Phosphorinane oxides

We wish to report here on the synthesis and biological properties of 0-[m-N,N,N-trimethylammoniophenyl"J 1,3,2-dioxa-phosphorinane 2-oxide iodide (TDPI I, X = TMPH). 

Dithiaphosphorinan-l-oxid setzt sich mit Chloral zunt 2-(l-Hydroxy-2,2,2-trichlor-ethyl)-l,3,2-dithia-phosphorinan-2-oxid (56% Schmp, 139—140°) um592 ... 

Sterisch gehinderte Phosphorsaure-diester, z.B. 5,5-Dimethyl-2-hydroxy-l,3,2-dioxa-phosphorinan-2-oxid (94%, Schmp. 174-176°), werden durch Erhitzen der Diester-ha-logenide mit Aceton/Wasser (1 1) hergestellt z.B.93 ... 

Ausgehend von Phosphorsaure-difluorid-dimethylamid wird mit l,3-Bis-[methylami-no]-butan/Triethylamin (2 Mol) bei 20° in Benzol 2-Fluor-l,3,4-trimethyl-1,3,2-diaza-phosphorinan-2-oxid (38% Isomerengemisch) erhalten388 ... 

The presumed stereochemistry of displacement of chlorine at a phosphoryl centre by a primary amine (benzylamine) and crystallographic determination of the configuration of 2-benzylamino-4-phenyl-l,3,2-dioxaphosphorinane 2-oxide has allowed an assignment of stereochemistry (trans chlorine and phenyl) in a diastereoisomeric 2-chloro-4-phenyl-l,3,2-dioxa-phosphorinane 2-oxide the more stable of the two cyclic phosphoryl chlorides has chlorine in the axial position. 

Both cis and trans forms of substituted phosphonium salts and phosphorinane oxides are known. In some cases a mixture of both isomers is obtained on hydrolysis of either pure cis or pure trans phosphonium salts (6.814) (Chapter 14). 

Inch and co-workerspioneered, in the 1970s, the preparation of many phosphorinane oxides and sulfides derived from carbohydrates, confirming their utility in the study of stereochemical aspects in nucleophilic substitutions at phosphorus. Some of the compounds they prepared are shown in Figure 3.9. 

Figure 3.9 P-stereogenic phosphorinane oxides and sulfides derived from carbohydrates.

Many other phosphorinane oxides have been prepared due to their pharmacological applications. Of particular importance are those containing fused bicyclic and tricyclic systems. They can be readily prepared by reaction of the chiral cyclic amino alcohol and the appropriate phosphonic dichloride and they are usually obtained as mixtures of epimers, often separable by column chromatography. A few examples are displayed in Figure 3.11. 

Figure 3.11 Examples of phosphorinane oxides with pharmaeological interest.

Phosphorinane, 4-t-butyl-1 -phenyl-synthesis, 1, 500 Phosphorinane, I-chloro-synthesis, 1, 500 Phosphorinane, 1-hydrocarbyl-I-sulfide synthesis, 1, 500 Phosphorinane, 1-phenyl-synthesis, 1, 499 Phosphorinanes, 1, 497-506 bicyclic bridged derivatives synthesis, 1, 501 conformation, 1, 503-504 NMR, 1, 497 oxidation, 1, 498 reactions, 1, 497 structure, 1, 497, 503-504 sulfuration, 1, 499 synthesis, 1, 499... 

Two heterocyclic systems have been investigated - the 1,3,2-dioxaphosphepene (45) and its oxide,13 1,3,2-dioxa-phosphorinanes and their oxides, sulphides and selenides (46).136,137 Three ring vibrations were involved in the conformational study of the amides (46, Y = NR2).137... 

Unlike 1,3,5-dioxaphosphorinanes the relative population of the con-former with the axial phenyl group at phosphorus decreases in 1,3,5-diazaphosphorinanes both for P(III) and for P(IV) compounds. Conformational analysis of 5-phenyl-1,3,5-diazaphosphorinanes and their oxides, sulfides, and selenides showed that the conformational equilibrium shifted toward the conformer with the axial phenyl group on changing from P(III) to P(1V) derivatives. The same conclusion made for 5-phenyl-l, 3,5-dioxaphosphorinanes, but it is contrary to that made for 1-phenyl-phosphorinane-4-ones and their derivatives (83MI1). 

Three main types of reaction are used to convert the phosphorinanes (P-GV = 3) into phosphorinanes (P-CN = 4) alkylation, oxidation and sulfuration. 

The most important transformations of phosphorinanes involve oxidation (by air, 3% H202, Bu OOH, O3, N204 (especially) or other oxidants). The products, 1-R-l-oxophosphorinanes (9 R = alkyl, aryl, OR, NR2, Cl, etc.) are much more stable than the phosphorinanes (P-CN = 3), and are mostly crystalline. A host of X-ray determinations of single crystals have been described. Oxidation with N204 (but also with some other oxidants) occurs without inversion <71PAC(25)549) and is therefore very useful for structure determinations of ring-substituted phosphorinanes (P-C1V = 3). The reverse reaction, reduction of the P=0 bond, is also an important route to three-coordinate phosphorinanes of known... 

Bicyclic bridged phosphorinane derivatives can be synthesized by different methods. When phenylphosphine is heated with cycloocta-2,7-dienone to 135 °C in the presence of polymerization inhibitors, e.g. hydroquinone, and the double Michael addition product is oxidized, the two crystalline syn and anti isomers (total yield 48-59%) are isolated. Separation by crystallization gives the pure compounds which can in turn be transformed at the carbonyl or the phosphorus group (equation 10) (75T33,76JOC589). 

Monocyclic tetrahydrophosphorin derivatives can be prepared, for example by dehydration of tertiary alcohols which are available by the action of lithium alkyls on 4-oxophos-phorinane derivatives (equation (16)). P- Oxidation and dehydrogenation of the ketone with Se02 is also possible (equation (17)) (66AG(E)588). Electrophilic substitution in position 2 (6) of phosphorinane 1-oxides and 1-sulfides can be achieved by a Wittig-Horner a-deprotonation, e.g. equation (18) (72BSF(2)402l, 79CJC723). 

The diagnostic coupling constant /P c for conformational analysis of phosphorinanes (P-CN = 3) is lost with phosphorinanes where P-CN = 4. Shifts and /P c values of two non-rigid and two cis-trans rigid phosphorinane 1-oxides and 1-sulfides should be studied for comparison (Tables 2 and 3). The large differences between the two classes are then evident. 

The reaction of 2-methyl-, 2,5-dimethyl-, and 2,2,5--trimethyl-phosphorinan-4-one with hydrogen peroxide or potassium permanganate, or with sulphur or selenium in a suitable solvent on boiling affords the corresponding 1-oxide, -sulphide, or -selenide in good yield (I.N. Azerbaev et at., ibid., 1976, 47). For the preparation, reactions, and... 

The C-nmr spectra of 1-methyl- and 1-ethyl-phosphor-anin-4-one and derivatives and also that of phosphorinane-4,4--diols in water at 30° have been recorded, along with the P-nmr spectra and equilibrium compositions for the hydration of some phosphorinan-4-ones. Also recorded the ir-and uv-spectra for 1-ethylphosphorinan-4-one and its 1-oxide and 1-sulphide (J.J. Breen, S.O. Lee, and L.D. Quin, J. org. Chem., 1975, 0, 2245). P-nmr spectral data of 1-phenyl-phosphorian-4-one (K. Ramarajan, M.D. Herd, and K.D. Berlin, Phosphorus Sulphur, 1981, 11, 199). 

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