METHOD FOR THE SYNTHESIS OF HETEROCYCLIC HYDROGEN PHOSPHINE OXIDE

Abstract

A method for the synthesis of a heterocyclic hydrogen phosphine oxide, having the general formula:

##STR00001##

wherein:
R is a aliphatic or aromatic divalent group optionally including one or more heteroatoms and optionally having one or more substituents and
X and Y are independently selected from —O—, —C(O)O— and —NR′—
wherein R′ is a monovalent group optionally having one or more heteroatoms including the steps of:
a) forming a reaction mixture by mixing a compound having the general formula HX—R—YH and tetraphosphorus hexaoxide; and
b) recovering the resulting compound comprising the heterocyclic hydrogen phosphine oxide.

Claims

1. A method for the synthesis of a heterocyclic hydrogen phosphine oxide, having the general formula: ##STR00004## wherein: R is a aliphatic or aromatic divalent group optionally comprising one or more heteroatoms and optionally comprising one or more substituents and X and Y are independently selected from —O—, —C(O)O— and —NR′— wherein R′ is a monovalent group optionally comprising one or more heteroatoms comprising the steps of: a) forming a reaction mixture by mixing a compound having the general formula HX—R—YH and tetraphosphorus hexaoxide; and b) recovering the resulting compound comprising the heterocyclic hydrogen phosphine oxide.

2. The method according to claim 1 wherein the molar ratio of the compound with general formula HX—R—YH to tetraphosphorus hexaoxide is comprised between 5.0 and 2.0.

3. The method according to claim 1, wherein the compound with general formula HX—R—YH is characterized in that: X and Y are independently selected from —O—, —C(O)O— and —NR′—, wherein R′ is an alkyl, alkenyl or alkynyl radical, having 1 to 10 carbon atoms, optionally comprising one or more heteroatoms selected from the group consisting of oxygen, nitrogen, sulphur and phosphorus, and optionally comprising one or more substituents selected from the group consisting of alkoxy, alkyl alkanoate, alkyl carboxylate, nitrile, carbamoyl, sulfanyl and halogen; R is an alkylene, alkenylene or alkynylene radical having 2 to 20 carbon atoms and optionally comprising one or more heteroatoms selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur and optionally comprising one or more substituents selected from the group consisting of aryl, alkaryl, alkenaryl, alkynaryl, alkoxy, alkyl alkanoate, alkyl carboxylate, nitrile, carbamoyl, sulfanyl and halogen or R is an aryl or biaryl radical, optionally comprising one or more heteroatoms selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur and optionally comprising one or more substituents R′; and X and Y are separated by 10 or less carbon-carbon and/or carbon-heteroatom single and/or double and/or triple bonds; whereby for cyclic aliphatic or aromatic compounds the lowest number of bonds is meant.

4. The method according to claim 1 wherein step a) comprises a solvent selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dichloromethane and mixtures thereof.

5. The method according to claim 1 wherein step a) comprises a dehydrating agent selected from the group consisting of organic dehydrating agents preferably an acid anhydride selected from the group consisting of acetic anhydride, trifluoroacetic anhydride and mixtures thereof; an orthoester such as trimethyl orthoformate or a carbodiimide such as N,N′-dicyclohexylcarbodiimide.

6. The method according to claim 1 wherein step a) comprises a dehydrating agent selected from the group consisting of inorganic dehydrating agents.

7. The method according to claim 1 wherein the dehydrating agent does not react with the reactants and wherein said dehydrating agent is added from the beginning of the reaction.

8. The method according to claim 1 wherein tetraphosphorus hexaoxide is added over a period of time comprised between 5 minutes and 2 hours to the compound with general formula HX—R—YH, comprising the solvent, standing at a temperature comprised between 10° C. and 80° C.

9. The method according to claim 1 wherein step a), after the completion of the tetraphosphorus hexaoxide addition, is maintained at a temperature comprised between 10° C. and 80° C. for a period of time comprised between 10 minutes and 20 hours.

10. The method according to claim 1 wherein the resulting compound comprising the heterocyclic hydrogen phosphine oxide is recovered in step b) through distilling off the solvent.

11. The method according to claim 1 wherein the resulting compound comprising the heterocyclic hydrogen phosphine oxide is recovered in step b) through crystallization.

12. The method according to claim 1 wherein the compound with general formula HX—R—YH is selected from the group consisting of ethylene glycol; 1,2-propanediol; 2,2-dimethyl-1,3-propanediol; 2-phenyl-1,2-propanediol; 3-allyloxy-1,2-propanediol; 3-chloro-1,2-propanediol; 1,3-butanediol; 2,3-butanediol; 2,3-dimethyl-2,3-butanediol; 1,1,2,2-tetraphenyl-1,2-ethanediol; triethylene glycol; 1,10-decanediol; 2,2′-biphenol, and 1,1′-bis-2-naphtol; 2-hydroxybenzoic acid; pinanediol and (S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol.

13. The method according to claim 1 wherein the weight ratio of solvent to the total amount of reactants in step a) is comprised between 0.5 and 5.

14. The method according to claim 1 wherein the molar ratio of the compound with general formula HX—R—YH to tetraphosphorus hexaoxide is comprised between 4.5 and 2.5.

15. The method according to claim 1 wherein the molar ratio of the compound with general formula HX—R—YH to tetraphosphorus hexaoxide is comprised between 4.0 and 3.0.

16. The method according to claim 1 wherein step a) comprises a dehydrating agent selected from the group consisting of zeolite with a pore size of 4 Å.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0056] The present invention provides an improved method that is safe, economic and environmental friendly, for the synthesis of heteroatom substituted phosphine oxides and in particular of heterocyclic hydrogen phosphine oxides.

[0057] The present invention provides, in particular, a process wherein use is made of no toxic or less toxic solvents, without the need of organic or inorganic bases and wherein no toxic by-products are formed, briefly worded a process attractive over prior art processes.

[0058] The method includes the steps of:

[0059] reacting tetraphosphorus hexaoxide and a compound having the general formula HX—R—YH, in the presence of a solvent, tetraphosphorus hexaoxide being gradually added to a compound having the general formula HX—R—YH, while controlling the temperature at a value of 80° C. or less, preferably at a value comprised between about 20° C. and about 50° C. to form a solution comprising a heterocyclic hydrogen phosphine oxide with a yield of 50% or more, preferably at least 70% and more preferably at least 90%;

[0060] further processing said solution through distilling off the solvent or cooling down said solution inducing the crystallization, and recovering the heterocyclic hydrogen phosphine.

[0061] The tetraphosphorus hexaoxide used within the scope of the present invention may be represented by a substantially pure compound containing at least 85%, preferably more than 90%, more preferably at least 95% and in one particular embodiment at least 97% of P.sub.4O.sub.6. While tetraphosphorus hexaoxide, suitable for use within the context of this invention, may be manufactured by any known technology, it is preferably prepared in accordance with the method described in WO 2009/068636 and/or WO 2010/055056 under the section entitled “Process for the manufacture of P.sub.4O.sub.6 with improved yield”. In detail, oxygen, or a mixture of oxygen and inert gas, and gaseous or liquid phosphorus are reacted in essentially stoichiometric amounts in a reaction unit at a temperature in the range from about 1600 to about 2000 K, by removing the heat created by the exothermic reaction of phosphorus and oxygen, while maintaining a preferred residence time of from about 0.5 to about 60 seconds followed by quenching the reaction product at a temperature below 700 K and refining the crude reaction product by distillation. The tetraphosphorus hexaoxide so prepared is a pure product containing usually at least 97% of the oxide.

[0062] The so produced P.sub.4O.sub.6 is generally represented by a liquid material of high purity containing in particular low levels of elementary phosphorus, P.sub.4, preferably below 1000 ppm, expressed in relation to the P.sub.4O.sub.6 being 100%. The preferred residence time is from about 5 to about 30 seconds, more preferably from about 8 to about 30 seconds. The reaction product can, in one preferred embodiment, be quenched to a temperature below 350 K.

[0063] It is presumed that the P.sub.4O.sub.6 participating in a reaction at a temperature of from 24° C. (melting t°) to 200° C. is necessarily liquid or gaseous although solid species can, academically speaking, be used in the preparation of the reaction medium.

[0064] For reasons of convenience and operational expertise, the tetraphosphorus hexaoxide, represented by P.sub.4O.sub.6, is of high purity containing very low levels of impurities, in particular elemental phosphorus, P.sub.4, at a level below 1000 ppm, usually below 500 ppm and preferably not more than 200 ppm, expressed in relation to the P.sub.4O.sub.6 being 100%.

[0065] The compound with general formula HX—R—YH is characterized in that: [0066] X and Y are independently selected from —O—, —C(O)O— and —NR′—, wherein R′ is an alkyl, alkenyl or alkynyl radical, having 1 to 10 carbon atoms, optionally comprising one or more heteroatoms selected from the group consisting of oxygen, nitrogen, sulphur and phosphorus, and optionally comprising one or more substituents selected from the group consisting of alkoxy, alkyl alkanoate, alkyl carboxylate, nitrile, carbamoyl, sulfanyl and halogen; [0067] R is an alkylene, alkenylene or alkynylene radical having 2 to 20 carbon atoms and optionally comprising one or more heteroatoms selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur and optionally comprising one or more substituents selected from the group consisting of aryl, alkaryl, alkenaryl, alkynaryl, alkoxy, alkyl alkanoate, alkyl carboxylate, nitrile, carbamoyl, sulfanyl and halogen or [0068] R is an aryl or biaryl radical, optionally comprising one or more heteroatoms selected from the group consisting of oxygen, nitrogen, phosphorus and sulfur and optionally comprising one or more substituents R′; [0069] X and Y are separated by 10 or less carbon-carbon and/or carbon-heteroatom single and/or double and/or triple bonds; when cyclic aliphatic or aromatic compounds are considered it is obvious that with said separation the lowest number of bonds is meant.

[0070] The compound with general formula HX—R—YH preferably is selected from the group consisting of ethylene glycol; 1,2-propanediol; 2,2-dimethyl-1,3-propanediol; 2-phenyl-1,2-propanediol; 3-allyloxy-1,2-propanediol; 3-chloro-1,2-propanediol; 1,3-butanediol; 2,3-butanediol; 2,3-dimethyl-2,3-butanediol; 1,1,2,2-tetraphenyl-1,2-ethanediol; triethylene glycol; 1,10-decanediol; 2,2′-biphenol; 1,1′-bis-2-naphtol; 2-hydroxybenzoic acid; pinanediol and (S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol.

[0071] In the method of the present invention the molar ratio of the compound with general formula HX—R—YH to tetraphosphorus hexaoxide is comprised between 5.0 and 2.0, preferably between 4.5 and 2.5 and more preferably between 4.0 and 3.0

[0072] The compound with general formula HX—R—YH is dissolved in a solvent where the weight ratio of solvent to the total weight of reactants is comprised between 0.5 and 5.0.

[0073] Typical examples of suitable solvents, optionally used in the method according to the present invention, are anisole, fluorobenzene, chlorobenzene, tetrachloroethane, tetrachloroethylene, dichloroethane, dichloromethane, diglyme, glyme, diphenyloxide, polyalkylene glycol derivatives with capped OH groups, hexane, heptane, cyclohexane, dibutyl ether, diethyl ether, diisopropyl ether, dipentylether, butylmethylether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, tetrahydropyran; cyclopentylmethylether, sulfolane, toluene, benzene, xylene, ethylacetate, acetonitrile, benzonitrile, polymethylphenyl siloxane or mixtures thereof and non-reactive ionic liquids like 1-n-butyl-imidazolium trifluoromethanesulfonate, and 1-ethyl-3-methyl-imidazolium bis(trifluoromethyl sulfonyl)imide or a mixture thereof.

[0074] The solvent preferably is selected from the group consisting of tetrahydrofuran, 2-methyltetrahydrofuran, acetonitrile, dichloromethane and mixtures thereof and is preferably substantially anhydrous. In general the substantial anhydrous solvent optionally is obtained through the addition of molecular sieve with a pore size of preferably 4 Angström.

[0075] Tetraphosphorus hexaoxide is gradually added to the mixture comprising the compound with general formula HX—R—YH and the solvent, preferably the anhydrous solvent, in order to control the strong exotherm and to control the temperature of the reaction at a value comprised between about 10° C. and 80° C. and preferable between 20° C. and 50° C.

[0076] Tetraphosphorus hexaoxide is added over a period of time comprised between about 5 minutes and about 2 hours, dependent on the capabilities of the reactor's heat exchanging means and the respective quantities of reactants, among others.

[0077] After the completion of the tetraphosphorus hexaoxide addition, a dehydrating agent preferably is added to the reaction mixture which is further stirred and reacted for an additional period of time comprised between about 10 minutes and about 20 hours at a temperature comprised between about 10° C. and about 80° C. and preferably between about 20° C. and about 50° C.

[0078] The dehydrating agents preferably used in the method of the present invention are organic dehydrating agents such as an acid anhydride selected from the group consisting of acetic anhydride, acetic formic anhydride, butyric anhydride, 3-chlorophthalic anhydride, 4-chlorophthalic anhydride, disulfuric acid, dodecenyl succinic anhydride, ethylenetetracarboxylic dianhydride, maleic anhydride, malonic anhydride, mellitic anhydride, methanesulfonic anhydride, phthalic anhydride, propionic anhydride, succinic anhydride, trifluoroacetic anhydride, trifluoromethanesulfonic anhydride and mixtures thereof; an orthoester such as for example trimethyl orthoformate or a carbodiimide such as for example N,N′-dicyclohexylcarbodiimide or inorganic dehydrating agents selected from the group consisting of calcium sulphate, sodium sulphate, magnesium sulphate, calcium chloride, aluminium oxide, all in their anhydrous form, and aluminosilicate minerals.

[0079] Within the context of the method of the present invention acetic anhydride and trifluoroacetic anhydride are preferred organic dehydrating agents.

[0080] The dehydrating agent preferably is added in such an amount that the ratio of equivalents of dehydrating agent to moles of tetraphosphorus hexaoxide is about 2.0.

[0081] Dehydrating agents which are non-reactive with respect to the initial reactants i.e. HX—R—YH compound and P.sub.4O.sub.6, can be added at the beginning of the reaction i.e. along with the HX—R—YH compound and the solvent. In general, this is the case for inorganic dehydration agents.

[0082] In a preferred embodiment of the present invention, molecular sieve with a pore size of 4 Å is used as dehydrating agent and is added at the beginning of the process. In general, 4 Å molecular sieve is added in an amount of about 50% weight of the HX—R—YH compound.

[0083] After completing step a) the solution comprising the heterocyclic hydrogen phosphine oxide is cooled down in step b) to room temperature or below, whereupon crystallization of the heterocyclic hydrogen phosphine oxide may be initiated. The precipitate is then separated from the filtrate using conventional filtration techniques well known in the art.

[0084] The precipitate being isolated subsequently may be washed and optionally recrystallized using a solvent selected among these enumerated as suitable solvents for performing step a).

[0085] In another approach, after completion of step a), the solvent is distilled off in step b) whereupon the product, thus recovered, may be recrystallized using a solvent selected among these enumerated as suitable solvents for performing step a). The selection of the right solvent is dependent on the type of heterocyclic hydrogen phosphine oxide prepared in step a) and is common practice for those skilled in the art.

[0086] The heterocyclic hydrogen phosphine oxide obtained by the method of the present invention is characterized by the general formula:

##STR00003##

wherein X, Y, R′ and R have the same meaning as for the HX—R—YH compound such as disclosed in [0030].

[0087] Typical and preferred examples of heterocyclic hydrogen phosphine oxide prepared using the method according to the present invention are 2-oxo-4,4,5,5-tetramethyl-1,3,2-dioxaphospholane; 2,4-dioxo-5,6-benzo-1,3,2-dioxaphosphorinane; 2-oxo-4,4,5,5-tetraphenyl-1,3,2-dioxaphospholane; 2-hydro-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane; 2-hydro-4,5-dimethyl-2-oxo-1,3,2-dioxaphospholane; 2-hydro-2-oxo-1,3,2-dioxaphosphorinane; 2-2,2′-biphenyl phosphite; 2-2,2′-binaphtyl phosphite; 2-oxo-4-allylyoxymethyl-1,3,2-dioxaphospholane; 2-oxo-4-methyl-4-phenyl-1,3,2-dioxaphospholane; 2-oxo-4-methyl-1,3,2-dioxaphospholane; 2-oxo-4-chloromethyl-1,3,2-dioxaphospholane; (2R,3aR,4R,6R,7aS)-3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaphosphole 2-oxide-rel-; (3S)-3,3-diphenylhexahydropyrrolo[1,2-c][1,2,3]oxazaphospholidine.

EXAMPLES

[0088] The following examples illustrate the invention; they are merely meant to exemplify the present invention but are not destined to limit or otherwise define the scope of the present invention.

[0089] The glassware used in the examples as described below, was dried in an oven for several hours (60° C.) prior being used in the reactions. Molecular sieves was activated for 2 to 4 hours at 220° C. and kept afterward at room temperature over P.sub.2O.sub.5 in a desiccator.

[0090] A magnetic stirring bar was used for the small scale reaction and a mechanical stirrer was used for the large scale reaction. The solvents and reagents were of analytical grade and used as received. In particular cases, anhydrous solvents were used as specified in the respective examples.

[0091] For product characterization, NMR spectra were recorded on a Bruker Avance 400 spectrometer using CDCl.sub.3 or CDCl.sub.3/TFA (3/1) as solvent. TMS and H.sub.3PO.sub.4 85% were used as reference for .sup.1H, .sup.13C and .sup.31P nuclei. For known products, the JP-H coupling constant was used to unambiguously identify the H-phosphonate.

Example 1

[0092] In a dried vial containing a magnetic stirring bar were successively added 5.9 g of pinacol 97% (50 mmole), and 15 ml of anhydrous tetrahydrofuran under N.sub.2. The vial was closed and to the stirred solution was added 2.75 g of P.sub.4O.sub.6 (12.5 mmole) slowly over 30 minutes at room temperature to avoid a strong exotherm. The reaction mixture was stirred overnight at room temperature under sonication. The volatiles were removed and to the residues was added 3 ml of ethyl acetate. This solution was kept closed at 4° C. overnight. The desired product crystallized upon cooling. The yield of 2-oxo-4,4,5,5-tetramethyl-1,3,2-dioxaphospholane was 79% as determined in the crude by .sup.31P NMR analysis (CDCl.sub.3). The target compound was isolated in 65% isolated yield with a purity of 90% (10% of H.sub.3PO.sub.3 as impurity).

Example 2

[0093] In a dried vial containing a magnetic stirring bar were successively added 1.18 g of pinacol 99% (10 mmole), and 1 ml of anhydrous tetrahydrofuran under N.sub.2. The vial was closed and to the stirred solution was added 0.615 g of P.sub.4O.sub.6 (2.8 mmole) slowly over 10 minutes at room temperature to avoid a strong exotherm. Once the addition of P.sub.4O.sub.6 was done, 1.2 g trifluoroacetic anhydride (5.7 mmole) were added as dehydrating agent. The crude mixture was stirred 2 hours at room temperature under sonication. The yield of 2-oxo-4,4,5,5-tetramethyl-1,3,2-dioxaphospholane was 82.5% as determined in the crude by .sup.31P NMR analysis (CDCl.sub.3).

Example 3

[0094] In a dried vial containing a magnetic stirring bar were successively added 1.18 g of pinacol 99% (10 mmole), 4 Å molecular sieves (50% wt/wt of diol) and 1 ml of 2-methyltetrahydrofuran. The vial was closed and to the stirred solution was added 0.66 g of P.sub.4O.sub.6 (3 mmole) slowly over 10 minutes at room temperature to avoid a strong exotherm. After stirring for 2 hours, the suspension was gently heated and transferred in a second vial. The desired product crystallized upon cooling. The yield of 2-oxo-4,4,5,5-tetramethyl-1,3,2-dioxaphospholane was 94% as determined in the crude by .sup.31P NMR analysis (CDCl.sub.3).

Example 4

[0095] In a dried vial containing a magnetic stirring bar were successively added 6.9 g of salicylic acid (50 mmole) and 15 ml of anhydrous tetrahydrofuran under N.sub.2. The vial was closed and to the stirred solution was added 2.75 g of P.sub.4O.sub.6 (12.5 mmole) slowly over 30 minutes at room temperature to avoid a strong exotherm. The crude was stirred overnight at room temperature under sonication. The yield of 2,4-dioxo-5,6-benzo-1,3,2-dioxaphosphorinane was 80% as determined in the crude by .sup.31P NMR analysis (CDCl.sub.3). The target compound was isolated after evaporation of the solvent and recrystallized from diethyl ether with an isolated yield of 70% and a purity of 85% (15% of H.sub.3PO.sub.3 as impurity).

Example 5

[0096] In a dried vial containing a magnetic stirring bar were successively added 18.3 g of benzo-pinacol 97% (50 mmole), and 25 ml of anhydrous tetrahydrofuran under N.sub.2. The vial was closed and to the stirred solution was added 2.75 g of P.sub.4O.sub.6 (12.5 mmole) slowly over 30 minutes at room temperature to avoid a strong exotherm. The crude was stirred overnight at room temperature under sonication. The yield of 2-oxo-4,4,5,5-tetraphenyl-1,3,2-dioxaphospholane was 40% as determined in the crude by .sup.31P NMR analysis (CDCl.sub.3).

Example 6

[0097] In a dried vial containing a magnetic stirring bar were successively added 1.04 g of 2,2-dimethyl-1,3-propanediol (10 mmole), 4 Å molecular sieves (50% wt/wt of diol) and 1 ml of 2-methyltetrahydrofuran. The vial was closed and to the stirred solution was added 0.66 g of P.sub.4O.sub.6 (3 mmole) slowly over 10 minutes at room temperature to avoid a strong exotherm. After stirring for 2 hours, the suspension was gently heated and transferred in a second vial. The desired product solidified upon cooling. The yield of 2-hydro-5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinane was 67% as determined in the crude by .sup.31P NMR analysis (CDCl.sub.3).

Example 7

[0098] In a dried flask of 250 ml containing a magnetic stirring bar were successively added 4 Å molecular sieves (50% wt/wt of diol), 50 ml of 2-methyltetrahydrofuran and 0.9 g of 2,3-butanediol (10 mmole). The magnetic agitation is used to obtain a perfectly dispersed solution before the addition of P.sub.4O.sub.6. Then, 0.66 g of P.sub.4O.sub.6 (3 mmole) is slowly added with a syringe at room temperature to avoid a strong exotherm. Subsequently the solution was stirred for 2 hours with a magnetic agitation around 400 rpm. The yield of 2-hydro-4,5-dimethyl-2-oxo-1,3,2-dioxaphospholane was 62% as determined in the crude by .sup.31P NMR analysis (CDCl.sub.3).

Examples 8 to 12

[0099] In table 1 a series of examples, prepared according to the method of the present invention and using the equipment, the molar quantities and the reaction conditions of Example 7, are reported.

[0100] In this table:

Column 1: indicates the identification number of the example.
Column 2: indicates the type of diol put into reaction with P.sub.4O.sub.6.
Column 3: indicates the type of the cyclic phosphite.
Column 4: indicates the yield (%) of cyclic phosphite, determined in the crude by .sup.31P NMR analysis (CDCl.sub.3).

TABLE-US-00001 TABLE 1 Ex Diol Cyclic phosphite Yield 8 1,3-butanediol 2-hydro-2-oxo-1,3,2-dioxaphosphorinane 43 9 2,2′-biphenol 2-2,2′-biphenyl phosphite 80 10 1,1′-bis-2-naphtol 2-2,2′-binaphtyl phosphite 80 11 3-allyloxy-1,2- 2-oxo-4-allylyoxymethyl-1,3,2- 46 propanediol dioxaphospholane 12 2-phenyl-1,2- 2-oxo-4-methyl-4-phenyl-1,3,2- 40 propanediol dioxaphospholane

Example 13

[0101] In a dried flask of 250 ml containing a magnetic stirring bar were successively added 4 Å molecular sieves (50% wt/wt of diol), 25 ml of 2-methyltetrahydrofuran and 1.5 g of triethylene glycol (10 mmole). The solution is heated at 50° C. and the magnetic agitation is used to stir the suspension before the addition of P.sub.4O.sub.6. Then, 0.66 g of P.sub.4O.sub.6 (3 mmole) is slowly added with a syringe at 50° C. After stirring for 2 hours with a magnetic agitation around 400 rpm, the solution was tested by .sup.31P NMR analysis (CDCl.sub.3) indicating a yield of 33% of cyclic phosphite.

Example 14

[0102] In a dried vial containing a magnetic stirring bar were successively added 1.86 g of 2,2′-biphenol (10 mmole), 4 Å molecular sieves (50% wt/wt of diol) and 5 ml of acetonitrile. The vial was closed and to the stirred suspension was added 0.66 g of P.sub.4O.sub.6 (3 mmole) slowly over 10 minutes at room temperature to avoid a strong exotherm. After stirring for 2 hours the solution was transferred in a second vial. The solvent was evaporated to give yellow oil. The yield of 2-2,2′-biphenyl phosphite was 75% as determined in the crude by .sup.31P NMR analysis (CDCl.sub.3).

Example 15

[0103] In a dried flask of 250 ml containing a magnetic stirring bar were successively added 1.1 g of 3-chloro-1,2-propanediol (10 mmole), 4 Å molecular sieves (50% wt/wt of diol) and 35 ml of 2-methyltetrahydrofuran. The magnetic agitation is used to obtain a perfectly dispersed solution before the addition of P.sub.4O.sub.6. Then, 0.55 g of P.sub.4O.sub.6 (2.5 mmole) was slowly added with a syringe at room temperature to avoid a strong exotherm. After stirring for 2 hours, the solution was transferred in a vial. 45% of cyclic phosphite, 31% of a mixture of CH.sub.2 and CH mono-phosphites and 18% of H.sub.3PO.sub.3 were found in the crude by .sup.31P NMR analysis (CDCl.sub.3).

Example 16

[0104] In a dried flask of 250 ml containing a magnetic stirring bar were successively added 4 Å molecular sieves (50% wt/wt of diol), 25 ml of 2-methyltetrahydrofuran and 0.76 g of 1,2-propanediol (10 mmole). The magnetic agitation is used to obtain a perfectly dispersed solution before the addition of P.sub.4O.sub.6. Then, 0.66 g of P.sub.4O.sub.6 (3 mmole) is slowly added with a syringe at room temperature to avoid a strong exotherm. Subsequently the reaction mixture was stirred for 2 hours with a magnetic agitation around 400 rpm. The yield of 2-oxo-4-methyl-1,3,2-dioxaphospholane was 46% as determined in the crude by .sup.31P NMR analysis (CDCl.sub.3).

Example 17

[0105] In a dried vial containing a magnetic stirring bar were successively added 0.86 g of (−) pinanediol (5.05 mmole), 4 Å molecular sieves (50% wt/wt of diol) and 5 ml of 2-methyltetrahydrofuran. The vial was closed and to the stirred solution was added 0.33 g of P.sub.4O.sub.6 (1.5 mmole) slowly over 10 minutes at room temperature to avoid a strong exotherm. After stirring for 2 hours, the suspension was gently stirred over poly-vinylpyridine (0.5 g). The filtrate was collected and evaporated. The yield of (2R,3aR,4R,6R,7aS)-3a, 5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaphosphole 2-oxide-rel- was 50% as determined in the crude by .sup.31P NMR analysis (CDCl.sub.3).

After filtration and evaporation, an oily product was isolated with a purity of 50% (20% of H.sub.3PO.sub.3 and 21% of half-hydrolysed phosphite).

Example 18

[0106] In a dried vial containing a magnetic stirring bar were successively added 1 g of (S)-(−)-α,α-diphenyl-2-pyrrolidinemethanol (3.9 mmole), 4 Å molecular sieves (50% wt/wt of amino alcohol) and 10 ml of solvent (2-methyltetrahydrofuran/acetonitrile 1/1 v/v). The vial was closed and to the stirred solution was added 0.26 g of P.sub.4O.sub.6 (1.18 mmole) slowly over 10 minutes at room temperature to avoid a strong exotherm. After stirring for 2 hours, the suspension was evaporated. (3S)-3,3-diphenylhexahydropyrrolo[1,2-c][1,2,3]oxazaphospholidine was detected at 64% by .sup.31P NMR analysis (CDCl.sub.3)(contaminant is 12% H.sub.3PO.sub.3). The overall conversion is 76%.

Example 19

[0107] In a dried vial containing a magnetic stirring bar were successively added 0.86 g of (−) pinanediol (5.05 mmole), 4 Å molecular sieves (50% wt/wt of diol) and 6 ml of 2-methyltetrahydrofuran. The vial was closed and to the stirred solution was added 0.33 g of P.sub.4O.sub.6 (1.5 mmole) slowly over 10 minutes at room temperature to avoid a strong exotherm. The solution was evaporated. The yield of (2R,3aR,4R,6R,7aS)-3a, 5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaphosphole 2-oxide-rel- was 57% as determined in the crude by .sup.31P NMR analysis (CDCl.sub.3). The overall conversion is 67% (13% of H.sub.3PO.sub.3).

Example 20

[0108] In a dried vial containing a magnetic stirring bar were successively added 1.18 g of pinacol 99% (10 mmole) and 1 ml of anhydrous tetrahydrofuran under nitrogen. The vial was closed and to the stirred solution was added 0.615 g of P.sub.4O.sub.6 (2.8 mmole) slowly over 10 min at room temperature to avoid a strong exotherm. Once the addition of P.sub.4O.sub.6 was done, 0.612 g of acetic anhydride (6 mmole) was added as dehydrating agent. The crude mixture was stirred for 2 hours at room temperature under sonication. The yield of 2-oxo-4,4,5,5-tetramethyl-1,3,2-dioxaphospholane was 82.5% as determined in the crude by .sup.31P NMR analysis (CDCl.sub.3).