Synthesis and steric structure of pyrrolidine-and piperidine-fused 1,3,4,2-oxadiazaphosphinanes

Pyrrolidine-and piperidine-fused 1,3,4,2-oxadiazaphosphinane 2-oxides were prepared by cyclization of the corresponding pyrrolidine-and piperidine-hydrazino alcohols by using phosphorus-containing reagents. Stereochemical and conformational analyses were carried out in order to determine the effect of the ring size on the conformational behavior of the nitrogen-bridged bicyclic system. It was found that the chair conformation in the pyrrolidine-fused 1,3,4,2-oxadiazaphosphinane 2-oxides can be shifted toward twisted or distorted conformations.


Synthesis
The hydrazino alcohols 3 and 4 required for the synthesis of the 1,3,4,2-oxadiazaphosphinane derivatives were prepared from the corresponding amino alcohols 1 or 2, the N-nitroso derivatives of which were reduced with LiAlH 4 according to literature procedures 13,14 (Scheme 1).

Scheme 1
The cyclizations of compounds 3 and 4 with phenylphosphonic dichloride, phenyl dichlorophosphate and bis-(2-chloroethyl)phosphoramidic dichloride were performed at ambient temperature by using a procedure similar to that described earlier 12  In each case, two diastereomers (a and b) differing in the configuration of the phosphorus atom were formed; they were separated by column chromatography.No significant differences in the reactivities of the pyrrolidine-and piperidine-hydrazino alcohols or in the stabilities of the ring-closed, homologous products were observed in the reactions.

Structure characterization
The conformational behavior of the nitrogen-bridgehead saturated bicyclic 1,3,4,2oxadiazaphosphinanes (5-9) can be described by an equilibrium of cis 1 -trans-cis 2 type. 15In the trans structure, the A/B hetero rings are trans-connected, with a trans-diaxial arrangement of the hydrogen at the annelation (H-an) and the nitrogen lone pair.In the two other configurations, the hetero rings are cis-connected: for the cis 1 -conformation, C-1 is in the inside, while for the cis 2 conformation, it is in the outside position (Figure 1).The phosphorus-containing 1,2,3heterocycles are prone to participate in a conformational equilibrium involving chair, twisted chair and other distorted conformations. 1,16he stereochemistry of the model compounds was determined in two steps.First, the predominant conformation was assigned on the basis of the characteristic 3 J couplings and NOE interactions.Second, the relative configuration of the P-phenyl substituent was observed by using the NOEs from the P-phenyl group to H-an (where applicable) and/or the significant differences in the chemical shifts for certain indicator nuclei.
The orientations of H-an (H-9a for 9; H-8a for 5 and 6) and the protons connected to the carbons adjacent to the annelation (H-1 and H-X; H-X: H-9 for 9; H-8 for 5 and 6) or the protons connected to the carbons adjacent to the nitrogen bridge (H-6) were assigned by using the vicinal coupling constants (Table 1) and the characteristic NOESY cross-peaks.
The data in Table 1 show that H-an has two high vicinal couplings to the axial protons connected to the carbons adjacent to the annelation indicating that H-an is in an axial position and the hetero rings are trans-connected.The NOESY cross-peaks detected for H-an and H-6 ax.corroborate the trans-connection of the hetero rings for all the compounds.The considerably lower 3 J(H-1 eq.-P) values for 5b and 6b indicate significant conformational flexibility in the oxadiazaphosphinane ring attached to the five-membered rings, potentially leading to the presence of twist and/or distorted conformations.a For the meanings of H-an and H-X, see Figure 1.
As concerns the orientation of the P-substituent, P-R -H-1 ax.NOE interactions could readily be detected in 9a, 6a and 5a.It is a trend that H-1 ax exhibits a relative downfield shift in compounds containing an axial P=O group (9b, 5b and 6b), this difference being augmented by the upfield shift of 1-H ax. in 5a due to the ring current shielding of the axial Ph group (Table 2).

Conclusions
Our results show that pyrrolidine-and piperidine-fused 1,3,4,2-oxadiazaphosphinane 2-oxides can conveniently be prepared by cyclization of the corresponding pyrrolidine-and piperidinehydrazino alcohols with phosphorus-containing reagents (e.g.RPOCl 2 ).The relative stereochemistry of the ring junction is trans for all the compounds studied.The conformation of the oxadiazaphosphinane ring is chair for 9a and 9b, while the five-membered ring allows more flexibility for the phosphorus-containing heterocycles.

Experimental Section
General Procedures.
The NMR spectra were recorded in CDCl 3 at 300 K on a Bruker AVANCE DRX 400 spectrometer.Chemical shifts are given in δ (ppm) relative to TMS as internal standard.Melting points were recorded on a Kofler hot plate microscope apparatus and are uncorrected.Elemental analyses were performed with a Perkin-Elmer 2400 CHNS elemental analyzer.Chemicals were generally of highest purity.For column chromatography, Silica gel 60 (0.063-0.200 mm) was used.Merck Kieselgel 60F 254 plates were used for TLC.The hydrazino alcohols 3 and 4 were prepared according to literature procedures. 13The syntheses and detailed NMR characterization of 1,3,4,2-oxadiazaphosphinanes 7a, 7b, 8a and 8b have been published earlier. 12neral method for ring-closure reactions.To a stirred solution of the appropriate amino alcohol (3 or 4, 10 mmol) and triethylamine (2 eq.) in 80 mL of dry THF at RT was added dropwise a solution of the appropriate phosphorus-containing reagent (phenylphosphonic dichloride, phenyl dichlorophosphate or bis-(2-chloroethyl)phosphoramidic dichloride, 1 equiv.) in 30 mL of dry THF.The reaction mixture was stirred for 48 hours at RT and then filtered to remove triethylamine hydrochloride.The filtrate was evaporated to dryness.