SYNTHESIS AND CONFORMATIONAL STUDIES ON CERTAIN N-NITROSO PIPERIDIN-4-ONES

Heterocyclic compounds gain importance owing to their pharmacological, agrohemical and in brief, biological activities. The piperidin-4-one units are present in a variety of alkaloids which are occurring naturally. They find wide applications as drugs. Further, the stereochemical studies of piperidinone chemistry are thought provoking and quiet interesting.


INTRODUCTION
Piperidones are an important group of heterocyclic compounds in the field of medicinal chemistry due to their broad spectrum of biological activities. One such class of compounds containing 4piperidones and their derivatives, whose synthesis and stereodynamics are well investigated (Prostokov and Gaivoronskaya, 1978). Many natural products and drugs contain the piperidine ring system as a structural element. Nitrogen heterocycles, in particular 4-piperidones display important biological properties such as antiviral, antitumor, analgesics and antihypertensive activities (Miyoshi et al., 1995;Riley et al., 1973). The importance of 4piperidones as intermediates in the synthesis of a variety of compounds of physiological activity has been reviewed by Prostokov and Gaivoronskaya (Shintani et al., 2004). The extensive studies undertaken in the past on 4-piperidones have their relation to the synthesis of drugs (Boach et al., 1948)The utility of 2-aryl, 2-heteroarylpiperidin-4ones in the construction of polycyclic systems such as benzo[a]quinolin-4-ones, indole alkaloids, have been disclosed by Rubiralta et al., 1989 recently in a series of papers.
They have also described the importance of the introduction of bulky substituent in the nitrogen side of 4-piperidones, thereby making the ring system to adopt favorable conformation for the intramolecular ring closure leading to the construction of benzomorphon related compounds. Piperidone derivatives have also been noted to act as potential inhibitors of human placental aromatase in vitro. 3,5-bis(arylidine)piperidin-4-ones behave as cytotoxic and anticancer agents. 2,2,6,6tetramethylpiperidin-4-one hydrochloride has been used as a spin trap in several EPR studies and it's hydrazones are used as antioxidants. 2-Aryl piperidin-4-ones are used as key intermediates for the synthesis of techykinin antagonists and indolizidine alkaloids (Boach et al., 1948).

EXPERIMENTAL SECTION
Melting points of all the compounds were determined on an electrically heated block (RAAGA make) with a calibrated thermometer and are uncorrected. The IR spectra were recorded on a FTIR instrument (Perkin-Elmer). The 1 H NMR and 13 C NMR spectra were recorded on a Bruker AMX 400 MHz spectrometer and 2D NMR spectra were recorded on a AV 500 MHz instrument in CDCl3 solution with TMS as an internal standard.
O piperidin -4-one (3). The signal integration values were also used for the assignment.
The 1 H NMR spectrum of 1 has only ABX systems for the heterocyclic ring protons (H6a, H5a & H5e) since no coupling partner is available at C3 for C2 proton, the benzylic proton at C2 appeared as a singlet at 3.79 ppm. The chemical shift value of H2 benzylic proton when compared to that of the 3methyl analog 3 indicated the axial position for the proton and equatorial orientation for the chlorophenyl group. The signal at 4.59 ppm with 3 J values of 11.1 ( 3 J6a, 5a) and 5.1 Hz ( 3 J6a, 5e), is assigned to the axial proton at C6 (H6) and it confirmed the equatorial orientation of the chlorophenyl group at C6. The coupling constant ( 3 J6a, 5a & 3 J6a, 5e) data were employed to calculate the dihedral angles between the vicinal protons (H6 & H5a, H5e) by DAERM. The cis (H6-C6-C5-H5e) and trans (H6-C6-C5-H5a) dihedral angles of 1 were found to be 45˚ & 165˚ respectively. The observed vicinal coupling constants and dihedral angles confirmed that the compound 1 prefer to exist in the chair conformation. The signal at 2.75 ppm which appears as double doublet ( 2 J5a, 5e = 14.0 Hz and 3 J6a, 5a = 12.0 Hz) can be assigned to the axial proton of C5 (H5a). Similarly the signal at 2.66 ppm appeared as a double doublet with coupling constant values of 14.0 Hz ( 2 J5a, 5e) and 3.5 Hz ( 3 J6a, 5e) can be assigned to the equatorial proton at C5 (H5e).
The presence of NH proton at 1.75 ppm was confirmed using the D2O exchange studies (Spectrum 3).
The 13 C NMR spectrum signals (Spectrum 4) of the Compound 1 were assigned on the basis of additivity and by comparison with those of the corresponding 2,6-bis (2-clorophenyl) -3-methyl piperidin -4-one( 3). On the basis of the above discussion, it has been concluded that r-2,c-6-bis (2-chlorophenyl) -c-3,t-3dimethylpiperidin-4-one (1) prefers to adopt a chair conformation with the equatorial orientation of

Scheme 1
The structure of the compound 1 was confirmed by IR spectra, 1 H, 13 C NMR, 2D NMR and mass spectral data .
The IR spectrum of piperidin-4-one 1 , showed the presence of >NH (stretching band observed at 3306 cm -1 ) and >C = O (stretching band observed at 1703 cm -1 ) groups, which confirmed the formation of the compound 1.

Fig. 1
The complete assignments of 1 H and 13 C NMR spectral data are presented in Table 1 & 2.

Scheme 2
The structure of the compound was confirmed by IR spectra, 1 H, 13 C NMR, 2D NMR and mass spectral data.
The presence of NH stretching band (3310 cm -1 ) and >C = O stretching band (1704 cm -1 ) in the IR spectrum of the compound 2 indicated the formation of the compound 2.
The compound 57 is symmetrical in nature and the assignment of 1 H NMR chemical shifts is very simple. The protons at C2 and C6 are chemically equivalent. Similarly the protons at C3 and C5 are also equivalent. Hence the 1 H NMR spectrum of 2 has only AX spin system for the heterocyclic ring protons.
The benzylic protons (H2a and H6a) showed a doublet at 4.38 ppm with 3 J2a, 3a ( = 3 J6a, 5a) value of 10.3 Hz, indicating that these two protons are diaxially oriented which in turn confirm the equatorial orientation of chlorophenyl groups at C2 & C6 and methyl groups at C3 & C5 respectively. The diaxial coupling constant of 10.3 Hz confirms the preference of chair conformation for the compound 2.
On the basis of the above observations, it has been concluded that r-2,c-6-bis (2chlorophenyl)-t-3,t-5-dimethylpiperidin-4-one (2), exist in chair conformation with the equatorial orientation of chlorophenyl substituent of C2 and C6 and methyl groups at C3 and C5 respectively similar to the previous compound .

Fig. 2
The complete assignments of 1 H and 13 C NMR spectral data are presented in the Table 3 and 4.

Scheme 3
The structure of the compound was confirmed by IR spectra, 1 H & 13 C NMR spectral data. In addition DEPT spectrum was also used for the assignment of 13 C NMR spectrum.
The 1 H NMR spectrum of 3 has ABX and AX spin systems for the heterocyclic ring protons. The H6a, H5a and H5e protons which belongs to the ABX spin system and the H6a and H5e protons (AX spin system) showed two double doublets at 4.07 and 2.62 ppm respectively, were assigned on the basis of the magnitudes of their coupling constant (J) values. The H5a of the ABX spin system was found to have been mingled with the H3a (multiplet) of the AX spin system. The signal at 4.07 ppm with 3 J values of 11.5 and 3.5 Hz, ascribable to 3 J6a,5a and 3 J6a,5e, respectively, was assigned to the axial proton at C6 (H6) which confirmed the equatorial orientation of the chlorophenyl group at C6. The signal at 2.62 ppm, can also be assigned to the equatorial proton at C5 (H5e). Similarly, the proton H2 of the AX spin system gave a doublet at 3.61 ppm with a 3 J2a,3a value of 10.5Hz, indicating that these two protons are diaxially oriented, which in turn confirmed the equatorial orientation of the chlorophenyl and methyl groups at C2 and C3, respectively. Due to the coupling with CH3 protons, the H3a proton appeared as a multiplet at 2.62 ppm. The coupling constant ( 3 J6,5a & 3 J6,5e) data were employed to calculate the dihedral angles between the vicinal protons (H6 & H5a, H5e) by DAERM. 74 The cis (H6-C6-C5-H5e) and trans (H6-C6-C5-H5a) dihedral angles of 3 were found to be 54 o and 174 o , respectively. The observed vicinal coupling constants and dihedral angles are consistent with the chair conformation for 3.

Fig. 3
The complete assignment of 1 H & 13 C NMR data are presented in the