F Panthier
email: fredericpanthier@gmail.com

O Traxer

L Yonneau

T Lebret

L Berthe

M O Timsit

A Méjean

S Doizi

F Audenet

Évaluation préclinique et clinique d'un outil développé pour la planification opératoire des chirurgies lithiasiques : « Kidney Stone Calculator »

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  Évaluation préclinique et clinique d'un outil développé pour la planification opératoire des chirurgies lithiasiques : " Kidney Stone Calculator " F. Panthier, Olivier P. Traxer, L. Yonneau, T. Lebret, Laurent Berthe, M.O. Timsit, A. Méjean, Steeve Doizi, F. Audenet To cite this version: F. Panthier, Olivier P. Traxer, L. Yonneau, T. Lebret, Laurent Berthe, et al.. Évaluation préclinique et clinique d'un outil développé pour la planification opératoire des chirurgies lithiasiques : " Kidney Stone Calculator ". Progrès en Urologie, 2020, 30 (13), pp.702-703. 10.1016/j.purol.2020.07.021. hal-03166513 Introduction Kidney Stone Calculator (KSC) est un outil que nous avons développé pour mesurer le volume lithiasique total (VLT) et Tableau 1 Caractéristiques démographiques de la population d'étude. estimer la durée opératoire de lithotritie laser endocorporelle (LLE) au cours de l'urétérorénoscopie souple (URS-S), à partir du scanner abdominopelvien préopératoire non injecté (TDM AP IV-). L'objectif de cette étude était de réaliser une évaluation préclinique et clinique de cet outil. Méthodes Une base de données scanographiques (17) était préalablement constituée : 9 calculs humains, 6 calculs synthétiques cubiques, 2 situations cliniques (calcul unique et coralliforme). Après formation, les VLT étaient mesurés en aveugle par trois opérateurs (interne, urologue senior, ingénieur). Une analyse des coefficients de corrélation inter-opérateurs et de Kendall était réalisée. Fut conduite ensuite une étude clinique multicentrique prospective en double aveugle incluant des patients avec calculs rénaux traités par URS-S avec LLE et TDM AP IV-préopératoire dans 3 centres, entre janvier et mars 2020. Étaient collectées les caractéristiques démographiques, lithiasiques (diamètre maximum, VLT, densité) et opératoires (matériel, durée et paramètres de LLE avec laser Holmium :YAG, énergie totale délivrée, complications). Les durées de LLE effective (EfLLE) et estimée (EsLLE) par KSC ont été comparées, ainsi que 5 facteurs influenc ¸ant potentiellement cette estimation : calcul caliciel inférieur non relocalisable ou non relocalisé, diamètre de la gaine d'accès, mode de LLE et expérience de l'opérateur. Résultats Aucune différence significative n'était retrouvée entre les opérateurs (Op1-Op2 : p = 0,35, Op1-Op3 : p = 0,69, Op2-Op3 : p = 0,29). Une forte concordance inter-opérateur était retrouvée (Kendall : 0,98 et corrélation Pearson : 0,99). Concernant l'évaluation clinique, 26 patients furent inclus dans trois centres, avec un âge médian de 55,5 ans. Le sex-ratio était de 2 hommes pour 1 femme, avec un IMC médian de 28,7 kg/m 2 . Les patients présentaient un calcul unique, caliciel inférieur et une densité > 1000 UH Tableau 2 Données périopératoires. Tableau 3 Facteurs influenc ¸ant l'estimation de la durée de LLE. dans 66 %, 42 % et 85 %, respectivement (Tableau 1). Une différence médiane de 14 % (5,4-24,8) entre EsLLE et EfLLE était constatée (p = 0,36), majorée en cas de calcul caliciel inférieur non relocalisable (p = 0,008), en mode Fragmentation (Tableaux 2 et 3). Le diamètre de la gaine d'accès urétérale et l'expérience de l'opérateur n'influenc ¸aient pas significativement cette différence (p = 0,46 et p = 0,07, respectivement). L'énergie par mm 3 et le débit d'ablation médians étaient de 17,6 J/mm 3 et 23,8 mm 3 /min, respectivement. Conclusion Kidney Stone Calculator est un outil de planification opératoire reproductible et fiable. Il permet d'estimer le VLT et la durée de LLE à partir du TDM AP IV-préopératoire avec fenêtrage osseux manuel sans prérequis. Les calculs caliciels inférieurs non relocalisables, le mode Fragmentation et l'expérience moindre de l'opérateur peuvent conduire à sous-estimer la durée de LLE. Une étude clinique sur un plus grand nombre de patients est nécessaire pour valider ces résultats. Déclaration de liens d'intérêts Les auteurs déclarent ne pas avoir de liens d'intérêts.


1. 2-Chloromethyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane 2. 2-Chloromethyl-2-oxo-4,5-o-phenyl-1,3,2-dioxaphospholane 3. Ylid Chemistry of Diphenyl Chloromethylphosphonate 4. 2-Chloromethyl-3,4-dimethyl-2-oxo-5-phenyl-1,3,2-oxazaphospholane 5. 3-t-Butyl-2-chloromethyl-6,6-dimethyl-2-oxo-1,3,2-oxazaphosphorinane 6. Bis(dimethylamino) Chloromethylphosphonamide 7. 2-Chloromethyl-1,3-dimethyl-2-oxo-1,3,2-diazaphospholane 8. N,N'-

I. Introduction

A number of reviews dealing with phosphonate chemistry have appeared over the years. 1 Most concern the use of phosphonate stabilized carbanions as olefination reagents in Horner-Wadsworth-Emmons (H.W.E.) reactions. A few deal with specific classes of compounds such as difluoromethyl or vinylphosphonates. This review will emphasize the peculiar properties of α-chloro-substituted phosphonates.

Horner-Wadsworth-Emmons reactions were not commonly observed from the chloromethylphosphonate carbanion since the chlorine atom is not a strong enough withdrawing group to induce the cleavage of the P-C bond (see reactions with carbonyl compounds, section III 4). Indeed, most of the chemistry of chloromethylphosphonate 1 deals with the cleavage of the carbon-chlorine bond by either a halogen-metal exchange reaction or action of nucleophiles. On the other hand, introduction of functional groups on the carbon bearing both the phosphorus group and chlorine make the P-C bond more labile and Horner-Wadsworth-Emmons reactions can thus occur. In this way, chloromethylphosphonate 1 can be used as a reagent for the preparation of a number of functionalized organic substrates such as alkenes or alkynes. To date, the finding of new methods based on these reactions is still of growing interest.

Both the preparation of α-substituted phosphonates from chloroalkyl derivatives and their applications to the synthesis of non phosphorylated organic compounds will be highlighted here. We will cover the literature from 1950 to the present date. At first, we shall give a detailed account of the properties of diethyl chloromethylphosphonate 1, as the parent compound. Literature reports on the higher analogues will be discussed in the final part of this review.

II. Synthesis of Diethyl Chloromethylphosphonate

Diethyl chloromethylphosphonate 1 is a stable, easy to handle liquid (b.p. 109-110 °C / 10 mmHg; NMR 31 P (CDCl 3 ) δ = +16.0 ppm, d 20 1.1992, n D 20 1.4415). It is a commercially available (Aldrich, Fluka), but expensive compound. Nevertheless, it is conveniently prepared, on laboratory scale, by ethanolysis of chloromethylphosphonyl dichloride 2 (b.p. 77-78 °C / 10 mmHg; NMR 31 P (CDCl 3 ) δ = +38.0 ppm, d 20 1.6361, n D 20 1.4978) which is itself commercially available (Aldrich, Fluka). The Kinnear-Perren reaction between phosphorus trichloride and dichloromethane in the presence of AlCl 3 is currently used on laboratory scale for the synthesis of 2 in 85 % yield. 2 On industrial scale, 2 is synthesised via the hydroxymethylphosphonic acid (obtained by heating phosphorous acid and paraformaldehyde at 100 °C). 4a The so formed 1-hydroxymethylphosphonic acid is converted into 2 under drastic conditions with phosgene (COCl 2 ) at 150 °C in the presence of Ph 3 P as catalyst; yields are almost quantitative. 3 Thionyl chloride (SOCl 2 ) at 55-65 °C in the presence of pyridine has also been introduced as chlorinating agent but the yield of 2 is lower (57 %). 4a-b An alternative two step method whereby the phosphorus acid is substituted with phosphorus trichloride can also be used. The mixture of phosphorus trichloride and anhydrous paraformaldehyde is heated at 250 °C for 10 h in an autoclave to give 2 with a maximum yield of 60-65 % (Scheme 1). 5 Treatment of phosphorus trichloride with excess paraformaldehyde yields 2 and other products such as the bis(chloromethyl) chloromethylphosphonate. 5d Standard alcoholysis of 2 with ethanol in anhydrous conditions yields diethyl chloromethylphosphonate 1.

Scheme 1.

Diester homologues of 1 are obtained from chloromethylphosphonyl dichloride 2 by alcoholysis in THF or CH 2 Cl 2 . The quenching alcohol can be simply added pure and the resulting hydrogen chloride removed with a stream of dry air or under vacuum, however the addition of a tertiary amine remains the most widely used method. The direct addition of sodium alcoholates is also a useful synthetic method (Scheme 2 and Table 1). Formation of organosilicon esters from 2 is not usual, it occurs via the reaction of trialkylsilanol acetates and 2 with continuous removal of the acetyl chloride formed by distillation. Compound 1 is also prepared by selective and successive chemical or electrochemical reduction of two chlorine atoms of the readily available diethyl trichloromethylphosphonate. The chemical procedure involves the double exchange of chlorine with n-butyllithium in the presence of chlorotrimethylsilane as protecting group (Scheme 3). After treatment, 1 is obtained in almost quantitative yield. 40 The electrochemical reduction of diethyl trichloromethylphosphonate was successfully applied to the synthesis of diethyl chloromethylphosphonate 1 on preparative scale. 41 It was formed with a small amount of diethyl dichloromethylphosphonate (less than 10 %), and was obtained in pure form and good yield (80 %) after distillation. This electrochemical method can compete with chemical reduction and is currently of increasing use. 42,43 Scheme 3.

(EtO) 2 P CCl 3 O (EtO) 2 P C H 2 -Cl O 1) 2 n-BuLi, TMSCl 2) LiOEt, EtOH 1 -78°C, THF
3) H 3 O +

III. Diethyl 1-Lithiochloromethylphosphonate : Preparation and Uses

Several phosphonate derivatives owe their use to the ease of formation of a carbanion in α to phosphorus. Similarly, by abstraction of a proton of the methylene group with a lithiated base, 1 forms the 1-lithiochloromethylphosphonate 3 which has wide applications. It has been shown, by application of known carbanionic reactions to 3 (Scheme 4), that it is a good nucleophile useful in providing several functionalised phosphonates with or without a chlorine atom on the α-carbon.

Scheme 4.

P C O Cl Li H 3 (EtO) 2 ( E t O ) 2 P C C l L i H O (EtO) 2 P C Cl D D O (EtO) 2 P C Cl H R O (EtO) 2 P C Cl H SiMe 3 O (EtO) 2 P C Cl C R 1 R 2 O (EtO) 2 P O P(OEt) 2 O (EtO) 2 P C Cl H C O 2 H O (EtO) 2 P C Cl H C O O R (EtO) 2 P C C-R O (EtO) 2 P C Cl R CHO O (EtO) 2 P C C O O R 1 R 2 (EtO) 2 P C Cl H C O O C O 2 R (EtO) 2 P C Br H R O (EtO) 2 P C Cl Cl H O (EtO) 2 P C Br Br H O (EtO) 2 P C C O N Ar 1 H Ar 2 (EtO) 2 P C Cl H C O 2 R O (EtO) 2 P C Cl H C O O CH(OEt) 2 H H C Cl H

Preparation and Stability

In THF at low temperature, n-butyllithium, s-butyllithium and lithium diisopropylamide (LDA) cleanly abstract a proton from the methylene group of 1 to give a quantitative yield of 1-lithiochloromethylphosphonate 3 (Scheme 5). Compound 1 is not very sensitive to the structure of these lithiated reagents and no significant effect on the nature of the reaction products has been observed. By contrast t-butyllithium gives in part H / Li and Cl / Li exchanges resulting in a mixture of 3 (90 %) and diethyl 1-lithiomethylphosphonate (10 %). Generated under these conditions, 3 is stable exclusively at low temperature. An αelimination is probably accomplished thermally producing chlorocarbene or diethyl phosphonocarbene in which the leaving group would be the diethyl phosphite or the chloride anion respectively. Complete reaction of 3 is often handicapped by its instability but this disadvantage can be overcome on generation of 3 from 1 and two equivalents of LDA. The first equivalent of LDA deprotonates the methylene group to give 3, while the second equivalent participates in the stabilisation of the carbanionic species by steric interaction between the phosphoryl group and the hindered amide. Under these conditions 3 can be kept at 0 °C (NMR 31 P (THF) δ = +45.3 ppm) for 30 min without apparent degradation. 44 The effect of hindered amides on the thermal stability of α-phosphorylated carbanions has also been observed with other lithiochloromethyl-and lithioalkylphosphonate carbanions.

Scheme 5.

Reaction with Chlorotrimethylsilane

At low temperature, 3 reacts readily and quantitatively with TMSCl to give the monosilylated compound only. When the reaction between 1 and TMSCl was accomplished at low temperature in the presence of two equivalents of lithiated reagent (n-BuLi or LDA), the 1-lithiochloro(trimethylsilyl)methylphosphonate 4 was obtained directly (Scheme 6). 40 The trimethylsilyl group has been shown to be useful as a directing group (Peterson reaction) as well as a protecting group for further reactions.

Scheme 6.

(EtO)

A. Peterson Reaction

When 1-lithiochloro(trimethylsilyl)methylphosphonate 4 reacted with carbonyl compounds, an unambiguous preference of a Peterson over a Horner-Wadsworth-Emmons reaction was observed. In this case the trimethylsilyl group acts as a directing group. Thus, vinylphosphonates 5 are formed from 4 and aldehydes or ketones by elimination of trimethylsilanolate. Usually mixtures of the E and Z isomers are obtained (Scheme 7). 45 This method of converting carbonyl to vinyl groups is an efficient approach for preparing both isomers of vinylphosphonates 5. The alternative approach to 5, the Horner-Wadsworth-Emmons reaction using 1-lithiochloromethylenebisphosphonates 50 (see section III 9), affords selectively the Z isomer. 46

Scheme 7.

When the carbonyl compound is an aromatic or heteroaromatic aldehyde, 1-alkynylphosphonates 6 are obtained in high yield (87-96%) from 1-chlorovinylphosphonates (E+Z) 5 in a one pot process by treatment at low temperature with LiHMDS or LDA and subsequent elimination (syn and anti) of LiCl (Scheme 8). 47 Compounds 6 are difficult to obtain by other methods. 48

Scheme 8.

The Peterson reaction also provides a route to phosphorylated sulfines by reaction of 4 with SO 2 . Compound 7 is rather unstable and was converted into a [4+2] cycloadduct 8 by Diels-Alder reaction with 2,3-dimethylbutadiene (Scheme 9). 49 (EtO

) 2 P C O Li SiMe 3 Cl (EtO) 2 P C O SiMe 3 Cl R 1 R 2 OLi C C Cl (EtO) 2 P O 4 5 -78°C,THF R 1 R 2 C=O R 1 R 2 H C R C Cl (EtO) 2 P O C R C (EtO

B. Deuteriation

Conditions have been devised to produce 1,1-dideuteriated diethyl chloromethylphosphonate 9. These involve the deuteriation and desilylation under basic conditions of the thermally stable 1-lithiochloro(trimethylsilyl)methylphosphonate 4. Trapping this carbanion at low temperature with D 2 O generates LiOD in the reaction medium which promotes the elimination of the protecting trimethylsilyl group by nucleophilic attack on the silicon atom. This process provides access to 1,1-dideuteriated chloromethylphosphonate 9 in nearly quantitative yield and with high incorporation of deuterium (D % > 95). 50 Trapping of the carbanion 4 with formic acid followed by removal of the trimethylsilyl group with LiOD / D 2 O provides access to monodeuteriated diethyl chloromethylphosphonate 10 (Scheme 10). 40 Scheme 10.

C. Alkylation

Formation of diethyl chloroalkylphosphonates 12 by direct alkylation of the lithiated reagent 3 with alkyl halides is not recommended. The acid-base equilibrium between 3 and 12 induces competing side formation of dialkylated products which renders this route not applicable on a preparative scale. By contrast the 1-lithiochloro(trimethylsilyl)methylphosphonate 4 in THF at low temperature is particularly well suited to the alkylation reaction. The trimethylsilyl group acts as a protecting group and desilylation of the adducts can be easily conducted under basic conditions with LiOH / H 2 O in THF or with LiOEt or NaOEt in ethanol to give pure diethyl chloroalkylphosphonates 12 in high yield (Scheme 11). Prior to elimination of the trimethylsilyl group the intermediates 11 can undergo at low temperature a halogen-metal exchange reaction to give the 1-lithio(trimethylsilyl)alkylphosphonates. These react with dibromoethane at a temperature lower than -80 °C to produce pure diethyl bromo(trimethylsilyl)alkylphosphonates 13 by a new halogen-metal exchange reaction. The trimethylsilyl group is eliminated under the same conditions as for chlorinated compounds 11 to give pure diethyl bromoalkylphosphonates 14 in good yield (Scheme 12). 40 Scheme 12.

Reaction with Carbon Tetrachloride / bromide and Further Transformations

A. Reaction with Carbon Tetrachloride

The lithiated reagent 3 abstracts a chlorine atom from carbon tetrachloride to produce, in a clean reaction, the transient diethyl 1,1-dichloromethylphosphonate 15 which is sufficiently acidic to undergo a hydrogen-lithium exchange with trichloromethyllithium generated in the reaction medium. The thus obtained 1-lithiodichloromethylphosphonate 16 is a carbenoid species capable of undergoing ambiphilic reactions depending on the temperature. At low temperature (-100 °C) where the carbon-lithium bond has mainly covalent character, 16 behaves as an ordinary nucleophile and reacts with various electrophiles to give The chlorination reaction described in Scheme 13 has been applied to the large scale synthesis of diethyl dichloromethylphosphonate 15 (the use of lithium salts, LiCl and LiBr, increases stability of the lithium intermediate 16 and increases yields of 15 up to 60-90%). 56,57 On preparative scale chlorination of carbanion 3 can also be effected with diethyl trichloromethylphosphonate to give 15 in an efficient reaction and respectable yield (80-86 %). 56 However, a recently reported procedure offers a safer, more efficient route to 15 via the Grignard reagent obtained from diethyl trichloromethylphosphonate and magnesium isopropylchloride. 58,59 In addition to their use in gem-dichloroolefins formation, 15 and 17 have further synthetic applications. Conversion to dichlorophosphines 19 followed by vacuum gas-solid HCl elimination (VGSR) provides a route to non-stabilized phosphaalkynes 20 which have been illustrated by the synthesis of series of derivatives. 60 Compound 15 on reaction with diaromatic ketones is also an efficient precursor of symmetrical or unsymmetrical diarylacetylenes through the Fritsch-Buttenberg-Wiechell rearrangement (Scheme 14).

B. Reaction with Carbon Tetrabromide

The lithium reagent 3 abstracts one bromine atom in tetrabromomethane to produce the transient diethyl 1-bromo-1-chloromethylphosphonate 21 which in turn is deprotonated by the tribromomethyllithium generated in the reaction medium to give the 1-lithio-1-bromo-1-chloromethylphosphonate 22. In the presence of lithium bromide in large excess, 22 formally undergoes a chlorine-bromine exchange to produce the 1-lithio-1,1-dibromomethylphosphonate 23. This lithium reagent is an excellent precursor to gem-dibromoolefins 24 via the Horner-Wadsworth-Emmons reaction (Scheme 15, Table 3). 62 gem-Dibromoolefins are used as source of alkynes (Fritsch-Buttenberg-Wiechell reaction). 63 On acidic hydrolysis, 23 gives the diethyl dibromomethylphosphonate 25 in 80-90 % yield.

P C R (EtO) 2 P C O R Cl Cl 2 0 K 2 C O 3 VGSR 1 5 or 17 H 2 P C R Cl Cl 1 9 AlHCl 2 -80°C, Et 2 O R H M e Et n-Bu SiMe 3 80 80 80 70 65
Yield (%) R = H or ≠ H R 1 R 2 Cl Cl 1 8 R 1 R 2 2 n-BuLi -78 to 0°C LiHMDS R 1 R 2 C=O -78°C, THF R = H 350°C C 6 H

Reaction with Carbonyl Compounds

A solution of 3 in THF at low temperature reacts with carbonyl compounds to give an intermediate chlorohydrin 26, stable under the reaction conditions. On heating, elimination of lithium chloride occurs to form the epoxyphosphorus derivatives 27 without side reactions (Darzens procedure). Formation of the chloroalkene via a Horner-Wadsworth-Emmons type rearrangement is never observed. The reaction is well suited to either aliphatic and aromatic aldehydes or ketones. Even sterically hindered or readily enolizable ketones react generally in good yield (Scheme 16, Table 4). 65 Several other metallic derivatives of diethyl chloromethylphosphonate 1, including sodium or potassium, have been reported to provide access to epoxyphosphonates, however they are not particularly effective for this method and the reaction remains synthetically limited. 66 A useful supplement to the Darzens condensation, applicable to aliphatic aldehydes, has been used to convert 1 into phosphonomycin.

P C O H Li Cl P C O C H Cl R 2 O R 1 P O C C O R 1 R 2 3 R 1 R 2 C=O 2 7 Δ H (EtO) 2 (EtO) 2 (EtO) 2 2 6 (R 1 , R 2 ≠ H) -78°C,THF Li -(CH 2 ) 4 - 76
This method of converting carbonyl compounds to epoxyphosphonates 27 has been extended to a large variety of acyclic and cyclic ketones, which lead to 2,2-disubstituted derivatives. Epoxyphosphonates 27 are well suited starting materials for the preparation of 1,1-disubstituted 1-formylmethylphosphonates 28. 68 Lewis acids, especially BF 3 . Et 2 O, are effective catalysts in the rearrangement of epoxyphosphonates 27 into 1,1-disubstituted 1-formylmethylphosphonates 28. The [1,2] transfer of the phosphorus moiety is conducted in dichloromethane with high selectivity and in good yield (Scheme 17, Table 5). 69 Scheme 17.

P O C C O R 1 R 2 P O C C R 2 R 1 O H 2 7
Lewis acid

2 8 H (EtO) 2 (EtO) 2 P O C H C -O R 1 R 2 (EtO) 2 + r.t., CH 2 Cl 2 n-Pr n-Pr 75 i-Pr i-Pr 76 i-Bu i-Bu 76 -(CH 2 ) 4 - 25 -(CH 2 ) 5 - 61 -C(Me) 2 (CH 2 ) 4 - 71 -(CH 2 ) 6 - 60
Side reactions do not usually occur except with cyclic ketones which undergo a competing proton migration and consequently give a mixture of 1,1-disubstituted formylphosphonates 28 and 1-hydroxyallylphosphonates 29 (Scheme 18). 69

Scheme 18.

A further application of the reaction between 3 and carbonyl compounds is the synthesis of β-ketophosphonates 32 when the intermediate chlorohydrin 30 issued from 3 and an aldehyde (R = aliphatic, aromatic or heteroaromatic) is treated at low temperature with excess LDA (2.2 equiv.). Under these conditions 30 undergoes deprotonation and subsequent elimination of lithium chloride to provide selectively the lithio phosphonoenolate 31 in its stable chelate form. Under acidic conditions 31 gives the synthetically useful βketophosphonates 32. The overall result is that diethyl 1-lithio-1-chloromethylphosphonate 3 allows the direct phosphonomethylation of a large variety of alkyl and aryl aldehydes under advantageous experimental conditions and in good overall yield (Scheme 19, Table 6).

P O C H 2 C O R (EtO) 2 P O Li O C C Cl R H (EtO) 2 P O Li O C C R H H LDA, THF H 3 O + 30 3 1 3 2 (EtO) 2 -78 to+20°C O O

Reaction with Imines

Reaction of 3 with aryl imines leads to the lithiated intermediate 33 which on elimination of LiCl cyclise to give the aziridines 34 in moderate to good yield. Elimination of the chlorine atom is preferred with respect to Horner-Wadsworth-Emmons reaction, presumably due to entropic considerations. Significant stereochemical control of the reaction is observed, the syn isomer of the aziridine 34 is mainly formed and represents 80 to 100 % of the final product (Scheme 20, Table 7). 71

Scheme 20.

Reaction with Carbon Dioxide and Further Transformation

Chlorocarboxymethylphosphonate 35 was first obtained as a crystalline compound from the reaction of 3 with carbon dioxide. In order to prevent any acid-base equilibrum on the formation of 35 it is important to quench a THF solution of 3 with dry ice in large excess in diethyl ether followed by treatment under acidic conditions. The dilithiated reagent 36 is a useful precursor for the conversion of carbonyl compounds into α-chloroacrylic acids 37 via a Horner-Wadsworth-Emmons type reaction (Scheme 21). 72 There is a stereochemical preference for production of the Z isomer with aromatic and heteroaromatic aldehydes whereas both Z and E isomers are produced with aliphatic aldehydes and ketones (Table 8).

Scheme 21. 73,74 However, sulfuryl chloride is much less selective than thionyl choride for the conversion of the carboxylic acid into its acid chloride, and it can also chlorinate the carbon in α to the phosphorus atom. 75 The crude carboxylic acid chloride 38 is used for further transformations, because it decomposes on distillation.

P O C Cl Li H P O C Cl H C O 2 H P O C Cl Li C O 2 Li C O 2 H Cl R 1 R 2 R 1 R 2 C=O H 3 O + 3 3 5 3 7 (EtO) 2 (EtO) 2 (EtO) 2

Scheme 22.

Diethyl chloroketylphosphonate 39 is the product formed when the carboxylic acid chloride 38 is treated with triethylamine or pyridine in ether at -40 °C (Scheme 23). 76 At room temperature the ketene solution gradually darkens indicating its instability. However, 39 has been trapped in situ and converted to series of cycloadducts such as cyclobutanone 40 or β- 24). In this way the thioates 42 were isolated in 95 % crude yield (32 % after column chromatography). 77 These derivatives are valuable synthetic intermediates, sufficiently pure for subsequent use without purification.

Scheme 24.

An almost quantitative yield of 43 results from reaction of 38 with sodium azide in biphasic medium (Et 2 O / H 2 O). This offers the advantages of mild conditions and thus provides a convenient preparation of acylazide 43 in 89 % yield. On heating in refluxing benzene, 43 undergoes a Curtius rearrangement into isocyanate 44 in 88 % yield (Scheme 25). 74 An early reported preparation of 44 used a Michaelis-Arbuzov reaction between triethylphosphite and dichloromethyl isocyanate, but the yield of pure diethyl 1chloromethylisocyanate 44 did not exceed 10-15 %. 78

Reaction with Esters

The lithium reagent 3 in the presence of one equivalent of LDA selectively attacks the carbonyl group of carboxylic esters and analogues to produce the lithio chloroenolates 45. In most cases, chelates 45 which are highly stabilised do not undergo Horner-Wadsworth-Emmons reactions with carbonyl compounds. Acidic hydrolysis of these enolates gives the 1-chloro-2-oxoalkylphosphonates 46 a-h which are isolated in high yields (Scheme 26 and Table 9). 79,80 This reaction can easily be used to provide a large scale conversion of various carboxylic esters into 1-chloro-2 oxoalkylphosphonates 46 a-d.

These compounds (46 a-d) can also be obtained from the lithiated derivative of diethyl trichloromethylphosphonate in reaction with acid chlorides. This occurs via a halogen-metal exchange reaction at -125 °C in a THF / diethyl ether mixture in moderate to good yield. 81 This route is analogous to that reported for the synthesis of triethyl 1chloromethylphosphonocarboxylate 49 (Scheme 29). 79,82 After acidic hydrolysis the 1-chloro phosphonopyruvates 46 e, f are isolated in moderate to good yield (Table 9). With the same process the reaction between 3 and ethyloxalatemonoamide gives 1-chloro phosphonopyruvamide (38 %). 80 In a similar manner, reaction of 3 with ethyl diethoxyacetate affords 1-chloro-3,3diethoxy-2-oxopropylphosphonate 46 g in 81 % yield after acidic hydrolysis of the corresponding lithio chelate (Scheme 26). The product is obtained in the keto form only. 79 Reaction of 3 at low temperature with ethyl formate, or DMF, produces in high yield the synthetically useful 1-chloro-2-oxoethylphosphonate 46 h (Scheme 26), an excellent precursor to imino or enaminophosphonates. This water soluble compound exists in keto-enol tautomeric forms (Scheme 27). 79,80 By a similar procedure the carbanion derived from chloroalkylphosphonates 12 (Scheme 11) reacts with ethyl formate, the most practical formylating agent, to give 1-formylchloroalkylphosphonates. 79 Scheme 27.

O (EtO) 2 P C Cl H C H (EtO) 2 P O H O C C Cl H O 46 h
An alternative procedure for the preparation of the 1-chloro-2-oxoethylphosphonate 46 h is the mild selective chlorination of the readily accessible diethyl 2-oxoethylphosphonate with gaseous chlorine in CCl 4 in 79 % yield. 83 This procedure was also used for the preparation of a series of 1-alkyl-1-chloro-1-formylmethylphosphonates. 84 A more recent approach consists in the chlorination of phosphorylated enol ethers in CCl 4 at room temperature, followed by hydrolysis of the phosphorylated α,β-dichloroethers. The resulting hemiacetal decomposes to form 46 h. 85

Reaction with Diethyl Carbonate

Reaction of 3 with diethyl carbonate affords the lithio chelated phosphonoenolate 47b by elimination of EtOH from the unstable intermediate 47a. When the reaction of carbanion 3 is performed in the presence of one equivalent of LDA the yield of phosphonoenolate 47b is quantitative, while a maximum yield of 50 % is achieved when no additional LDA is used. Generated in situ, 47b has been used as a source of triethyl α-chlorophosphonocarboxylate 49 prepared in 87 % yield or as a precursor to α-chloroacrylic ethyl esters 48 in a Horner-Wadsworth-Emmons type reaction with carbonyl compounds. These α,β-unsaturated esters usually have Z geometry when prepared from aromatic aldehydes or a mixture of Z and E geometries when prepared from aliphatic aldehydes (Scheme 28 and Table 10). 86 Of significant synthetic importance is the application of the halogen-metal exchange reaction to the generation of lithiodichloromethylphosphonate from n-butyllithium and diethyl trichloromethylphosphonate at -90 °C in a mixture of THF / diethyl ether. Trapping with ethylchloroformate provides a convenient and advantageous route to 49 in 80 % yield (Scheme 29). 87 An alternative procedure for the preparation of 49 via a carbanionic pathway is the reaction of ethyl trichloroacetate in THF at room temperature with the sodium carbanion of triethyl phosphonocarboxylate. Despite mild experimental conditions the yield of 49 remains modest (52 %). 88

Scheme 29.

The other available synthetic procedures for the preparation of triethyl αchlorophosphonocarboxylate 49 are multi-step procedures. A nearly quantitative yield of triethyl 1,1-dichlorophosphonocarboxylate was obtained from triethylphosphonocarboxylate and sodium hypochlorite at pH 7.1 by moderating the reaction temperature. The subsequent selective reduction of the dichlorophosphonocarboxylate to the corresponding monochloro ester 49 was efficiently accomplished with sodium sulfite (Scheme 30).

Reaction with Phosphoryl Chlorides

Condensation of 3 with phosphoryl chlorides, in the presence of LDA, results in the lithiochloromethylenebisphosphonate 50. 46 The intermediate 50 acts as a phosphonomethylenation reagent in reaction with carbonyl compounds providing an efficient route to vinylphosphonates 53 of controlled geometry via a Horner-Wadsworth-Emmons reaction (Scheme 31, Table 11). 90,91 This olefination reaction using 50 has been found to be the method of choice for preparing Z vinylphosphonates.

The intermediate bisphosphonate 50 can be a symmetrical or unsymmetrical reagent obtained by condensation of 3 with a variety of phosphoryl chlorides including acyclic or cyclic chlorophosphates, chlorophosphoramides, chlorodiphenylphosphine oxide 92 , chlorothiophosphates, etc. In the case of unsymmetrical bisphosphonates, condensation of 50 with carbonyl compounds is accompanied by the elimination of the more electrophilic phosphorus moiety. The chemistry of 50 also provides novel routes to chloromethylenebisphosphonates 51 and 52 after either acidic hydrolysis (HCl 6 M) (except where Y=NMe 2 ) or reaction with an alkyl halide, respectively. This chemistry is well suited to the preparation of bisphosphonates bearing various substituents on carbon (R 3 ) and phosphorus (Y) atoms. 90,93,94a When considering this reaction, it should be noted that formation of methylenebisphosphonates is work-up dependent. On treatment in acidic medium (HCl 6 M) 51 is obtained in moderate to good yield (Table 12). On treatment in basic medium only formation of diethyl chloromethylphosphonate 1 and diethylphosphate is observed resulting from total cleavage of a P-C bond by attack of the LiOH on one of the phosphoryl groups. 90 The chloromethylenebisphosphonates 51 can also be obtained by monodehalogenation of the corresponding dichloromethylenebisphosphonates which are readily prepared by the direct chlorination 94 of tetraalkyl methylenebisphosphonates with sodium hypochlorite (as in Scheme 30). Positive chlorine abstraction has been observed during the reaction between potassium fluoride and tetraisopropyl dichloromethylenebisphosphonate in the presence of 18crown-6 ether. This reaction requires seven days for completion and is followed by work-up and chromatography (55 %). 95 A more effective reaction involving chlorine abstraction occurs between tetraethyl dichloromethylenebisphosphonate and n-BuLi at -80 °C followed by hydrolysis with a saturated NaHCO 3 solution to yield the monochloromethylphosphonate derivative 51 in 79 % yield (Scheme 32). The same result can be achieved by reduction with NaSH at approximately 0 °C, although reductions are particularly sensitive to the nature of the phosphonate esters. Yields are also closely dependent on the reaction temperature used, for example lower temperatures are required for ethyl esters (0°C, 91 % yield; 25 °C, 49 % yield) than for isopropyl (0 °C, 84 % yield; 25 °C, 94 % yield). 97 This dehalogenation reaction was also performed using Na 2 SO 3 as the reducing agent. 94c,d A recently introduced procedure is the selective electrochemical reduction of one chlorine atom of tetraethyl dichloromethylenebisphosphonate which has been accomplished in 70 % yield using a buffered medium. 98

Scheme 31.

IV. Diethyl Chloromethylphosphonate : Chlorine Substitution

Nucleophilic substitution of the chlorine atom in 1 with other groups (amines, thiols, phenols, thiophenols) produces several useful derivatives. It is particularly important to note that nucleophilic substitution of the chlorine atom (route a) competes with the direct attack of the nucleophile on the carbon atom of the ester groups resulting in the cleavage of a C-O bond (route b) (Scheme 33). However, the undesirable alkylation reaction (route b) can be avoided by using phosphonate esters bearing electron withdrawing groups (R = CCl 3 or CF 3 ). 102 The attack of the nucleophilic reagent on the ester carbon atom is thus slowed down. Alkylation can also be avoided by using phosphonamides instead of phosphonate esters. An almost quantitative yield of azidophosphonate results from reaction of bis(trifluoroethyl) chloromethylphosphonate 56 with sodium azide in DMSO at 90 °C. This reaction offers the advantages of mild conditions and higher yields than those obtained from other dialkylesters issued from 2. Chloromethylphosphonates bearing less attracting groups than the trifluoromethyl lead to increasing C-O bond cleavage instead of C-Cl cleavage. Reduction of the intermediate azido phosphonate with H 2 over Pd / C followed by acidic hydrolysis delivers the aminomethylphosphonic acid 59 in 66 % overall yield (Scheme 35). 102 The process has been applied to the synthesis of 1,1-dideuteriomethylphosphonic acid 60 (55 % overall yield from dideuteriated 56, (%D)>95). 102 Azidophosphonamides have been An unsuccessful attempt to prepare the triazole derivatives of 1 was by reaction of diethyl chloromethylphosphonate 1 with potassium-1H-1,2,4-triazole in DMSO as solvent. Rather 1-ethyl-1H-1,2,4-triazole was isolated in this experiment. 104 A novel rearrangement involving an intramolecular substitution of the chlorine atom by an aromatic amine has recently been described. When the unsymmetrical phosphonic diamide 61 is treated with alkoxide, loss of a proton from the anilino-group leads to the synthesis of 63 via a highly reactive three membered ring intermediate 62 (Scheme 36). 105a This reaction has been extended to chlorophosphonamidates in which the N-phenyl group has been replaced by N-alkyl. In this case the reaction can give two products: by P-N cleavage of the three membered ring to give an α-aminophosphonate, or by P-C cleavage to give a phosphoramidate. Scheme 36.

Sulfur-containing Derivatives

Nucleophilic displacements of chlorine in 1 by sulfur containing reagents has been well developed. This reaction is of synthetic importance because it gives access to synthetically useful α-phosphoryl sulfide derivatives 64. However, full utilization of this reaction is often handicapped by the formation of alkyl sulfide through the dealkylation process. 106 Reaction of 1 with sodium alkyl or aryl mercaptides in boiling ether produces the α-phosphoryl sulfides 64 in low to reasonable yield (15-58 %) (Scheme 37). 107 Recently the reaction has been extended to sodium mercaptoethanol which reacts with 1 in boiling THF to give the substitution product in only 40 % yield. 108 Sodium sulfide (Na 2 S) on reaction with compound 1 undergoes a double substitution to provide the corresponding sulfide in low yield (6 %). 107

Scheme 37

A variation of this reaction with sulfur containing reagents is exemplified by the reaction of 1 with dimethyl sulfide. This gives a sulfonium salt which via its ylid is converted into an epoxyphosphonate by reaction with acetaldehyde and thence to phosphonomycin. 67 The reaction between 1 and thiourea was also reported. It was found that thiourea in excess at 125-130 °C without solvent effects both a substitution reaction of the chlorine and a dealkylation reaction of the phosphonate 1 leading to the formation of the salt 65 as the main product (20 %, Scheme 38

Phosphorus Derivatives

The methylenebisphosphonate 66 is obtained from 1 and sodium diethylphosphite (Scheme 39). Apart from diphosphonate 66, a large quantity of solid products is formed as the result of dealkylation of phosphonate esters 1 by sodium dialkyl phosphite, thus the yield of 66 (47 %) 110 is significantly lower than that obtained by other methods.

Scheme 39.

Reaction of 1 with triethylphosphite under drastic conditions (190 °C for 8 h) affords 66 in 27 % yield, according to a Michaelis-Arbuzov process. 111 Under analogous conditions, tetraethylpentamethylene-1,5-diphosphonite reacts with 1 to afford the pentamethylene-1,5bis(diethoxyphosphonylmethyl)phosphinates 67 in high yield (88 %, Scheme 40). 112 The Michaelis-Arbuzov reaction between 1 and the tris(trimethylsilyl)phosphite is also described. 113 Scheme 40.

(EtO) 2 P C H 2 O Cl 2 (H 2 N) 2 C S + 1 O P O OEt C H 2 -S C NH 2 NH 2 + + Et-S C NH 2 NH 2 + Cl - 6 5 - 125-130°C (EtO) 2 P C H 2 O Cl + 1 (EtO) 2 P C H 2 O P(OEt) 2 NaOP(OEt) 2 O 6 6 C 6 H 6 (EtO) 2 P C H 2 O Cl + 1 (EtO) 2 P C H 2 O P(OEt) 2 P(OEt) 3 O 6 6 190°C, 8h

Malonate Derivatives

By a similar procedure, compounds containing an activated methylene group react in their anionic form with 1 to give substituted derivatives, e.g. sodiomalonate reacts with 1 leading to a mixture of ethyl phosphonomalonate 69 and ethyl malonate resulting from a dealkylation of 68. After acidic hydrolysis and decarboxylation, 69 is converted into βphosphonopropionic acid 70 (Scheme 41). 101b

Scheme 41.

Friedel-Crafts Reactions

Reaction of 2 with four equivalents of aniline in acetonitrile gives 70 % yield of chloromethylphosphonodianilide 71. Attemps to cyclize 71 by treatment with AlCl 3 at 160-170 °C give unidentified polymeric materials probably because of the presence of the secondary nitrogen atom. By contrast, the corresponding N,N'-dimethylphosphonodianilide 72, prepared either by bismethylation of 71 or by reaction of 2 with N-methylaniline, undergoes an intramolecular Friedel-Crafts cyclisation on heating with AlCl 3 at 160-170 °C to give 73 in 63 % yield (Scheme 42). Extension of the cyclization reaction to monoamide derivatives by treatment of 2 with two equivalents of N-methylaniline and AlCl 3 was unsuccessful and the starting material recovered. It seems that the propensity for cyclisation is reserved for phosphonodiamides bearing tertiary nitrogen atoms. 114

Aromatic Derivatives

A variety of compounds 74 containing a phosphonomethyl group bonded to an aryl group have been prepared in one step from 1 and aryl bromides when combined in THF at first with t-butyllithium at -78 °C and then with cuprous iodide at 0 °C (Scheme 43). The carboncarbon coupling takes place slowly at room temperature. A series of compounds can be obtained in 56-69 % overall yield using this process. 115 Scheme 43.

Radical Reaction

This new approach to the synthesis of γ-functionalized phosphonates 76 and 77 (R 1 or R 2 = alkyl, ethoxy, butoxy, acetoxy, acetyl, and cyanide groups) is based on the addition reaction of α-phosphorylmethyl radicals to terminal alkenes and alkynes. 116 The radical species are formed in benzene or toluene from 1-halogenophosphonates, using tin or silicon hydrides as radical sources (Scheme 44). The reaction has been applied to both electron-rich and electron-deficient alkenes and alkynes. Under these conditions the direct generation of the diethoxyphosphonylmethyl radical 75 from diethyl chloromethylphosphonate 1 allows moderate yields of functionalized phosphonates 76 and 77 (10-62 %). The only by-product is diethyl methylphosphonate, which is formed via recombination of the intermediate radical with an hydrogen atom. Thus, this methodology is an alternative to the Michaelis-Abuzov and Michaelis-Becker methods for the synthesis of phosphonates, which suffer from a lack of generality.

Scheme 44

V. Other Chloromethylphosphonic Acid Derivatives

Several chloromethylphosphonic acid derivatives, other than 1, have been utilized as synthetic intermediates. The literature concerning their preparation and properties also reports their utility in organic synthesis. The structure of these chloromethylphosphonic acid derivatives plays an important role in determining the outcome of their reactions. The presence

Br (EtO) 2 P C H 2 O Cl 1 (EtO) 2 P O (EtO) 2 P C H 2 O (EtO) 2 P C H 2 O CH=CH-R 2 -(CH 2 ) 3 -R 1 R 1 R 2 R 3 MH / AIBN (R = n-Bu, Me; M = Si, Sn) C 6 H 6 7 5 7 6 7 7
on the phosphorus atom of suitable alkoxy or aminoalkoxy groups promotes specific transformations and allows better stereochemical control of the reactions.

1. 2-Chloromethyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane 2-Chloromethyl-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane 78 is a stable, easy to handle solid (mp 116-118 °C; NMR 31 P (CDCl 3 ) δ = +11.4 ppm). An early reported preparation of 78 includes condensation of 2 with 2,2-dimethylpropane-1,3-diol in dioxane in the presence of pyridine with a modest yield (42 %). 26 On laboratory scale, a recently reported synthesis offers an easy and efficient route to 78 (93 % yield) from the same starting materials. The reaction takes place in dichloromethane without base using a vacuum procedure. 27 The product is soluble in THF, benzene, acetone, ethanol, and water (Scheme 45).

Scheme 45.

Generation of the lithio derivative of 78 is accomplished with LDA at low temperature. The carbanion 79 is very unstable and has to be kept at low temperature, however it is stabilized when generated from two equivalents of LDA. This method of generating 79 was found to be preferable to the use of n-BuLi, as 79 is formed in high yield with LDA with only a trace of by-products. 44 Metallation of 78 in the presence of TMSCl gives 80 as the equatorial conformer (NMR 31 P (CDCl 3 ) δ = +42.6 ppm) which is stable at 0 °C (Scheme 46).

Other silyl chlorides, TESCl, TIPSCl, and TBDMSCl, condense to give their respective organosilylated derivatives. 53 78 has been used on reaction with ethylchloroformate in the presence of two equivalents of LDA for the preparation of 81 which, on reaction with aldehydes, undergoes a typical Horner-Wadsworth-Emmons reaction. 118 The selectivity observed is never high and the thus obtained α-chlorinated acrylic esters 48 show a Z / E ratio of 25 / 75 (Scheme 47). Other applications of 78 include condensation with diphenylchlorophosphine and α,β-unsaturated aldehydes 82 to give 1,3-butadienylphosphine 84 (Scheme 48). 119 The newly formed double bond shows a Z / E ratio of 70 / 30. 120 This method gives better results than that described earlier from 2-chloro-4,5-benzo-1,3,2-dioxaphosphole 86 and paraformaldehyde at high temperature (200 °C) for 3 h for which the yield did not exceed 50 % (Scheme 49). 5a Compound 85 can be used in the synthesis of alkyl and aryl (o-oxyphenoxymethyl) phosphinic acids 89. Attack at the phosphorus atom of 85 by a Grignard reagent leads to ring opening. 121 The magnesium atom appears to be bonded to the phosphoryl group rather than the phenolic oxygen and thus the intermediate magnesium ion does not undergo intramolecular chloride displacement. After neutralisation with HCl, it gives the o-phenyl esters 87, which upon reflux in toluene in the presence of triethylamine cyclise to give the phosphorines 88 (Scheme 50). The cyclic esters 88 are very easily hydrolysed to the phosphinic acids 89. Cleavage of the phosphorine ring is observed on contact with atmospheric moisture. Compounds 89 are able to eliminate water on reflux in xylene, thereby quantitatively reverting to the cyclic esters 88.

Scheme 50.

A similar reaction using various alkoxides in absolute alcohol instead of the Grignard reagents is equally described. 120 This leads to the ring opened compound 90 which recyclises, when heated under reflux in an inert solvent, to give mixtures of the dioxaphosphorin-2-oxides 91 and phosphonates 92 in ratio depending on the amount of residual alcohol in the reaction mixture (Scheme 51).

Ylid Chemistry of Diphenyl Chloromethylphosphonate

Diphenyl chloromethylphosphonate has been utilized as an ylid precursor (bis-ochlorophenyl chloromethylphosphonate is also described). The triphenyl(diphenylphosphonomethylene)phosphorane 95 is obtained on a large scale by quaternarization of triphenylphosphine with diphenyl chloromethylphosphonate 93 at 175 °C for 4 h followed by treatment with an aqueous solution of sodium hydroxide. The desired ylid 95 was recrystallized from ethyl acetate (mp 149-150 °C) in an overall yield of 77 %. It proved to be very stable towards storage at room temperature but reacted smoothly with a variety of aromatic and aliphatic aldehydes at 100-110 °C in DMSO to produce only the trans isomers of the appropriate diphenyl vinylphosphonates 96 (Scheme 52). 122 The use of stabilized ylids such as 95 offers the advantage of not requiring strongly basic reagents for carbanion formation. Deprotonation of each diastereomer with n-BuLi in THF at low temperature followed by alkylation at the same temperature results in formation of the corresponding α-substituted oxazaphospholanes 98a and 98b in moderate yield (40 to 65 %) potassium phthalimide in toluene at 50 °C under sonication conditions gives the corresponding N-phthalimido oxazaphospholanes which are converted into (R) and (S) aminoalkylphosphonic acids 99a and 99b after acidic hydrolysis followed by treatment with ethanolic hydrazine (Scheme 54). 123 Scheme 54.

3-t-Butyl-2-chloromethyl-6, 6-dimethyl-2-oxo-1,3,2-oxazaphosphorinane

The readily available N-t-butyl-3, 3-dimethyl-1,3-amino alcohol is coupled with 2 in dichloromethane in the presence of triethylamine to afford racemic 2-chloromethyl-1,3,2oxazaphosphorinane 100 in 72 % yield. Displacement of the chloride is accomplished by treatment with an allylic potassium alkoxide in the presence of a stoichiometric amount of 18crown-6 ether . 124 In the rearrangement, a single product is observed when R 1 =R 2 =H or R 1 =Me, R 2 =H; a mixture of two diastereomeric products is observed when R 1 =H and R 2 =Me.

The same reaction sequence has been performed starting from optically pure 4-(N-tbutylamino)-2-butanol. The corresponding rearrangement products were obtained in enantiomerically pure form.

Scheme 55.

Bis(dimethylamino) chloromethylphosphonamide

Bis(dimethylamino) chloromethylphosphonamide 103 is a highly hygroscopic white crystalline solid (bp 117-118 °C / 4 mmHg; mp 48.5-49.5 °C; NMR 31 P(CDCl 3 ) δ = +30.4 ppm). The compound is prepared by the reaction of 2 with excess dimethylamine in THF. The

O R 2 R 1 K + P O O N M e M e t-Bu O R 2 R 1 P O O N M e M e t-Bu O R 2 R 1 Li P O O N M e M e t-Bu R 2 R 1 OH 18-crown-6 n-BuLi -70°C, THF + - THF 1 0 0 1 0 1 1 0 2 NEt 3
reaction proceeds in nearly quantitative crude yield. The lithium reagent 104 prepared at low temperature from 103 and n-butyllithium, reacts with aldehydes to give an intermediate chlorohydrin 105. In the presence of a second equivalent of metalating agent, 105 undergoes dehydrochlorination to produce, after hydrolysis, the synthetically useful 2oxoalkylphosphonamides 107 in high yield (Scheme 56). 70,125 Scheme 56.

2-Chloromethyl

-1,3-dimethyl-2-oxo-1,3,2-diazaphospholane 2-Chloromethyl-1,3-dimethyl-2-oxo-1,3,2-
diazaphospholane 108 is a stable but moisture sensitive solid (mp 75-77 °C, NMR 31 P (CDCl 3 ) δ = +29.8 ppm). 117 The compound is prepared in THF by reaction of chloromethylphosphonyl dichloride 2 with N,N'dimethylethylenediamine in the presence of triethylamine. The reaction proceeds in nearly quantitative crude yield. When reacted simultaneously with 2 equivalents of LDA and a chloroformate, 108 yields the lithium enolate 109. On reaction with an aldehyde, the αchlorinated acrylic esters 48 are formed. The cyclic diazaphospholane moiety appears to exert a major influence on the stereoselectivity of the reaction and 48 show predominantly E stereochemistry (Scheme 57 and Table 14). 118 By contrast, 48 are obtained from the triethyl α-chlorophosphonocarboxylate 49 as either isomeric mixtures or pure Z isomers (Scheme 28 and Compound 110 is synthesised in benzene from the reaction between chloromethylphosphonyl dichloride 2 and 1,2-bis(N-methylamino)cyclohexane in the presence of triethylamine. When the (R,R)-1,2-bis(N-methylamino)cyclohexane (a readily available C 2 symmetrical template) is used, the resulting phosphonamide 110 is obtained. In the presence of a base such as n-BuLi or LDA in THF at -100 °C, 110 can be alkylated at the prochiral α- 15). 126 Attack takes place from the "pro R" side of the planar anion, through a Li-coordinated intermediate. Furthermore these phosphonamides can easily be hydrolysed under mild conditions to give optically pure (R)-αchloroalkylphosphonic acids again in excellent yields. The opposite enantiomer (S) of the phosphonic acids 112 can be obtained starting from the phosphonamide 110 prepared from the (S,S)-diamine.

Scheme 58. α-Aminoalkylphosphonic acids 115, which are probably the most important analogues of α-amino acids in biological systems, 127 can be synthesised in enantiomerically pure or enriched form via a similar methodology by using the chloromethylphosphonamide 110 and sodium azide as precursor of the amino group (Scheme 59 and Table 16). 103 Scheme 59. C 6 H 5 CH 2 Br >1 : 99 86 An alternative approach for the asymmetric synthesis of α-aminoalkylphosphonic acids from 110 is based on the stereoselective addition of the corresponding lithiated carbanion to imines. The thus obtained aziridines 116 are then ring opened by hydrogenolytic cleavage to give the α-aminoalkylphosphonamides 117 which are in turn hydrolysed to the corresponding phosphonic acids, isolated as the dimethyl phosphonate 118 (Scheme 60). 128

Scheme 60.

The chloromethylphosphonamide 110 is also used as chiral starting material for the synthesis of the enantiomerically pure cyclopropylphosphonamides 119. The stereocontrolled conjugate addition of anion derived from 110 to α,β-unsaturated esters leads to the corresponding 1-chloro-3-carboxypropyl phosphonate adduct which undergoes intramolecular expulsion of the chlorine atom to give the corresponding cyclopropanes 119 (Scheme 61). Further transformations of 119 allowed the synthesis of 2-aminocyclopropylphosphonic acid 120 in optically pure form.

VI. Conclusion

This review demonstrates the versatility of chloromethylphosphonyl compounds as starting materials for preparing a vast array of useful functionalized phosphonates and nonphosphorylated organic materials. These can be realised either by the use of 1lithiochloromethylphosphonate or by nucleophilic substitution of the chlorine atom. The rich and various chemistry of chloromethylphosphonic acid derivatives, esters and amides, covers a large area from the formation of synthetically useful derivatives to the preparation of phosphorus compounds possessing biological activity. In addition, many of the methods described in this aricle can be accomplished with complete stereochemical control thanks to the suitable choice of substituents of the phosphorus atom. We hope that this review will help the exploration of this valuable area of phosphorus chemistry.

VII. 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 for financial support to R. W. and J. C.

VIII. References

  Scheme 9.

40

 40

  Scheme 11.

67

 67

  Scheme 16.

  Scheme 23.

  Scheme 25.

  Scheme 26.

  Scheme 28.

89

 89

  Scheme 30.

96

 96

  Scheme 32.

  Scheme 35.

  Scheme 48.

  Scheme 51

  Scheme 52.

  to give the corresponding racemic 1,3,2-oxazaphosphorinane 101. Deprotonation of 101 at -70 °C with n-BuLi in THF generated the phosphorus-stabilized anion which underwent a[2,3]-Wittig rearrangement to afford the 2-(1'-hydroxybut-3'-enyl)-1,3,2- good yield (Scheme 55)

  position to give essentially a single diastereoisomer of the alkylated phosphonamides 111 in O excellent optical purity (Scheme 58 and Table

  129

  Scheme 61

  Johnson, A.W. Ylid Chemistry; Academic Press: New York, 1966. (b) Boutagy, J.; Thomas, R. Chem.Rev. 1974, 74, 87. (c) Wadsworth, W. Org. React.. 1977, 25, 73. (d)

6

  Scheme 2.

	PCl 3 + CH 2 Cl 2	1) AlCl 3 2) H 2 O
	PCl 3	+ (CH 2 O) n		250	°C	Cl 2 P C H 2 O	Cl
							2
							3 COCl 2 Ph 3 P cat. 150 °C
	(HO) 2 PH O	+ (CH 2 O) n	100	°C	(HO) 2 P C H 2 O	OH
	O Cl 2 P C H 2 2	Cl	2 EtOH -2 HCl	(EtO) 2 P C H 2 O 1	Cl
	O			R 1 OH neat or with	O
	Cl 2 P	2 CH 2 Cl	THF or CH 2 Cl 2 vacuum or R 3 N stream of dry air,	(R 1 O) 2 P CH 2	Cl

Table 1 .

 1 Reactions of 2 with alcohols

	R 1 OH	Yield (%)	Ref.
	methanol	66 or 90	7 or 8,
	ethanol	72-95	5c, 7,8, 10-14
	1-chloro-2-ethanol	66 or 72	5f or
	2-ethylsulfanyl-ethanol	32	16
	2-2'-(5'-vinylpyridyl)-ethanol		17
	1,1,1-trichloro-2-ethanol	59 or 90	5f or
	1,1,1-trifluoro-2-ethanol	92	11
	2-morpholino-ethanol	76	18
	n-propanol	82	19
	isopropanol	74-79 or 85	8,14, 20 or 11
	butanol	55-94	8, 20, 21
	isopentanol	79	20
	4-hydroxy-2,2,6,6-tetramethyl-	97	22
	piperidinoxide
	n-pentanol, hexanol, nonanol,		19
	decanol, 6-methylheptanol
	2-ethyl-hexanol	94-99	19, 9
	octanol	51	23
	ethanediol	63	24
	1,2-propanediol	81	24
	1,3-propanediol	47 or 94	25

Table 2 .

 2 Gem-dichloroolefins from H-W-E reactions of

	Dichloroolefin 18	Yield (%)	Ref
	X				X = F	80
				Cl
		H		Cl	X = Cl	67
	O				62 *
	O			Cl
		H		Cl
		R		Cl	R = H	77
				Cl
					R = Me	78
		Me
				Cl
				Cl
		Me			71
		Me Me	Cl	84
				Cl
		i-Pr		Cl	70
				Cl
	Me
		Me
				Cl
				Cl
	H 2 C				88
		Me
		Me
		C	Me
				Cl
				Cl	90
	Me
	Me	Me Me Cl	80 *
				Cl

  61

		Cl
		Cl
		Cl
		Cl
		Me OMe
	Me Me	O	Cl
			Cl
		Cl
		Cl
	Scheme 14.

Table 3 .

 3 Gem

	R 1	R 2	Yield (%)
	5 p-MeC 6 H 4 p-MeOC 6 H 4 C 6 H 5 C 6 H 5 C 6 H 5 p-FC 6 H 4 p-FC 6 H 4 p-MeOC 6 H 4 p-MeOC 6 H 4 86 95 93 88 89

-dibromoolefins from H-W-E reactions Dibromoolefin 24

Yield (%) Ref.

Table 4 .

 4 1,2-Epoxyalkylphosphonates 2765

	R 1	R 2	Yield (%)
	Me	Me	80
	Et	Et	89
	i-Pr	i-Pr	88
	Me	Et	85
	Me	i-Pr	86
	Me	t-Bu	75
	Me	i-Bu	81
	Me	-CH=CH 2	36
	Me	-C(Me)=CH 2	75
	Me	-CH(OMe) 2	76
	Me	cyclo-Pr	90
	Me	C 6 H 5	51
	H	Me	65
	H	i-Pr	66
	H	i-Bu	56

Table 5 .

 5 1-Formylphosphonates 2869

	R 1	R 2	Yield (%)
	Me	Me	76
	Me	Et	78
	i-Pr	Me	75
	Me	n-Pr	75
	cyclo-Pr	Me	72
	t-Bu	Me	62
	Me	n-Pent	68
	C 6 H 5	Me	68 68a, 69
	Et	Et	78

  70

Table 7 .

 7 1,2-Aziridinealkylphosphonates 3471

	P O 3 (EtO) 2	C Cl Li	H	Ar 1 -CH=N-Ar 2 -78°C,THF	O P Cl (EtO) 2 3 3	C Li	C N H	H Ar 1 Ar 2
					Ar 2
			Δ	P O (EtO) 2	C C N	Ar 1
				3 4	H H
	Ar 1	Ar 2	Yield (%)
	C 6 H 5	C 6 H 5		85
	3-Cl-C 6 H 4	C 6 H 5		30
	4-Cl-C 6 H 4	C 6 H 5		95
	3-NO 2 -C 6 H 4	C 6 H 5		67
	4-NO 2 -C 6 H 4	C 6 H 5		51
	3-Me-C 6 H 4	C 6 H 5		70
	O
		C 6 H 5		94
	O
	4-MeO-C 6 H 4	C 6 H 5		53
	C 6 H 5	4-Br-C 6 H 4	80

Table 8 .

 8 α-Chloroacrylic acids 3772

	R 1	R 2	Isomer	Yield (%)
	C 6 H 5	H	Z	67
	2-MeO-C 6 H 4	H	Z	83
	4-MeO-C 6 H 4	H	Z	83
	4-(Me) 2 N-C 6 H 4	H	Z	86
	4-Cl-C 6 H 4	H	Z	86
		H	Z	91
	3-pyridyl	H	Z	41
	2-thiophenyl	H	E+Z	85
	C 6 H 5 -CH=CH-	H	E+Z	96

Table 9 .

 9 1-Chloro-2-oxoalkylphosphonates 46

	46	R	Yield(%)	Ref.
	a	Me	82	79
	b	Et	81	79
	c	(CH 2 ) 4 Me	75	79
	d	C 6 H 5	72	79
	e	CO 2 Et	76	79, 80
	f	CO 2 -i-Pr	40	79, 80
	g	CH(OEt) 2	81	79
	h	H	85	79, 82

Reaction of 3 with ethyl or isopropyl oxalate provides a convenient preparation of αchlorinated phosphonopyruvates 46 e, f. The reaction proceeds in the presence of LDA via the formation of a transient lithio enolate 45 (R = CO 2 Et, R = CO 2 i-Pr) and without any byproducts (Scheme 26).

Table 10 .

 10 α-Chloroacrylic esters 4886

	R	Z / E ratio	Yield (%)
	i-Pr	60 / 40	33
	C 6 H 5	100 / 0	75
	2-Cl-C 6 H 4	100 / 0	81
	4-Me-C 6 H 4	100 / 0	44
	4-F-C 6 H 4	100 / 0	62
	2-thiophenyl	100 / 0	88

Table 11 .

 11 1-Chloro-1-vinylphosphonates 53

	Y	R 1	R 2	Z / E	Yield (%)	Ref.
	EtO	H	Me	89 / 11	89
	EtO	H	Et	90 / 10	90
	EtO	H	i-Pr	80 / 20	91
	EtO	H	n-Pr	*	61
	EtO	H	i-Bu	85 / 15	91
	EtO	H	C 6 H 5	90 / 10	80
	EtO	H	4-MeO-C 6 H 4	*	92
	EtO	H	3-Br-C 6 H 4	*	78
	EtO	Me	Me		84
	EtO	Me	C 6 H 5		28
	EtO		-(CH 2 ) 5 -		59
	EtO		-(CH 2 ) 4 -		60
	C 6 H 5	H	Me	83 / 17	60
	C 6 H 5	H	C 6 H 5	85 / 15	50
	(Me) 2 N	H	Me	72 / 28	65
	*= unknown ratio

Table 12 .

 12

		1-Chloromethylenebisphosphonates 51 90
	Y	Yield (%)
	EtO	81
		51
	(Me) 2 N	53
	C 6 H 5	69

  [START_REF] Kirby | The Organic Chemistry of Phosphorus[END_REF] It has been increasingly recognized that a number of aminophosphonic acids structurally related to natural aminocarboxylic acids are able to inhibit or perturb a given metabolic reaction. So it is common to find the introduction of a phosphonic acid group in place of the normal carboxylic acid group.This analogy has induced a lot of work devoted to the nucleophilic amination of 1, the aminating agents being NH 4 OH, 100 R 1 R 2 NH 101 or NaN3 . 102 The first method for the preparation of diethyl aminomethylphosphonate involved the amination of 1 with a 25 % aqueous solution of NH 3 in a sealed tube at 150 °C.100 It has been demonstrated that the replacement of Cl by NH 2 is more rapid in H 2 O than in absolute ethanol. The only product obtained was 54(45 % yield); 54 treated with aqueous solution of HCl at 120-140 °C for 3 h gives 55 in 94 % yield (Scheme 34).100 Other methods for the preparation of 55 involve the interaction of chloromethylphosphonic acid with NH 4 OH (25 h at 100 °C), 100 an aqueous solution of methylamine (7 h at 150 °C and 25 bar), 101a aniline in excess (20 h at 160-170 °C), 101b hydrazine hydrate 101c or polymethylenediamines (20 h at reflux in water).

	P O (EtO) 2 1. Amino Derivatives	C H 2	P(OEt) 2 O	NaOCl	P O (EtO) 2	C Cl	P(OEt) 2 O
											Cl
											n-BuLi
											-78°C,THF
	P O (EtO) 2	C H	P(OEt) 2 O				P O (EtO) 2	C Li -+	P(OEt) 2 O
	5 1	Cl								Cl
	RCH 2 O RCH 2 O	O P	C H 2 Cl a b	+	Nu	-	b a	RCH 2 O RCH 2 O RCH 2 O -O	O P P O	C H 2 Nu C H 2 Cl
	Scheme 33.

101d

By the reaction of tertiary amines with 1 (120-130 °C for 12 h in a sealed tube) a series of diethoxyphosphinylmethyl trialkylammonium salts were obtained in low yield

(15-19 %)

. 101e Scheme 34.

Table 13 . 1-Arylmethylphosphonates 74 115

 13

	Ar-Br	Yield (%)
		65
		64
		56

  . Reaction of each isomer with

	O ( C 6 H 5 O) 2 P C H 2 9 3 Cl	( C 6 H 5 ) 3 P 175°C	( C 6 H 5 O) 2 P C H 2 O NaOH P(C 6 H 5 ) 3 -+ Cl 9 4
							H 2 O
						O	-	+
					( C 6 H 5 O) 2 P C H	P(C 6 H 5 ) 3
						9 5	RCHO
	R			Yield (%)		toluene, 110°C
	2-naphthyl 4-chlorobenzyl 4-nitrobenzyl valeryl	66 84 92 95	( C 6 H 5 O) 2 P O H 9 6	C	C	H R
	O Cl 2 P C H 2 Cl 2		NEt 3 ,THF	C 6 H 5 M e 9 7 a	N O M e P	C H 2 O Cl
	+
	H MeN M e	OH C 6 H 5			9 7 b M e C 6 H 5	N M e P O	C H 2 Cl O

Table 10 )

 10 .

	(Me 2 N) 2 P O 1 0 3	C H 2 Cl	n-BuLi -78°C,THF	O (Me 2 N) 2 P 1 0 4	Li C Cl H
								RCHO
	O	Li	O		n-BuLi, THF		O	Li	O
	(Me 2 N) 2 P 1 0 6	C H	C	R	-70 to +20°C	(Me 2 N) 2 P Cl 1 0 5	C	C H	H R
			H 2 O
						R	Yield (%)
	P O (Me 2 N) 2 1 0 7	C H 2 C O	R	i-Pr C 6 H 5 2-thienyl		76 88 87

Table 14 .

 14 α-Chlorinated acrylic esters 48118

	R	Yield (%)	Z / E
	n-Pr	94	2 / 98
	i-Bu	99	3 / 97
	Et 2 CH	99	3 / 97
	n-C 6 H 12	96	2 / 98
	cyclo-C 6 H 12	98	2 / 98
	n-C 9 H 19	99	2 / 98
	C 6 H 5	99	9 / 91
	8. N,N'-Dimethyl-N,N'-(1,2-cyclohexyl) Chloromethylphosphonamide

Table 15 .

 15 Optically active 1-chloroalkylphosphonic acids 112126

	(R, R) Series RX	Ratio (R : S) of 111	Yield of 112(%)
	MeI	90 : 10	95 (R)
	EtI	>99 : 1	98
	n-PrI	>99 : 1	97
	CH 2 =CHCH 2 Br	>99 : 1	quant
	C 6 H 5 CH 2 Br	91 : 9	quant
	(S, S) series RX
	C 6 H 5 CH 2 Br	7 : 93	98 (S)
	EtI	>1 : 99	97

Table 16 .

 16 Optically active 1-aminoalkylphosphonic acids 115103

	(R, R) Series RX	Ratio (R : S) of 114	Yield of 115 (%)
	MeI	90 : 10	82 (R)
	EtI	>95 : 5	84
	n-PrI	>99 : 1	86
	CH 2 =CHCH 2 Br	>99 : 1	88
	C 6 H 5 CH 2 Br	>99 : 1	87
	(S, S) series RX
	MeI	8 : 92	84 (S)


Rachel Dizière

Philippe Savignac

A New Simple Method for the Synthesis of 1-Alkynylphosphonates using (EtO) 2 P(O)CCl 3 as Precursor

1-Alkynylphosphonates 4 were obtained from (EtO) 2 P(O)CCl 3 1 and aldehydes in a one-pot procedure. It involves the formation of α-chlorovinyl phosphonate intermediates 3 by a Peterson olefination reaction followed by dehydrochlorination with LiHMDS.

Diethyl trichloromethylphosphonate 1, which is readily available on a laboratory scale 1 and also commercially, has already been cited as a useful reagent. 2 In preceding papers we described syntheses of medium size (4-6 membered) cycloalkylphosphonates 3 and 1formylalkylphosphonates 4 both relying upon the successive exchange of the three-chlorine atoms of the phosphonate 1. Based on the same approach, we would like to report in this paper our preliminary results on a promising one-pot synthesis of 1-alkynylphosphonates 4 which are of growing interest as useful synthetic intermediates. 5 Petrov in 1962, Sturtz in 1967 then Chattha and Aguiar in 1971, reported the synthesis of 1-alkynylphosphonates via an alkylation strategy between halophosphates and salts (Na, Mg) of terminal alkynes. 6 It is currently the best alternative to the present synthesis, however this method, in terms of generality, is closely dependent on the availability of the acetylenic substracts R-C∫C-H and moreover yields are only reasonable (51-70%). Other routes are rather elaborated and / or give low overall yields. 7 Our method is based on the formation of α-chlorovinylphosphonates via a Peterson reaction followed by dehydrochlorination to generate the triple bond. It can be described in a three-step sequence (Scheme 1). In the first step, addition of a mixture of diethyl trichloromethylphosphonate 1 and chlorotrimethylsilane to butyllithium (2.1 equiv.) in tetrahydrofuran at low temperature takes place through a double chlorine -lithium exchange conducing to the stabilized α-phosphorylated α-silylated α-chlorinated carbanion 2 [δ P (THF) +46.9].

Scheme 1

Carbanion 2 can be trapped at -78 °C with a variety of aldehydes (aromatic, heteroaromatic, aliphatic saturated or unsaturated) yielding α-silylated α-chlorinated βlithiatedhydroxyphosphonates which spontaneously eliminate via a Peterson olefination reaction to give in quantitative yield an isomeric mixture of the two expected αchlorovinylphosphonates 3 easily identified by 31 P NMR analysis [δ P (THF) (E) ♠ +11 and (Z) ♠ +7]. We assumed that the vinylic proton of 3 was acidic enough to be removed by a base. Three lithiated amides, LDA, LiTMP and LiHMDS were tested at low temperature with compound 3a (R = Ph). LDA was not usable here because it gives not only the compound 4a but also by-products detected by 31 P analysis and resulting probably from nucleophilic attack on the generated Michael acceptor 4a. Being more bulky, LiTMP and LiHMDS both give a clean and selective conversion without contamination of the products 4. We selected LiHMDS (1.5 equiv) which is cheaper than LiTMP and easily eliminated on acidic work-up so increasing the ease of isolation of the products. The evolution of the reaction being monitored by 31 P NMR spectroscopy, we observed that 1-alkynylphosphonates 4, which appeared at high field in 31 P NMR analysis [δ P (THF) ♠ -6], are rapidly generated from the (Z) isomer through an anti-dehydrochlorination reaction whereas the (E) isomer is consumed more slowly. When R is aromatic (4a-f) the temperature of the reaction mixture is slowly elevated from -78°C to 0 °C and hydrolysed at that temperature ; during the process it appeared a slight brownish coloration which disappeared on acidic treatment. By contrast when R is heteroaromatic (4g-l) the reaction mixture is kept at low temperature all along the reaction before hydrolysis otherwise on warming we observe a dark brown colour corresponding to the decomposition of compounds 4. As could be expected when R is aliphatic, the vinylic proton of 3 is much less reactive than previously and we obtained 4 mixed with by-products resulting from Michael addition type reaction. We are currently extending the field of bases to inorganic or covalent bases in order to generalize the utility of the process. All the 1-alkynylphosphonates 4 reported in Table 1 were isolated with very good yields (87 -96 %) and high purity after purification by bulb-to-bulb distillation or chromatography.

Table 1 .

 1 Characteristics of 1-Alkynylphosphonates 4a-l

	-R	Reaction	δ 31 P (ppm)	δ 13 C of P-C 1 ∫C 2 (ppm)	Yields
		temp.	(CDCl 3 )	(CDCl 3 )	(%)
	a	-78 ∅ 0 °C	-7.8	78.0 (d, 1 J CP =298.7, C 1 ), 98.4 (d, 2 J CP =51.9, C 2 ).	89 a, c
	b	-78 ∅ 0 °C	-8.0	78.3 (d, 1 J CP =298.6, C 1 ), 97.8 (d, 2 J CP =53.2, C 2 ).	92 a, c
	c	-78 ∅ 0 °C	-7.6	77.5 (d, 1 J CP =299.1, C 1 ), 99.0 (d, 2 J CP =53.1, C 2 ).	87 a, d
	d	-78 ∅ 0 °C	-7.2	77.0 (d, 1 J CP =300.6, C 1 ), 99.5 (d, 2 J CP =53.4, C 2 ).	91 a, d
		-78 ∅ 0 °C	-7.5	76.5 (d, 1 J CP =299.1, C 1 ),	96 a, d
	e			98.8 (d, 2 J CP =53.4, C 2 ).
	f	-78 ∅ 0 °C	-6.3	76.3 (d, 1 J CP =303.7, C 1 ), 102.2 (d, 2 J CP =55.0, C 2 ).	93 b, d
	g	-60 °C (3h)	-9.0	77.1 (d, 1 J CP =292.3, C 1 ), 96.5 (d, 2 J CP =50.4, C 2 ).	95 b, e
	h	-60 °C (3h)	-8.8	81.9 (d, 1 J CP =295.4, C 1 ), 95.3 (d, 2 J CP =52.1, C 2 ).	96 b, e
		-60 °C (2h)	-7.1	83.1 (d, 1 J CP =300.8, C 1 ), 92.2 (d, 2 J CP =54.9, C 2 ).	96 b, d
	i
	j	-50 °C (2h)	-8.6	83.9 (d, 1 J CP =296.1, C 1 ), 88.9 (d, 2 J CP =53.4, C 2 ).	89 a, d
	k	-50 °C (2h)	-8.1	82.0 (d, 1 J CP =297.5, C 1 ), 91.7 (d, 2 J CP =54.1, C 2 ).	91 a, d
	l	-50 °C (2h)	-7.7	78.2 (d, 1 J CP =299.3, C 1 ), 94.5 (d, 2 J CP =54.5, C 2 ).	89 a, c
	a Work-up with 2 N HCl

b Work-up with a saturated solution of NH 4 Cl c Purified by distillation (appropriated for 4 if b. p. of corresponding R-CHO ≤ 200 °C) d Purified by chromatography (hexane / AcOEt) e Crude yield : product unstable toward distillation and too polar for purification by chromatography.

ACKNOWLEDGMENTS

We gratefully acknowledge the financial support by the Centre National de la Recherche Scientifique for one of us (R. D.).


John Carran

Rachel Waschbüsch

Angela Marinetti

Philippe Savignac

An Improved Synthesis of Dichloroalkylphosphonates, Chloroalkynes and Terminal Alkynes via Diethyl Dichloromethylphosphonate

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An Improved Synthesis of Dichloroalkylphosphonates, Chloroalkynes and Terminal

Alkynes via Diethyl Dichloromethylphosphonate

John Carran, Rachel Waschbüsch, Angela Marinetti, Philippe Savignac Hétéroatomes et Coordination, URA CNRS 1499, DCPH, Ecole Polytechnique, 91128 Palaiseau Cedex, France.

Diethyl 1,1-dichloromethylphosphonate (2) was synthesised in good yield from the reduction of 1,1,1-trichloromethylphosphonate (1) with i-C 3 H 7 MgCl and subsequent hydrolysis. The reactivity of 2 towards α-alkylation and its utility in the synthesis of chloroalkynes and terminal alkynes was investigated.

1,1-Dichloromethylphosphonate (2) is a useful Wittig-Horner olefination reagent giving dichloroalkenes on reaction with carbonyl compounds. [1][2][3][4] Suitable dichloroalkenes are in turn potential intermediates in the synthesis of chloroalkynes and terminal alkynes via elimination reactions. 4 Given its wide synthetic potential an optimized large scale synthesis of 1,1-dichloromethylphosphonate using simple, cheap, and easily available materials with the minimum of purification requirements is desired. This compound was first synthesised by Cadogan 5 but in moderate yield (65%) and in the presence of side products which make purification difficult. Attempts to synthesise this target compound by means of the Michaelis-Arbuzov reaction between triethyl phosphite and chloroform failed to yield any product even under forcing conditions. 6 1,1,1-Trichloromethylphosphonate (1), which is commercially available and readily prepared on laboratory scale, 7 has been envisaged by many authors as a synthetic precursor for 1,1dichloromethylphosphonate. This group and other researchers have attempted optimisation of the synthesis of 2 from 1. Various approaches have been tried, e.g. abstraction or exchange of one chlorine atom with a base or reductive procedures. Thus, the reactions of 1 with covalent organic bases (such as (EtO) 3 P 5 and (Me 2 N) 3 P ) and charged organic bases (such as n-1,4 and s-BuLi), with tributyl tin hydride, Cl 3 SiH/Et 3 N 8 , and molecular hydrogen have been studied.

In each of these cases the reaction gave the required product 2, often in reasonable yield, but always in the presence of undesirable side-products. In the reaction between (EtO) 3 P and 1 in hexanol as solvent and proton source, 2 is formed jointly with hexyl diethyl phosphate ((EtO) 2 P(O)OHex), which is very difficult to eliminate.

In the case of (Me 2 N) 3 P (Table 1) the final product 2, isolated after reduction at room temperature with EtOH as protonating agent, is contaminated with (Me 2 N) 3 P(O) (6-8%) despite several acidic washings. With Cl 3 SiH and Et 3 N in C 6 H 6 at room temperature the reduction is complete but SiCl 4 is formed which is difficult to remove in a large scale synthesis without degradation of the desired phosphonate 2. When 1 was subjected to catalytic hydrogenation in EtOH over a palladium catalyst or reduction with Bu 3 SnH in THF the desired product was obtained in a non-separable mixture of dichloro-, monochloro-, and methylphosphonates. The lithium-chlorine exchange reaction by means of alkyl lithium reagents in THF at -78°C (with or without the addition of lithium salts) (Table 1) results in the formation of many different side-products (generally four or five are detected by 31 P NMR spectroscopy) which are again inseparable from the desired compound 2. These side-products can be assumed to arise from unfavourable reactions between the strong nucleophilic base and the phosphorus moiety and/or formation of the carbene via halogen abstraction from the unstable carbanion. Finally, we found that by using isopropyl-magnesium chloride at low temperature and by conducting the hydrolysis with ethanolic HCl, pure 2 could be obtained on a molar scale in 94% yield from 1 (Scheme 1). 9

Scheme 1

The use of the Grignard reagent favours the metal-halogen exchange reaction and avoids problems such as attack at phosphorus and carbene formation because of the increased thermal stability of the dichloroanion. This synthesis is much more efficient than those previously reported and fulfills our previous requirements by : a) Utilizing a stable, cheap and widely available laboratory reagent. b) Giving an easily eliminable co-product (i-C 3 H 7 Cl).

c) The final product being easily purified by means of a simple distillation and obtained in greater than 90% yield.

We then conducted a series of experiments with 2 to optimise its reactivity and potential in organic synthesis. Two types of reactions were considered: metalation-alkylation, leading to α-alkylmethylphosphonates, 10 and Wittig-Horner like reactions with aldehydes. Both sets of experiments were conducted in mild, internal quenching conditions in order to trap the unstable dichloroanion derived from 2. However the magnesium derivative of 2 is neither sufficiently basic nor nucleophilic to undergo further alkylation or olefination reactions, it has been replaced by the more powerful lithium reagent. By simultaneous addition of the phosphonate reactant and the prospective electrophile to the lithiated base the lifetime of the carbanion is very short and carbene formation via chloride elimination is thus avoided.

Addition of dichloromethylphosphonate 2 and the alkyl halide to LiHMDS at low temperature led to the alkylphosphonates 3a-h in yields ranging from 67% to 97% (Scheme 2, Table 2).

Scheme 2 LiHMDS was selected because it is a fairly weak, sterically hindered base which specifically forms the anion of the dichloromethylphosphonate by proton abstraction and avoids the problems of more nucleophilic, less hindered bases such as n-BuLi, i.e. the formation of unwanted side products from nucleophilic attack on the phosphorus moiety. The instantaneous formation and reaction between the unstable anion and the electrophile leads to high yields of pure products via a simple experimental procedure. The process is a one-pot reaction which shows no traces of anion decomposition (the characteristic darkening of the reaction medium typical of these unstable anions) and no special preparation of reagents is required. In all cases, except those of allyl bromide and crotyl bromide, the above reaction smoothly proceeds to give the required alkylated product 3 in about 90% yield. With allyl bromide and crotyl bromide a competing side-reaction appears to occur under the conditions used (the respective iodides gave similar results). The side product, which is present as a series of small peaks in the vinylic portion of the 1 H spectrum, is supposed to be an elimination product formed by reaction of the small amount of excess base with the intermediate allyl phosphonate. When 2.3 equivalents of LiHMDS were used in the reaction the side product was observed in greater proportion than before. The elimination product is usually formed in less than 5% yield under the conditions employed and can be removed by careful distillation under water pump pressure. Quantitative formation of the trimethylsilyl substituted derivative 3h was observed by 31 P NMR spectroscopy (δ (THF) = 12.9 ppm) of the reaction mixture prior to hydrolysis, on reaction of 1 with chlorotrimethylsilane at low temperature. Compound 3h proved to be fragile and decomposed after hydrolysis with HCl to a mixture of several compounds giving major peaks in the 31 P NMR spectrum at 23.0, 15.3, 10.5, and -1.0 ppm.

(EtO) 2 P CCl 3 O (EtO) 2 P CCl 2 H O (i) i-PrMgCl / THF / -78°C (ii) EtOH / HCl 3M 1 2 (EtO) 2 P CCl 2 H O 2 (ii) HCl 2M (EtO) 2 P CCl 2 R O 3 3 a b c d e f g h R Et Pr Bu Hept Benzyl Allyl Crotyl TMS X I I I I Br Br Br Cl + RX (i) LiHMDS/THF/-78°C
h d,e 12.9 (THF) ----------- ---------- --------------
We next examined the synthesis of chloroacetylenes by reaction of the anion of 2 with aldehydes. A variety of chloroacetylenes (5a-e) were synthesized under internal quench conditions by using 2.2 equivalents of a lithium amide (acting successively as metalating agent and as base) (Scheme 3).

Scheme 3

The initial step is a classical Wittig-Horner reaction between the phosphonate carbanion and the aldehyde giving the gem dichloroolefin 4. The second step, which occurs on warming, is a trans elimination affording chloroacetylene 5. LiHMDS is a well suited base for the clean conversion of aromatic aldehydes into the corresponding chloroacetylenes however it was insufficiently strong enough to effect the trans elimination of HCl when aliphatic aldehydes were used as starting materials. Thus, the gem-dichloroolefins 4f and 4g were obtained as the sole products (60-80% yield) in the reactions with phenylpropionaldehyde and decanal with LiHMDS as base. The corresponding chloroacetylenes 5f and 5g could be obtained from these compounds by further reaction with one equivalent of LDA or directly from dichloromethyl phosphonate and the above aldehydes in the presence of 2.2 equivalents of LDA. Alkynes 5a-g are moderately stable in their pure state and should be stored at -10°C.

Reaction of a mixture of 2 and an aldehyde in internal quench conditions with one equivalent of LDA in THF at -78°C followed by addition of 2.1 equivalents of n-BuLi at -78°C affords compounds 7a-e in high yields and high degrees of purity after careful acidic hydrolysis (pH 5-6) (Scheme 4). BuLi is supposed to effect the chlorine-lithium exchange reaction on the intermediate dichloroolefin 4 and LDA, reformed from the second equivalent of n-BuLi, to effect the elimination reaction leading to the lithiated alkyne 6. LiHMDS is not a strong enough base to act in this manner whatever the nature of the aldehyde. Alkynes 7a-c were unstable in crude form and rapidly decomposed at room temperature. We found that the decomposition could be somewhat reduced by keeping the alkynes as solutions in hexane if they are not to be purified or used immediately. Alkynes 7d and 7e were found to be relatively stable in their pure form and could be conserved in the refrigerator without significant decomposition. Alternative synthesis of terminal acetylenes from aldehydes have been reported previously by Corey and Fuchs using the reagent couple Ph 3 P/CBr 4 , 11 and by both Colvin et al and Gilbert and Weerasooriya using dimethyl diazomethylphosphonate. 12,13 The amount of triphenylphosphine involved and of triphenylphosphine oxide formed in the former reaction and the difficult and hazardous preparation of the reagent in the latter are obstacles for large scale synthesis. By contrast the present route, which is a modification of the Villieras approach, 4 (which can occasionally give mixtures of compounds as reported recently by Lowen and Almond), 14 seems well suited for the synthesis of a wide variety of pure acetylenic compounds on a large scale. It is clear from the above results that we now have at our disposal a large scale, high yielding preparation of 2, an extremely useful synthetic reagent. The correct choice of deprotonating agent according to its basicity, (n-BuLi, LiHMDS, LDA) when applied together with internal quench conditions to reactions of 2, controls the selective formation of gem dichloroolefins, chloroalkynes and alkynes, in high yields and one pot procedures without formation of side products. All these useful reagents can now be accessed on preparative scale by the above procedures from 2.

NMR spectra were recorded on a Bruker AC 200 spectrometer operating at 200 MHz for proton, 50.3 MHz for carbon and 81.01 MHz for phosphorus. 31 P downfield shifts (δ) are expressed with a positive sign, in ppm, relative to external 85% H 3 PO 4 in H 2 O. 1 H and 13 C chemical shifts (δ) are reported in ppm relative to CDCl 3 as internal standard. Coupling constants (J) are given in Hertz. The following abbreviations are used: s, d, t, q, m for singlet, doublet, triplet, quadruplet and multiplet respectively. Organic solvents were purified by standard procedures. THF was distilled under an inert atmosphere from purple solutions of sodium: benzophenone ketyl.

The synthesis of all compounds were carried out under dry nitrogen.

Diethyl 1,1-Dichloromethylphosphonate 2:

To a stirred mixture of previously standardised 1.9 M solution of isopropylmagnesium chloride (83 ml; 158 mmol) and THF (400 ml) cooled to -78°C, was added dropwise a solution of diethyl 1,1,1trichloromethylphosphonate (38.3 g; 150 mmol) in THF (50 ml) over a period of 15 min The resulting mixture was stirred at -78°C for a further 15 min and then a solution of absolute ethanol (12 g; 260 mmol) in THF (15 ml) was added dropwise to the reaction mixture. After 5 min the mixture was allowed to warm to -40°C and was then poured into a beaker containing a mixture of 3M HCl (70 ml), an equal volume of crushed ice, and CH 2 Cl 2 .

The phases were separated and the aqueous phase was extracted with CH 2 Cl 2 (60 ml X 2). The combined organic phases were dried over MgSO 4 , filtered and evaporated to yield a yellow oil which when distilled gave the title compound as a colourless oil. (32 g, 94%; b.p. 133°C at 10 mm Hg). δ 31 P (CDCl 3 ) +11.1. To a stirred mixture of a previously standardised 1.38 M solution of n-BuLi (16 ml; 22 mmol) and THF (20 ml) at -78°C was added a solution of HMDS (3.7 g; 23 mmol) in THF (10 ml) dropwise over several minutes. The reaction mixture was stirred at -78°C for 15 min and then a mixture of diethyl 1,1-dichloromethylphosphonate (4.42 g; 20 mmol) and the alkyl halide (25 mmol) in THF (10 ml) were added dropwise maintaining the reaction temperature at -78°C. After the addition was complete the reaction mixture was stirred for 15 min at -78°C and then allowed to warm to -20°C. 2M HCl (20 ml) was then added and the mixture stirred for a further 10 min

The phases were separated and the aqueous phase was extracted with CH 2 Cl 2 (2 X 30 ml). The combined organic phases were dried over MgSO 4 , filtered and evaporated to yield an oil which when distilled gave the title compounds as colourless to pale yellow oils.

1-Alkyl or 1-Aryl-2-chloroalkynes 5a-g; General Procedure:

To a stirred mixture of a previously standardised 1.38 M solution of n-BuLi (37 ml, 50 mmol) and THF (40 ml) at -78°C was added a solution of HMDS (8.96 g, 56 mmol, with aromatic aldehydes), or a solution of diisopropylamine (5.66 g, 56 mmol, with aliphatic aldehydes) in THF (20 ml) dropwise over several minutes.

The reaction mixture was stirred at -78°C for 15 min and then a mixture of diethyl 1,1dichloromethylphosphonate (4.42 g; 20 mmol) and the aldehyde (20 mmol) in THF (10 ml) was added dropwise maintaining the temperature at -78°C. After stirring for 15 min the temperature was allowed to rise to 0°C and the mixture was stirred for two hours at this temperature. Water (20 ml) was then added dropwise, the phases separated and the aqueous phase washed with dichloromethane (2 X 30 ml). The combined organic phases were dried over MgSO 4 , filtered and evaporated on a rotary evaporator. The crude residue was then passed through a silica plug with hexane as eluent to obtain the title compounds as mobile oils.

Arylalkynes 7a-e; General Procedure:

To a 1.5 M sol; of n-BuLi (14 ml; 21 mmol) cooled to -20°C is added a solution of diisopropylamine (2.23 g; 22 mmol) in THF (30 ml) dropwise with stirring over 15 min The resulting clear solution is then cooled to -78°C and a solution of diethyl 1,1-dichloromethylphosphonate (4.42 g; 20 mmol), and the aldehyde (20 mmol) in THF (30 ml) is added dropwise over a 30 min interval. The resulting red solution is then stirred at -78°C for a further 30 min and then allowed to slowly warm to 0°C. The now brown reaction mixture is then cooled to -78°C and a 1.5M solution of n-BuLi (28 ml; 42 mmol) is added dropwise over 30 min The solution is once again allowed to warm to 0°C and is then quenched by the dropwise addition of 3M HCl (30 ml) until the solution is pH 5-6. The phases are separated and the aqueous phase is extracted with diethyl ether (2 X 50 ml). The combined organic phases are then washed with water (10 ml) and dried over MgSO 4 and then filtered and evaporated. The crude alkynes are then distilled to give the title compounds as pure colourless oils.

  MeO-Ph o-MeO-Ph Ph CH 3 CH(Ph)CH 2 -CH 3 (CH 2

Table 1 .

 1 Synthesis of Diethyl 1,1-Dichloromethylphosphonate 2 from 1.

	Base Used	Conditions	Yield (%)
	n-BuLi	-78°C, THF, 3M HCl quench	85 a
	n-BuLi	LiCl/LiBr addn., 3M HCl	85 a
		quench
	s-BuLi	-78°C, THF, EtOH, 3M HCl	80 a
		quench
	s-BuLi	LiCl/LiBr addn., 3M HCl	80 a
		quench
	(EtO) 3 P	Hexanol, reflux	65
	(Me 2 N) 3 P	R.T., THF, EtOH, 4M HCl	92 a
		quench
	i-PrMgCl	-78°C, THF, 3M HCl quench	94

a obtained in the presence of non-separable side-products

Table 2 .

 2 Synthesis of Diethyl 1,1-Dichloroalkylphosphonates 3a-h

	Product	31 P NMR (CDCl 3 ) bp (°C)/Torr	Yield a (%)	Molecular formula f
	3			(reported yield)
	a b	12.9 15	150/20	93	C 7 H 15 Cl 2 O 3 P (249.1)
	b b	12.6 15	95/0.6	88	C 8 H 17 Cl 2 O 3 P (263.1)
	c b	12.5 15	101/0.6	97	C 9 H 19 Cl 2 O 3 P (277.1)
	d b	12.8	230/20	94	C 12 H 25 Cl 2 O 3 P (319.2)
	e c	11.9	170/0.6	92	C 12 H 17 Cl 2 O 3 P (311.1)
	f c	12.4 15	152/20	67	C 8 H 15 Cl 2 O 3 P (261.1)
	g c	12.5 15	140/20	87	C 9 H 17 Cl 2 O 3 P (275.1)

Table 3 .

 3 Synthesis of Alkenes 7a-e

	(EtO) 2 P CCl 2 H O 2	+ RCHO	(ii) HCl 2M (i) 2.2eq.LiHMDS or LDA/THF/-78°C/0°C	H R	Cl Cl	R	5	Cl
						B -	4
	5	a	b	c		d	e	f	g
	R p-Me-Ar-p-MeO-Ar-o-MeO-Ar-p-NMe 2 -Ar	Ar-CH 3 CH(Ph)CH 2 -CH 3 (CH 2 ) 8 -
	%	90	91 16	85 4	unstable	50	85		83 4

a Yield of distilled products b The microanalyses were in agreement with the calculated values; maximum deviation found : C, ±0.05; H, ±0.06.

-Dichloroalkylphosphonates 3a-f from Alkyl Iodides and Bromides; General Procedure:

				n D	25 1.4513.
	C 5 H 11 Cl 2 O 3 P	calc.	C 27.17	H 5.02
	(221.02)	found	27.38	4.91
	Diethyl 1,1

Table 4 .

 4 1 H and 13 C NMR Data of Diethyl 1,1-Dichloromethylphosphonate 2

	1 H NMR (CDCl 3 , 200 MHz) δ, J (Hz)	13 C NMR (CDCl 3 , 50 MHz) δ, J C, P (Hz)
	1.3 (t, J=7, 6H, CH 3 CH 2 O), 4.15-4.4 (m, 4H, OCH 2 ),	16.02 (CH 3 CH 2 O), 58.51-63.04 (d, J=178, CCl 2 ),
	5.65 (d, J=2, 1H, CCl 2 H)	64.60 (CH 3 CH 2 O)

Table 5 .

 5 1 H and 13 C NMR Data of Diethyl 1,1-Dichloroalkylphosphonates 3a-f CH 3 (CH 2 ) 3 ), 16.27 (CH 3 CH 2 O), 21.91 (CH 2 ), 25.58 (CH 2 ), 42.06 (CH 2 ), 65.16 (CH 3 CH 2 O), 81.54-85.12 (d, J=178, CCl 2 ) d 0.9 (t, J=7, 3H, CH 3 (CH 2 ) 2 ), 1.15-1.3 (m, xH, CH 2 ), 1.3 (t, J=7, 6H, CH 3 CH 2 O), 1.6-1.9 (m, xH, CH 2 ), 2.2-2.4 (m, xH, CH 2 ), 4.15-4.4 (m, 4H, OCH 2 ) 14.17 (CH 3 ), 16.61 (CH 3 CH 2 ), 22.71 (CH 2 ), 23.67 (CH 2 ), 29.03 (CH 2 ), 29.07 (CH 2 ), 31.81 (CH 2 ), 42.60 (CH 2 ), 65.39 (CH 3 CH 2 ), 81.7 (d, J=179,

	Prod-	1 H NMR (CDCl 3 , 200 MHz)	13 C NMR (CDCl 3 , 50 MHz)
	uct 3	δ, J (Hz)	δ, J C, P (Hz)
	a	1.23 (t, J=7, 3H, CH 3 CH 2 ), 1.3 (t, J=7, 6H,	7.97	(CH 3 CH 2 ),	16.34(CH 3 CH 2 O),	35.97
		CH 3 CH 2 O), 2.2-2.4 (m, 2H, CH 2 CH 3 ), 4.15-	(CH 3 CH 2 ), 65.22 (CH 3 CH 2 O), 84 (d, J=179,
		4.4 (m, 4H, OCH 2 )	PCCl 2 )
	b	0.9 (t, J=7, 3H, CH 3 (CH 2 ) 2 ), 1.3 (t, J=7, 6H,	13.55 (CH 3 (CH 2 ) 2 ), 16.48 (CH 3 CH 2 O), 17.16
		CH 3 CH 2 O), 1.6-1.8 (m, 2H, CH 2 ), 2.1-2.3 (m,	(CH 2 ), 44.61 (CH 2 ), 65.57 (CH 3 CH 2 O), 81.67-
		2H, CH 2 ), 4.15-4.4 (m, 4H, OCH 2 )	85.25 (d, J=178, CCl 2 )
	c	0.9 (t, J=7, 3H, CH 3 (CH 2 ) 3 ), 1.2-1.4 (m, 2H, CH 2 ), 1.3 (t, J=7, 6H, CH 3 CH 2 O), 1.6-1.8 (m, 2H, CH 2 ), 2.15-2.3 (m, 2H, CH 2 ), 4.15-4.4 (m, 4H, OCH 2 )	13.68 (CCl 2 )
	e	1.3 (t, J=7, 6H, CH 3 CH 2 O), 3.56 (d, J=6, 2H,	16.15 (CH 3 CH 2 ), 47.21 (ArCH 2 ), 65.33
		ArCH 2 ), 4.15-4.5 (m, 4H, OCH 2 ), 7.2-7.6 (m,	(CH 3 CH 2 ), 81.7 (d, J=179, CCl 2 ), 127.6 (Ar),
		5H, Ar)	131.64 (Ar), 132 (Ar)
	f	1.3 (t, J=7, 6H, CH 3 CH 2 O), 3.0 (t, J=6, 2H,	16.9 (CH 3 CH 2 ), 47.13 (CH 2 CH), 65.9 (CH 3 CH 2 ),
		CCl 2 CH 2 ), 4.15-4.4 (m, 4H, OCH 2 ), 5.15-5.4	81.7 (d, J=179, CCl 2 ), 121.75 (CH 2 =), 120.88
		(m, 2H, =CH 2 ), 5.8-6.15 (m, 1H, =CH)	(CH=)

Table 6 .

 6 1 H and 13 C NMR Data of Chloroalkynes 5a-g

	Prod-	1 H NMR (CDCl 3 , 200 MHz)	13 C NMR (CDCl 3 , 50 MHz)
	uct 5	δ, J (Hz)	δ, J C, P (Hz)
	a	2.43 (s, 3H, CH 3 ), 7.18 (d, J=8, 2H, Ar-H), 7.4	21.82 (CH 3 ), 64.0 (Ar-C≡), 71.0 (≡C-Cl), 119.8
		(d, J=8, 2H, Ar-H)	(Ar), 129.58 (Ar), 132.31 (Ar), 139.17 (Ar)
	b	3.9 (s, 3H, CH 3 O), 6.91 (d, J=8, 2H, Ar-H),	55.41 (CH 3 O), 67.5 (Ar-C≡), 70.0 (≡C-Cl), 114.3
		7.45 (d, J=8, 2H, Ar-H)	(Ar), 123.5 (Ar), 159.8 (Ar)
	c	3.8 (s, 3H, OCH 3 ), 6.82 (t, J=9, 1H, Ar-H),	55.85 (CH 3 O), 66.5 (Ar-C≡), 72.2 (≡C-Cl), 111.03
		7.12-7.35 (m, 3H, Ar-H)	(Ar), 112.0 (Ar), 120.83 (Ar), 130.51 (Ar), 134.21

(Ar), 161.12 (Ar)


Keywords:

Abstract. (MCF) Multidimensional continued fractions algorithms (Jacobi-Perron, ...), in the context of Diophantine approximation, are applied to characterize the maxima of almost-periodic functions deduced from finite icosahedral clusters, and generalizations are envisaged using more sophisticated techniques for infinite icosahedral clusters. Pseudo-inflation rules in reciprocal space are investigated. These clusters are the building blocks of quasicrystals and approximant crystals. An Interpenetration (IPIC) Formalism for quasicrystals provides formal power series for the intensity. The present number theoretic approach describes the behaviour of the constant terms of these series.