl 4,4-diethoxy-3-hydroxybutylphosphonate 72 in 78% yield. Unmasking of the aldehyde functionality was accomplished using 0.1M HCl at 40°C to give the diethyl 3-hydroxy-3-formylpropyl-phosphonate 73 (Fig. 31). 57,76 Fig. 31. Synthesis of diethyl 3-hydroxy-3-formylpropylphosphonate by epoxide ring opening 57 .

An attractive application of the oxidative cleavage of phosphorylated 1,2-glycols 75 with sodium metaperiodate (Malaprade reaction) has been demonstrated in the synthesis of diethyl 3formylalkylphosphonates 76 (Fig. 32). It was accomplished on preparative scale using the 1,2:5,6-di-Oisopropylidene-α-D-glucofuranose 74. This mild method is advantageous and the resulting aldehyde was obtained in almost quantitative yield. 77 Fig. 32. Synthesis of diethyl 3-formylphosphonate 76 by oxidation of 1,2-glycols 77 . Several variations on the preparation of phenylphosphonates containing a formyl group in the γ-position have been reported. They are based on the phosphorylation, via Michaelis-Arbuzov or Michaelis-Becker reactions, of aromatic substrates 77 containing a protected primary alcohol (Fig. 33). Further oxidation of the alcohol into aldehyde 78 was accomplished under a wide range of conditions using activated MnO 2 in CHCl 3 at room temperature (53%), 78 PCC in CH 2 Cl 2 (83-86%) 71 or the Swern reaction (>95%). 79 Fig. 33. Synthesis of diethyl 3-formylphosphonate by primary alcohol oxidation 78 .

(EtO) 2 P R 2 O R 1 O (EtO) 2 P R 2 O R 1 O M (EtO) 2 P R 2 O R 1 O M' M O M' H (EtO) 2 P R 2 O R 1 O O H H (EtO) 2 P R 2 O R 1 O O H 1) NaH, 20°C, THF 2) 2 LDA, 0°C, THF HCO 2 Et -70°C to 0°C 4M HCl R 1 = H, Me R 2 = H,
The preparation of the configurationally unstable diethyl 3-(S)-tert-butoxycarbonylamino-3formylpropyl-phosphonate has also been reported, and involves reduction of a methyl ester group with DIBAL-H in toluene at -78°C. 80 An interesting procedure for the preparation of arylphosphonates bearing a formyl group is the phosphate-phosphonate rearrangement of the protected phosphorylated 4-hydroxybenzyl alcohol 79. On treatment with LDA in THF at -78°C, compound 79 underwent an o-metallation with spontaneous migration of the phosphoryl group to give the phenylphosphonate 80 in 77% yield. Subsequent benzylation of the phenolic OH and desilylation afforded 81, which was oxidized with activated MnO 2 in THF at room temperature to give the dimethyl m-formylphenylphosphonate 82 in 96% yield (Fig. 34). 81 Fig. 34. Synthesis of dimethyl 3-formylphosphonate by phosphate-phosphonate rearrangement 81 .

An efficient synthesis of a variety of arylmethylphosphonates bearing electron-withdrawing groups (CO 2 Et, CN, SO 2 Me) at the α-carbon and a formyl group on the aromatic ring has been reported. They were prepared by treatment of diethylphosphoryl-stabilized carbanions with aryl halides in DMF or HMPA in the presence of CuI at 100°C for 5h. In the case of protected o-formyliodobenzene, the coupling reaction with the sodium derivative of triethyl phosphonocarboxylate gave, after acid work-up, the corresponding diethyl oformylbenzylphosphonate in 75% yield. 82 2.5. n=4.

96%

aldehyde functionality, as demonstrated by experiments involving (EtO) 3 P and bromoaldehydes 83. At 100-110°C, the MA reaction provided the diethyl 4-formylalkylphosphonate 84 (m=1). However, the yields were much lower for the cis-cyclopropylaldehydes compared to those of the trans isomers (27% versus 62%).

Presumably, this can be attributed to unwanted condensation with the cis-disposed aldehyde group (Fig. 35). 71 The reaction has been extended to the preparation of 84 (m=2) with comparable results (12 and 58%). 71 Fig. 35. Synthesis of diethyl 4-formylalkylphosphonate from unmasked aldehydes 71 .

In search for a flexible route to a wide range of variously substituted arylidene cyclopropanes, the carbene derived by metallic copper-induced decomposition of diethyl diazomethylphosphonate was added to an unsaturated acetal to give the diethyl 2-(3,3-dialkoxy-2,2-dimethylpropyl)cyclopropylphosphonate in 53-73% yields. It was found that cuprous trifluoromethanesulfonate was a particularly effective catalyst for this reaction. 191 The second reaction has been observed with lactones which have been shown to be useful in several synthetic schemes. The reaction is phosphorus reagent dependent. When submitted to diethyl 1-lithiomethylphosphonate, the γ-lactone 85 underwent a ring opening reaction to give an hydroxyphosphonate 86 retaining the carbonyl group in β-position to phosphorus (Fig. 36). Subsequent Swern oxidation of the hydroxyphosphonate 86 provided the diethyl 4-formyl-2-oxobutylphosphonate 87. 84 Fig. 36. Synthesis of diethyl 4-formyl-2-oxobutylphosphonates from γ-lactones 84 .

By contrast, reduction of the lactone to the lactol followed by reaction with the sodium derivative of tetraethyl methylenediphosphonate gives an hydroxyphosphonate 88 containing a double bond α,β to phosphorus. Catalytic hydrogenation of the double bond followed by Swern oxidation of the hydroxyphosphonate 89 lead to the aldehyde 90 (Fig. 37). The alcohol 89 was also oxidized using SO 3 . Py complex in DMSO and NEt 3 . This procedure allows the use of higher temperatures than the Swern protocol and provide the aldehyde in good yield. Thus lactones appear to be valuable synthetic intermediates wellsuited to the preparation of a variety of phosphorylated aldehydes. 85 Fig. 37. Synthesis of diethyl 4-formylalkylphosphonate from γ-lactones 85 .

A quite similar process was used in the preparation of phosphonic acid analogs of pyridoxal phosphate (Fig. 38). The sodium derivative of tetraethyl methylenediphosphonate was condensed with α 4 ,3-Oisopropylidene-isopyridoxal 91 to give diethyl α 4 ,3-O-isopropylidene-α 5 -pyridoxylidenemethylphosphonate 92 in yields up to 65%. Selective acid hydrolysis with 10% HCO 2 H at reflux gave the key intermediate diethyl

O 98% 65%

The Michael addition, using an activated vinylphosphonate 94 and the magnesium derivative of the 2-(2-bromoethyl)-1,3-dioxolane, has been found to be a good method for chain-lengthening of formylphosphonates (Fig. 39). Unmasking of the aldehyde functionality produced 95. 88 Fig. 39. Synthesis of dimethyl 4-formylalkylphosphonate via Michael addition 88 .

Two routes to diethyl 4-formylalkylphosphonates from 1,2-glycols and lactols demonstrated once more the importance of these substrates. The first route provided diethyl 4-formylalkylphosphonates in almost quantitative yield (98%) from the mild oxidation of phosphorylated 1,2-didesoxy-3,4:5,6-di-O-isopropyliden-D-arabinose with NaIO 4 at 0°C in H 2 O or in a H 2 O/EtOH mixture. 89 In the second route, diethyl 4formylalkylphosphonates were obtained by opening of the unprotected 5-phosphorylated-D-ribofuranose with EtSH in HCl to give a dithioacetal. Subsequent acetylation followed by removal of the thioethyl groups generated the aldehyde. 90 The aromatic version of the MA reaction between (i-PrO) 3 P and p-bromobenzaldehyde at 160°C, catalyzed by NiCl 2 , afforded the diisopropyl p-formylphenylphosphonate in 54% yield. The reaction has been extensively studied and it has been shown that electron-donor substituents facilitate reaction, while electronacceptor substituents make reaction with P(III) compounds more difficult, regardless of their position in the aromatic nucleus. 189 Several other preparative procedures have been reported including the phosphorylation of aromatic substrates containing a free formyl group, a protected formyl group or a potential formyl group. The first procedure was used for the preparation of diethyl 4-or 6-methoxy-3-formylbenzylphosphonates in 83 and 74% yields by a MA reaction between (EtO) 3 P and corresponding methoxyformylbenzyl chlorides at 170-180°C. 83 The second procedure used the Pd(PPh 3 ) 4 -catalyzed coupling reaction between diethylphosphite and mbromobenzaldehyde protected as 1,3-dioxolane with ethylene glycol. 91 In the third procedure the phosphorylation of substrates was achieved according to a Michaelis-Arbuzov or a Michaelis-Becker reaction, followed by generation of the formyl group. The latter operation is usually based on typical formylation reaction using HCO 2 Et in basic medium 92 or by oxidation of benzylic bromide for example. 93 A single case of generation of aldehyde group by hydrolysis of a dibromomethylthiophene with diluted H 2 SO 4 in dioxane at reflux for 1.5h in 95% yield was recently reported. 186 Under the modified Heck reaction conditions (Ag 2 CO 3 / Pd(OAc) 2 / PPh 3 ), the coupling of diethyl (Z)-2-iodovinylphosphonate with acrolein in MeCN at room temperature for 24h afforded the diethyl (1Z, 3E)dienylphosphonate with high stereoselectivity in 94% yield. 94 2.6. n=5 to 9

The previously reported preparation of diethyl 4-formylalkylphosphonates 84 (m=1) from unprotected aldehyde functionality (Fig. 35) has been extended to provide one of the few known methods for the transformation of a bromo aldehydes moiety to the corresponding diethyl 5-formylalkylphosphonates 84 (m=2). 71 By a similar procedure to that described for n=3, the copper-mediated coupling reaction of diethylphosphoryl stabilized carbanions with aryl halides was applied to protected p-formyliodobenzene to produce diethyl p-formylbenzylphosphonate in 68% yield. 82 Most of the diethyl 5-and 6-formylalkylphosphonates containing an o-substituted aromatic ring with a masked aldehyde group were obtained by direct displacement of an alkyl halide or mesylate by a Michaelis-Becker reaction. For example, the masked aldehyde group was introduced on 2-methylbenzyl alcohol 96 by treatment with n-BuLi and alkylation of the resulting carbanion for 48h by 2-(2-bromoethyl)-1,3-dioxolane (18%) or bromoacetaldehyde dimethylacetal (8.41%). The benzylic alcohols 97 were mesylated and displaced with sodium diethylphosphite to introduce the phosphoryl group (83% and 51%). The aldehydes 98 were unmasked by treatment with a 1:1 THF / 3M HCl at 25°C for 5h (93% and 100%) (Fig. 40). 93 Fig. 40. Synthesis of diethyl 5-and 6-formylalkylphosphonates.

An interesting gap has been realized with the use of α-hydroxyphosphonates, as illustrated by the synthesis of 102 (Fig. 41). Treatment of terephthalaldehyde, containing monoprotected aldehyde function, with the readily acid labile di-tert-butylphosphite (Pudovik reaction) in the presence of basic alumina oxide has allowed the facile synthesis of the α-hydroxyphosphonate 99. Radical deoxygenation of the secondary alcohol 99 was achieved in a two step process through the intermediacy of xanthate 100 with n-Bu 3 SnH to provide 101.

The diethyl acetal was converted to 102 (29%) by further treatment with CHCl 3 saturated with 1M HCl. 95 Fig. 41. Synthesis of di-tert-butyl 5-formylalkylphosphonate from α-hydroxyphosphonate 95 .

OH

toluene, 110°C 29%

Readily accessible diethyl 2-oxo-3-alkenylphosphonates 103 are effective heterodienes in the Diels-Alder reaction. Cycloaddition reactions with vinyl ethers in benzene in a sealed tube at 85°C or above 130°C gave satisfactory yields (57-88%) of dihydro-2H-pyrans 104. All these reactions were regioselective, however, the stereoselectivity was poor. The isolated products were always the mixture of 2,4-trans-and 2,4-cisisomers. The hemiacetal moiety of 104 was readily hydrolysed when treated with 4M HCl in THF to provide diethyl 5-formyl-2-oxo-pentylphosphonates 105 in excellent yields (72-92%) (Fig. 42). It was found that aldehydes 105 (R 1 =R 2 =H) underwent smooth cyclisation leading to diethyl 2-oxocyclohexenephosphonate 106. 96 Fig. 42. Synthesis of diethyl 5-formyl-2-oxo-pentylphosphonate from 2-oxo-propylphosphonate 96 .

A recently introduced method is the ring opening reaction by oxygen of furans 107 bearing a diethyl ethyl-or propylphosphonate moiety in position 2 (Fig. 43). The reaction occurred in methanol at 0°C under irradiation followed by reaction with dimethyl sulphide thus providing the corresponding diethyl 5-formyl-3-oxo-pent-4-enylphosphonate 108 and 6-formyl-4-oxo-hex-5-enylphosphonate 109. By reduction of the double bond compounds 108 and 109 were converted to diethyl 5-formyl-3-oxopentylphosphonate 110 and 6formyl-4-oxo-hexylphosphonate 111 in excellent yield (92-96%). 97 Fig. 43. Synthesis of diethyl 5-or 6-formyl-3 or 4-oxo-alkylphosphonates 97 .

In a series of experiments, it has been found that the ene reactions of trimethyl phosphonoacrylate with alkenes was catalyzed by EtAlCl 2 and occurred at 25°C (Fig. 44). Lewis acid catalysis offers significant advantages over the corresponding thermal ene reactions that occur at 200-300°C. This property has been applied with success to the synthesis of dimethyl 6-formylalkylphosphonates 114. Reaction of the alcohol 112 with trimethyl 2-phosphono-acrylate in CH 2 Cl 2 at 0°C for 1h gave the ene adduct 113 in 40% yield. Oxidation of 113 with pyridinium dichromate (PDC) gave the dimethyl 6-formylalkylphosphonate 114 in 68% yield, which can undergo an intramolecular HWE reaction. 98

R 2 R 1 O (EtO) 2 P O O P(OEt) 2 R 3 O R 2 R 1 O OR 3 OHC P(OEt) 2 R 1 R 2 O O O P(OEt) 2 O 4M HCl r.t., THF silica gel R 1 = R 2 = H 1 0 3 1 0 4 1 0 5 1 0 6 (EtO) 2 P O O (EtO) 2 P OH O R 1 R 2 O 1) NaH, n-BuLi, THF 2) R 1 COR 2 MeSO 2 Cl Et 3 N 72-92% O P(OEt) 2 O H O O H O 1) O 2 , MeOH, Rose Bengal, h ν 2) DMS ( ) m O P(OEt) 2 ( ) m O P(OEt) 2 ( ) m O NaI, HCl, acetone, H 2 O 1 1 0 , m=2, 92% 1 1 1 , m=3, 96% 1 0 7 1 0 8 , m=2 1 0 9 , m=3
Fig. 44. Synthesis of dimethyl 6-formylalkylphosphonate via ene reaction 98 .

The palladium-catalyzed arylation of diethyl vinylphosphonate with p-bromobenzaldehyde (MeCN, 100°C, 4h) afforded diethyl p-formylstyrylphosphonate in 60% yield. 99 Once more the methodology using lactones has been developed with success. The mixed anhydride 115, stemming from the opening of a δ-lactone, was treated, after suitable protection, with diethyl α-cupromethylphosphonate to produce the β-ketophosphonate 116 in good yield (69%). Finally, the ozonolysis of 116 gave the diethyl 7-formylalkylphosphonate 117 in high yield (Fig. 45). 100 Fig. 45. Synthesis of diethyl 7-formylmethylphosphonate from δ-lactone 100 .

Similarly, a lactam was submitted to a ring opening reaction using dimethyl 1-lithiomethylphosphonate in THF at -78°C. On work-up, the N-methyl imine generated the dimethyl 6-formylalkylphosphonate, which in turn gave perhydroazulenone on treatment with tert-BuOK/tert-BuOH. 162 In an approach to the central eight-membered ring of ceroplastol I, the use of an intramolecular HWE reaction was explored starting from a diethyl 7-formylalkylphosphonate. This C 7 aldehyde, protected as a 1,3dioxolane, was obtained in 20% yield as a 1:1 mixture of keto acetals by Michael addition in THF at -78°C of an alkenyllithium to the 2-(diethoxyphosphinyl)cyclopentenone. Hydrolysis of the acetal in refluxing acetone/H 2 O, TsOH afforded 89% of the desired phosphorylated keto / aldehyde. 101 Phosphonates containing an aldehyde group at C 9 are important intermediates have been employed in the incorporation of a C 1 -C 9 fragment into macrolide antibiotics (pikronolide, 102 carbonolide B, 103 erythromycin A 104 ). They were prepared by treatment of a C 7 dialdehyde, protected at one extremity (double bond or tert-butyldimethylsilyl (TBS) ether), with the dimethyl 1-lithiomethylphosphonate at -80°C in THF, which gave the β-hydroxyphosphonates in 74-79% yield. Subsequent oxidation (PDC/DMF 102 or TPAP/NMO/CH 2 Cl 2 103,104 ) produced the corresponding β-ketophosphonate in excellent overall yield. Generation of the terminal aldehyde at C 9 was performed by oxidation of the primary alcohol with TPAP/NMO 103 or of the double bond with OsO 4 /NMO/acetone followed by cleavage with NaIO

(OEt) 2 O O O OSEM P(OEt) 2 O O 3 1 1 6 1 1 7 1 1 5 H + SEM=2-(trimethylsilyl)ethoxymethyl- 69%
The phosphorylated aldehydes reported in the previous sections can participate, as reagents or substrates, in several useful synthetic schemes including HWE reaction, Strecker and related reactions, reductive amination and formation of heterocycles. By contrast, the phosphorylated aldehydes 118 described in the present section are almost exclusively prepared to achieve formation of macrocycles 119 (11-to 17-membered carbon chain) via an intramolecular HWE reaction (Fig. 46). This widely used cyclisation step represents the best way for preparing macrocyclization products.

The phosphonate group is frequently incorporated at one extremity of the chain using a carbanionic approach. The more widely used method involves the displacement of halogenated derivatives with phosphoryl stabilized carbanions (Z=CN, CO 2 R, COR). [105][106][107][108][109] The others are accomplished by displacement of chlorine from diethyl chlorophosphate with lithiated functional derivatives, 110 or by treatment of a carboxylate with the lithium derivative of a dialkyl methylphosphonate. 111,112,163 At the other extremity of the chain oxidation of a primary alcohol generates the aldehyde group.

REACTIONS OF PHOSPHORYLATED ALDEHYDES

As a consequence of their ready accessibility coupled with their versatile chemical properties, phosphorylated aldehydes represent now an important class of compounds in organic and organophosphorus chemistry. As synthetic intermediates, these compounds owe their interest to the presence in the same molecule of a phosphoryl and a formyl group which govern their chemical reactivity. The purpose of this section is to provide a general overview of the important synthetic reactions which have been designed and developed from phosphorylated aldehydes.

Reactions of the carbonyl group

Several properties of the formyl group have been demonstrated in the past. For instance, the reaction of phosphorylated acetals with diols yielded phosphorylated 1,3-dioxolanes, 113 1,3-dioxans, 114 and polymethylene acetals. 115 The reaction is carried out by heating equimolar amounts of the reactants with simultaneous distillation of the alcohol liberated. The reduction of phosphorylated aldehydes over a platinum catalyst 42a or by sodium borohydride 116 leads to the corresponding hydroxy derivatives in high yields. Phosphorylated aldehydes are oxidized by peracids 117 or by alkaline potassium permanganate 118 to the corresponding phosphorylated carboxylic acids. The dimethylhydrazones of 4 are known and prepared at room temperature in 40-98% yields. 195 At 110°C, p-toluenesulfonamide adds to 6 to give an adduct which eliminates ethanol when strongly heated to give in 68-80% yields the corresponding phosphorylated vinylsulfonamide, also available from p-toluenesulfonamide and 4. 119 The aldolase-catalysed reaction of 4 with dihydroxyacetone phosphate (DHAP) gives a diphosphorylated sugar in 90% yield. 193 In chloroform solution phosphorylated

CH 2 O CH 2 -I 2) base (R 2 O) 2 P CH 2 -Z O 1) CH 2 O CH 2 -CH-P(OR 2 ) 2 O Z CH CH 2 Z CH 2 -CH-P(OR 2 ) 2 O Z 1) deprotection 2) oxidation Z = CN, CO 2 R, COR R 1 = protecting group R 2 = Me, Et R 1 R 1 C H O 1 1 8 1 1 9
acetaldehydes are in equilibrium with the enol form and when treated with HNO 2 they afford the nitrosoenols, which are dimeric in aqueous solution. 120,121 Although the phosphorylated acetaldehydes condense with sodium derivatives of nitroalkanes to give mainly the phosphonylnitroalcohols, there is also detectable a second sequence, leading to a dienol. 122 Because of the resultant tautomerism, the course and end-point of the reaction between phosphonylacetaldehydes and active methylene compounds (acetylacetone, cyanoacetic ester, dimedone) can vary. For acidic active-methylene compounds, further reaction with the initial condensation product can occur. The final position of tautomeric equilibrium depends on the nature of the dicarbonyl compound and of the substituents on phosphorus. 123 Diethyl 1-formylmethylphosphonate 4 reacts with n-BuLi at low temperature in THF to give a lithium enolate. By contrast, the reaction of 4 with n-BuLi or Zn(OCOMe) 2 at room temperature for several days preferentialy yields the metal complexes of the diphosphorylated butadienolate or the free E-enol via aldol condensation (Fig. 47). 124 The self-condensation of 4 in basic media has been the subject of several reports. 192 The transformation of diethyl 1-formyl-or 1-alkyl-1-formylmethylphosphonates (4 or 19) into diethyl 2-oxoalkylphosphonates via diethyl 2-dialkylaminovinylphosphonates has been reported with moderate to good yields (22-85%). 125 Starting with diethyl 1-formylalkylphosphonates, the synthetically attractive trans-2,3-epoxy-4oxoalkyl-phosphonates are easily available by two methods. The first method employs the Wittig reaction of diethyl 1-formylalkylphosphonates 4, 19 or 29 with 2-oxoalkylidene-triphenylphosphoranes and subsequent epoxidation of the resulting E-4-oxo-2-alkenyl derivatives with H 2 O 2 / Na 2 CO 3 in MeOH. 126a The second procedure involves the Sn(OTf) 2 -mediated aldol reaction of 4, 19 or 29 with bromomethylketones and subsequent cyclization of the bromohydrins. These epoxides are readily isomerized into 2,4-dioxoalkylphosphonates (49 to 81%) on heating in toluene in the presence of catalytic amounts of Pd(PPh 3 ) 4 and 1,2-bis(diphenylphosphino)ethane (dppe). 126b

Preparation and reactions of diethyl chloroformyl-and dichloroformylmethyl-phosphonates

Reaction of dialkyl 1-formylmethylphosphonates 120 with Cl 2 /CCl 4 results in formation of either chloromethyl 121 or dichloromethyl 122 derivatives (Fig. 48). Several variations on the preparation of these two compounds have been reported. It was shown that chlorination at the α-CH bond of dialkyl 1-formylmethylphosphonates with Cl 2 was selective and temperature dependent, namely: a) in CCl 4 between -10 and -15°C the monochlorinated aldehydes were formed in 70-80% (appearance of a yellow colour indicates the completion of monochlorination), while b) raising the temperature to 0°C resulted in dichlorination (80-90%). Raising the temperature to r.t. can lead to the cleavage of the P-C bond under the action of HCl with the formation of phosphorochloridates. Full utilization of gaseous chlorine being handicapped by the sensitivity of the P-C bond in acid medium, an alternative procedure for the preparation of 121 in 90% yield is the chlorination of 2-ethoxyvinylphosphonates 6 in CCl 4 at r.t. followed by hydrolysis. 127 Preparation of

(EtO) 2 P O (EtO) 2 P O O H H Li O P X O EtO EtO X = Li, Zn
compound 121 has also been accomplished in high yield by reaction between the dialkyl 1-lithio-1chloromethylphosphonates and HCO 2 Et at low temperature (70-85%). 37 By carefully choosing the experimental conditions, it has been found that dialkyl 2,2-diethoxyethylphosphonates react in a similar manner with chlorine in refluxing CCl 4 to provide dichloro acetals. 127f Fig. 48. Synthesis of chloroformyl-and dichloroformylmethylphosphonates 127 .

Systematic studies on the chemistry of the chloroformyl-121 and dichloroformyl-122 methylphosphonates showed their high reactivity and extensive synthetic possibilities. For example, the nitration of 4 with acetyl nitrate gives a low yield of nitromethylphosphonate. 194 The nitrosation of 121 with HNO 2 /HCl below 0°C results in hydrolytic rupture of the C-C bond in the initially formed 1-nitroso compound, loss of the formyl group and formation of the oximes of the dialkoxyphosphinylformyl chloride in 95% yield. With increasing reaction temperature, however, loss of chlorine and formation of the α-nitroso derivative of 1formylmethylphosphonate takes over. 127e,128 The oximes react with 1,4-phenylenediamine, 4-aminoantipyrine, benzhydrazide or thiosemicarbazide as a result of nucleophilic attack by a nitrogen atom on the electrophilic carbon center of the halo oxime to give products of amino-or thiosemicarbazide-oxime structure. 129 In the presence of NEt 3 , these oximes can serve as a source of nitrile oxide, which easily enter into dipolar cycloaddition with terminal acetylenes at 20°C to give 3-phosphorylated isoxazoles in good yields (69-94%). 18b,130 It has also been found that in the reactions between 121 and aryldiazonium salts (chlorides or tetrafluoroborates) in AcONa/H 2 O, the formyl group is split off and the corresponding arylhydrazones of 121 are formed. 131 A study of the kinetics of these reactions has been realized. 132 The arylhydrazones react with a variety of nucleophiles (NH 4 OH, R-NH 2 , N 2 H 4 . H 2 O, Na 2 S, Na 2 SO 3 , Na 2 S 2 O 3 , NaSCN, (H 2 N) 2 CS) with replacement of the halogen by the nucleophile. 133 The diethyl 1,1-dichloro-1-formylmethylphosphonate 122 readily takes part in the Abramov reaction with diethyl phosphite to form the 1,1-dichloro-2-hydroxyethyldiphosphonate in 70% yield. 127d Under the action of alcoholic solutions of alkalis or secondary amines, 122 undergoes decomposition in the manner of the haloform reaction with the formation of diethyl dichloromethylphosphonate (88% or 72%). 127d The diethyl 1,1-dichloro-1-formylmethylphosphonate 122 reacts with HC(OEt) 3 /H 2 SO 4 to give the acetal in almost quantitative yield (92%). 127c Reaction of 122 with Ph 3 P in benzene or toluene results in the formation of diethyl 1,2-dichloro-vinylphosphonate (51%). 134 The reaction of 122 with isocyanates of trivalent phosphorus compounds proceeds by a [3+2] cycloaddition reaction with formation of oxazaphospholines (72-75%). 135 With iso-PrSH, 122 forms a hemithioacetal, the trimethylsilyl derivative of which, in boiling xylene, undergoes a transposition of the (original) carbonyl group to the α-position via an epoxyphosphonate. 136

Heterocyclic systems with phosphorylated substituents

One of the most thoroughly investigated synthetic applications of phosphorylated aldehydes is the synthesis of heterocyclic compounds containing a phosphoryl group in the side chain. 137 Historically, the first attempt to synthesise the diethyl 1-formylmethylphosphonate 4 was undertaken with the aim of its subsequent 1 2 0 1 2 1 1 2 2 (RO) 2 P O employment in the synthesis of phosphorylated heterocycles. 2 In many cases phosphorylated acetals or enamines were used instead of phosphorylated aldehydes. Diethyl 1,1-diethoxymethylphosphonate has been utilized in condensation with amino, hydroxy or mercapto 1,2-disubstituted benzene derivatives to produce a series of benzoheterocyclic phosphorus compounds. The yields of benzoxazole and benzothiazole derivatives are acceptable (68% and 30%), [138][139][140] but benzimidazoles are obtained in poor yields (7%). 141 The yield of benzimidazoles has been since improved to 65% by reacting the hydrazone derivative of 121 with o-phenylenediamine in refluxing CHCl 3 for 2.5h. 142 Catechol and naphthalene-2,3-diol upon reaction with diethyl 1,1-diethoxymethylphosphonate are converted into dioxolane phosphonates in a similar manner. 143 Under Fischer indole synthesis conditions, diethyl 2,2diethoxyethyl-phosphonate 5 reacts with phenylhydrazine to afford the 2-indolylphosphonate in low yield. It has been postulated that the initially formed product is the indolyl-3-phosphonate, which rearranges to the 2derivative in the presence of an excess of ZnCl 2 . 14f,144 By a similar procedure, diethyl 1-formylmethylphosphonate 4 reacts with a variety of arylhydrazines in refluxing toluene in the presence of PPA to give the indolyl-3-phosphonates in moderate yields (35-45%). 145 A wide range of heterocycles can also be obtained by the condensation of diethyl 2,2-diethoxyethylphosphonate 5 with aromatic o-disubstituted compounds containing mobile hydrogen atoms such as o-phenylenediamine, o-aminophenol, oaminothiophenol and others. These reactions, which are common to a large class of phosphorylated acetals, were carried out by heating equimolecular amounts of reactants at 160-180°C, whereupon alcohol was evolved. The yields of benzimidazoles, benzoxazoles and benzothiazoles are commonly in the range 30-50%. [138][139][140][141] Further applications of the Fischer reaction have been demonstrated in the reaction of diethyl 2formylethylphosphonate 36 (R 1 =H) with a large number of arylhydrazine chlorohydrates in anhydrous ethanol at reflux for 2 to 12 h. The indolyl-3-methylphosphonates are isolated in variable yields from 4 to 83%. 145 The diethyl 1-chloro-1-formylmethylphosphonate 121 is also a precursor to heterocycles via the intermediacy of the phenylhydrazones. Treatment of hydrazones of 121 with benzylamine gives the N 3 -benzyl-amidrazones, which on oxidation using H 2 O 2 , KMnO 4 or Ag 2 O in biphasic medium yields the 3-phosphorylated-1,2,4-triazoles in 40-80%. 133d In a similar way, the oxime of 121 is a precursor of 3-phosphorylated isoxazoles via the nitrile oxide. 130 Enamine phosphonates bearing a functional group (CHO, COMe, COPh, CO 2 Et) in α-position 123 have been shown to undergo similar nucleophilic cyclisation reactions with compounds containing mobile hydrogen atoms, providing the basis of another synthesis of phosphorylated heterocycles (Fig. 49). The dimethylamino group of enamine phosphonates 123 can be selectively and totally transaminated by treatment with symmetrical or unsymmetrical hydrazines, guanidine, acetamidine and methylisothiourea in refluxing ethanol. The corresponding phosphorylated pyrazolones 124 (R 1 =OH, R 2 =H), pyrazoles 124a,b and pyrimidines 125a,b are isolated in excellent yield (90-95%). 35 The ethyl dialkylphosphonylformylacetates were also used as precursors of phosphorylated pyrazolones in moderate to good yields. 190 Fig. 49. Synthesis of phosphorylated pyrazoles and pyrimidines 35 .

Of special interest is the report of an efficient, one-pot procedure for the preparation of 3phosphorylated indole 127 in 88% yield using 126 (Fig. 50). The presence of a nitro group in the ortho position promotes, after reduction, a spontaneous transamination offering an easy approach to 3-phosphorylated indole derivatives. 35a The addition of tosylazide to diethyl 1-formylalkylphosphonate 4 yields the triazoline which under the reaction conditions produces the diethyl diazomethylphosphonate and the triazole, respectively, according to the nature of α-substituent. 146

Horner-Wadsworth-Emmons (HWE) reaction

The Wittig and the Horner-Wadsworth-Emmons reactions are among the most important reactions for the two carbon elongation of a carbonyl functional group to a more complex aldehyde or ketone. 150 They can be described as a general synthetic protocol for the conversion of aldehydes and ketones into α,β-unsaturated carbonyl compounds 131 (R=H or ≠H) and their derivatives. But whereas the reaction of the resonancestabilized phosphonium ylids (Wittig reaction) proceeds readily with aldehydes, the reaction with ketones is more effectively achieved using the more nucleophilic anions of phosphonate reagents (HWE reaction). 151 The first reagent for the formylolefination of ketones as well as aldehydes, diethyl 2-(cyclohexylimino)ethylphosphonate 128 was described in 1968 (Fig. 51). 23,152 The carbanion 129 is generated conveniently by treatment of 128 with NaH then coupled with a variety of aldehydes and ketones. Satisfactory results were obtained when hydrolysis of the intermediate aldimines 130 was carried out in a two-phase system. Other procedures were reported for the hydrolysis of imines such as dilute oxalic acid or acetate buffer and SiO 2 / weak acid. Several variations on the formylolefination reaction have been reported utilizing protecting reagents for aldehydes such as oxazine (Fig. 5) 25 semicarbazide 153 and 1,1-dimethylhydrazine. 154 An alternative and efficient route leading to E-α,β-unsaturated aldehydes 131 (R=H) is based upon the metallation of the N-tert-Butylacetaldimine 132 (Fig. 52). In this attractive one-pot procedure, 132 was treated with LDA and then with diethyl chlorophosphate to give the lithiated enamine phosphonate 133, thus avoiding the preparation of the phosphonate imine reagent, which required three steps from commercial materials. 155 Fig. 52. One-pot synthesis of α,β-unsaturated aldehydes 155 .

(EtO) 2 P O C CH NMe 2 R 1 O (EtO) 2 P O (EtO) 2 P O N N NH 2 R 1 H 2 N-NHR 2 (H 2 N) 2 C=NH N N R 1 (EtO) 2 P O N N R 2 R 1 (EtO) 2 P O N N Y R 1 R 2 H 2 N-NHR 2 C NH H 2 N Y R 2 = H, alkyl R 2 = alkyl, aryl R 1 = H,
In addition to the previous methods for generating E-α,β-unsaturated aldehydes 131, an advantageous one-pot preparation of α,β-unsaturated-α-substituted aldehydes 135 was reported (Fig. 53). The procedure involves the intermediacy of the lithiated α,β-enamine phosphonate 134 prepared by nucleophilic addition of diethyl α-lithioalkylphosphonates to ethyl N-phenyl-formimidate. 156 On reaction with aliphatic or aromatic aldehydes 134 produces α,β-unsaturated-α-substituted imines, which may be efficiently converted to α,βunsaturated-α-substituted aldehydes 135 by acid hydrolysis in yields ranging from 45 to 78%. 157

(EtO) 2 P C CH N O H (EtO) 2 P CH CH N O R R 1 C R 2 O (EtO) 2 P CH C O O H (EtO) 2 P C C N O R R 1 C R 2 C R CHO NaH, THF, 0°C (CO 2 H) 2 THF, r.t. Na + molecular sieves MeOH, 25°C R R 1 9 1 3 1 1 3 0 1 2 9 1 2 8 R = H or ≠ H C 6 H 11 -NH 2 R 1 C R 2 C R CH N (E) Me CH N (EtO) 2 P O R 1 C R 2 O R 1 C R 2 C H 2) (CO 2 H) 2 1) LDA, -78°C 2)( EtO) 2 P(O)Cl 1) N Li CHO 1 3 3 1 3 2 1 3 1 (E)
Fig. 53. One-pot synthesis of α,β-unsaturated-α-substituted aldehydes 157 .

Of significant synthetic importance is the intramolecular version of the HWE methodology. It has been recognized as the method of choice for preparing five-, 88 six- [158][159][160][161] and seven-162 membered ring systems as well as macrocyclic ring systems, including rings containing 11, 163 12, 105,110 14, 105-109,111 15, 112,164 16, 112 and 17 75,164 atoms. In the preparation of larger ring sizes high-dilution procedures have usually been required to achieve satisfactory yields. The use of a mild base (LiCl / DBU) or crown ether catalysis has also been shown to be of importance. As an illustration of the utility of this technique, some typical macrocyclisations providing biologically active compounds (with conditions in brackets) are given : 11-membered ring (-)bertyadionol (NaH / toluene / 42°C, 28-32%), 163 12-membered ring (+)-cleomeolide (K 2 CO 3 / 18-crown-6 / toluene / r.t., 38%), 110 12-membered ring pseudopterane and 14-membered ring furanocembrane systems (LiCl / DBU / MeCN / r.t., 50% and 42%), 105 14-membered ring (-)-asperdiol and (+)-desepoxyasperdiol (LiCl / DBU / MeCN / r.t., 61% and 30%), 106 14-membered ring (±)-methyl ceriferate-I (NaH / DME / 80°C, 24%), 107 14-membered ring anisomelic acid (LiCl / DBU / MeCN / r.t., 71%), 108 14-membered ring cembratrienediols and thunbergols (LiCl / DBU / MeCN / 40°C, 63%), 109 14-membered ring macrocyclic trienone (LiCl / DBU / MeCN / r.t., 63%), 111 15-membered ring muscone precursor (NaH / DME / high dilution, 50%), 112 17-membered ring civetone precursor (tert-BuOH / H 2 O / KHCO 3 / reflux, 56%) 164 and 17membered ring lankacidin (K 2 CO 3 / 18-crown-6 / toluene / 100°C, 37%). 75 The stereochemistry, as well as the ease of the intramolecular reaction is largely determined by the nature of the carbon chain that forms the ring. In a paper appearing in 1987 the authors concluded that "the intramolecular ketophosphonate-aldehyde condensation reaction is a most powerful method for constructing macrorings, and, therefore, it should be placed high on the list of choices for such operations when applicable". 165

Phosphonoacetaldehyde in nature

In 1972 it was demonstrated that not only phosphoenolpyruvate (PEP) is the immediate precursor of phosphonates in Tetrahymena, but that phosphonoacetaldehyde (PAAl) is a direct precursor of 2-aminoethylphosphonate (AEP) (Fig. 54). [166][167][168][169] Phosphonoalanine (PAla) is a side product in the synthesis and apparently is not directly converted to AEP. In Tetrahymena the radioactive carbon atom in phosphonoenol [3-14 C] pyruvate is incorporated into the phosphonate carbon atom in 2-aminoethylphosphonic acid (AEP) confirming that an intramolecular rearrangement of PEP takes place during the biosynthesis of AEP. The incorporation of

(EtO) 2 P CH 2 R 1 O (EtO) 2 P CHLi R 1 O (EtO) 2 P O CH R 1 C N Ph OEt Li (EtO) 2 P O CH R 1 C N Ph H (EtO) 2 P O C R 1 C N Ph H Li R 2 C H C R 1 CHO 1) R 2 CHO / 0°C 2) H 3 O + i-Pr 2 NLi -78°C,THF i-Pr 2 NLi -78°C,THF EtO-CH=N-Ph -EtOLi -78°C,THF 1 3 4 1 3 5
label into AEP is inhibited to a greater extent by PAAl than by PAla : hence the latter may not be on the main biosynthetic pathway to AEP. The phosphonopyruvate (PnPyr) initially formed by the intramolecular rearrangement of PEP is probably decarboxylated to phosphonoacetaldehyde before amination to AEP occurs and the latter is then incorporated into phosphonolipids. Since the discovery of enzymes, PEP phosphonomutases, responsible for C-P bond formation from Tetrahymena or from Streptomyces hygroscopicus, new systems have been reported. 170 Recently, another enzyme (phosphonoacetaldehyde hydrolase (phosphonatase) from Bacillus cereus), which catalyzes the dephosphonylation reaction of phosphonoacetaldehyde (PAAl) to inorganic phosphate and acetaldehyde, was highlighted. This enzymatic process involves activation of C-P bond cleavage by formation of a Schiff base between PAAl and an active site lysine in phosphonatase. 171 All these results clearly demonstrate the importance of phosphorylated aldehydes in biological processes. Fosfomycin, a clinically used antibiotic, is biosynthetically derived from a P-C 2 unit, most likely to be phosphonoacetaldehyde, and a methyl group from L-methionine (Fig. 55). As shown above for AEPA, the phosphoenolpyruvate (PEP) was suggested as the most likely precursor of carbons 1 and 2 of fosfomycin. 172 Fig. 55. Pathway for the biosynthesis of fosfomycin 172 .

Reductive amination

Since the phosphonoacetaldehyde is an ideal precursor for the generation of AEP, an attractive procedure for the preparation of 2-aminoalkylphosphonic acids 137 from 1-formylalkyl-phosphonates 4 (R 1 =H) and 19 (R 1 =Me) has been developed using reductive amination of the carbonyl in the presence of NaBH 3 CN (Fig. 56). This method appears to be fairly general and may be used for the preparation of 2aminoalkylphosphonates 136 containing primary, secondary or tertiary amino groups simply by treating the carbonyl compound at room temperature with a primary or secondary aliphatic or aromatic amine. 17a When AcONH 4 , as a source of ammonia, was subjected to this reaction it required lengthy reaction times and produced a mixture of primary aminophosphonate (7%) and iminobis(ethylphosphonate) (30%). 173 The primary aminophosphonate being considerably more nucleophilic than ammonia, the second attack upon the carbonyl group is an unavoidable competing side reaction. Finally, hydrolysis of 136 with 8M HCl followed by The reductive amination reaction has been modified for the preparation of primary aminophosphonic acids 141 (Fig. 57). It has been observed that the use of benzylamine in reaction with phosphorylated aldehydes 138 increases chemospecificity, reaction rates and yields. Aminobenzylphosphonates 139 have been isolated in 85% yield, then converted to aminophosphonates 140 by catalytic hydrogenation followed by acid hydrolysis and purification to give aminoalkylphosphonic acids 141. 174 Together with its modifications, the reductive amination is one of the most useful and general methods available for the preparation of a wide variety of aminoalkylphosphonic acids from phosphorylated aldehydes. Of synthetic importance is the preparation of AEP via the reduction of oxime of diethyl 1-formylmethylphosphonate 4. The oxime was prepared from 4 and hydroxylamine hydrochloride in EtOH / pyridine, treated with (AcO) 2 O / AcOH and reduced using 5% Pd / C / H 2 . After acid hydrolysis for 48h using HCl 6M followed by Dowex 50 (H + ) purification, AEP was isolated in 43% yield. 118 The synthesis of 1-aminoalkyldiphosphonic acids 144 from phosphorylated aldehydes 142 has also been described. The preparation is based on the thioureidoalkylphosphonate method (Fig. 58). Thus, starting from phosphorylated aldehydes 142 (m=1,2,3), N-phenylthiourea and diphenylphosphite, the corresponding thioureidoalkylphosphonates 143 were prepared in good yields in glacial AcOH. The hydrolytic degradation in a refluxing mixture of AcOH / HCl led to satisfactory overall yields (50-70%) of the 1-aminoalkyldiphosphonic acids 144. These compounds were purified by ion-exchange chromatography using acidic resin (Dowex 50). 18a

(EtO) 2 P O CH R 1 (EtO) 2 P O CH R 1 CH 2 (HO) 2 P O CH R 1 CH 2 4, R 1 = H NaBH 3 CN C H O N R 2 R 3 MeOH, HCl, 25°C 8M HCl N R 2 = R 3 = Me R 2 = H, R 3 = Me, Et, C 6 H 5 R 2 R 3 H N R 2 R 3 1 3 6 1 3 7 1 9 , R 1 = Me Amberlite IRA-410 C (CH 2 ) m (EtO) 2 P O m = 0, 1 H O CH R 1 NH (CH 2 ) m+1 (EtO) 2 P O CH R 1 NH 2 (CH 2 ) m+1 (

Aminocarboxylation (Strecker and related reactions)

Receptors for glutamic and aspartic acids 175,176 have been implicated in the pathology of several neurological and neurodegenerative illnesses, including, for example, epilepsy, cerebral ischemia, hypoglycaemia, Huntington's and Alzheimer's diseases, and Parkinsonism. The growing number of these disorders, in which excitatory amino acids (EAA) have been implicated, has resulted in considerable attention being focused on the development of compounds which antagonize excitatory amino acids neurotransmission. Compounds which act selectively and competitively at the subclass of EAA receptor selectively activated by N-methyl-D-aspartate (NMDA) have received particular attention. 177 Several amino phosphonocarboxylic acids have been characterized as being potent and selective competitive NMDA antagonists [178][179][180][181][182] (Fig. 59) and have been found to be efficacious against neuronal damage. With these considerations in mind, the Strecker and Bucherer-Bergs reactions for the synthesis of ω-amino-ω-carboxyalkylphosphonic acids have been applied to a variety of phosphorylated aldehydes. Fig. 59. Structures of some NMDA antagonists. Phosphorylated aldehydes 138 are first smoothly converted to amino nitriles 145, which are further treated with concentrated HCl to provide the amino acids 146 (Fig. 60). In this method, treatment (in the absence of light) of freshly purified phosphorylated aldehydes at room temperature in water (or MeOH/water or MeCN) with NaCN (or KCN) and NH 4 Cl (or NH 4 OH or HCO 2 NH 4 ) (or (NH 4 ) 2 CO 3 at 50-60°C in the Bucherer-Bergs reaction 79,85 ) produces selectively the amino nitriles in moderate to high yields (44-91%). 17b,71,72a,83,85,93,183 Improved yields have been reported through the use of alumina/ultrasound 71 or a modified Strecker reaction. 196 Hydrolysis of the amino nitriles 145 with 6-8M HCl at reflux delivers the crude amino acids 146, which were purified by ion-exchange chromatography using strongly acidic resin (Dowex 1 8x100). The Bucherer-Bergs route is not so efficacious because of difficulties in the hydrolysis of the hydantoin. 17b Though initially prepared and evaluated as a racemic, it was recognized that the NMDA antagonist activity was likely to reside primarily in a single enantiomer. The stereoselective nature of the NDMA receptor is well established, albeit not completely understood. Consequently, several attempts were undertaken to develop synthetic protocol which would allow to prepare optically active compounds. Early reported preparations of optically active ω-amino-ω-carboxyalkylphosphonic acids included a Strecker reaction using (S)(-)-α-methyl-benzylamine as the amination agent. However, the enantiomeric excess was only 50%. 184 Recently reported procedures, which use chemoenzymatic processes, offer a more convenient approach for the mild obtention of optically pure aminophosphonic acids. The enzymatic hydrolysis either of amide (using penicillinacylase, EC 3.5.1.11, from Escherichia coli) 83 or ester (with Subtilisin A 85 or Carlsberg esterase 185 ) groups provides a high yielding method of resolution of the racemic mixture. In the case of the hydantoin resulting from Bucherer-Bergs reaction, the resolution of two diastereomeric compounds, epimeric at the C-5 hydantoin carbon atom, was made using D-hydantoinase from Agrobacterium, in alkaline buffer. 85 Another attractive route to aminocarboxylalkylphosphonic acids involves the intermediacy of the ethyl α-azidoacetate (Fig. 61). Addition of methanolic sodium methoxide to a solution of 147 and ethyl αazidoacetate in methanol at -30°C, provides the vinyl azide 148. Hydrogenation of 148 (10% Pd/C/MeOH) gives the aminoester 149, which at reflux with 3M HCl delivers the free amino acid 150. 95b,c The copper(I) catalyzed cycloaddition of an aldehyde with ethyl isocyanoacetate 197 to form the corresponding oxazoline has also been found to be an interesting method for introducing the amino acid group. However, this procedure is not diastereoselective and the yield is moderate (33%). 198 Similarly, a promising methodology using an Horner-Wadsworth-Emmons reaction between an aldehyde and the sodium derivative of N-acyl-2-(dialkoxyphosphinyl)glycine ester has been described. 199 Unfortunately, the dehydro amino acid is obtained in poor yield. 85 By contrast, the use of diethyl 2,4dioxoimidazoline-5-phosphonate 200 and LiOH/MeOH leads to a rapid and high yielding conversion of aldehyde to dehydrohydantoin as a mixture of E-and Z-isomers.

CONCLUSION

Since their discovery in 1952, phosphorylated aldehydes have found widespread prominence in organic chemistry and their popularity emanates from their efficiency and versatility. They are functionally rich molecules very useful in organic synthesis and frequently involved in biological processes. The present review highlights three major developments of this chemistry. First, significant progress in the preparation of phosphorylated aldehydes has been achieved resulting in various new reactions to arrive at a high level of structural diversity and complexity. Second, olefination reaction based on the Horner-Wadsworth-Emmons reaction is an ever-growing area and the intramolecular version has became the most powerful tool for the construction of macrorings. Finally, the utility of phosphorylated aldehydes for the synthesis of biologically active compounds has blossomed during the last ten years. The diversity of phosphono amino acid analogues prepared attests to the wide acceptance and general utility of phosphorylated aldehydes.

ACKNOWLEDGEMENTS

In collecting the literature, the authors have benefited greatly from collaboration with Mrs Françoise Girard, who is gratefully acknowledged. We are also grateful to the Centre National de la Recherche Scientifique and Ecole Polytechnique for financial support to B.I.

Fig. 1 .

 1 Fig. 1. Dialkyl ω-formylalkylphosphonates.

  CH=CH-CH 2 , Cl(CH 2 ) 3 , Cl(CH 2 ) 4

Fig. 18 .

 18 Fig. 18. Synthesis of dialkyl 3,3-dialkoxypropenylphosphonates from alkyl allyl ethers 54 .

Fig. 23 .

 23 Fig.23. Addition of (EtO) 3 P to α,β-unsaturated aldehydes in the presence of ethanol 66a .

Fig. 24 .

 24 Fig. 24. Addition of trialkylphosphite to crotonaldehyde in the presence of Me 3 SiCl 68 .

Fig. 25 .

 25 Fig. 25. Synthesis of diethyl 2-formylalkylphosphonates from aldimines 70 .

Fig. 28 .

 28 Fig. 28. Synthesis of dialkyl 3-formylallylphosphonates via the MA reaction 72c .

2 -

 2 (3-hydroxy-4-hydroxymethyl-2-methyl-5-pyridyl)vinylphosphonate in 98% yield. After catalytic hydrogenation of the double bond using 5% Pd/C in EtOH, several oxidation methods were studied, including MnO 2 in water, CrO 3 . Py and DMSO-DCC. Finally, oxidation with activated MnO 2 in CHCl 3 proceeded smoothly to give the diethyl 2-(4-formyl-3-hydroxy-2-methyl-5-pyridyl)ethylphosphonate 93.86

Fig. 38 .

 38 Fig. 38. Synthesis of phosphonic analog of pyridoxal phosphate 86 .

Fig. 46 .

 46 Fig. 46. Formation of macrocycles by intramolecular HWE reaction.

Fig. 47 .

 47 Fig. 47. Reaction of 4 with n-BuLi 124 .

Fig. 50 .

 50 Fig. 50. Synthesis of 3-(diethoxyphosphinyl)indole 35a .

Fig. 51 .

 51 Fig. 51. Synthesis of α,β-unsaturated aldehydes 152 .

Fig. 54 .

 54 Fig. 54. Pathway for the biosynthesis of AEP.

Fig. 56 .

 56 Fig. 56. Reductive amination of phosphonoacetaldehydes 17a .

Fig. 57 .

 57 Fig. 57. Reductive amination in the presence of benzylamine 174 .

Fig. 58 .

 58 Fig. 58. Synthesis of 1-aminoalkyldiphosphonic acids 18a .

Fig. 60 .

 60 Fig. 60. Synthesis of amino carboxyalkylphosphonic acids via the Strecker reaction.

85

 85

Fig. 61 .

 61 Fig. 61. Synthesis of amino carboxyalkylphosphonic acids via α-azidoacetate 95b .

  2 , Cl, CH=CH 2 , CH=CHCl, C 6 H 5 ,

	o-ClC 6 H 4 , p-ClC 6 H 4 and SEt are inert. Formyl deprotection can be realized at room temperature either by
	treatment with 3M HCl in biphasic medium (Z=o-or p-NO 2 C 6 H 4 , CO 2 R, CONR 2 ) or with 2M NaOH. The
	yields are generally excellent

Table 1 .

 1 Synthesis of diethyl 1,1-dialkyl-1-formylmethylphosphonates48 .

	(EtO) 2 P O	CH 2 Z	(MeO) 2 CH-NMe 2 -2 MeOH	(EtO) 2 P O	C CH NMe 2	H 2 O	O (EtO) 2 P		CH C	O H
		2 5					2 6				2 7
	Z = CN, COMe, COEt, CO i-Pr, COPh,						O	H	O
	CO 2 Et, CONMe 2 , CO-CO 2 Et,						(EtO) 2 P	C	C	H
		NO 2										Z
	29	a	b	c	d	e	f	g	h	i	j	k		l
	R 1	Me	Me Me Me	Me	Me	Me	Me	Et n-Pr i-Pr i-Bu
	R 2	Me	Et i-Pr n-Pr		t-Bu n-Pent Ph	Et n-Pr i-Pr i-Bu

  Two reactions were found to be best suited to the synthesis of diethyl 4-formylalkylphosphonates. The first one is a straightforward method to diethyl 4-formylalkylphosphonates 84 (m=1) from unprotected

	Me	O		Me	O				CHO
	Me	O	CH 2 Cl	Me	O		CH 2 P(OEt) 2	HO	CH 2 P(OEt) 2
			(EtO) 2 P(O)Na			O	1) HCl	O
	Me	N	Me	N		2) MnO 2	Me	N
			7 7					53%	7 8
	OP(O)(OMe) 2	OH			OBz		OH
				P(O)(OMe) 2	P(O)(OMe) 2	P(O)(OMe) 2
			LDA		PhCH 2 Br		MnO 2
		-78°C,THF		Bu 4 NF,THF		20°C,THF
	7 9	OSiMe 2 t-Bu	OSiMe 2 t-Bu 8 0	OH 8 1		O	8 2	H

11 to 16.

	HOH 2 C						HOH 2 C			OHC
	1 1 2	+	EtAlCl 2 0°C, CH 2 Cl 2	MeO 2 C		PDC 25°C, CH 2 Cl 2 68%	MeO 2 C
	(MeO) 2 P O			CO 2 Me		1 1 3	P(OMe) 2 O	1 1 4	P(OMe) 2 O
	OSEM	O	O	N	CuCH 2	P(OEt) 2 O	OSEM	O	P

4 . 102 2.7. n =

  Me, Et, n-C 5 H 11 , C 6 H 11 , Ph

	1 2 4 a					1 2 5 a
				1 2 3
				Y = Me, SMe
	1 2 4 b					1 2 5 b
	(EtO) 2 P O	CH 2	NO 2	(MeO) 2 CH-NMe 2 -2 MeOH	(EtO) 2 P O	H 2 , Pt / C NO 2 C CH NMe 2 1 2 6
						25°C, EtOH
						NH 2
	(EtO) 2 P O		NH		(EtO) 2 P O	C CH NMe 2
		1 2 7


Bogdan Iorga

Frédéric Eymery

Philippe Savignac

An efficient synthesis of tetraethyl fluoromethylenediphosphonate and derivatives from diethyl dibromofluoromethylphosphonate

Tetraalkyl fluoromethylenediphosphonates are isopolar analogues of pyrophosphates. 1 In the acid form they have been proposed as a therapeutic preparation for the treatment of diseases associated with increased desorption of bones. Several procedures for the synthesis of tetraalkyl monofluoromethylenediphosphonates were developed in the past, but these methods appear to have only limited potential. In 1981, two groups reported independently the electrophilic fluorination of tetraisopropyl methylenediphosphonate by treatment of the corresponding carbanion (Li, Na, K) with FClO 3 . [START_REF] Mckenna | [END_REF]3 The reaction gives an hardly separable mixture of mono-and difluoromethylenediphosphonates, which is the major drawback with the electrophilic fluorination. Another variation using the reaction of diisopropyl 1lithio-1-fluoromethylphosphonate with the diisopropyl chlorophosphate gave the desired tetraisopropyl fluoromethylenediphosphonate in moderate yield (37%). 4 The tetraisopropyl fluoromethylenediphosphonate was also isolated in 40% yield in attempts to react the diisopropyl 1-lithio-1-chloro-1fluoromethylphosphonate with electrophiles. 4 We describe here an attractive route to the tetraethyl fluoromethylenediphosphonate 4a, and its derivatives, through a self-trapping reaction between 1 and its metallated derivative, the 1-lithio-1-bromo-1-fluoromethylphosphonate 5. Carbanion 5 is generated by an halogen-metal exchange reaction between the n-BuLi and the diethyl fluorodibromomethylphosphonate 1, which is a readily accessible starting material prepared in pure form with 85% yield 5 from (EtO) 3 P and CFBr 3 .

Throughout our experiments we observed that the reaction of 1 with TMSCl must be effectively controlled. Thus, simultaneous addition of phosphonate 1 and TMSCl (1.1 eq.) (route A) to a THF solution of * Fax. (+33) 01 69 33 39 90.E-mail : dcph@poly.polytechnique.fr n-BuLi (2 eq.) at low temperature gives the previously described 6 carbanion 2 (δ 31 P(THF)=+52.8 ppm, d, 2 J PF =67.2). Reaction of 2 with diethyl chlorophosphate produces mainly the diethyl chlorofluoromethylphosphonate resulting of an halogen-metal exchange reaction. The desired product 4a is formed in less than 10% (Scheme 1). By contrast, addition of phosphonate 1 to a THF solution of n-BuLi (1 eq.) in the absence of TMSCl (route B) proceeds at low temperature to give cleanly and quantitatively the stable lithiated tetraethyl fluoromethylenediphosphonate 3, fully identified by its spectroscopic data (δ 31 P(THF)=+34.7 ppm, d, 2 J PF =57 Hz and δ 19 F(THF)=-280 ppm, t, 2 J FP =57 Hz). Subsequent addition of the brownish solution of 3 to an aqueous solution of HCl 3M produces the tetraethyl fluoromethylenediphosphonate 4a in quantitative yield. Scheme 1.

The formation of 3 may be reasonably interpreted in terms of steric and electronic factors. It is due to the attack of the diethyl 1-lithio-1-bromo-1-fluoromethylphosphonate 5 on the phosphoryl group of the phosphonate 1 to give the transient tetraethyl bromofluoromethylenediphosphonate 6 (Scheme 2). This intermediate undergoes an halogen-metal exchange reaction with n-BuLi to give 3. The complete transformation of 1 to 3 needs 1 eq. of n-BuLi and the LiCFBr 2 formed does not participate in the reaction.

To support this mechanism, the reaction was performed in the presence of 2,3-dimethyl-2-butene in excess. The anion 3 was generated as above and the carbene resulting from the decomposition of LiCFBr 2 was trapped to produce the 1-bromo-1-fluoro-2,2,3,3-tetramethylcyclopropane identified in 19 F-NMR as a singlet at -138.8 ppm. 7 Scheme 2.

When the reaction was applied in the experimental conditions of route B to an electrophilic and sterically more hindered phosphonate partner, [START_REF] Kirby | The Organic Chemistry of Phosphorus[END_REF] the diethyl trichloromethylphosphonate, the ethyl 1,1dichloro-propylphosphonic salt resulting from a dealkylation at phosphorus was the only reaction product (Scheme 3). 9

96

As is evident from electronic factors, the carbanion 3 does not possess the same extent of significant synthetic advantages than the carbanion 2. Effectively, the stabilizing effect of the three attracting groups profoundly affects its reactivity toward electrophilic reagents. However, the tertiary carbon of 3 may also be further elaborated by either alkylation, halogenation or olefination with the appropriate reagents (Scheme 4). For example, treatment of 3 with methyl iodide (3 eq.) and hexachloroethane (2 eq.) at low temperature, followed by warming to room temperature provided the derivatives 4b and 4c in good yields (Table 1). Ethyl iodide does not react in these conditions even at 30°C, as well as 1,2-dibromo-1,1,2,2-tetrafluoroethane. Attempts to brominate the carbanion 2 with 1,2-dibromo-1,1,2,2-tetrachloroethane result exclusively in the chlorinated derivative 4b instead of the brominated one. Scheme 5.

A clear illustration of the advantages of this novel synthetic procedure is provided by the conversion of 3 to vinylphosphonates 8 of controlled geometry. 10 In this regard, the anion 3 has been found to be a highly useful reagent for the facile transformation of a variety of aromatic and heteroaromatic aldehydes into diethyl 1-fluorovinylphosphonates 8 (Scheme 5). The olefination reaction proceeds readily and cleanly at low temperature to afford the formation of the E isomer with a high degree of stereoselectivity (88 to 93%) in 2). In this regard, the previously reported 6c Peterson reaction between 2 and aromatic aldehydes was not highly stereoselective and gave a mixture of E and Z isomers in about 70/30 ratio. With enolisable ketones, the anion 3 undergoes mainly protonation as a consequence of its low nucleophilicity, whereas 2 is a better nucleophile as previously demonstrated. 6c These present preliminary results clearly demonstrate that the diethyl fluorodibromomethylphosphonate 1 is an ideal precursor for the preparation of the tetraethyl fluoromethylenediphosphonate 4a and derivatives. It gives superior results than 2 for the preparation of (E)vinylphosphonates.

Aknowledgements

We are grateful to the CNRS and Ecole Polytechnique for financial support to B.I. Thanks are addressed to Dr. Jean Villieras (UMR CNRS 6513) for fruitful discussion.

  yields as exemplified by the preparation of 8a-e (Table

Table 1 .

 1 Scheme 4.

		F	A	2 n-BuLi, Me 3 SiCl THF, -90°C	(EtO) 2 P C O Li F 2	SiMe 3	1) (EtO) 2 P(O)Cl 2) H 3 O +	F
	(EtO) 2 P CBr 2						(EtO) 2 P CH	P(OEt) 2
	O	1	B	THF, -78°C n-BuLi	(EtO) 2 P C O 3 Li F	O P(OEt) 2	H 3 O +	O	4 a	O

1 J FC =185.3)

Table 2

 2

	8	R	δ 31 P (ppm) (CDCl 3 )	δ PCF 19 F (ppm) (CDCl 3 )	δ RCH 1 H (ppm) (CDCl 3 )	E:Z (%) ( 19 F-NMR)	Yields (%)*
	a		4.0 (d, 2 J PF =98.0)	-127.2 (d, 2 J PF =98.2)	6.76 (dd, 3 J PH =8.7,	93:7	92
					3 J FH =42.2)
	b		4.3 (d, 2 J PF =97.7)	-128.4 (d, 2 J PF =97.8)	6.77 (dd, 3 J PH =8.5,	93:7	90
					3 J FH =42.5)
	c		3.8 (d, 2 J PF =97.5)	-128.3 (d, 2 J PF =97.3)	6.77 (dd, 3 J PH =8.7,	93:7	90
					3 J FH =42.2)
	d		3.6 (d, 2 J PF =91.9)	-125.7 (d, 2 J PF =92.0)	6.78 (dd, 3 J PH =7.9,	92:8	87
					3 J FH =39.8)
	e		3.8 (d, 2 J PF =98.7)	-126.9 (d, 2 J PF =99.8)	6.94 (dd, 3 J PH =8.5,	88:12	83
					3 J FH =42.5)

* After flash chromatography (hexane / AcOEt, 70 / 30).


Abstract:

The selective electrophilic monofluorination and monochlorination of a wide variety of diethyl benzylphosphonates have been realized in a one-pot procedure. The monohalogenation was accomplished by intermediate of a benzylic carbanion protected with TMSCl using N-fluorobenzenesulfonimide (NFBS) and hexachloroethane, respectively. After mild removal of protecting group, this procedure delivers the α-monohalogenobenzylphosphonates in high yields (68-97%) and pure form.

The α-monofluoro-and α-monochlorophosphonates are recognized as important and useful compounds for independent reasons. The first ones behave as phosphate mimics for biological systems. 1 Due to the fluorine electronegativity, the monofluorophosphonate function has a pKa almost identical to that of the corresponding phosphates. These analogues could be complexed similarly to the natural ligands but could not be hydrolyzed. 2 By contrast, the monochlorophosphonates are widely utilized synthetic reagents and especially as ideal precursors for the generation of symmetrical or unsymmetrical acetylenic compounds in mild conditions by the Wittig-Horner reaction. 3 The preparation of monohalogenophosphonates by selective electrophilic halogenation at the α-CH 2 position by carbanionic way is a delicate and difficult to control process. This reaction generates unavoidably a monohalogenated derivative more acidic than the initial phosphonate, thus inducing an acid-base equilibrium which evolves toward the formation of a mixture of mono-and dihalogenophosphonates. 4 This methodology has been succesfully exploited lately to prepare the α,α-difluorinated phosphonates 5a-c or to introduce fluorine on a tertiary carbon. 6 The α,α-difluorinated phosphonates can also be obtained by a CuCl promoted coupling reaction between aryl iodides and difluoromethylcadmium reagents. 5d We report here a highly selective and attractive one-pot procedure for the synthesis of diethyl α-monofluoro-5 and α-monochloro-6 benzylphosphonates from diethyl benzylphosphonates 1, based on the electrophilic halogenation of a benzylic carbanion transiently protected by a trimethylsilyl group. The starting * Fax. (+33) 01 69 33 39 90.E-mail : dcph@poly.polytechnique.fr materials 1 are commercially available or prepared on laboratory scale by the Michaelis-Arbuzov reaction between triethyl phosphite and corresponding benzyl bromides or chlorides. [7][8][9][10][11] We chose N-fluorobenzenesulfonimide (NFBS) 4 as fluorinating agent and hexachloroethane as chlorinating agent because they are stable, crystalline, easy to handle and commercially available reagents.

Moreover, the by-product of chlorination is volatile and easy to eliminate.

The diethyl benzylphosphonates 1 are first deprotonated with lithium hexamethyldisilazane (LiHMDS) 3.3 eq. at low temperature to give stable benzylic anions which are reacted at room temperature with Me 3 SiCl (TMSCl) to afford quantitatively silylated benzylic anions 2 (δ 31 P(THF)=+45-47 ppm). At low temperature, the resulting carbanions 2 undergo halogenation reaction to give the protected diethyl αfluoro-3 and α-chloro-4 benzylphosphonates which, after deprotection, produce the desired fluorinated 5 a-f and chlorinated 6 a-f materials (Scheme 1). To explore the scope and applicability of this method, the synthesis was monitored by 31 P-NMR spectrometry.

Scheme 1

We chose LiHMDS as base because HMDS, after regeneration in the reaction medium, is compatible with TMSCl even at room temperature, whereas both diisopropylamine and tetramethylpiperidine react with TMSCl, generating a chlorhydrate able to protonate the carbanions 2.

We observed that silylation takes place completely only at room temperature with 1.1 eq. of TMSCl. The use of an excess of TMSCl has a detrimental effect since it reacts with NFBS inducing an halogen exchange.

While the first deprotonation is a fast reaction at low temperature, it appears that the second is slow and for complete generation of 2 it is necessary to operate with an excess of LiHMDS (3.3 eq.). In these conditions, carbanions 2 are obtained quickly and cleanly at room temperature. The need for an excess of base was confirmed independently by metallation of diethyl α-(trimethylsilyl)benzylphosphonate, which was achieved with at least 2 eq. of LiHMDS. This result confirms that the second deprotonation is slowed down by the low nucleophilicity and steric requirements of LiHMDS.

The halogenation with NFBS or hexachloroethane (1.2 eq.) is efficiently and rapidly carried out at -78°C in THF. Thereafter, the reaction mixture is warmed up to room temperature. In the case of the chlorination, the resulting compounds 4 are treated in situ with an excess of EtOLi in anhydrous EtOH which effects the facile and clean removal of the trimethylsilyl group. We found that this methodology was not δ CHF 19 F (ppm)(CDCl 3) suited for the fluorinated derivatives 3 despite the total cleavage of the C-Si bond, because the resulting Nethylbenzenesulfonimide is very difficult to separate from the desired products. Thus, we replaced this treatment by an hydrolysis with an aqueous solution of LiOH 1M which affords at the same time a smooth, immediate removal of the trimethylsilyl moiety and the best way to retain the benzenesulfonimide in the aqueous layer. Employment of NaOH 1M is however not so satisfying because the benzenesulfonimide is not completely retained in water in these conditions. After acidic work-up and extraction, the desired αhalogenobenzylphosphonates 5 a-f and 6 a-f are isolated in good to excellent yields. Examination of the spectral data ( 31 P, 19 F, 1 H, 13 C-RMN) shows that further purifications (distillation or chromatography) are not necessary. A clear illustration of the advantages of this novel synthetic procedure is provided by some representative examples collected in Tables 1 and2.

δ CHF 1 H (ppm) (CDCl 3 ) δ CHF 13 C (ppm) (CDCl 3 ) a 97 13.0 (d, 2 J PF =85.6) -200.6 (d, 2 J PF =85.6) 5.75 (dd, 2 J PH =7.9, 2 J FH =44.6) 89.9 (dd, 1 J PC =170.5, 1 J FC =184.2) b 90 13.5 (d, 2 J PF =87.7) -199.2 (d, 2 J PF =86.9) 5.70 (dd, 2 J PH =7.5, 2 J FH =44.4) 89.6 (dd, 1 J PC =172.4, 1 J FC =183.2) c 68 12.9 (d, 2 J PF =85.6) -199.2 (d, 2 J PF =85.8) 5.62 (dd, 2 J PH =7.5, 2 J FH =44.5) 88.7 (dd, 1 J PC =171.5, 1 J FC =183.9) d 74 12.6 (d, 2 J PF =83.3) -201.4 (d, 2 J PF =83.6) 5.70 (dd, 2 J PH =7.3, 2 J FH =44.5) 88.9 (dd, 1 J PC =172.9, 1 J FC =184.0) e 76 14.4 (d, 2 J PF =85.1) -199.7 (d, 2 J PF =85.4) 5.77 (dd, 2 J PH =8.0, 2 J FH =44.6) 89.1 (dd, 1 J PC =171.0, 1 J FC =184.
We are currently extending this methodology to the synthesis of α-monobromo-and α-monoiodobenzylphosphonates as well as heterocyclic analogs.

Aknowledgements

We are grateful to the CNRS and Ecole Polytechnique for financial support to B.I.

A Highly Selective Synthesis of

  α-Monofluoro-and α-Monochlorobenzylphosphonates

Using Electrophilic Halogenation of Benzylphosphonates Carbanions Bogdan Iorga, Frédéric Eymery and Philippe Savignac

	Laboratoire Hétéroéléments et Coordination, DCPH, CNRS et Ecole Polytechnique
	91128 Palaiseau Cedex, France.

*

Table 2 .

 2 Diethyl α-chlorobenzylphosphonates 6

	6)